Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides

Article abstract of DOI:10.1021/acs.joc.0c02971

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.

Full text of DOI:10.1021/acs.joc.0c02971

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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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Supporting Information
ACCESS
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.
by alcohol activation and amine substitution.1a−d While direct
catalytic 1,2-diamination of 2 represents an ideal strategy for
diamine synthesis, the amino-groups added across the π-system
INTRODUCTION
■
Chiral vicinal diamines are extremely valuable and important
motifs in organic chemistry that are exploited by both nature
are typically identical leading to the formation of diamines with
and the pharmaceutical industry for their biological activ-
identical substituents (i.e., R3 = R4 in 1),8,9 and a recent
approach employing electrochemistry9b suffers from potentially
forming high-energy/explosive diazocompounds13 en route to
the desired diamines. Additionally, the aziridination/ring-
opening strategy can suffer from poor stereoselectivity in the
aziridination step and regiochemistry issues in the subsequent
opening step, while the aminohydroxylation route requires
regiocontrol in the aminohydroxylation step followed by
additional transformations to convert 4 to the desired diamine.
Alternatively, synthesis of 1 through C−C bond formation can
be achieved through aza-pinacol coupling of two imines,14
nitro-Mannich,15 or glycine-Mannich16 reactions (Scheme 1B).
Typical aza-pinacol coupling protocols only afford symmetrical
diamines through homocoupling of a single imine; however,
recent photoredox strategies14h−l enabling the generation of α-
aminoradicals17 from amines have enabled cross-selective
coupling of imines and N-methylamines.14j−l Furthermore,
nucleophilic additions to imines using α-aminoanion deriva-
ities,1,2 and in stereoselective organic synthesis as powerful
chiral inducers through application as organocatalysts,3 chiral
ligands4 for transition metal catalyzed reactions, and as chiral
auxiliaries.5 For example, a variety of biologically active
pharmaceuticals and natural products are given in Figure 1
possessing either the chiral 1,2-diamino-fragment or its
corresponding urea form.2 Representative therapeutics being
developed for the treatment of important human diseases
include antibiotics (penicillin,2e jogyamycin2j), anticancer
compounds (cisplatin derivatives,6 LP992c), HIV protease
inhibitors (NBD-110212d), NK1-antagonists7 (CP-99,994;2a
Sch4250782g) for central-nervous-system (CNS) related
diseases and rheumatoid arthritis, and influenza (tamiflu).2b
Due to the biological and synthetic value of chiral 1,2-
diamines, stereoselective methods for their preparation are an
important endeavor in organic chemistry.1a,c,d,8 Potential
synthetic options to access the chiral vicinal diamine moiety
can be envisioned to occur either by formation of the two C−
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
(Scheme 1B).1a,c,d,8 Using a C−N bond forming approach
(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
Received: December 17, 2020
Published: March 16, 2021
© 2021 The Authors. Published by
American Chemical Society
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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
offer another entry into the diamine core 1.
envisioned that use of an amino-substituted allyl reagent 12
in addition reactions with imine electrophiles would be a
powerful strategy to prepare 1,2-diamines (13) with differential
substitution patterns on nitrogen and containing an olefin
motif for further functional group manipulations. Surprisingly,
only a single example of such a strategy for the preparation of
1,2-diamines has been reported, which employs a lithiated
derivative of 12 (M = Li) with chiral tert-butanesulfinimide
derived aldimines affording products in moderate yields with
mixtures of branched and linear allylation products.20 In
contrast, amino-substituted allyl reagents 12 have been used in
reactions employing carbonyl electrophiles to provide 1,2-
aminoalcohols (16).21−23 Recently, the Krische22 group and
In regards to chiral amine synthesis, asymmetric allylation of
imines using allyl organometallic nucleophiles (10) by direct
addition or through catalyst control has been an area of intense
research in organic chemistry (Scheme 2).19 The chiral
allylamine products (11) are highly valuable in the context
of the synthesis of complex amine-containing organic
compounds because of the high versatility of the olefin
functional group present within 11. Substituted allylorgano-
metallic reagents (e.g., 12) allow for increased molecular
complexity by introducing two stereocenters in the allyl
addition reaction (e.g., 13, Scheme 2B). Therefore, we
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Scheme 2. Proposed Allylation Strategy toward the
Synthesis of 1,2-Diamines
Table 1. Ligand Optimization for the Reductive Coupling
Using 15a
a
b
b
b
Entry
Ligand
dcpe
PCy3
P(adam)3
XPhos
P(NMe2)3
P(OEt)3
(PhO)2PNMe2
SIMes
PCy3
PCy3
PCy3
PCy3
%Yield 18a
%Yield 19a
% 9a
1
2
3
4
5
6
7
8
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
90
58
86
28
22
66
60
66
8
51
54
52
31
<5
20
<5
31
38
<5
<5
<5
67
<5
<5
21
14
<5
c
9
d
10
e
11
f
12
g
13
PCy3
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
b
1
Supporting Information for further details. Yield determined by H
NMR spectroscopy on the unpurified reaction mixture using
c
dimethylfumarate as analytical standard. Reaction performed in
d
e
MTBE. Reaction performed in dioxane. Reaction performed in
our own lab23 have developed reductive coupling24,25
procedures for the catalytic generation of amino-substituted
allyl reagents 12 and have studied their reactions with carbonyl
electrophiles (Scheme 2C). These techniques represent
orthogonal methodologies whereby the Krische22a system
employs a chiral Ir-catalyst and processes aldehyde electro-
philes using an achiral allenamide (15), while our work utilizes
a Cu-catalyst and a chiral allenamide (15a) for reactions using
ketone electrophiles.23 Based on our success in the stereo-
selective Cu-catalyzed reductive coupling of ketones and chiral
allenamides to afford branched chiral 1,2-aminoalcohols 1623a
or the corresponding linear products,23b and the lack of
literature data for imine allylation reaction utilizing amino-
substituted allylic nucleophiles, we began to investigate the
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.
f
g
CH2Cl2. Reaction performed in THF. Performed using 2.0 equiv of
t-BuOH as additive. DMB = 2,4-dimethoxybenzyl.
lability to allow for chemoselective differentiation of the two
amine protecting groups in the final products (18a/19a).
Gratifyingly, a variety of phosphine ligands (entries 1−7)
afforded urea product 19a presumably resulting from migration
of the carbamate carbonyl (Scheme 3), whereas an N-
heterocyclic carbene (NHC) ligand provided poor conversion
(entry 8). In all cases, a single diastereomer of product was
obtained as determined by 1H NMR spectroscopy of the
Scheme 3. Proposed Reaction Catalytic Cycle
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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a
Scheme 4. Imine Generality in the Cu-Catalyzed Reductive Coupling To Access 1,2-Diamino Synthons 18
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
b
c
isolated yield. Reaction performed at 65 °C. Isolated as an inseparable mixture of 18 and urea 19.
unpurified reaction mixture. Notably, the bidentate phosphine
dcpe that has been utilized previously in Cu-catalyzed
reductive coupling of C-substituted allenes and imines25c
afforded only a moderate yield with a substantial amount of
unreacted imine (20%, entry 1). Monodentate phosphine
ligands (entries 2−7) worked well with the exception of
sterically demanding ligands that afforded poor conversion of
the imine (entries 3, 4). Ultimately, the use of PCy3 as ligand
afforded the highest yield of 19a in the reaction (entry 2). Use
of solvents other than toluene in the reaction (entries 9−12)
offered no improvements. Finally, addition of 2 equiv of t-
BuOH to the reaction led to the exclusive formation of 18a in
excellent yield and diastereoselectivity.
An initial working hypothesis to understand the difference in
product selectivity between the formation of urea 19a in the
absence of t-BuOH versus the exclusive formation of diamino-
derivative 18a when t-BuOH was used as an additive is given in
Scheme 3. Regioselective hydrocupration of allenamide 15a by
the LCuH23,25c catalyst 20 initially is expected to afford
substituted linear allylcopper reagent 21 that may undergo E/Z
isomerization through σ−π−σ equilibration prior to reaction
with the imine electrophile. Then, diastereoselective reaction
of intermediate 21 with imine 9a provides Cu-amide
intermediate 22. To afford product 18a from 22, direct
silylation of the amine by the silane must occur to regenerate
the LCuH catalyst 20; however, this step is expected to be slow
due to the weak strength of the N−Si bond (BDE ≈ 104 kcal/
mol).27 Due to the strong basicity of the N-anion in 22,
intramolecular attack of the oxazolidinone carbonyl may occur
competitively to provide 23 containing an O−Cu bond that
should more easily silylate due to the high bond strength of the
O−Si bond (BDE ≈ 190 kcal/mol)28 affording urea 24 and
regenerating the LCuH catalyst (20). Alternatively, when t-
BuOH is present, protonation of the Cu−N bond of 22 by t-
BuOH to afford product 18a directly and generate LCuOtBu is
thermodynamically favorable based on the pKa values for a
secondary amine (pyrrolidine: ∼44)29 vs t-BuOH (32) and
supported by DFT calculations (vide infra).30 The LCu-OtBu
intermediate can then undergo silylation to regenerate the
LCuH catalyst 20. The role of alcohol additives to facilitate
catalyst turnover by protonation of Cu−N intermediates has
been documented previously.25c,31 Sterically hindered alcohols
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
with bulky alcohols.31
Table 3. Imine Generality in the Cu-Catalyzed Reductive
Coupling To Access Chiral Ureas
a
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-
a
Table 2. Effect of Imine N-Substitution on Reactivity
b
Entry
Ar2
% yield
a
Conditions: 9 (0.40 mmol), 15a (96.6 mg, 0.48 mmol), Cu(OAc)2
1
2
3
4
5
2,4-dimethoxyphenyl (9pa)
4-methoxyphenyl (9pb)
Phenyl (9pc)
4-fluorophenyl (9pd)
4-trifluoromethylphenyl (9pe)
17 (19pa)
58 (19pb)
70 (19pc)
71 (19pd)
79 (19pe)
(5 mol %), PCy3 (6.5 mol %), 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. Reaction performed at 65 °C. Isolated as
an inseparable mixture of urea 19 and 18.
b
c
a
Conditions: 9p (0.400 mmol), 106 mg (0.480 mmol) of 15a, 5 mol
% Cu(OAc)2, 6 mol % PCy3, 99 μL (0.80 mmol) of (MeO)2MeSiH,
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. Yield determined by H NMR spectroscopy on the
unpurified reaction mixture using dimethylfumarate as analytical
standard.
employed in good yields affording single diastereomers of
product at room temperature when Ar1 was a simple phenyl
group (19b), heterocyclic (19k, 19s, 19t), or substituted at the
para-position with an electron-donating group (19l, 19n) or an
electron-withdrawing group (19a). However, reactions em-
ploying imines containing halogenated arenes or more
sterically demanding aryl groups were not successful utilizing
the N-DMB derived imine and instead required heating and
the use of either an N-Bn or an N-CH2-p-CF3Ph group on the
aldimine (see 19de, 19ee, 19j and 19m, 19pe, respectively).
Stereochemical assignment of the products obtained in the
Cu-catalyzed reductive coupling reaction as the (S,S,S)-
diastereomer was determined unequivocally by X-ray crystal-
lography (Scheme 5). While the branched products 18 were
typically noncrystalline, formation of the HCl-salt of 18c
afforded crystalline material whose structure was determined
by single-crystal Xray analysis. Furthermore, conversion of
products 18 to the urea 19 could also be achieved after
b
1
DMB-imine (9pa) afforded a poor yield in the desired reaction
(entry 1). A strong influence on reactivity and the electronic
character of the aryl group (Ar2) of the imine was found
(entries 1−5). Use of an electron-poor aryl group (entry 5)
afforded the best reaction yield; however, a simple benzyl
group also provided good reactivity (entry 3). As a result, for
problematic DMB-derived imines, the reactivity can be
improved by utilizing PMB, Bn, or p-CF3-benzyl as the N-
substituent on the aldimine.
Based on the results from Table 2, the substrate scope for
the urea-forming Cu-catalyzed reductive coupling reaction in
the absence of t-BuOH was investigated using this new
knowledge (Table 3). DMB-substituted imines could be
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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.
Scheme 5. Stereochemistry Determination
Mechanistic Modeling by DFT Analysis. To shed light
onto the mechanism and origin of diastereoselectivity, we used
dispersion-corrected DFT calculations (see Supporting In-
formation for details). Specifically, we performed extensive
conformational analysis on all intermediates and transition
states using the B3LYP-D3 functional and a def2-SVP basis
set33 with toluene as the solvent using the CPCM solvation
model34 as implemented in Gaussian16. Further, to refine the
energetics and compare methods, single-point calculations
using the M06-L functional,35 as well as a larger basis set (def2-
TZVPP) with B3LYP-D3, which yielded similar energetic
profiles, were subsequently performed. For simplicity, only
B3LYP-D3/def2-SVP optimization energetics will be discussed
in the text. Structures were visualized using CYLview Version
1.0.561.36
isolation of 18 by subsequent treatment with n-BuLi (e.g., 18a
→ 19a). The urea product obtained from this sequence was
identical to the material made from the reductive coupling
reaction performed in the absence of t-BuOH by NMR
spectroscopy confirming that the same stereoisomer of product
was formed in both reductive coupling processes (i.e., with or
without t-BuOH as additive).
The synthetic utility of the reaction products obtained in the
allenamide/imine reductive coupling reaction is highlighted in
Scheme 6. The phenethyl group of urea 19a derived from the
Scheme 6. Synthetic Applications
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
isomerize (barrier of only 6.9 and 10.0 kcal/mol via TS−II-III
cis or TS−II-III trans, respectively) to form the nearly
isoenergetic cis or trans linear allylcopper intermediates (III cis
and III trans). Intermediate III cis was slightly favorable
compared to intermediate III trans (by 0.6 kcal/mol), as was
the cis isomerization transition state (TS−I-III cis was favored
by 3.1 kcal/mol), presumably due to coordination between the
oxazolidinone and the copper (Cu−O bond distance = 2.37
Evans oxazolidinone of the allenamide starting material could
be cleaved in a three-step sequence consisting of alcohol
activation (MsCl), base induced elimination, and enamide
hydrolysis with aqueous acid to provide urea 25 in good overall
yield without isolation of intermediates. Furthermore, synthon
27 is a viable intermediate to access chiral aminopiperidine 28
for the preparation of the potent NK-1 inhibitor compounds
CP-99,994 and CP-122,721,2a,7 which could easily be accessed
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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,
the trans conformation (III′ trans) becomes significantly more
favored (as seen in Figure 3), likely due to unfavorable steric
hindrance between the imine and the oxazolidinone in the III′
cis conformation (see Supporting Information for further
details).
