Diastereoselective synthesis of γ- And δ-lactams from imines and sulfone-substituted anhydrides

Article abstract of DOI:10.1021/jo500050n

Sulfone-substituted γ- and δ-lactams have been prepared in a single step with high diastereoselectivity. Sulfonylglutaric anhydrides produce intermediates that readily decarboxylate to provide δ-lactams with high diastereoselectivity. Substituents at the 3- or 4-position of the glutaric anhydride induce high levels of stereocontrol. Sulfonylsuccinic anhydrides produce intermediate carboxylic acids that can be trapped as methyl esters or allowed to decarboxylate under mild conditions. This method has been applied to a short synthesis of the pyrrolizidine alkaloid (±)-isoretronecanol.

Full text of DOI:10.1021/jo500050n

Article
pubs.acs.org/joc
Diastereoselective Synthesis of γ- and δ‑Lactams from Imines and
Sulfone-Substituted Anhydrides
Nohemy A. Sorto, Michael J. Di Maso, Manuel A. Munoz, Ryan J. Dougherty, James C. Fettinger,
̃
and Jared T. Shaw*
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: Sulfone-substituted γ- and δ-lactams have been prepared
in a single step with high diastereoselectivity. Sulfonylglutaric anhydrides
produce intermediates that readily decarboxylate to provide δ-lactams
with high diastereoselectivity. Substituents at the 3- or 4-position of the
glutaric anhydride induce high levels of stereocontrol. Sulfonylsuccinic
anhydrides produce intermediate carboxylic acids that can be trapped as
methyl esters or allowed to decarboxylate under mild conditions. This
method has been applied to a short synthesis of the pyrrolizidine alkaloid
( )-isoretronecanol.
Scheme 1. Proposed Mechanism for the Formation of
Sulfone-Substituted γ- and δ-Lactams
INTRODUCTION
■
The γ- and δ-lactam scaffolds are found in various biologically
relevant compounds.1−3 Additionally, these core structures are
crucial intermediates in the synthesis of various natural
products as well as pharmaceuticals, prompting the develop-
ment of new methods for the synthesis of these valuable
structures.4−7 Our group has explored the synthesis of γ-
lactams by the reactions of aryl-,8,9 thioaryl-,10 and cyano-
substituted anhydrides.11,12 Furthermore, we have demonstra-
ted that one-pot four-component reactions (4CRs) are possible
in the case of thioaryl substitution.13,14 Recent computational
studies of the cyanosuccinic anhydride reactions demonstrate
that they proceed by a Mannich-like mechanism via the enol
tautomer of the anhydride.15 Related reactions reported by
Castagnoli, Cushman, and Haimova likely proceed by this
mechanism as well.16−21 Castagnoli reported the first reactions
of imines with succinic and glutaric anhydrides. Consistent with
the proposed mechanism, those anhydrides are poorly
enolizable and require forcing conditions. Two decades later,
Cushman and Haimova reported analogous reactions with
homophthalic anhydride, which is highly enolizable. The high
reactivity of this anhydride at lower temperatures is consistent
with the Mannich-like mechanism.
These results prompted us to explore Mannich-type
reactions and related 4CRs of variously substituted anhydrides.
Although aryl-substituted succinic anhydrides showed some
variation in reactivity based on the substituents attached to the
aromatic ring, direct attachment of an electron-withdrawing
group resulted in higher reactivity.12 Furthermore, in the case
of cyanosuccinic anhydrides, the diastereoselectivity was
reversed relative to the aryl and thioaryl cases and could be
controlled by resident stereogenic centers.11,15 We envisioned
that the electron-withdrawing capability of a sulfone would
impart the anhydride with similar reactivity as the nitrile-
substituted anhydride, albeit with drastically different steric
requirements (Scheme 1). Herein we report the development
of anhydride Mannich reactions (AMRs) using sulfone-
substituted anhydrides for the synthesis of γ- and δ-lactams as
well as a six-step formal synthesis of ( )-isoretronecanol.22,23
RESULTS AND DISCUSSION
■
Multigram-scale syntheses of anhydrides 3a−d were achieved
from readily available starting materials. Anhydride 3a was
synthesized by conjugate addition of benzenesulfinic acid
sodium salt (7) to maleic anhydride to yield a diacid,24 which
was cyclized in one step (Scheme 2A). The syntheses of
Received: January 9, 2014
Published: February 19, 2014
© 2014 American Chemical Society
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Scheme 2. Synthesis of (A) Sulfone Succinic Anhydride 3a
and (B) Sulfone Glutaric Anhydrides 3b−d
Figure 1. X-ray structures of 5f, 10f, and 10g and J values for 10e and
10j.
anhydrides 3b−d were achieved by Michael addition of sulfone
acetate 8 to various tert-butyl acrylates followed by ester
cleavage and cyclization (Scheme 2B).
Anhydride 3a readily reacted with imines to form γ-lactams.
As with previous AMRs, the carboxylic acid 5 (Table 1) is the
first-formed product. Unlike all previous related intermediates,
these carboxylic acids were prone to facile decarboxylation.
Mild heating drove the decarboxylation to completion, allowing
isolation of the sulfone-substituted lactams in high yields with
cyano-substituted anhydrides suggests that the anti-configured
carboxylic acids are the kinetic products of the AMRs.12,15
Subsequent decarboxylation leads to the anti-sulfones, which
would also be expected to be thermodynamically preferred.
The stereochemical outcome of the reactions of imines with
3a is adequately explained by a transition state that is analogous
to what is operative for cyanosuccinic anhydrides (eq 1). The
iminium ion is attacked by the enolate of the anhydride, and the
cyclic transition state is stabilized by hydrogen bonding to the
sulfone. After the Mannich reaction, subsequent rapid trans-
annular acylation forms the lactam product.
1
only the anti diastereomer detectable by H NMR spectrosco-
py. In all cases, non-enolizable substrates were well-tolerated.
The lack of reactivity of ketones and enolizable aldehydes in the
AMR probably stems from the rapid equilibration to the
enamine tautomer, which is unreactive in the Mannich addition
step.
Table 1. Scope of Sulfone-Substituted Anhydride 3a in
Reactions with Various Imines
The carboxylic acid intermediates could be trapped with
trimethylsilyldiazomethane (TMSCHN2). Initial attempts at
methylation using conventional methods (H2SO4/CH3OH or
CH3I/K2CO3)25 yielded only the decarboxylated products.
After many esterification conditions were tried, treatment of
crude mixtures of 5 with a commercially available solution of
TMSCHN2 resulted in reasonable yields of methyl esters 11a−
c (Table 2).26 These intermediates could also be smoothly
desulfonylated with magnesium in methanol to produce the
corresponding esters 12 in good yield. Although this reaction
was successful for 11a and 11b, no ester product was observed
in the attempted desulfonylation of 11c.27
Sulfone-substituted glutaric anhydrides 3b−d formed δ-
lactams with high efficiency. The reactions initially formed
carboxylic acids with modest (∼80:20) diastereoselectivity.
Unlike the analogous γ-lactams, these intermediates were
impossible to isolate, thus preventing assignment of the
configuration of the predominant diastereomer. Upon decar-
boxylation, sulfone lactams 13 were formed as single isomers in
high yields (Table 3).
This change in diastereoselectivity upon decarboxylation
suggests the formation of a planar anion followed by selective
protonation from one face of the anion. This result is in
accordance with experimental data and models of sulfone
anions proposed by Corey.28,29 Similar to our results with the
succinic anhydride, the reaction tolerated a variety of non-
enolizable aldehydes and a variety of alkylamines and anilines.
While some of our initial reactions gave low yields (40−50%),
entry
product
R1
R2
yield
83%
1
2
10a
10b
10c
10d
10e
10f
Bn
Ph
Ph
Ph
b
CH3
83%
54%
50%
87%
80%
65%
82%
70%
78%
84%
3
CH2CCH
4
n-Pr
2-furyl
5
n-Pr
Ph
c
6
n-Pr
4-CNC6H4
2-MeOC6H4
(E)-PhCHCH
Ph
7
10g
10h
10i
n-Pr
8
Bn
9
i-Pr
10
11
10j
CH2CHCH2
Ph
10k
n-Pr
4-MeOC6H4
a
b
1
Determined by H NMR spectroscopy. Yield using commercially
available imine. Decarboxylation was done at room temperature.
c
The stereochemical configuration of the products was
assigned by X-ray crystallography. Lactam 10e has an anti
configuration between the aromatic ring and the sulfonyl group.
The other lactams were assigned by comparison of the coupling
constants of the adjacent protons (e.g., 10f; Figure 1A).
Furthermore, acid intermediate 5f, which leads to 10f by
decarboxylation, was also crystalline and was found to have an
anti configuration between the sulfone and aromatic sub-
stituents (Figure 1B). Our previous mechanistic work on the
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Table 2. Formation of 11 and Desulfonylation To Give 12
entry
R1
Bn
R2
11, yield (dr)
12, yield (dr)
1
2
3
Ph
11a, 66% (>95:5)
11b, 57% (>95:5)
11c, 67% (>95:5)
12a, 76% (>95:5)
12b, 77% (90:10)
n-Pr
3,5-(MeO)2C6H3
Ph
a
CH3
12c, −
a
Desulfonylation of 11c yielded a mixture of products as determined by NMR spectroscopy.
formation of a preferred stereoisomer. Studies are ongoing in
our laboratory to develop an enantioselective Michael addition
with sulfone acetate 8 to provide the anhydrides as single
enantiomers, which would presumably provide enantiomerically
pure lactam products.
