Tfoh-catalyzed formal [3 + 2] cycloaddition of cyclopropane 1,1-diesters with nitriles

Article abstract of DOI:10.1021/jo402383a

A triflic acid-catalyzed formal [3 + 2] cycloaddition of cyclopropane 1,1-diesters with nitriles was developed. This reaction was expeditious, and the scope of the substituents in both cyclopropanes and nitriles was broad. This supplies an efficient and practical method for the synthesis of 1-pyrrolines.

Full text of DOI:10.1021/jo402383a

Note
pubs.acs.org/joc
TfOH-Catalyzed Formal [3 + 2] Cycloaddition of Cyclopropane 1,1-
Diesters with Nitriles
Bo Cui, Jun Ren, and Zhongwen Wang*
State Key Laboratory and Institute of Elemento-Organic Chemistry, Synergetic Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, 94 Weijin Road, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A triflic acid-catalyzed formal [3 + 2] cycloaddition of
cyclopropane 1,1-diesters with nitriles was developed. This reaction
was expeditious, and the scope of the substituents in both
cyclopropanes and nitriles was broad. This supplies an efficient
and practical method for the synthesis of 1-pyrrolines.
ecause cyclic skeletons broadly exist in biologically active
natural and unnatural products, developing highly efficient
under promotion of SnCl4 (2.0 equiv). Subsequently,
Srinivasan et al.8b reported a similar reaction. In the latter
two methods, the scope of the substituents in cyclopropane 1,1-
diesters is limited to aryls. We herein report a TfOH-catalyzed
[3 + 2] cycloaddition but with a more broad scope of
substituents in the constructed 1-pyrrolines.
B
strategies to construct such skeletons is important for the
synthesis of natural products, pharmaceuticals, agrochemicals,
and other functional molecules. As a kind of cyclic imines, 1-
pyrroline (3,4-dihydro-2H-pyrrole) is a core cyclic skeleton
existing in natural products and synthetic biological molecules
(Scheme 1).1,2 Additionally, 1-pyrroline is also a key
The reaction of cyclopropane 1a and nitrile 2a was
performed for our initial investigation. We found that TfOH
could efficiently promote the reaction to give the [3 + 2]
cycloadduct 3a and/or γ-lactone 4. Because the nitriles might
be protonated with TfOH, excess 2a was needed to complete
the reaction. Several Bronsted acids were screened (Table 1),
and the optimal reaction conditions were selected as 0.5 equiv
of TfOH, room temperature, 1a/2a = 1:5, and without solvent
(entry 11). Under the optimal conditions, [3 + 2] cycloadduct
3a was obtained solely within 5 min and in an excellent yield
(96%). When the reaction was performed in dichloromethane
(DCM), we found that a competing ring-opening cyclization
happened to afford γ-lactone 4 (entries 7−10).9 With the
increase of temperature, the ratio of 4 to 3a increased, and 4
was obtained quantitatively when the reaction was carried out
at room temperature. The formation of 4 might be due to the
hydrolysis of ester with contaminated water in the reaction
system followed by cyclization of the resulting carboxylic acid
(entry 13). This provides a mild and efficient method for
synthesis of γ-lactones, an important core in natural products.
Under the optimal conditions, the scope of nitriles was
investigated, and the result is summarized in Table 2. [3 + 2]
cycloadditions of 1a with various nitriles were successful. The
nitrile substrates proved to be structurally diverse. Various alkyl
nitriles (2b−f), including the tertiary one (2d), those with vinyl
groups (2e and 2f), and most of the aryl ones (2g−j), worked
well. α,β-Unsaturated nitrile 2k also gave an excellent result.
The reactions of 2-nitrobenzonitrile and 4-nitrobenzonitrile
gave γ-lactones 4 in moderate yields.
Scheme 1. Representative Natural Products Containing a 1-
Pyrroline Core
intermediate3,4 for the synthesis of pyrrole or pyrrolidine-
containing alkaloids and related biologically active molecules.
Many efforts have been made to develop new synthetic routes
for the construction of 1-pyrrolines.3,5,6
Donor−acceptor cyclopropanes have proved to be versatile
building blocks in Lewis acid (LA)-promoted formal cyclo-
additions for the construction of various cyclic skeletons.7
Although a [3 + 2] cycloaddition of cyclopropanes with nitriles
is seemingly a promising method for the efficient construction
of 1-pyrroline, only limited examples have been reported
(Scheme 2).8 Pagenkopf et al.8i reported a [3 + 2]
cycloaddition of cyclopropanol-based donor−acceptor cyclo-
propanes with nitriles, by which carbohydrate-derived 1-
pyrrolines were prepared. Trushkov et al.8a,c reported the first
[3 + 2] cycloaddition of cyclopropane 1,1-diesters with nitriles
Received: October 25, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Scheme 2. Reported Examples for Preparation of 1-Pyrrolines by [3 + 2] Cycloadditions of Cyclopropanes with Nitriles
a b c
, ,
Table 1. Optimization of the Reaction Conditions
Table 2. TfOH-Catalyzed [3 + 2] Cycloadditions of Various
a b
,
Nitriles (2b−k) with Cyclopropane 1a
a
b
c
entry
acid (equiv)
T (°C)
solvent
yield
3a/4
1
TfOH (1.0)
TFA (1.0)
25
25
25
25
25
25
−78
−40
0
99
0
3a only
c
2
3
CSA (1.0)
0
4
HCl (1.0)
0
5
H2SO4 (1.0)
PTSA (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (0.5)
TfOH (0.2)
TfOH (0.5)
0
6
0
7
DCM
DCM
DCM
DCM
31
41
37
99
96
55
98
3a only
4:1
8
a
Reaction conditions: 1.0 mmol of 1a, 5.0 mmol of 2, 0.5 mmol of
9
1:1
b
c
TfOH, 25 °C, 5 min. Isolated yields. 2.0 mmol of 2i or 2j was used.
