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org/joc Article

Access to Chiral Diamine Derivatives through Stereoselective Cu-

Catalyzed Reductive Coupling of Imines and Allenamides
Toolika Agrawal, Robert T. Martin, Stephen Collins, Zachary Wilhelm, Mytia D. Edwards,
Osvaldo Gutierrez,* and Joshua D. Sieber*
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ABSTRACT: Chiral 1,2-diamino compounds are important building

blocks in organic chemistry for biological applications and as
asymmetric inducers in stereoselective synthesis that are challenging
to prepare in a straightforward and stereoselective manner. Herein,
we disclose a cost-effective and readily available Cu-catalyzed system
for the reductive coupling of a chiral allenamide with N-alkyl
substituted aldimines to access chiral 1,2-diamino synthons as single
stereoisomers in high yields. The method shows broad reaction scope
and high diastereoselectivity and can be easily scaled using standard
Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of
stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of
catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.

■ INTRODUCTION
Chiral vicinal diamines are extremely valuable and important
by alcohol activation and amine substitution.1a−d While direct
catalytic 1,2-diamination of 2 represents an ideal strategy for
motifs in organic chemistry that are exploited by both nature diamine synthesis, the amino-groups added across the π-system
and the pharmaceutical industry for their biological activ- are typically identical leading to the formation of diamines with
ities,1,2 and in stereoselective organic synthesis as powerful identical substituents (i.e., R3 = R4 in 1),8,9 and a recent
chiral inducers through application as organocatalysts,3 chiral approach employing electrochemistry9b suffers from potentially
ligands4 for transition metal catalyzed reactions, and as chiral forming high-energy/explosive diazocompounds13 en route to
auxiliaries.5 For example, a variety of biologically active the desired diamines. Additionally, the aziridination/ring-
pharmaceuticals and natural products are given in Figure 1 opening strategy can suffer from poor stereoselectivity in the
possessing either the chiral 1,2-diamino-fragment or its aziridination step and regiochemistry issues in the subsequent
corresponding urea form.2 Representative therapeutics being opening step, while the aminohydroxylation route requires
developed for the treatment of important human diseases regiocontrol in the aminohydroxylation step followed by
include antibiotics (penicillin,2e jogyamycin2j), anticancer additional transformations to convert 4 to the desired diamine.
compounds (cisplatin derivatives,6 LP992c), HIV protease Alternatively, synthesis of 1 through C−C bond formation can
inhibitors (NBD-110212d), NK1-antagonists7 (CP-99,994;2a be achieved through aza-pinacol coupling of two imines,14
Sch4250782g) for central-nervous-system (CNS) related nitro-Mannich,15 or glycine-Mannich16 reactions (Scheme 1B).
diseases and rheumatoid arthritis, and influenza (tamiflu).2b Typical aza-pinacol coupling protocols only afford symmetrical
Due to the biological and synthetic value of chiral 1,2- diamines through homocoupling of a single imine; however,
diamines, stereoselective methods for their preparation are an recent photoredox strategies14h−l enabling the generation of α-
important endeavor in organic chemistry.1a,c,d,8 Potential aminoradicals17 from amines have enabled cross-selective
synthetic options to access the chiral vicinal diamine moiety
coupling of imines and N-methylamines.14j−l Furthermore,
can be envisioned to occur either by formation of the two C−
nucleophilic additions to imines using α-aminoanion deriva-
N bonds starting from unsaturated hydrocarbons (2, Scheme
1A) or through direct C−C bond formation between C1 and
C2 of the 1,2-diamine from two N-substituted reagents Received: December 17, 2020
(Scheme 1B).1a,c,d,8 Using a C−N bond forming approach Published: March 16, 2021
(Scheme 1A), diamination may be achieved by forming both
C−N bonds at the same time,8,9 or sequentially through either
aziridination10 followed by ring-opening with an amine
nucleophile1a,c,d,11 or through aminohydroxylation12 followed
© 2021 The Authors. Published by
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Figure 1. Selected examples of chiral 1,2-diamine- and urea-derived biologically active molecules.

Scheme 1. Synthetic Strategies toward the Synthesis of 1,2-Diamines

tives18 from nitroalkanes (7)15 or protected glycines (8)16 envisioned that use of an amino-substituted allyl reagent 12
offer another entry into the diamine core 1. in addition reactions with imine electrophiles would be a
In regards to chiral amine synthesis, asymmetric allylation of powerful strategy to prepare 1,2-diamines (13) with differential
imines using allyl organometallic nucleophiles (10) by direct substitution patterns on nitrogen and containing an olefin
addition or through catalyst control has been an area of intense motif for further functional group manipulations. Surprisingly,
research in organic chemistry (Scheme 2).19 The chiral only a single example of such a strategy for the preparation of
allylamine products (11) are highly valuable in the context 1,2-diamines has been reported, which employs a lithiated
of the synthesis of complex amine-containing organic derivative of 12 (M = Li) with chiral tert-butanesulfinimide
compounds because of the high versatility of the olefin derived aldimines affording products in moderate yields with
functional group present within 11. Substituted allylorgano- mixtures of branched and linear allylation products.20 In
metallic reagents (e.g., 12) allow for increased molecular contrast, amino-substituted allyl reagents 12 have been used in
complexity by introducing two stereocenters in the allyl reactions employing carbonyl electrophiles to provide 1,2-
addition reaction (e.g., 13, Scheme 2B). Therefore, we aminoalcohols (16).21−23 Recently, the Krische22 group and
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Scheme 2. Proposed Allylation Strategy toward the Table 1. Ligand Optimization for the Reductive Coupling
Synthesis of 1,2-Diamines Using 15aa

Entry Ligand %Yield 18ab %Yield 19ab % 9ab

1 dcpe <5 58 20
2 PCy3 <5 86 <5
3 P(adam)3 <5 28 31
4 XPhos <5 22 38
5 P(NMe2)3 <5 66 <5
6 P(OEt)3 <5 60 <5
7 (PhO)2PNMe2 <5 66 <5
8 SIMes <5 8 67
9c PCy3 <5 51 <5
10d PCy3 <5 54 <5
11e PCy3 <5 52 21
12f PCy3 <5 31 14
13g PCy3 90 <5 <5
a
129 mg (0.400 mmol) 9a, 96.6 mg (0.480 mmol) 15a, 5 mol %
Cu(OAc)2, 6 mol % ligand, and 1.0 mL of toluene. A single
diastereomer of product was obtained in all cases by analysis of the
unpurified reaction mixture by 1H NMR spectroscopy. See the
Supporting Information for further details. bYield determined by 1H
NMR spectroscopy on the unpurified reaction mixture using
dimethylfumarate as analytical standard. cReaction performed in
MTBE. dReaction performed in dioxane. eReaction performed in
our own lab23 have developed reductive coupling24,25 CH2Cl2. fReaction performed in THF. gPerformed using 2.0 equiv of
procedures for the catalytic generation of amino-substituted t-BuOH as additive. DMB = 2,4-dimethoxybenzyl.
allyl reagents 12 and have studied their reactions with carbonyl
electrophiles (Scheme 2C). These techniques represent
orthogonal methodologies whereby the Krische22a system lability to allow for chemoselective differentiation of the two
employs a chiral Ir-catalyst and processes aldehyde electro- amine protecting groups in the final products (18a/19a).
philes using an achiral allenamide (15), while our work utilizes Gratifyingly, a variety of phosphine ligands (entries 1−7)
a Cu-catalyst and a chiral allenamide (15a) for reactions using afforded urea product 19a presumably resulting from migration
ketone electrophiles.23 Based on our success in the stereo- of the carbamate carbonyl (Scheme 3), whereas an N-
selective Cu-catalyzed reductive coupling of ketones and chiral heterocyclic carbene (NHC) ligand provided poor conversion
allenamides to afford branched chiral 1,2-aminoalcohols 1623a (entry 8). In all cases, a single diastereomer of product was
or the corresponding linear products,23b and the lack of obtained as determined by 1H NMR spectroscopy of the
literature data for imine allylation reaction utilizing amino-
substituted allylic nucleophiles, we began to investigate the Scheme 3. Proposed Reaction Catalytic Cycle
reaction of allenamide 15a with imine electrophiles 9 for the
stereoselective synthesis of chiral 1,2-diamine synthons 17
(Scheme 2D). The results of these studies leading to the
identification of a practical and highly stereoselective synthesis
of diamine synthons 17 using Cu-catalyzed reductive coupling
are disclosed herein.

■ RESULTS AND DISCUSSION

Reaction Optimization. To investigate the proposed Cu-
catalyzed reductive coupling of imines and allenamides, initial
studies examined the ligand effect when employing DMB-
protected imine 9a with chiral allenamide 15a in the reaction
(Table 1). The phenyl-derived Evans oxazolidinone of
allenamide 15a was specifically targeted due to its low-cost
and high-availability,26 and because it allows for more
deprotection options of the desired diamine products over
other alkyl-substituted oxazolidinones (i.e., hydrogenolysis).
The DMB-group of the aldimine was employed due to its acid
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Scheme 4. Imine Generality in the Cu-Catalyzed Reductive Coupling To Access 1,2-Diamino Synthons 18a

a
Conditions: 9 (0.400 mmol), 15a (96.6 mg, 0.48 mmol), Cu(OAc)2 (5 mol %), PCy3 (6.5 mol %), t-BuOH (76 μL, 0.80 mmol), Me(MeO)2SiH
(99 μL, 0.80 mmol), and 1.0 mL of toluene, rt 24 h followed by treatment with NH4F/MeOH. See the Supporting Information for more details. A
single diastereomer of product was obtained in all cases by analysis of the unpurified reaction mixture by 1H NMR spectroscopy. Yields represent
isolated yield. bReaction performed at 65 °C. cIsolated as an inseparable mixture of 18 and urea 19.

unpurified reaction mixture. Notably, the bidentate phosphine of intermediate 21 with imine 9a provides Cu-amide
dcpe that has been utilized previously in Cu-catalyzed intermediate 22. To afford product 18a from 22, direct
reductive coupling of C-substituted allenes and imines25c silylation of the amine by the silane must occur to regenerate
afforded only a moderate yield with a substantial amount of the LCuH catalyst 20; however, this step is expected to be slow
unreacted imine (20%, entry 1). Monodentate phosphine due to the weak strength of the N−Si bond (BDE ≈ 104 kcal/
ligands (entries 2−7) worked well with the exception of mol).27 Due to the strong basicity of the N-anion in 22,
sterically demanding ligands that afforded poor conversion of intramolecular attack of the oxazolidinone carbonyl may occur
the imine (entries 3, 4). Ultimately, the use of PCy3 as ligand competitively to provide 23 containing an O−Cu bond that
afforded the highest yield of 19a in the reaction (entry 2). Use should more easily silylate due to the high bond strength of the
of solvents other than toluene in the reaction (entries 9−12) O−Si bond (BDE ≈ 190 kcal/mol)28 affording urea 24 and
offered no improvements. Finally, addition of 2 equiv of t-
regenerating the LCuH catalyst (20). Alternatively, when t-
BuOH to the reaction led to the exclusive formation of 18a in
BuOH is present, protonation of the Cu−N bond of 22 by t-
excellent yield and diastereoselectivity.
An initial working hypothesis to understand the difference in BuOH to afford product 18a directly and generate LCuOtBu is
product selectivity between the formation of urea 19a in the thermodynamically favorable based on the pKa values for a
absence of t-BuOH versus the exclusive formation of diamino- secondary amine (pyrrolidine: ∼44)29 vs t-BuOH (32) and
derivative 18a when t-BuOH was used as an additive is given in supported by DFT calculations (vide infra).30 The LCu-OtBu
Scheme 3. Regioselective hydrocupration of allenamide 15a by intermediate can then undergo silylation to regenerate the
the LCuH23,25c catalyst 20 initially is expected to afford LCuH catalyst 20. The role of alcohol additives to facilitate
substituted linear allylcopper reagent 21 that may undergo E/Z catalyst turnover by protonation of Cu−N intermediates has
isomerization through σ−π−σ equilibration prior to reaction been documented previously.25c,31 Sterically hindered alcohols
with the imine electrophile. Then, diastereoselective reaction such as t-BuOH have been shown to be preferred since the rate
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of competitive protonation of the Cu−H catalyst is reduced Table 3. Imine Generality in the Cu-Catalyzed Reductive
with bulky alcohols.31 Coupling To Access Chiral Ureasa
Next, the substrate scope of the Cu-catalyzed reductive
coupling reaction using t-BuOH as additive to provide
branched diamino-derived products 18 was examined (Scheme
4). In all cases, a single diastereomer (the (S,S,S)-
diastereomer) of product was obtained as determined by
analysis of the unpurified reaction mixture by 1H NMR
spectroscopy. In general, a wide variety of imines could be
employed in the reaction in good to excellent yields. Electron-
deficient (18a − 18k) and electron-rich (18l−18o) aryl groups
both performed well in the reaction. Heterocyclic imines (18k,
18s−18u) and C-substituted arenes (18p−18r) were also well
tolerated. Finally, a sterically demanding imine (18m) or a m-
NO2Ph group (18i) required heating at 65 °C to afford good
reactivity. Use of an aliphatic aldimine (i.e., Ar1 = Me) did not
provide any desired products.
Initial analysis of the substrate scope for the urea-forming
Cu-catalyzed reductive coupling reaction employing DMB-
substituted imines in the absence of t-BuOH proved to be less
general than the analogous reaction conducted with t-BuOH as
the additive. In these problematic cases, a poor yield of desired
product was obtained even at 65 °C; however, the imine
remained while the allenamide had been consumed. As a result,
the effect of the N-substituent of the imine electrophile was
examined to improve the efficiency of the reaction to the
desired product (Table 2). As an example, the 2-naphthyl N-