Table 3. Scope of Sulfone-Substituted Glutaric Anhydride 3b
with Various Imines
This new AMR was applied to a formal synthesis of
( )-isoretronecanol (Scheme 4). The reaction of imine 16 with
Scheme 4. Formal Synthesis of ( )-Isoretronecanol
entry
product
R1
R2
yield
b
1
2
13a
13b
13c
13d
13e
13f
CH3
i-Pr
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
80%
84%
85%
74%
89%
72%
91%
68%
69%
87%
61%
64%
75%
b
b
b
b
b
3
4
CH2CCH
5
CH2CHCH2
6
Ph
7
13g
13h
13i
n-Pr
i-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
8
(E)-PhCHCH
4-MeOC6H4
4-ClC6H4
9
b
b
10
11
12
13
13j
13k
13l
2-EtC6H4
3,5-(MeO)2C6H3
13m
2-furyl
a
b
1
Determined by H NMR spectroscopy. Yield using commercially
available or purified imine.
the use of commercially available imines or those purified by
distillation significantly increased the yields of the lactam
products.
Methyl-substituted anhydrides 3c and 3d provided trisub-
stituted δ-lactams in high yields with good diastereomeric ratios
(Scheme 3). These results suggest that substitution on the
anhydride provides excellent facial selectivity, resulting in the
formation of only two diastereomers of the intermediate
carboxylic acids. Again, decarboxylation seemed to enable the
anhydride 3a followed by ring-closing metathesis provides the
pyrrolizidine core of the natural product from cinnamaldehyde,
allylamine, and 3a in two steps. The elimination of 18 yields 21,
which has been converted to ( )-isoretronecanol in two steps
in low yield.23 Alternatively, reduction and elimination provides
lactam 20. Further reduction yields lactam ester 22, which has
been converted to ( )-isoretronecanol in one step.22 While this
second route is redox-inefficient,30 it provides material in a
much higher yield and avoids the high-pressure conditions
necessary to reduce pyrrole 21. This synthetic route showcases
the versatility of the anhydride Michael reaction of the sulfone-
substituted anhydride, exemplifying its usefulness in the
assembly of heterocyclic targets. This synthesis demonstrates
that the AMR of sulfone-substituted anhydrides will be useful
for the assembly of many heterocyclic targets, natural and
otherwise.
Scheme 3. AMRs with Methyl-Substituted Sulfone Glutaric
Anhydrides and X-ray Crystal Structures of the Products
CONCLUSION
■
In summary, we have successfully synthesized various sulfone-
substituted γ- and δ-lactams in good yields with high
diastereoselectivities (>95:5) by an anhydride Mannich
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K2CO3 and heating at reflux for 4 h, unless otherwise stated. The
reaction mixture was allowed to cool to rt and then extracted two
times with EtOAc. The combined organic layers were washed with
brine and dried over Na2SO4. The solvent was evaporated in vacuo,
and the crude mixture was purified by flash chromatography using an
EtOAc/30−50% gradient, unless otherwise stated.
trans-1-Benzyl-5-phenyl-4-(phenylsulfonyl)pyrrolidin-2-one
(10a). General procedure A was used with sulfone anhydride 3a (0.24
g, 0.99 mmol), benzylamine (109 μL, 0.99 mmol), and benzaldehyde
(102 μL, 1.0 mmol) to yield 10a (0.32 g, 83%) as a foam (50:50
EtOAc/hex, Rf = 0.59). 1H NMR (600 MHz, CDCl3) δ 7.68−7.64 (m,
2H), 7.62 (tt, J = 7.5, 1.3 Hz, 1H), 7.48−7.41 (m, 2H), 7.32−7.23 (m,
6H), 7.09−7.06 (m, 2H), 6.83−6.79 (m, 2H), 5.09 (d, J = 14.9 Hz,
1H), 4.70 (d, J = 3.3 Hz, 1H), 3.66 (ddd, J = 9.9, 4.4, 3.3 Hz, 1H), 3.44
(d, J = 14.9 Hz, 1H), 3.03 (dd, J = 18.2 (gem), 4.3 Hz, 1H), 2.95 (ddd,
J = 18.2 (gem), 9.9, 1.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
170.5, 137.7, 136.4, 134.7, 134.4, 129.5, 129.3, 128.9, 128.7, 128.7,
128.4, 127.8, 126.1, 63.5, 60.6, 44.5, 30.7; IR (thin film) 1692 (CO),
1322 (SO) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C23H21NO3SNa 414.1140, found 414.1120.
reaction. We have previously studied the reactivity of several
different substituted succinic anhydrides, but these are the first
new results employing glutaric anhydyrides since the original
work of Castagnoli.20,21 Unlike previous reactions of this type
to date, the carboxylic acid products were prone to
decarboxylation. Although the γ-lactam acids derived from the
substituted succinic anhydride could be trapped as esters, the
analogous δ-lactam products could not be intercepted. Another
important difference was observed in the diastereoselectivity of
the initial Mannich-type reaction. Although the reactions of
succinic anhydyrides were very selective, the acid products
derived from the glutaric anhydrides were generally formed as
diastereomeric mixtures. In both cases, high selectivity was
observed for the decarboxylation process. We have shown that
this methodology is highly robust and have showcased it in the
formal synthesis of a biologically active natural product. Further
studies into the synthesis of additional natural product targets
are underway.
trans-1-Methyl-5-phenyl-4-(phenylsulfonyl)pyrrolidin-2-one
(10b). General procedure A was used with sulfone anhydride 3a (0.30
g, 1.26 mmol) and (E)-N-methyl-1-phenylmethanimine (156 μL, 1.26
mmol). Because the commercially available imine was used in this
experiment, the anhydride was added immediately after the imine was
dissolved instead of waiting for 3 h or overnight. The reaction yielded
10b (0.332 g, 83%) as a foam (50:50 EtOAc/hex, Rf = 0.35). 1H NMR
(600 MHz, CDCl3) δ 7.89 (d, J = 7.5 Hz, 2H), 7.69 (t, J = 7.5 Hz,
1H), 7.58 (t, J = 7.8 Hz, 2H), 7.36−7.31 (m, 3H), 7.06−7.02 (m, 2H),
4.97 (d, J = 3.5 Hz, 1H), 3.66 (dt, J = 9.8, 4.1 Hz, 1H), 2.90 (dd, J =
18.1 (gem), 4.7 Hz, 1H), 2.82 (dd, J = 18.1 (gem), 9.8 Hz, 1H), 2.64
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 170.6, 138.2, 136.8, 134.6,
129.7, 129.5, 129.0, 128.9, 126.1, 64.3, 63.6, 31.0, 28.4; IR (thin film)
1690 (CO), 1308 (SO) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C17H17NO3SNa 338.0827, found 338.0818.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise specified, all commercially
available reagents were used as received. All reactions using dried
solvents were carried out under an atmosphere of argon in flame-dried
glassware with magnetic stirring. Dry solvent was dispensed from a
solvent purification system that passes solvent through two columns of
dry neutral alumina. 1H NMR spectra and proton-decoupled 13C
NMR spectra were obtained on a 400 or 600 MHz NMR
spectrometer. Chemical shifts (δ) are reported in parts per million
(ppm) relative to residual solvent (CHCl3, s, δ 7.26). Multiplicities are
given as s (singlet), d (doublet), t (triplet), dd (doublet of doublets),
m (multiplet), br m (broad multiplet), or br s (broad singlet); 13C
NMR chemical shifts are reported relative to CDCl3 (t, δ 77.23) unless
otherwise noted. High-resolution mass spectra were recorded in
positive ESI mode in methanol or acetonitrile. Silica gel chromato-
graphic purifications were performed by flash chromatography with
silica gel packed in glass columns. The eluting solvent for each
purification was determined by thin-layer chromatography (TLC) on
glass plates coated with silica gel and visualized by UV light or by
staining with ceric ammonium molybdate (CAM) followed by gentle
heating. The following abbreviations are used throughout: ethyl
acetate (EtOAc), hexanes (hex), dichloromethane (DCM), triethyl-
amine (TEA), diisopropylethylamine (DIPEA).
3-(Phenylsulfonyl)dihydrofuran-2,5-dione (3a). Benzenesul-
finic acid sodium salt (10.0 g, 60.9 mmol) was dissolved in 100 mL
of H2O at 0 °C. Maleic anhydride (5.97 g, 60.9 mmol) was added. The
reaction mixture was allowed to warm slowly overnight. Then 10%
HCl was added, and the mixture was extracted two times with EtOAc.