10
11
12
25
25
25
25
4 only
3a only
3a only
4 only
monoactivated cyclopropane 1h also worked well in a nearly
quantitative yield. It should be noted that the bicyclic or
tricyclic core skeletons in 3p−r broadly exist in natural
products.10
When we performed the reaction of fused cyclopropane
ketoester 1i with 2g, two isomers (3s and 3t) were obtained
with a ratio of 1:1 (Scheme 3). The fused 8-aza-[4.3.0]nonane
and bridged 7-aza-[4.2.1]nonane compact cores in 3s and 3t are
important skeletons in natural products.1f,11 The relative
stereochemistry of 3s was determined to be cis by 2D
NOESY NMR.
An enantiopure substrate, (S)-1c, was synthesized and
subjected to subsequent [3 + 2] cycloaddition with 2a (Scheme
4). Unlike the SnCl4-promoted negative result reported by
Trushkov et al.,8a the reaction proceeded successfully, and
cycloadduct 3m was obtained in 97% yield and 73% ee. Further
treatment of 3m under the same reaction conditions for 0.5 h
did not show any loss of the ee value. The decrease of the ee
value probably arose from the partial racemization of
d
13
DCM
a
Reactions were performed by the addition of acid to a mixture of 5.0
b
mmol of 2a and 1.0 mmol of 1a (with or without solvent). Isolated
c
d
yields. Ratio of 3a/4 was determined by 1H NMR. A control
experiment was performed in the absence of acetonitrile 2a.
Benzonitrile (2g) was then selected to test the scope of the
cyclopropane 1,1-diesters (Table 3). [3 + 2] cycloadditions of
various cyclopropanes 1 with 2g were successfully carried out.
Nonsubstituted cyclopropane 1l, which was generally less
reactive, also worked well (40 °C, 2 h). Phenyl (1c), 2,2-
disubstituted (1d), and benzyl (1e) substrates all worked well.
The fused (cis-1f) and spiro (1g) cyclopropanes also gave the
desired bicyclic 7-aza-[4.3.0]nonane (3p) and 2-aza-spiro[4.5]-
decane (3q) cycloadducts, respectively, in excellent yields. The
relative stereochemistry of 3p was determined to be trans by
2D NOESY NMR. To our surprise, oxindole derivate
B
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Note
Table 3. TfOH-Catalyzed [3 + 2] Cycloadditions of Various
Cyclopropans (1b−h) with 2g
Scheme 4. [3 + 2] Cycloaddition of (S)-1c with 2a
ab
,
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1.0 mmol of 1, 5.0 mmol of 2g, 0.5 mmol of
b
c
TfOH, 25 °C, 5 min. Isolated yields. Reacted at 40 °C for 2 h.
cyclopropane 1c under the stronger acidic conditions.12 This
example was important for the potential application of the
method to natural products synthesis and for understanding the
mechanism.
Although the absolute configuration of (+)-3m was not
determined, the maintained ee value together with the
configuration reversal in the reaction of 1f to 3p suggested
an SN2 mechanism in which a Ritter nitrilium intermediate was
involved (Scheme 5). Different from the one proposed by
Trushkov et al., this mechanism is supposed to be similar to
that of the [3 + 2] cycloaddition of cyclopropane 1,1-diesters
with aldehydes suggested by Johnson et al.12
Nuclear magnetic resonance spectra were recorded in deuteriochloro-
form (CDCl3), unless otherwise indicated, at ambient temperature
1
operating at 400 MHz for H and 100 MHz for 13C. The chemical
shifts (δ) were measured in ppm and with the solvents as references
1
(for CDCl3, H: δ = 7.26 ppm and 13C δ = 77.1 ppm). Infrared
absorption spectra were recorded as a film on KBr. Melting points
were obtained on a apparatus and are uncorrected. High-resolution
mass spectra were recorded with MALDI-TOF resource. All HPLC
were performed with an AD-H column using n-hexane/isopropanol as
the mobile phase.
Cyclopropane 1,1-diester 1a,13 1b,14 1g,15 and 1i16 were known
compounds and prepared according to literature procedures. Cyclo-
propane 1,1-diester 1h was prepared from dimethyloxosulfonium
methylide and 3-(propan-2-ylidene)indolin-2-one17 according to a
reported procedure.18 Cyclopropane 1,1-diesters 1c, 1d, 1e, and 1f
were prepared from dimethyl 2-diazomalonate and the corresponding
alkene, which was catalyzed by Rh2(esp)2. (S)-1c was prepared
according to Johnson’s procedure.12
A [4 + 2] cycloaddition of 3k and ketene 5 was carried out to
exhibit the potential application of the method (Scheme 6).
The obtained compound 6 contains an indolizidine core, which
broadly exists in natural products.