Next, we focused on the key C−C bond formation steps. As
shown in Figure 3, after performing extensive conformational
analysis on the subsequent diastereomeric C−C bond forming
transition states with the allylcopper intermediates and the
imine substrate (see Supporting Information for details), the
most favorable pathway for diastereoselective C−C bond
formation was identified to proceed from the trans linear
intermediate III′ trans through a Zimmerman−Traxler
transition state TS-III′-IV trans (S,S,S) (barrier of only 7.4
kcal/mol from complexed III′ trans intermediate) to branched
addition product IV (S,S,S). Further, in agreement with
experiment, the competing diastereomeric transition state TS-
III′-IV trans (R,R,S) which would lead to the opposite
diastereomer was determined to be much higher in energy.
Notably, all C−C bond formation steps from III′trans are
reversible, as the branched addition products IV (S,S,S) and IV
(R,R,S) were each uphill in energy (by ∼2 kcal/mol and ∼6
kcal/mol respectively), which can have implications for
rational catalyst and reaction design (vide infra).
To gain insights into the origin of diastereoselectivity, we
performed distortion−interaction and NCI analysis (Figure 4).
Overall, comparing the structures of the lowest energy
competing diastereomeric transition states TS-III′-IV trans
(S,S,S) and TS-III′-IV trans (R,R,S) reveals that the structures
of these transition states were remarkably similar, with key C−
C and C−Cu bond distances differing by no more than 0.05 Å.
However, the orientation of the chiral auxiliary is different, as
the TS-III′-IV trans (S,S,S) transition state has the
oxazolidinone moiety of the enamide group of the substituted
Cu(allyl) ligand in an s-trans conformation while the TS-III′-
IV trans (R,R,S) has this group in an s-cis conformation that,
as shown in Figure 5, leads to a 2.2 kcal/mol energy
destabilization. Furthermore, the ground state structures of
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
analysis39 (Figure 4a) showed that the distortion energy of
the TS-III′-IV trans (S,S,S) transition state was higher than
that of the corresponding TS-III′-IV trans (R,R,S) transition
state (by 3.9 kcal/mol). However, the (S,S,S) system benefited
from much stronger interaction energy (by 8.5 kcal/mol).
Overall, this favorable interaction between the imine and
allylcopper makes the TS-III′-IV trans (S,S,S) the favorable
diastereomeric transition state. Finally, noncovalent interaction
(NCI) analysis (performed using Multiwfn40 software and
visualized using VMD41 software) further supports the
presence of favorable interactions in the TS-III′-IV trans
(S,S,S) transition state (Figure 4b). Specifically, in both
transition states, there appeared to be favorable C−H···π
interactions between the ligand and the benzyl group of the
imine (highlighted inside the blue circle). However, comparing
the areas in red circles, the TS-III′-IV trans (S,S,S) system had
stronger noncovalent interactions between the oxazolidinone
group and the phenyl ring on the imine. This suggests that
noncovalent interactions (i.e., between the oxazolidinone
moiety and the protecting group) are critical for control of
diastereoselectivity. Taken together, these results suggest that
both the conformational preference for the s-trans geometry
about the N-enamide group of the substituted Cu(allyl) ligand
and favorable noncovalent interactions between the oxazolidi-
none group and the imine are the major contributing factors
for diastereocontrol in these reactions.
Following C−C bond formation, intermediate IV serves as a
fork between two reaction pathways depending on whether or
not there is t-BuOH present (as supported by experiments;
vide supra). Specifically, in the presence of t-BuOH, the alcohol
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
copper. From this, the silane reagent can exchange hydride for
the alkoxide group, reforming the catalyst. While this
protonation of the amine moiety and concomitant release of
the t-BuO-CuL was calculated to be initially energetically
unfavorable (uphill by ∼4 kcal/mol), the exchange of hydride
for the alkoxide was thermodynamically favorable (downhill by
∼10 kcal/mol), rendering this overall process energetically
feasible. In the absence of t-BuOH, a thermodynamically
favorable rearrangement of intermediate IV can yield the Cu-
alkoxide urea intermediate V (∼7 kcal/mol exergonic), which
can then readily undergo transmetalation with silane to reform
the LCuH catalyst and furnish the silylated product of urea 19.
This mechanistic model is consistent with experimental
findings that the presence of t-BuOH has a profound effect
on the product selectivity (but not diastereoselectivity) of the
reaction toward either of the products (vide supra).
As previously noted, computational modeling of the imine
addition predicts this step should be reversible. This
phenomenon has important impacts for future developments
of catalyst controlled enantioselective reactions utilizing a
chiral catalyst in conjunction with an achiral allenamide. In this
regard, reaction of achiral allenamide 15b with imine 9a using
(S,S)-Ph-BPE as a chiral ligand was examined with and without
t-BuOH as the additive (Scheme 7). Again, branched product
29 was formed as a single diastereomer when t-BuOH was
present in the reaction, and urea 30 was formed as a single
diastereomer in the absence of t-BuOH. Separate conversion of
29 to 30 using n-BuLi confirmed that the same relative
stereochemistry was formed in both reactions. Importantly, 29
and 30 were formed in different enantiopurities (57:43 vs
80:20 er, respectively), supporting a reversible imine addition step
in these reactions. For example, if imine addition were
irreversible, reaction of 15b with a chiral catalyst to afford
the analogous intermediate to 22 (Scheme 3) must be
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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. H NMR spectra were recorded on Bruker 600 MHz
■
1
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
proton decoupling. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent as the internal standard (CDCl3:
77.0 ppm). Liquid chromatography was performed using forced flow
(flash chromatography) on silica gel purchased from Silicycle. Thin
layer chromatography (TLC) was performed on glass-backed 250 μm
silica gel F254 plates purchased from Silicycle. Visualization was
achieved by using UV light, a 10% solution of phosphomolybdic acid
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
the literature.26 Aldehydes were purchased from Sigma-Aldrich,
Combi-Blocks, TCI America, Alfa Aesar, or Oakwood Chemicals
and used as received. Tricyclohexylphosphine and Cu(OAc)2 were
purchased from the Strem Chemical Company and used as received.
All other materials were purchased from VWR, Sigma-Aldrich,
Combi-Blocks, or Alfa Aesar and used as received. Imines 9a,42
9b,43 9c,44 9ee,45 9h,46 9i,47 9j,48 9l,45 9m,47 9pb,49 9pc,50 and 9u45
were synthesized as described in the literature.
General Procedure A for the Synthesis of Imines. A 25 mL
round-bottom flask equipped with a magnetic stirring bar was charged
with aldehyde (6.0 mmol, 1.0 equiv) and dichloromethane (8 mL).
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
crude reaction mixture was filtered through Celite to remove
magnesium sulfate. The filtrate was concentrated in vacuo to yield
the pure imine, which was stored under nitrogen in the fridge.
(E)-1-(4-Chlorophenyl)-N-(2,4-dimethoxybenzyl)methanimine
(9d). Following General Procedure A, 4-chloro benzaldehyde (0.84 g,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
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
−59.5−60.5 °C. 1H NMR (600 MHz, CDCl3) δ 8.28 (s, 1H), 7.70 (d,
J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.21−7.15 (m, 1H), 6.51−
6.43 (m, 2H), 4.75 (s, 2H), 3.81 (s, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 160.3, 160.2, 158.3, 136.4, 134.9, 130.2, 129.4, 128.8, 119.6,
104.1, 98.5, 58.9, 55.4. HRMS (DART) m/z calcd for C16H17ClNO2
[M + H]+: 290.0948; Found [M + H]+: 290.0950.
Figure 5. Energetic comparison of s-trans and s-cis conformations of
an (E)-enamide system with chiral oxazolidinone, with steric
hindrance causing allylic strain highlighted. Structures optimized
using B3LYP-D3/def2SVP-CPCM(toluene) (Hrel and Grel shown in
kcal/mol).
Scheme 7. Mechanistic Implications Relevant to Catalyst-
Controlled Enantioinduction
enantiodetermining and requires that urea product 30 formed
from rearrangement of the intermediate 22 derivative to have
identical enantiopurity to that of 29. However, when a chiral
ligand is employed, rearrangement of the two enantiomers of
intermediate 22 may occur at different rates because the
transition states will be diastereomeric due to the chirality on
the ligand. Therefore, the carbamate migration step may also
be enantiodetermining if the imine addition step becomes
reversible enabling different enantiomeric ratios to be obtained
for a 29-selective vs a 30-selective process as was observed.
CONCLUSION
■
In conclusion, a highly stereoselective method for the reductive
coupling of imines with a chiral allenamide was developed as a
convenient strategy for the asymmetric synthesis of valuable
1,2-diamino synthons. The method employs readily available
and cost-effective starting materials26 and catalyst (Cu(OAc)2/
PCy3)32 and can be performed on the “bench-top” using
standard Schlenk techniques without issues. Use of tert-butanol
as an additive was shown to aid in the amine release and
catalyst regeneration to avoid the formation of urea products
that are exclusively obtained in the absence of this additive.
The oxazolidinone moiety of the final products could be
removed chemoselectively without disruption of the pendant
terminal alkene, and an orthogonally protected chiral amino-
piperidine derivative en route to important biologically active
pharmaceuticals was demonstrated. Finally, mechanistic
investigations by density functional theory calculations
identified the mechanism for stereoselection in these processes
as determined from the relative transition state barriers of N-
substituted allylcopper complexes to the imine electrophile.
This C−C bond forming addition step was shown to be
reversible by calculation and was experimentally supported by
(E)-1-(4-Chlorophenyl)-N-(4-(trifluoromethyl)benzyl)-
methanimine (9de). Following General Procedure A, 4-chloro
benzaldehyde (0.84 g, 6.0 mmol), 4-trifluoromethyl benzylamine
(1.05 g, 6.0 mmol), magnesium sulfate (2.0 g), and dichloromethane
(8 mL) were used. The title compound was obtained as brown solid
1
(1.5 g, 84%). Mp −39.7−41.3 °C. H NMR (600 MHz, CDCl3) δ
8.39 (s, 1H), 7.80 (dd, J = 8.5, 5.6 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H),
7.47 (d, J = 7.9 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 4.85 (s, 2H).
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13C{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
C17H18NO4 [M + H]+: 300.1236; Found [M + H]+: 300.1253.
(E)-1-(2,3-Dihydrobenzofuran-5-yl)-N-(2,4-dimethoxybenzyl)-
methanimine (9o). Following General Procedure A, 2,3-dihydro-
benzofuran-5-carbaldehyde (0.886 g, 6.0 mmol), 2,4-dimethoxy-
benzylamine (1.0 g, 6.0 mmol), magnesium sulfate (2.0 g), and
dichloromethane (8 mL) were used. The title compound was
2
2
129.66 (C−F, J C−F = 33.22 Hz), 129.5, 129.45 (C−F, J C−F =
2
33.22 Hz), 129.23 (C−F, J C−F = 33.22 Hz), 128.9, 128.1, 126.97
1
3
(C−F, J C−F = 273.31 Hz), 125.49 (C−F, J C−F = 3.02 Hz),
125.46 (C−F, 3J C−F = 3.02 Hz), 125.44 (C−F, 3J C−F = 3.02 Hz),
125.41 (C−F, J C−F = 3.02 Hz), 125.17 (C−F, J C−F = 273.31
Hz), 123.36 (C−F, J C−F = 273.31 Hz), 121.56 (C−F, J C−F =
273.31 Hz), 64.3. 19F NMR (565 MHz, CDCl3) δ −108.88. HRMS
(DART) m/z calcd for C15H12ClF3N [M + H]+: 298.0610; Found [M
+ H]+: 298.0640.
3
1
1
1
1
obtained as a pale-yellow oil (1.94 g, 72% purity, 78% yield). H
NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 7.73 (s, 1H), 7.44 (d, J = 12
Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.49−
6.43 (m, 2H), 4.71 (s, 2H), 4.60 (t, J = 8.7 Hz, 2H), 3.80 (s, 6H),
3.20 (t, J = 8.7 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.3,
161.3, 160.0, 158.2, 130.0, 129.8, 129.6, 127.7, 124.2, 120.3, 109.0,
104.0, 98.4, 71.7, 58.7, 55.3, 29.2. HRMS (DART) m/z calcd for
C18H20NO3 [M + H]+: 298.1443; Found [M + H]+: 298.1466.
(E)-N-(2,4-Dimethoxybenzyl)-1-(naphthalen-2-yl)methanimine
(9pa). Following General Procedure A, 2-naphthaldehyde (0.937 g,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
compound was obtained as a white solid (1.78 g, 98%). Mp −91.5−
93.9 °C. 1H NMR (600 MHz, CDCl3) δ: 8.48 (s, 1H), 8.05−8.03 (m,
2H), 7.89−7.87 (m, 1H), 7.85−7.83 (m, 2H), 7.51−7.49 (m, 2H),
7.24 (d, J = 8.9 Hz, 1H), 6.49−6.48 (m, 2H), 4.82 (s, 2H), 3.82 (s,
3H), 3.81 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ: 161.7,
160.1, 158.3, 134.6, 134.1, 133.1, 130.1, 129.9, 128.5, 128.3, 127.8,
127.0, 126.3, 124.0, 119.9, 104.9, 104.0, 98.5, 59.0, 55.4. HRMS
(DART) m/z calcd for C20H20NO2 [M + H]+: 306.1494; Found [M
+ H]+: 306.1506.
(E)-N-(2,4-Dimethoxybenzyl)-1-(4-fluorophenyl)methanimine
(9e). Following General Procedure A, 4-fluorobenzaldehyde (0.742 g,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
compound was obtained as a yellow solid (1.36 g, 84%). Mp −39.7−
1
41.1 °C. H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 7.76 (dd, J =
8.5, 5.7 Hz, 2H), 7.23−7.16 (m, 1H), 7.08 (t, J = 8.6 Hz, 2H), 6.52−
6.45 (m, 2H), 4.76 (s, 2H), 3.81 (s, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 165.06 (C−F, 1J C−F = 250.66 Hz), 163.40 (C−F, 1J C−F
3
= 250.66 Hz), 160.23, 160.21, 158.32, 132.80 (C−F, J C−F = 3.02
Hz), 132.78 (C−F, 3J C−F = 3.02 Hz), 132.2, 130.15, 130.11, 130.06,
2
2
119.84, 115.66 (C−F, J C−F = 22.65 Hz), 115.51 (C−F, J C−F =
22.65 Hz), 104.1, 98.54, 58.85. 19F NMR (565 MHz, CDCl3) δ
−109.87. HRMS (DART) m/z calcd for C16H17FNO2 [M + H]+:
274.1243; Found [M + H]+: 274.1269.
(E)-4-(2,4-Dimethoxybenzyl iminomethyl)benzonitrile (9f). Fol-
lowing General Procedure A, 4-formyl benzonitrile (0.784 g, 6.0
mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
compound was obtained as a yellow solid (1.59 g, 95%). Mp −54.0−
56.2 °C. 1H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.84 (d, J = 8.0
Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 9.0 Hz, 1H), 6.51−
6.44 (m, 2H), 4.80 (s, 2H), 3.80 (s, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 160.4, 159.6, 158.4, 140.3, 132.3, 130.3, 128.6, 119.0, 118.6,
113.7, 104.2, 98.5, 59.1, 55.4. HRMS (DART) m/z calcd for
C17H17N2O2 [M + H]+: 281.1290; Found [M + H]+: 281.1306.