The combined organic layers were dried over Na2SO4, and the solvent
was removed in vacuo to yield a white solid, which was dissolved in 50
mL of toluene. Ac2O (70 mL, 20 mmol) was added, and the reaction
mixture was heated at reflux for 3 h. The solvent was evaporated in
vacuo, and the resulting brown solid was washed several times with
cold DCM and collected in a fritted funnel, yielding a white to light-
brown solid (6.8 g, 46% yield over the two steps). Mp 132.4−133.1 °C
(dec.); 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.4, 1.3 Hz, 2H),
7.86−7.76 (m, 1H), 7.72−7.63 (m, 2H), 4.52 (dd, J = 10.3, 4.4 Hz,
1H), 3.68 (dd, J = 19.9 (gem), 4.4 Hz, 1H), 3.39 (dd, J = 19.7 (gem),
10.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.0, 162.9, 135.8,
135.4, 129.9, 129.7, 64.4, 30.1; IR (neat) 1782, 1739 (CO), 1169
(SO) cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H9O5S
241.0171, found 241.0165.
trans-5-Phenyl-4-(phenylsulfonyl)-1-(prop-2-yn-1-yl)pyrrolidin-2-
one (10c). General procedure A was used with sulfone anhydride 3a
(0.240 g, 1.00 mmol), prop-2-yn-1-amine (64.0 μL, 1.00 mmol), and
benzaldehyde (102 μL, 1.00 mmol) to yield 10c (0.182 g, 54%) as a
foam. The residue was purified by flash column chromatography
1
(50:50 EtOAc/hex, Rf =0.53). H NMR (600 MHz, CDCl3) δ 7.89
(m, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.60−7.53 (t, 2H), 7.35−7.29 (m,
3H), 7.07−7.02 (m, 2H), 5.23 (d, J = 4.0 Hz, 1H), 4.51 (dd, J = 17.6,
2.6 Hz, 1H), 3.75 (ddd, J = 9.4, 5.1, 4.0 Hz, 1H), 3.25−3.20 (m, 1H),
2.96 (dd, J = 18.2 (gem), 5.1 Hz, 1H), 2.89 (ddd, J = 18.2 (gem), 9.8,
1.1 Hz, 1H), 2.25 (t, J = 2.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
169.9, 137.3, 136.6, 134.6, 129.6, 129.4, 129.0, 128.9, 126.4, 76.2, 73.3,
63.9, 60.9, 31.1, 30.5; IR (thin film) 1699 (CO), 1414, 1322 (S
O) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C19H17NO3SNa 362.0827, found 362.0831.
trans-5-(Furan-2-yl)-4-(phenylsulfonyl)-1-propylpyrrolidin-2-one
(10d). General procedure A was used with sulfone anhydride 3a (0.24
g, 0.99 mmol), propylamine (82 μL, 0.99 mmol), and furan-2-
carbaldehyde (83 μL, 1.00 mmol) to yield 10d (0.167 g, 50%) as a
foam. The residue was purified by flash column chromatography
(50:50 EtOAc/hex, Rf = 0.47). 1H NMR (600 MHz, CDCl3) δ 7.90−
7.86 (m, 2H), 7.70−7.65 (m, 1H), 7.57 (dd, J = 8.3, 7.2 Hz, 2H), 7.32
(d, J = 1.8 Hz, 1H), 6.27 (dd, J = 3.3, 1.9 Hz, 1H), 6.19 (d, J = 3.3 Hz,
1H), 5.07 (d, J = 4.1 Hz, 1H), 3.96 (ddd, J = 8.9, 6.1, 4.1 Hz, 1H), 3.40
(ddd, J = 13.9, 8.8, 7.1 Hz, 1H), 2.95−2.85 (m, 2H), 2.65 (ddd, J =
13.9, 8.6, 5.2 Hz, 1H), 1.47−1.37 (m, 1H), 1.33−1.24 (m, 1H), 0.82
(t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.9, 149.4, 143.5,
136.7, 134.5, 129.6, 128.6, 110.6, 109.8, 60.8, 55.2, 42.7, 31.2, 20.1,
11.1; IR (thin film) 1690 (CO), 1416, 1308 (SO) cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C17H19NO4SNa 356.0932, found
356.0929.
General Procedure A. The amine and the aldehyde were
dissolved in THF (0.10 M), and 3 equiv of triethyl orthoformate
was added. The reaction mixture was allowed to stir for 3 h or
overnight. The anhydride was added, and then the reaction mixture
was allowed to stir for 3 h. Water was added to the mixture (final
concentration 0.05 mmol), followed by the addition of 3 equiv of
trans-5-Phenyl-4-(phenylsulfonyl)-1-propylpyrrolidin-2-one
(10e). General procedure A was used with sulfone anhydride 3a (0.3 g,
1.2 mmol), propylamine (100 μL, 1.2 mmol), and benzaldehyde (126
μL, 1.2 mmol) to yield 10e (0.36 g, 87%) as a solid (50:50 EtOAc/
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1
hex, Rf = 0.36). Mp 149.8−150.4 °C; H NMR (400 MHz, CDCl3) δ
μL, 1.26 mmol) to yield 10j (0.33 g, 78%) as a foam (50:50 EtOAc/
hex, Rf = 0.42). H NMR (600 MHz, CDCl3) δ 7.88 (dt, J = 8.5, 2.0
1
7.89 (dt, J = 8.5, 1.4 Hz, 2H), 7.76−7.54 (m, 3H), 7.43−7.24 (m, 3H),
7.13−6.98 (m, 2H), 5.09 (d, J = 3.5 Hz, 1H), 3.70−3.56 (m, 2H),
2.97−2.76 (m, 2H), 2.54 (dddd, J = 13.7, 8.4, 5.1, 1.1 Hz, 1H), 1.55−
1.31 (m, 2H), 0.85 (td, J = 7.3, 1.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.6, 138.4, 136.7, 134.5, 129.6, 129.3, 128.8, 128.7, 126.0,
63.8, 61.1, 42.6, 30.9, 19.9, 11.1; IR (thin film) 1688 (CO) cm−1;
HRMS (ESI-TOF) m/z [M − H]− calcd for C19H20NO3S 342.1164,
found 342.1155.
4-(trans-5-Oxo-3-(phenylsulfonyl)-1-propylpyrrolidin-2-yl)-
benzonitrile (10f). General procedure A (except that the decarbox-
ylation was performed at room temperature overnight) was used with
sulfone anhydride 3a (0.3 g, 1.2 mmol), propylamine (102 μL, 1.2
mmol), and 4-cyanobenzaldehyde (0.164 g, 1.3 mmol) to yield 10f
(0.36 g, 80%) as a foam (50:50 EtOAc/hex, Rf = 0.35). 1H NMR (600
MHz, CDCl3) δ 7.89 (dt, J = 8.5, 1.8 Hz, 2H), 7.77−7.54 (m, 5H),
7.26 (m, 2H), 5.20 (d, J = 3.6 Hz, 1H), 3.67 (dt, J = 13.7, 8.0 Hz, 1H),
3.57 (dt, J = 10.0, 4.3 Hz, 1H), 2.88 (dd, J = 18.2 (gem), 4.5 Hz, 1H),
2.76 (dd, J = 18.1 (gem), 10.0 Hz, 1H), 2.52 (ddd, J = 13.8, 8.6, 5.0
Hz, 1H), 1.44 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (600 MHz,
CDCl3) δ 170.7, 144.1, 136.6, 134.9, 133.3, 129.9, 128.9, 127.2, 118.1,
113.1, 63.8, 60.6, 43.1, 31.3, 20.1, 11.2; IR (thin film) 1692 (CO),
1445, 1412 (SO) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C20H20N2O3SNa 391.1092, found 391.1098.
Hz, 2H), 7.77−7.67 (m, 1H), 7.59 (m, 2H), 7.43−7.27 (m, 3H), 6.99
(m, 2H), 5.55 (dddd, J = 17.6, 10.0, 7.8, 4.3 Hz, 1H), 5.23−5.15 (m,
1H), 5.14−5.02 (m, 2H), 4.40 (ddt, J = 15.4, 3.9, 1.9 Hz, 1H), 3.75−
3.65 (m, 1H), 2.95 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 170.42,
138.2, 136.8, 134.5, 131.0, 129.7, 129.5, 129.4, 128.9, 126.2, 119.0,
63.9, 60.7, 43.4, 31.0; IR (thin film) 1691 (CO), 1145 (SO)
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H19NO3SNa
364.0983, found 364.0974.
trans-5-(4-Methoxyphenyl)-4-(phenylsulfonyl)-1-propylpyrroli-
din-2-one (10k). General procedure A was used with sulfone
anhydride 3a (0.30 g, 1.2 mmol), propylamine (100 μL, 1.2 mmol),
and 4-methoxybenzaldehyde (151 μL, 1.2 mmol) to yield 10k (0.38 g,
1
84%) as a foam (50:50 EtOAc/hex, Rf = 0.27). H NMR (600 MHz,
CDCl3) δ 7.92−7.86 (d, J = 7.8 Hz, 2H), 7.69 (m, 1H), 7.58 (t, J = 7.8
Hz, 2H), 6.96 (dd, J = 9.2, 2.5 Hz, 2H), 6.84 (dd, J = 9.0, 2.5 Hz, 2H),
5.04 (d, J = 3.5 Hz, 1H), 3.80 (sharp s, 3H), 3.66−3.53 (m, 2H), 2.90
(dd, J = 18.2 (gem), 4.7 Hz, 1H), 2.85−2.76 (dd, J = 18.2 (gem), 10.2
Hz, 1H), 2.52 (m, 1H), 1.51−1.32 (m, 2H), 0.88−0.79 (t, J = 7.8 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 170.4, 159.9, 136.9, 134.4,
130.3, 129.6, 128.8, 127.4, 114.7, 64.1, 60.7, 55.3, 42.5, 31.1, 20.0, 11.1;
IR (thin film) 1687 (CO), 1354, 1144 (SO) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C20H23NO4SNa 396.1245, found
396.1252.
