Gold-catalyzed oxidative cyclization of chiral homopropargyl amides: Synthesis of enantioenriched γ-lactams

Article abstract of DOI:10.1021/jo400127x

A gold-catalyzed tandem cycloisomerization/oxidation of homopropargyl amides has been developed, which provides ready access to synthetically useful chiral γ-lactams with excellent ee by combining the chiral tert-butylsulfinimine chemistry and gold cataly

Full text of DOI:10.1021/jo400127x

Article
pubs.acs.org/joc
Gold-Catalyzed Oxidative Cyclization of Chiral Homopropargyl
Amides: Synthesis of Enantioenriched γ‑Lactams
Chao Shu, Meng-Qi Liu, Shan-Shan Wang, Long Li, and Long-Wu Ye*
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, Fujian, PR China
S
* Supporting Information
ABSTRACT: A gold-catalyzed tandem cycloisomerization/
oxidation of homopropargyl amides has been developed, which
provides ready access to synthetically useful chiral γ-lactams
with excellent ee by combining the chiral tert-butylsulfinimine
chemistry and gold catalysis. The utility of this methodology
has also been demonstrated in the synthesis of biologically
active compound S-MPP and natural product (−)-bgugaine.
The use of readily available starting materials, a simple procedure, and mild reaction conditions are other significant features of
this method.
this context, we describe herein the synthesis of a variety of
chiral mutifunctionalized γ-lactams, by successful combination
of the aforementioned gold catalysis and the chiral tert-
butylsulfinimine chemistry. The utility of this strategy was then
showcased by the synthesis of biologically active compound S-
MPP and natural product (−)-bgugaine.
INTRODUCTION
■
Functionalized γ-lactams are widespread among the structures
of a large number of biologically active natural (Figure 1) and
non-natural products.1 In addition, they also serve as important
intermediates for the synthesis of some complex molecules
because of their latent reactivity and highly stereoselective
transformation.2 Therefore, numerous strategies have been
developed for their construction,3 including metal carbene
intramolecular C−H insertions,4 ring expansion of β-lactam
derivatives5 and formal [3 + 2] annulations.6 However, few
examples have been reported about the enantioselective
synthesis of γ-lactams, especially those with high efficiency,
flexibility, and good modularity.7
Homogeneous gold catalysis has proven to be a powerful
tool in organic synthesis8 and is undergoing continual
refinement specially as an effective means of preparing
heterocycles.9 Very recently, we have developed an efficient
way for the synthesis of γ-lactones from readily available
homopropargyl alcohols.10 Interestingly, mechanistic studies
revealed that this reaction presumably went through a tandem
Au-catalyzed oxycyclization followed by an acid-accelerated
oxidation sequence, which was distinctively different from the
related ruthenium-catalyzed reactions where the intermediacy
of ruthenium vinylidene was proposed. Moreover, it was found
that the conversion of chiral homopropargyl alcohols
proceeded well with retention of the stereochemistry, enabling
access to chiral γ-lactones.
RESULTS AND DISCUSSION
■
Considering that N-homopropargyl carboxamides are not
suitable substrates because of the competing gold-catalyzed
amide 6-exodig cyclization,11 the N-tosyl amide substrates were
chosen for our initial study. First, we synthesized the
homopropargylic amide 1a as the model substrate to examine
the reaction. To our delight, the reaction could work well to
1
give the desired product 2a in 75% H NMR yield (Table 1,
entry 1) under the previously optimized reaction conditions for
the lactone synthesis.10 Attempts to improve the yield of this
reaction by the screening of other gold catalysts and the use of
other acids was unsuccessful (Table 1, entries 2−13). Of note,
in the presence of 2.5 mol % gold catalyst, γ-lactam 2a could
also be formed in 68% yield (Table 1, entry 14). However,
without using any gold catalyst, no desired product 2a was
observed under the acidic reaction conditions, and PtCl2 and
AgNTf2 could not catalyze this reaction.
With the optimal reaction conditions, we then decided to
synthesize the chiral homopropargyl amide substrates 1 by
using Ellman’s tert-butylsulfinimine chemistry.12 Delightfully,
the N-homopropargylsulfonamide 1 could be prepared with
excellent enantiomeric excesses upon subsequent removal of
tert-butylsulfinyl group and tosyl protection (Scheme 2).
With chiral homopropargyl amides in hand, we then probed
the reaction scope. As shown in Table 2, all of the reactions
Inspired by these results, we envisaged that this tandem
reaction might also be applied to the preparation of various γ-
lactams from the corresponding N-homopropargyl amides
(Scheme 1). First, 5-endodig cyclization of homopropargyl
amide 1 could result in the formation of vinyl gold intermediate
A. Next, in the presence of acid, intermediate A would then be
transformed into iminium intermediate B, which may finally
undergo a m-CPBA oxidation to produce the final product 2. In
Received: January 29, 2013
Published: February 25, 2013
© 2013 American Chemical Society
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Figure 1. Some examples of natural γ-lactams.
enantioselectivities were achieved in all cases, and essentially no
epimerization was observed. This protocol constitutes a good
combination of chiral tert-butylsulfinimine chemistry with gold
catalysis.13 It is worth noting that the same oxidative cyclization
underwent smoothly using (S)-(+)-tert-butylsulfinamide-de-
rived homopropargyl amide 1a′ instead of (R)-(+)-tert-
butylsulfinamide-derived substrate 1a to give the opposite
enantioselectivity with 99% ee (Table 2, entry 14). Thus, both
enantiomers of γ-lactam 2 could be obtained easily just by the
choice of the starting chiral source.
Scheme 1. Formation of γ-Lactams through Gold-Catalyzed
Oxidative Cyclization
a
Table 1. Reaction Conditions Optimization
The reaction could also be extended to the synthesis of 5,5-
disubstituted γ-lactam 2n in serviceable yield but with low
enantioselectivity (23% ee) from the corresponding tertiary
homopropargyl amide 1n (23% ee) prepared according to the
Ellman’s Method (eq 1).12c In addition, substates 1o and 1p
b
entry
gold catalyst
acid
yield (%)
c
1
(4-CF3C6H4)3PAuNTf2
(C6F5)3PAuNTf2
Ph3PAuNTf2
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
1.0 equiv MsOH
0.5 equiv MsOH
1.3 equiv MsOH
1.0 equiv CF3CO2H
1.0 equiv HNTf2
1.0 equiv MsOH
75
2
35
44
33
53
32
37
60
56
58
59
60
6
3
4
Cy-JohnPhosAuNTf2
XPhosAuNTf2
5
6
BrettPhosAuNTf2
B3PAuNTf2
7
8
IPrAuNTf2
d
9
Au(III)
10
11
12
13
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
e
14
68
a
b
c
Reaction conditions: [1a] = 0.05 M; DCE: 1,2-dichloroethane.
1
Estimated by H NMR using dibromomethane as internal reference.
d
e
Yield of isolated 2a was 72%. Dichloro(2-picolinato)gold(III). 2.5
mol % gold catalyst was used, 10 h.
Scheme 2. Synthesis of Chiral Homopropargyl Amide
Substrates 1 Using Ellman’s Method
were also employed, leading to the corresponding γ-lactams in
47 and 50% yield, respectively (eqs 2 and 3). When aromatic
substate 1q was subjected to this tandem reaction, however,
only indole compound 2q′ was observed (eq 4).14 Attempts to
expand this chemistry to the synthesis of 6-membered lactam
took place smoothly and afforded the corresponding chiral γ-
lactams in moderate to good yields. Except for the substrate 2l
(Table 2, entry 12), which only afforded 86% ee, excellent
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Removal of the tosyl group was then examined using 2g as
the model substrate. As illustrated in Scheme 3, lactam
Table 2. Reaction Scope for the Formation of
Enantioenriched γ-Lactams
a
Scheme 3. Synthesis of S-MPP 4
compound 3 could be obtained in 70% yield by treating 2g
with Li/Naphthalene, and its specific rotation was almost
identical to those reported in the literature,15 which further
confirmed the configuration assumed by Ellman’s chemistry.12
Of note, chiral compound 3 could be easily transformed into
biologically active S-MPP 416 by N-methylation and LiAlH4
reduction in 52% yield (two steps).