Methyl (E)-4-(2,4-Dimethoxybenzyl iminomethyl)benzoate (9g).
Following General Procedure A, methyl-4-formyl benzoate (0.982 g,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
compound was obtained as a yellow solid (1.87 g, 100%). Mp −54.5−
56.3 °C. 1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H), 8.06 (d, J = 8.0
Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 9.0 Hz, 1H), 6.48 (m,
2H), 4.79 (s, 2H), 3.91 (s, 3H), 3.79 (s, 6H). 13C{1H} NMR (151
MHz, CDCl3) δ 166.7, 160.6, 160.2, 158.3, 140.3, 131.6, 130.2, 129.7,
128.0, 119.4, 104.1, 98.5, 59.1, 55.3, 55.3, 52.2. HRMS (DART) m/z
calcd for C18H20NO4 [M + H]+: 314.1392; Found [M + H]+:
314.1422.
(E)-N-(2,4-Dimethoxybenzyl)-1-(pyridin-3-yl)methanimine (9k).
Following General Procedure A, 3-pyridinecarboxaldehyde (0.64 g,
6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium
sulfate (2.0 g), and dichloromethane (8 mL) were used. The title
compound was obtained as a pale-yellow oil (1.51 g, 99%). 1H NMR
(600 MHz, CDCl3) δ: 8.85 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.34 (s,
1H), 8.14 (d, J = 7.9 Hz, 1H), 7.33−7.31 (dd, J = 7.9 Hz, 4.8 Hz,
1H), 7.19 (d, J = 8.9 Hz, 1H), 6.49−6.47 (m, 2H), 4.78 (s, 2H), 3.81
(s, 3H), 3.80 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.3,
158.7, 158.3, 151.3, 150.2, 134.5, 131.9, 130.3, 123.6, 119.2, 104.1,
98.5, 59.1, 55.3. HRMS (DART) m/z calcd for C15H17N2O2 [M +
H]+: 257.1290; Found [M + H]+: 257.1297.
(E)-N-(4-Fluorobenzyl)-1-(naphthalen-2-yl)methanimine (9pd).
Following General Procedure A, 2-naphthaldehyde (0.937 g, 6.0
mmol), 4-fluoro benzylamine (1.05 g, 6.0 mmol), magnesium sulfate
(2.0 g), and dichloromethane (8 mL) were used. The title compound
was obtained as an off-white solid (1.28 g, 90% purity, 73% yield). Mp
−87.7−88.9 °C. 1H NMR (600 MHz, CDCl3) δ 8.53 (s, 1H), 8.09 (s,
1H), 8.08 (d, J = 12.0 Hz, 1H), 7.92−7.86 (m, 3H), 7.54 (tdd, J = 8.0,
6.1, 3.3 Hz, 2H), 7.36 (dd, J = 8.4, 5.5 Hz, 2H), 7.07 (t, J = 8.7 Hz,
2H), 4.85 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.8 (C−F,
1
1J C−F = 244.62 Hz), 162.1, 161.2 (C−F, J C−F = 244.62 Hz),
135.14 (C−F, 3J C−F = 3.02 Hz), 135.12 (C−F, 3J C−F = 3.02 Hz),
134.8, 133.7, 133.1, 130.2, 129.6, 129.5, 128.6, 128.5, 127.9, 127.2,
126.5, 123.9, 115.4 (C−F, 2J C−F = 21.14 Hz), 115.2 (C−F, 2J C−F
= 21.14 Hz), 64.37. 19F NMR (565 MHz, CDCl3) δ − 115.92. HRMS
(DART) m/z calcd for C18H15FN [M + H]+: 264.1189; Found [M +
H]+: 264.1193.
(E)-1-(Naphthalen-2-yl)-N-(4-(trifluoromethyl)benzyl)-
methanimine (9pe). Following General Procedure A, 2-naphthalde-
hyde (0.937 g, 6.0 mmol), 4-trifluoromethyl benzylamine (1.05 g, 6.0
mmol), magnesium sulfate (2.0 g), and dichloromethane (8 mL) were
used. The title compound was obtained as an off-white solid (1.71 g,
91%). Mp −105.9−107.9 °C. 1H NMR (600 MHz, CDCl3) δ 8.56 (s,
1H), 8.10 (s, 1H), 8.09 (d, J = 6 Hz, 1H), 7.95−7.85 (m, 3H), 7.64
(d, J = 8.0 Hz, 2H), 7.58−7.49 (m, 4H), 4.92 (s, 2H). 13C{1H} NMR
(151 MHz, CDCl3) δ 162.7, 143.6, 134.9, 133.6, 133.1, 130.4, 129.61
2
2
(C−F, J C−F = 31.71 Hz), 129.40 (C−F, J C−F = 31.71 Hz),
2
2
129.18 (C−F, J C−F = 31.71 Hz), 129.18 (C−F, J C−F = 31.71
1
Hz), 128.69, 128.63, 128.1, 127.9, 127.3, 127.04 (C−F, J C−F =
271.8 Hz), 126.6, 125.50 (C−F, 3J C−F = 3.02 Hz), 125.47 (C−F, 3J
C−F = 3.02 Hz), 125.45 (C−F, 3J C−F = 3.02 Hz), 125.42 (C−F, 3J
1
C−F = 3.02 Hz), 125.24 (C−F, J C−F = 271.8 Hz), 123.8, 123.43
(C−F, 1J C−F = 271.8 Hz), 121.63 (C−F, 1J C−F = 271.8 Hz), 64.4.
19F NMR (565 MHz, CDCl3) δ −62.28. HRMS (DART) m/z calcd
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2,4-dimethoxybenzyl)-
methanimine (9n). Following General Procedure A, piperonal (0.89
g, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol),
magnesium sulfate (2.0 g), and dichloromethane (8 mL) were used.
The title compound was obtained as a pale-yellow solid (1.77 g, 99%).
Mp −54.3−55.7 °C. 1H NMR (600 MHz, CDCl3) δ: 8.2 (s, 2H), 7.4
(s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.8 (d, J =
7.9 Hz, 1H), 6.47−6.46 (m, 2H), 5.9 (s, 2H), 4.71 (s, 2H), 3.808 (s,
3H), 3.802 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.8,
160.0, 158.2, 149.7, 148.2, 131.3, 130.0, 124.3, 120.1, 107.9, 106.7,
for C19H15F3N [M + H]+: 314.1157; Found [M + H]+: 314.1154.
(E)-1-([1,1′-Biphenyl]-4-yl)-N-(2,4-dimethoxybenzyl)-
methanimine (9q). Following General Procedure A, 4-phenyl-
benzaldehyde (1.09 g, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g,
6.0 mmol), magnesium sulfate (2.0 g), and dichloromethane (8 mL)
were used. The title compound was obtained as a white solid (1.82 g,
1
94% purity, 86% yield). Mp −91.3−93.9 °C. H NMR (600 MHz,
CDCl3) δ 8.41 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.70−7.63 (m, 4H),
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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Article
6.55−6.50 (m, 2H), 4.83 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 161.3, 160.1, 158.3, 143.2, 140.5, 135.4,
130.3, 130.1, 129.0, 128.8, 128.7, 128.5, 127.7, 127.4, 127.2, 127.1,
120.0, 104.1, 98.5, 59.0, 55.4. HRMS (DART) m/z calcd for
C22H22NO2 [M + H]+: 332.1651; Found [M + H]+: 332.1667.
(E)-N-(2,4-Dimethoxybenzyl)-1-(p-tolyl)methanimine (9r). Fol-
lowing General Procedure A, p-tolualdehyde (0.72 g, 6.0 mmol),
2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium sulfate (2.0
g), and dichloromethane (8 mL) were used. The title compound was
138.2, 132.6, 130.5, 129.94 (C−F, 2J C−F = 31.71 Hz), 129.73 (C−F,
2J C−F = 31.71 Hz), 129.51 (C−F, 2J C−F = 31.71 Hz), 129.29 (C−
F, 2J C−F = 31.71 Hz), 129.17, 129.11, 128.8, 127.8, 126.90 (C−F, 1J
C−F = 271.8 Hz), 125.12 (C−F, 3J C−F = 4.53 Hz), 125.09 (C−F, 2J
C−F = 4.53 Hz), 123.29 (C−F, 1J C−F = 271.8 Hz), 121.49 (C−F, 1J
C−F = 271.8 Hz), 120.5, 119.6, 103.6, 98.6, 70.2, 63.4, 61.2, 59.3,
55.4, 55.2, 46.0. 19F NMR (565 MHz, CDCl3) δ − 62.36. HRMS
(DART) m/z calcd for C29H30F3N2O4 [M + H]+: 527.2158; Found
[M + H]+: 527.2153.
1
obtained as a pale-yellow oil (1.28 g, 80%). H NMR (600 MHz,
(S)-3-((1S,2S)-1-((2,4-dimethoxybenzyl)amino)-1-phenylbut-3-
en-2-yl)-4-phenyloxazolidin-2-one (18b). According to General
Procedure B, the product was purified by silica gel chromatography
(10% E.A. in DCM) to provide 147 mg (80%) of 18b as a colorless
CDCl3) δ 8.36 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.4 Hz,
3H), 6.55−6.51 (m, 2H), 4.81 (s, 2H), 3.86 (s, 6H), 2.38 s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 161.7, 160.1, 158.2, 140.7,
133.8, 130.0, 129.8, 129.7, 129.2, 128.2, 120.1, 104.0, 98.5, 58.9, 55.3,
21.5. HRMS (DART) m/z calcd for C17H20NO2 [M + H]+:
270.1494; Found [M + H]+: 270.1495.
1
foam as a single diastereomer. Rf = 0.35 (50% EtOAc/hexanes). H
NMR (600 MHz, CDCl3) δ 7.32 (dd, J = 4.5, 2.3 Hz, 3H), 7.25−7.22
(d, J = 6 Hz, 2H), 7.22−7.19 (d, J = 6 Hz, 1H), 7.18−7.16 (d, J = 12
Hz, 2H), 7.15−7.14 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.48 (s, 1H),
6.46 (d, J = 8.3 Hz, 1H), 5.05−4.97 (dt, J = 18 Hz, 12 Hz, 1H), 4.70
(d, J = 17.0 Hz, 1H), 4.64 (d, J = 10.2 Hz, 1H), 4.59 (t, J = 6 Hz, 1H),
4.46 (t, J = 8.6 Hz, 1H), 4.12−4.04 (dt, J = 18 Hz, 6 Hz, 2H), 3.99 (d,
J = 10.0 Hz, 1H), 3.81 (s, 6H), 3.67 (d, J = 13.4 Hz, 1H), 3.34 (d, J =
13.4 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8,
158.6, 140.6, 138.9, 133.3, 130.6, 128.98, 128.96, 128.4, 128.2, 127.8,
127.4, 120.9, 119.0, 103.6, 98.6, 70.2, 63.2, 61.5, 58.9, 55.4, 55.2, 45.8.
HRMS (DART) m/z calcd for C28H31N2O4 [M + H]+: 459.2284;
Found [M + H]+: 459.2300.
(S)-3-((1S,2S)-1-((4-Methoxybenzyl)amino)-1-phenylbut-3-en-2-
yl)-4-phenyloxazolidin-2-one (18c). According to General Procedure
B, the product was purified by silica gel chromatography (10% E.A. in
DCM) to provide 153 mg (89%) of 18c as a white solid as a single
diastereomer. Mp 101−104 °C. Rf = 0.41 (50% EtOAc/hexanes). 1H
NMR (600 MHz, CDCl3) δ 7.37−7.33 (m, 3H), 7.31 (m, 2H), 7.27
(m, 3H), 7.20 (d, J = 6 Hz, 2H), 7.18−7.14 (m, 2H), 6.96 (d, J = 12
Hz, 2H), 5.10 (dt, J = 16.5, 9.6 Hz, 1H), 4.76−4.69 (m, 2H), 4.66 (t,
J = 8.4 Hz, 1H), 4.60 (t, J = 12 Hz, 1H), 4.18 (t, J = 12 Hz, 1H), 4.12
(t, J = 12 Hz, 1H), 4.02 (d, J = 10.2 Hz, 1H), 3.86 (s, 3H), 3.64 (d, J
= 13.0 Hz, 1H), 3.41 (d, J = 12.9 Hz, 1H), 1.91 (s, 1H). 13C{1H}
NMR (151 MHz, CDCl3) δ 159.1, 158.7, 140.5, 138.5, 133.2, 132.5,
129.8, 128.9, 128.9, 128.4, 128.2, 127.8, 127.5, 119.2, 113.7, 70.3,
63.2, 61.5, 60.4, 59.0, 55.3, 49.9, 21.0, 14.2. HRMS (DART) m/z
calcd for C27H29N2O3 [M + H]+: 429.2178; Found [M + H]+:
429.2196.
(E)-N-(2,4-Dimethoxybenzyl)-1-(furan-2-yl)methanimine (9s).
Following General Procedure A, furfural (0.57 g, 6.0 mmol), 2,4-
dimethoxybenzylamine (1.0 g, 6.0 mmol), magnesium sulfate (2.0 g),
and dichloromethane (8 mL) were used. The title compound was
obtained as a brown oil (1.6 g, 91% purity, 99% yield). 1H NMR (600
MHz, CDCl3) δ: 8.08 (s, 1H), 7.49 (s, 1H), 7.18 (d, J = 8.1 Hz, 1H),
6.73 (d, J = 3.4 Hz, 1H), 6.47−6.45 (m, 3H), 4.73 (s, 2H), 3.80 (s,
3H), 3.79 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ: 160.28,
158.46, 151.96, 150.13, 144.51, 130.69, 119.30, 113.59, 111.53,
104.07, 98.47, 58.89, 55.40, 55.33. HRMS (DART) m/z calcd for
C14H16NO3 [M + H]+: 246.1130; Found [M + H]+: 246.1126.
(E)-N-(2,4-Dimethoxybenzyl)-1-(thiophen-2-yl)methanimine
(9t). Following General Procedure A, thiophene-2-carboxaldehyde
(0.67 g, 6.0 mmol), 2,4-dimethoxybenzylamine (1.0 g, 6.0 mmol),
magnesium sulfate (2.0 g), and dichloromethane (8 mL) were used.
The title compound was obtained as a yellow solid (1.15 g, 74%). Mp
−47.4−50.2 °C. 1H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H), 7.37 (d,
J = 6 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.06
(t, J = 6 Hz, 1H), 6.50−6.46 (m, 2H), 4.74 (s, 2H), 3.80 (s, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.3, 154.8, 142.9,
130.3, 130.2, 128.6, 127.2, 119.6, 104.1, 98.4, 58.2, 55.4, 55.3. HRMS
(DART) m/z calcd for C14H16NO2S [M + H]+: 262.0902; Found [M
+ H]+: 262.0915.