Methyl trans-1-Benzyl-5-oxo-2-phenyl-3-(phenylsulfonyl)-
pyrrolidine-3-carboxylate (11a). N-Benzylidenebenzylamine (0.1
mL, 0.53 mmol) was added to a round-bottom flask containing
Na2SO4 (0.37 g, 2.6 mmol) and THF (6 mL), and then sulfone
anhydride 3a (0.13 g, 0.54 mmol) was added. The reaction mixture
was allowed to stir for 1.5 h, after which the Na2SO4 was removed by
filtration and the solvent was removed in vacuo. The residue was
redissolved in EtOAc, transferred to a separatory funnel, and washed
with HCl (1.2 M or 10%) and brine. The combined organic layers
were dried over Na2SO4, and the solvent removed in vacuo. The
resulting acid was redissolved in a mixture of toluene and methanol
(12 mL:7 mL) and cooled to 0 °C. To the cold solution, TMSCHN2
(0.53 mL, 1.1 mmol, 2 M solution in hexanes) was added dropwise
over a period of 5 min. The reaction was monitored by TLC for the
disappearance of starting material. After ∼2 h the solvent was removed
in vacuo, and the resulting material was purified by column
chromatography (30−60% EtOAc:hex) to yield 11a (0.157 g, 66%
over the two steps) as an amorphous solid (50:50 EtOAc/hex, Rf =
0.47). 1H NMR (600 MHz, CDCl3) δ 7.64−7.18 (m, 15H), 5.21 (d, J
= 14.5 Hz, 1H), 4.89 (s, 1H), 3.70 (d, J = 18.7 (gem) Hz, 1H), 3.38−
3.30 (m, 2H), 3.13 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 170.0,
164.9, 134.9, 134.8, 134.8, 134.4, 131.1, 129.6, 129.5, 129.5, 129.0,
128.9, 128.9, 128.2, 76.2, 63.9, 52.7, 44.9, 35.0; IR (thin film) 1783,
1784 (CO), 1124 (SO) cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C25H23NO5SNa 472.1195, found 472.1176.
Methyl trans-2-(3,5-Dimethoxyphenyl)-5-oxo-3-(phenylsul-
fonyl)-1-propylpyrrolidine-3-carboxylate (11b). Propylamine
(68 μL, 0.83 mmol) and 3,5-dimethoxybenzaldehyde (0.14 g, 0.84
mmol) were dissolved in THF (8 mL). Na2SO4 (0.59 g, 4.2 mmol)
was added, and the mixture was allowed to stir for 1.5 h. Sulfone
anhydride 3a (0.20 g, 0.83 mmol) was added, and the reaction was
allowed to stir for an additional 1 h. The Na2SO4 was filtered off, and
the solvent was removed in vacuo. The residue was redissolved in
EtOAc, transferred to a separatory funnel, and washed with HCl (1.2
M or 10%) and brine. The combined organic layers were dried over
Na2SO4, and the solvent was removed in vacuo. The resulting crude
acid was dissolved in a mixture of toluene and methanol (13 mL:7
mL) and cooled to 0 °C. To the cold solution, TMSCHN2 (0.83 mL,
1.7 mmol, 2 M solution in hexanes) was added dropwise over a period
of 5 min, and the reaction was monitored by TLC for the
disappearance of starting material. After ∼2 h the solvent was
removed in vacuo, and the resulting material was purified by column
chromatography (30−60% EtOAc:hex) to yield 11b (0.22 g, 57% over
the two steps) as an amorphous solid (50:50 EtOAc/hex, Rf = 0.31).
1H NMR (600 MHz, CDCl3) δ 8.01−7.83 (m, 2H), 7.81−7.68 (m,
trans-5-(2-Methoxyphenyl)-4-(phenylsulfonyl)-1-propylpyrroli-
din-2-one (10g). General procedure A was used with sulfone
anhydride 3a (88 mg, 0.36 mmol), propylamine (30 μL, 0.36
mmol), and aldehyde (50 mg, 0.37 mmol) to yield 10g (87 mg, 65%)
1
as a solid (50:50 EtOAc/hex, Rf = 0.17). Mp 125.3−126.1 °C; H
NMR (600 MHz, CDCl3) δ 7.92−7.86 (m, 2H), 7.69−7.62 (m, 1H),
7.55 (t, J = 7.9 Hz, 2H), 7.28 (m, 1H), 6.93−6.82 (m, 3H), 5.16 (s,
1H), 3.80 (d, J = 9.8 Hz, 1H), 3.69 (s, 3H), 3.49 (dt, J = 13.5, 8.1 Hz,
1H), 2.96 (dd, J = 17.9 (gem), 4.0 Hz, 1H), 2.85 (dd, J = 17.9 (gem),
9.9 Hz, 1H), 2.48 (ddd, J = 13.7, 8.5, 5.2 Hz, 1H), 1.46−1.28 (m, 2H),
0.82 (t, J = 7.3 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 171.2, 157.5,
137.7, 134.2, 130.5, 129.5 (2C), 129.0 (2C), 125.7, 121.1, 111.5, 62.8,
55.6, 42.8, 31.7, 20.3, 11.3; IR (thin film) 1681 (CO) cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C20H23NO4SNa 396.1245, found
396.1252.
trans-1-Benzyl-4-(phenylsulfonyl)-5-((E)-styryl)pyrrolidin-2-one
(10h). General procedure A was used with sulfone anhydride 3a (0.18
g, 0.73 mmol), benzylamine (76 μL, 0.69 mmol), and aldehyde (0.1
mL, 0.79 mmol) to yield 10h (0.25 g, 82%) as a foam (50:50 EtOAc/
1
hex, Rf = 0.36). H NMR (600 MHz, CDCl3) δ 7.81−7.74 (m, 2H),
7.65−7.14 (m, 13H), 6.12 (d, J = 15.8 Hz, 1H), 5.74 (dd, J = 15.6, 8.5
Hz, 1H), 4.93 (d, J = 15.0 Hz, 1H), 4.38 (dd, J = 8.8, 4.3 Hz, 1H), 3.90
(d, J = 15.0 Hz, 1H), 3.65 (dt, J = 9.9, 5.1 Hz, 1H), 3.01 (dd, J = 18.0
(gem), 5.5 Hz, 1H), 2.86 (dd, J = 18.1 (gem), 10.0 Hz, 1H); 13C NMR
(151 MHz, CDCl3) δ 170.1, 136.8, 135.3, 135.2, 135.0, 134.4, 129.5,
128.8, 128.7, 128.7, 128.4, 127.7, 126.8, 126.7, 125.3, 61.7, 59.9, 44.7,
30.8; IR (thin film) 1690 (CO), 1146 (SO) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C25H23NO3SNa 440.1296, found
440.1282.
trans-1-Isopropyl-5-phenyl-4-(phenylsulfonyl)pyrrolidin-2-one
(10i). General procedure A was used with sulfone anhydride 3a (0.3 g,
1.26 mmol), isopropylamine (100 μL, 1.22 mmol), and benzaldehyde
(128 μL, 1.26 mmol) to yield 10i (0.297 g, 70%) as a foam (50:50
EtOAc/hex, Rf = 0.42). 1H NMR (600 MHz, CDCl3) δ 7.98−7.86 (m,
2H), 7.72 (tt, J = 7.2, 1.5 Hz, 1H), 7.68−7.56 (m, 2H), 7.40−7.26 (m,
3H), 7.17−6.97 (m, 2H), 5.10 (d, J = 2.3 Hz, 1H), 4.20−3.98 (m,
1H), 3.57 (ddd, J = 9.6, 2.6, 2.1 Hz, 1H), 2.93 (ddd, J = 18.2 (gem),
9.6, 1.9 Hz, 1H), 2.88−2.75 (m, 1H), 1.21 (dd, J = 6.8, 2.0 Hz, 3H),
0.85 (dd, J = 6.9, 1.9 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.7,
140.7, 136.6, 134.5, 129.6, 129.2, 128.8, 128.7, 125.9, 64.5, 60.1, 45.5,
31.2, 20.8, 19.5; IR (thin film) 1693 (CO), 1145 (SO) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H21NO3SNa
366.1140, found 366.1147.
trans-1-Allyl-5-phenyl-4-(phenylsulfonyl)pyrrolidin-2-one (10j).
General procedure A was used with sulfone anhydride 3a (0.30 g,
1.26 mmol), allylamine (93 μL, 1.24 mmol), and benzaldehyde (128
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Article
1H), 7.68−7.52 (m, 2H), 6.39 (d, J = 2.3 Hz, 1H), 6.22 (s, 2H), 5.38
(s, 1H), 3.74 (s, 6H), 3.66−3.59 (m, 1H), 3.55 (d, J = 18.4 (gem) Hz,
1H), 3.26 (m, 3H), 3.14 (d, J = 18.5 (gem) Hz, 1H), 2.58 (ddd, J =
13.8, 8.7, 5.2 Hz, 1H), 1.65−1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 169.9, 164.7, 160.9, 137.3, 135.3,
134.9, 130.4, 129.2, 100.8, 76.7, 64.3, 55.4, 52.8, 43.2, 35.8, 20.2 (2C),
11.3; IR (thin film) 1748, 1702 (CO), 1144, 1457 (SO) cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H27NO7SNa
484.1406, found 484.1404.
tert-Butyl 2-(Phenylsulfonyl)acetate (8). To a 500 mL round-
bottom flask were added benzenesulfinic acid sodium salt (5.1 g, 30.8
mmol), tert-butyl bromoacetate (3.8 mL, 25.6 mmol), and 170 mL of
ethanol. The reaction mixture was refluxed for 4 h and then
concentrated in vacuo. The crude mixture was suspended in Et2O
(150 mL) and washed with water (2 × 150 mL) and brine (150 mL).