In conclusion, we developed a TfOH-catalyzed formal
intermolecular [3 + 2] cycloaddition of cyclopropane 1,1-
diesters with nitriles. To the best of our knowledge, this is the
first catalytic version of [3 + 2] cycloaddition between donor−
acceptor cyclopropanes with nitriles. Features of this method
include an expeditious process, mild conditions, and a broad
scope of substituents in both of the substrates. This supplies an
efficient and practical method for the synthesis of structurally
diverse 1-pyrrolines.
General Procedure for the Cycloaddition Reaction of
Cyclopropanes with Nitriles. Cyclopropanes 1 (1 equiv, 1 mmol)
and nitrile (5 equiv, 5 mmol) were mixed, and TfOH (0.5 equiv, 45
μL, 0.5 mmol) was added at 0 °C. The reaction mixture was then
warmed to 25 °C. The reaction was monitored by TLC. After the
cyclopropane 1,1-diester was fully consumed, the reaction mixture was
filtered thought a short pad of neutral aluminum oxide and washed
with 25 mL of petroleum ether/ethyl acetate (1:1). After removal of
the solvent under pressure, the crude product was purified by flash
column chromatography to give the corresponding product.
Preparation of 2,2-Dimethylspiro[cyclopropane-1,3′-indo-
lin]-2′-one (1h). In a mixture of oxindole (10 mmol, 1.33 g) and
acetone (10 mL) were added ethanol (10 mL) and piperidine (4 mL).
The mixture was heated at 35 °C until all of the solid dissolved and
stirred at room temperature overnight. When the reaction completed,
60 mL of ethyl acetate was added. The mixture was washed with 1 M
KHSO4, water, and saturated aqueous NaCl. After being dried by
MgSO4, the solvent was removed under pressure, and the crude 3-
EXPERIMENTAL SECTION
■
General Information. All reactions were performed open to the
air. Nitriles were purchased and used without further purification.
Flash column chromatography was performed on neutral aluminum
oxide (100−300 mesh) using petroleum ether/ethyl acetate as eluting
solvents. Thin-layer chromatography (TLC) was performed on silica
gel GF254 plates and visualized by UV light (254 nm) or KMnO4.
Scheme 3. TfOH-Catalyzed [3 + 2] Cycloaddition of 1i with 2g
C
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The Journal of Organic Chemistry
Note
Scheme 6. [4 + 2] Cycloaddition of 3k with Ketene 5
(propan-2-ylidene)indolin-2-one was obtained as a yellow solid that
was used in the next step without further purification. In a mixture of
NaH (2.6 mmol, 0.104 g, 1.3 equiv) and trimethylsulfoxonium iodide
(2.2 mmol, 0.486 g, 1.1 equiv) in DMSO (3 mL) was added a solution
of 3-(propan-2-ylidene)indolin-2-one (2 mmol, 0.346 g, 1 equiv) in
DMSO (3 mL) under Ar. The mixture was stirred at room
temperature overnight. After the reaction completed, the mixture
was quenched with 3 mL of saturated aqueous NH4Cl. Ethyl acetate
(20 mL) was added, and the organic layer was separated and dried by
MgSO4. After removal of the solvent under pressure, the crude
product was purified by flash column chromatography on silica gel
(200−300 mesh, petroleum ether/ethyl acetate, 1:1). Yield: 172 mg,
20:1). Yield: 243 mg, 91%, colorless oil. 1H (400 MHz, CDCl3) δ 5.86
(ddd, J = 17.0, 10.3, 6.5 Hz, 1H), 5.13 (ddd, J = 13.2, 10.3, 1.2 Hz,
2H), 4.51 (q, J = 7.0 Hz, 1H), 3.75 (d, J = 5.7 Hz, 6H), 2.77 (dd, J =
13.0, 7.1 Hz, 1H), 2.37 (dd, J = 13.0, 7.0 Hz, 1H), 1.24 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 178.8, 170.2, 169.7, 138.4, 115.9, 71.8,
70.4, 52.9, 52.8, 43.6, 38.0, 29.9. IR (film, cm−1): 2080, 2956, 2912,
1732, 1616, 1435, 1264, 1197, 1107, 1069, 1008, 924. HRMS
(MALDI-TOF) m/z: [M + H]+ calcd for C14H22NO4, 268.1549;
found, 268.1548.
Dimethyl 2-(Pent-4-en-1-yl)-5-vinyl-4,5-dihydro-3H-pyrrole-
3,3-dicarboxylate (3e). 3e was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
92%, yellow solid. H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 7.10
1
20:1). Yield: 229 mg, 82%, colorless oil. H (400 MHz, CDCl3) δ
(dt, J = 7.6, 4.5 Hz, 1H), 6.89 (t, J = 5.8 Hz, 3H), 1.78 (d, J = 4.6 Hz,
5.92−5.72 (m, 2H), 5.17 (dd, J = 38.3, 13.8 Hz, 2H), 5.05−4.91 (m,
2H), 4.56 (d, J = 6.8 Hz, 1H), 3.76 (d, J = 2.1 Hz, 6H), 2.81 (dd, J =
13.4, 7.4 Hz, 1H), 2.54−2.44 (m, 2H), 2.28 (dd, J = 13.4, 6.9 Hz, 1H),
2.11 (q, J = 7.1 Hz, 2H), 1.84−1.73 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 169.3, 168.8, 138.5, 138.4, 116.0, 115.0, 72.6, 71.9, 53.2,
53.1, 39.7, 33.4, 31.0, 25.8. IR (film, cm−1): 2959, 2923, 2854, 1735,
1687, 1460, 1437, 1260, 1103, 1081, 1016, 797. HRMS (MALDI-
TOF) m/z: [M + H]+ calcd for C15H22NO4, 280.1549; found,
280.1549.
