Asymmetric organocatalytic allylic substitution of Morita-Baylis-Hillman carbonates with allylamines for the synthesis of 2,5-dihydropyrroles

Article abstract of DOI:10.1021/jo2011522

(Figure presented) The asymmetric allylic substitution reaction of MBH carbonates with allylamines has been developed, which affords N-allyl-β-amino-α-methylene esters in high yields and enantioselectivities. After a subsequent ring-closure metathesis of

Full text of DOI:10.1021/jo2011522

ARTICLE
pubs.acs.org/joc
Asymmetric Organocatalytic Allylic Substitution of
MoritaÀBaylisÀHillman Carbonates with Allylamines for the
Synthesis of 2,5-Dihydropyrroles
Wangsheng Sun,† Xiaozhou Ma,† Liang Hong,*,† and Rui Wang*,†,‡
†Key Laboratory of Preclinical Study for New Drugs of Gansu Province, State Key Laboratory of Applied Organic Chemistry and
Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou, 730000 China
‡State Key Laboratory of Chiroscience, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong
S Supporting Information
b
ABSTRACT:
The asymmetric allylic substitution reaction of MBH carbonates with allylamines has been developed, which affords N-allyl-
β-amino-R-methylene esters in high yields and enantioselectivities. After a subsequent ring-closure metathesis of the products, a
series of optically active 2,5-dihydropyrroles could be obtained smoothly in high yields without any loss of enantioselectivity. Finally,
a tentative mechanism for rationalization of the reaction has been proposed.
’ INTRODUCTION
wondered whether this tactic might be extended to other
nucleophiles, such as synthetically useful allylamines. Herein,
we describe the asymmetric allylic substitution of MBH carbo-
nates with allylamines, which could efficiently afford N-allyl-
β-amino-R-methylene esters with high stereocontrol (path b,
Scheme 1).
2,5-Dihydropyrroles are a privileged structural core of bioac-
tive natural and unnatural products, which exhibit important
biological and medicinal activity (Figure 1).1À8 For this reason,
the development of methods allowing for efficient and facile
construction of 2,5-dihydropyrroles is an important goal in
modern organic chemistry that has received considerable atten-
tion over the years.9À17 Over the past decade, N-allyl-β-amino-
R-methylene esters were recognized as the key intermediates for
the preparation of 2,5-dihydropyrroles through transition metal-
catalyzed ring-closure metathesis (RCM) reactions.18À21 Con-
struction of the N-allyl-β-amino-R-methylene ester skeletons
by N-allylation of aza-BaylisÀHillman adducts has been docu-
mented in the literature (path a, Scheme 1).22À25 However, to
the best of our knowledge, there are no reports on the direct
enantioselective route to these complex molecules.
Given the importance of these valuable 2,5-dihydropyrroles
and their potential biological properties as well as the lack of
efficient asymmetric methods for the preparation of these
important agents, the development of new methodologies for
their preparation in an enantioselective fashion is of great
importance for organic and medicinal chemistry. Recently, the
metal-free organic Lewis base-catalyzed substitution of MoritaÀ
BaylisÀHillman (MBH) adducts has emerged as a powerful tool
for the construction of multifunctional products in one step.26À35
Our group has also developed some organic Lewis base-catalyzed
asymmetric transformations.36À40 With the aim of expanding our
previous studies on the asymmetric allylic substitution,39,40 we
’ RESULTS AND DISCUSSION
First, we examined the feasibility of the reaction between the
N-tosyl allylamine 1a and MBH carbonate 2a in the presence of
DABCO (20 mol %) in toluene at ambient temperature. To our
delight, the reaction proceeded smoothly to furnish the desired
product in high conversion (Table 1, entry 1). Encouraged by
this result, we examined a range of cinchona alkaloids41À47 as
enantioselective variants for their catalytic ability to promote the
substitution reaction. As outlined in Table 1, natural cinchona
alkaloid quinidine exhibited the best reactivity and enantioselec-
tivity in the model reaction and proved to be worthy of further
investigation (Table 1, entries 2À10). Subsequent screening
of the protecting group (Figure 2) on allylamines showed that
a variety of substituted arylsulfonyls can be candidates but that
p-tosyl was optimal (Table 1, entries 2 and 11À18). A survey of
solvents revealed that the reaction media had a significant effect
on the reaction (Table 1, entries 2 and 19À27). For example, the
use of an arene solvent could greatly improve both the reactivity
Received: June 7, 2011
Published: August 03, 2011
r
2011 American Chemical Society
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Figure 1. 2,5-Dihydropyrrole structural motifs.