With above established sequence, the total synthesis of
(−)-bgugaine (5)17 was carried out as outlined in Scheme 4.
Scheme 4. Synthesis of S-MPP 4
Starting from commercially available pentadecanal, (−)-bgu-
gaine was synthesized in eight steps in 21% overall yield. Thus,
this protocol provides a general and efficient way for the
synthesis of versatile optically active N-methyl pyrrolidine
derivatives.18
CONCLUSION
■
In conclusion, we have developed a gold-catalyzed tandem
cycloisomerization/oxidation of homopropargyl amides, leading
to the efficient formation of optically active γ-lactams in
combination with chiral tert-butylsulfinimine chemistry. To the
best of our knowledge, this is the first example for γ-lactam
synthesis from a readily accessible homopropargyl amide. As
was demonstrated in the enantioselective synthesis of bio-
logically active compound S-MPP 4 and natural product
(−)-bgugaine 5, we believe this could find great interest in the
synthesis of highly functionalized molecules and especially in
the synthesis of natural products. Further investigations on this
novel tandem gold-catalyzed cycloisomerization/oxidation
process are under way.
a
Reactions run in vials; [1] = 0.05 M; isolated yields are reported; ees
b
are determined using HPLC on a chiral stationary phase. Using (S)-
(+)-tert-butylsutfinamide-derived homopropargyl amide 1a′ as the
substrate.
EXPERIMENTAL SECTION
General Information. Ethyl acetate (ACS grade), hexanes (ACS
grade), and anhydrous 1,2-dichloroethane (ACS grade) were obtained
commercially and used without further purification. Methylene
■
were not successful, presumably because of the competing gold-
catalyzed 5-exodig cyclization, and further studies in this
direction are currently ongoing (eq 5).
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chloride, tetrahydrofuran and diethyl ether were purified according to
standard methods unless otherwise noted. Commercially available
reagents were used without further purification. Reactions were
monitored by thin layer chromatography (TLC) using silicycle
precoated silica gel plates. Flash column chromatography was
performed over silica gel (300−400 mesh). High-resolution mass
spectra were obtained using electrospray ionization using an ICR
analyzer (ESI-MS).
= 8.0 Hz), 3.50−3.41 (m, 1H), 2.35 (s, 3H), 2.28−2.19 (m, 2H), 1.95
(t, 1H, J = 3.0 Hz), 1.75−1.50 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 168.3, 143.4, 137.9, 133.9, 131.9, 129.6, 126.9, 123.1, 79.1, 71.7, 51.2,
37.1, 30.9, 25.0, 24.7, 21.4; IR (neat) 3278(bs), 2923, 2852, 2118,
1770, 1708, 1438, 1398, 1330, 1159, 721; MS (ESI, m/z) 449 (M +
K+); HRESIMS Calcd for [C22H22KN2O4S]+ (M + K+) 449.0937,
found 449.0939.
(R)-N-(7-Azidohept-1-yn-4-yl)-4-methylbenzenesulfonamide
20
1H NMR spectra were recorded in chloroform-d3. Chemical shifts
are reported in ppm with the internal TMS signal at 0.0 ppm as a
standard. The data is reported as follows: s = singlet, d = doublet, t =
triplet, m = multiplet or unresolved, brs = broad singlet, coupling
constant(s) in Hz, integration.
(1f). Pale yellow oil (0.58 g, 38%, 3 steps): [α]D = +38.5° (c = 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, 2H, J = 8.0 Hz), 7.32
(d, 2H, J = 8.0 Hz), 5.10 (d, 1H, J = 12.0 Hz), 3.39−3.32 (m, 1H),
3.20 (t, 2H, J = 4.0 Hz), 2.43 (s, 3H), 2.28−2.23 (m, 2H), 2.00 (t, 1H,
J = 3.0 Hz), 1.65−1.46 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
143.7, 137.9, 129.8, 126.9, 78.9, 71.9, 51.2, 50.8, 31.2, 30.9, 25.0, 21.5;
IR (neat) 3287(bs), 2924, 2853, 1711, 1261, 1159, 750; MS (ESI, m/
z) 329 (M + Na+); HRESIMS Calcd for [C14H18N4NaO2S]+ (M +
Na+) 329.1048, found 329.1046.
13C NMR spectra were recorded in chloroform-d3. Chemical shifts
are reported in ppm with the internal chloroform signal at 77.0 ppm as
a standard.
Compounds 1a−1n, 1p and 1r were prepared from the
corresponding sulfinyl aldimines (5.0 mmol scale) in three steps
according to the known procedures.11a
(S)-4-Methyl-N-(1-phenylbut-3-yn-1-yl)benzenesulfonamide
20
(1g). White solid (mp 129−131 °C, 0.52 g, 35%, 3 steps): [α]D
=
1
−68.2° (c = 0.50, CHCl3); H NMR (500 MHz, CDCl3) δ 7.62 (d,
2H, J = 8.5 Hz), 7.22−7.13 (m, 7H), 5.26 (d, 1H, J = 7.0 Hz), 4.52−
4.48 (m, 1H), 2.64 (dd, 2H, J = 3.0 Hz, J = 6.0 Hz), 2.38 (s, 3H), 1.97
(t, 1H, J = 3.0 Hz); 13C NMR (125 MHz, CDCl3) δ 143.3, 139.2,
137.3, 129.4, 128.4, 127.8, 127.2, 126.6, 79.1, 72.1, 55.7, 27.2, 21.4; IR
(neat) 3298(bs), 3262, 2920, 1461, 1317, 1165, 663; MS (ESI, m/z)
322 (M + Na+); HRESIMS Calcd for [C17H17NNaO2S]+ (M + Na+)
322.0878, found 322.0886.
(R)-4-Methyl-N-(undec-1-yn-4-yl)benzenesulfonamide (1a).
20
Pale yellow oil (0.82 g, 51%, 3 steps): [α]D = +44.9° (c = 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.77 (d, 2H, J = 8.0 Hz), 7.29
(d, 2H, J = 8.0 Hz), 4.80 (d, 1H, J = 9.0 Hz), 3.36−3.29 (m, 1H), 2.42
(s, 3H), 2.29−2.27 (m, 2H), 1.97 (t, 1H, J = 2.5 Hz), 1.57−1.43 (m,
2H), 1.26−1.08 (m, 10H), 0.86 (t, 3H, J = 7.5 Hz); 13C NMR (125
MHz, CDCl3) δ 143.3, 138.1, 129.6, 127.0, 79.5, 71.4, 51.7, 34.0, 31.6,
29.0, 25.5, 25.0, 22.6, 21.4, 14.0; IR (neat) 3289(bs), 2926, 2856, 1326,
1159, 1093, 669; MS (ESI, m/z) 344 (M + Na+); HRESIMS Calcd for
[C18H27NNaO2S]+ (M + Na+) 344.1660, found 344.1658.