The organic layer was dried over sodium sulfate and concentrated in
1
vacuo to yield 8 (6.31 g, 96%) as a clear oil. H NMR (300 MHz,
CDCl3) δ 7.90 (m, 2H), 7.68 (m, 1H), 7.55 (m, 2H), 4.03 (s, 2H),
1.33 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 161.2, 138.8, 134.1,
129.1, 128.5, 83.6, 62.0, 27.6. These data are in accordance with the
literature.31
Methyl trans-1-Methyl-5-oxo-2-phenyl-3-(phenylsulfonyl)-
pyrrolidine-3-carboxylate (11c). N-Benzylidenemethylamine (0.1
mL, 0.81 mmol) was added to a round-bottom flask containing
Na2SO4 (0.57 g, 4.0 mmol) and THF (8 mL), and then sulfone
anhydride 3a (0.19 g, 0.80 mmol) was added. The reaction mixture
was allowed to stir for 1.5 h, after which the Na2SO4 was removed by
filtration and the solvent removed in vacuo. The residue was
redissolved in EtOAc, transferred to a separatory funnel, and washed
with HCl (1.2 M or 10%) and brine. The combined organic layers
were dried over Na2SO4, and the solvent was removed in vacuo. The
crude acid was redissolved in a mixture of toluene and methanol (13
mL:7 mL) and cooled to 0 °C. To the cold solution, TMSCHN2 (0.81
mL, 1.6 mmol, 2 M solution in hexanes) was added dropwise over a
period of 5 min, and the reaction was monitored by TLC for the
disappearance of starting material. After ∼2 h the solvent was removed
in vacuo, and the resulting material was purified by column
chromatography (30−60% EtOAc:hex) to yield 11c (0.20 g, 67%
over the two steps) as an amorphous solid (50:50 EtOAc/hex, Rf =
Di-tert-butyl 2-(Phenylsulfonyl)pentanedioate (3ba). To a
dry 250 mL round-bottom flask were added 8 (6.31 g, 24.6 mmol),
cesium carbonate (400 mg, 1.23 mmol), tert-butyl acrylate (3.6 mL,
24.6 mmol), and 80 mL of acetonitrile. The reaction mixture was
heated to 50 °C overnight and then diluted with water and extracted
with ethyl acetate (3 × 100 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The crude product was
purified on silica gel (20:80 EtOAc/hex) to yield 3ba (4.91 g, 52%) as
1
an amorphous solid. H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 7.3
Hz, 2H), 7.68 (m, 1H), 7.57 (dd, J = 8.4, 6.9 Hz, 2H), 3.99 (m, 1H),
2.24 (m, 4H), 1.42 (s, 9H), 1.35 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 170.9, 164.4, 137.4, 134.1, 129.4, 129.0, 83.5, 81.0, 70.1, 32.1, 28.0,
27.7, 22.3; IR (thin film) 2979, 1730, 1309, 1138 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H28O6SNa 407.1504, found
407.1502.
Di-tert-butyl 3-Methyl-2-(phenylsulfonyl)pentanedioate
(3ca). To a dry 250 mL round-bottom flask were added 8 (3.00 g,
11.7 mmol), cesium carbonate (382 mg, 1.17 mmol), tert-butyl
crotonate (1.90 mL, 11.7 mmol), and 40 mL of acetonitrile. The
reaction mixture was heated to reflux overnight and then diluted with
water and extracted with ethyl acetate (3 × 100 mL). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified on silica gel (20:80 EtOAc/hex) to yield
3ca (3.75 g, 80%) as an amorphous solid (mixture of diastereomers).
NMR data for one diastereomer: 1H NMR (600 MHz, CDCl3) δ 7.90
(m, 3H), 7.64 (m, 2H), 7.53 (m, 3H), 4.10 (d, J = 8.0 Hz, 1H), 2.71
(m, 2H), 2.43 (m, 1H), 1.42 (s, 16H, overlap with minor
diastereomer), 1.27 (s, 14H, overlap with minor diastereomer), 1.12
(d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.7, 164.4,
138.4, 134.0, 129.2, 128.9, 83.3, 80.8, 73.7, 39.9, 29.6, 28.1, 27.6, 17.1;
IR (thin film) 2980, 1729, 1325, 1135 cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C20H30O6SNa 421.1661, found 421.1653.
Di-tert-butyl 2-Methyl-4-(phenylsulfonyl)pentanedioate
(3da). To a dry 250 mL round-bottom flask were added 8 (3.00 g,
11.7 mmol), cesium carbonate (382 mg, 1.17 mmol), tert-butyl
methacrylate (1.90 mL, 11.7 mmol), and 40 mL of acetonitrile. The
reaction mixture was heated to reflux for 48 h and then diluted with
water and extracted with ethyl acetate (3 × 100 mL). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified on silica gel (20:80 EtOAc/hex) to yield
3da (4.20 g, 90%) as an amorphous solid (mixture of diastereomers).
NMR data for one diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.89
(m, 2H), 7.69 (m, 1H), 7.58 (m, 2H), 4.03 (dd, J = 11.9, 3.3 Hz, 1H),
2.28 (m, 2H), 1.99 (m, 1H), 1.43 (s, 9H), 1.37 (s, 9H), 1.16 (d, J = 6.6
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 174.2, 164.7, 137.6, 134.3,
129.5, 129.2, 83.6, 81.1, 69.6, 38.2, 30.6, 28.2, 27.8, 18.4; IR (thin film)
2978, 2936, 1727, 1325, 1138 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C20H30O6SNa 421.1661, found 421.1662.
1
0.28). H NMR (400 MHz, CDCl3) δ 7.88 (dt, J = 8.6, 2.2 Hz, 2H),
7.72−7.63 (m, 1H), 7.64−7.50 (m, 2H), 7.36−7.23 (m, 4H), 7.05 (d, J
= 7.2 Hz, 2H), 5.31 (s, 1H), 3.49 (d, J = 18.4 (gem) Hz, 1H), 3.15 (d,
J = 2.3 Hz, 3H), 3.01 (d, J = 18.5 (gem) Hz, 1H), 2.58 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 169.75, 164.51, 135.32, 135.1, 134.3,
130.2, 129.4, 129.3, 128.7, 127.6, 76.7, 66.5, 52.9, 35.5, 28.3; IR (thin
film) 1736, 1690 (CO), 1177, 1360 (SO) cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H19NO5SNa 396.0882, found
396.0887.
Methyl trans-1-Benzyl-5-oxo-2-phenylpyrrolidine-3-carbox-
ylate (12a). Ester 11a (0.104 g, 0.23 mmol) was dissolved in
anhydrous MeOH (12 mL), and magnesium turnings (169 mg, 6.9
mmol, flame-dried under argon) were added to the reaction mixture.
The mixture was heated to 50 °C for 15 min and then to 64 °C for 1.5
h, cooled to rt, poured into an Erlenmeyer flask containing 10% HCl
(20 mL), and extracted with diethyl ether. The organic layer was dried
over Na2SO4, and the solvent was removed in vacuo. Purification by
flash chromatography (30−50% EtOAc/hex) yielded 12a as an oil
1
(0.54 g, 76%). H NMR data for the major diastereomer (600 MHz,
CDCl3): δ 7.41−7.33 (m, 4H), 7.30−7.23 (m, 3H), 7.18−7.13 (m,
1H), 7.05−7.01 (m, 2H), 5.11 (d, J = 14.7 Hz, 1H), 4.63−4.56 (d, J =
5.4 Hz, 1H), 3.64 (s, 3H), 3.48 (d, J = 14.9 Hz, 1H), 3.07 (m, 1H),
1
2.94−2.75 (m, 2H). The H NMR data are in accordance with the
literature.6
Methyl trans-2-(3,5-Dimethoxyphenyl)-5-oxo-1-propylpyr-
rolidine-3-carboxylate (12b). Ester 11b (75.4 mg, 0.163 mmol)
was dissolved in anhydrous MeOH (12 mL), and magnesium turnings
(162 mg, 6.67 mmol, flame-dried under argon) were added to the
reaction mixture. The mixture was heated to 50 °C for 15 min and
then to 64 °C for 1.5 h, cooled to rt, poured into an Erlenmeyer flask
containing 10% HCl (30 mL), and extracted with diethyl ether. The
organic layer was dried over Na2SO4, and the solvent was removed in
vacuo. Purification by flash chromatography (30−50% EtOAc/hex)
3-(Phenylsulfonyl)dihydro-2H-pyran-2,6(3H)-dione (3b). To
a dry 250 mL flask were added 3ba (4.91 g, 12.7 mmol), CH2Cl2 (50
mL), and trifluoroacetic acid (50 mL). The reaction mixture was
stirred for 1 h and then concentrated in vacuo and azeotropically
distilled with CH2Cl2 (3 × 10 mL). The crude mixture was taken up in
45 mL of trifluoroacetic anhydride and stirred overnight. The reaction
mixture was concentrated in vacuo and azeotroped with toluene (3 ×
10 mL). Filtering the off-white solid with diethyl ether yielded 3b
1
yielded 12b as an oil (0.35 g, 67%). H NMR (400 MHz, CDCl3) δ
6.42 (t, J = 2.2 Hz, 1H), 6.35 (d, J = 2.3 Hz, 2H), 4.83 (d, J = 5.3 Hz,
1H), 3.79 (s, 6H), 3.74 (s, 3H), 3.66 (dt, J = 13.6, 8.1 Hz, 1H), 3.04
(ddd, J = 9.6, 7.0, 5.2 Hz, 1H), 2.84 (dd, J = 17.2, 9.8 Hz, 1H), 2.76 (d,
J = 7.0 Hz, 1H), 2.61 (ddd, J = 13.6, 8.3, 5.2 Hz, 1H), 1.54−1.37 (m,
2H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.1,
172.7, 161.5, 142.0, 104.5, 100.1, 64.2, 55.5, 52.6, 45.9, 42.5, 33.8, 20.2,
11.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H23NO5Na
344.1474, found 344.1465.
1
(3.01 g, 93%) as a white solid. Mp 122.2−122.8 °C; H NMR (600
MHz, CD3CN) δ 7.97 (m, 2H), 7.83 (m, 1H), 7.70 (m, 2H), 4.55 (m,
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1H), 3.06 (m, 1H), 2.87 (m, 1H), 2.50 (m, 2H); 13C NMR (150 MHz,
CD3CN) δ 165.3, 160.7, 137.3, 135.0, 129.5, 129.0, 63.4, 27.1, 17.1; IR
(thin film) 3098, 2929, 1816, 1746 1322, 1152 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C11H10O5SNa 277.0147, found
277.0145.