1H), 1.48 (d, J = 2.6 Hz, 4H), 1.33 (s, 3H).
Dimethyl 2-Methyl-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-di-
carboxylate (3a). 3a was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
10:1). Yield: 216 mg, 96%, light yellow oil. H (400 MHz, CDCl3) δ
5.85 (ddd, J = 17.2, 10.3, 6.7 Hz, 1H), 5.24−5.09 (m, 2H), 4.57−4.44
(m, 1H), 3.77 (d, J = 1.9 Hz, 6H), 2.83 (dd, J = 13.3, 7.3 Hz, 1H), 2.26
(dd, J = 13.4, 7.1 Hz, 1H), 2.19 (d, J = 2.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 169.2, 168.5, 168.1, 138.3, 116.1, 72.6, 71.7, 53.2,
39.8, 18.3. IR (film, cm−1): 2956, 2926, 1733, 1650, 1435, 1274, 1215,
1200, 1110, 1076, 924. HRMS (MALDI-TOF) m/z: [M + H]+ calcd
for C11H16NO4, 226.1079; found, 226.1077.
Dimethyl 2-Isopropyl-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-di-
carboxylate (3b). 3b was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
20:1). Yield: 220 mg, 87%, colorless oil. 1H (400 MHz, CDCl3) δ 5.86
(ddd, J = 17.1, 10.3, 6.7 Hz, 1H), 5.20 (d, J = 17.2 Hz 1H), 5.11 (dt, J
= 10.3 Hz, 1H), 4.61−4.54 (m, 1H), 3.77 (d, J = 1.3 Hz, 6H), 2.91−
2.82 (m, 1H), 2.79 (dd, J = 13.4, 7.5 Hz, 1H), 2.28 (dd, J = 13.4, 6.7
Hz, 1H), 1.18 (dd, J = 9.0, 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3)
δ 176.8, 169.6, 169.2, 138.7, 115.9, 72.7, 71.9, 53.2, 53.1, 39.6, 30.8,
22.2, 22.0. IR (film, cm−1): 2972, 2965, 2873, 1734, 1647, 1630, 1435,
1270, 1198, 914, 746. HRMS (MALDI-TOF) m/z: [M + H]+ calcd for
C13H19NO4, 254.1392; found, 254.1394.
Dimethyl 2-Butyl-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-dicar-
boxylate (3c). 3c was prepared according to the general procedure.
Purification by column chromatography on neutral aluminum oxide
(100−300 mesh, petroleum ether/ethyl acetate, 20:1). Yield: 257 mg,
96%, colorless oil. 1H (400 MHz, CDCl3) δ 5.86 (ddd, J = 17.1, 10.3,
6.7 Hz, 1H), 5.16 (dd, J = 38.4, 13.7 Hz, 2H), 4.57−4.52 (m, 1H),
3.76 (d, J = 2.0 Hz, 6H), 2.80 (dd, J = 13.3, 7.3 Hz, 1H), 2.49−2.42
(m, 2H), 2.27 (dd, J = 13.3, 6.9 Hz, 1H), 1.71−1.60 (m, 2H), 1.35
(m,2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
171.4, 169.5, 168.9, 138.6, 115.9, 72.7, 71.9, 53.2, 53.1, 39.7, 31.4, 28.8,
22.6, 14.0. IR (film, cm−1): 2957, 2873, 1735, 1648, 1435, 1271, 1200,
1172, 1116, 1066, 992, 924. HRMS (MALDI-TOF) m/z: [M + H]+
calcd for C14H22NO4, 268.1549; found, 268.1549.
Dimethyl 2-(Hex-5-en-1-yl)-5-vinyl-4,5-dihydro-3H-pyrrole-
3,3-dicarboxylate (3f). 3f was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
20:1). Yield: 231 mg, 79%, colorless oil. H (400 MHz, CDCl3) δ
5.87−5.81 (m, 2H), 5.25−5.11 (m, 2H), 5.04−4.89 (m, 2H), 4.56 (q, J
= 7.2 Hz, 1H), 3.77 (d, J = 2.0 Hz, 6H), 2.82 (dd, J = 13.4, 7.4 Hz,
1H), 2.48 (ddd, J = 9.1, 6.9, 2.2 Hz, 2H), 2.28 (dd, J = 13.3, 6.9 Hz,
1H), 2.07 (q, J = 7.1 Hz, 2H), 1.76−1.66 (m, 2H), 1.48−1.41 (m,
2H). 13C NMR (101 MHz, CDCl3) δ 169.4, 168.9, 138.9, 138.5, 116.0,
114.5, 72.7, 71.9, 53.2, 53.2, 39.8, 33.7, 31.5, 28.8, 26.1. IR (film,
cm−1): 3076, 3009, 2953, 2932, 2855, 1733, 1640, 1434, 1268, 1199,
1171, 1101, 1070, 992, 918. HRMS (MALDI-TOF) m/z: [M + H]+
calcd for C16H24NO4, 294.1705; found, 294.1703.