(S)-N-(1-(4-Chlorophenyl)but-3-yn-1-yl)-4-methylbenzene-
sulfonamide (1h). White solid (mp 135−137 °C, 0.68 g, 41%, 3
20
steps): [α]D = −83.0° (c = 1.0, CHCl3); 1H NMR (500 MHz,
(S)-N-(1-Cyclohexylbut-3-yn-1-yl)-4-methylbenzenesulfona-
CDCl3) δ 7.6 (d, 2H, J = 8.5 Hz), 7.18−7.14 (m, 4H), 7.08 (d, 2H, J =
8.5 Hz), 5.61 (d, 1H, J = 7.5 Hz), 4.48 (dd, 1H, J = 7.5 Hz, J = 13.5
Hz), 2.59 (dd, 2H, J = 2.5 Hz, J = 5.5 Hz), 2.38 (s, 3H), 1.97 (t, 1H, J
= 2.5 Hz); 13C NMR (125 MHz, CDCl3) δ 143.5, 137.7, 137.1, 133.6,
129.4, 128.4, 128.0, 127.1, 78.7, 72.3, 55.2, 27.1, 21.4; IR (neat)
3283(bs), 2917, 1596, 1491, 1452, 1324, 1158, 1088, 667; MS (ESI,
m/z) 356 (M + Na+); HRESIMS Calcd for [C17H16ClNNaO2S]+ (M
+ Na+) 356.0488, found 356.0490.
mide (1b). White solid (mp 103−105 °C, 0.65 g, 43%, 3 steps):
20
1
[α]D = +46.0° (c = 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
7.77 (d, 2H, J = 8.5 Hz), 7.29 (d, 2H, J = 8.5 Hz), 4.88 (d, 1H, J = 9.5
Hz), 3.14−3.08 (m, 1H), 2.42 (s, 3H), 2.34−2.28 (m, 1H), 2.21−2.15
(m, 1H), 1.93 (t, 1H, J = 2.5 Hz), 1.81 (d, 1H, J = 12.5 Hz), 1.69 (d,
2H, J = 13.0 Hz), 1.63−1.51 (m, 3H), 1.23−1.02 (m, 3H), 0.96−0.88
(m, 1H), 0.85−0.76 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 143.2,
138.1, 129.5, 127.0, 79.6, 71.2, 56.4, 40.1, 29.4, 28.5, 26.1, 25.9, 25.8,
22.1, 21.4; IR (neat) 3289(bs), 2929, 2851, 1448, 1329, 1159, 666; MS
(ESI, m/z) 328 (M + Na+); HRESIMS Calcd for [C17H23NNaO2S]+
(M + Na+) 328.1347, found 328.1345.
(S)-N-(1-(4-Bromophenyl)but-3-yn-1-yl)-4-methylbenzene-
sulfonamide (1i). White solid (mp 155−157 °C, 0.60 g, 32%, 3
20
steps): [α]D = −84.1° (c = 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.60 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H, J = 8.5 Hz), 7.17 (d,
2H, J = 8.0 Hz), 7.02 (d, 2H, J = 8.5 Hz), 5.42 (d, 1H, J = 7.0 Hz),
4.46 (dd, 1H, J = 7.0 Hz, J = 13.0 Hz), 2.60−2.58 (m, 2H), 2.40 (s,
3H), 1.99 (t, 1H, J = 2.5 Hz); 13C NMR (125 MHz, CDCl3) δ 143.6,
138.2, 137.2, 131.5, 129.5, 128.4, 127.1, 121.8, 78.6, 72.5, 55.2, 27.1,
21.5; IR (neat) 3293(bs), 2923, 1596, 1488, 1432, 1331, 1159, 1093,
718, 663; MS (ESI, m/z) 400 (M + Na+), 402 (M + Na+); HRESIMS
Calcd for [C17H16BrNNaO2S]+ (M + Na+) 399.9983, found 399.9981.
(S)-N-(1-(2-Bromophenyl)but-3-yn-1-yl)-4-methylbenzene-
sulfonamide (1j). White solid (mp 144−145 °C, 0.55 g, 29%, 3
(R)-4-Methyl-N-(1-phenylhex-5-yn-3-yl)benzenesulfonamide
20
(1c). White solid (mp 126−127 °C, 0.80 g, 49%, 3 steps): [α]D
=
+17.0° (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.76 (d, 2H,
J = 8.5 Hz), 7.28 (d, 2H, J = 7.5 Hz), 7.23 (t, 2H, J = 7.0 Hz), 7.16 (t,
1H, J = 7.5 Hz), 7.04 (d, 2H, J = 7.0 Hz), 5.05 (d, 1H, J = 9.0 Hz),
3.42−3.35 (m, 1H), 2.63−2.57 (m, 1H), 2.52−2.46 (m, 1H), 2.41 (s,
3H), 2.28 (dd, 2H, J = 2.5 Hz, J = 5.0 Hz), 1.97 (t, 1H, J = 2.5 Hz),
1.90−1.77 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.5, 140.9,
138.0, 129.7, 128.4, 128.3, 127.1, 126.0, 79.1, 71.8, 51.3, 35.7, 31.8,
24.9, 21.5; IR (neat) 3286(bs), 2926, 1326, 1155, 1090, 666; MS (ESI,
m/z) 350 (M + Na+); HRESIMS Calcd for [C19H21NNaO2S]+ (M +
Na+) 350.1191, found 350.1189.
20
steps): [α]D = −51.3° (c = 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.65 (d, 2H, J = 8.5 Hz), 7.42 (dd, 1H, J = 1.0 Hz, J = 8.0
Hz), 7.29 (dd, 1H, J = 1.5 Hz, J = 7.5 Hz), 7.17−7.13 (m, 3H), 7.06−
7.03 (m, 1H), 5.56 (d, 1H, J = 7.5 Hz), 4.95 (dd, 1H, J = 6.0 Hz, J =
13.5 Hz), 2.71−2.66 (m, 1H), 2.59−2.54 (m, 1H), 2.35 (s, 3H), 1.98
(t, 1H, J = 6.0 Hz); 13C NMR (125 MHz, CDCl3) δ 143.4, 138.2,
136.8, 132.8, 129.4, 129.1, 128.6, 127.3, 127.2, 122.2, 78.4, 72.5, 54.6,
26.1, 21.4; IR (neat) 3283(bs), 2917, 1591, 1468, 1438, 1344, 1080,
1018, 947, 746, 770; MS (ESI, m/z) 400 (M + Na+), 402 (M + Na+);
HRESIMS Calcd for [C17H16BrNNaO2S]+ (M + Na+) 399.9983,
found 399.9983.
(R)-N-(7-(Benzyloxy)hept-1-yn-4-yl)-4-methylbenzenesulfo-
namide (1d). White solid (mp 90−92 °C, 0.83 g, 45%, 3 steps):
20
1
[α]D = +28.3° (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.73 (d, 2H, J = 8.4 Hz,), 7.37−7.26 (m, 7H), 5.00 (d, 1H, J = 8.4 Hz),
4.46 (s, 2H), 3.40−3.30 (m, 3H), 2.41 (s, 3H), 2.34−2.20 (m, 2H),
1.97 (t, 1H, J = 2.4 Hz), 1.74−1.61 (m, 2H), 1.58−1.50 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 143.3, 138.2, 137.9, 129.6, 128.4, 127.7,
127.6, 127.0, 79.5, 72.9, 71.5, 69.5, 51.7, 30.9, 25.6, 24.9, 21.5; IR
(neat) 3283(bs), 2922, 2853, 2118, 1597, 1452, 1325, 1159, 1092, 664;
MS (ESI, m/z) 394 (M
+
Na+); HRESIMS Calcd for
(S)-4-Methyl-N-(1-(p-tolyl)but-3-yn-1-yl)benzenesulfon-
[C21H25NNaO3S]+ (M + Na+) 394.1453, found 394.1453.