General Procedure B for the Synthesis of 18. To a 20 mL
crimp cap vial with a stir bar in an Ar filled glovebox were charged
Cu(OAc)2 (3.6 mg, 20 μmol) and PCy3 (7.3 mg, 26 μmol) followed
by toluene (1.0 mL) and tert-butanol (76.5 μL, 2 equiv). The mixture
was stirred for 5 min. Allenamide 15a (96.6 mg, 480 μmol) followed
by imine (400 μmol) was then charged, and the vial was sealed with a
crimp-cap septum and removed from the glovebox. Dimethoxy-
methylsilane (0.099 mL, 2 equiv) was then charged to the reaction
mixture (Caution:dimethoxymethylsilane should be handled in a well-
ventilated fume hood because it is known to cause blindness. Syringes were
quenched with 2 M NaOH, gas evolution! prior to disposal). The mixture
was then stirred at rt for 24 h. The reaction was quenched by addition
of 200 mg of NH4F and 2.5 mL of MeOH followed by agitation at rt
for 30 min. A 10 mL volumen of 5% NaHCO3 was then added to the
mixture followed by extraction with DCM (2 × 5 mL). The combined
organics were dried with Na2SO4, filtered, and concentrated in vacuo.
Crude product was purified by flash chromatography on silica gel to
afford the desired product.
(S)-3-((1S,2S)-1-(4-Chlorophenyl)-1-((2,4-dimethoxybenzyl)-
amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18d). According
to General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 146 mg (74%) of 18d
as a colorless foam and a single diastereomer. Rf = 0.33 (50% EtOAc/
1
hexanes). H NMR (600 MHz, CDCl3) δ 7.36−7.33 (m, 3H), 7.23
(d, J = 8.2 Hz, 2H), 7.20−7.16 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H),
6.99 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.2 Hz, 1H), 5.11−
5.03 (dt, J = 18 Hz, 12 Hz, 1H), 4.72 (s, 1H), 4.69 (d, J = 7.9 Hz,
1H), 4.60 (t, J = 8.1 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 4.10 (t, J = 7.9
Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.95 (t, J = 9.6 Hz, 1H), 3.83 (s,
6H), 3.66 (d, J = 13.4 Hz, 1H), 3.33 (d, J = 13.4 Hz, 1H), 2.08 (s,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.3, 158.8, 158.4, 139.3,
138.4, 133.0, 132.8, 130.6, 129.8, 129.10, 129.07, 128.4, 127.8, 120.6,
119.4, 103.6, 98.6, 70.2, 63.4, 60.8, 59.2, 55.4, 55.2, 45.9. HRMS
(DART) m/z calcd for C28H30ClN2O4 [M + H]+: 493.1894; Found
[M + H]+: 493.1929.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-(trifluoro-
methyl)phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18a). Ac-
cording to General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 180 mg (85%) of 18a
as a white foam as a single diastereomer. Rf = 0.43 (50% EtOAC/
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-fluoro-
phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18e). According
to General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 147 mg (77%) of 18e
as a colorless foam and a single diastereomer. Rf = 0.35 (50% EtOAc/
hexanes). 1H NMR (600 MHz, CDCl3) δ 7.37−7.32 (m, 3H), 7.20−
7.12 (m, 4H), 7.00 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 8.6 Hz, 2H), 6.50
(s, 1H), 6.48 (d, J = 6 Hz, 1H), 5.06 (dt, J = 18.2, 9.5 Hz, 1H), 4.70
(d, J = 16.6 Hz, 2H), 4.60 (t, J = 8.1 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H),
4.10 (t, J = 7.9 Hz, 1H), 4.05 (d, J = 10.1 Hz, 1H), 3.96 (t, J = 9.6 Hz,
1H), 3.83 (s, 6H), 3.66 (d, J = 13.4 Hz, 1H), 3.34 (d, J = 13.5 Hz,
1
hexanes). H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H),
7.36 (dd, J = 5.1, 1.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.21−7.17
(m, 1H), 6.99 (d, J = 6 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.3 Hz,
1H), 5.15−5.09 (dt, J = 18 Hz, 12 Hz, 1H), 4.73 (d, J = 12 Hz, 1H),
4.70 (d, J = 17.1 Hz, 1H), 4.61 (t, J = 8.2 Hz, 1H), 4.52 (t, J = 12 Hz,
1H), 4.17 (d, J = 6 Hz, 1H), 4.11 (t, J = 8.0 Hz, 1H), 3.93 (t, J = 9.6
Hz, 1H), 3.83 (s, 6H). 3.66 (d, J = 12 Hz, 1H), 3.36 (d, J = 18 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.3, 158.8, 158.3, 145.2,
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−
F, 1J C−F = 244.62 Hz), 161.31 (C−F, 1J C−F = 244.62 Hz), 160.2,
158.8, 158.4, 138.5, 136.4, 133.0, 130.5, 129.9, 129.8, 129.07 (C−F, 3J
132.1, 129.4, 129.3, 129.2, 128.49, 128.47, 127.7, 127.3, 123.3, 122.8,
120.3, 70.2, 63.5, 61.5, 59.6, 50.9. HRMS (DART) m/z calcd for
C26H26N3O4 [M + H]+: 444.1923; Found [M + H]+: 444.1952.
(S)-3-((1S,2S)-1-(Benzylamino)-1-(3-bromophenyl)but-3-en-2-
yl)-4-phenyloxazolidin-2-one (18j). The reaction was set up
according to General Procedure B and stirred at 65 °C for 24 h.
The product was purified by silica gel chromatography (2.5% E.A. in
DCM) to provide 173 mg (82%) of 18j as a pale-yellow foam and a
single diastereomer. Rf = 0.53 (50% EtOAc/hexanes). 1H NMR (600
MHz, CDCl3) δ 7.41−7.29 (m, 10H), 7.16 (t, J = 7.7 Hz, 1H), 7.14−
7.09 (m, 3H), 5.14 (dt, J = 16.8, 9.5 Hz, 1H), 4.75 (dd, J = 18 Hz, 12
Hz, 2H), 4.60 (t, J = 8.3 Hz, 1H), 4.55 (t, J = 8.5 Hz, 1H), 4.09 (t, J =
8.0 Hz, 1H), 4.04 (d, J = 10.2 Hz, 1H), 3.99 (t, J = 9.5 Hz, 1H), 3.68
(d, J = 13.2 Hz, 1H), 3.45 (d, J = 13.2 Hz, 1H), 1.96 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 159.0, 143.1, 140.1, 138.1,
3
C−F = 4.53 Hz), 129.05 (C−F, J C−F = 4.53 Hz), 127.8, 120.7,
2
2
119.2, 115.13 (C−F, J C−F = 21.14 Hz), 114.99 (C−F, J C−F =
21.14 Hz), 103.6, 98.6, 70.2, 63.5, 60.7, 59.1, 55.4, 55.2, 45.9. 19F
NMR (565 MHz, CDCl3) δ −115.14. HRMS (DART) m/z calcd for
C28H30FN2O4 [M + H]+: 477.2190; Found [M + H]+: 477.2204.
4-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-2-((S)-2-oxo-4-
phenyloxazolidin-3-yl)but-3-en-1-yl)benzonitrile (18f). According
to General Procedure B, the product was purified by silica gel
chromatography (10% E.A. in DCM) to provide 157 mg (81%) of 18f
as a colorless foam and a single diastereomer. Rf = 0.36 (50% EtOAc/
1
hexanes). H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 2H),
7.39−7.34 (m, 3H), 7.30 (d, J = 7.9 Hz, 2H), 7.22−7.18 (m, 2H),
6.95 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.14
(dt, J = 16.9, 9.8 Hz, 1H), 4.73 (d, J = 10.1 Hz, 1H), 4.66 (d, J = 17.0
Hz, 1H), 4.59 (t, J = 8.2 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.20 (d, J =
10.0 Hz, 1H), 4.12 (t, J = 8.1 Hz, 1H), 3.82 (s, 7H), 3.63 (d, J = 13.5
Hz, 1H), 3.32 (d, J = 13.5 Hz, 1H), 2.20 (s, 1H). 13C{1H} NMR
(151 MHz, CDCl3) δ 160.4, 158.7, 158.2, 146.8, 137.9, 132.0, 130.5,
129.3, 129.2, 129.1, 127.8, 120.3, 119.9, 118.8, 111.2, 103.7, 98.6,
70.2, 63.4, 61.3, 59.4, 55.4, 55.2, 46.2. HRMS (DART) m/z calcd for
C29H30N3O4 [M + H]+: 484.2236; Found [M + H]+: 484.2255.
Methyl 4-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-2-((S)-2-oxo-
4-phenyloxazolidin-3-yl)but-3-en-1-yl)benzoate (18g). According
to General Procedure B, the product was purified by silica gel
chromatography (10% E.A. in DCM) to provide 137 mg (66%) of
18g as a colorless foam and a single diastereomer. Rf = 0.34 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz,
2H), 7.35 (dd, J = 4.6, 1.6 Hz, 3H), 7.29−7.24 (m, 3H), 7.21−7.15
(m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.2 Hz,
1H), 5.07 (dt, J = 14.2, 9.5 Hz, 1H), 4.67 (d, J = 16.5 Hz, 2H), 4.61
(t, J = 8.1 Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 4.11 (m, 2H), 4.01 (t, J =
9.6 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 6H), 3.66 (d, J = 13.4 Hz, 1H),
3.33 (d, J = 13.4 Hz, 1H), 2.18 (s, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ 166.9, 160.3, 158.8, 158.4, 146.4, 138.4, 132.7, 130.6, 129.5,
129.4, 129.1, 129.0, 128.5, 127.8, 120.6, 119.5, 103.6, 98.6, 70.2, 63.3,
61.3, 59.1, 55.4, 55.2, 52.0, 46.0. HRMS (DART) m/z calcd for
C30H33N2O6 [M + H]+: 517.2339; Found [M + H]+: 517.2378.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-nitro-
phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18h). According
to General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 106 mg (53%) of 18h
as a pale-yellow foam and a single diastereomer. Rf = 0.39 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.13−8.07 (m,
2H), 7.40−7.32 (m, 5H), 7.21 (dd, J = 6.3, 2.4 Hz, 2H), 6.95 (d, J =
8.1 Hz, 1H), 6.49 (s, 1H), 6.46 (d, J = 8.1 Hz, 1H), 5.17 (dt, J = 16.9,
9.8 Hz, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.66 (d, J = 17.0 Hz, 1H),
4.61 (t, J = 8.3 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 4.27 (d, J = 10.0 Hz,
1H), 4.16−4.10 (m, 1H), 3.82 (s, 6H), 3.64 (d, J = 13.5 Hz, 1H),
3.33 (d, J = 13.5 Hz, 1H), 2.28 (s, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ 160.4, 158.7, 158.2, 147.4, 137.9, 132.2, 130.5, 129.4, 129.3,
129.2, 127.8, 123.4, 120.2, 120.0, 103.7, 98.7, 70.2, 63.5, 61.1, 59.5,
55.4, 55.2, 46.2. HRMS (DART) m/z calcd for C28H30N3O6 [M +
H]+: 504.2135; Found [M + H]+: 504.2119.
132.6, 131.2, 130.7, 130.0, 129.1, 129.0, 128.5, 128.4, 127.8, 127.2,
126.8, 122.6, 119.7, 70.2, 63.3, 61.4, 59.3, 50.7. HRMS (DART) m/z
calcd for C26H26BrN2O2 [M + H]+: 477.1178; Found [M + H]+:
477.1182.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(pyridin-3-yl)-
but-3-en-2-yl)-4-phenyloxazolidin-2-one (18k). According to Gen-
eral Procedure B, the product was purified by silica gel
chromatography (40% E.A. in DCM) to provide 143 mg (78%) of
18k as a pale-yellow foam as a single diastereomer. Rf = 0.1 (60%
1
EtOAc/hexanes). H NMR (600 MHz, CDCl3) δ 8.40 (d, J = 73.8
Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.38−7.31 (m, 3H), 7.23−7.14 (m,
3H), 6.99 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 8.1 Hz, 1H),
5.09 (dt, J = 17.0, 9.8 Hz, 1H), 4.72 (d, J = 10.2 Hz, 1H), 4.68 (d, J =
17.1 Hz, 1H), 4.57 (t, J = 8.1 Hz, 1H), 4.50 (t, J = 8.6 Hz, 1H), 4.16−
4.08 (m, 2H), 3.93 (t, J = 9.7 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H),
3.67 (d, J = 13.5 Hz, 1H), 3.35 (d, J = 13.5 Hz, 1H), 2.24 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.4, 158.8, 158.3, 150.5,
149.0, 138.1, 136.3, 135.6, 132.5, 130.6, 129.2, 129.1, 127.8, 123.5,
120.3, 120.0, 103.7, 98.7, 70.2, 63.4, 59.2, 59.0, 55.4, 55.2, 46.0.
HRMS (DART) m/z calcd for C27H30N3O4 [M + H]+: 460.2236;
Found [M + H]+: 460.2264.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(4-methoxy-
phenyl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18l). According to
General Procedure B, the product was purified by silica gel
chromatography (10% E.A. in DCM) to provide 143 mg (73%) of
18l as a colorless foam and a single diastereomer. Rf = 0.25 (50%
1
EtOAc/hexanes). H NMR (600 MHz, CDCl3) δ 7.33 (dd, J = 4.4,
2.3 Hz, 3H), 7.16 (dd, J = 5.9, 2.7 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H),
7.04 (d, J = 8.1 Hz, 1H), 6.83−6.78 (m, 2H), 6.50 (s, 1H), 6.49−6.45
(d, J = 12 Hz, 1H), 5.06−4.98 (dt, J = 18 Hz, 12 Hz, 1H), 4.73 (d, J =
17.0 Hz, 1H), 4.67 (d, J = 10.1 Hz, 1H), 4.59 (t, J = 7.9 Hz, 1H), 4.47
(t, J = 12 Hz, 1H), 4.11−4.04 (m, 2H), 3.97 (d, J = 10.0 Hz, 1H),
3.83 (s, 6H), 3.78 (s, 3H), 3.68 (d, J = 13.5 Hz, 1H), 3.35 (d, J = 13.4
Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.21, 158.9, 158.8,
158.5, 138.9, 133.4, 132.5, 130.6, 129.4, 128.96, 128.94, 127.8, 121.0,
118.9, 113.5, 103.6, 98.6, 70.2, 63.3, 60.8, 58.9, 55.4, 55.2, 55.1, 45.7.
HRMS (DART) m/z calcd for C29H33N2O5 [M + H]+: 489.2389;
Found [M + H]+: 489.2386.
(S)-3-((1S,2S)-1-(Benzylamino)-1-(2-methoxyphenyl)but-3-en-2-
yl)-4-phenyloxazolidin-2-one (18m). The reaction was set up
according to General Procedure B and stirred at 65 °C for 24 h.