Scheme 1. Synthetic Strategy
Table 1. Catalyst Screening and Reaction Optimizationa
entry
catalyst
DABCO
1
solvent
conversion (%)b ee (%)c
1
1a toluene
1a toluene
1a toluene
1a toluene
1a toluene
1a toluene
1a toluene
99
88
86
75
73
<5
<5
79
68
72
85
86
89
78
85
85
86
84
76
68
46
58
78
89
90
89
89
78
88
26
À
2
quinidine
quinine
80
27
67
17
n.d.
n.d.
80
81
70
78
75
76
78
79
79
70
76
48
56
78
69
69
78
78
80
83
85
87
88
3
4
cinchonine
cinchonidine
β-ICD
5
6
7
QD-TMSd
8
(DHQD)2PHAL 1a toluene
9
(DHQD)2AQN
(DHQD)2PYR
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidinee
quinidinee,f
quinidinee,f,g
1a toluene
1a toluene
1b toluene
1c toluene
1d toluene
1e toluene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1f
toluene
Figure 2. The structures of various allylamines.
1g toluene
1h toluene
and enantioselectivity, and p-xylene gave the highest enantio-
selectivity (Table 1, entry 27). The concentration and ratio of the
substrates can also influence the reactivity and enantioselectivity
(Table 1, entries 27À29). In addition, lowering the reaction
temperature to 0 °C did not have a positive effect on enantio-
selectivity and greatly decreased the reactivity (Table 1, entry 30).
With the optimized reaction conditions in hand, we next
explored the generality of the substitution process (Table 2).
Most of the reactions evaluated proceeded smoothly to furnish
the desired product 3 in high yields and enantioselectivities.
It appears that the position and electronic properties of sub-
stituents on aromatic rings have a limited effect on the efficiency
of this process (Table 2, entries 1À13). The use of an alkyl-
substituted MBH carbonate failed to yield the desired product
with high enantioselectivity (Table 2, entry 14). Furthermore,
the scope of the reaction can be successfully extended to the
allylamine bearing a phenyl group, and good results were also
attained (Table 2, entry 15).
1i
toluene
1a CH2Cl2
1a CHCl3
1a ether
1a THF
1a CF3Ph
1a xylenes
1a o-xylene
1a m-xylene
1a p-xylene
1a p-xylene
1a p-xylene
1a p-xylene
a Unless otherwise specified, the reaction was carried out with 1 (0.20
mmol) and 2a (0.20 mmol) in the presence of catalyst (0.04 mmol) in
solvent (1.0 mL) at ambient temperature for 24 h. b Determined by 1H
NMR analysis of the crude mixture. c Determined by chiral HPLC on a
Chiralcel OD-H column. d QD-TMS = The hydroxyl group of quinidine
was protected by TMSCl. e 2.0 mL solvent was used. f The reaction was
carried out with 1a (0.30 mmol) and 2a (0.20 mmol). g The reaction was
performed under 0 °C.
To demonstrate the suitability of the current methodology for
the synthesis of 2,5-dihydropyrroles, the RCM reaction of com-
pound 3 was examined. To our delight, in all cases, the corre-
sponding 2,5-dihydropyrrole derivatives 4 could be obtained
smoothly in excellent yields. As anticipated, the cyclization reaction
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Table 2. Scope of the Reactiona
a Unless otherwise specified, the reaction was carried out with 1 (0.30 mmol) and 2 (0.20 mmol) in the presence of 20 mol % quinidine in 2.0 mL of
p-xylene at ambient temperature for 40 h. b Isolated yield. c For analysis of the ee values of the products, see the Supporting Information.