amide (1k). White solid (mp 131−132 °C, 0.66 g, 42%, 3 steps):
20
1
[α]D = −77.2° (c = 0.50, CHCl3); H NMR (500 MHz, CDCl3) δ
7.62 (d, 2H, J = 8.0 Hz), 7.17 (d, 2H, J = 8.0 Hz), 7.01 (dd, 4H, J = 5.5
Hz, J = 13.5 Hz), 5.35 (d, 1H, J = 7.0 Hz), 4.44 (dd, 1H, J = 7.0 Hz, J
= 13.0 Hz), 2.63−2.61 (m, 2H), 2.38 (s, 3H), 2.27 (s, 3H),1.94 (t, 1H,
J = 3.0 Hz); 13C NMR (125 MHz, CDCl3) δ 143.2, 137.5, 137.3,
136.2, 129.4, 129.0, 127.1, 126.5, 79.3, 71.9, 55.6, 27.2, 21.4, 21.0; IR
(R)-N-(7-(1,3-Dioxoisoindolin-2-yl)hept-1-yn-4-yl)-4-methyl-
benzenesulfonamide (1e). This compound was prepared from 1f
(2. 0 mmol scale) in two steps according to the literature procedures.10
Pale yellow oil (0.29 g, 36%, 2 steps): [α]D20 = +8.0° (c = 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.84−7.82 (m, 2H), 7.77−7.71 (m,
4H), 7.27 (d, 2H, J = 8.0 Hz), 5.02 (d, 1H, J = 12.0 Hz), 3.60 (t, 2H, J
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(neat) 3286(bs), 3244, 2915, 1514, 1453, 1419, 1318, 1154, 1092, 807,
667; MS (ESI, m/z) 336 (M + Na+); HRESIMS Calcd for
[C18H19NNaO2S]+ (M + Na+) 336.1034, found 336.1036.
(m, 2H), 1.32−1.10 (m, 24H), 0.88 (t, 3H, J = 7.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 143.3, 138.1, 129.6, 127.1, 79.5, 71.4, 51.7, 34.0,
31.9, 29.7, 29.6(4), 29.6(3), 29.6(1), 29.5, 29.3(9), 29.3(8), 29.1, 25.5,
25.0, 22.7, 21.5, 14.1; IR (neat) 3311(bs), 2924, 2853, 2120, 1465,
1429, 1328, 1161, 1094, 814, 666, 551; MS (ESI, m/z) 442 (M +
Na+); HRESIMS Calcd for [C25H41NNaO2S]+ (M + Na+) 442.2756,
found 442.2754.
General Procedure of the Gold-Catalyzed Oxidative Cycliza-
tion of Chiral Homopropargyl Amides. m-CPBA (85%, 91.5 mg,
0.45 mmol), MsOH (3.0 mL, 0.10 M in DCE), and (4-
CF3Ph)3PAuNTf2 (14.2 mg, 0.015 mmol) were added in this order
to a solution of the homopropargyl amide 1 (0.30 mmol) in DCE (3.0
mL) at room temperature. The reaction mixture was stirred at rt, and
the progress of the reaction was monitored by TLC. The reaction
typically took 5 h. Upon completion, the reaction was diluted with
DCM (30 mL) and washed with saturated aqueous NaHCO3 (2 × 15
mL). The resulting solution was extracted again with DCM (30 mL),
and the combined organic layers were dried with MgSO4. The mixture
was then concentrated, and the residue was purified by chromatog-
raphy on silica gel (eluent: hexanes/ethyl acetate) to afford the desired
products 2.
(R)-5-Heptyl-1-tosylpyrrolidin-2-one (2a). Pale yellow oil (75.9
mg, 75%): [α]D20 = −65.2° (c = 0.1, CHCl3); 99% ee (determined by
HPLC: Chiralcel AD-H Column, 10/90 i-PrOH/hexane, 1.0 mL/min,
200 nm; tR = 13.29 min (major), 12.46 min (minor)); 1H NMR (500
MHz, CDCl3) δ 7.95 (d, 2H, J = 8.5 Hz), 7.32 (d, 2H, J = 8.5 Hz),
4.41−4.35 (m, 1H), 2.55−2.47 (m, 1H), 2.43 (s, 3H), 2.37−2.30 (m,
1H), 2.21−2.12 (m, 1H), 1.98−1.91 (m, 1H), 1.87−1.82 (m, 1H),
1.68−1.61 (m, 1H), 1.33−1.16 (m, 10H), 0.89 (t, 3H, J = 7.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 173.5, 144.8, 136.2, 129.4, 128.3, 60.4,
34.6, 31.7, 30.8, 29.3, 29.1, 25.1, 23.6, 22.6, 21.6, 14.0; IR (neat) 2926,
2854, 1737(s), 1361, 1167, 1091, 669; MS (ESI, m/z) 360 (M + Na+);
HRESIMS Calcd for [C18H27NNaO3S]+ (M + Na+) 360.1609, found
360.1611.
(S)-N-(1-(4-Methoxyphenyl)but-3-yn-1-yl)-4-methylbenze-
nesulfonamide (1l). White solid (mp 106−108 °C, 0.59 g, 36%, 3
20
steps): [α]D = −83.6° (c = 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.62 (d, 2H, J = 8.5 Hz), 7.18 (d, 2H, J = 8.0 Hz), 7.06 (d,
4H, J = 8.5 Hz), 6.72 (d, 2H, J = 8.5 Hz), 5.26 (d, 1H, J = 7.0 Hz),
4.44 (dd, 1H, J = 6.5 Hz, J = 13.0 Hz), 3.75 (s, 3H), 2.61 (d, 2H, J =
9.0 Hz), 2.38 (s, 3H), 1.96 (t, 1H, J = 2.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 159.2, 143.2, 137.4, 131.3, 129.4, 127.8, 127.2, 113.8, 79.4,
71.9, 55.3, 55.2, 27.2, 21.4; IR (neat) 3285(bs), 2933, 2837, 1611,
1514, 1440, 1159, 830, 666; MS (ESI, m/z) 352 (M + Na+);
HRESIMS Calcd for [C18H19NNaO3S]+ (M + Na+) 352.0983, found
352.0988.
(S)-4-Methyl-N-(1-(naphthalen-1-yl)but-3-yn-1-yl)benzene-
sulfonamide (1m). White solid (mp 103−105 °C, 0.52g, 30%, 3
20
steps): [α]D = −29.0° (c = 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.85−7.79 (m, 2H), 7.69 (d, 1H, J = 8.0 Hz), 7.55 (d, 2H, J
= 8.0 Hz), 7.45−7.43 (m, 3H), 7.30 (t, 1H, J = 8.0 Hz), 7.03 (d, 2H, J
= 8.0 Hz), 5.53 (d, 1H, J = 7.5 Hz), 5.35 (dd, 1H, J = 6.5 Hz, J = 13.0
Hz), 2.88−2.75 (m, 2H), 2.30 (s, 3H), 1.96 (t, 1H, J = 2.5 Hz); 13C
NMR (125 MHz, CDCl3) δ 143.2, 137.1, 134.5, 133.7, 130.1, 129.2,
128.9, 128.4, 127.1, 126.4, 125.6, 125.0, 124.3, 122.1, 79.2, 72.3, 51.8,
26.7, 21.3; IR (neat) 3290(bs), 2923, 2121, 1598, 1425, 1332, 1159,
1090, 776, 667; MS (ESI, m/z) 372 (M + Na+); HRESIMS Calcd for
[C21H19NNaO2S]+ (M + Na+) 372.1034, found 372.1038.