Table 2. Effect of Imine N-Substitution on Reactivitya

Entry Ar2 % yieldb a

Conditions: 9 (0.40 mmol), 15a (96.6 mg, 0.48 mmol), Cu(OAc)2
1 2,4-dimethoxyphenyl (9pa) 17 (19pa) (5 mol %), PCy3 (6.5 mol %), Me(MeO)2SiH (99 μL, 0.80 mmol),
2 4-methoxyphenyl (9pb) 58 (19pb) and 1.0 mL of toluene, rt 24 h followed by treatment with NH4F/
3 Phenyl (9pc) 70 (19pc) MeOH. See the Supporting Information for more details. A single
4 4-fluorophenyl (9pd) 71 (19pd) diastereomer of product was obtained in all cases by analysis of the
5 4-trifluoromethylphenyl (9pe) 79 (19pe) unpurified reaction mixture by 1H NMR spectroscopy. Yields
a
Conditions: 9p (0.400 mmol), 106 mg (0.480 mmol) of 15a, 5 mol represent isolated yield. bReaction performed at 65 °C. cIsolated as
% Cu(OAc)2, 6 mol % PCy3, 99 μL (0.80 mmol) of (MeO)2MeSiH, an inseparable mixture of urea 19 and 18.
and 1.0 mL of toluene. A single diastereomer of product was obtained
in all cases by analysis of the unpurified reaction mixture by 1H NMR employed in good yields affording single diastereomers of
spectroscopy. bYield determined by 1H NMR spectroscopy on the product at room temperature when Ar1 was a simple phenyl
unpurified reaction mixture using dimethylfumarate as analytical
group (19b), heterocyclic (19k, 19s, 19t), or substituted at the
standard.
para-position with an electron-donating group (19l, 19n) or an
electron-withdrawing group (19a). However, reactions em-
DMB-imine (9pa) afforded a poor yield in the desired reaction ploying imines containing halogenated arenes or more
(entry 1). A strong influence on reactivity and the electronic sterically demanding aryl groups were not successful utilizing
character of the aryl group (Ar2) of the imine was found the N-DMB derived imine and instead required heating and
(entries 1−5). Use of an electron-poor aryl group (entry 5) the use of either an N-Bn or an N-CH2-p-CF3Ph group on the
afforded the best reaction yield; however, a simple benzyl aldimine (see 19de, 19ee, 19j and 19m, 19pe, respectively).
group also provided good reactivity (entry 3). As a result, for Stereochemical assignment of the products obtained in the
problematic DMB-derived imines, the reactivity can be Cu-catalyzed reductive coupling reaction as the (S,S,S)-
improved by utilizing PMB, Bn, or p-CF3-benzyl as the N- diastereomer was determined unequivocally by X-ray crystal-
substituent on the aldimine. lography (Scheme 5). While the branched products 18 were
Based on the results from Table 2, the substrate scope for typically noncrystalline, formation of the HCl-salt of 18c
the urea-forming Cu-catalyzed reductive coupling reaction in afforded crystalline material whose structure was determined
the absence of t-BuOH was investigated using this new by single-crystal Xray analysis. Furthermore, conversion of
knowledge (Table 3). DMB-substituted imines could be products 18 to the urea 19 could also be achieved after
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Scheme 5. Stereochemistry Determination from reductive coupling product 18c (Scheme 6). The Cu-
catalyzed reductive coupling was scaled to 1.0 g without the
need for an inert atmosphere glovebox by performing the
reaction on the “benchtop” using standard Schlenk techniques
and preparing the (PCy3)Cu-catalyst by adding the PCy3 as a
20 wt % solution in toluene that is commercially available.32
The catalyst loading could be reduced to 2.0 mol % Cu
providing 18c in good yield and excellent diastereocontrol in
only 2 h of reaction time. Considering the low cost and high
availability of the Cu-precatalyst,32 the ligand employed
(PCy3),32 and the chiral allenamide 15a,26 along with the
high catalytic activity of this system (2 mol % catalyst loading),
the current method represents a highly practical and scalable
method for the synthesis of diamino-synthons 18/19.
Allylation of 18c was then carried out using allyl bromide,
followed by ring-closing metathesis with the Hoveyda−Grubbs
second generation catalyst to provide access to compound 27
as an orthogonally protected aminopiperidine derivative as a
single stereoisomer.
Mechanistic Modeling by DFT Analysis. To shed light
onto the mechanism and origin of diastereoselectivity, we used
isolation of 18 by subsequent treatment with n-BuLi (e.g., 18a dispersion-corrected DFT calculations (see Supporting In-
→ 19a). The urea product obtained from this sequence was formation for details). Specifically, we performed extensive
identical to the material made from the reductive coupling conformational analysis on all intermediates and transition
reaction performed in the absence of t-BuOH by NMR states using the B3LYP-D3 functional and a def2-SVP basis
spectroscopy confirming that the same stereoisomer of product set33 with toluene as the solvent using the CPCM solvation
was formed in both reductive coupling processes (i.e., with or model34 as implemented in Gaussian16. Further, to refine the
without t-BuOH as additive). energetics and compare methods, single-point calculations
The synthetic utility of the reaction products obtained in the using the M06-L functional,35 as well as a larger basis set (def2-
allenamide/imine reductive coupling reaction is highlighted in TZVPP) with B3LYP-D3, which yielded similar energetic
Scheme 6. The phenethyl group of urea 19a derived from the profiles, were subsequently performed. For simplicity, only
B3LYP-D3/def2-SVP optimization energetics will be discussed
Scheme 6. Synthetic Applications in the text. Structures were visualized using CYLview Version
1.0.561.36
As shown in Figure 2, initial investigations were conducted
by first analyzing the hydrocupration of allenamide 15a with
(PCy3)CuH as catalyst. Following coordination of the copper
and allenamide π-bond, the energetically favored hydro-
cupration proceeds via TS−I-II (barrier of 10.4 kcal/mol
with respect to separated 15a and LCuH structures) to form
the branched allylcopper species II. Presumably this transition
state benefits from lack of steric hindrance between the ligand
and the chiral auxiliary, which were present in the alternative
transition states. Specifically, alternate hydrocupration tran-
sition states leading to linear allylcopper species (TS−I-III cis
and TS−I-III trans) were found to be much higher in energy
by ∼3 kcal/mol for TS−I-III trans and by >7 kcal/mol for all
other pathways and were therefore not productive.
In turn, the branched allylcopper intermediate is expected to
undergo isomerization to linear allylcopper species by σ−π−σ
isomerization. Recently, Buchwald and co-workers reported
branched-linear allylcopper isomerizations for a system with a
bidentate phosphine ligand25c as well as with a CuH-catalyzed
allylation of ketones and dienes.37 In our case, it was calculated
that the branched allylcopper intermediate II can readily
Evans oxazolidinone of the allenamide starting material could isomerize (barrier of only 6.9 and 10.0 kcal/mol via TS−II-III
be cleaved in a three-step sequence consisting of alcohol cis or TS−II-III trans, respectively) to form the nearly
activation (MsCl), base induced elimination, and enamide isoenergetic cis or trans linear allylcopper intermediates (III cis
hydrolysis with aqueous acid to provide urea 25 in good overall and III trans). Intermediate III cis was slightly favorable
yield without isolation of intermediates. Furthermore, synthon compared to intermediate III trans (by 0.6 kcal/mol), as was
27 is a viable intermediate to access chiral aminopiperidine 28 the cis isomerization transition state (TS−I-III cis was favored
for the preparation of the potent NK-1 inhibitor compounds by 3.1 kcal/mol), presumably due to coordination between the
CP-99,994 and CP-122,721,2a,7 which could easily be accessed oxazolidinone and the copper (Cu−O bond distance = 2.37
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Figure 2. Structures and relative free energies (in kcal/mol, with respect to separate LCuH catalyst and reactants) of possible hydrocupration
pathways, optimized using B3LYP-D3/def2SVP-CPCM(toluene), M06-L/def2SVP-gas//B3LYP-D3/def2SVP-CPCM(toluene) (in parentheses),
and B3LYP-D3/def2TZVPP-gas//B3LYP-D3/def2SVP-CPCM(toluene) {in braces}.

Å). However, upon coordination of the imine to the copper, Notably, all C−C bond formation steps f rom III′trans are
the trans conformation (III′ trans) becomes significantly more reversible, as the branched addition products IV (S,S,S) and IV
favored (as seen in Figure 3), likely due to unfavorable steric (R,R,S) were each uphill in energy (by ∼2 kcal/mol and ∼6
hindrance between the imine and the oxazolidinone in the III′ kcal/mol respectively), which can have implications for
cis conformation (see Supporting Information for further rational catalyst and reaction design (vide infra).
details). To gain insights into the origin of diastereoselectivity, we
Next, we focused on the key C−C bond formation steps. As performed distortion−interaction and NCI analysis (Figure 4).
shown in Figure 3, after performing extensive conformational Overall, comparing the structures of the lowest energy
analysis on the subsequent diastereomeric C−C bond forming competing diastereomeric transition states TS-III′-IV trans
transition states with the allylcopper intermediates and the (S,S,S) and TS-III′-IV trans (R,R,S) reveals that the structures
imine substrate (see Supporting Information for details), the of these transition states were remarkably similar, with key C−
most favorable pathway for diastereoselective C−C bond C and C−Cu bond distances differing by no more than 0.05 Å.
formation was identified to proceed from the trans linear However, the orientation of the chiral auxiliary is different, as
intermediate III′ trans through a Zimmerman−Traxler the TS-III′-IV trans (S,S,S) transition state has the
transition state TS-III′-IV trans (S,S,S) (barrier of only 7.4 oxazolidinone moiety of the enamide group of the substituted
kcal/mol from complexed III′ trans intermediate) to branched Cu(allyl) ligand in an s-trans conformation while the TS-III′-
addition product IV (S,S,S). Further, in agreement with IV trans (R,R,S) has this group in an s-cis conformation that,
experiment, the competing diastereomeric transition state TS- as shown in Figure 5, leads to a 2.2 kcal/mol energy
III′-IV trans (R,R,S) which would lead to the opposite destabilization. Furthermore, the ground state structures of
diastereomer was determined to be much higher in energy. chiral oxazolidinone-derived enamides are known to favor an s-
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Figure 3. Structures and relative free energies (in kcal/mol, with respect to separate LCuH catalyst and reactants) for proposed mechanistic
pathway, optimized using B3LYP-D3/def2SVP-CPCM(toluene), M06-L/def2SVP-gas//B3LYP-D3/def2SVP-CPCM(toluene) (in parentheses),
and B3LYP-D3/def2TZVPP-gas//B3LYP-D3/def2SVP-CPCM(toluene) {in braces}. Optimized structures of transition states visualized with
CYLview are shown (with PCy3 ligand faded out for clarity).

trans conformation.38 In addition, distortion−interaction the areas in red circles, the TS-III′-IV trans (S,S,S) system had
analysis39 (Figure 4a) showed that the distortion energy of stronger noncovalent interactions between the oxazolidinone
the TS-III′-IV trans (S,S,S) transition state was higher than group and the phenyl ring on the imine. This suggests that
that of the corresponding TS-III′-IV trans (R,R,S) transition noncovalent interactions (i.e., between the oxazolidinone
state (by 3.9 kcal/mol). However, the (S,S,S) system benefited moiety and the protecting group) are critical for control of
from much stronger interaction energy (by 8.5 kcal/mol). diastereoselectivity. Taken together, these results suggest that
Overall, this favorable interaction between the imine and both the conformational preference for the s-trans geometry
allylcopper makes the TS-III′-IV trans (S,S,S) the favorable about the N-enamide group of the substituted Cu(allyl) ligand
diastereomeric transition state. Finally, noncovalent interaction and favorable noncovalent interactions between the oxazolidi-
(NCI) analysis (performed using Multiwfn40 software and none group and the imine are the major contributing factors
visualized using VMD41 software) further supports the for diastereocontrol in these reactions.
presence of favorable interactions in the TS-III′-IV trans Following C−C bond formation, intermediate IV serves as a
(S,S,S) transition state (Figure 4b). Specifically, in both fork between two reaction pathways depending on whether or
transition states, there appeared to be favorable C−H···π not there is t-BuOH present (as supported by experiments;
interactions between the ligand and the benzyl group of the vide supra). Specifically, in the presence of t-BuOH, the alcohol
imine (highlighted inside the blue circle). However, comparing can act as a proton source to protonate the Cu−N bond and
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Figure 4. (A) Distortion−Interaction analysis of key diastereomeric C−C bond formation transition states. Electronic energies reported at B3LYP-
D3/def2SVP-CPCM(toluene) level of theory. (B) Noncovalent Interaction analysis of key diastereomeric C−C bond formation transition states.
Color code for the atoms is shown.

yield branched product 18, while the alkoxide binds to the As previously noted, computational modeling of the imine
copper. From this, the silane reagent can exchange hydride for addition predicts this step should be reversible. This
the alkoxide group, reforming the catalyst. While this phenomenon has important impacts for future developments
protonation of the amine moiety and concomitant release of of catalyst controlled enantioselective reactions utilizing a
the t-BuO-CuL was calculated to be initially energetically chiral catalyst in conjunction with an achiral allenamide. In this
unfavorable (uphill by ∼4 kcal/mol), the exchange of hydride regard, reaction of achiral allenamide 15b with imine 9a using
for the alkoxide was thermodynamically favorable (downhill by (S,S)-Ph-BPE as a chiral ligand was examined with and without
t-BuOH as the additive (Scheme 7). Again, branched product
∼10 kcal/mol), rendering this overall process energetically
29 was formed as a single diastereomer when t-BuOH was
feasible. In the absence of t-BuOH, a thermodynamically
present in the reaction, and urea 30 was formed as a single
favorable rearrangement of intermediate IV can yield the Cu- diastereomer in the absence of t-BuOH. Separate conversion of
alkoxide urea intermediate V (∼7 kcal/mol exergonic), which 29 to 30 using n-BuLi confirmed that the same relative
can then readily undergo transmetalation with silane to reform stereochemistry was formed in both reactions. Importantly, 29
the LCuH catalyst and furnish the silylated product of urea 19. and 30 were formed in different enantiopurities (57:43 vs
This mechanistic model is consistent with experimental 80:20 er, respectively), supporting a reversible imine addition step
findings that the presence of t-BuOH has a profound effect in these reactions. For example, if imine addition were
on the product selectivity (but not diastereoselectivity) of the irreversible, reaction of 15b with a chiral catalyst to afford
reaction toward either of the products (vide supra). the analogous intermediate to 22 (Scheme 3) must be
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The Journal of Organic Chemistry pubs.acs.org/joc Article

the catalytic asymmetric reaction of a chiral catalyst with an

achiral allenamide. These mechanistic insights are important
for the development of future asymmetric catalyst-controlled
procedures and are currently under further investigation in
these laboratories.

■ EXPERIMENTAL SECTION
General. 1H NMR spectra were recorded on Bruker 600 MHz
spectrometers. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard
(CDCl3: 7.26 ppm). Data are reported as follows: chemical shift,
integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, p = pentet, h = hextet, hept = heptet, br = broad, m =
multiplet), and coupling constants (Hz). 13C NMR spectra were
recorded on a Bruker 600 MHz (151 MHz) instrument with complete
Figure 5. Energetic comparison of s-trans and s-cis conformations of
proton decoupling. Chemical shifts are reported in ppm from
an (E)-enamide system with chiral oxazolidinone, with steric
tetramethylsilane with the solvent as the internal standard (CDCl3:
hindrance causing allylic strain highlighted. Structures optimized
77.0 ppm). Liquid chromatography was performed using forced flow
using B3LYP-D3/def2SVP-CPCM(toluene) (Hrel and Grel shown in (flash chromatography) on silica gel purchased from Silicycle. Thin
kcal/mol). layer chromatography (TLC) was performed on glass-backed 250 μm
silica gel F254 plates purchased from Silicycle. Visualization was
Scheme 7. Mechanistic Implications Relevant to Catalyst- achieved by using UV light, a 10% solution of phosphomolybdic acid
Controlled Enantioinduction in EtOH, or potassium permanganate in water followed by heating.
HRMS was collected using a Jeol AccuTOF-DART mass
spectrometer using DART source ionization. All reactions were
conducted in oven or flame-dried glassware under an inert
atmosphere of nitrogen or argon with magnetic stirring unless
otherwise noted. Solvents were obtained from VWR as HPLC grade
and transferred to septa sealed bottles, degassed by argon sparge, and
analyzed by Karl Fischer titration to ensure water content was ≤600
ppm. Me(MeO)2SiH was purchased from Alfa Aesar and used as
received. Allenamides 15 were prepared in one step as described in
enantiodetermining and requires that urea product 30 formed the literature.26 Aldehydes were purchased from Sigma-Aldrich,
from rearrangement of the intermediate 22 derivative to have Combi-Blocks, TCI America, Alfa Aesar, or Oakwood Chemicals
identical enantiopurity to that of 29. However, when a chiral and used as received. Tricyclohexylphosphine and Cu(OAc)2 were
ligand is employed, rearrangement of the two enantiomers of purchased from the Strem Chemical Company and used as received.
All other materials were purchased from VWR, Sigma-Aldrich,
intermediate 22 may occur at different rates because the Combi-Blocks, or Alfa Aesar and used as received. Imines 9a,42
transition states will be diastereomeric due to the chirality on 9b,43 9c,44 9ee,45 9h,46 9i,47 9j,48 9l,45 9m,47 9pb,49 9pc,50 and 9u45
the ligand. Therefore, the carbamate migration step may also were synthesized as described in the literature.
be enantiodetermining if the imine addition step becomes General Procedure A for the Synthesis of Imines. A 25 mL
reversible enabling different enantiomeric ratios to be obtained round-bottom flask equipped with a magnetic stirring bar was charged
for a 29-selective vs a 30-selective process as was observed. with aldehyde (6.0 mmol, 1.0 equiv) and dichloromethane (8 mL).