Table 3. Synthesis of 2,5-Dihydropyrrolesa
entry
2, R2
product
yield (%)b
ee (%)c
1
2
3
4
5
2a, C6H5
4a
4b
4c
4d
4e
90
87
84
86
92
86
83
87
86
87
2c, 2-ClC6H4
2g, 3-MeC6H4
2k, 4-BrC6H4
2l, 4-MeC6H4
a Reaction conditions: see Experimental Section. b Isolated yield of the RCM reaction step. For analysis of the ee values of the products, see the
c
Supporting Information.
does not affect the newly formed stereogenic center and provides
enantioenriched 2,5-dihydropyrroles (Table 3).
the pronucleophile allylamine to produce a nucleophilic anion
that attacks the olefinic bond of the cation intermediate to afford
the observed products.
The absolute configuration of the product 3a was determined to be
Ras shown in Scheme 2. According to the literature,25,48,49 we prepared
(S)-3a in seven steps from commercially available (1R,2S,5R)-(À)-
menthyl (S)-p-toluenesulfinate (6). Comparison of both the optical
rotation values and chiral HPLC retention times allowed us to establish
the absolute stereochemistry of the substituted product 3a to be R.
To rationalize our experimental observations, we suggest the
mechanism presented in Scheme 3 which parallels that proposed
by Lu et al. in 2004.30,31 First, substrate 2a undergoes a conjugate
addition followed by elimination of carbon dioxide to form
adduct A. The in situ-generated tert-butoxide anion can deprotonate
’ CONCLUSIONS
In summary, we have disclosed an enantioselective allylic
substitution reaction of MBH carbonates with allylamines using
a commercially available cinchona alkaloid catalyst, yielding
highly enantioenriched N-allyl-β-amino-R-methylene esters,
which can be readily transformed to chiral 2,5-dihydropyrroles
by easily operative RCM reactions. We have also proposed a
tentative mechanism for rationalization of the reaction. Further
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Scheme 2. Absolute Configuration Assignment for 3a
2 (0.20 mmol) in the presence of 20 mol % quinidine in p-xylene
(2.0 mL) was added allylamines 1 (0.30 mmol), and the resulting solution
was stirred for 40 h at ambient temperature. The reaction mixture was
directly purified by silica gel chromatography without workup, and
fractions were collected and concentrated in vacuo to provide the pure
desired products 3.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(phenyl)methyl)-
acrylate (3a, Table 2, entry 1). The title compound (71.3 mg, 93% yield)
was prepared as a pale yellow oil by the general procedure and eluted from
silica gelwith petroleum ether/AcOEt (4:1). 1HNMR(300 MHz,CDCl3)
δ 7.69 (d, J = 8.3 Hz, 2H), 7.33À7.17 (m, 5H), 7.06À6.95 (m, 2H), 6.45
(d, J = 0.9 Hz, 1H), 6.11 (s, 1H), 5.73 (d, J = 1.5 Hz, 1H), 5.36À5.14 (m,
1H), 4.85 (dd, J = 1.2, 5.7 Hz, 1H), 4.80 (s, 1H), 3.91À3.70 (m, 2H), 3.60
(s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.3, 143.2, 139.1,
137.7, 137.0, 134.2, 129.4, 128.5, 128.4, 128.0, 127.9, 127.4, 117.6, 61.7,
51.9, 48.6, 21.5; IR: 3064, 2953, 1724, 1636, 1438, 1342, 1286, 1193, 1116,
1034, 925, 812, 703, 664 cmÀ1; [R]rtD = À135 (c = 0.97, CHCl3); HRMS
(ESI): C21H23NO4S+H, Calcd: 386.1421, Found: 386.1414; HPLC:
CHIRALCEL OD-H, hexane/iPrOH = 90/10, flow rate = 1.0 mL/min,
retention time: tmajor = 13.0, tminor = 17.8, 87% ee.