(R)-N-(4-Ethyloct-1-yn-4-yl)-4-methylbenzenesulfonamide
20
(1n). Pale yellow oil (0.41 g, 27%, 3 steps): [α]D = −1.2° (c = 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.79 (d, 2H, J = 8.5 Hz), 7.27
(d, 2H, J = 7.5 Hz), 4.64 (s, 1H), 2.42 (s, 3H), 1.97 (t, 1H, J = 3.0
Hz), 1.73−1.65 (m, 1H), 1.64−1.57 (m, 2H), 1.54−1.48 (m, 1H),
1.19−1.07 (m, 4H), 0.80 (t, 3H, J = 7.0 Hz), 0.77 (t, 3H, J = 7.0 Hz);
13C NMR (125 MHz, CDCl3) δ 143.0, 140.2, 129.4, 127.1, 80.0, 71.4,
61.8, 35.5, 29.0, 27.8, 25.2, 22.8, 21.4, 13.8, 7.5; IR (neat) 3282(bs),
2956, 2933, 2871, 1456, 1320, 1158, 1094, 1001, 814, 665; MS (ESI,
m/z) 330 (M + Na+); HRESIMS Calcd for [C17H25NNaO2S]+ (M +
Na+) 330.1504, found 330.1512.
(S)-5-Heptyl-1-tosylpyrrolidin-2-one (2a′). Pale yellow oil (73.9
mg, 73%): [α]D20 = +63.2° (c = 0.1, CHCl3); 99% ee (determined by
HPLC: Chiralcel AD-H Column, 10/90 i-PrOH/hexane, 0.8 mL/min,
200 nm; tR = 14.73 min (major), 15.87 min (minor)).
(S)-5-Cyclohexyl-1-tosylpyrrolidin-2-one (2b). Pale yellow oil
(54.9 mg, 57%): [α]D20 = +5.3° (c = 0.5, CHCl3); 99% ee (determined
by HPLC: Chiralcel AD-H Column, 10/90 i-PrOH/hexane, 1.0 mL/
N-(But-3-yn-1-yl)-4-methylbenzenesulfonamide (1o). This
compound was prepared from but-3-yn-1-ol (2. 0 mmol scale) in
two steps according to the literature procedures, and the spectroscopic
data match those reported.19 Pale yellow oil (0.29 g, 65%, 2 steps): 1H
NMR (500 MHz, CDCl3) δ 7.77 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H, J =
8.0 Hz), 5.34 (t, 1H, J = 6.5 Hz), 3.09 (dd, 2H, J = 6.5 Hz, J = 13.5
Hz), 2.42 (s, 3H), 2.35−2.32 (m, 2H), 2.00 (t, 1H, J = 2.5 Hz); 13C
NMR (125 MHz, CDCl3) δ 143.4, 136.7, 129.6. 126.9. 80.3. 70.6. 41.5.
21.3. 19.6.
1
min, 200 nm; tR = 24.55 min (major), 22.12 min (minor)); H NMR
(500 MHz, CDCl3) δ 7.96 (d, 2H, J = 8.5 Hz), 7.32 (d, 2H, J = 8.0
Hz), 4.35−4.32 (m, 1H), 2.43 (s, 3H), 2.42−2.31 (m, 2H), 2.15−2.02
(m, 2H), 1.96−1.90 (m, 1H), 1.76 (d, 1H, J = 13.0 Hz), 1.71−1.63
(m, 3H), 1.37−1.25 (m, 2H), 1.15−1.01 (m, 3H), 0.88−0.80 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 173.9, 144.8, 136.0, 129.3, 128.3, 64.7,
41.6, 31.7, 29.5, 26.3, 26.1, 25.8, 25.7, 21.6, 19.7; IR (neat) 2927, 2853,
1732(s), 1358, 1170, 1093, 953; MS (ESI, m/z) 344 (M + Na+);
HRESIMS Calcd for [C17H23NNaO3S]+ (M + Na+) 344.1296, found
344.1298.
4-Methyl-N-(1-(prop-2-yn-1-yl)cyclopentyl)benzenesulfon-
1
amide (1p). Pale yellow oil (0.69 g, 50%, 3 steps): H NMR (500
MHz, CDCl3) δ 7.78 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz),
4.79 (s, 1H), 2.48 (d, 2H, J = 8.0 Hz), 2.42 (s, 3H), 2.00 (t, 1H, J = 2.5
Hz), 1.93−1.88 (m, 2H), 1.69−1.62 (m, 2H), 1.57−1.53 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 143.1, 139.8, 129.5, 127.1, 80.8, 70.9, 66.2,
37.2, 29.7, 23.0, 21.5; IR (neat) 3298, 2950, 2123, 1596, 1496, 1455,
1304, 1151, 1095, 1035, 664; MS (ESI, m/z) 300 (M + Na+);
HRESIMS Calcd for [C15H19NNaO2S]+ (M + Na+) 300.1034, found
300.1034.
(R)-5-Phenethyl-1-tosylpyrrolidin-2-one (2c). Pale yellow oil
20
(63.8 mg, 62%): [α]D = −27.0° (c = 1.0, CHCl3); 99% ee
(determined by HPLC: Chiralcel AD-H Column, 10/90 i-PrOH/
hexane, 1.0 mL/min, 200 nm; tR = 27.34 min (major), 24.43 min
1
(minor)); H NMR (500 MHz, CDCl3) δ 7.93 (d, 2H, J = 8.0 Hz),
7.30 (t, 4H, J = 7.0 Hz), 7.21 (t, 1H, J = 7.5 Hz), 7.17 (d, 2H, J = 7.0
Hz), 4.45−4.40 (m, 1H), 2.71−2.61 (m, 2H), 2.58−2.51 (m, 1H),
2.42 (s, 3H), 2.40−2.32 (m, 2H), 2.24−2.16 (m, 1H), 2.00−1.88 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 173.4, 144.9, 140.4, 136.0,
129.5, 128.5, 128.3, 128.2, 126.2, 59.9, 36.0, 31.4, 30.7, 23.6, 21.6; IR
(neat) 2923, 1734(s), 1357, 1165, 668; MS (ESI, m/z)366 (M + Na+);
HRESIMS Calcd for [C19H21NNaO3S]+ (M + Na+) 366.1140, found
366.1140.
N-(2-Ethynylphenyl)-4-methylbenzenesulfonamide (1q).
This compound was prepared from 2-ethynylaniline (2. 0 mmol
scale) according to the literature procedures, and the spectroscopic
data match those reported.20 Pale yellow oil (0.38 g, 70%): H NMR
1
(500 MHz, CDCl3) δ 7.69 (d, 2H, J = 8.5 Hz), 7.59 (d, 1H, J = 8.0
Hz), 7.34−7.19 (m, 4H), 7.01 (t, 1H, J = 8.0 Hz), 3.37 (s, 1H), 2.35
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.0, 138.4, 135.9, 132.4,
130.1, 129.6, 127.3, 124.1, 119.3, 112.7, 84.4, 78.5, 21.4.
(R)-5-(3-(Benzyloxy)propyl)-1-tosylpyrrolidin-2-one (2d).
20
(R)-4-Methyl-N-(octadec-1-yn-4-yl)benzenesulfonamide (1r).