7.64 (m, 1H), 7.60 (m, 2H), 7.30 (m, 3H), 7.15 (m, 2H), 5.40 (s, 1H),
4.68 (m, 1H), 3.28 (m, 1H), 2.78 (m, 1H), 2.49 (ddd, J = 12.3, 11.9,
9.8 Hz, 1H), 1.92 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 7.0
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.7, 141.6, 137.5, 134.3,
129.6, 129.0, 128.6, 128.0, 126.0, 65.0, 53.8, 47.6, 28.5, 20.3, 20.1, 17.5;
IR (thin film) 2967, 2945, 1641, 1303, 1143 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C20H23NO3SNa 380.1296, found 380.1306.
trans-1-Benzyl-6-phenyl-5-(phenylsulfonyl)piperidin-2-one (13c).
General procedure C. The residue was purified by flash column
chromatography (70:30 EtOAc/hex, Rf = 0.48) to yield 13c as a foam
4-Methyl-3-(phenylsulfonyl)dihydro-2H-pyran-2,6(3H)-
dione (3c). To a dry 250 mL flask were added 3ca (3.73 g, 9.30
mmol), CH2Cl2 (50 mL), and trifluoroacetic acid (50 mL). The
reaction mixture was stirred for 1 h and then concentrated in vacuo
and azeotropically distilled with CH2Cl2 (3 × 10 mL). To the crude
mixture was added acetic anhydride (33 mL), and the mixture was
taken up in 100 mL of toluene and stirred overnight. The mixture was
concentrated in vacuo and azeotroped with benzene (3 × 10 mL).
Trituration with diethyl ether afforded 3c (2.31 g, 92%) as a solid
(mixture of diastereomers). NMR data for one diastereomer: 1H NMR
(600 MHz, CD3CN) δ 7.93 (m, 2H), 7.84 (m, 1H), 7.70 (m, 2H),
4.40 (m, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.75 (m, 1H), 1.18 (m,
3H); 13C NMR (151 MHz, CD3CN) δ 164.8, 160.4, 135.2, 129.6,
129.3, 128.9, 69.6, 33.9, 24.4, 19.4; IR (thin film) 2991, 2957, 1814,
1758, 1311, 1146 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C12H12O5SNa 291.0293, found 291.0303.
3-Methyl-5-(phenylsulfonyl)dihydro-2H-pyran-2,6(3H)-
dione (3d). To a dry 250 mL flask were added 3da (4.00 g, 10.0
mmol), CH2Cl2 (50 mL), and trifluoroacetic acid (50 mL). The
reaction mixture was stirred for 1 h and then concentrated in vacuo
and azeotropically distilled with CH2Cl2 (3 × 10 mL). To the crude
mixture were added acetic anhydride (33 mL) and 100 mL of toluene,
and the resulting mixture was stirred overnight, concentrated in vacuo,
and azeotroped with benzene (3 × 10 mL). Trituration with diethyl
ether afforded 3d (2.53 g, 94%) as a solid (mixture of diastereomers).
NMR data for one diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.90
(m, 2H), 7.74 (m, 1H), 7.62 (m, 3H, overlap with minor diasteromer),
4.22 (dd, J = 3.0, 9.0 Hz, 1H), 2.95 (ddd, J = 2.1, 6.1, 15.2 Hz, 1H),
2.76−2.58 (m, 1H), 2.13 (ddd, J = 6.2, 13.2, 15.2 Hz, 1H), 1.44 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 160.3, 137.1, 135.2,
129.8, 129.4, 64.8, 32.6, 25.5, 16.4; IR (thin film) 3066, 2970, 1803,
1755, 1310, 1154 cm−1; HRMS (ESI-TOF) m/z [M + H2O + Na]+
calcd for C12H14O6SNa 309.0409, found 309.0402.
General Procedures for the Glutaric Anhydride Mannich
Reaction. General Procedure B. To a dry 10 mL flask were added 2
mL of acetonitrile, triethyl orthoformate (0.11 mL, 0.63 mmol), amine
(0.39 mmol), and aldehyde (0.39 mmol). The reaction mixture was
stirred overnight. Anhydride 3b (0.39 mmol) in 2 mL of acetonitrile
was added, and the reaction mixture was stirred for 30 min at room
temperature and then refluxed for 4 h. The mixture was cooled to
room temperature and concentrated in vacuo. The product was
purified by flash column chromatography (conditions given for each
compound).
General Procedure C. To a dry 10 mL flask was added 4 mL of
acetonitrile, triethyl orthoformate (0.11 mL, 0.63 mmol), the prepared
imine (0.39 mmol), and anhydride 3b−d (0.39 mmol). The reaction
mixture was stirred for 30 min at room temperature and then refluxed
for 4 h. The mixture was cooled to room temperature and
concentrated in vacuo. The residue was purified by flash column
chromatography (conditions given for each compound).
1
(130 mg, 85%). H NMR (600 MHz, CDCl3) δ 7.63 (t, J = 7.4 Hz,
1H), 7.39 (m, 7H), 7.30 (m, 3H), 7.25 (t, J = 6.1 Hz, 2H), 6.79 (m,
2H), 5.76 (d, J = 14.6 Hz, 1H), 4.69 (s, 1H), 3.22 (d, J = 14.6 Hz, 1H),
3.17 (m, 1H), 3.07 (m, 1H), 2.67 (dd, J = 18.1 (gem), 6.8 Hz, 1H),
2.43 (m, 1H), 2.18 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 169.0,
138.8, 137.0, 136.1, 134.0, 129.5, 129.4, 129.3, 128.6, 128.6, 128.5,
127.7, 125.9, 63.9, 57.2, 47.6, 28.3, 16.1; IR (thin film) 3059, 2936,
1642, 1307, 1144 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C24H23NO3SNa 428.1296, found 428.1303.
trans-6-Phenyl-5-(phenylsulfonyl)-1-(prop-2-yn-1-yl)piperidin-2-
one (13d). General procedure C. The residue was purified by flash
column chromatography (60:40 EtOAc/hex, Rf = 0.40) to yield 13d as
a foam (103 mg, 75%). 1H NMR (600 MHz, CDCl3) δ 7.99 (m, 2H),
7.69 (m, 1H), 7.59 (m, 2H), 7.30 (m, 3H), 6.98 (dd, J = 7.3, 2.0 Hz,
2H), 5.40 (d, J = 2.4 Hz, 1H), 4.95 (dd, J = 17.5, 2.6 Hz, 1H), 3.38 (td,
J = 5.0, 2.5 Hz, 1H), 3.30 (dd, J = 17.5, 2.5 Hz, 1H), 2.81 (ddd, J =
17.7, 10.5, 6.9 Hz, 1H), 2.52 (ddd, J = 18.0 (gem), 6.7, 4.3 Hz, 1H),
2.28 (m, 1H), 2.12 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 168.7,
138.4, 137.3, 134.4, 129.5, 129.3, 128.9, 128.6, 126.2, 77.7, 73.1, 64.6,
57.9, 34.3, 28.3, 17.3; IR (thin film) 3303, 3055, 1650, 1267, 1148
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C20H19NO3SNa
376.0983, found 376.0977.
trans-1-Allyl-6-phenyl-5-(phenylsulfonyl)piperidin-2-one (13e).
General procedure C. The residue was purified by flash column
chromatography (60:40 EtOAc/hex, Rf = 0.40) to yield 13e as a foam
1
(124 mg, 89%). H NMR (600 MHz, CDCl3) δ 7.92 (m, 2H), 7.71
(m, 1H), 7.60 (m Hz, 2H), 7.29 (m, 3H), 6.96 (dd, J = 7.5, 1.9 Hz,
2H), 5.83 (dddd, J = 17.7, 10.5, 8.2, 4.3 Hz, 1H), 5.21 (m, 2H), 5.11
(s, 1H), 4.86 (ddd, J = 15.0, 4.3, 2.0 Hz, 1H), 3.31 (td, J = 4.7, 1.8 Hz,
1H), 3.00−2.82 (m, 2H), 2.54 (ddd, J = 18.0 (gem), 6.8, 3.7 Hz, 1H),
2.19 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 169.1, 139.1, 137.3,
134.4, 132.4, 129.5, 129.3, 128.7, 128.4, 126.0, 118.8, 64.4, 57.2, 47.9,
28.0, 17.1; IR (thin film) 3054, 2988, 1641, 1307, 1148 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C20H21NO3SNa 378.1140, found
378.1136.
trans-1,6-Diphenyl-5-(phenylsulfonyl)piperidin-2-one (13f). Gen-
eral procedure C. The residue was purified by flash column
chromatography (70:30 EtOAc/hex, Rf = 0.40) to yield 13f as a
1
foam (110 mg, 72%). H NMR (600 MHz, CDCl3) δ 7.92 (m, 2H),
7.67 (t, J = 7.5 Hz, 1H), 7.56 (m, 2H), 7.32 (m, 2H), 7.27 (m, 3H),
7.19 (m, 5H), 5.54 (s, 1H), 3.48 (m, 1H), 2.95 (m, 1H), 2.66 (dt, J =
18.1 (gem), 6.2 Hz, 1H), 2.20 (m, 2H); 13C NMR (150 MHz, CDCl3)
δ 169.8, 142.3, 139.7, 137.2, 134.4, 129.6, 129.2, 129.1, 128.6, 128.3,
127.3, 127.0, 126.2, 64.9, 62.2, 28.8, 18.2; IR (thin film) 3066, 3008,
2946, 1654, 1304, 1143 cm−1; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C23H21NO3SNa 414.1140, found 414.1131.
trans-1-Methyl-6-phenyl-5-(phenylsulfonyl)piperidin-2-one
(13a). General procedure C. The residue was purified by flash column
chromatography (70:30 EtOAc/hex, Rf = 0.40) to yield 13a as a solid
(105 mg, 80%). Mp 152.6−153.1 °C; 1H NMR (300 MHz, CDCl3) δ
7.91 (m, 2H), 7.69 (m, 1H), 7.59 (m, 2H), 7.32 (m, 3H), 7.04 (m,
2H), 5.10 (s, 1H), 3.36 (ddd, J = 5.0, 4.9, 2.3 Hz, 1H), 2.84 (s, 3H),
2.73 (m, 1H), 2.45 (ddd, J = 17.9 (gem), 6.6, 4.6 Hz, 1H), 2.08 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 169.3, 139.0, 137.3, 134.4, 129.6,
129.3, 128.6, 128.4, 126.0, 65.0, 60.7, 34.4, 27.9, 17.8; IR (thin film)
3057, 2930, 1635, 1302, 1142 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C18H19NO3SNa 352.0983, found 352.0973.
trans-6-Phenyl-5-(phenylsulfonyl)-1-propylpiperidin-2-one (13g).