■ CONCLUSION
In conclusion, a highly stereoselective method for the reductive
Anhydrous magnesium sulfate was added to this solution while
stirring followed by 2,4-dimethoxy benzylamine (6.0 mmol, 1.0 equiv)
dropwise. The reaction mixture was stirred at room temperature for
12 h under a nitrogen atmosphere. After the reaction is complete the
coupling of imines with a chiral allenamide was developed as a crude reaction mixture was filtered through Celite to remove
convenient strategy for the asymmetric synthesis of valuable magnesium sulfate. The filtrate was concentrated in vacuo to yield
1,2-diamino synthons. The method employs readily available the pure imine, which was stored under nitrogen in the fridge.
and cost-effective starting materials26 and catalyst (Cu(OAc)2/ (E)-1-(4-Chlorophenyl)-N-(2,4-dimethoxybenzyl)methanimine
PCy3)32 and can be performed on the “bench-top” using (9d). Following General Procedure A, 4-chloro benzaldehyde (0.84 g,
standard Schlenk techniques without issues. Use of tert-butanol 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
as an additive was shown to aid in the amine release and sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
compound was obtained as a pale-yellow solid (1.54 g, 89%). Mp
catalyst regeneration to avoid the formation of urea products −59.5−60.5 °C. 1H NMR (600 MHz, CDCl3) δ 8.28 (s, 1H), 7.70 (d,
that are exclusively obtained in the absence of this additive. J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.21−7.15 (m, 1H), 6.51−
The oxazolidinone moiety of the final products could be 6.43 (m, 2H), 4.75 (s, 2H), 3.81 (s, 6H). 13C{1H} NMR (151 MHz,
removed chemoselectively without disruption of the pendant CDCl3) δ 160.3, 160.2, 158.3, 136.4, 134.9, 130.2, 129.4, 128.8, 119.6,
terminal alkene, and an orthogonally protected chiral amino- 104.1, 98.5, 58.9, 55.4. HRMS (DART) m/z calcd for C16H17ClNO2
piperidine derivative en route to important biologically active [M + H]+: 290.0948; Found [M + H]+: 290.0950.
pharmaceuticals was demonstrated. Finally, mechanistic (E)-1-(4-Chlorophenyl)-N-(4-(trifluoromethyl)benzyl)-
investigations by density functional theory calculations methanimine (9de). Following General Procedure A, 4-chloro
benzaldehyde (0.84 g, 6.0 mmol), 4-trifluoromethyl benzylamine
identified the mechanism for stereoselection in these processes (1.05 g, 6.0 mmol), magnesium sulfate (2.0 g), and dichloromethane
as determined from the relative transition state barriers of N- (8 mL) were used. The title compound was obtained as brown solid
substituted allylcopper complexes to the imine electrophile. (1.5 g, 84%). Mp −39.7−41.3 °C. 1H NMR (600 MHz, CDCl3) δ
This C−C bond forming addition step was shown to be 8.39 (s, 1H), 7.80 (dd, J = 8.5, 5.6 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H),
reversible by calculation and was experimentally supported by 7.47 (d, J = 7.9 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 4.85 (s, 2H).

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13
C{1H} NMR (151 MHz, CDCl3) δ 161.2, 143.3, 137.0, 134.4, 104.0, 101.4, 98.5, 58.6, 55.3. HRMS (DART) m/z calcd for
129.66 (C−F, 2J C−F = 33.22 Hz), 129.5, 129.45 (C−F, 2J C−F = C17H18NO4 [M + H]+: 300.1236; Found [M + H]+: 300.1253.
33.22 Hz), 129.23 (C−F, 2J C−F = 33.22 Hz), 128.9, 128.1, 126.97 (E)-1-(2,3-Dihydrobenzofuran-5-yl)-N-(2,4-dimethoxybenzyl)-
(C−F, 1J C−F = 273.31 Hz), 125.49 (C−F, 3J C−F = 3.02 Hz), methanimine (9o). Following General Procedure A, 2,3-dihydro-
125.46 (C−F, 3J C−F = 3.02 Hz), 125.44 (C−F, 3J C−F = 3.02 Hz), benzofuran-5-carbaldehyde (0.886 g, 6.0 mmol), 2,4-dimethoxy-
125.41 (C−F, 3J C−F = 3.02 Hz), 125.17 (C−F, 1J C−F = 273.31 benzylamine (1.0 g, 6.0 mmol), magnesium sulfate (2.0 g), and
Hz), 123.36 (C−F, 1J C−F = 273.31 Hz), 121.56 (C−F, 1J C−F = dichloromethane (8 mL) were used. The title compound was
273.31 Hz), 64.3. 19F NMR (565 MHz, CDCl3) δ −108.88. HRMS obtained as a pale-yellow oil (1.94 g, 72% purity, 78% yield). 1H
(DART) m/z calcd for C15H12ClF3N [M + H]+: 298.0610; Found [M NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 7.73 (s, 1H), 7.44 (d, J = 12
+ H]+: 298.0640. Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.49−
(E)-N-(2,4-Dimethoxybenzyl)-1-(4-fluorophenyl)methanimine 6.43 (m, 2H), 4.71 (s, 2H), 4.60 (t, J = 8.7 Hz, 2H), 3.80 (s, 6H),
(9e). Following General Procedure A, 4-fluorobenzaldehyde (0.742 g, 3.20 (t, J = 8.7 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.3,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium 161.3, 160.0, 158.2, 130.0, 129.8, 129.6, 127.7, 124.2, 120.3, 109.0,
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title 104.0, 98.4, 71.7, 58.7, 55.3, 29.2. HRMS (DART) m/z calcd for
compound was obtained as a yellow solid (1.36 g, 84%). Mp −39.7− C18H20NO3 [M + H]+: 298.1443; Found [M + H]+: 298.1466.
41.1 °C. 1H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 7.76 (dd, J = (E)-N-(2,4-Dimethoxybenzyl)-1-(naphthalen-2-yl)methanimine
8.5, 5.7 Hz, 2H), 7.23−7.16 (m, 1H), 7.08 (t, J = 8.6 Hz, 2H), 6.52− (9pa). Following General Procedure A, 2-naphthaldehyde (0.937 g,
6.45 (m, 2H), 4.76 (s, 2H), 3.81 (s, 6H). 13C{1H} NMR (151 MHz, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
CDCl3) δ 165.06 (C−F, 1J C−F = 250.66 Hz), 163.40 (C−F, 1J C−F sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
= 250.66 Hz), 160.23, 160.21, 158.32, 132.80 (C−F, 3J C−F = 3.02 compound was obtained as a white solid (1.78 g, 98%). Mp −91.5−
Hz), 132.78 (C−F, 3J C−F = 3.02 Hz), 132.2, 130.15, 130.11, 130.06, 93.9 °C. 1H NMR (600 MHz, CDCl3) δ: 8.48 (s, 1H), 8.05−8.03 (m,
119.84, 115.66 (C−F, 2J C−F = 22.65 Hz), 115.51 (C−F, 2J C−F = 2H), 7.89−7.87 (m, 1H), 7.85−7.83 (m, 2H), 7.51−7.49 (m, 2H),
22.65 Hz), 104.1, 98.54, 58.85. 19F NMR (565 MHz, CDCl3) δ 7.24 (d, J = 8.9 Hz, 1H), 6.49−6.48 (m, 2H), 4.82 (s, 2H), 3.82 (s,
−109.87. HRMS (DART) m/z calcd for C16H17FNO2 [M + H]+: 3H), 3.81 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ: 161.7,
274.1243; Found [M + H]+: 274.1269. 160.1, 158.3, 134.6, 134.1, 133.1, 130.1, 129.9, 128.5, 128.3, 127.8,
(E)-4-(2,4-Dimethoxybenzyl iminomethyl)benzonitrile (9f). Fol- 127.0, 126.3, 124.0, 119.9, 104.9, 104.0, 98.5, 59.0, 55.4. HRMS
lowing General Procedure A, 4-formyl benzonitrile (0.784 g, 6.0 (DART) m/z calcd for C20H20NO2 [M + H]+: 306.1494; Found [M
mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium + H]+: 306.1506.
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title (E)-N-(4-Fluorobenzyl)-1-(naphthalen-2-yl)methanimine (9pd).
compound was obtained as a yellow solid (1.59 g, 95%). Mp −54.0− Following General Procedure A, 2-naphthaldehyde (0.937 g, 6.0
56.2 °C. 1H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.84 (d, J = 8.0 mmol), 4-fluoro benzylamine (1.05 g, 6.0 mmol), magnesium sulfate
Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 9.0 Hz, 1H), 6.51− (2.0 g), and dichloromethane (8 mL) were used. The title compound
6.44 (m, 2H), 4.80 (s, 2H), 3.80 (s, 6H). 13C{1H} NMR (151 MHz, was obtained as an off-white solid (1.28 g, 90% purity, 73% yield). Mp
CDCl3) δ 160.4, 159.6, 158.4, 140.3, 132.3, 130.3, 128.6, 119.0, 118.6, −87.7−88.9 °C. 1H NMR (600 MHz, CDCl3) δ 8.53 (s, 1H), 8.09 (s,
113.7, 104.2, 98.5, 59.1, 55.4. HRMS (DART) m/z calcd for 1H), 8.08 (d, J = 12.0 Hz, 1H), 7.92−7.86 (m, 3H), 7.54 (tdd, J = 8.0,
C17H17N2O2 [M + H]+: 281.1290; Found [M + H]+: 281.1306. 6.1, 3.3 Hz, 2H), 7.36 (dd, J = 8.4, 5.5 Hz, 2H), 7.07 (t, J = 8.7 Hz,
Methyl (E)-4-(2,4-Dimethoxybenzyl iminomethyl)benzoate (9g). 2H), 4.85 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.8 (C−F,
1
Following General Procedure A, methyl-4-formyl benzoate (0.982 g, J C−F = 244.62 Hz), 162.1, 161.2 (C−F, 1J C−F = 244.62 Hz),
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium 135.14 (C−F, 3J C−F = 3.02 Hz), 135.12 (C−F, 3J C−F = 3.02 Hz),
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title 134.8, 133.7, 133.1, 130.2, 129.6, 129.5, 128.6, 128.5, 127.9, 127.2,
compound was obtained as a yellow solid (1.87 g, 100%). Mp −54.5− 126.5, 123.9, 115.4 (C−F, 2J C−F = 21.14 Hz), 115.2 (C−F, 2J C−F
56.3 °C. 1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 8.06 (d, J = 8.0 = 21.14 Hz), 64.37. 19F NMR (565 MHz, CDCl3) δ − 115.92. HRMS
Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 9.0 Hz, 1H), 6.48 (m, (DART) m/z calcd for C18H15FN [M + H]+: 264.1189; Found [M +
2H), 4.79 (s, 2H), 3.91 (s, 3H), 3.79 (s, 6H). 13C{1H} NMR (151 H]+: 264.1193.
MHz, CDCl3) δ 166.7, 160.6, 160.2, 158.3, 140.3, 131.6, 130.2, 129.7, (E)-1-(Naphthalen-2-yl)-N-(4-(trifluoromethyl)benzyl)-
128.0, 119.4, 104.1, 98.5, 59.1, 55.3, 55.3, 52.2. HRMS (DART) m/z methanimine (9pe). Following General Procedure A, 2-naphthalde-
calcd for C18H20NO4 [M + H]+: 314.1392; Found [M + H]+: hyde (0.937 g, 6.0 mmol), 4-trifluoromethyl benzylamine (1.05 g, 6.0
314.1422. mmol), magnesium sulfate (2.0 g), and dichloromethane (8 mL) were
(E)-N-(2,4-Dimethoxybenzyl)-1-(pyridin-3-yl)methanimine (9k). used. The title compound was obtained as an off-white solid (1.71 g,
Following General Procedure A, 3-pyridinecarboxaldehyde (0.64 g, 91%). Mp −105.9−107.9 °C. 1H NMR (600 MHz, CDCl3) δ 8.56 (s,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium 1H), 8.10 (s, 1H), 8.09 (d, J = 6 Hz, 1H), 7.95−7.85 (m, 3H), 7.64
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title (d, J = 8.0 Hz, 2H), 7.58−7.49 (m, 4H), 4.92 (s, 2H). 13C{1H} NMR
compound was obtained as a pale-yellow oil (1.51 g, 99%). 1H NMR (151 MHz, CDCl3) δ 162.7, 143.6, 134.9, 133.6, 133.1, 130.4, 129.61
(600 MHz, CDCl3) δ: 8.85 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.34 (s, (C−F, 2J C−F = 31.71 Hz), 129.40 (C−F, 2J C−F = 31.71 Hz),
1H), 8.14 (d, J = 7.9 Hz, 1H), 7.33−7.31 (dd, J = 7.9 Hz, 4.8 Hz, 129.18 (C−F, 2J C−F = 31.71 Hz), 129.18 (C−F, 2J C−F = 31.71
1H), 7.19 (d, J = 8.9 Hz, 1H), 6.49−6.47 (m, 2H), 4.78 (s, 2H), 3.81 Hz), 128.69, 128.63, 128.1, 127.9, 127.3, 127.04 (C−F, 1J C−F =
(s, 3H), 3.80 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.3, 271.8 Hz), 126.6, 125.50 (C−F, 3J C−F = 3.02 Hz), 125.47 (C−F, 3J
158.7, 158.3, 151.3, 150.2, 134.5, 131.9, 130.3, 123.6, 119.2, 104.1, C−F = 3.02 Hz), 125.45 (C−F, 3J C−F = 3.02 Hz), 125.42 (C−F, 3J
98.5, 59.1, 55.3. HRMS (DART) m/z calcd for C15H17N2O2 [M + C−F = 3.02 Hz), 125.24 (C−F, 1J C−F = 271.8 Hz), 123.8, 123.43
H]+: 257.1290; Found [M + H]+: 257.1297. (C−F, 1J C−F = 271.8 Hz), 121.63 (C−F, 1J C−F = 271.8 Hz), 64.4.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-dimethoxybenzyl)- 19
F NMR (565 MHz, CDCl3) δ −62.28. HRMS (DART) m/z calcd
methanimine (9n). Following General Procedure A, piperonal (0.89 for C19H15F3N [M + H]+: 314.1157; Found [M + H]+: 314.1154.
g, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), (E)-1-([1,1′-Biphenyl]-4-yl)-N-(2, 4-dimethoxybenzyl)-
magnesium sulfate (2.0 g), and dichloromethane (8 mL) were used. methanimine (9q). Following General Procedure A, 4-phenyl-
The title compound was obtained as a pale-yellow solid (1.77 g, 99%). benzaldehyde (1.09 g, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g,
Mp −54.3−55.7 °C. 1H NMR (600 MHz, CDCl3) δ: 8.2 (s, 2H), 7.4 6.0 mmol), magnesium sulfate (2.0 g), and dichloromethane (8 mL)
(s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.8 (d, J = were used. The title compound was obtained as a white solid (1.82 g,
7.9 Hz, 1H), 6.47−6.46 (m, 2H), 5.9 (s, 2H), 4.71 (s, 2H), 3.808 (s, 94% purity, 86% yield). Mp −91.3−93.9 °C. 1H NMR (600 MHz,
3H), 3.802 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.8, CDCl3) δ 8.41 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.70−7.63 (m, 4H),
160.0, 158.2, 149.7, 148.2, 131.3, 130.0, 124.3, 120.1, 107.9, 106.7, 7.49 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 6 Hz, 1H), 7.29−7.23 (m, 1H),