Dimethyl 2-Phenyl-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-di-
carboxylate (3g). 3g was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
20:1). Yield: 281 mg, 98%, colorless oil. H (400 MHz, CDCl3) δ
7.93−7.82 (m, 2H), 7.45−7.31 (m, 3H), 5.99 (ddd, J = 17.0, 10.3, 6.5
Hz, 1H), 5.31 (d, J = 17.2 Hz, 1H), 5.20 (d, J = 10.3 Hz, 1H), 4.78 (q,
J = 6.9 Hz, 1H), 3.72 (d, J = 19.1 Hz, 6H), 3.05 (dd, J = 13.0, 7.0 Hz,
1H), 2.49 (dd, J = 13.0, 7.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
170.0, 169.3, 167.6, 138.1, 133.0, 130.7, 128.8, 128.2, 116.4, 72.6, 70.3,
53.3, 53.2, 42.9. IR (film, cm−1): 3607, 3006, 2954, 2845, 1729, 1643,
1608, 1573, 1495, 1446, 1258, 1198, 1070, 1022, 993, 923, 796, 760,
692. HRMS (MALDI-TOF) m/z: [M + H]+ calcd for C16H18NO4,
288.1236; found, 228.1237.
Dimethyl 2-(p-Tolyl)-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-di-
carboxylate (3h). 3h was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
20:1). Yield: 277 mg, 92%, colorless oil. 1H (400 MHz, CDCl3) δ 7.78
(d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 5.99 (ddd, J = 17.0, 10.3,
Dimethyl 2-(tert-Butyl)-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-
dicarboxylate (3d). 3d was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
D
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The Journal of Organic Chemistry
Note
6.5 Hz, 1H), 5.30 (d, J = 17.2 Hz, 1H), 5.18 (d, J = 10.3 Hz, 1H), 4.76
(q, J = 6.9 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.03 (dd, J = 12.9, 7.0
Hz, 1H), 2.47 (dd, J = 12.9, 7.2 Hz, 1H), 2.36 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 170.1, 169.3, 167.4, 141.0, 138.3, 130.2, 129.0, 128.8,
116.3, 72.5, 70.2, 53.3, 53.1, 42.9, 21.5. IR (film, cm−1): 3083, 3007,
2953, 1733, 1608, 1565, 1513, 1434, 1292, 1266, 1199, 1068, 991, 924,
826. HRMS (MALDI-TOF) m/z: [M + H]+ calcd for C17H20NO4,
302.1390; found, 302.1390.
calcd for C20H20NO4, 338.1392; found, 338.1390. For (+)-3m, αD25
+26.6 (c 1.0, MeOH).
Dimethyl 5-Methyl-2,5-diphenyl-4,5-dihydro-3H-pyrrole-
3,3-dicarboxylate (3n). 3n was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
20:1). Yield: 305 mg, 87%, white solid, mp 153−155 °C. H (400
MHz, CDCl3) δ 7.97−7.91 (m, 2H), 7.45−7.36 (m, 5H), 7.31 (t, J =
7.6 Hz, 2H), 7.27−7.18 (m, 1H), 3.76 (s, 3H), 3.45 (s, 3H), 3.04 (d, J
= 5.7 Hz, 2H), 1.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.3,
169.6, 165.7, 147.3, 133.3, 130.6, 129.0, 128.4, 128.3, 126.8, 125.5,
71.1, 53.3, 53.0, 50.5, 29.9. IR (film, cm−1): 2961, 2920, 2851, 1736,
1609, 1518, 1440, 1260, 1093, 1022, 800, 739, 695. HRMS (MALDI-
TOF) m/z: [M + H]+ calcd for C21H22NO4, 352.1549; found,
352.1551.
Dimethyl 2-(4-Methoxyphenyl)-5-vinyl-4,5-dihydro-3H-pyr-
role-3,3-dicarboxylate (3i). 3i was prepared according to the
general procedure except 2 equiv of 2i was used instead. Purification
by column chromatography on neutral aluminum oxide (100−300
mesh, petroleum ether/ethyl acetate, 10:1). Yield: 266 mg, 84%,
1
colorless oil. H (400 MHz, CDCl3) δ 7.86 (d, J = 8.7 Hz, 2H), 6.88
(d, J = 8.8 Hz, 2H), 5.98 (ddd, J = 17.0, 10.3, 6.7 Hz, 1H), 5.31 (d, J =
17.2 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 4.75 (dd, J = 13.6, 6.7 Hz,
1H), 3.84 (s, 3H), 3.73 (d, J = 15.0 Hz, 6H), 3.04 (dd, J = 12.9, 7.0 Hz,
1H), 2.47 (dd, J = 12.9, 7.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
170.2, 169.4, 166.8, 161.6, 138.4, 130.6, 125.5, 116.2, 113.6, 72.4, 70.2,
55.4, 53.3, 53.2, 43.0. IR (film, cm−1): 1731, 1607, 1514, 1258, 913,
745. HRMS (MALDI-TOF) m/z: [M + H]+ calcd for C17H20NO5,
318.1341; found, 318.1339.
Dimethyl 2-(4-Chlorophenyl)-5-vinyl-4,5-dihydro-3H-pyr-
role-3,3-dicarboxylate (3j). 3j was prepared according to the
general procedure exept 2 equiv of 2j was used instead. Purification by
column chromatography on neutral aluminum oxide (100−300 mesh,
petroleum ether/ethyl acetate, 10:1). Yield: 260 mg, 81%, colorless oil.