(S)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(2-fluorophenyl)-
methyl)acrylate (3b, Table 2, entry 2). The title compound (62.7 mg, 78%
yield) was prepared as a pale yellow oil by the general procedure and eluted
from silica gel with petroleum ether/AcOEt (4:1). 1H NMR (300 MHz,
CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.33À7.15 (m, 4H), 7.05 (t, J = 7.5 Hz,
1H), 6.90 (t, J = 8.7 Hz, 1H), 6.54 (s, 1H), 6.28 (s, 1H), 5.88 (d, J = 1.4 Hz,
1H), 5.43À5.29 (m, 1H), 4.82 (dd, J = 13.5, 2.2 Hz, 2H), 3.92 (ddd,
J = 37.3, 16.1, 6.5 Hz, 2H), 3.60 (s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz,
CDCl3); δ 165.9, 160.6 (J = 247.5 Hz), 143.0, 138.4, 137.8, 133.7, 129.9
(J = 3.0 Hz), 129.8 (J = 3.0 Hz), 129.2, 128.6, 127.4, 124.6 (J = 13.5 Hz),
123.9 (J = 3.75 Hz), 117.7, 115.4 (J = 21.75 Hz), 56.1 (J = 3.75 Hz), 51.9,
application and exploration of this methodology and biological
evaluation are ongoing in our laboratory.
’ EXPERIMENTAL SECTION
General Procedure for Enantioselective Allylic Substitu-
tion Reactions. To a solution of MoritaÀBaylisÀHillman carbonates
Scheme 3. Proposed Mechanism
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49.6, 21.4; IR: 3071, 2953, 1723, 1636, 1490, 1439, 1343, 1286, 1159,
1437, 1344, 1287, 1160, 1117, 1091, 1036, 929, 812, 732, 663 cmÀ1
;
1118, 1093, 1034, 930, 811, 763, 665 cmÀ1; [R]rt = À83 (c = 1.11,
[R]rt = À91 (c = 1.14, CHCl3); HRMS (ESI): C21H22BrNO4S+H,
D
D
CHCl3); HRMS (ESI): C21H22FNO4S+H, Calcd: 404.1326, Found:
404.1337; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/20, flow
rate = 1.0 mL/min, retention time: tmajor = 8.4, tminor = 10.0, 77% ee.
(S)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(2-chlorophenyl)-
methyl)acrylate (3c, Table 2, entry 3). The title compound (75.9 mg,
91% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.57 (d, J = 8.3 Hz, 2H), 7.32À7.16 (m, 6H), 6.54
(s, 1H), 6.30 (s, 1H), 5.75 (d, J = 1.3 Hz, 1H), 5.52À5.36 (m, 1H), 4.87
(d, d, J = 1.2 Hz, 1H), 4.82 (dd, J = 1.2, 4.8 Hz, 1H), 3.98 (qd, J = 16.0,
6.4 Hz, 2H), 3.59 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 165.8, 142.9, 138.4, 137.6, 135.2, 134.4, 133.9, 130.1, 129.7, 129.5,
129.2, 129.1, 127.5, 126.6, 117.7, 59.5, 52.0, 50.2, 21.4; IR: 3069, 2922,
1724, 1636, 1440, 1343, 1284, 1159, 1115, 1090, 1037, 911, 812, 731,
663 cmÀ1; [R]rtD = À32 (c = 1.07, CHCl3); HRMS (ESI): C21H22ClNO4S
+H, Calcd: 420.1031, Found: 420.1024; HPLC: CHIRALCEL OD-H,
Calcd: 464.0526, Found: 464.0532; HPLC: CHIRALCEL OD-H,
hexane/iPrOH = 80/20, flow rate = 1.0 mL/min, retention time: tmajor
7.4, tminor = 10.0, 83% ee.