The product was purified by silica gel chromatography (10% E.A. in
DCM) to provide 127 mg (74%) of 18m as a colorless foam as a
single diastereomer and as a 95:5 mixture of the branched 18m to
(S)-3-((1S,2S)-1-(Benzylamino)-1-(3-nitrophenyl)but-3-en-2-yl)-
4-phenyloxazolidin-2-one (18i). The reaction was set up according
to General Procedure B and stirred at 65 °C for 24 h. The product
was purified by silica gel chromatography (5% E.A. in DCM) to
provide 88 mg (50%) of 18i as a pale-yellow foam and a single
diastereomer and as a 91:9 mixture of the branched 18i to the
1
rearranged product 19m. Rf = 0.36 (50% EtOAc/hexanes). H NMR
(600 MHz, CDCl3) δ 7.27−7.20 (m, 4H), 7.20−7.11 (m, 5H), 7.10
(t, J = 6 Hz, 1H), 6.92 (d, J = 6 Hz, 3H), 6.76 (t, J = 7.4 Hz, 1H),
6.68 (d, J = 8.1 Hz, 1H), 4.76 (dt, J = 18.1, 9.4 Hz, 1H), 4.61 (d, J =
16.8 Hz, 1H), 4.48 (t, J = 8.3 Hz, 2H), 4.42 (d, J = 10.1 Hz, 1H), 4.38
(t, J = 8.7 Hz, 1H), 4.08−3.95 (m, 1H), 3.92 (t, J = 7.9 Hz, 1H), 3.60
(d, J = 8.2 Hz, 1H), 3.59 (s, 3H), 3.29 (d, J = 13.0 Hz, 1H), 2.11 (s,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 159.4, 157.9, 140.8, 139.3,
134.3, 129.0, 128.68, 128.65, 128.49, 128.45, 128.2, 128.0, 127.0,
120.4, 118.0, 110.6, 70.2, 58.3, 55.1, 50.7. HRMS (DART) m/z calcd
for C27H29N2O3 [M + H]+: 429.2178; Found [M + H]+: 429.2194.
1
rearranged product 19i. Rf = 0.71 (20% EtOAc/DCM). H NMR
(600 MHz, CDCl3) δ 7.98 (d, J = 6.0 Hz, 1H), 7.91 (s, 1H), 7.47 (d, J
= 7.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.28−7.16 (m, 9H), 7.05 (d, J
= 6.7 Hz, 2H), 5.16 (dt, J = 17.0, 9.7 Hz, 1H), 4.69 (d, J = 10.1 Hz,
1H), 4.59 (d, J = 17.0 Hz, 1H), 4.53 (t, J = 8.4 Hz, 1H), 4.47 (t, J =
8.6 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.02 (t, J = 8.2 Hz, 1H), 3.77
(t, J = 9.8 Hz, 1H), 3.56 (d, J = 13.3 Hz, 1H), 3.36 (d, J = 13.2 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 158.7, 148.3, 137.5, 134.3,
5038
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The Journal of Organic Chemistry
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Article
(S)-3-((1S,2S)-1-(Benzo[d][1,3]dioxol-5-yl)-1-((2,4-dimethoxy-
benzyl)amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18n). Ac-
cording to General Procedure B, the product was purified by silica gel
chromatography (15% E.A. in DCM) to provide 163 mg (81%) of
18n as a colorless foam and a single diastereomer. Rf = 0.26 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.37−7.31 (m,
3H), 7.19−7.11 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.69
(d, J = 7.9 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.49 (s, 1H), 6.48 (d, J =
7.3 Hz, 1H), 5.92 (s, 2H), 5.05 (dt, J = 17.3, 8.6 Hz, 1H), 4.75 (d, J =
17.0 Hz, 1H), 4.71 (d, J = 10.2 Hz, 1H), 4.58 (t, J = 8.0 Hz, 1H), 4.47
(t, J = 8.6 Hz, 1H), 4.08 (t, J = 7.8 Hz, 1H), 3.97 (m, 2H), 3.84 (s,
3H), 3.83 (s, 3H), 3.70 (d, J = 12.0 Hz, 1H), 3.36 (d, J = 13.4 Hz,
1H), 2.02 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8,
158.4, 147.7, 146.8, 138.6, 134.6, 133.2, 130.6, 129.0, 127.8, 122.0,
120.9, 119.0, 108.1, 107.7, 103.6, 100.9, 98.6, 70.2, 63.4, 61.1, 59.0,
55.4, 55.2, 45.8. HRMS (DART) m/z calcd for C29H31N2O6 [M +
H]+: 503.2182; Found [M + H]+: 503.2200.
(S)-3-((1S,2S)-1-(2,3-Dihydrobenzofuran-5-yl)-1-((2,4-dimethoxy-
benzyl)amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18o). Ac-
cording to General Procedure B, the product was purified by silica gel
chromatography (15% E.A. in DCM) to provide 151 mg (75%) of
18o as a colorless foam and a single diastereomer. Rf = 0.18 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.30 (m,
3H), 7.19−7.13 (m, 2H), 7.07−7.03 (m, 2H), 6.86 (d, J = 8.1 Hz,
1H), 6.65 (d, J = 8.1 Hz, 1H), 6.52−6.45 (m, 2H), 5.00 (dt, J = 16.9,
9.6 Hz, 1H), 4.75 (d, J = 17.0 Hz, 1H), 4.67 (d, J = 10.2 Hz, 1H),
4.58 (t, J = 7.9 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.47 (t, J = 8.6 Hz,
1H), 4.08 (t, J = 8.0 Hz, 2H), 3.92 (d, J = 10.1 Hz, 1H), 3.83 (s, 3H),
3.82 (s, 3H) 3.69 (d, J = 13.4 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 3.15
(t, J = 8.7 Hz, 2H), 2.06 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3)
δ 160.2, 159.4, 158.8, 138.9, 133.5, 132.5, 130.6, 128.96, 128.93,
128.4, 127.8, 127.1, 124.4, 121.0, 118.9, 108.6, 103.6, 98.6, 71.2, 70.2,
63.3, 61.0, 58.8, 55.4, 55.2, 45.7, 29.7. HRMS (DART) m/z calcd for
C30H33N2O5 [M + H]+: 501.2389; Found [M + H]+: 501.2426.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(naphthalen-2-
yl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18p). According to
General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 151 mg (74%) of
18p as a colorless foam as a single diastereomer. Rf = 0.30 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.83−7.75 (m,
3H), 7.63 (s, 1H), 7.45 (tdd, J = 7.7, 5.9, 3.2 Hz, 2H), 7.36 (dt, J =
6.4, 2.7 Hz, 4H), 7.23−7.19 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.49
(m, 2H), 5.10 (dt, J = 17.4, 8.8 Hz, 1H), 4.71 (d, J = 17.0 Hz, 1H),
4.66 (t, J = 8.0 Hz, 1H), 4.62 (d, J = 10.2 Hz, 1H), 4.51 (t, J = 8.6 Hz,
1H), 4.22 (d, J = 7.4 Hz, 2H), 4.11 (t, J = 7.6 Hz, 1H), 3.83 (s, 6H),
3.70 (d, J = 13.4 Hz, 1H), 3.40 (d, J = 13.4 Hz, 1H), 2.23 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 158.6, 138.8,
Procedure B, the product was purified by silica gel chromatography
(5% E.A. in DCM) to provide 143 mg (76%) of 18r as a colorless
foam and a single diastereomer. Rf = 0.29 (50% EtOAc/hexanes). 1H
NMR (600 MHz, CDCl3) δ 7.33 (dd, J = 4.6, 2.3 Hz, 3H), 7.18−7.14
(m, 2H), 7.08 (s, 4H), 7.05 (d, J = 8.1 Hz, 1H), 6.51−6.46 (m, 2H),
5.00 (dt, J = 18.1, 9.6 Hz, 1H), 4.74 (d, J = 17.0 Hz, 1H), 4.66 (d, J =
10.2 Hz, 1H), 4.61 (t, J = 7.9 Hz, 1H), 4.47 (t, J = 8.6 Hz, 1H), 4.13
(t, J = 9.6 Hz, 1H), 4.08 (t, J = 6 Hz, 1H), 3.95 (d, J = 9.9 Hz, 1H),
3.83 (s, 6H), 3.68 (d, J = 13.4 Hz, 1H), 3.35 (d, J = 13.3 Hz, 1H),
2.31 (s, 3H), 2.02 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ
160.2, 158.8, 158.6, 139.0, 137.5, 137.0, 133.50, 130.6, 128.96, 128.94,
128.91, 128.3, 127.8, 121.0, 118.9, 103.6, 98.6, 70.3, 63.1, 61.2, 58.8,
55.4, 55.2, 45.7, 21.1. HRMS (DART) m/z calcd for C29H33N2O4 [M
+ H]+: 473.2440; Found [M + H]+: 473.2459.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(furan-2-yl)-
but-3-en-2-yl)-4-phenyloxazolidin-2-one (18s). According to Gen-
eral Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 154 mg (86%) of
18s as a colorless foam and as a single diastereomer. Rf = 0.33 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.32 (s, 4H), 7.20−
7.14 (m, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.48 (dd, J = 7.9, 1.4 Hz, 2H),
6.26 (d, J = 1.7 Hz, 1H), 6.16 (d, J = 3.2 Hz, 1H), 5.18−5.07 (dt, J =
18 Hz, 12 Hz, 1H), 4.89 (d, J = 17.0 Hz, 1H), 4.75 (d, J = 10.2 Hz,
1H), 4.60 (t, J = 8.1 Hz, 1H), 4.49 (t, J = 12 Hz, 1H), 4.32 (t, J = 9.6
Hz, 1H), 4.12 (d, J = 10.2 Hz, 1H), 4.07 (t, = 6 Hz, 1H), 3.82 (s,
J
6H), 3.73 (d, J = 13.2 Hz, 1H), 3.47 (d, J = 13.1 Hz, 1H), 1.91 (s,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 158.7, 153.1,
141.9, 138.9, 133.0, 130.8, 128.9, 128.9, 127.7, 120.6, 118.8, 109.8,
108.7, 103.7, 98.6, 70.3, 60.8, 60.4. 58.8, 55.4, 55.2, 45.8. HRMS
(DART) m/z calcd for C26H29N2O5 [M + H]+: 449.2076; Found [M
+ H]+: 449.2068.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(thiophen-2-
yl)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18t). According to
General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 137 mg (74%) of
18t as a pale-yellow foam and as a single diastereomer. Rf = 0.33 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.31 (m,
3H), 7.21 (d, J = 5.1 Hz, 1H), 7.18−7.13 (m, 2H), 7.07 (d, J = 8.1
Hz, 1H), 6.90 (ddd, J = 4.8, 3.5, 1.1 Hz, 1H), 6.85 (d, J = 3.4 Hz,
1H), 6.50 (s, 1H), 6.48 (d, J = 7.9 Hz, 1H), 5.15 (dt, J = 16.2, 9.6 Hz,
1H), 4.84 (d, J = 17.0 Hz, 1H), 4.77 (d, J = 10.2 Hz, 1H), 4.56 (dd, J
= 8.6, 7.2 Hz, 1H), 4.47 (td, J = 8.6, 1.1 Hz, 1H), 4.39 (d, J = 9.6 Hz,
1H), 4.08 (ddd, J = 11.6, 6.7, 2.8 Hz, 2H), 3.82 (s, 3H), 3.83 (s, 3H),
3.80 (d, J = 13.4 Hz, 1H), 3.48 (d, J = 13.4 Hz, 1H), 2.11 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.3, 158.8, 158.3, 145.5,
138.6, 132.8, 130.8, 129.0, 127.7, 126.2, 126.0, 124.8, 120.6, 119.3,
103.6, 98.6, 70.3, 63.5, 60.4, 59.0, 57.2, 55.4, 55.2, 46.0. HRMS
(DART) m/z calcd for C26H29N2O4S [M + H]+: 465.1848; Found
[M + H]+: 465.1852.
(S)-3-((1S,2S)-1-(5-Bromothiophen-2-yl)-1-((2,4-dimethoxy-
benzyl)amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18u). Ac-
cording to General Procedure B, the product was purified by silica gel
chromatography (3% E.A. in DCM) to provide 172 mg (79%) of 18u
as a pale-yellow foam as a single diastereomer and a 95:5 mixture of
the branched to rearranged product. Rf = 0.38 (50% EtOAc/hexanes).
1H NMR (600 MHz, CDCl3) δ 7.35 (dd, J = 4.2, 2.5 Hz, 3H), 7.17
(dd, J = 6.0, 2.6 Hz, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 6 Hz,
1H), 6.59 (d, J = 6 Hz, 1H), 6.50 (s, 1H), 6.48 (d, J = 12 Hz, 1H),
5.24 (dt, J = 16.7, 9.5 Hz, 1H), 4.89−4.83 (m, 2H), 4.54 (t, J = 8.0
Hz, 1H), 4.50 (t, J = 12 Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 4.11 (t, J =
12 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (d, J = 13.5 Hz, 1H),
3.51 (d, J = 13.4 Hz, 1H), 2.24 (s, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ 160.3, 158.8, 158.0, 147.7, 138.0, 132.2, 130.7, 129.2, 129.1,
129.1, 127.7, 126.4, 120.3, 119.8, 111.6, 103.6, 98.6, 70.2, 63.6, 59.4,
57.7, 55.4, 55.2, 46.1. HRMS (DART) m/z calcd for C26H28BrN2O4S
[M + H]+: 543.0953; Found [M + H]+: 543.0949.
General Procedure C for the Synthesis of 19. To a 20 mL
crimp cap vial with a stir bar in an Ar filled glovebox were charged
Cu(OAc)2 (3.6 mg, 20 μmol) and PCy3 (7.3 mg, 26 μmol) followed
by toluene (1.0 mL), and the mixture was stirred for 5 min.
138.1, 133.22, 133.21, 133.1, 130.6, 129.0, 128.1, 127.88, 127.80,
127.7, 125.9, 125.8, 125.7, 120.9, 119.2, 103.6, 98.6, 70.3, 63.2, 61.7,
59.1, 55.5, 55.3, 46.0. HRMS (DART) m/z calcd for C32H33N2O4 [M
+ H]+: 509.2440; Found [M + H]+: 509.2411.