General procedure C. The residue was purified by flash column
chromatography (70:30 EtOAc/hex, Rf = 0.46) to yield 13g as a foam
1
(126 mg, 91%). H NMR (600 MHz, CDCl3) δ 7.91 (m, 2H), 7.69
(m, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.31 (dd, J = 8.4, 6.6 Hz, 2H), 7.25
(m, 1H), 7.05 (d, J = 7.4 Hz, 2H), 5.22 (s, 1H), 3.95 (dtd, J = 13.6,
6.8, 3.3 Hz, 1H), 3.32 (td, J = 5.0, 2.0 Hz, 1H), 2.81 (m, 1H), 2.43 (m,
2H), 1.99 (m, 2H), 1.61 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 169.2, 139.7, 137.4, 134.3, 129.6, 129.2, 128.5,
128.3, 126.1, 64.7, 57.9, 48.0, 28.0, 20.3, 17.6, 11.3; IR (thin film)
2967, 2929, 2871, 1639, 1308, 1147 cm−1; HRMS (ESI-TOF) m/z [M
+ Na]+ calcd for C20H23NO3SNa 380.1296, found 380.1290.
trans-1-Isopropyl-6-phenyl-5-(phenylsulfonyl)piperidin-2-one
(13b). General procedure B. The residue was purified by flash column
chromatography (60:40 EtOAc/hex, Rf = 0.40) to yield 13b as a foam
trans-1-Isopropyl-5-(phenylsulfonyl)-6-((E)-styryl)piperidin-2-one
(13h). General procedure B. The residue was purified by flash column
1
(117 mg, 84%). H NMR (300 MHz, CDCl3) δ 7.92 (m, 2H), 7.74−
2607
dx.doi.org/10.1021/jo500050n | J. Org. Chem. 2014, 79, 2601−2610

The Journal of Organic Chemistry
Article
chromatography (60:40 EtOAc/hex, Rf = 0.50) to yield 13h as an
orange amorphous solid (101 mg, 68%). 1H NMR (300 MHz, CDCl3)
δ 7.93 (dd, J = 7.2, 1.6 Hz, 2H), 7.70 (m, 1H), 7.60 (dd, J = 8.2, 6.6
Hz, 2H), 7.32 (m, 5H), 6.37 (dd, J = 16.0, 1.2 Hz, 1H), 6.07 (dd, J =
15.8, 6.4 Hz, 1H), 4.94 (dt, J = 6.6, 1.6 Hz, 1H), 4.66 (m, 1H), 3.35
(td, J = 6.4, 2.0 Hz, 1H), 2.68 (dt, J = 17.2, 7.0 Hz, 1H), 2.40 (dt, J =
17.2, 7.1 Hz, 1H), 2.09 (dt, J = 14.4, 7.2 Hz, 1H), 1.99 (dt, J = 14.4,
7.2 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 169.7, 137.6, 135.4, 134.2, 132.0, 129.8,
129.6, 128.8, 128.6, 128.4, 126.5, 63.5, 51.8, 47.3, 29.1, 20.7, 20.2,
18.78; IR (thin film) 3059, 2975, 1639, 1446, 1305, 1145 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C22H25NO3SNa 406.1453, found
406.1447.
trans-6-(4-Methoxyphenyl)-5-(phenylsulfonyl)-1-propylpiperidin-
2-one (13i). General procedure B. The residue was purified by flash
column chromatography (60:40 EtOAc/hex, Rf = 0.42) to yield 13i as
a foam (96 mg, 69%). 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 8.4
Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.8 Hz, 2H), 6.97 (d, J =
8.6 Hz, 2H), 6.84 (m, 2H), 5.18 (m, 1H), 3.93 (m, 1H), 3.77 (s, 3H),
3.30 (m, 1H), 2.81 (m, 1H), 2.45 (m, 2H), 2.01 (m, 2H), 1.61 (m,
2H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 169.2,
159.5, 134.2, 131.5, 129.5, 128.6, 127.3, 114.5, 105.0, 64.9, 57.5, 55.3,
48.0, 28.1, 20.3, 17.6, 11.3; IR (thin film) 2964, 2920, 1633, 1250,
1144 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C21H25NO4SNa 410.1402, found 410.1400.
trans-6-(4-Chlorophenyl)-5-(phenylsulfonyl)-1-propylpiperidin-2-
one (13j). General procedure C. The residue was purified by flash
column chromatography (60:40 EtOAc/hex, Rf = 0.40) to yield 13j as
a foam (133 mg, 87%). 1H NMR (600 MHz, CDCl3) δ 7.89 (m, 2H),
7.69 (m, 1H), 7.59 (m, 2H), 7.28 (m, 2H), 7.01 (m, 2H), 5.21 (s, 1H),
3.92 (ddd, J = 13.6, 9.0, 7.4 Hz, 1H), 3.27 (td, J = 5.1, 2.2 Hz, 1H),
2.78 (ddd, J = 17.4, 10.1, 6.8 Hz, 1H), 2.41 (m, 2H), 1.96 (m, 2H),
1.59 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 169.2, 138.3, 137.2, 134.4, 134.2, 129.6, 129.4, 128.5, 127.5, 64.6,
57.5, 48.0, 28.1, 20.3, 17.9, 11.3; IR (thin film) 2964, 2937, 1641, 1306,
1146 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C20H22ClNO3SNa 414.0907, found 414.0921.
2.43 (dt, J = 17.5, 6.6 Hz, 1H), 2.09 (m, 2H), 1.58 (m, 1H), 1.49 (m,
1H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 169.4,
151.3, 143.0, 137.3, 134.2, 129.5, 128.5, 110.6, 108.4, 61.8, 52.9, 47.8,
28.5, 20.4, 19.0, 11.3; IR (thin film) 2965, 2933, 2875, 1647, 1503,
1306, 1148 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C18H21NO4SNa 370.1089, found 370.1076.
rel-(4R,5S,6R)-1,4-Dimethyl-6-phenyl-5-(phenylsulfonyl)piperidin-
2-one (14). General procedure C with anhydride 3c. The residue was
purified by flash column chromatography (70:30 EtOAc/hex, Rf1 =
0.35) to yield 14 as a solid (111 mg, 87%). Mp 127.4−128.1 °C; H
NMR (600 MHz, CDCl3) δ 7.99 (m, 2H), 7.74 (m, 1H), 7.65 (m,
2H), 7.35 (dd, J = 8.4, 7.1 Hz, 2H), 7.28 (m, 1H), 7.05 (d, J = 6.8 Hz,
2H), 5.21 (s, 1H), 3.45 (d, J = 6.9 Hz, 1H), 2.91 (s, 3H), 2.53 (m,
1H), 2.45 (dd, J = 15.7, 5.3 Hz, 1H), 2.11 (dd, J = 15.8, 11.6 Hz, 1H),
0.91 (d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 171.1, 139.3,
137.0, 134.5, 129.6, 129.4, 129.1, 127.9, 125.3, 73.7, 60.3, 38.1, 34.4,
29.1, 22.4; IR (thin film) 2912, 1658, 1305, 1130 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H21NO3SNa 366.1140, found
366.1145.
rel-(3S,5R,6S)-1,3-Dimethyl-5-(phenylsulfonyl)-6-(2,4,6-
trimethoxyphenyl)piperidin-2-one (15). General procedure C with
anhydride 3d. The residue was purified by flash column chromatog-
raphy (80:20 EtOAc/hex, Rf = 0.35) to yield 15 as a white solid (169
1
mg, 79%). Mp 143.7−144.3 °C; H NMR (600 MHz, CDCl3) δ 7.70
(d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H),
5.89 (s, 2H), 5.31 (d, J = 9.5 Hz, 1H), 4.22 (ddd, J = 13.4, 9.5, 3.6 Hz,
1H), 3.72 (s, 3H), 3.71 (s, 6H), 2.48 (m, 4H, NCH3 and 1 methylene
H), 2.40 (m, 1H), 1.84 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 173.1, 161.4, 158.6, 137.4, 133.4, 128.50, 128.48,
106.8, 90.6, 61.9, 55.6, 55.2, 51.9, 35.0, 31.8, 29.3, 17.1; IR (thin film)
3006, 2939, 1614, 1286, 1134 cm−1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C22H28NO6S 434.1637, found 434.1649.