=
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(m-tolyl)methyl)-
acrylate (3g, Table 2, entry 7). The title compound (69.9 mg, 88%
yield) was prepared as a pale yellow oil by the general procedure and
eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR (300
MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.10
(t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.68
(s, 1H), 6.44 (d, J = 0.8 Hz, 1H), 6.05 (s, 1H), 5.75 (d, J = 1.5 Hz, 1H),
5.38À5.19 (m, 1H), 4.88 (t, J = 1.5 Hz, 1H), 4.30 (dt, J = 3.0, 1.2 Hz,
1H), 3.79 (d, J = 6.4 Hz, 2H), 3.61 (s, 3H), 2.43 (s, 3H), 2.20 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 166.3, 143.2, 139.2, 138.1, 137.7, 136.8,
134.4, 129.3, 129.2, 128.7, 128.3, 127.8, 127.5, 125.4, 117.5, 61.7, 52.0,
48.7, 21.4, 21.2; IR: 2952, 1724, 1636, 1601, 1491, 1438, 1343, 1286,
1160, 1117, 1091, 1036, 924, 816, 779, 706, 663 cmÀ1; [R]rtD = À101
(c = 1.11, CHCl3); HRMS (ESI): C22H25NO4S+Na, Calcd: 422.1397,
Found: 422.1394; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/
20, flow rate = 1.0 mL/min, retention time: tmajor = 6.6, tminor = 8.9,
90% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(3-methoxyphenyl)-
methyl)acrylate (3h, Table 2, entry 8). The title compound (81.8 mg,
99% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 7.27 (d,
J = 2.3 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.77 (dd, J = 8.2, 2.2 Hz, 1H),
6.60 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 4.8 Hz, 2H), 6.06 (s, 1H), 5.76
(s, 1H), 5.40À5.17 (m, 1H), 4.88 (d, J = 5.2 Hz, 1H), 4.84 (s, 1H), 3.81
(d, J = 6.4 Hz, 2H), 3.65 (s, 3H), 3.62 (s, 3H), 2.42 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.3, 159.6, 143.2, 139.1, 138.5, 137.8, 134.4,
129.5, 129.4, 128.0, 127.6, 120.7, 117.7, 113.9, 113.9, 61.7, 55.1, 52.0,
48.7, 21.5; IR: 2953, 1723, 1636, 1601, 1490, 1437, 1342, 1270, 1160,
1117, 1091, 1038, 920, 874, 815, 782, 704, 664 cmÀ1; [R]rtD = À127
(c = 1.06, CHCl3); HRMS (ESI): C22H25NO5S+H, Calcd: 416.1526,
Found: 416.1528; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/
20, flow rate = 1.0 mL/min, retention time: tmajor = 9.0, tminor = 12.6,
86% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(4-fluorophenyl)-
methyl)acrylate (3i, Table 2, entry 9). The title compound (70.4 mg,
87% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.67 (d, J = 8.3 Hz, 2H), 7.28 (s, 1H), 7.26 (d,
J = 2.3 Hz, 1H), 7.05À6.97 (m, 2H), 6.92 (t, J = 8.6 Hz, 2H), 6.44 (d, J =
0.9 Hz, 1H), 6.07 (s, 1H), 5.72 (d, J = 1.6 Hz, 1H), 5.36À5.22 (m, 1H),
4.86 (s, 1H), 4.82 (dd, J = 8.2, 1.0 Hz, 1H), 3.81 (qd, J = 16.1, 6.4 Hz,
2H), 3.61 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.2,
162.3 (J = 246 Hz), 143.3, 138.9, 137.8, 134.2, 133.0 (J = 3.0 Hz), 130.3
(J = 8.25 Hz), 129.5, 128.1, 127.4, 115.5 (J = 21.75 Hz), 61.1, 52.1, 48.8,
21.5; IR: 2953, 2924, 1724, 1636, 1602, 1509, 1438, 1342, 1227, 1159,
1117, 1091, 1035, 930, 815, 662 cmÀ1; [R]rtD = À93 (c = 0.98, CHCl3);
HRMS (ESI): C21H22FNO4S+H, Calcd: 404.1326, Found: 404.1318;
HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/20, flow rate =
1.0 mL/min, retention time: tmajor = 7.2, tminor = 9.2, 88% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(4-chlorophenyl)-
methyl)acrylate (3j, Table 2, entry 10). The title compound (77.3 mg,
92% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H),
7.21 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.46 (d, J = 1.1 Hz, 1H),
6.06 (s, 1H), 5.73 (d, J = 1.6 Hz, 1H), 5.40À5.21 (m, 1H), 4.89 (s, 1H),
4.84 (dd, J = 6.4, 1.2 Hz, 1H), 3.82 (dt, J = 5.7, 1.2 Hz, 2H), 3.61 (s, 3H),
2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.0, 143.3, 138.6, 137.6,
hexane/iPrOH = 80/20, flow rate = 1.0 mL/min, retention time: tmajor
8.9, tminor = 13.1, 83% ee.