(S)-3-((1S,2S)-1-([1,1′-Biphenyl]-4-yl)-1-((2,4-dimethoxybenzyl)-
amino)but-3-en-2-yl)-4-phenyloxazolidin-2-one (18q). According
to General Procedure B, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 144 mg (67%) of 18q
as a colorless foam and a single diastereomer. Rf = 0.26 (50% EtOAc/
1
hexanes). H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.9 Hz, 2H),
7.51 (d, J = 7.9 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.37−7.30 (m, 4H),
7.26 (d, J = 6.0 Hz, 3H), 7.21−7.16 (m, 2H), 7.08 (d, J = 8.0 Hz,
1H), 6.52−6.47 (m, 2H), 5.08 (dt, J = 18.1, 9.6 Hz, 1H), 4.76 (d, J =
17.0 Hz, 1H), 4.70 (d, J = 10.2 Hz, 1H), 4.63 (t, J = 8.0 Hz, 1H), 4.50
(t, J = 8.6 Hz, 1H), 4.17−4.05 (m, 3H), 3.84 (s, 3H), 3.83 (s, 3H),
3.73 (d, J = 13.5 Hz, 1H), 3.42 (d, J = 13.4 Hz, 1H), 2.07 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 158.8, 158.6, 140.7,
140.1, 139.8, 138.8, 133.2, 130.6, 129.0, 128.9, 128.8, 128.7, 127.8,
127.2, 126.9, 126.8, 121.0, 119.2, 103.6, 98.6, 70.3, 63.2, 61.3, 59.0,
55.4, 55.2, 45.9. HRMS (DART) m/z calcd for C34H35N2O4 [M +
H]+: 535.2597; Found [M + H]+: 535.2631.
(S)-3-((1S,2S)-1-((2,4-Dimethoxybenzyl)amino)-1-(p-tolyl)but-3-
en-2-yl)-4-phenyloxazolidin-2-one (18r). According to General
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J. Org. Chem. 2021, 86, 5026−5046

The Journal of Organic Chemistry
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Article
Allenamide 15a (96.6 mg, 480 μmol) followed by imine (400 μmol)
was then charged, and the vial was sealed with a crimp-cap septum
and removed from the glovebox. Dimethoxymethylsilane (0.099 mL,
2 equiv) was then charged to the reaction mixture (Caution:dime-
thoxymethylsilane should be handled in a well-ventilated fume hood
because it is known to cause blindness. Syringes were quenched with 2 M
NaOH, gas evolution! prior to disposal). The mixture was then stirred at
rt for 24 h. The reaction was quenched by addition of 200 mg of
NH4F and 2.5 mL of MeOH followed by agitation at rt for 30 min. A
10 mL volume of 5% NaHCO3 was then added to the mixture
followed by extraction with DCM (2 × 5 mL). The combined
organics were dried with Na2SO4, filtered, and concentrated in vacuo.
Crude product was purified by flash chromatography on silica gel to
afford the desired product 19.
= 273.31 Hz), 125.72 (C−F, 3J C−F = 3.02 Hz), 125.69 (C−F, 3J C−
F = 3.02 Hz), 125.67 (C−F, 3J C−F = 3.02 Hz), 125.64 (C−F, 3J C−
F = 3.02 Hz), 124.97 (C−F, J C−F = 273.31 Hz), 123.16 (C−F, J
C−F = 273.31 Hz), 121.7, 121.36 (C−F, 1J C−F = 273.31 Hz), 66.4,
64.6, 63.2, 61.8, 45.4. 19F NMR (565 MHz, CDCl3) δ −62.50. HRMS
(DART) m/z calcd for C27H25ClF3N2O2 [M + H]+: 501.1557; Found
[M + H]+: 501.1583.
1
1
(4S,5S)-4-(4-Fluorophenyl)-1-((S)-2-hydroxy-1-phenylethyl)-3-(4-
(trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19ee). The re-
action was set up according to general procedure C and stirred at 65
°C for 24 h. The product was purified by silica gel chromatography
(5% E.A. in DCM) to provide 149 mg (74%) of 19ee as a colorless
1
foam as a single diastereomer. Rf = 0.40 (50% EtOAc/hexanes). H
NMR (600 MHz, CDCl3) δ 7.45 (d, J = 7.9 Hz, 2H), 7.25 (t, J = 7.7
Hz, 2H), 7.20−7.14 (m, 3H), 7.11 (d, J = 7.9 Hz, 2H), 6.94 (dd, J =
8.4, 5.3 Hz, 2H), 6.88 (t, J = 8.5 Hz, 2H), 5.53−5.45 (ddd, J = 17.0,
10.1, 8.7 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.79 (t, J = 15.6 Hz,
2H), 4.58 (t, J = 6.5 Hz, 1H), 4.24−4.19 (m, 2H), 4.01−3.95 (m,
1H), 3.84 (d, J = 8.0 Hz, 1H), 3.64 (d, J = 15.1 Hz, 1H), 3.41 (t, J =
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyleth-
yl)-5-(4-(trifluoromethyl)phenyl)-4-vinylimidazolidin-2-one (19a).
According to General Procedure C, the product was purified by
silica gel chromatography (5% E.A. in DCM) to provide 198 mg
(94%) of 19a as a colorless foam as a single diastereomer. Rf = 0.36
1
1
8.3 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 163.63 (C−F, J
(50% EtOAc/hexanes). H NMR (600 MHz, CDCl3) δ 7.53 (d, J =
1
8.0 Hz, 2H), 7.35−7.30 (m, 2H), 7.26 (m, 4H), 7.18 (d, J = 8.0 Hz,
2H), 7.03 (d, J = 8.2 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.35 (d, J =
2.4 Hz, 1H), 5.59 (ddd, J = 17.0, 9.3, 8.7, 1.0 Hz, 1H), 5.20 (d, J =
10.1 Hz, 1H), 4.90 (t, J = 7.0 Hz, 1H), 4.85 (d, J = 17.1 Hz, 1H), 4.78
(d, J = 14.7 Hz, 1H), 4.32 (m, 1H), 4.25 (dd, J = 7.9, 3.4 Hz, 1H),
4.06−4.03 (m, 1H), 4.01 (d, J = 7.9 Hz, 1H), 3.86 (d, J = 14.7 Hz,
1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.39 (t, J = 8.3 Hz, 1H). 13C{1H}
NMR (151 MHz, CDCl3) δ 161.1, 160.7, 158.6, 143.0, 137.6, 134.8,
C−F = 249.15 Hz), 161.98 (C−F, J C−F = 249.15 Hz), 160.7,
140.2, 137.4, 134.4, 133.01 (C−F, 3J C−F = 3.02 Hz), 132.99 (C−F,
3J C−F = 3.02 Hz), 130.31 (C−F, 2J C−F = 31.71 Hz), 130.09 (C−F,
2J C−F = 31.71 Hz), 129.88 (C−F, 2J C−F = 31.71 Hz), 129.66 (C−
F, 2J C−F = 31.71 Hz), 129.1, 129.0, 128.8, 128.7, 127.9, 127.6,
1
3
126.78 (C−F, J C−F = 273.31 Hz), 125.69 (C−F, J C−F = 3.02
Hz), 125.67 (C−F, 3J C−F = 3.02 Hz), 125.64 (C−F, 3J C−F = 3.02
3
1
Hz), 125.61 (C−F, J C−F = 3.02 Hz), 124.97 (C−F, J C−F =
2
2
131.7, 130.55 (C−F, J C−F = 31.71 Hz), 130.39 (C−F, J C−F =
31.71 Hz), 130.18 (C−F, 2J C−F = 31.71 Hz), 129.96 (C−F, 2J C−F
= 31.71 Hz), 128.7, 127.8, 127.6, 127.4, 126.7 (C−F, 1J C−F = 271.8
Hz), 125.51 (C−F, 3J C−F = 3.02 Hz), 125.48 (C−F, 3J C−F = 3.02
273.31 Hz), 123.16 (C−F, 1J C−F = 273.31 Hz), 121.6, 121.35 (C−
1
2
F, J C−F = 273.31 Hz), 116.09 (C−F, J C−F = 21.14 Hz), 115.95
(C−F, J C−F = 21.14 Hz), 66.6, 64.7, 63.2, 61.9, 45.3. 19F NMR
2
(565 MHz, CDCl3) δ −62.52, −112.82. HRMS (DART) m/z calcd
for C27H25F4N2O2 [M + H]+: 485.1852; Found [M + H]+: 485.1861.
(4S,5S)-1-Benzyl-5-(3-bromophenyl)-3-((S)-2-hydroxy-1-phenyl-
ethyl)-4-vinylimidazolidin-2-one (19j). The reaction was set up
according to general procedure C and stirred at 65 °C for 24 h. The
product was purified by silica gel chromatography (5% E.A. in DCM)
to provide 131 mg (69%) of 19j as a colorless foam as a single
diastereomer. Rf = 0.46 (50% EtOAc/hexanes). 1H NMR (600 MHz,
CDCl3) δ 7.42 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.34−
7.24 (m, 8H), 7.17 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 6.6 Hz, 2H), 7.01
(d, J = 7.6 Hz, 1H), 5.59 (ddd, J = 17.0, 10.0, 8.7 Hz, 1H), 5.21 (d, J
= 10.1 Hz, 1H), 4.98 (d, J = 14.9 Hz, 1H), 4.91 (d, J = 17.0 Hz, 1H),
4.82 (t, J = 7.0 Hz, 1H), 4.38−4.27 (m, 2H), 4.08−4.05 (m, 1H),
3.94 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 14.9 Hz, 1H), 3.48 (t, J = 8.1 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.6, 140.3, 137.5, 135.9,
134.5, 131.6, 130.4, 130.2, 128.8, 128.7, 128.6, 127.9, 127.7, 127.6,
125.9, 123.0, 121.4, 66.2, 64.8, 62.8, 62.0, 45.7. HRMS (DART) m/z
calcd for C26H26BrN2O2 [M + H]+: 477.1178; Found [M + H]+:
477.1207.
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl-
ethyl)-5-(pyridin-3-yl)-4-vinylimidazolidin-2-one (19k). According
to General Procedure C, the product was purified by silica gel
chromatography (50% E.A. in DCM) to provide 183 mg (99%) of
19k as a pale-yellow foam as a single diastereomer and as a 86:14
mixture of the rearranged 19k to branched product 18k. Rf = 0.10
(60% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H),
8.26 (s, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.36−7.30 (m, 3H), 7.28−7.24
(m, 4H), 7.06 (d, J = 8.2 Hz, 1H), 6.40 (dd, J = 8.3, 2.4 Hz, 1H), 6.35
(d, J = 2.4 Hz, 1H), 5.58 (ddd, J = 17.1, 10.0, 8.7 Hz, 1H), 5.20 (d, J
= 10.1 Hz, 1H), 4.90 (t, J = 6.9 Hz, 1H), 4.85 (d, J = 17.1 Hz, 1H),
4.76 (d, J = 14.6 Hz, 1H), 4.34−4.29 (m, 1H), 4.26 (dd, J = 7.8, 3.3
Hz, 1H), 4.07−4.02 (m, 1H), 3.97 (d, J = 8.1 Hz, 1H), 3.86 (dd, J =
18.0 6.0 Hz 2H), 3.79 (s, 3H), 3.60 (s, 3H), 3.43 (t, J = 8.4 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 161.1, 160.7, 158.6, 149.6,
1
1
Hz), 124.89 (C−F, J C−F = 271.8 Hz), 123.09 (C−F, J C−F =
2
271.8 Hz), 121.4, 121.29 (C−F, J C−F = 271.8 Hz), 116.2, 104.2,
98.1, 66.2, 64.9, 63.3, 61.9, 55.3, 54.9, 40.8. 19F NMR (565 MHz,
CDCl3) δ −62.54. HRMS (DART) m/z calcd for C29H30F3N2O4 [M
+ H]+: 527.2158; Found [M + H]+: 527.2173.
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl-
ethyl)-5-phenyl-4-vinylimidazolidin-2-one (19b). According to
General Procedure C, the product was purified by silica gel
chromatography (10% E.A. in DCM) to provide 158 mg (86%) of
19b as a colorless foam as a single diastereomer. Rf = 0.31 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.33 (t, J = 7.5 Hz,
3H), 7.30−7.24 (m, 7H), 7.07 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 8.2
Hz, 1H), 6.40 (dd, J = 8.2, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 5.61
(ddd, J = 17.0, 10.1, 8.7 Hz, 1H), 5.18 (d, J = 10.1 Hz, 1H), 5.12 (t, J
= 7.8 Hz, 1H), 4.86 (d, J = 17.0 Hz, 1H), 4.81 (d, J = 14.8 Hz, 1H),
4.34−4.24 (m, 2H), 4.04 (m, 1H), 3.98 (d, J = 7.7 Hz, 1H), 3.83 (d, J
= 6.6 Hz, 2H), 3.80 (s, 3H), 3.63 (s, 3H), 3.46 (t, J = 8.2 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 161.1, 160.5, 158.7, 138.8,
137.8, 135.2, 131.5, 128.6, 128.5, 128.0, 127.6, 127.1, 120.8, 116.6,
104.0, 98.1, 66.4, 65.1, 63.6, 61.9, 55.3, 55.0, 40.6. HRMS (DART)
m/z calcd for C28H31N2O4 [M + H]+: 459.2284; Found [M + H]+:
459.2304.
(4S,5S)-4-(4-Chlorophenyl)-1-((S)-2-hydroxy-1-phenylethyl)-3-(4-
(trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19de). The re-
action was set up according to general procedure C and stirred at 65
°C for 24 h. The product was purified by silica gel chromatography
(5% E.A. in DCM) to provide 143 mg (71%) of 19de as a colorless
1
foam as a single diastereomer. Rf = 0.46 (50% EtOAc/hexanes). H
NMR (600 MHz, CDCl3) δ 7.52 (d, J = 7.9 Hz, 2H), 7.31 (t, J = 7.4
Hz, 2H), 7.24 (dd, J = 8.5, 6.5 Hz, 5H), 7.19 (d, J = 7.9 Hz, 2H), 6.98
(d, J = 8.1 Hz, 2H), 5.59 (ddd, J = 17.1, 10.1, 8.7 Hz, 1H), 5.17 (d, J
= 10.1 Hz, 1H), 4.89 (d, J = 15.1 Hz, 1H), 4.85 (d, J = 17.0 Hz, 1H),
4.65 (s, 1H), 4.29 (m, 2H), 4.06 (m, 1H), 3.90 (d, J = 7.9 Hz, 1H),
3.70 (d, J = 15.1 Hz, 1H), 3.48 (t, J = 8.4 Hz, 1H). 13C{1H} NMR
(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,
116.1, 104.2, 98.1, 66.3, 64.8, 61.8, 61.5, 55.3, 55.0, 40.7. HRMS
(DART) m/z calcd for C27H30N3O4 [M + H]+: 460.2236; Found [M
+ H]+: 460.2247.