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6.55−6.50 (m, 2H), 4.83 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H). 13C{1H} 138.2, 132.6, 130.5, 129.94 (C−F, 2J C−F = 31.71 Hz), 129.73 (C−F,
NMR (151 MHz, CDCl3) δ 161.3, 160.1, 158.3, 143.2, 140.5, 135.4, 2
J C−F = 31.71 Hz), 129.51 (C−F, 2J C−F = 31.71 Hz), 129.29 (C−
130.3, 130.1, 129.0, 128.8, 128.7, 128.5, 127.7, 127.4, 127.2, 127.1, F, 2J C−F = 31.71 Hz), 129.17, 129.11, 128.8, 127.8, 126.90 (C−F, 1J
120.0, 104.1, 98.5, 59.0, 55.4. HRMS (DART) m/z calcd for C−F = 271.8 Hz), 125.12 (C−F, 3J C−F = 4.53 Hz), 125.09 (C−F, 2J
C22H22NO2 [M + H]+: 332.1651; Found [M + H]+: 332.1667. C−F = 4.53 Hz), 123.29 (C−F, 1J C−F = 271.8 Hz), 121.49 (C−F, 1J
(E)-N-(2,4-Dimethoxybenzyl)-1-(p-tolyl)methanimine (9r). Fol- C−F = 271.8 Hz), 120.5, 119.6, 103.6, 98.6, 70.2, 63.4, 61.2, 59.3,
lowing General Procedure A, p-tolualdehyde (0.72 g, 6.0 mmol), 55.4, 55.2, 46.0. 19F NMR (565 MHz, CDCl3) δ − 62.36. HRMS
2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium sulfate (2.0 (DART) m/z calcd for C29H30F3N2O4 [M + H]+: 527.2158; Found
g), and dichloromethane (8 mL) were used. The title compound was [M + H]+: 527.2153.
obtained as a pale-yellow oil (1.28 g, 80%). 1H NMR (600 MHz, (S)-3-((1S,2S)-1-((2,4-dimethoxybenzyl)amino)-1-phenylbut-3-
CDCl3) δ 8.36 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.4 Hz, en-2-yl)-4-phenyloxazolidin-2-one (18b). According to General
3H), 6.55−6.51 (m, 2H), 4.81 (s, 2H), 3.86 (s, 6H), 2.38 s, 3H). Procedure B, the product was purified by silica gel chromatography
13
C{1H} NMR (151 MHz, CDCl3) δ 161.7, 160.1, 158.2, 140.7, (10% E.A. in DCM) to provide 147 mg (80%) of 18b as a colorless
133.8, 130.0, 129.8, 129.7, 129.2, 128.2, 120.1, 104.0, 98.5, 58.9, 55.3, foam as a single diastereomer. Rf = 0.35 (50% EtOAc/hexanes). 1H
21.5. HRMS (DART) m/z calcd for C17H20NO2 [M + H]+: NMR (600 MHz, CDCl3) δ 7.32 (dd, J = 4.5, 2.3 Hz, 3H), 7.25−7.22
270.1494; Found [M + H]+: 270.1495. (d, J = 6 Hz, 2H), 7.22−7.19 (d, J = 6 Hz, 1H), 7.18−7.16 (d, J = 12
(E)-N-(2,4-Dimethoxybenzyl)-1-(furan-2-yl)methanimine (9s). Hz, 2H), 7.15−7.14 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.48 (s, 1H),
Following General Procedure A, furfural (0.57 g, 6.0 mmol), 2,4- 6.46 (d, J = 8.3 Hz, 1H), 5.05−4.97 (dt, J = 18 Hz, 12 Hz, 1H), 4.70
dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium sulfate (2.0 g), (d, J = 17.0 Hz, 1H), 4.64 (d, J = 10.2 Hz, 1H), 4.59 (t, J = 6 Hz, 1H),
and dichloromethane (8 mL) were used. The title compound was 4.46 (t, J = 8.6 Hz, 1H), 4.12−4.04 (dt, J = 18 Hz, 6 Hz, 2H), 3.99 (d,
obtained as a brown oil (1.6 g, 91% purity, 99% yield). 1H NMR (600 J = 10.0 Hz, 1H), 3.81 (s, 6H), 3.67 (d, J = 13.4 Hz, 1H), 3.34 (d, J =
MHz, CDCl3) δ: 8.08 (s, 1H), 7.49 (s, 1H), 7.18 (d, J = 8.1 Hz, 1H), 13.4 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8,
6.73 (d, J = 3.4 Hz, 1H), 6.47−6.45 (m, 3H), 4.73 (s, 2H), 3.80 (s, 158.6, 140.6, 138.9, 133.3, 130.6, 128.98, 128.96, 128.4, 128.2, 127.8,
3H), 3.79 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ: 160.28, 127.4, 120.9, 119.0, 103.6, 98.6, 70.2, 63.2, 61.5, 58.9, 55.4, 55.2, 45.8.
158.46, 151.96, 150.13, 144.51, 130.69, 119.30, 113.59, 111.53, HRMS (DART) m/z calcd for C28H31N2O4 [M + H]+: 459.2284;
104.07, 98.47, 58.89, 55.40, 55.33. HRMS (DART) m/z calcd for Found [M + H]+: 459.2300.
C14H16NO3 [M + H]+: 246.1130; Found [M + H]+: 246.1126. (S)-3-((1S,2S)-1-((4-Methoxybenzyl)amino)-1-phenylbut-3-en-2-
(E)-N-(2,4-Dimethoxybenzyl)-1-(thiophen-2-yl)methanimine yl)-4-phenyloxazolidin-2-one (18c). According to General Procedure
(9t). Following General Procedure A, thiophene-2-carboxaldehyde B, the product was purified by silica gel chromatography (10% E.A. in
(0.67 g, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), DCM) to provide 153 mg (89%) of 18c as a white solid as a single
magnesium sulfate (2.0 g), and dichloromethane (8 mL) were used. diastereomer. Mp 101−104 °C. Rf = 0.41 (50% EtOAc/hexanes). 1H
The title compound was obtained as a yellow solid (1.15 g, 74%). Mp NMR (600 MHz, CDCl3) δ 7.37−7.33 (m, 3H), 7.31 (m, 2H), 7.27
−47.4−50.2 °C. 1H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H), 7.37 (d, (m, 3H), 7.20 (d, J = 6 Hz, 2H), 7.18−7.14 (m, 2H), 6.96 (d, J = 12
J = 6 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.06 Hz, 2H), 5.10 (dt, J = 16.5, 9.6 Hz, 1H), 4.76−4.69 (m, 2H), 4.66 (t,
(t, J = 6 Hz, 1H), 6.50−6.46 (m, 2H), 4.74 (s, 2H), 3.80 (s, 6H). J = 8.4 Hz, 1H), 4.60 (t, J = 12 Hz, 1H), 4.18 (t, J = 12 Hz, 1H), 4.12
13
C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.3, 154.8, 142.9, (t, J = 12 Hz, 1H), 4.02 (d, J = 10.2 Hz, 1H), 3.86 (s, 3H), 3.64 (d, J
130.3, 130.2, 128.6, 127.2, 119.6, 104.1, 98.4, 58.2, 55.4, 55.3. HRMS = 13.0 Hz, 1H), 3.41 (d, J = 12.9 Hz, 1H), 1.91 (s, 1H). 13C{1H}
(DART) m/z calcd for C14H16NO2S [M + H]+: 262.0902; Found [M NMR (151 MHz, CDCl3) δ 159.1, 158.7, 140.5, 138.5, 133.2, 132.5,
+ H]+: 262.0915. 129.8, 128.9, 128.9, 128.4, 128.2, 127.8, 127.5, 119.2, 113.7, 70.3,
General Procedure B for the Synthesis of 18. To a 20 mL 63.2, 61.5, 60.4, 59.0, 55.3, 49.9, 21.0, 14.2. HRMS (DART) m/z
crimp cap vial with a stir bar in an Ar filled glovebox were charged calcd for C27H29N2O3 [M + H]+: 429.2178; Found [M + H]+:
Cu(OAc)2 (3.6 mg, 20 μmol) and PCy3 (7.3 mg, 26 μmol) followed 429.2196.
by toluene (1.0 mL) and tert-butanol (76.5 μL, 2 equiv). The mixture (S)-3-((1S,2S)-1-(4-Chlorophenyl)-1-((2,4-dimethoxybenzyl)-
was stirred for 5 min. Allenamide 15a (96.6 mg, 480 μmol) followed amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18d). According
by imine (400 μmol) was then charged, and the vial was sealed with a to General Procedure B, the product was purified by silica gel
crimp-cap septum and removed from the glovebox. Dimethoxy- chromatography (5% E.A. in DCM) to provide 146 mg (74%) of 18d
methylsilane (0.099 mL, 2 equiv) was then charged to the reaction as a colorless foam and a single diastereomer. Rf = 0.33 (50% EtOAc/
mixture (Caution:dimethoxymethylsilane should be handled in a well- hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.33 (m, 3H), 7.23
ventilated f ume hood because it is known to cause blindness. Syringes were (d, J = 8.2 Hz, 2H), 7.20−7.16 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H),
quenched with 2 M NaOH, gas evolution! prior to disposal). The mixture 6.99 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.2 Hz, 1H), 5.11−
was then stirred at rt for 24 h. The reaction was quenched by addition 5.03 (dt, J = 18 Hz, 12 Hz, 1H), 4.72 (s, 1H), 4.69 (d, J = 7.9 Hz,
of 200 mg of NH4F and 2.5 mL of MeOH followed by agitation at rt 1H), 4.60 (t, J = 8.1 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 4.10 (t, J = 7.9
for 30 min. A 10 mL volumen of 5% NaHCO3 was then added to the Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.95 (t, J = 9.6 Hz, 1H), 3.83 (s,
mixture followed by extraction with DCM (2 × 5 mL). The combined 6H), 3.66 (d, J = 13.4 Hz, 1H), 3.33 (d, J = 13.4 Hz, 1H), 2.08 (s,
organics were dried with Na2SO4, filtered, and concentrated in vacuo. 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.3, 158.8, 158.4, 139.3,
Crude product was purified by flash chromatography on silica gel to 138.4, 133.0, 132.8, 130.6, 129.8, 129.10, 129.07, 128.4, 127.8, 120.6,
afford the desired product. 119.4, 103.6, 98.6, 70.2, 63.4, 60.8, 59.2, 55.4, 55.2, 45.9. HRMS
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-(trifluoro- (DART) m/z calcd for C28H30ClN2O4 [M + H]+: 493.1894; Found
methyl)phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18a). Ac- [M + H]+: 493.1929.
cording to General Procedure B, the product was purified by silica gel (S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-fluoro-
chromatography (5% E.A. in DCM) to provide 180 mg (85%) of 18a phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18e). According
as a white foam as a single diastereomer. Rf = 0.43 (50% EtOAC/ to General Procedure B, the product was purified by silica gel
hexanes). 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), chromatography (5% E.A. in DCM) to provide 147 mg (77%) of 18e
7.36 (dd, J = 5.1, 1.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.21−7.17 as a colorless foam and a single diastereomer. Rf = 0.35 (50% EtOAc/
(m, 1H), 6.99 (d, J = 6 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.3 Hz, hexanes). 1H NMR (600 MHz, CDCl3) δ 7.37−7.32 (m, 3H), 7.20−
1H), 5.15−5.09 (dt, J = 18 Hz, 12 Hz, 1H), 4.73 (d, J = 12 Hz, 1H), 7.12 (m, 4H), 7.00 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 8.6 Hz, 2H), 6.50
4.70 (d, J = 17.1 Hz, 1H), 4.61 (t, J = 8.2 Hz, 1H), 4.52 (t, J = 12 Hz, (s, 1H), 6.48 (d, J = 6 Hz, 1H), 5.06 (dt, J = 18.2, 9.5 Hz, 1H), 4.70
1H), 4.17 (d, J = 6 Hz, 1H), 4.11 (t, J = 8.0 Hz, 1H), 3.93 (t, J = 9.6 (d, J = 16.6 Hz, 2H), 4.60 (t, J = 8.1 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H),
Hz, 1H), 3.83 (s, 6H). 3.66 (d, J = 12 Hz, 1H), 3.36 (d, J = 18 Hz, 4.10 (t, J = 7.9 Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.96 (t, J = 9.6 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.3, 158.8, 158.3, 145.2, 1H), 3.83 (s, 6H), 3.66 (d, J = 13.4 Hz, 1H), 3.34 (d, J = 13.5 Hz,

5037 https://doi.org/10.1021/acs.joc.0c02971
J. Org. Chem. 2021, 86, 5026−5046
The Journal of Organic Chemistry pubs.acs.org/joc Article