Methyl trans-1-Allyl-5-oxo-3-(phenylsulfonyl)-2-((E)-styryl)-
pyrrolidine-3-carboxylate (17). Allylamine (0.29 mL, 3.8 mmol)
and trans-cinammaldehyde (0.53 mL, 4.2 mmol) were added to a
round-bottom flask containing THF (38 mL) and Na2SO4 (3.3 g, 23.0
mmol), and the mixture was allowed to stir for 1 h. The anhydride
(0.92 g, 3.8 mmol) was added, and the resulting mixture was allowed
to stir for 2 h. The Na2SO4 was filtered off, and the solvent was
evaporated in vacuo. The residue was redissolved in EtOAc and
washed with 10% HCl and brine. The organic layer was dried over
Na2SO4 and evaporated to dryness. The residue was triturated with
hexanes, transferred to a fritted funnel, and washed in portions with
hexanes five times (5 mL) and two times with a 9:1 mixture of cold
hexanes and CHCl3 (10 mL total), yielding 1.2 g of an off-white solid,
which was ∼85% pure by NMR. A portion of the resulting acid (0.885
g, 2.2 mmol) was redissolved in anhydrous toluene and methanol (60
mL:30 mL), and TMSCHN2 (2.2 mL, 4.4 mmol, 2 M in hexanes) was
added at 0 °C dropwise over a period of 5 min. The mixture was
allowed to stir for 1.5 h and monitored by TLC for disappearance of
the starting material. The solvent was removed in vacuo, and the crude
mixture was purified by flash column chromatography (EtOAc/hex
30−60%), yielding 17 (0.85 g, 92%) as an amorphous solid (50:50
EtOAc/hex, Rf = 0.44). 1H NMR (600 MHz, CDCl3) δ 7.98−7.89 (m,
2H), 7.81−7.56 (m, 3H), 7.41−7.24 (m, 5H), 6.54 (d, J = 15.8 Hz,
1H), 5.84−5.72 (m, 2H), 5.34−5.25 (m, 2H), 5.02 (d, J = 8.4 Hz,
1H), 4.40 (ddt, J = 15.3, 4.7, 1.7 Hz, 1H), 3.71−3.42 (m, 3H), 3.44−
3.27 (m, 2H), 3.13 (d, J = 18.2 (gem) Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 169.4, 165.3, 136.7, 135.8, 135.2, 135.0, 131.7, 130.6, 129.3,
128.9, 128.9, 126.8, 121.9, 119.4, 76.1, 62.0, 53.4, 43.8, 35.6. IR (thin
film) 1736, 1715, 1694 (CO), 1309, 1148 (SO) cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C23H23NO5SNa 448.1195, found
448.1195.
trans-6-(2-Ethylphenyl)-5-(phenylsulfonyl)-1-propylpiperidin-2-
one (13k). General procedure C. The residue was purified by flash
column chromatography (60:40 EtOAc/hex, Rf = 0.42) to yield 13k as
1
a foam (92 g, 61%). H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.4
Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.9 Hz, 2H), 7.24 (m,
1H), 7.17 (m, 2H), 7.05 (d, J = 7.8 Hz, 1H), 5.51 (s, 1H), 3.97 (m,
1H), 3.14 (m, 1H), 2.94 (m, 1H), 2.53 (dd, J = 18.3 (gem), 7.4 Hz,
1H), 2.42 (m, 1H), 2.34 (m, 2H), 2.07 (m, 1H), 1.98 (m, 1H), 1.69
(m, 2H), 1.14 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR
(151 MHz, CDCl3) δ 168.9, 141.1, 137.6, 136.1, 134.3, 129.63, 129.60,
128.63, 128.60, 126.5, 126.1, 62.5, 54.2, 48.2, 27.3, 24.3, 20.4, 16.3,
15.4, 11.5; IR (thin film) 3006, 2966, 1639, 1300, 1144 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C22H27NO3SNa 408.1609, found
408.1620.
trans-6-(3,5-Dimethoxyphenyl)-5-(phenylsulfonyl)-1-propylpiper-
idin-2-one (13l). General procedure B. The residue was purified by
flash column chromatography (80:20 EtOAc/hex, Rf = 0.50) to yield
13l as a foam (104 mg, 64%). 1H NMR (600 MHz, CDCl3) δ 7.92 (m,
2H), 7.69 (t, J = 7.1 Hz, 1H), 7.60 (m, 2H), 6.32 (s, 1H), 6.16 (d, J =
2.1 Hz, 2H), 5.14 (d, J = 2.1 Hz, 1H), 3.95 (ddd, J = 13.4, 9.6, 6.5 Hz,
1H), 3.72 (s, 6H), 3.34 (td, J = 4.8, 1.9 Hz, 1H), 2.79 (m, 1H), 2.46
(m, 2H), 2.03 (m, 2H), 1.63 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 169.1, 161.5, 142.3, 137.4, 134.2, 129.6,
128.6, 104.2, 99.5, 64.6, 58.0, 55.4, 48.2, 28.0, 20.3, 17.7, 11.3; IR (thin
film) 2962, 2937, 1641, 1594, 1306, 1145 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C22H27NO5SNa 440.1508, found 440.1517.
trans-6-(Furan-2-yl)-5-(phenylsulfonyl)-1-propylpiperidin-2-one
(13m). General procedure B. The residue was purified by flash column
chromatography (70:30 EtOAc/hex, Rf = 0.35) to yield 13m as a foam
Methyl trans-3-Oxo-1-(phenylsulfonyl)-2,3,5,7a-tetrahydro-
1H-pyrrolizine-1-carboxylate (18). Ester 17 (0.602 g, 1.41 mmol)
was dissolved in anhydrous benzene (114 mL), which was degassed by
bubbling with argon for approximately 5 min. Then Grubbs second-
generation catalyst (35 mg, 3 mol %) was added, and the mixture was
heated to reflux for 9 h. The solvent was evaporated in vacuo, and the
residue was redissolved in EtOAc (30 mL). Saturated NH4Cl (10 mL)
1
(101 mg, 75%). H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz,
2H), 7.65 (m, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.27 (dd, J = 1.9, 1.0 Hz,
1H), 6.24 (m, 1H), 6.10 (m, 1H), 5.16 (d, J = 2.9 Hz, 1H), 3.78 (ddd,
J = 13.6, 9.6, 6.4 Hz, 1H), 3.59 (td, J = 6.1, 3.1 Hz, 1H), 2.71 (m, 2H),
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Article
was added, and the mixture was allowed to stir for 30 min. The
mixture was transferred to a separtory funnel, and the organic layer
was washed with brine, dried over Na2SO4, and then purified (EtOAc/
hex 30−60%), yielding 18 (0.39 g, 86%) as an amorphous solid (50:50
EtOAc/hex, Rf = 0.16). 1H NMR (600 MHz, CDCl3) δ 8.02−7.93 (m,
2H), 7.74 (td, J = 7.4, 1.3 Hz, 1H), 7.61 (t, J = 7.9 Hz, 2H), 5.90 (dq, J
= 6.0, 2.1 Hz, 1H), 5.55 (dq, J = 6.2, 2.2 Hz, 1H), 5.38 (tt, J = 4.3, 1.8
Hz, 1H), 4.33 (ddt, J = 15.7, 4.2, 2.1 Hz, 1H), 3.78−3.67 (m, 2H),
3.62 (s, 3H), 3.00 (d, J = 15.7 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ 172.8, 165.7, 136.9, 134.9, 130.6, 130.3, 129.3, 129.2, 79.0, 70.1, 53.3,
50.7, 39.5; IR (thin film) 1735, 1716, 1687 (CO), 1311, 1148 (S
O) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H15NO5SNa 344.0569, found 344.0568.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra and crystallographic data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jtshaw@ucdavis.edu.
Notes
■
The authors declare no competing financial interest.
Methyl trans-3-Oxo-1-(phenylsulfonyl)hexahydro-1H-pyrro-
lizine-1-carboxylate (19). Alkene 18 (0.25 g, 0.77 mmol) was
dissolved in anhydrous MeOH (30 mL), and the reaction mixture was
degassed by bubbling with argon for 5 min. Then Pd/C (45 mg) was
added and H2 was bubbled into the reaction flask, and the mixture was
allowed to stir for 3 h (monitored by TLC). The Pd/C was filtered off
and washed with EtOAc (3 × 10 mL). The solvent was removed in
vacuo, yielding 19 (0.246 g, 99%) as an amorphous solid (50:50
ACKNOWLEDGMENTS
■
The authors thank the NIH (NIGMS P41GM089153) and
NSF (CAREER Award CHE-0846189) for supporting this
work. N.A.S. was supported by a fellowship in the Sloan MPHD
Program. M.J.D. thanks UC Davis for a Bradford Borge
Graduate Fellowship, the Corson/Dow Graduate Fellowship,
and the GAANN Fellowship. M.A.M. was supported by a
CURE internship from the UC Davis CBST. R.J.D. was
supported by NSF-REU (CHE-1004925).
1
EtOAc/hex, Rf = 0.1). H NMR (600 MHz, CDCl3) δ 7.98−7.90 (m,
2H), 7.79−7.70 (m, 1H), 7.60 (dd, J = 8.5, 7.3 Hz, 2H), 4.61 (dd, J =
9.7, 5.9 Hz, 1H), 3.72 (s, 3H), 3.62−3.49 (m, 2H), 3.17 (d, J = 17.1
Hz, 1H), 3.15−3.05 (m, 1H), 2.07−1.93 (m, 2H), 1.91 (dtd, J = 12.2,
6.0, 3.9 Hz, 1H), 1.25 (dq, J = 12.6, 9.3 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 170.6, 166.0, 134.9, 130.3, 130.2, 129.2, 75.6, 63.9,
53.4, 42.1, 39.4, 28.5, 25.8; IR (thin film) 1734, 1686 (CO), 1146
(SO) cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H17NO5SNa 346.0725, found 346.0730.
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