2
2
(C−F, J C−F = 31.71 Hz), 130.11 (C−F, J C−F = 31.71 Hz),
2
2
129.90 (C−F, J C−F = 31.71 Hz), 129.68 (C−F, J C−F = 31.71
Hz), 129.2, 128.8, 128.79, 128.73, 127.9, 127.6, 126.77 (C−F, 1J C−F
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-
ethyl)-5-(4-methoxyphenyl)-4-vinylimidazolidin-2-one (19l). Ac-
cording to General Procedure C, the product was purified by silica
gel chromatography (10% E.A. in DCM) to provide 184 mg (94%) of
19l as a colorless foam as a single diastereomer. Rf = 0.29 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.35 (t, J = 7.7 Hz,
2H), 7.31−7.25 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.4
Hz, 2H), 6.83 (d, J = 6.0 Hz, 2H), 6.42−6.40 (m, 2H), 5.64−5.56
(ddd, J = 17.0, 9.3, 8.6 Hz, 1H), 5.18 (d, J = 10.3 Hz, 1H), 5.15 (t, J =
7.1 Hz, 1H), 4.87 (d, J = 17.0 Hz, 1H), 4.79 (d, J = 14.8 Hz, 1H),
4.35−4.24 (m, 2H), 4.07−4.04 (m, 1H), 3.94 (d, J = 7.8 Hz, 1H),
3.81 (s, 3H), 3.79 (s, 3H), 3.67 (s, 3H), 3.46 (t, J = 8.2 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 161.0, 160.5, 159.4, 158.7,
the rearranged 19t to the branched product 18t. Rf = 0.34 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.37−7.32 (m,
2H), 7.30−7.25 (m, 4H), 7.24 (d, J = 5.1 Hz, 1H), 7.08−7.04 (m,
1H), 6.92 (t, J = 6.0 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 6.43 (m, 2H),
5.63−5.54 (ddd, J = 17.0, 10.1, 8.6 Hz, 1H), 5.21 (d, J = 10.1 Hz,
1H), 5.06 (t, J = 7.0 Hz, 1H), 4.98 (d, J = 18.0 Hz, 1H), 4.82 (d, J =
14.8 Hz, 1H), 4.35−4.25 (m, 3H), 4.01 (m, 1H), 3.94 (d, J = 14.9 Hz,
1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.59 (d, J = 8.7 Hz, 1H). 13C{1H}
NMR (151 MHz, CDCl3) δ 160.6, 160.4, 158.7, 142.9, 137.6, 135.0,
131.4, 128.7, 127.7, 127.6, 126.6, 125.8, 125.7, 121.1, 116.5, 104.0,
98.2, 66.7, 65.1, 62.0, 59.2, 55.3, 55.1, 40.8. HRMS (DART) m/z
calcd for C26H29N2O4S [M + H]+: 465.1848; Found [M + H]+:
465.1881.
(4S,5S)-1-((S)-2-Hydroxy-1-phenylethyl)-4-(naphthalen-2-yl)-3-
(4-(trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19pe). The
reaction was set up according to general procedure C and stirred at 65
°C for 24 h. The product was purified by silica gel chromatography
(5% E.A. in DCM) to provide 130 mg (79%) of 19pe as a colorless
137.9, 135.3, 131.4, 130.6, 128.6, 128.4, 127.7, 127.6, 120.8, 116.7,
113.9, 104.0, 98.1, 66.6, 65.1, 63.1, 61.8, 55.3, 55.2, 55.1, 40.5. HRMS
(DART) m/z calcd for C29H33N2O5 [M + H]+: 489.2389; Found [M
+ H]+: 489.2387.
(4S,5S)-1-Benzyl-3-((S)-2-hydroxy-1-phenylethyl)-5-(2-methoxy-
phenyl)-4-vinylimidazolidin-2-one (19m). The reaction was set up
according to general procedure C and stirred at 65 °C for 24 h. The
product was purified by silica gel chromatography (10% E.A. in
DCM) to provide 118 mg (69%) of 19m as a colorless foam as a
single diastereomer. Rf = 0.37 (50% EtOAc/hexanes). 1H NMR (600
MHz, CDCl3) δ 7.26 (tdd, J = 14.3, 11.1, 7.6 Hz, 10H), 7.13 (d, J =
6.9 Hz, 3H), 6.94 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.68
(ddd, J = 16.8, 10.0, 8.3 Hz, 1H), 5.20−5.14 (m, 2H), 4.94 (dd, J =
16.1, 12.9 Hz, 2H), 4.50 (m, 1H), 4.33−4.27 (m, 2H), 4.06−4.00 (m,
1H), 3.70 (d, J = 15.0 Hz, 1H), 3.61 (s, 3H), 3.59 (m, 1H). 13C{1H}
NMR (151 MHz, CDCl3) δ 160.7, 157.5, 138.0, 136.8, 135.6, 129.3,
128.5, 128.4, 127.6, 127.5, 127.3, 120.6, 119.7, 110.9, 65.2, 61.9, 55.1,
45.6. HRMS (DART) m/z calcd for C27H29N2O3 [M + H]+:
429.2178; Found [M + H]+: 429.2195.
(4S,5S)-4-(Benzo[d][1,3]dioxol-5-yl)-3-(2,4-dimethoxybenzyl)-1-
((S)-2-hydroxy-1-phenylethyl)-5-vinylimidazolidin-2-one (19n). Ac-
cording to General Procedure C, the product was purified by silica gel
chromatography (10% E.A. in DCM) to provide 197 mg (98%) of
19n as a colorless foam as a single diastereomer. Rf = 0.26 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.36−7.32 (m,
2H), 7.29−7.25 (m, 4H), 7.03 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 7.9
Hz, 1H), 6.57 (s, 1H), 6.49 (d, J = 7.9 Hz, 1H), 6.42−6.38 (m, 2H),
5.95−5.91 (m, 2H), 5.61−5.53 (ddd, J = 17.1, 9.3, 8.5 Hz, 1H), 5.18
(d, J = 10.1 Hz, 1H), 5.06 (d, J = 7.9 Hz, 1H), 4.88 (d, J = 17.0 Hz,
1H), 4.77 (d, J = 14.8 Hz, 1H), 4.33−4.22 (m, 2H), 4.03 (m, 1H),
3.89 (d, J = 7.7 Hz, 1H), 3.83 (d, J = 14.8 Hz, 1H), 3.80 (s, 3H), 3.68
(s, 3H), 3.42 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3)
δ 160.9, 160.5, 158.7, 147.4, 137.8, 135.2, 132.6, 131.4, 128.6, 127.6,
120.9, 120.8, 116.6, 108.0, 107.1, 104.0, 101.1, 98.1, 66.5, 65.1, 63.5,
61.8, 55.3, 55.1, 40.6. HRMS (DART) m/z calcd for C29H31N2O6 [M
+ H]+: 503.2182; Found [M + H]+: 503.2211.
1
foam as a single diastereomer. Rf = 0.43 (50% EtOAc/hexanes). H
NMR (600 MHz, CDCl3) δ 7.59−7.56 (m, 1H), 7.55 (d, J = 8.5 Hz,
1H), 7.52−7.49 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.27−7.22 (m,
3H), 7.11 (t, J = 7.6 Hz, 2H), 7.08−7.02 (m, 3H), 7.01−6.95 (m,
4H), 5.46−5.38 (ddd, J = 17.2, 10.0, 8.6 Hz, 1H), 4.96 (d, J = 10.1
Hz, 1H), 4.72 (d, J = 15.1 Hz, 1H), 4.62 (d, J = 17.0 Hz, 1H), 4.13−
4.09 (m, 2H), 3.90 (d, J = 7.8 Hz, 1H), 3.86 (d, J = 8.9 Hz, 1H), 3.53
(d, J = 15.2 Hz, 1H), 3.42 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (151
MHz, CDCl3) δ 160.8, 140.4, 137.5, 134.64, 134.62, 133.4, 133.1,
130.2 (C−F, 2J C−F = 31.71 Hz), 130.01 (C−F, 2J C−F = 31.71 Hz),
2
2
129.80 (C−F, J C−F = 31.71 Hz), 129.58 (C−F, J C−F = 31.71
Hz), 129.2, 128.9, 128.7, 127.9, 127.86, 127.81, 127.7, 127.1, 126.82
(C−F, 1J C−F = 273.31 Hz), 126.68, 126.62, 125.66 (C−F, 3J C−F =
3.02 Hz), 125.63 (C−F, 3J C−F = 3.02 Hz), 125.61 (C−F, 3J C−F =
3.02 Hz), 125.58 (C−F, 3J C−F = 3.02 Hz), 125.02 (C−F, 1J C−F =
273.31 Hz), 124.2, 123.21 (C−F, 1J C−F = 273.31 Hz), 121.5, 121.41
1
(C−F, J C−F = 273.31 Hz), 66.3, 64.8, 64.0, 62.0, 45.4. 19F NMR
(565 MHz, CDCl3) δ −62.47. HRMS (DART) m/z calcd for
C31H28F3N2O2 [M + H]+: 517.2103; Found [M + H]+: 517.2121.
(4S,5S)-1-Benzyl-3-((S)-2-hydroxy-1-phenylethyl)-5-(naphthalen-
2-yl)-4-vinylimidazolidin-2-one (19pc). The reaction was set up
according to general procedure C and stirred at 65 °C for 24 h. The
product was purified by silica gel chromatography (5% E.A. in DCM)
to provide 125 mg (70%) of 19pc as a colorless foam as a single
1
diastereomer. Rf = 0.60 (20% EtOAc/DCM). H NMR (600 MHz,
CDCl3) δ 7.81−7.71 (m, 3H), 7.49 (s, 1H), 7.48−7.43 (m, 2H),
7.34−7.19 (m, 9H), 7.10 (d, J = 12.0 Hz, 2H), 5.62 (ddd, J = 17.0,
10.1, 8.7 Hz, 1H), 5.15 (d, J = 10.1 Hz, 1H), 5.00 (d, J = 14.9 Hz,
1H), 4.82 (d, J = 17.0 Hz, 1H), 4.35−4.27 (m, 2H), 4.14 (d, J = 7.8
Hz, 1H), 4.08 (dd, J = 11.2, 2.5 Hz, 1H), 3.63−3.58 (m, 2H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.9, 137.7, 136.2, 135.1,
134.9, 133.3, 133.1, 129.0, 128.74, 128.70, 128.6, 127.9, 127.8, 127.79,
127.74, 127.6, 127.1, 126.5, 126.4, 124.3, 121.3, 66.3, 64.9, 63.5, 62.0,
45.6. HRMS (DART) m/z calcd for C30H29N2O2 [M + H]+:
449.2229; Found [M + H]+: 449.2259.
(4S,5S)-1-(2,4-Dimethoxybenzyl)-5-(furan-2-yl)-3-((S)-2-hydroxy-
1-phenylethyl)-4-vinylimidazolidin-2-one (19s). According to Gen-
eral Procedure C, the product was purified by silica gel
chromatography (5% E.A. in DCM) to provide 149 mg (83%) of
19s as a colorless foam as a single diastereomer. Rf = 0.28 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.34−7.28 (m,
3H), 7.27−7.21 (m, 4H), 7.06 (d, J = 8.0 Hz, 1H), 6.41−6.37 (m,
2H), 6.26−6.23 (m, 1H), 6.08 (d, J = 3.2 Hz, 1H), 5.61 (ddd, J =
17.1, 10.1, 8.7 Hz, 1H), 5.16 (d, J = 10.1 Hz, 1H), 5.08−5.05 (m,
1H), 4.98 (d, J = 18.0 Hz, 1H), 4.71 (d, J = 15.0 Hz, 1H), 4.30−4.23
(m, 2H), 4.08 (d, J = 6.7 Hz, 1H), 3.98−3.94 (m, 1H), 3.85 (d, J =
15.0 Hz, 1H), 3.77 (s, 3H), 3.74−3.69 (m, 4H). 13C{1H} NMR (151
MHz, CDCl3) δ 160.5, 160.2, 158.6, 151.0, 142.8, 137.7, 135.1, 131.0,
128.6, 127.6, 127.6, 120.6, 116.8, 110.2, 108.7, 104.0, 98.3, 65.2, 62.7,
62.0, 57.1, 55.3, 55.2, 40.7. HRMS (DART) m/z calcd for
C26H29N2O5 [M + H]+: 449.2076; Found [M + H]+: 449.2066.
(4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenyl-
ethyl)-5-(thiophen-2-yl)-4-vinylimidazolidin-2-one (19t). According
to General Procedure C, the product was purified by silica gel
chromatography (3% E.A. in DCM) to provide 184 mg (99%) of 19t
as a colorless foam as a single diastereomer and as a 92:8 mixture of
(4S,5S)-1-(4-Fluorobenzyl)-3-((S)-2-hydroxy-1-phenylethyl)-5-
(naphthalen-2-yl)-4-vinylimidazolidin-2-one (19pd). The reaction
was set up according to general procedure C and stirred at 65 °C for
24 h. The product was purified by silica gel chromatography (5% E.A.
in DCM) to provide 132 mg (71%) of 19pd as a colorless foam as a
1
single diastereomer. Rf = 0.62 (20% EtOAc/DCM). H NMR (600
MHz, CDCl3) δ 7.85−7.75 (m, 3H), 7.54−7.48 (m, 3H), 7.36 (t, J =
7.6 Hz, 2H), 7.33−7.26 (m, 3H), 7.25−7.22 (m, 1H), 7.09 (dd, J =
8.4, 5.5 Hz, 2H), 6.98 (t, J = 8.6 Hz, 2H), 5.69 (ddd, J = 17.0, 10.2,
8.6 Hz, 1H), 5.20 (d, J = 10.1 Hz, 1H), 4.96 (d, J = 14.9 Hz, 1H),
4.91 (t, J = 6.1 Hz, 1H), 4.86 (d, J = 17.0 Hz, 1H), 4.39−4.30 (m,
2H), 4.15−4.08 (m, 2H), 3.68−3.61 (m, 2H). 13C{1H} NMR (151
1
MHz, CDCl3) δ 163.12 (C−F, J C−F = 246.13 Hz), 161.49 (C−F,
1J C−F = 246.13 Hz), 160.8, 137.6, 134.8, 134.7, 133.3, 133.1, 130.46,
132.02 (C−F, 3J C−F = 4.53 Hz), 131.99 (C−F, 3J C−F = 4.53 Hz),
130.46, 130.41, 129.1, 128.7, 127.87, 127.80, 127.7, 127.1, 126.6,
126.5, 124.3, 121.4, 115.60 (C−F, 2J C−F = 21.14 Hz), 115.46 (C−F,
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2J C−F = 21.14 Hz), 66.3, 64.9, 63.6, 62.0, 45.0. 19F NMR (565 MHz,
CDCl3) δ − 114.61. HRMS (DART) m/z calcd for C30H28FN2O2 [M
+ H]+: 467.2135; Found [M + H]+: 467.2105.
all the Cu(OAc)2 dissolved. A 50 mL two-neck round-bottom flask
was then charged with imine 9c (1.0 g, 4.44 mmol) and allene 15a
(1.07 g, 5.33 mmol), and the flask was evacuated and backfilled with
nitrogen 3 times. The flask was then charged with toluene (5 mL).
The imine/allene flask was then charged with the catalyst solution.
Dimethoxymethyl silane (1.1 mL, 8.89 mmol) was charged to the
reaction mixture (caution:dimethoxymethylsilane should be handled in a
well-ventilated fume hood because it is known to cause blindness. Syringes
were quenched with 2 M NaOH, gas evolution! prior to disposal), and the
reaction was allowed to stir at rt for 2 h. A 50 mL round-bottom flask
was charged with NH4F (2 g) and MeOH (20 mL), and the reaction
mixture was transferred via pipet to this flask and allowed to stir at rt
for 30 min. The volatiles were concentrated in vacuo, and 50 mL of
5% NaHCO3 solution were added to the flask. The mixture was
extracted with CH2Cl2 (2 × 20 mL), and the combined organics were
dried over Na2SO4 and concentrated in vacuo. The crude residue was
purified by silica gel chromatography (5% EtOAc/DCM) to afford
1.655 g (91%) of 18c as a white solid as a single diastereomer.