1H), 2.10 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.93 (C− 132.1, 129.4, 129.3, 129.2, 128.49, 128.47, 127.7, 127.3, 123.3, 122.8,
F, 1J C−F = 244.62 Hz), 161.31 (C−F, 1J C−F = 244.62 Hz), 160.2, 120.3, 70.2, 63.5, 61.5, 59.6, 50.9. HRMS (DART) m/z calcd for
158.8, 158.4, 138.5, 136.4, 133.0, 130.5, 129.9, 129.8, 129.07 (C−F, 3J C26H26N3O4 [M + H]+: 444.1923; Found [M + H]+: 444.1952.
C−F = 4.53 Hz), 129.05 (C−F, 3J C−F = 4.53 Hz), 127.8, 120.7, (S)-3-((1S,2S)-1-(Benzylamino)-1-(3-bromophenyl)but-3-en-2-
119.2, 115.13 (C−F, 2J C−F = 21.14 Hz), 114.99 (C−F, 2J C−F = yl)-4-phenyloxazolidin-2-one (18j). The reaction was set up
21.14 Hz), 103.6, 98.6, 70.2, 63.5, 60.7, 59.1, 55.4, 55.2, 45.9. 19F according to General Procedure B and stirred at 65 °C for 24 h.
NMR (565 MHz, CDCl3) δ −115.14. HRMS (DART) m/z calcd for The product was purified by silica gel chromatography (2.5% E.A. in
C28H30FN2O4 [M + H]+: 477.2190; Found [M + H]+: 477.2204. DCM) to provide 173 mg (82%) of 18j as a pale-yellow foam and a
4-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-2-((S)-2-oxo-4- single diastereomer. Rf = 0.53 (50% EtOAc/hexanes). 1H NMR (600
phenyloxazolidin-3-yl)but-3-en-1-yl)benzonitrile (18f). According MHz, CDCl3) δ 7.41−7.29 (m, 10H), 7.16 (t, J = 7.7 Hz, 1H), 7.14−
to General Procedure B, the product was purified by silica gel 7.09 (m, 3H), 5.14 (dt, J = 16.8, 9.5 Hz, 1H), 4.75 (dd, J = 18 Hz, 12
chromatography (10% E.A. in DCM) to provide 157 mg (81%) of 18f Hz, 2H), 4.60 (t, J = 8.3 Hz, 1H), 4.55 (t, J = 8.5 Hz, 1H), 4.09 (t, J =
as a colorless foam and a single diastereomer. Rf = 0.36 (50% EtOAc/ 8.0 Hz, 1H), 4.04 (d, J = 10.2 Hz, 1H), 3.99 (t, J = 9.5 Hz, 1H), 3.68
hexanes). 1H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 2H), (d, J = 13.2 Hz, 1H), 3.45 (d, J = 13.2 Hz, 1H), 1.96 (s, 1H).
7.39−7.34 (m, 3H), 7.30 (d, J = 7.9 Hz, 2H), 7.22−7.18 (m, 2H), 13
C{1H} NMR (151 MHz, CDCl3) δ 159.0, 143.1, 140.1, 138.1,
6.95 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.14 132.6, 131.2, 130.7, 130.0, 129.1, 129.0, 128.5, 128.4, 127.8, 127.2,
(dt, J = 16.9, 9.8 Hz, 1H), 4.73 (d, J = 10.1 Hz, 1H), 4.66 (d, J = 17.0 126.8, 122.6, 119.7, 70.2, 63.3, 61.4, 59.3, 50.7. HRMS (DART) m/z
Hz, 1H), 4.59 (t, J = 8.2 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.20 (d, J = calcd for C26H26BrN2O2 [M + H]+: 477.1178; Found [M + H]+:
10.0 Hz, 1H), 4.12 (t, J = 8.1 Hz, 1H), 3.82 (s, 7H), 3.63 (d, J = 13.5 477.1182.
Hz, 1H), 3.32 (d, J = 13.5 Hz, 1H), 2.20 (s, 1H). 13C{1H} NMR (S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(pyridin-3-yl)-
(151 MHz, CDCl3) δ 160.4, 158.7, 158.2, 146.8, 137.9, 132.0, 130.5, but-3-en-2-yl)-4-phenyloxazolidin-2-one (18k). According to Gen-
129.3, 129.2, 129.1, 127.8, 120.3, 119.9, 118.8, 111.2, 103.7, 98.6, eral Procedure B, the product was purified by silica gel
70.2, 63.4, 61.3, 59.4, 55.4, 55.2, 46.2. HRMS (DART) m/z calcd for chromatography (40% E.A. in DCM) to provide 143 mg (78%) of
C29H30N3O4 [M + H]+: 484.2236; Found [M + H]+: 484.2255. 18k as a pale-yellow foam as a single diastereomer. Rf = 0.1 (60%
Methyl 4-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-2-((S)-2-oxo- EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.40 (d, J = 73.8
4-phenyloxazolidin-3-yl)but-3-en-1-yl)benzoate (18g). According Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.38−7.31 (m, 3H), 7.23−7.14 (m,
to General Procedure B, the product was purified by silica gel 3H), 6.99 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.1 Hz, 1H),
chromatography (10% E.A. in DCM) to provide 137 mg (66%) of 5.09 (dt, J = 17.0, 9.8 Hz, 1H), 4.72 (d, J = 10.2 Hz, 1H), 4.68 (d, J =
18g as a colorless foam and a single diastereomer. Rf = 0.34 (50% 17.1 Hz, 1H), 4.57 (t, J = 8.1 Hz, 1H), 4.50 (t, J = 8.6 Hz, 1H), 4.16−
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 4.08 (m, 2H), 3.93 (t, J = 9.7 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H),
2H), 7.35 (dd, J = 4.6, 1.6 Hz, 3H), 7.29−7.24 (m, 3H), 7.21−7.15 3.67 (d, J = 13.5 Hz, 1H), 3.35 (d, J = 13.5 Hz, 1H), 2.24 (s, 1H).
(m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.2 Hz, 13
C{1H} NMR (151 MHz, CDCl3) δ 160.4, 158.8, 158.3, 150.5,
1H), 5.07 (dt, J = 14.2, 9.5 Hz, 1H), 4.67 (d, J = 16.5 Hz, 2H), 4.61 149.0, 138.1, 136.3, 135.6, 132.5, 130.6, 129.2, 129.1, 127.8, 123.5,
(t, J = 8.1 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 4.11 (m, 2H), 4.01 (t, J = 120.3, 120.0, 103.7, 98.7, 70.2, 63.4, 59.2, 59.0, 55.4, 55.2, 46.0.
9.6 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 6H), 3.66 (d, J = 13.4 Hz, 1H), HRMS (DART) m/z calcd for C27H30N3O4 [M + H]+: 460.2236;
3.33 (d, J = 13.4 Hz, 1H), 2.18 (s, 1H). 13C{1H} NMR (151 MHz, Found [M + H]+: 460.2264.
CDCl3) δ 166.9, 160.3, 158.8, 158.4, 146.4, 138.4, 132.7, 130.6, 129.5, (S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-methoxy-
129.4, 129.1, 129.0, 128.5, 127.8, 120.6, 119.5, 103.6, 98.6, 70.2, 63.3, phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18l). According to
61.3, 59.1, 55.4, 55.2, 52.0, 46.0. HRMS (DART) m/z calcd for General Procedure B, the product was purified by silica gel
C30H33N2O6 [M + H]+: 517.2339; Found [M + H]+: 517.2378. chromatography (10% E.A. in DCM) to provide 143 mg (73%) of
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-nitro- 18l as a colorless foam and a single diastereomer. Rf = 0.25 (50%
phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18h). According EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.33 (dd, J = 4.4,
to General Procedure B, the product was purified by silica gel 2.3 Hz, 3H), 7.16 (dd, J = 5.9, 2.7 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H),
chromatography (5% E.A. in DCM) to provide 106 mg (53%) of 18h 7.04 (d, J = 8.1 Hz, 1H), 6.83−6.78 (m, 2H), 6.50 (s, 1H), 6.49−6.45
as a pale-yellow foam and a single diastereomer. Rf = 0.39 (50% (d, J = 12 Hz, 1H), 5.06−4.98 (dt, J = 18 Hz, 12 Hz, 1H), 4.73 (d, J =
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.13−8.07 (m, 17.0 Hz, 1H), 4.67 (d, J = 10.1 Hz, 1H), 4.59 (t, J = 7.9 Hz, 1H), 4.47
2H), 7.40−7.32 (m, 5H), 7.21 (dd, J = 6.3, 2.4 Hz, 2H), 6.95 (d, J = (t, J = 12 Hz, 1H), 4.11−4.04 (m, 2H), 3.97 (d, J = 10.0 Hz, 1H),
8.1 Hz, 1H), 6.49 (s, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.17 (dt, J = 16.9, 3.83 (s, 6H), 3.78 (s, 3H), 3.68 (d, J = 13.5 Hz, 1H), 3.35 (d, J = 13.4
9.8 Hz, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.66 (d, J = 17.0 Hz, 1H), Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.21, 158.9, 158.8,
4.61 (t, J = 8.3 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 4.27 (d, J = 10.0 Hz, 158.5, 138.9, 133.4, 132.5, 130.6, 129.4, 128.96, 128.94, 127.8, 121.0,
1H), 4.16−4.10 (m, 1H), 3.82 (s, 6H), 3.64 (d, J = 13.5 Hz, 1H), 118.9, 113.5, 103.6, 98.6, 70.2, 63.3, 60.8, 58.9, 55.4, 55.2, 55.1, 45.7.
3.33 (d, J = 13.5 Hz, 1H), 2.28 (s, 1H). 13C{1H} NMR (151 MHz, HRMS (DART) m/z calcd for C29H33N2O5 [M + H]+: 489.2389;
CDCl3) δ 160.4, 158.7, 158.2, 147.4, 137.9, 132.2, 130.5, 129.4, 129.3, Found [M + H]+: 489.2386.
129.2, 127.8, 123.4, 120.2, 120.0, 103.7, 98.7, 70.2, 63.5, 61.1, 59.5, (S)-3-((1S,2S)-1-(Benzylamino)-1-(2-methoxyphenyl)but-3-en-2-
55.4, 55.2, 46.2. HRMS (DART) m/z calcd for C28H30N3O6 [M + yl)-4-phenyloxazolidin-2-one (18m). The reaction was set up
H]+: 504.2135; Found [M + H]+: 504.2119. according to General Procedure B and stirred at 65 °C for 24 h.
(S)-3-((1S,2S)-1-(Benzylamino)-1-(3-nitrophenyl)but-3-en-2-yl)- The product was purified by silica gel chromatography (10% E.A. in
4-phenyloxazolidin-2-one (18i). The reaction was set up according DCM) to provide 127 mg (74%) of 18m as a colorless foam as a
to General Procedure B and stirred at 65 °C for 24 h. The product single diastereomer and as a 95:5 mixture of the branched 18m to
was purified by silica gel chromatography (5% E.A. in DCM) to rearranged product 19m. Rf = 0.36 (50% EtOAc/hexanes). 1H NMR
provide 88 mg (50%) of 18i as a pale-yellow foam and a single (600 MHz, CDCl3) δ 7.27−7.20 (m, 4H), 7.20−7.11 (m, 5H), 7.10
diastereomer and as a 91:9 mixture of the branched 18i to the (t, J = 6 Hz, 1H), 6.92 (d, J = 6 Hz, 3H), 6.76 (t, J = 7.4 Hz, 1H),
rearranged product 19i. Rf = 0.71 (20% EtOAc/DCM). 1H NMR 6.68 (d, J = 8.1 Hz, 1H), 4.76 (dt, J = 18.1, 9.4 Hz, 1H), 4.61 (d, J =
(600 MHz, CDCl3) δ 7.98 (d, J = 6.0 Hz, 1H), 7.91 (s, 1H), 7.47 (d, J 16.8 Hz, 1H), 4.48 (t, J = 8.3 Hz, 2H), 4.42 (d, J = 10.1 Hz, 1H), 4.38
= 7.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.28−7.16 (m, 9H), 7.05 (d, J (t, J = 8.7 Hz, 1H), 4.08−3.95 (m, 1H), 3.92 (t, J = 7.9 Hz, 1H), 3.60
= 6.7 Hz, 2H), 5.16 (dt, J = 17.0, 9.7 Hz, 1H), 4.69 (d, J = 10.1 Hz, (d, J = 8.2 Hz, 1H), 3.59 (s, 3H), 3.29 (d, J = 13.0 Hz, 1H), 2.11 (s,
1H), 4.59 (d, J = 17.0 Hz, 1H), 4.53 (t, J = 8.4 Hz, 1H), 4.47 (t, J = 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 159.4, 157.9, 140.8, 139.3,
8.6 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.02 (t, J = 8.2 Hz, 1H), 3.77 134.3, 129.0, 128.68, 128.65, 128.49, 128.45, 128.2, 128.0, 127.0,
(t, J = 9.8 Hz, 1H), 3.56 (d, J = 13.3 Hz, 1H), 3.36 (d, J = 13.2 Hz, 120.4, 118.0, 110.6, 70.2, 58.3, 55.1, 50.7. HRMS (DART) m/z calcd
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 158.7, 148.3, 137.5, 134.3, for C27H29N2O3 [M + H]+: 429.2178; Found [M + H]+: 429.2194.

5038 https://doi.org/10.1021/acs.joc.0c02971
J. Org. Chem. 2021, 86, 5026−5046
The Journal of Organic Chemistry pubs.acs.org/joc Article

(S)-3-((1S,2S)-1-(Benzo[d][1,3]dioxol-5-yl)-1-((2,4-dimethoxy- Procedure B, the product was purified by silica gel chromatography

benzyl)amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18n). Ac- (5% E.A. in DCM) to provide 143 mg (76%) of 18r as a colorless
cording to General Procedure B, the product was purified by silica gel foam and a single diastereomer. Rf = 0.29 (50% EtOAc/hexanes). 1H
chromatography (15% E.A. in DCM) to provide 163 mg (81%) of NMR (600 MHz, CDCl3) δ 7.33 (dd, J = 4.6, 2.3 Hz, 3H), 7.18−7.14
18n as a colorless foam and a single diastereomer. Rf = 0.26 (50% (m, 2H), 7.08 (s, 4H), 7.05 (d, J = 8.1 Hz, 1H), 6.51−6.46 (m, 2H),
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.37−7.31 (m, 5.00 (dt, J = 18.1, 9.6 Hz, 1H), 4.74 (d, J = 17.0 Hz, 1H), 4.66 (d, J =
3H), 7.19−7.11 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.69 10.2 Hz, 1H), 4.61 (t, J = 7.9 Hz, 1H), 4.47 (t, J = 8.6 Hz, 1H), 4.13
(d, J = 7.9 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.49 (s, 1H), 6.48 (d, J = (t, J = 9.6 Hz, 1H), 4.08 (t, J = 6 Hz, 1H), 3.95 (d, J = 9.9 Hz, 1H),
7.3 Hz, 1H), 5.92 (s, 2H), 5.05 (dt, J = 17.3, 8.6 Hz, 1H), 4.75 (d, J = 3.83 (s, 6H), 3.68 (d, J = 13.4 Hz, 1H), 3.35 (d, J = 13.3 Hz, 1H),
17.0 Hz, 1H), 4.71 (d, J = 10.2 Hz, 1H), 4.58 (t, J = 8.0 Hz, 1H), 4.47 2.31 (s, 3H), 2.02 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ
(t, J = 8.6 Hz, 1H), 4.08 (t, J = 7.8 Hz, 1H), 3.97 (m, 2H), 3.84 (s, 160.2, 158.8, 158.6, 139.0, 137.5, 137.0, 133.50, 130.6, 128.96, 128.94,
3H), 3.83 (s, 3H), 3.70 (d, J = 12.0 Hz, 1H), 3.36 (d, J = 13.4 Hz, 128.91, 128.3, 127.8, 121.0, 118.9, 103.6, 98.6, 70.3, 63.1, 61.2, 58.8,
1H), 2.02 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 55.4, 55.2, 45.7, 21.1. HRMS (DART) m/z calcd for C29H33N2O4 [M
158.4, 147.7, 146.8, 138.6, 134.6, 133.2, 130.6, 129.0, 127.8, 122.0, + H]+: 473.2440; Found [M + H]+: 473.2459.
120.9, 119.0, 108.1, 107.7, 103.6, 100.9, 98.6, 70.2, 63.4, 61.1, 59.0, (S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(furan-2-yl)-
55.4, 55.2, 45.8. HRMS (DART) m/z calcd for C29H31N2O6 [M + but-3-en-2-yl)-4-phenyloxazolidin-2-one (18s). According to Gen-
H]+: 503.2182; Found [M + H]+: 503.2200. eral Procedure B, the product was purified by silica gel
(S)-3-((1S,2S)-1-(2,3-Dihydrobenzofuran-5-yl)-1-((2,4-dimethoxy- chromatography (5% E.A. in DCM) to provide 154 mg (86%) of
benzyl)amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18o). Ac- 18s as a colorless foam and as a single diastereomer. Rf = 0.33 (50%
cording to General Procedure B, the product was purified by silica gel EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.32 (s, 4H), 7.20−
chromatography (15% E.A. in DCM) to provide 151 mg (75%) of 7.14 (m, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.48 (dd, J = 7.9, 1.4 Hz, 2H),
18o as a colorless foam and a single diastereomer. Rf = 0.18 (50% 6.26 (d, J = 1.7 Hz, 1H), 6.16 (d, J = 3.2 Hz, 1H), 5.18−5.07 (dt, J =
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.30 (m, 18 Hz, 12 Hz, 1H), 4.89 (d, J = 17.0 Hz, 1H), 4.75 (d, J = 10.2 Hz,
3H), 7.19−7.13 (m, 2H), 7.07−7.03 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 4.60 (t, J = 8.1 Hz, 1H), 4.49 (t, J = 12 Hz, 1H), 4.32 (t, J = 9.6
1H), 6.65 (d, J = 8.1 Hz, 1H), 6.52−6.45 (m, 2H), 5.00 (dt, J = 16.9, Hz, 1H), 4.12 (d, J = 10.2 Hz, 1H), 4.07 (t, J = 6 Hz, 1H), 3.82 (s,
9.6 Hz, 1H), 4.75 (d, J = 17.0 Hz, 1H), 4.67 (d, J = 10.2 Hz, 1H), 6H), 3.73 (d, J = 13.2 Hz, 1H), 3.47 (d, J = 13.1 Hz, 1H), 1.91 (s,
4.58 (t, J = 7.9 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.47 (t, J = 8.6 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 158.7, 153.1,
1H), 4.08 (t, J = 8.0 Hz, 2H), 3.92 (d, J = 10.1 Hz, 1H), 3.83 (s, 3H), 141.9, 138.9, 133.0, 130.8, 128.9, 128.9, 127.7, 120.6, 118.8, 109.8,
3.82 (s, 3H) 3.69 (d, J = 13.4 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 3.15 108.7, 103.7, 98.6, 70.3, 60.8, 60.4. 58.8, 55.4, 55.2, 45.8. HRMS
(t, J = 8.7 Hz, 2H), 2.06 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) (DART) m/z calcd for C26H29N2O5 [M + H]+: 449.2076; Found [M
δ 160.2, 159.4, 158.8, 138.9, 133.5, 132.5, 130.6, 128.96, 128.93, + H]+: 449.2068.
128.4, 127.8, 127.1, 124.4, 121.0, 118.9, 108.6, 103.6, 98.6, 71.2, 70.2, (S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(thiophen-2-
63.3, 61.0, 58.8, 55.4, 55.2, 45.7, 29.7. HRMS (DART) m/z calcd for yl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18t). According to
C30H33N2O5 [M + H]+: 501.2389; Found [M + H]+: 501.2426. General Procedure B, the product was purified by silica gel
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(naphthalen-2- chromatography (5% E.A. in DCM) to provide 137 mg (74%) of
yl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18p). According to 18t as a pale-yellow foam and as a single diastereomer. Rf = 0.33 (50%
General Procedure B, the product was purified by silica gel EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.31 (m,
chromatography (5% E.A. in DCM) to provide 151 mg (74%) of 3H), 7.21 (d, J = 5.1 Hz, 1H), 7.18−7.13 (m, 2H), 7.07 (d, J = 8.1
18p as a colorless foam as a single diastereomer. Rf = 0.30 (50% Hz, 1H), 6.90 (ddd, J = 4.8, 3.5, 1.1 Hz, 1H), 6.85 (d, J = 3.4 Hz,
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.83−7.75 (m, 1H), 6.50 (s, 1H), 6.48 (d, J = 7.9 Hz, 1H), 5.15 (dt, J = 16.2, 9.6 Hz,
3H), 7.63 (s, 1H), 7.45 (tdd, J = 7.7, 5.9, 3.2 Hz, 2H), 7.36 (dt, J = 1H), 4.84 (d, J = 17.0 Hz, 1H), 4.77 (d, J = 10.2 Hz, 1H), 4.56 (dd, J
6.4, 2.7 Hz, 4H), 7.23−7.19 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.49 = 8.6, 7.2 Hz, 1H), 4.47 (td, J = 8.6, 1.1 Hz, 1H), 4.39 (d, J = 9.6 Hz,
(m, 2H), 5.10 (dt, J = 17.4, 8.8 Hz, 1H), 4.71 (d, J = 17.0 Hz, 1H), 1H), 4.08 (ddd, J = 11.6, 6.7, 2.8 Hz, 2H), 3.82 (s, 3H), 3.83 (s, 3H),
4.66 (t, J = 8.0 Hz, 1H), 4.62 (d, J = 10.2 Hz, 1H), 4.51 (t, J = 8.6 Hz, 3.80 (d, J = 13.4 Hz, 1H), 3.48 (d, J = 13.4 Hz, 1H), 2.11 (s, 1H).
1H), 4.22 (d, J = 7.4 Hz, 2H), 4.11 (t, J = 7.6 Hz, 1H), 3.83 (s, 6H), 13
C{1H} NMR (151 MHz, CDCl3) δ 160.3, 158.8, 158.3, 145.5,
3.70 (d, J = 13.4 Hz, 1H), 3.40 (d, J = 13.4 Hz, 1H), 2.23 (s, 1H). 138.6, 132.8, 130.8, 129.0, 127.7, 126.2, 126.0, 124.8, 120.6, 119.3,
13
C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 158.6, 138.8, 103.6, 98.6, 70.3, 63.5, 60.4, 59.0, 57.2, 55.4, 55.2, 46.0. HRMS
138.1, 133.22, 133.21, 133.1, 130.6, 129.0, 128.1, 127.88, 127.80, (DART) m/z calcd for C26H29N2O4S [M + H]+: 465.1848; Found
127.7, 125.9, 125.8, 125.7, 120.9, 119.2, 103.6, 98.6, 70.3, 63.2, 61.7, [M + H]+: 465.1852.
59.1, 55.5, 55.3, 46.0. HRMS (DART) m/z calcd for C32H33N2O4 [M (S)-3-((1S,2S)-1-(5-Bromothiophen-2-yl)-1-((2,4-dimethoxy-
+ H]+: 509.2440; Found [M + H]+: 509.2411. benzyl)amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18u). Ac-
(S)-3-((1S,2S)-1-([1,1′-Biphenyl]-4-yl)-1-((2,4-dimethoxybenzyl)- cording to General Procedure B, the product was purified by silica gel
amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18q). According chromatography (3% E.A. in DCM) to provide 172 mg (79%) of 18u
to General Procedure B, the product was purified by silica gel as a pale-yellow foam as a single diastereomer and a 95:5 mixture of
chromatography (5% E.A. in DCM) to provide 144 mg (67%) of 18q the branched to rearranged product. Rf = 0.38 (50% EtOAc/hexanes).
as a colorless foam and a single diastereomer. Rf = 0.26 (50% EtOAc/ 1
H NMR (600 MHz, CDCl3) δ 7.35 (dd, J = 4.2, 2.5 Hz, 3H), 7.17
hexanes). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.9 Hz, 2H), (dd, J = 6.0, 2.6 Hz, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 6 Hz,
7.51 (d, J = 7.9 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.37−7.30 (m, 4H), 1H), 6.59 (d, J = 6 Hz, 1H), 6.50 (s, 1H), 6.48 (d, J = 12 Hz, 1H),
7.26 (d, J = 6.0 Hz, 3H), 7.21−7.16 (m, 2H), 7.08 (d, J = 8.0 Hz, 5.24 (dt, J = 16.7, 9.5 Hz, 1H), 4.89−4.83 (m, 2H), 4.54 (t, J = 8.0
1H), 6.52−6.47 (m, 2H), 5.08 (dt, J = 18.1, 9.6 Hz, 1H), 4.76 (d, J = Hz, 1H), 4.50 (t, J = 12 Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 4.11 (t, J =
17.0 Hz, 1H), 4.70 (d, J = 10.2 Hz, 1H), 4.63 (t, J = 8.0 Hz, 1H), 4.50 12 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (d, J = 13.5 Hz, 1H),
(t, J = 8.6 Hz, 1H), 4.17−4.05 (m, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.51 (d, J = 13.4 Hz, 1H), 2.24 (s, 1H). 13C{1H} NMR (151 MHz,
3.73 (d, J = 13.5 Hz, 1H), 3.42 (d, J = 13.4 Hz, 1H), 2.07 (s, 1H). CDCl3) δ 160.3, 158.8, 158.0, 147.7, 138.0, 132.2, 130.7, 129.2, 129.1,
13
C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 158.6, 140.7, 129.1, 127.7, 126.4, 120.3, 119.8, 111.6, 103.6, 98.6, 70.2, 63.6, 59.4,
140.1, 139.8, 138.8, 133.2, 130.6, 129.0, 128.9, 128.8, 128.7, 127.8, 57.7, 55.4, 55.2, 46.1. HRMS (DART) m/z calcd for C26H28BrN2O4S
127.2, 126.9, 126.8, 121.0, 119.2, 103.6, 98.6, 70.3, 63.2, 61.3, 59.0, [M + H]+: 543.0953; Found [M + H]+: 543.0949.
55.4, 55.2, 45.9. HRMS (DART) m/z calcd for C34H35N2O4 [M + General Procedure C for the Synthesis of 19. To a 20 mL
H]+: 535.2597; Found [M + H]+: 535.2631. crimp cap vial with a stir bar in an Ar filled glovebox were charged
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(p-tolyl)but-3- Cu(OAc)2 (3.6 mg, 20 μmol) and PCy3 (7.3 mg, 26 μmol) followed
en-2-yl)-4-phenyloxazolidin-2-one (18r). According to General by toluene (1.0 mL), and the mixture was stirred for 5 min.