1H (400 MHz, CDCl3) δ 7.83 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz,
Dimethyl 5-Benzyl-2-phenyl-4,5-dihydro-3H-pyrrole-3,3-di-
carboxylate (3o). 3o was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
20:1). Yield: 252 mg, 72%, yellow oil. H (400 MHz, CDCl3) δ 7.82
(d, J = 7.0 Hz, 2H), 7.41−7.15 (m, 8H), 4.45 (dt, J = 14.3, 7.0 Hz,
1H), 3.65 (d, J = 9.6 Hz, 6H), 3.31 (dd, J = 13.6, 5.7 Hz, 1H), 2.76
(ddd, J = 22.2, 13.4, 7.7 Hz, 2H), 2.35 (dd, J = 13.2, 7.5 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 170.13, 169.24, 166.54, 138.68, 133.05,
132.53, 130.42, 129.36, 128.99, 128.70, 128.47, 128.13, 126.42, 72.25,
70.21, 53.09, 53.06, 42.06, 41.84. IR (film, cm−1): 2958, 2918, 1850,
1735, 1639, 1263, 1090, 1021, 801, 765, 697. HRMS (MALDI-TOF)
m/z: [M + H]+ calcd for C21H22NO4, 352.1549; found, 352.1549.
Dimethyl 2-Phenyl-3a,4,5,6,7,7a-hexahydro-3H-indole-3,3-
dicarboxylate (3p). 3p was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
2H), 5.98 (ddd, J = 17.0, 10.3, 6.5 Hz, 1H), 5.31 (dt, J = 17.3, 1.4 Hz,
1H), 5.21 (dt, J = 10.4, 1.3 Hz, 1H), 4.77 (q, J = 6.9 Hz, 1H), 3.76 (s,
3H), 3.72 (s, 3H), 3.09−3.01 (m, 1H), 2.48 (dd, J = 13.0, 7.3 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 169.7, 168.9, 137.5, 130.5, 128.7,
1
116.9, 72.3, 70.2, 53.5, 53.4, 42.6. IR (film, cm−1): 3009, 2961, 1716,
1645, 1611, 1251, 1077, 933, 775. HRMS (MALDI-TOF) m/z: [M]+
calcd for C16H16ClNO4, 321.0768; found, 321.0774.
20:1). Yield: 287 mg, 91%, colorless oil. H (400 MHz, CDCl3) δ
7.76−7.68 (m, 2H), 7.45−7.32 (m, 3H), 3.80 (s, 3H), 3.64 (s, 3H),
3.44 (td, J = 11.3, 3.6 Hz, 1H), 2.61−2.46 (m, 2H), 2.06−1.98 (m,
1H), 1.93 (d, J = 12.5 Hz, 1H), 1.89−1.82 (m, 1H), 1.60−1.31 (m,
5H). 13C NMR (101 MHz, CDCl3) δ 169.6, 169.4, 167.3, 134.0, 130.3,
128.2, 128.0, 73.4, 72.1, 56.9, 53.0, 52.7, 31.9, 26.5, 26.1, 25.6. IR (film,
cm−1): 3032, 2930, 2857, 1732, 1597, 1568, 1521, 1441, 1365, 1254,
1214, 1099, 1063, 1025, 915, 799, 774, 689. HRMS (MALDI-TOF)
m/z: [M + H]+ calcd for C18H22NO4, 315.1471; found, 315.1470.
Dimethyl 2-Phenyl-1-azaspiro[4.5]dec-1-ene-3,3-dicarboxy-
late (3q). 3q was prepared according to the general procedure.
Purification by column chromatography on neutral aluminum oxide
(100−300 mesh, petroleum ether/ethyl acetate, 20:1). Yield: 309 mg,
94%, colorless oil. 1H (400 MHz, CDCl3) δ 7.83 (d, J = 6.9 Hz, 2H),
7.42−7.30 (m, 3H), 3.72 (s, 6H), 2.63 (s, 2H), 1.81 (dd, J = 16.5, 9.9
Hz, 5H), 1.55−1.36 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 170.5,
163.4, 133.5, 130.3, 128.9, 128.2, 75.6, 70.6, 53.2, 46.3, 37.9, 37.9, 25.6,
23.4. IR (film, cm−1): 2875, 1740, 1611, 1587, 1544, 1227, 1136, 1044,
915, 689. HRMS (MALDI-TOF) m/z: [M]+ calcd for C19H23NO4,
329.1627; found, 329.1633.
Dimethyl (E)-2-Styryl-5-vinyl-4,5-dihydro-3H-pyrrole-3,3-di-
carboxylate (3k). 3k was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
20:1). Yield: 275 mg, 88%, light brown oil. H (400 MHz, CDCl3) δ
7.51 (m, 3H), 7.41−7.31 (m, 3H), 6.93 (d, J = 16.3 Hz, 1H), 5.94
(ddd, J = 17.1, 10.3, 6.8 Hz, 1H), 5.37−5.26 (m, 1H), 5.19 (d, J = 10.3
Hz, 1H), 4.72 (d, J = 7.1 Hz, 1H), 3.80 (d, J = 1.4 Hz, 6H), 2.98 (dd, J
= 13.3, 7.3 Hz, 1H), 2.36 (dd, J = 13.3, 7.1 Hz, 1H).). 13C NMR (101
MHz, CDCl3) δ 169.5, 168.7, 138.3, 135.9, 129.4, 128.9, 127.8, 120.4,
116.6, 72.8, 70.6, 53.5, 53.4, 40.5. IR (film, cm−1): 3028, 3005, 2954,
2925, 1733, 1634, 1586, 1510, 1494, 1449, 1434, 1260, 1200, 1099,
1071, 1019, 992, 924, 799, 749, 699. HRMS (MALDI-TOF) m/z: [M
+ H]+ calcd for C18H20NO4, 314.1392; found, 314.1388.