Pale yellow oil (69.8 mg, 60%): [α]D = +65.0° (c = 1.0, CHCl3);
20
Pale yellow oil (1.51 g, 72%, 3 steps): [α]D = +34.9° (c = 0.5,
98% ee (determined by HPLC: Chiralcel AD-H Column, 10/90 i-
PrOH/hexane, 0.8 mL/min, 200 nm; tR = 36.18 min (major), 33.59
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.77 (d, 2H, J = 8.0 Hz), 7.30
(d, 2H, J = 8.0 Hz), 4.68 (d, 1H, J = 9.0 Hz), 3.36−2.30 (m, 1H), 2.43
(s, 3H), 2.28 (d, 2H, J = 7.5 Hz), 1.97 (t, 1H, J = 2.5 Hz), 1.55−1.44
1
min (minor)); H NMR (400 MHz, CDCl3) δ 7.93 (d, 2H, J = 8.4
Hz), 7.38−7.26 (m, 7H), 4.51 (s, 2H), 4.90−4.39 (m, 1H), 3.54−3.46
3296
dx.doi.org/10.1021/jo400127x | J. Org. Chem. 2013, 78, 3292−3299

The Journal of Organic Chemistry
Article
(m, 2H), 2.58−2.47 (m, 1H), 2.42 (s, 3H), 2.40−2.29 (m, 1H), 2.22−
2.14 (m, 1H), 2.12−2.02 (m, 1H), 1.88− 1.74 (m, 2H), 1.72− 1.60
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.4, 144.8, 138.4, 136.1,
129.5, 128.4, 128.3, 127.7, 127.6, 73.1, 69.7, 60.2, 31.6, 30.7, 25.6, 23.6,
21.6; IR (neat) 2924, 2854, 1730(s), 1596, 1494, 1453, 1355, 1165,
1088, 771, 667; MS (ESI, m/z) 410 (M + Na+); HRESIMS Calcd for
[C21H25NNaO4S]+ (M + Na+) 410.1402, found 410.1408.
(S)-5-(2-Bromophenyl)-1-tosylpyrrolidin-2-one (2j). White
solid (mp 163−164 °C, 89.8 mg, 76%): [α]D = −114.2° (c = 0.5,
20
CHCl3); 98% ee (determined by HPLC: Chiralcel AD-H Column, 10/
90 i-PrOH/hexane, 1.0 mL/min, 200 nm; tR = 23.01 min (major),
32.61 min (minor)); 1H NMR (500 MHz, CDCl3) δ 7.82 (d, 2H, J =
8.5 Hz), 7.59 (d, 1H, J = 9.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.24−7.16
(m, 2H), 7.10 (d, 1H, J = 9.5 Hz), 5.77 (d, 1H, J = 8.0 Hz), 2.61−2.52
(m, 2H), 2.44 (s, 3H), 2.42−2.37 (m, 1H), 2.01−1.93 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 173.8, 145.2, 139.4, 135.4, 133.5, 129.4,
128.7, 127.6, 121.7, 62.4, 30.0, 27.3, 21.6; IR (neat) 2924, 1742(s),
1595, 1468, 1442, 1360, 1320, 1280, 1169, 1112, 952, 814, 665; MS
(ESI, m/z) 416 (M + Na+), 418 (M + Na+); HRESIMS Calcd for
[C17H16BrNNaO3S]+ (M + Na+) 415.9932, found 415.9938.
(R)-2-(3-(5-Oxo-1-tosylpyrrolidin-2-yl)propyl)isoindoline-
1,3-dione (2e). Pale yellow oil (79.2 mg, 62%): [α]D20 = −32.0° (c =
0.5, CHCl3); >99% ee (determined by HPLC: Chiralcel OD-H
Column, 10/90 i-PrOH/hexane, 0.6 mL/min, 200 nm; tR =181.16 min
1
(major), 168.94 min (minor)); H NMR (400 MHz, CDCl3) δ 7.93
(d, J = 8.0 Hz, 2H), 7.87−7.83 (m, 2H), 7.75−7.70 (m, 2H), 7.32 (d, J
= 8.0 Hz, 2H), 4.42 (t, J = 8.0 Hz, 1H), 3.72 (t, J = 7.2 Hz, 2H), 2.55−
2.48 (m, 1H), 2.44 (s, 3H), 2.40−2.30 (m, 1H), 2.24−2.16 (m, 1H),
2.09−1.99 (m, 1H), 1.86−1.80 (m, 1H), 1.73−1.67 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 173.3, 168.3, 144.9, 135.9, 134.0, 132.0,
129.5, 128.4, 123.3, 59.7, 37.5, 31.9, 30.6, 24.4, 23.6, 21.7; IR (neat)
2924, 2853, 1710(s), 1357, 1219, 1088, 772; MS (ESI, m/z) 449 (M +
Na+); HRESIMS Calcd for [C22H22N2NaO5S]+ (M + Na+) 449.1147,
found 449.1149.
(S)-5-(p-Tolyl)-1-tosylpyrrolidin-2-one (2k). Pale yellow oil
20
(71.2 mg, 72%): [α]D = −42.1° (c = 0.5, CHCl3); >99% ee
(determined by HPLC: Chiralcel AD-H Column, 10/90i-PrOH/
hexane, 0.8 mL/min, 254 nm; tR = 37.31 min (major), 29.11 min
1
(minor)); H NMR (500 MHz, CDCl3) δ 7.39 (d, 2H, J = 8.5 Hz),
7.17 (d, 2H, J = 8.0 Hz), 7.09 (d, 2H, J = 8.0 Hz), 7.01 (d, 2H, J = 8.0
Hz), 5.41 (dd, 1H, J = 6.5 Hz, J = 8.5 Hz), 2.71−2.64 (m, 1H), 2.60−
2.45 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 1.98−1.92 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 173.5, 144.8, 137.8, 137.7, 135.6, 129.4,
129.1, 128.5, 126.0, 62.9, 30.6, 28.5, 21.6, 21.1; IR (neat) 2923, 2854,
1738(s), 1596, 1515, 1360, 1324, 1169, 953, 814, 669; MS (ESI, m/z)
352 (M + Na+); HRESIMS Calcd for [C18H19NNaO3S]+ (M + Na+)
352.0983, found 352.0988.
(R)-5-(3-Azidopropyl)-1-tosylpyrrolidin-2-one (2f). Pale yellow
20
oil (60.8 mg, 63%): [α]D = −51.5° (c = 0.5, CHCl3); 99% ee
(determined by HPLC: Chiralcel AD-H Column, 10/90 i-PrOH/
hexane, 1.0 mL/min, 200 nm; tR = 32.81 min (major), 35.61 min
1
(minor)); H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H), 4.41 (t, J = 8.4 Hz, 1H), 3.40−3.29 (m, 2H),
2.59−2.48 (m, 1H), 2.44 (s, 3H), 2.40−2.32 (m, 1H), 2.67−2.16 (m,
1H), 2.08−2.00 (m, 1H), 1.87−1.72 (m, 2H), 1.68−1.54 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 173.2, 145.1, 135.9, 129.5, 128.3, 59.7,
51.0, 32.1, 30.6, 24.8, 23.8, 21.6; IR (neat) 2958, 2924, 2093, 1729(s),
1596, 1461, 1356, 1260, 1086, 812, 665; MS (ESI, m/z) 345 (M +
Na+); HRESIMS Calcd for [C14H18N4NaO3S]+ (M + Na+) 345.0997,
found 345.0999.
(S)-5-(4-Methoxyphenyl)-1-tosylpyrrolidin-2-one (2l). Pale
20
yellow oil (70.5 mg, 68%): [α]D = −20.3° (c = 0.3, CHCl3); 86%
ee (determined by HPLC: Chiralcel AD-H Column, 10/90 i-PrOH/
hexane, 1.0 mL/min, 200 nm; tR = 39.82 min (major), 31.29 min
1
(minor)); H NMR (500 MHz, CDCl3) δ 7.56 (d, 2H, J = 8.5 Hz),
7.17 (d, 2H, J = 8.0 Hz), 7.05 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5
Hz), 5.40 (dd, 1H, J = 6.5 Hz, J = 8.5 Hz), 3.81 (s, 3H), 2.72−2.65 (m,
1H), 2.60−2.47 (m, 2H), 2.39 (s, 3H), 1.98−1.93 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 173.4, 159.4, 144.7, 135.6, 132.8, 129.1, 128.5,
127.4, 114.1, 62.6, 55.3, 30.7, 28.3, 21.6; IR (neat) 2923, 2852,
1739(s), 1490, 1410, 1359, 1168, 1104, 1009, 953, 667; MS (ESI, m/
z) 368 (M + Na+); HRESIMS Calcd for [C18H19NNaO4S]+ (M +
Na+) 368.0932, found 368.0930.