5039 https://doi.org/10.1021/acs.joc.0c02971
J. Org. Chem. 2021, 86, 5026−5046
The Journal of Organic Chemistry pubs.acs.org/joc Article

Allenamide 15a (96.6 mg, 480 μmol) followed by imine (400 μmol) = 273.31 Hz), 125.72 (C−F, 3J C−F = 3.02 Hz), 125.69 (C−F, 3J C−
was then charged, and the vial was sealed with a crimp-cap septum F = 3.02 Hz), 125.67 (C−F, 3J C−F = 3.02 Hz), 125.64 (C−F, 3J C−
and removed from the glovebox. Dimethoxymethylsilane (0.099 mL, F = 3.02 Hz), 124.97 (C−F, 1J C−F = 273.31 Hz), 123.16 (C−F, 1J
2 equiv) was then charged to the reaction mixture (Caution:dime- C−F = 273.31 Hz), 121.7, 121.36 (C−F, 1J C−F = 273.31 Hz), 66.4,
thoxymethylsilane should be handled in a well-ventilated fume hood 64.6, 63.2, 61.8, 45.4. 19F NMR (565 MHz, CDCl3) δ −62.50. HRMS
because it is known to cause blindness. Syringes were quenched with 2 M (DART) m/z calcd for C27H25ClF3N2O2 [M + H]+: 501.1557; Found
NaOH, gas evolution! prior to disposal). The mixture was then stirred at [M + H]+: 501.1583.
rt for 24 h. The reaction was quenched by addition of 200 mg of (4S,5S)-4-(4-Fluorophenyl)-1-((S)-2-hydroxy-1-phenylethyl)-3-(4-
NH4F and 2.5 mL of MeOH followed by agitation at rt for 30 min. A (trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19ee). The re-
10 mL volume of 5% NaHCO3 was then added to the mixture action was set up according to general procedure C and stirred at 65
followed by extraction with DCM (2 × 5 mL). The combined °C for 24 h. The product was purified by silica gel chromatography
organics were dried with Na2SO4, filtered, and concentrated in vacuo. (5% E.A. in DCM) to provide 149 mg (74%) of 19ee as a colorless
Crude product was purified by flash chromatography on silica gel to foam as a single diastereomer. Rf = 0.40 (50% EtOAc/hexanes). 1H
afford the desired product 19. NMR (600 MHz, CDCl3) δ 7.45 (d, J = 7.9 Hz, 2H), 7.25 (t, J = 7.7
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyleth- Hz, 2H), 7.20−7.14 (m, 3H), 7.11 (d, J = 7.9 Hz, 2H), 6.94 (dd, J =
yl)-5-(4-(trifluoromethyl)phenyl)-4-vinylimidazolidin-2-one (19a). 8.4, 5.3 Hz, 2H), 6.88 (t, J = 8.5 Hz, 2H), 5.53−5.45 (ddd, J = 17.0,
According to General Procedure C, the product was purified by 10.1, 8.7 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.79 (t, J = 15.6 Hz,
silica gel chromatography (5% E.A. in DCM) to provide 198 mg 2H), 4.58 (t, J = 6.5 Hz, 1H), 4.24−4.19 (m, 2H), 4.01−3.95 (m,
(94%) of 19a as a colorless foam as a single diastereomer. Rf = 0.36 1H), 3.84 (d, J = 8.0 Hz, 1H), 3.64 (d, J = 15.1 Hz, 1H), 3.41 (t, J =
(50% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.53 (d, J = 8.3 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 163.63 (C−F, 1J
8.0 Hz, 2H), 7.35−7.30 (m, 2H), 7.26 (m, 4H), 7.18 (d, J = 8.0 Hz, C−F = 249.15 Hz), 161.98 (C−F, 1J C−F = 249.15 Hz), 160.7,
2H), 7.03 (d, J = 8.2 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.35 (d, J = 140.2, 137.4, 134.4, 133.01 (C−F, 3J C−F = 3.02 Hz), 132.99 (C−F,
2.4 Hz, 1H), 5.59 (ddd, J = 17.0, 9.3, 8.7, 1.0 Hz, 1H), 5.20 (d, J = 3
J C−F = 3.02 Hz), 130.31 (C−F, 2J C−F = 31.71 Hz), 130.09 (C−F,
10.1 Hz, 1H), 4.90 (t, J = 7.0 Hz, 1H), 4.85 (d, J = 17.1 Hz, 1H), 4.78 2
J C−F = 31.71 Hz), 129.88 (C−F, 2J C−F = 31.71 Hz), 129.66 (C−
(d, J = 14.7 Hz, 1H), 4.32 (m, 1H), 4.25 (dd, J = 7.9, 3.4 Hz, 1H),
F, 2J C−F = 31.71 Hz), 129.1, 129.0, 128.8, 128.7, 127.9, 127.6,
4.06−4.03 (m, 1H), 4.01 (d, J = 7.9 Hz, 1H), 3.86 (d, J = 14.7 Hz,
126.78 (C−F, 1J C−F = 273.31 Hz), 125.69 (C−F, 3J C−F = 3.02
1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.39 (t, J = 8.3 Hz, 1H). 13C{1H}
Hz), 125.67 (C−F, 3J C−F = 3.02 Hz), 125.64 (C−F, 3J C−F = 3.02
NMR (151 MHz, CDCl3) δ 161.1, 160.7, 158.6, 143.0, 137.6, 134.8,
Hz), 125.61 (C−F, 3J C−F = 3.02 Hz), 124.97 (C−F, 1J C−F =
131.7, 130.55 (C−F, 2J C−F = 31.71 Hz), 130.39 (C−F, 2J C−F =
273.31 Hz), 123.16 (C−F, 1J C−F = 273.31 Hz), 121.6, 121.35 (C−
31.71 Hz), 130.18 (C−F, 2J C−F = 31.71 Hz), 129.96 (C−F, 2J C−F
F, 1J C−F = 273.31 Hz), 116.09 (C−F, 2J C−F = 21.14 Hz), 115.95
= 31.71 Hz), 128.7, 127.8, 127.6, 127.4, 126.7 (C−F, 1J C−F = 271.8
(C−F, 2J C−F = 21.14 Hz), 66.6, 64.7, 63.2, 61.9, 45.3. 19F NMR
Hz), 125.51 (C−F, 3J C−F = 3.02 Hz), 125.48 (C−F, 3J C−F = 3.02
Hz), 124.89 (C−F, 1J C−F = 271.8 Hz), 123.09 (C−F, 1J C−F = (565 MHz, CDCl3) δ −62.52, −112.82. HRMS (DART) m/z calcd
271.8 Hz), 121.4, 121.29 (C−F, 2J C−F = 271.8 Hz), 116.2, 104.2, for C27H25F4N2O2 [M + H]+: 485.1852; Found [M + H]+: 485.1861.
98.1, 66.2, 64.9, 63.3, 61.9, 55.3, 54.9, 40.8. 19F NMR (565 MHz, (4S,5S)-1-Benzyl-5-(3-bromophenyl)-3-((S)-2-hydroxy-1-phenyl-
ethyl)-4-vinylimidazolidin-2-one (19j). The reaction was set up
CDCl3) δ −62.54. HRMS (DART) m/z calcd for C29H30F3N2O4 [M
according to general procedure C and stirred at 65 °C for 24 h. The
+ H]+: 527.2158; Found [M + H]+: 527.2173.
product was purified by silica gel chromatography (5% E.A. in DCM)
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl-
ethyl)-5-phenyl-4-vinylimidazolidin-2-one (19b). According to to provide 131 mg (69%) of 19j as a colorless foam as a single
General Procedure C, the product was purified by silica gel diastereomer. Rf = 0.46 (50% EtOAc/hexanes). 1H NMR (600 MHz,
chromatography (10% E.A. in DCM) to provide 158 mg (86%) of CDCl3) δ 7.42 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.34−
19b as a colorless foam as a single diastereomer. Rf = 0.31 (50% 7.24 (m, 8H), 7.17 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 6.6 Hz, 2H), 7.01
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.33 (t, J = 7.5 Hz, (d, J = 7.6 Hz, 1H), 5.59 (ddd, J = 17.0, 10.0, 8.7 Hz, 1H), 5.21 (d, J
3H), 7.30−7.24 (m, 7H), 7.07 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 8.2 = 10.1 Hz, 1H), 4.98 (d, J = 14.9 Hz, 1H), 4.91 (d, J = 17.0 Hz, 1H),
Hz, 1H), 6.40 (dd, J = 8.2, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.61 4.82 (t, J = 7.0 Hz, 1H), 4.38−4.27 (m, 2H), 4.08−4.05 (m, 1H),
(ddd, J = 17.0, 10.1, 8.7 Hz, 1H), 5.18 (d, J = 10.1 Hz, 1H), 5.12 (t, J 3.94 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 14.9 Hz, 1H), 3.48 (t, J = 8.1 Hz,
= 7.8 Hz, 1H), 4.86 (d, J = 17.0 Hz, 1H), 4.81 (d, J = 14.8 Hz, 1H), 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.6, 140.3, 137.5, 135.9,
4.34−4.24 (m, 2H), 4.04 (m, 1H), 3.98 (d, J = 7.7 Hz, 1H), 3.83 (d, J 134.5, 131.6, 130.4, 130.2, 128.8, 128.7, 128.6, 127.9, 127.7, 127.6,
= 6.6 Hz, 2H), 3.80 (s, 3H), 3.63 (s, 3H), 3.46 (t, J = 8.2 Hz, 1H). 125.9, 123.0, 121.4, 66.2, 64.8, 62.8, 62.0, 45.7. HRMS (DART) m/z
13
C{1H} NMR (151 MHz, CDCl3) δ 161.1, 160.5, 158.7, 138.8, calcd for C26H26BrN2O2 [M + H]+: 477.1178; Found [M + H]+:
137.8, 135.2, 131.5, 128.6, 128.5, 128.0, 127.6, 127.1, 120.8, 116.6, 477.1207.
104.0, 98.1, 66.4, 65.1, 63.6, 61.9, 55.3, 55.0, 40.6. HRMS (DART) (4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl-
m/z calcd for C28H31N2O4 [M + H]+: 459.2284; Found [M + H]+: ethyl)-5-(pyridin-3-yl)-4-vinylimidazolidin-2-one (19k). According
459.2304. to General Procedure C, the product was purified by silica gel
(4S,5S)-4-(4-Chlorophenyl)-1-((S)-2-hydroxy-1-phenylethyl)-3-(4- chromatography (50% E.A. in DCM) to provide 183 mg (99%) of
(trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19de). The re- 19k as a pale-yellow foam as a single diastereomer and as a 86:14
action was set up according to general procedure C and stirred at 65 mixture of the rearranged 19k to branched product 18k. Rf = 0.10
°C for 24 h. The product was purified by silica gel chromatography (60% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H),
(5% E.A. in DCM) to provide 143 mg (71%) of 19de as a colorless 8.26 (s, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.36−7.30 (m, 3H), 7.28−7.24
foam as a single diastereomer. Rf = 0.46 (50% EtOAc/hexanes). 1H (m, 4H), 7.06 (d, J = 8.2 Hz, 1H), 6.40 (dd, J = 8.3, 2.4 Hz, 1H), 6.35
NMR (600 MHz, CDCl3) δ 7.52 (d, J = 7.9 Hz, 2H), 7.31 (t, J = 7.4 (d, J = 2.4 Hz, 1H), 5.58 (ddd, J = 17.1, 10.0, 8.7 Hz, 1H), 5.20 (d, J
Hz, 2H), 7.24 (dd, J = 8.5, 6.5 Hz, 5H), 7.19 (d, J = 7.9 Hz, 2H), 6.98 = 10.1 Hz, 1H), 4.90 (t, J = 6.9 Hz, 1H), 4.85 (d, J = 17.1 Hz, 1H),
(d, J = 8.1 Hz, 2H), 5.59 (ddd, J = 17.1, 10.1, 8.7 Hz, 1H), 5.17 (d, J 4.76 (d, J = 14.6 Hz, 1H), 4.34−4.29 (m, 1H), 4.26 (dd, J = 7.8, 3.3
= 10.1 Hz, 1H), 4.89 (d, J = 15.1 Hz, 1H), 4.85 (d, J = 17.0 Hz, 1H), Hz, 1H), 4.07−4.02 (m, 1H), 3.97 (d, J = 8.1 Hz, 1H), 3.86 (dd, J =
4.65 (s, 1H), 4.29 (m, 2H), 4.06 (m, 1H), 3.90 (d, J = 7.9 Hz, 1H), 18.0 6.0 Hz 2H), 3.79 (s, 3H), 3.60 (s, 3H), 3.43 (t, J = 8.4 Hz, 1H).
3.70 (d, J = 15.1 Hz, 1H), 3.48 (t, J = 8.4 Hz, 1H). 13C{1H} NMR
13
C{1H} NMR (151 MHz, CDCl3) δ 161.1, 160.7, 158.6, 149.6,
(151 MHz, CDCl3) δ 160.7, 140.1, 137.4, 135.8, 134.6, 134.3, 130.33 149.1, 137.6, 134.5, 131.8, 129.1, 128.7, 127.85, 127.82, 127.6, 121.6,
(C−F, 2J C−F = 31.71 Hz), 130.11 (C−F, 2J C−F = 31.71 Hz), 116.1, 104.2, 98.1, 66.3, 64.8, 61.8, 61.5, 55.3, 55.0, 40.7. HRMS
129.90 (C−F, 2J C−F = 31.71 Hz), 129.68 (C−F, 2J C−F = 31.71 (DART) m/z calcd for C27H30N3O4 [M + H]+: 460.2236; Found [M
Hz), 129.2, 128.8, 128.79, 128.73, 127.9, 127.6, 126.77 (C−F, 1J C−F + H]+: 460.2247.