Dimethyl 2-Phenyl-4,5-dihydro-3H-pyrrole-3,3-dicarboxy-
late (3l). 3l was prepared according to the general procedure at 40
°C instead of 25 °C. Purification by column chromatography on
neutral aluminum oxide (100−300 mesh, petroleum ether/ethyl
acetate, 20:1). Yield: 206 mg, 79%, colorless oil. The NMR data
coincided with the literature.19 1H NMR (400 MHz, CDCl3) δ 7.94−
7.79 (m, 2H), 7.46−7.32 (m, 3H), 4.12 (t, J = 6.7 Hz, 2H), 3.73 (s,
6H), 2.77 (t, J = 6.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 169.7,
167.6, 133.0, 130.4, 128.5, 128.2, 69.8, 59.3, 53.1, 37.2.
5′,5′-Dimethyl-2′-phenyl-4′,5′-dihydrospiro[indoline-3,3′-
pyrrol]-2-one (3r). 3r was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
1
10:1). Yield: 281 mg, 97%, white solid, mp 187−189 °C. H (400
MHz, CDCl3) δ 8.98−8.62 (br, s, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.29−
7.19 (m, 2H), 7.19−7.08 (m, 3H), 7.01 (t, J = 7.6 Hz, 1H), 6.92 (d, J =
7.8 Hz, 1H), 2.67 (d, J = 13.4 Hz, 1H), 2.24 (d, J = 13.4 Hz, 1H), 1.63
(d, J = 11.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 179.5, 140.5,
132.9, 130.6, 128.9, 128.5, 127.9, 123.9, 123.5, 110.5, 73.4, 67.5, 51.6,
31.2, 30.8. IR (film, cm−1): 2957, 2925, 2859, 1734, 1706, 1443, 1384,
1332, 1261, 1211, 1136, 1094, 1022, 913, 802, 759. HRMS (MALDI-
TOF) m/z: [M + H]+ calcd for C19H19N2O, 291.1497 found
291.1493.
Dimethyl 2,5-Diphenyl-4,5-dihydro-3H-pyrrole-3,3-dicar-
boxylate (3m). 3m was prepared according to the general procedure.
Purification by column chromatography on neutral aluminum oxide
(100−300 mesh, petroleum ether/ethyl acetate, 20:1). Yield: 306 mg,
1
91%, white solid, mp 134−136 °C. H (400 MHz, CDCl3) δ 7.91−
7.85 (m, 2H), 7.35−7.23 (m, 7H), 7.21−7.16 (m, 1H), 5.25 (dd, J =
8.5, 6.9 Hz, 1H), 3.69 (s, 3H), 3.55 (s, 3H), 3.26 (dd, J = 13.0, 6.9 Hz,
1H), 2.48 (dd, J = 13.0, 8.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
170.0, 168.9, 167.8, 142.3, 132.9, 130.7, 128.8, 128.6, 128.2, 127.4,
126.7, 73.5, 70.7, 53.3, 53.1, 45.9. IR (film, cm−1): 3060, 3028, 2953,
1732, 1607, 1573, 1519, 1494, 1447, 1434, 1292, 1268, 1172, 1070,
1027, 967, 919, 796, 757, 695. HRMS (MALDI-TOF) m/z: [M + H]+
Methyl 4-Oxo-3-phenyl-1,4,5,6,7,7a-hexahydro-3aH-isoin-
dole-3a-carboxylate (3s). 3s was prepared according to the general
procedure. Purification by column chromatography on neutral
aluminum oxide (100−300 mesh, petroleum ether/ethyl acetate,
E
dx.doi.org/10.1021/jo402383a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
10:1). Yield: 127 mg, 47%, white solid, bp 144−146 °C. H (400
MHz, CDCl3) δ 7.78−7.73 (m, 2H), 7.40−7.32 (m, 3H), 4.04 (dd, J =
16.1, 6.7 Hz, 1H), 3.77−3.68 (m, 4H), 3.41−3.34 (m, 1H), 2.72−2.62
(m, 1H), 2.30 (dt, J = 14.1, 5.9 Hz, 1H), 2.05−1.91 (m, 3H), 1.69
(ddt, J = 10.7, 7.8, 4.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 206.9,
170.1, 130.6, 128.5, 128.4, 75.5, 63.0, 53.1, 50.2, 41.0, 25.3, 23.8. IR
(film, cm−1): 2946, 2859, 1714, 1607, 1572, 1440, 1308, 1247, 1188,
1103, 1055, 1026, 913, 792, 740, 693. HRMS (MALDI-TOF) m/z:
[M]+ calcd for C16H17NO3, 271.1208; found, 271.1208.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wzwrj@nankai.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (nos. 21172109 and 21121002), MOST
(973 Project, no. 2010CB126106), and National Key
Technologies R&D Program (no. 2011BAE06B05) for financial
support.