Synthesis of 25. To a solution of 207.5 mg (393 μmol) of 19a in
2 mL of CH2Cl2 at 0 °C were charged 66 μL (473 μmol) of
triethylamine followed by dropwise addition of 30.5 μL (393 μmol) of
MsCl. The mixture was stirred for 30 min at 0 °C, and then 4 mL of
10% NH4Cl were added. The mixture was extracted with CH2Cl2 (3
× 5 mL). The combined organics were dried with anhydrous Na2SO4
and filtered, and the volatiles were removed in vacuo. The crude
residue was then dissolved in 2 mL of THF and cooled to 0 °C. A 1.0
M concentration of potassium tert-butoxide (433 μL, 433 μmol) in
THF was then added, and the mixture was warmed to room
temperature and stirred for 30 min. To the mixture was added 5 mL
of 10% brine followed by extraction with CH2Cl2 (3 × 5 mL). The
combined organics were dried with anhydrous Na2SO4 and filtered,
and the volatiles were removed in vacuo. The crude residue was then
dissolved in 4 mL of THF in a crimp cap vial. To the solution were
then added 788 μL (3.94 mmol) of 5.0 M aqueous H2SO4. The vial
was purged with argon, sealed, and immersed in an oil bath at 50 °C.
After 3 h the reaction mixture was cooled to room temperature, and
15 mL of saturated aqueous NaHCO3 were added. The mixture was
extracted with CH2Cl2 (3 × 5 mL). The combined organics were
dried with anhydrous Na2SO4 and filtered, and the volatiles were
removed in vacuo. The crude residue was purified by flash
chromatography (20% EtOAc/DCM) to afford 112 mg (70%) of
Synthesis of 29 from Achiral Allenamide 15b. To a 20 mL
crimp cap vial with a stir bar in an Ar filled glovebox were charged
Cu(OAc)2 (1.8 mg, 10 μmol) and Ph-BPE (5.1 mg, 10 μmol)
followed by toluene (2.5 mL) and tert-butanol (26.3 μL, 275 μmol).
The mixture was stirred for 5 min. Allenamide 15b (37.5 mg, 300
μmol) followed by imine 9a (250 μmol) was then charged, and the
vial was sealed with a crimp-cap septum and removed from the
glovebox. Dimethoxymethylsilane (0.061 mL, 2 equiv) was charged to
the reaction mixture, and the reaction mixture was stirred at rt for 24
h. The reaction was quenched by addition of 100 mg of NH4F and 1.5
mL of MeOH followed by agitation at rt for 30 min. A 5 mL volume
of 5% NaHCO3 was then added to the mixture followed by extraction
with DCM (2 × 3 mL). The combined organics were dried with
Na2SO4, filtered, and concentrated in vacuo. Crude product was
purified by flash chromatography on silica gel (25% EtOAc/hexanes)
to afford 78 mg (69%) of 29 as a white solid as a single diastereomer
and as a 57:43 mixture of enantiomers as determined via chiral HPLC
analysis (Chiracel AD-3 85:15 heptane/isopropanol 1.50 mL/min,
1
254 nm). Rf = 0.45 (50% EtOAc/hexanes). H NMR (600 MHz,
CDCl3) δ 7.60 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 6.91 (d, J
= 8.2 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 6.40 (dd, J = 8.1, 2.4 Hz,
1H), 5.47 (ddd, J = 17.2, 10.5, 6.9 Hz, 1H), 5.05 (d, J = 10.6 Hz, 1H),
4.99 (d, J = 17.2 Hz, 1H), 4.46 (t, J = 6.0 Hz, 1H), 4.29 (q, J = 12.0
Hz, 1H), 4.21 (q, J = 12.0 Hz, 1H), 3.79 (s, 6H), 3.75 (d, J = 9.6 Hz,
1H), 3.71 (d, J = 13.7 Hz, 1H), 3.42 (q, J = 8.1 Hz, 1H), 3.25 (d, J =
13.7 Hz, 1H), 3.16 (td, J = 8.7, 6.4 Hz, 1H). 13C{1H} NMR (151
MHz, CDCl3) δ 160.3, 158.7, 158.6, 144.8, 131.4, 130.7, 130.6, 130.2
(q, J = 31.71 Hz), 128.9, 128.7, 125.3 (q, J = 3.02 Hz), 119.7, 103.6,
98.6, 98.6, 62.2, 62.1, 61.7, 60.9, 55.3, 55.2, 46.1, 40.8. 19F NMR (565
MHz, CDCl3) δ −62.36. HRMS (DART) m/z calcd for
C23H26F3N2O4 [M + H]+: 451.1845; Found [M + H]+: 451.1881.
Synthesis of 30 from Achiral Allenamide 15b. To a 20 mL
crimp cap vial with a stir bar in an Ar filled glovebox were charged
Cu(OAc)2 (1.8 mg, 10 μmol) and Ph-BPE (5.1 mg, 10 μmol)
followed by toluene (0.5 mL). The mixture was stirred for 5 min.
Allenamide 15b (37.5 mg, 300 μmol) followed by imine 9a (250
μmol) was then charged, and the vial was sealed with a crimp-cap
septum and removed from the glovebox. Dimethoxymethylsilane
(0.061 mL, 2 equiv) was then charged to the reaction mixture. The
mixture was then stirred at rt for 24 h. The reaction was quenched by
addition of 100 mg of NH4F and 1.5 mL of MeOH followed by
agitation at rt for 30 min. A 5 mL volume of 5% NaHCO3 was then
added to the mixture followed by extraction with DCM (2 × 3 mL).
The combined organics were dried with Na2SO4, filtered, and
concentrated in vacuo. Crude product was purified by flash
chromatography on silica gel (50% EtOAc/hexanes) to afford 68
mg (60%) of 30 as a colorless liquid and as an 80:20 mixture of
enantiomers as determined via chiral HPLC analysis (Chiracel AD-3
90:10 heptane/isopropanol 1.00 mL/min, 220 nm). Rf = 0.28 (50%
EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz,
2H), 7.28 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 6.37 (dd, J =
8.3, 2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 5.62 (ddd, J = 17.1, 10.1,
8.6 Hz, 1H), 5.22 (d, J = 10.1 Hz, 1H), 5.04 (d, J = 17.0 Hz, 1H),
4.70 (d, J = 14.7 Hz, 1H), 4.01 (d, J = 8.2 Hz, 1H), 3.86 (d, J = 14.7
Hz, 1H), 3.78 (s, 3H), 3.76−3.68 (m, 2H), 3.63 (t, J = 8.4 Hz, 1H),
3.55 (s, 3H), 3.36−3.31 (m, 1H), 3.26−3.22 (m, 1H). 13C{1H} NMR
(151 MHz, CDCl3) δ 162.3, 160.6, 158.6, 142.7, 135.0, 131.7, 130.6
(q, J = 31.71 Hz), 127.6, 126.7 (q, J = 273.31 Hz), 125.5 (q, J = 3.02
Hz), 121.2, 116.2, 104.1, 98.0, 68.2, 63.8, 62.2, 55.3, 54.8, 46.1, 40.8.
19F NMR (565 MHz, CDCl3) δ −62.50. HRMS (DART) m/z calcd
for C23H26F3N2O4 [M + H]+: 451.1845; Found [M + H]+: 451.1882.
Synthesis of 18c on 1.0 g Scale. To a 20 mL crimp cap vial was
charged Cu(OAc)2 (16.1 mg, 88.9 μmol), and the vial was sealed with
a crimp-cap septum. The vial was evacuated and backfilled with
nitrogen 3 times and then charged with toluene (5 mL), 20% PCy3
solution in toluene (194 μL, 111 μmol), and tert-butanol (0.85 mL,
8.89 mmol), and the mixture was allowed to stir at rt for 10 min until
1
25 as a colorless foam. Rf = 0.22 (50% EtOAc/hexanes). H NMR
(600 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz,
2H), 7.02 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.31 (d, J =
2.4 Hz, 1H), 5.74 (ddd, J = 17.2, 10.2, 7.2 Hz, 1H), 5.41 (s, 1H), 5.12
(d, J = 10.2 Hz, 1H), 5.10 (d, J = 12 Hz, 1H), 4.67 (d, J = 14.8 Hz,
1H), 4.06 (d, J = 7.5 Hz, 1H), 3.86−3.82 (m, 2H), 3.76 (s, 3H), 3.54
(s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.6, 160.5, 158.5,
143.2, 136.1, 131.4, 130.6 (q, J = 33.22 Hz), 127.5, 126.7 (q, J = 271.8
Hz), 125.5 (q, J = 3.02 Hz), 118.0, 116.5, 104.1, 97.9, 65.5, 62.1, 55.3,
54.9, 39.8. 19F NMR (565 MHz, CDCl3) δ −62.49. HRMS (DART)
m/z calcd for C21H22F3N2O3 [M + H]+: 407.1583; Found [M + H]+:
407.1600.
Synthesis of 19a from 18a. To a solution of 100 mg (190 μmol)
of 18a in 1.0 mL of THF at −10 °C were added 114 μL (285 μmol)
n
of 2.5 M solution of BuLi in hexanes. The reaction mixture was
allowed to warm to room temperature and stirred for 1 h. To the
mixture were added 2 mL of saturated NH4Cl, and the mixture was
extracted with CH2Cl2 (3 × 3 mL). The combined organics were
dried with anhydrous Na2SO4 and filtered, and the volatiles were
removed in vacuo. The crude residue was purified by flash
chromatography (5% EtOAc/DCM) to afford 94 mg (94%) of 19a
as a colorless foam.
Synthesis of 26. A crimp cap vial was charged with 100 mg (233
μmol) of 18c, CH3CN (1 mL), K2CO3 (161 mg, 1.17 mmol), TBAI
(17.2 mg, 46.7 μmol), and allyl bromide (101 μL, 1.17 mmol). The
mixture was heated at 85 °C for 18 h. The reaction was quenched
with 5 mL of water, and the mixture was extracted with MTBE (3 × 3
mL). The combined organics were dried with anhydrous Na2SO4 and
filtered, and the volatiles were removed in vacuo. The crude residue
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was purified by flash chromatography (20% EtOAc/hexanes) to afford
90 mg (82%) of 26 as a yellow solid. Rf = 0.60 (50% EtOAc/hexanes).
1H NMR (600 MHz, CDCl3) δ 7.38−7.31 (m, 4H), 7.29−7.25 (m,
3H), 7.25−7.20 (m, 3H), 7.18 (d, J = 6.0 Hz, 2H), 6.98 (d, J = 8.5
Hz, 2H), 6.93−6.88 (m, 2H), 5.95 (dtd, J = 17.2, 9.5, 4.0 Hz, 1H),
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),
4.08 (dd, J = 7.4, 5.3 Hz, 1H), 3.87 (d, J = 11.7 Hz, 1H), 3.85 (s, 3H),
3.82 (d, J = 13.3 Hz, 1H), 3.66−3.61 (m, 1H), 2.96 (d, J = 13.2 Hz,
1H), 2.56 (dd, J = 13.3, 9.1 Hz, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ 159.0, 158.7, 140.1, 137.1, 134.7, 131.8, 131.0, 130.0, 128.7,
128.6, 128.0, 127.8, 127.6, 119.2, 118.0, 113.8, 70.4, 62.4, 56.9, 56.7,
55.4, 52.9, 52.5. HRMS (DART) m/z calcd for C30H33N2O3 [M +
H]+: 469.2491; Found [M + H]+: 469.2504.
Synthesis of 27. To a 20 mL crimp cap vial with a stir bar in an
Ar filled glovebox were added 48 mg (0.10 mmol) of 26 followed by 2
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
solution was heated at 90 °C for 12 h. The reaction mixture was
concentrated, and the crude residue was purified by flash
chromatography (50% EtOAc/hexanes) to afford 35 mg (78%) of
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,
6H), 7.15 (d, J = 6.0 Hz, 2H), 6.88 (d, J = 7.9 Hz, 2H), 5.41−5.37
(m, 1H), 5.20 (dd, J = 8.7, 2.8 Hz, 1H), 5.15−5.09 (m, 1H), 4.72−
4.68 (m, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.99 (d, J = 4.4 Hz, 1H), 3.97
(s, 1H), 3.96−3.93 (m, 1H), 3.80 (s, 3H), 3.24 (dt, J = 17.9, 2.5 Hz,
1H), 2.95 (d, J = 13.2 Hz, 1H), 2.76 (dd, J = 18.0, 2.8 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 158.7, 157.9, 142.8, 138.2,
130.7, 129.5, 128.8, 128.7, 128.6, 128.5, 128.1, 128.0, 126.4, 123.2,
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]+:
441.2205.
Robert T. Martin − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
Stephen Collins − Department of Chemistry, Virginia
Commonwealth University, Richmond, Virginia 23284-3208,
United States
Zachary Wilhelm − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
Mytia D. Edwards − Department of Chemistry, Virginia
Commonwealth University, Richmond, Virginia 23284-3208,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02971
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Startup funding from the Virginia Commonwealth University
and the Bill and Melinda Gates Foundation (The Medicines
for All Institute, grant number OPP#1176590) is gratefully
acknowledged. We thank Dr. Faik Musayev (VCU) for X-ray
crystallographic analysis that was partially supported by
Structural Biology resources provided by NIH Shared
Instrumentation Grant S10OD021756 (MKS) and Virginia
General Assembly Higher Education Equipment Trust Fund
(HEETF) to VCU. M.D.E. acknowledges the NSF for a
summer REU fellowship (CHE-1851916). We thank Dr.
Joseph Turner (VCU) for assistance in collecting HRMS data.
O.G. is grateful to the University of Maryland College Park for
start-up funds, the NSF (CAREER 1751568) and by the
NIGMS of the NIH (R35GM137797), and computational
resources from UMD Deepthought2 and MARCC/BlueCrab
HPC clusters and XSEDE (CHE160082 and CHE160053).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02971.
■
sı
Computational details, intermediate and transition state
1
coordinates, copies of H and 13C NMR spectra of all
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AUTHOR INFORMATION
Corresponding Authors
■
Osvaldo Gutierrez − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States; orcid.org/0000-0001-
8151-7519; Email: ogs@umd.edu
Joshua D. Sieber − Department of Chemistry, Virginia
Commonwealth University, Richmond, Virginia 23284-3208,
United States; orcid.org/0000-0001-6607-5097;
Email: jdsieber@vcu.edu
Authors
Toolika Agrawal − Department of Chemistry, Virginia
Commonwealth University, Richmond, Virginia 23284-3208,
United States
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