5040 https://doi.org/10.1021/acs.joc.0c02971
J. Org. Chem. 2021, 86, 5026−5046
The Journal of Organic Chemistry pubs.acs.org/joc Article

(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl- the rearranged 19t to the branched product 18t. Rf = 0.34 (50%
ethyl)-5-(4-methoxyphenyl)-4-vinylimidazolidin-2-one (19l). Ac- EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.37−7.32 (m,
cording to General Procedure C, the product was purified by silica 2H), 7.30−7.25 (m, 4H), 7.24 (d, J = 5.1 Hz, 1H), 7.08−7.04 (m,
gel chromatography (10% E.A. in DCM) to provide 184 mg (94%) of 1H), 6.92 (t, J = 6.0 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 6.43 (m, 2H),
19l as a colorless foam as a single diastereomer. Rf = 0.29 (50% 5.63−5.54 (ddd, J = 17.0, 10.1, 8.6 Hz, 1H), 5.21 (d, J = 10.1 Hz,
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.35 (t, J = 7.7 Hz, 1H), 5.06 (t, J = 7.0 Hz, 1H), 4.98 (d, J = 18.0 Hz, 1H), 4.82 (d, J =
2H), 7.31−7.25 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.4 14.8 Hz, 1H), 4.35−4.25 (m, 3H), 4.01 (m, 1H), 3.94 (d, J = 14.9 Hz,
Hz, 2H), 6.83 (d, J = 6.0 Hz, 2H), 6.42−6.40 (m, 2H), 5.64−5.56 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.59 (d, J = 8.7 Hz, 1H). 13C{1H}
(ddd, J = 17.0, 9.3, 8.6 Hz, 1H), 5.18 (d, J = 10.3 Hz, 1H), 5.15 (t, J = NMR (151 MHz, CDCl3) δ 160.6, 160.4, 158.7, 142.9, 137.6, 135.0,
7.1 Hz, 1H), 4.87 (d, J = 17.0 Hz, 1H), 4.79 (d, J = 14.8 Hz, 1H), 131.4, 128.7, 127.7, 127.6, 126.6, 125.8, 125.7, 121.1, 116.5, 104.0,
4.35−4.24 (m, 2H), 4.07−4.04 (m, 1H), 3.94 (d, J = 7.8 Hz, 1H), 98.2, 66.7, 65.1, 62.0, 59.2, 55.3, 55.1, 40.8. HRMS (DART) m/z
3.81 (s, 3H), 3.79 (s, 3H), 3.67 (s, 3H), 3.46 (t, J = 8.2 Hz, 1H). calcd for C26H29N2O4S [M + H]+: 465.1848; Found [M + H]+:
13
C{1H} NMR (151 MHz, CDCl3) δ 161.0, 160.5, 159.4, 158.7, 465.1881.
137.9, 135.3, 131.4, 130.6, 128.6, 128.4, 127.7, 127.6, 120.8, 116.7, (4S,5S)-1-((S)-2-Hydroxy-1-phenylethyl)-4-(naphthalen-2-yl)-3-
113.9, 104.0, 98.1, 66.6, 65.1, 63.1, 61.8, 55.3, 55.2, 55.1, 40.5. HRMS (4-(trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19pe). The
(DART) m/z calcd for C29H33N2O5 [M + H]+: 489.2389; Found [M reaction was set up according to general procedure C and stirred at 65
+ H]+: 489.2387. °C for 24 h. The product was purified by silica gel chromatography
(4S,5S)-1-Benzyl-3-((S)-2-hydroxy-1-phenylethyl)-5-(2-methoxy- (5% E.A. in DCM) to provide 130 mg (79%) of 19pe as a colorless
phenyl)-4-vinylimidazolidin-2-one (19m). The reaction was set up foam as a single diastereomer. Rf = 0.43 (50% EtOAc/hexanes). 1H
according to general procedure C and stirred at 65 °C for 24 h. The NMR (600 MHz, CDCl3) δ 7.59−7.56 (m, 1H), 7.55 (d, J = 8.5 Hz,
product was purified by silica gel chromatography (10% E.A. in 1H), 7.52−7.49 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.27−7.22 (m,
DCM) to provide 118 mg (69%) of 19m as a colorless foam as a 3H), 7.11 (t, J = 7.6 Hz, 2H), 7.08−7.02 (m, 3H), 7.01−6.95 (m,
single diastereomer. Rf = 0.37 (50% EtOAc/hexanes). 1H NMR (600 4H), 5.46−5.38 (ddd, J = 17.2, 10.0, 8.6 Hz, 1H), 4.96 (d, J = 10.1
MHz, CDCl3) δ 7.26 (tdd, J = 14.3, 11.1, 7.6 Hz, 10H), 7.13 (d, J = Hz, 1H), 4.72 (d, J = 15.1 Hz, 1H), 4.62 (d, J = 17.0 Hz, 1H), 4.13−
6.9 Hz, 3H), 6.94 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.68 4.09 (m, 2H), 3.90 (d, J = 7.8 Hz, 1H), 3.86 (d, J = 8.9 Hz, 1H), 3.53
(ddd, J = 16.8, 10.0, 8.3 Hz, 1H), 5.20−5.14 (m, 2H), 4.94 (dd, J = (d, J = 15.2 Hz, 1H), 3.42 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (151
16.1, 12.9 Hz, 2H), 4.50 (m, 1H), 4.33−4.27 (m, 2H), 4.06−4.00 (m, MHz, CDCl3) δ 160.8, 140.4, 137.5, 134.64, 134.62, 133.4, 133.1,
1H), 3.70 (d, J = 15.0 Hz, 1H), 3.61 (s, 3H), 3.59 (m, 1H). 13C{1H} 130.2 (C−F, 2J C−F = 31.71 Hz), 130.01 (C−F, 2J C−F = 31.71 Hz),
NMR (151 MHz, CDCl3) δ 160.7, 157.5, 138.0, 136.8, 135.6, 129.3, 129.80 (C−F, 2J C−F = 31.71 Hz), 129.58 (C−F, 2J C−F = 31.71
128.5, 128.4, 127.6, 127.5, 127.3, 120.6, 119.7, 110.9, 65.2, 61.9, 55.1, Hz), 129.2, 128.9, 128.7, 127.9, 127.86, 127.81, 127.7, 127.1, 126.82
45.6. HRMS (DART) m/z calcd for C27H29N2O3 [M + H]+: (C−F, 1J C−F = 273.31 Hz), 126.68, 126.62, 125.66 (C−F, 3J C−F =
429.2178; Found [M + H]+: 429.2195. 3.02 Hz), 125.63 (C−F, 3J C−F = 3.02 Hz), 125.61 (C−F, 3J C−F =
(4S,5S)-4-(Benzo[d][1,3]dioxol-5-yl)-3-(2,4-dimethoxybenzyl)-1- 3.02 Hz), 125.58 (C−F, 3J C−F = 3.02 Hz), 125.02 (C−F, 1J C−F =
((S)-2-hydroxy-1-phenylethyl)-5-vinylimidazolidin-2-one (19n). Ac- 273.31 Hz), 124.2, 123.21 (C−F, 1J C−F = 273.31 Hz), 121.5, 121.41
cording to General Procedure C, the product was purified by silica gel (C−F, 1J C−F = 273.31 Hz), 66.3, 64.8, 64.0, 62.0, 45.4. 19F NMR
chromatography (10% E.A. in DCM) to provide 197 mg (98%) of (565 MHz, CDCl3) δ −62.47. HRMS (DART) m/z calcd for
19n as a colorless foam as a single diastereomer. Rf = 0.26 (50% C31H28F3N2O2 [M + H]+: 517.2103; Found [M + H]+: 517.2121.
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.32 (m, (4S,5S)-1-Benzyl-3-((S)-2-hydroxy-1-phenylethyl)-5-(naphthalen-
2H), 7.29−7.25 (m, 4H), 7.03 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 7.9 2-yl)-4-vinylimidazolidin-2-one (19pc). The reaction was set up
Hz, 1H), 6.57 (s, 1H), 6.49 (d, J = 7.9 Hz, 1H), 6.42−6.38 (m, 2H), according to general procedure C and stirred at 65 °C for 24 h. The
5.95−5.91 (m, 2H), 5.61−5.53 (ddd, J = 17.1, 9.3, 8.5 Hz, 1H), 5.18 product was purified by silica gel chromatography (5% E.A. in DCM)
(d, J = 10.1 Hz, 1H), 5.06 (d, J = 7.9 Hz, 1H), 4.88 (d, J = 17.0 Hz, to provide 125 mg (70%) of 19pc as a colorless foam as a single
1H), 4.77 (d, J = 14.8 Hz, 1H), 4.33−4.22 (m, 2H), 4.03 (m, 1H), diastereomer. Rf = 0.60 (20% EtOAc/DCM). 1H NMR (600 MHz,
3.89 (d, J = 7.7 Hz, 1H), 3.83 (d, J = 14.8 Hz, 1H), 3.80 (s, 3H), 3.68 CDCl3) δ 7.81−7.71 (m, 3H), 7.49 (s, 1H), 7.48−7.43 (m, 2H),
(s, 3H), 3.42 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) 7.34−7.19 (m, 9H), 7.10 (d, J = 12.0 Hz, 2H), 5.62 (ddd, J = 17.0,
δ 160.9, 160.5, 158.7, 147.4, 137.8, 135.2, 132.6, 131.4, 128.6, 127.6, 10.1, 8.7 Hz, 1H), 5.15 (d, J = 10.1 Hz, 1H), 5.00 (d, J = 14.9 Hz,
120.9, 120.8, 116.6, 108.0, 107.1, 104.0, 101.1, 98.1, 66.5, 65.1, 63.5, 1H), 4.82 (d, J = 17.0 Hz, 1H), 4.35−4.27 (m, 2H), 4.14 (d, J = 7.8
61.8, 55.3, 55.1, 40.6. HRMS (DART) m/z calcd for C29H31N2O6 [M Hz, 1H), 4.08 (dd, J = 11.2, 2.5 Hz, 1H), 3.63−3.58 (m, 2H).
+ H]+: 503.2182; Found [M + H]+: 503.2211.
13
C{1H} NMR (151 MHz, CDCl3) δ 160.9, 137.7, 136.2, 135.1,
(4S,5S)-1-(2,4-Dimethoxybenzyl)-5-(furan-2-yl)-3-((S)-2-hydroxy- 134.9, 133.3, 133.1, 129.0, 128.74, 128.70, 128.6, 127.9, 127.8, 127.79,
1-phenylethyl)-4-vinylimidazolidin-2-one (19s). According to Gen- 127.74, 127.6, 127.1, 126.5, 126.4, 124.3, 121.3, 66.3, 64.9, 63.5, 62.0,
eral Procedure C, the product was purified by silica gel 45.6. HRMS (DART) m/z calcd for C30H29N2O2 [M + H]+:
chromatography (5% E.A. in DCM) to provide 149 mg (83%) of 449.2229; Found [M + H]+: 449.2259.
19s as a colorless foam as a single diastereomer. Rf = 0.28 (50% (4S,5S)-1-(4-Fluorobenzyl)-3-((S)-2-hydroxy-1-phenylethyl)-5-
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.34−7.28 (m, (naphthalen-2-yl)-4-vinylimidazolidin-2-one (19pd). The reaction
3H), 7.27−7.21 (m, 4H), 7.06 (d, J = 8.0 Hz, 1H), 6.41−6.37 (m, was set up according to general procedure C and stirred at 65 °C for
2H), 6.26−6.23 (m, 1H), 6.08 (d, J = 3.2 Hz, 1H), 5.61 (ddd, J = 24 h. The product was purified by silica gel chromatography (5% E.A.
17.1, 10.1, 8.7 Hz, 1H), 5.16 (d, J = 10.1 Hz, 1H), 5.08−5.05 (m, in DCM) to provide 132 mg (71%) of 19pd as a colorless foam as a
1H), 4.98 (d, J = 18.0 Hz, 1H), 4.71 (d, J = 15.0 Hz, 1H), 4.30−4.23 single diastereomer. Rf = 0.62 (20% EtOAc/DCM). 1H NMR (600
(m, 2H), 4.08 (d, J = 6.7 Hz, 1H), 3.98−3.94 (m, 1H), 3.85 (d, J = MHz, CDCl3) δ 7.85−7.75 (m, 3H), 7.54−7.48 (m, 3H), 7.36 (t, J =
15.0 Hz, 1H), 3.77 (s, 3H), 3.74−3.69 (m, 4H). 13C{1H} NMR (151 7.6 Hz, 2H), 7.33−7.26 (m, 3H), 7.25−7.22 (m, 1H), 7.09 (dd, J =
MHz, CDCl3) δ 160.5, 160.2, 158.6, 151.0, 142.8, 137.7, 135.1, 131.0, 8.4, 5.5 Hz, 2H), 6.98 (t, J = 8.6 Hz, 2H), 5.69 (ddd, J = 17.0, 10.2,
128.6, 127.6, 127.6, 120.6, 116.8, 110.2, 108.7, 104.0, 98.3, 65.2, 62.7, 8.6 Hz, 1H), 5.20 (d, J = 10.1 Hz, 1H), 4.96 (d, J = 14.9 Hz, 1H),
62.0, 57.1, 55.3, 55.2, 40.7. HRMS (DART) m/z calcd for 4.91 (t, J = 6.1 Hz, 1H), 4.86 (d, J = 17.0 Hz, 1H), 4.39−4.30 (m,
C26H29N2O5 [M + H]+: 449.2076; Found [M + H]+: 449.2066. 2H), 4.15−4.08 (m, 2H), 3.68−3.61 (m, 2H). 13C{1H} NMR (151
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl- MHz, CDCl3) δ 163.12 (C−F, 1J C−F = 246.13 Hz), 161.49 (C−F,
1
ethyl)-5-(thiophen-2-yl)-4-vinylimidazolidin-2-one (19t). According J C−F = 246.13 Hz), 160.8, 137.6, 134.8, 134.7, 133.3, 133.1, 130.46,
to General Procedure C, the product was purified by silica gel 132.02 (C−F, 3J C−F = 4.53 Hz), 131.99 (C−F, 3J C−F = 4.53 Hz),
chromatography (3% E.A. in DCM) to provide 184 mg (99%) of 19t 130.46, 130.41, 129.1, 128.7, 127.87, 127.80, 127.7, 127.1, 126.6,
as a colorless foam as a single diastereomer and as a 92:8 mixture of 126.5, 124.3, 121.4, 115.60 (C−F, 2J C−F = 21.14 Hz), 115.46 (C−F,