(S)-5-Phenyl-1-tosylpyrrolidin-2-one (2g). White solid (mp
129−130 °C, 69.0 mg, 73%): [α]D20 = −53.4° (c = 1.0, CHCl3); 99%
ee (determined by HPLC: Chiralpak IB Column, 10/90 i-PrOH/
hexane, 0.8 mL/min, 200 nm; tR = 22.16 min (major), 24.67 min
1
(minor)); H NMR (400 MHz, CDCl3) δ 7.57 (d, 2H, J = 10.5 Hz),
7.31−7.25 (m, 3H), 7.18−7.11 (m, 4H), 5.45 (dd, 1H, J = 2.0 Hz, J =
8.4 Hz), 2.75−2.51 (m, 3H), 2.39 (s, 3H), 2.01−1.94 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 173.5, 144.8, 140.6, 135.4, 129.1, 128.7,
128.5, 128.0, 126.0, 62.9, 30.6, 28.3, 21.6; IR (neat) 2923, 1738(s),
1451, 1360, 1168, 1088, 668; MS (ESI, m/z) 338 (M + Na+);
HRESIMS Calcd for [C17H17NNaO3S]+ (M + Na+) 338.0827, found
338.0827.
(S)-5-(Naphthalen-1-yl)-1-tosylpyrrolidin-2-one (2m). White
solid (mp 189−191 °C, 74.4 mg, 68%): [α]D = −166.0° (c = 0.5,
CHCl3); 99% ee (determined by HPLC: Chiralcel AD-H Column, 10/
20
90 i-PrOH/hexane, 1.0 mL/min, 200 nm; tR = 30.69 min (major),
1
40.12 min (minor)); H NMR (500 MHz, CDCl3) δ 7.94−7.78 (m,
5H), 7.59−7.52 (m, 2H), 7.29−7.25 (m, 3H), 7.13 (d, J = 7.0 Hz,
1H), 6.29 (d, J = 8.5 Hz, 1H), 2.73−2.55 (m, 2H), 2.46−2.41 (m,
4H), 2.07−2.03 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 173.9,
145.1, 135.5, 135.4, 134.1, 129.6, 129.3, 129.1, 128.8, 128.5, 126.7,
126.0, 124.9, 122.4, 60.1, 30.5, 28.0, 21.6; IR (neat) 2924, 2854,
1736(s), 1597, 1360, 1260, 1168, 1089, 773, 667; MS (ESI, m/z) 388
(M + Na+); HRESIMS Calcd for [C21H19NNaO3S]+ (M + Na+)
388.0983, found 388.0985.
(S)-5-(4-Chlorophenyl)-1-tosylpyrrolidin-2-one (2h). White
20
solid (mp 143−145 °C, 72.4 mg, 69%): [α]D = −31.8° (c = 0.5,
CHCl3); 98% ee (determined by HPLC: Chiralpak IB Column, 10/90
i-PrOH/hexane, 0.8 mL/min, 200 nm; tR = 24.74 min (major), 27.64
1
min (minor)); H NMR (500 MHz, CDCl3) δ 7.60 (d, 2H, J = 10.0
Hz), 7.30 (d, 2H, J = 5.0 Hz), 7.20 (d, 2H, J = 10.0 Hz), 7.10 (d, 2H, J
= 10.0 Hz), 5.4 (dd, 1H, J = 2.0 Hz, J = 7.5 Hz), 2.69−2.47 (m, 3H),
2.41 (s, 3H), 1.95−1.90 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
173.2, 145.1, 139.4, 135.5, 134.0, 129.2, 129.0, 128.5, 127.4, 62.3, 30.5,
28.3, 21.6; IR (neat) 2923, 1738(s), 1492, 1359, 1168, 1089, 665; MS
(ESI, m/z) 372 (M + Na+); HRESIMS Calcd for [C17H16ClNNaO3S]+
(M + Na+) 372.0437, found 372.0435.
(R)-5-Butyl-5-ethyl-1-tosylpyrrolidin-2-one (2n). Pale yellow
20
oil (54.4 mg, 56%): [α]D = −2.7° (c = 0.3, CHCl3); 23% ee
(determined by HPLC: Chiralcel AD-H Column, 5/95 i-PrOH/
hexane, 1.0 mL/min, 200 nm; tR = 21.63 min (major), 17.55 min
1
(minor)); H NMR (500 MHz, CDCl3) δ 8.00 (d, 2H, J = 8.5 Hz),
7.32 (d, 2H, J = 8.0 Hz), 2.45 (s, 3H), 2.40−2.36 (m, 2H), 2.29−2.22
(m, 1H), 2.21−2.15 (m, 1H), 2.00−1.94 (m, 2H), 1.90−1.78 (m, 2H),
1.42−1.24 (m, 4H), 0.97 (t, 3H, J = 7.5 Hz), 0.92 (t, 3H, J = 7.5 Hz);
13C NMR (125 MHz, CDCl3) δ 174.8, 144.7, 136.5, 129.2, 129.0, 74.2,
40.0, 33.0, 30.3, 28.2, 26.3, 23.0, 21.6, 14.0, 8.5; IR (neat) 2928,
1732(s), 1597, 1466, 1358, 1172, 1158, 1087, 814, 672, 562; MS (ESI,
m/z) 346 (M + Na+); HRESIMS Calcd for [C17H25NNaO3S]+ (M +
Na+) 346.1453, found 346.1452.
(S)-5-(4-Bromophenyl)-1-tosylpyrrolidin-2-one (2i). White
20
solid (mp 132−134 °C, 75.7 mg, 64%): [α]D = −16.0° (c = 0.5,
CHCl3); 98% ee (determined by HPLC: Chiralpak IB Column, 10/90
i-PrOH/hexane, 0.8 mL/min, 200 nm; tR = 27.73 min (major), 31.21
1
min (minor)); H NMR (500 MHz, CDCl3) δ 7.62 (d, 2H, J = 8.5
Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.21 (d, 2H, J = 8.5 Hz), 7.02 (d, 2H, J
= 8.5 Hz), 5.39 (dd, 1H, J = 6.0 Hz, J = 8.0 Hz), 2.68−2.47 (m, 3H),
2.42 (s, 3H), 1.95−1.90 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
173.2, 145.1, 139.9, 135.4, 131.9, 129.3, 128.5, 127.8, 122.0, 62.4, 30.5,
28.2, 21.6; IR (neat) 2923, 1736(s), 1612, 1514, 1359, 1169, 1088,
669, 607; MS (ESI, m/z) 416 (M + Na+), 418 (M + Na+); HRESIMS
Calcd for [C17H16BrNNaO3S]+ (M + Na+) 415.9932, found 415.9940.