Methyl 2-Oxo-8-phenyl-7-azabicyclo[4.2.1]non-7-ene-1-car-
boxylate (3t). 3t was prepared according to the general procedure.
Purification by column chromatography on neutral aluminum oxide
(100−300 mesh, petroleum ether/ethyl acetate, 10:1). Yield: 128 mg,
47%, colorless oil. 1H (400 MHz, CDCl3) δ 7.98−7.90 (m, 2H), 7.44−
7.32 (m, 3H), 5.01−4.94 (m, 1H), 3.67 (s, 3H), 2.80 (ddd, J = 15.7,
13.3, 2.5 Hz, 1H), 2.69 (d, J = 13.4 Hz, 1H), 2.61 (ddt, J = 15.4, 6.6,
1.3 Hz, 1H), 2.57−2.49 (m, 1H), 2.32 (dq, J = 14.2, 3.9 Hz, 1H), 1.90
(dddd, J = 14.1, 12.7, 4.1, 2.6 Hz, 1H), 1.73 (ddd, J = 13.8, 6.7, 3.5 Hz,
1H), 1.34−1.21 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 204.9,
170.7, 166.8, 132.8, 130.7, 128.8, 128.2, 74.5, 69.7, 52.6, 44.3, 41.5,
33.3, 20.1. IR (film, cm−1): 2947, 2861, 1738, 1607, 1573, 1442, 1309,
1252, 1101, 1055, 1029, 791, 695. HRMS (MALDI-TOF) m/z: [M]+
calcd for C16H17NO3, 271.1208; found, 271.1210.
Methyl 2-Oxo-5-vinyltetrahydrofuran-3-carboxylate (4). Di-
methyl 2-vinylcyclopropane-1,1-diester 1a (1 equiv, 184 mg, 1 mmol)
was dissolved in 5 mL of DCM, and TfOH (0.5 equiv, 45 μL, 0.5
mmol) was then added. The reaction mixture was stirred at 25 °C for
10 min. The solvent was evaporated, and the crude product was
purified by flash column chromatography on silica gel (200−300 mesh,
petroleum ether/ethyl acetate, 20:1) to obtain γ-lactone 4 as a pair of
unseparable diastereoisomers (1:1, 167 mg, 98%). The NMR data
coincided with the literature.20 1H NMR (400 MHz, CDCl3) δ 5.89
(dddd, J = 22.9, 16.8, 10.5, 6.3 Hz, 1H), 5.40 (ddt, J = 17.1, 7.8, 1.1
Hz, 1H), 5.30 (tt, J = 10.5, 1.0 Hz, 1H), 5.11 (qd, J = 6.6, 5.9, 1.3 Hz,
1/2H), 4.93−4.83 (m, 1H), 3.80 (d, J = 1.5 Hz, 3H), 3.71−3.57 (m,
1H), 2.79 (ddd, J = 13.2, 7.2, 5.9 Hz, 1/2H), 2.63 (ddd, J = 13.0, 9.1,
6.3 Hz, 1/2H), 2.47 (ddd, J = 13.0, 11.0, 9.4 Hz, 1/2H), 2.24 (ddd, J =
13.1, 9.2, 6.6 Hz, 1/2H).
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Et3N (84 μL, 0.6 mmol, 1.2 equiv) was added to the solution at
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petroleum ether/ethyl acetate, 20:1) to obtain compound 6 as a pair of
1
unseparable diastereoisomers (178 mg, 94%), colorless oil. H NMR
(400 MHz, CDCl3) δ 7.30−7.24 (m, 3H), 7.23−7.18 (m, 1H), 7.13−
7.08 (m, 1H), 5.78 (tdd, J = 16.6, 10.4, 6.3 Hz, 1H), 5.40 (t, J = 4.9
Hz, 1H), 5.27−5.14 (m, 2H), 4.83−4.74 (m, 1H), 3.78 (d, J = 2.5 Hz,
3H), 3.76 (s, 3H), 2.92 (ddd, J = 13.7, 8.5, 2.4 Hz, 1H), 2.56 (ddd, J =
13.6, 6.1, 3.6 Hz, 1H), 1.28 (d, 3H), 0.94 (d, 3H). 13C NMR (101
MHz, CDCl3) δ 173.5, 173.5, 169.6, 169.3, 168.8, 140.0, 139.8, 136.4,
136.3, 136.2, 136.1, 129.3, 129.2, 128.4, 128.3, 127.2, 116.5, 116.3,
106.0, 105.7, 77.5, 61.6, 58.2, 57.8, 53.6, 53.6, 53.5, 53.4, 51.3, 51.1,
42.7, 42.6, 37.4, 37.3, 25.7, 25.6, 21.0, 20.5. IR (film, cm−1): 2956,
2930, 2859, 1739, 1672, 1443, 1387, 1260, 1029, 1097, 1022, 801, 701.
HRMS (MALDI-TOF) m/z: [M]+ calcd for C22H25NO5, 383.1733;
found, 383.1735.
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* Supporting Information
Spectra (1H and 13C) of all new compounds, 2D NOESY
spectra for 3p and 3s, and HPLC method for 1c and 3m. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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dx.doi.org/10.1021/jo402383a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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