=
(S)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(2-bromophenyl)-
methyl)acrylate (3d, Table 2, entry 4). The title compound (80.5 mg,
87% yield) was prepared as a white solid by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.67 (dd, J = 7.5, 1.5 Hz, 2H), 7.46 (dd, J = 7.9,
1.3 Hz, 1H), 7.34 (dd, J = 7.8, 1.7 Hz, 1H),7.24 (td, J = 7.2, 1.2 Hz, 1H),
7.20 (d, J = 7.8 Hz, 2H), 7.15 (td, J = 7.8, 1.8 Hz, 1H), 6.54 (s, 1H), 6.26
(s, 1H), 5.68 (d, J = 1.3 Hz, 1H), 5.55À5.44 (m, 1H), 4.90 (dd, J = 3.9,
1.2 Hz, 1H), 4.86 (dd, J = 2.1, 0.9 Hz, 1H), 4.02 (dd, J = 3.6, 1.2 Hz, 2H),
3.58 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.7, 142.9,
138.4, 137.7, 136.9, 133.9, 133.1, 130.3, 130.0, 129.3, 129.1, 127.6, 127.2,
124.8, 117.8, 61.9, 52.0, 50.5, 21.4; IR: 3068, 2953, 1724, 1636, 1439,
1343, 1283, 1160, 1114, 1091, 1031, 925, 812, 756, 662 cmÀ1; [R]rtD = À8
(c = 1.16, CHCl3); HRMS (ESI): C21H22BrNO4S+H, Calcd: 464.0526,
Found: 464.0525; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/
20, flow rate = 1.0 mL/min, retention time: tmajor = 8.5, tminor = 15.8,
82% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(3-chlorophenyl)-
methyl)acrylate (3e, Table 2, entry 5). The title compound (83.8 mg,
95% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H),
7.18 (dd, J = 12.6, 4.9 Hz, 2H), 6.95 (dt, J = 6.9, 1.5 Hz, 1H), 6.87
(s, 1H), 6.48 (d, J = 1.0 Hz, 1H), 6.05 (s, 1H), 5.73 (d, J = 1.6 Hz, 1H),
5.44À5.27 (m, 1H), 4.88 (ddd, J = 12.0, 6.8, 1.3 Hz, 2H), 3.84 (d, J =
6.4 Hz, 2H), 3.62 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 166.0, 143.5, 139.3, 138.4, 137.5, 134.4, 134.1, 129.7, 129.5, 128.8,
128.6, 128.1, 127.3, 126.6, 117.9, 61.1, 52.1, 49.0, 21.5; IR: 3068, 2954,
1723, 1636, 1597, 1575, 1437, 1342, 1286, 1160, 1117, 1091, 1036, 911,
813, 734, 664 cmÀ1; [R]rt = À93 (c = 1.10, CHCl3); HRMS (ESI):
D
C21H22ClNO4S+H, Calcd: 420.1031, Found: 420.1043; HPLC: CHIR-
ALCEL OD-H, hexane/iPrOH = 80/20, flow rate = 1.0 mL/min,
retention time: tmajor = 7.1, tminor = 9.4, 82% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(3-bromophenyl)-
methyl)acrylate (3f, Table 2, entry 6). The title compound (89.2 mg,
97% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1H),
7.27 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H),
6.48 (s, 1H), 6.03 (s, 1H), 5.74 (d, J = 1.1 Hz, 1H), 5.44À5.26 (m, 1H),
4.89 (dd, J = 13.4, 8.0 Hz, 2H), 3.83 (d, J = 6.3 Hz, 2H), 3.63 (s, 3H),
2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.0, 143.5, 139.5, 138.4,
137.5, 134.1, 131.5, 131.0, 130.0, 129.5, 128.9, 127.4, 127.1, 122.6, 118.0,
61.0, 52.1, 49.0, 21.5; IR: 3066, 2953, 2925, 1724, 1636, 1596, 1570,
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ARTICLE
135.8, 134.0, 133.8, 129.9, 129.4, 128.6, 128.5, 127.4, 117.9, 61.0, 52.0,
142.9, 141.1, 138.1, 138.0, 135.6, 129.3, 128.4, 128.3, 127.9, 127.5, 126.0,
117.7, 57.1, 51.9, 48.3, 33.8, 33.0, 21.5; IR: 2950, 1721, 1438, 1337, 1157,
48.9, 21.5; IR: 2952, 1723, 1491, 1342, 1160, 1036, 815 cmÀ1; [R]rt
=
D
À114 (c = 1.04, CHCl3); HRMS (ESI): C21H22ClNO4S+H, Calcd:
420.1031, Found: 420.1028; HPLC: CHIRALCEL OD-H, hexane/
iPrOH = 80/20, flow rate = 1.0 mL/min, retention time: tmajor = 7.0,
tminor = 8.7, 88% ee.