5041 https://doi.org/10.1021/acs.joc.0c02971
J. Org. Chem. 2021, 86, 5026−5046
The Journal of Organic Chemistry pubs.acs.org/joc Article
2
J C−F = 21.14 Hz), 66.3, 64.9, 63.6, 62.0, 45.0. 19F NMR (565 MHz, all the Cu(OAc)2 dissolved. A 50 mL two-neck round-bottom flask
CDCl3) δ − 114.61. HRMS (DART) m/z calcd for C30H28FN2O2 [M was then charged with imine 9c (1.0 g, 4.44 mmol) and allene 15a
+ H]+: 467.2135; Found [M + H]+: 467.2105. (1.07 g, 5.33 mmol), and the flask was evacuated and backfilled with
Synthesis of 29 from Achiral Allenamide 15b. To a 20 mL nitrogen 3 times. The flask was then charged with toluene (5 mL).
crimp cap vial with a stir bar in an Ar filled glovebox were charged The imine/allene flask was then charged with the catalyst solution.
Cu(OAc)2 (1.8 mg, 10 μmol) and Ph-BPE (5.1 mg, 10 μmol) Dimethoxymethyl silane (1.1 mL, 8.89 mmol) was charged to the
followed by toluene (2.5 mL) and tert-butanol (26.3 μL, 275 μmol). reaction mixture (caution:dimethoxymethylsilane should be handled in a
The mixture was stirred for 5 min. Allenamide 15b (37.5 mg, 300 well-ventilated f ume hood because it is known to cause blindness. Syringes
μmol) followed by imine 9a (250 μmol) was then charged, and the were quenched with 2 M NaOH, gas evolution! prior to disposal), and the
vial was sealed with a crimp-cap septum and removed from the reaction was allowed to stir at rt for 2 h. A 50 mL round-bottom flask
glovebox. Dimethoxymethylsilane (0.061 mL, 2 equiv) was charged to was charged with NH4F (2 g) and MeOH (20 mL), and the reaction
the reaction mixture, and the reaction mixture was stirred at rt for 24 mixture was transferred via pipet to this flask and allowed to stir at rt
h. The reaction was quenched by addition of 100 mg of NH4F and 1.5 for 30 min. The volatiles were concentrated in vacuo, and 50 mL of
mL of MeOH followed by agitation at rt for 30 min. A 5 mL volume 5% NaHCO3 solution were added to the flask. The mixture was
of 5% NaHCO3 was then added to the mixture followed by extraction extracted with CH2Cl2 (2 × 20 mL), and the combined organics were
with DCM (2 × 3 mL). The combined organics were dried with dried over Na2SO4 and concentrated in vacuo. The crude residue was
Na2SO4, filtered, and concentrated in vacuo. Crude product was purified by silica gel chromatography (5% EtOAc/DCM) to afford
purified by flash chromatography on silica gel (25% EtOAc/hexanes) 1.655 g (91%) of 18c as a white solid as a single diastereomer.
to afford 78 mg (69%) of 29 as a white solid as a single diastereomer Synthesis of 25. To a solution of 207.5 mg (393 μmol) of 19a in
and as a 57:43 mixture of enantiomers as determined via chiral HPLC 2 mL of CH2Cl2 at 0 °C were charged 66 μL (473 μmol) of
analysis (Chiracel AD-3 85:15 heptane/isopropanol 1.50 mL/min, triethylamine followed by dropwise addition of 30.5 μL (393 μmol) of
254 nm). Rf = 0.45 (50% EtOAc/hexanes). 1H NMR (600 MHz, MsCl. The mixture was stirred for 30 min at 0 °C, and then 4 mL of
CDCl3) δ 7.60 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 6.91 (d, J 10% NH4Cl were added. The mixture was extracted with CH2Cl2 (3
= 8.2 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 6.40 (dd, J = 8.1, 2.4 Hz, × 5 mL). The combined organics were dried with anhydrous Na2SO4
1H), 5.47 (ddd, J = 17.2, 10.5, 6.9 Hz, 1H), 5.05 (d, J = 10.6 Hz, 1H), and filtered, and the volatiles were removed in vacuo. The crude
4.99 (d, J = 17.2 Hz, 1H), 4.46 (t, J = 6.0 Hz, 1H), 4.29 (q, J = 12.0 residue was then dissolved in 2 mL of THF and cooled to 0 °C. A 1.0
Hz, 1H), 4.21 (q, J = 12.0 Hz, 1H), 3.79 (s, 6H), 3.75 (d, J = 9.6 Hz, M concentration of potassium tert-butoxide (433 μL, 433 μmol) in
1H), 3.71 (d, J = 13.7 Hz, 1H), 3.42 (q, J = 8.1 Hz, 1H), 3.25 (d, J = THF was then added, and the mixture was warmed to room
13.7 Hz, 1H), 3.16 (td, J = 8.7, 6.4 Hz, 1H). 13C{1H} NMR (151 temperature and stirred for 30 min. To the mixture was added 5 mL
MHz, CDCl3) δ 160.3, 158.7, 158.6, 144.8, 131.4, 130.7, 130.6, 130.2 of 10% brine followed by extraction with CH2Cl2 (3 × 5 mL). The
(q, J = 31.71 Hz), 128.9, 128.7, 125.3 (q, J = 3.02 Hz), 119.7, 103.6, combined organics were dried with anhydrous Na2SO4 and filtered,
98.6, 98.6, 62.2, 62.1, 61.7, 60.9, 55.3, 55.2, 46.1, 40.8. 19F NMR (565 and the volatiles were removed in vacuo. The crude residue was then
MHz, CDCl 3 ) δ −62.36. HRMS (DART) m/z calcd for dissolved in 4 mL of THF in a crimp cap vial. To the solution were
C23H26F3N2O4 [M + H]+: 451.1845; Found [M + H]+: 451.1881. then added 788 μL (3.94 mmol) of 5.0 M aqueous H2SO4. The vial
Synthesis of 30 from Achiral Allenamide 15b. To a 20 mL was purged with argon, sealed, and immersed in an oil bath at 50 °C.
crimp cap vial with a stir bar in an Ar filled glovebox were charged After 3 h the reaction mixture was cooled to room temperature, and
Cu(OAc)2 (1.8 mg, 10 μmol) and Ph-BPE (5.1 mg, 10 μmol) 15 mL of saturated aqueous NaHCO3 were added. The mixture was
followed by toluene (0.5 mL). The mixture was stirred for 5 min. extracted with CH2Cl2 (3 × 5 mL). The combined organics were
Allenamide 15b (37.5 mg, 300 μmol) followed by imine 9a (250 dried with anhydrous Na2SO4 and filtered, and the volatiles were
μmol) was then charged, and the vial was sealed with a crimp-cap removed in vacuo. The crude residue was purified by flash
septum and removed from the glovebox. Dimethoxymethylsilane chromatography (20% EtOAc/DCM) to afford 112 mg (70%) of
(0.061 mL, 2 equiv) was then charged to the reaction mixture. The 25 as a colorless foam. Rf = 0.22 (50% EtOAc/hexanes). 1H NMR
mixture was then stirred at rt for 24 h. The reaction was quenched by (600 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz,
addition of 100 mg of NH4F and 1.5 mL of MeOH followed by 2H), 7.02 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.31 (d, J =
agitation at rt for 30 min. A 5 mL volume of 5% NaHCO3 was then 2.4 Hz, 1H), 5.74 (ddd, J = 17.2, 10.2, 7.2 Hz, 1H), 5.41 (s, 1H), 5.12
added to the mixture followed by extraction with DCM (2 × 3 mL). (d, J = 10.2 Hz, 1H), 5.10 (d, J = 12 Hz, 1H), 4.67 (d, J = 14.8 Hz,
The combined organics were dried with Na2SO4, filtered, and 1H), 4.06 (d, J = 7.5 Hz, 1H), 3.86−3.82 (m, 2H), 3.76 (s, 3H), 3.54
concentrated in vacuo. Crude product was purified by flash (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.6, 160.5, 158.5,
chromatography on silica gel (50% EtOAc/hexanes) to afford 68 143.2, 136.1, 131.4, 130.6 (q, J = 33.22 Hz), 127.5, 126.7 (q, J = 271.8
mg (60%) of 30 as a colorless liquid and as an 80:20 mixture of Hz), 125.5 (q, J = 3.02 Hz), 118.0, 116.5, 104.1, 97.9, 65.5, 62.1, 55.3,
enantiomers as determined via chiral HPLC analysis (Chiracel AD-3 54.9, 39.8. 19F NMR (565 MHz, CDCl3) δ −62.49. HRMS (DART)
90:10 heptane/isopropanol 1.00 mL/min, 220 nm). Rf = 0.28 (50% m/z calcd for C21H22F3N2O3 [M + H]+: 407.1583; Found [M + H]+:
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 407.1600.
2H), 7.28 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 6.37 (dd, J = Synthesis of 19a from 18a. To a solution of 100 mg (190 μmol)
8.3, 2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 5.62 (ddd, J = 17.1, 10.1, of 18a in 1.0 mL of THF at −10 °C were added 114 μL (285 μmol)
8.6 Hz, 1H), 5.22 (d, J = 10.1 Hz, 1H), 5.04 (d, J = 17.0 Hz, 1H), of 2.5 M solution of nBuLi in hexanes. The reaction mixture was
4.70 (d, J = 14.7 Hz, 1H), 4.01 (d, J = 8.2 Hz, 1H), 3.86 (d, J = 14.7 allowed to warm to room temperature and stirred for 1 h. To the
Hz, 1H), 3.78 (s, 3H), 3.76−3.68 (m, 2H), 3.63 (t, J = 8.4 Hz, 1H), mixture were added 2 mL of saturated NH4Cl, and the mixture was
3.55 (s, 3H), 3.36−3.31 (m, 1H), 3.26−3.22 (m, 1H). 13C{1H} NMR extracted with CH2Cl2 (3 × 3 mL). The combined organics were
(151 MHz, CDCl3) δ 162.3, 160.6, 158.6, 142.7, 135.0, 131.7, 130.6 dried with anhydrous Na2SO4 and filtered, and the volatiles were
(q, J = 31.71 Hz), 127.6, 126.7 (q, J = 273.31 Hz), 125.5 (q, J = 3.02 removed in vacuo. The crude residue was purified by flash
Hz), 121.2, 116.2, 104.1, 98.0, 68.2, 63.8, 62.2, 55.3, 54.8, 46.1, 40.8. chromatography (5% EtOAc/DCM) to afford 94 mg (94%) of 19a
19
F NMR (565 MHz, CDCl3) δ −62.50. HRMS (DART) m/z calcd as a colorless foam.
for C23H26F3N2O4 [M + H]+: 451.1845; Found [M + H]+: 451.1882. Synthesis of 26. A crimp cap vial was charged with 100 mg (233
Synthesis of 18c on 1.0 g Scale. To a 20 mL crimp cap vial was μmol) of 18c, CH3CN (1 mL), K2CO3 (161 mg, 1.17 mmol), TBAI
charged Cu(OAc)2 (16.1 mg, 88.9 μmol), and the vial was sealed with (17.2 mg, 46.7 μmol), and allyl bromide (101 μL, 1.17 mmol). The
a crimp-cap septum. The vial was evacuated and backfilled with mixture was heated at 85 °C for 18 h. The reaction was quenched
nitrogen 3 times and then charged with toluene (5 mL), 20% PCy3 with 5 mL of water, and the mixture was extracted with MTBE (3 × 3
solution in toluene (194 μL, 111 μmol), and tert-butanol (0.85 mL, mL). The combined organics were dried with anhydrous Na2SO4 and
8.89 mmol), and the mixture was allowed to stir at rt for 10 min until filtered, and the volatiles were removed in vacuo. The crude residue

5042 https://doi.org/10.1021/acs.joc.0c02971
J. Org. Chem. 2021, 86, 5026−5046
The Journal of Organic Chemistry pubs.acs.org/joc Article

was purified by flash chromatography (20% EtOAc/hexanes) to afford Robert T. Martin − Department of Chemistry and
90 mg (82%) of 26 as a yellow solid. Rf = 0.60 (50% EtOAc/hexanes). Biochemistry, University of Maryland, College Park,
1
H NMR (600 MHz, CDCl3) δ 7.38−7.31 (m, 4H), 7.29−7.25 (m, Maryland 20742, United States
3H), 7.25−7.20 (m, 3H), 7.18 (d, J = 6.0 Hz, 2H), 6.98 (d, J = 8.5 Stephen Collins − Department of Chemistry, Virginia
Hz, 2H), 6.93−6.88 (m, 2H), 5.95 (dtd, J = 17.2, 9.5, 4.0 Hz, 1H), Commonwealth University, Richmond, Virginia 23284-3208,
5.25 (d, J = 10.1 Hz, 1H), 5.20 (d, J = 17.2 Hz, 1H), 5.12−5.05 (m,
1H), 4.88−4.82 (m, 1H), 4.61−4.52 (m, 2H), 4.52−4.45 (m, 2H), United States
4.08 (dd, J = 7.4, 5.3 Hz, 1H), 3.87 (d, J = 11.7 Hz, 1H), 3.85 (s, 3H), Zachary Wilhelm − Department of Chemistry and
3.82 (d, J = 13.3 Hz, 1H), 3.66−3.61 (m, 1H), 2.96 (d, J = 13.2 Hz, Biochemistry, University of Maryland, College Park,
1H), 2.56 (dd, J = 13.3, 9.1 Hz, 1H). 13C{1H} NMR (151 MHz, Maryland 20742, United States
CDCl3) δ 159.0, 158.7, 140.1, 137.1, 134.7, 131.8, 131.0, 130.0, 128.7, Mytia D. Edwards − Department of Chemistry, Virginia
128.6, 128.0, 127.8, 127.6, 119.2, 118.0, 113.8, 70.4, 62.4, 56.9, 56.7, Commonwealth University, Richmond, Virginia 23284-3208,
55.4, 52.9, 52.5. HRMS (DART) m/z calcd for C30H33N2O3 [M + United States
H]+: 469.2491; Found [M + H]+: 469.2504.
Synthesis of 27. To a 20 mL crimp cap vial with a stir bar in an Complete contact information is available at:
Ar filled glovebox were added 48 mg (0.10 mmol) of 26 followed by 2 https://pubs.acs.org/10.1021/acs.joc.0c02971
mL of toluene and 3.2 mg (5.1 μmol) of a Hoveyda−Grubbs II
catalyst. The vial was sealed and removed from the glovebox. The Notes
solution was heated at 90 °C for 12 h. The reaction mixture was The authors declare no competing financial interest.

■
concentrated, and the crude residue was purified by flash
chromatography (50% EtOAc/hexanes) to afford 35 mg (78%) of ACKNOWLEDGMENTS
27 as a colorless foam. 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 7.3
Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.35−7.31 (m, 1H), 7.28−7.21 (m, Startup funding from the Virginia Commonwealth University
6H), 7.15 (d, J = 6.0 Hz, 2H), 6.88 (d, J = 7.9 Hz, 2H), 5.41−5.37 and the Bill and Melinda Gates Foundation (The Medicines
(m, 1H), 5.20 (dd, J = 8.7, 2.8 Hz, 1H), 5.15−5.09 (m, 1H), 4.72− for All Institute, grant number OPP#1176590) is gratefully
4.68 (m, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.99 (d, J = 4.4 Hz, 1H), 3.97 acknowledged. We thank Dr. Faik Musayev (VCU) for X-ray
(s, 1H), 3.96−3.93 (m, 1H), 3.80 (s, 3H), 3.24 (dt, J = 17.9, 2.5 Hz, crystallographic analysis that was partially supported by
1H), 2.95 (d, J = 13.2 Hz, 1H), 2.76 (dd, J = 18.0, 2.8 Hz, 1H). Structural Biology resources provided by NIH Shared
13
C{1H} NMR (151 MHz, CDCl3) δ 158.7, 157.9, 142.8, 138.2, Instrumentation Grant S10OD021756 (MKS) and Virginia
130.7, 129.5, 128.8, 128.7, 128.6, 128.5, 128.1, 128.0, 126.4, 123.2, General Assembly Higher Education Equipment Trust Fund
113.8, 70.7, 67.8, 59.4, 59.3, 55.3, 53.5, 51.6. HRMS (DART) m/z
calcd for C28H29N2O3 [M + H]+: 441.2178; Found [M + H]+: (HEETF) to VCU. M.D.E. acknowledges the NSF for a
441.2205. summer REU fellowship (CHE-1851916). We thank Dr.

■
Joseph Turner (VCU) for assistance in collecting HRMS data.
ASSOCIATED CONTENT O.G. is grateful to the University of Maryland College Park for
start-up funds, the NSF (CAREER 1751568) and by the
* Supporting Information
sı
NIGMS of the NIH (R35GM137797), and computational
The Supporting Information is available free of charge at resources from UMD Deepthought2 and MARCC/BlueCrab
https://pubs.acs.org/doi/10.1021/acs.joc.0c02971. HPC clusters and XSEDE (CHE160082 and CHE160053).
Computational details, intermediate and transition state
coordinates, copies of 1H and 13C NMR spectra of all
new compounds, and X-ray diffraction analysis data of
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