1-Tosylpyrrolidin-2-one (2o). Pale yellow oil (33.7 mg, 47%): 1H
NMR (500 MHz, CDCl3) δ 7.93 (d, 2H, J = 8.5 Hz), 7.33 (d, 2H, J =
8.0 Hz), 3.90 (t, 2H, J = 7.0 Hz), 2.44 (s, 3H), 2.43 (t, 2H, J = 8.0 Hz),
2.12−2.02 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 173.3, 145.1,
135.2, 129.6, 128.1, 47.2, 32.2, 21.6, 18.2; IR (neat) 2918, 1728(s),
3297
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Article
1594, 1351, 1298, 1197, 1170, 1117, 961; MS (ESI, m/z) 262 (M +
Na+); HRESIMS Calcd for [C11H13NNaO3S]+ (M + Na+) 262.0514,
found 262.0514.
column chromatography (hexane/EtOAc/20% aq. ammonia: 90/10/
0.5) to afford 4 (91 mg, 91% yield as a yellow oil). This compound is
known, and the spectroscopic data match those reported:22 1H NMR
(500 MHz, CDCl3) δ 7.35−7.29 (m, 4H), 7.26−7.22 (m, 1H), 3.26−
3.22 (m, 1H), 3.03 (t, 1H, J = 8.5 Hz), 2.28 (dd, 1H, J = 9.0 Hz, J =
17.5 Hz), 2.21−2.13 (m, 4H), 2.02−1.91 (m, 1H), 1.83−1.74 (m,
1-Tosyl-1-azaspiro[4.4]nonan-2-one (2p). Pale yellow oil (44.2
1
mg, 50%): H NMR (500 MHz, CDCl3) δ 7.94 (d, 2H, J = 8.0 Hz),
7.31 (d, 2H, J = 8.0 Hz), 2.66−2.60 (m, 2H), 2.43 (s, 3H), 2.38 (t, 2H,
J = 8.0 Hz), 1.96 (t, 4H, J = 7.5 Hz), 1.78−1.72 (m, 2H), 1.67−1.60
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 174.3, 144.6, 136.8, 129.3,
128.5, 75.4, 37.6, 36.2, 30.3, 24.0, 21.6; IR (neat) 3359, 2923, 1732,
1597, 1452, 1345, 1289, 1164, 1087, 665; MS (ESI, m/z) 316 (M +
Na+); HRESIMS Calcd for [C15H19NNaO3S]+ (M + Na+) 316.0983,
found 316.0986.
2H); 13C NMR (125 MHz, CDCl3) δ 143.2, 128.4, 127.5, 127.0, 71.7,
57.1, 40.5, 35.1, 22.5; [α]D20 = −34.6° (c = 0.2, CHCl3) {lit.22 [α]D
−73.2° (c = 1.0, CH2Cl2)}.
=
20
(R)-1-Methyl-2-tetradecylpyrrolidine (5).17 Compound 5 (1.0
mmol scale) was prepared according to the same procedures as
described for the synthesis of compound 4. Pale yellow oil (157 mg,
1
56%, 3 steps): H NMR (500 MHz, CDCl3) δ 3.07−3.03 (m, 1H),
1-Tosyl-1H-indole (2q′). This compound is known, and the
spectroscopic data match those reported.21 Pale yellow oil (70.6 mg,
2.29 (s, 3H), 2.11 (dd, 1H, J = 18.0 Hz, J = 8.5 Hz), 1.97−1.88 (m,
2H), 1.80−1.71 (m, 1H), 1.69−1.62 (m, 2H), 1.46−1.38 (m, 1H),
1.33−1.17 (m, 25H), 0.88 (t, 3H, J = 7.0 Hz); 13C NMR (125 MHz,
1
87%): H NMR (500 MHz, CDCl3) δ 7.99 (d, 1H, J = 8.5 Hz), 7.75
(d, 2H, J = 8.5 Hz), 7.56 (d, 1H, J = 4.0 Hz), 7.53 (d, 1H, J = 8.5 Hz),
7.32−7.28 (m, 1H), 7.23−7.20 (m, 3H), 6.65 (dd, 1H, J = 0.5 Hz, J =
3.5 Hz), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 144.9, 135.5,
134.9, 130.8, 129.8, 126.8, 126.3, 124.5, 123.2, 121.3, 113.6, 109.0,
21.5.
CDCl3) δ 66.5, 57.4, 40.5, 33.9, 31.9, 30.8, 30.0, 29.7, 29.6(9), 29.6(8),
20
29.6(7), 29.6(6), 29.6(5), 29.6(2), 29.3, 26.7, 22.7, 21.8, 14.1; [α]D
=
−41.5° (c = 1.0, MeOH) {lit.17c [α]D29 = −42.5° (c = 1.65, MeOH)}.
(R)-5-Tetradecyl-1-tosylpyrrolidin-2-one (2r). Pale yellow oil
ASSOCIATED CONTENT
■
20
(73.1 mg, 56%): [α]D = −44.2° (c = 0.6, CHCl3); 99% ee
S
* Supporting Information
(determined by HPLC: Chiralcel AS-H Column, 10/90 i-PrOH/
hexane, 0.6 mL/min, 200 nm; tR = 12.79 min (major), 9.50 min
1H and 13C NMR spectra and HPLC chromatograms for all
described compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
(minor)); H NMR (500 MHz, CDCl3) δ 7.95 (d, 2H, J = 8.5 Hz),
7.32 (d, 2H, J = 8.0 Hz), 4.41−4.36 (m, 1H), 2.55−2.46 (m, 1H), 2.43
(s, 3H), 2.36−2.30 (m, 1H), 2.21−2.12 (m, 1H), 1.98−1.92 (m, 1H),
1.87−1.82 (m, 1H), 1.68−1.63 (m, 1H), 1.33−1.15 (m, 24H), 0.88 (t,
3H, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 173.5, 144.8, 136.2,
129.4, 128.3, 60.4, 34.6, 31.9, 30.8, 29.7, 29.6(6), 29.6(5), 29.6(3),
29.6(1), 29.5, 29.4, 29.3, 25.1, 23.6, 22.7, 21.6, 14.1; IR (neat) 2914,
2850, 1725(s), 1471, 1359, 1198, 1171, 1087, 954, 671; MS (ESI, m/
z) 458 (M + Na+); HRESIMS Calcd for [C25H41NNaO3S]+ (M +
Na+) 458.2705, found 458.2710.
AUTHOR INFORMATION
Corresponding Author
*E-mail: longwuye@xmu.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(S)-5-Phenylpyrrolidin-2-one (3). Naphthalene (1.80 g, 14.0
mmol) was dissolved in previously degassed THF (30 mL). Lithium
(0.10 g, 14.0 mmol) was added, and the mixture was sonicated for 30
min and then stirred at room temperature for 2 h in order to obtain a
0.5 M dark green Li-naphthalenide solution. N-Tosyl lactam 2g (0.45
g, 1.43 mmol) was dissolved in THF (10 mL), and the resulting
solution was cooled to −78 °C. The Li-naphthalenide was then added
dropwise until the reaction mixture stayed permanently dark green (ca.
10 mL). The mixture was stirred at −78 °C for 30 min and at room
temperature for 30 min before quenching with 1.0 M NaHCO3 (ca. 10
mL). The aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography
afforded 3 (0.16 g, 70% yield as a yellow oil). This compound is
known, and the spectroscopic data match those reported:15 1H NMR
(500 MHz, CDCl3) δ 7.38−7.34 (m, 2H), 7.31−7.28 (m, 3H), 6.56 (s,
1H), 4.75 (t, 1H, J = 7.0 Hz), 2.60−2.53 (m, 1H), 2.50−2.36 (m, 2H),
2.00−1.93 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 178.5, 142.5,
128.9, 127.8, 125.6, 58.0, 31.3, 30.2; [α]D20 = −48.5° (c = 1.0, CHCl3)
■
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21102119 and
21272191), the Natural Science Foundation of Fujian Province
of China (No. 2012J01051), NFFTBS (No. J1210014) and
PCSIRT.
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