929, 814 cmÀ1; [R]rt = À28 (c = 0.95, CHCl3); HRMS (ESI):
D
C23H27NO4S+H, Calcd: 414.1734, Found: 414.1730; HPLC: CHIRALCEL
AD, hexane/iPrOH = 90/10, flow rate = 1.0 mL/min, retention time: tmajor
14.2, tminor = 19.4, 35% ee.
=
(R,E)-Methyl 2-((N-Cinnamyl-4-methylphenylsulfonamido)(p-tolyl)-
methyl)acrylate (3o, Table 2, entry 15). The title compound (81.9 mg,
86% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.33À7.14 (m, 5H), 7.03
(dd, J = 6.8, 4.8 Hz, 4H), 6.91 (d, J = 8.0 Hz, 2H), 6.44 (s, 1H), 6.14
(s, 1H), 6.00 (d, J = 15.9 Hz, 1H), 5.78 (s, 1H), 5.46 (dt, J = 15.7, 6.7 Hz,
1H), 4.01 (dd, J = 15.9, 7.3 Hz, 1H), 3.86 (dd, J = 16.1, 6.2 Hz, 1H), 3.58
(s, 3H), 2.39 (s, 3H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.3,
143.1, 139.3, 137.9, 137.8, 136.4, 133.9, 132.4, 129.4, 129.2, 128.4, 128.3,
127.5, 127.4, 127.3, 126.1, 125.4, 61.4, 51.9, 47.8, 21.4, 20.9; IR: 2952,
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(4-bromophe-
nyl)methyl)acrylate (3k, Table 2, entry 11). The title compound
(83.5 mg, 90% yield) was prepared as a pale yellow oil by the general
procedure and eluted from silica gel with petroleum ether/AcOEt (4:1).
1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 2H), 7.37 (d, J =
1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 7.25
(s, 1H), 6.93 (s, 1H), 6.90 (s, 1H), 6.46 (d, J = 1.1 Hz, 1H), 6.03 (s, 1H),
5.73 (d, J = 1.6 Hz, 1H), 5.41À5.22 (m, 1H), 4.89 (s, 1H), 4.85 (dd, J =
6.6, 1.2 Hz, 1H), 3.82 (dt, J = 4.5, 0.9 Hz, 2H), 3.61 (s, 3H), 2.43 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 166.0, 143.3, 138.5, 137.6, 136.3, 134.0,
131.6, 130.2, 129.4, 128.6, 127.4, 122.0, 117.9, 61.1, 52.0, 48.9, 21.5; IR:
2952, 2925, 1723, 1636, 1596, 1488, 1438, 1342, 1286, 1160, 1116, 1091,
1723, 1438, 1339, 1158, 914, 814 cmÀ1; [R]rt = À88 (c = 1.08,
D
1036, 930, 815, 730, 691 cmÀ1; [R]rt = À105 (c = 0.95, CHCl3);
CHCl3); HRMS (ESI): C28H29NO4S+H, Calcd: 476.1890, Found:
476.1882; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/20, flow
rate = 1.0 mL/min, retention time: tmajor = 10.9, tminor = 12.8, 85% ee.
General Procedure for the Synthesis of 2,5-Dihydropyr-
roles 4. To a solution of MoritaÀBaylisÀHillman carbonates 2(0.20 mmol)
in the presence of 20 mol % quinidine in p-xylene (2.0 mL) was added
allylamine 1a (0.30 mmol), and the resulting solution was stirred for 40 h at
ambient temperature. After purification, to a solution of products 3in CH2Cl2
was added 5 mol % Zhan-1B catalyst, and the mixture was refluxed for 4 h.
Theresulting mixturewas then loaded onto silica gel, and the products 4were
obtained by column chromatography.
D
HRMS (ESI): C21H22BrNO4S+H, Calcd: 464.0526, Found: 464.0534;
HPLC: CHIRALCEL OD-H, hexane/iPrOH = 90/10, flow rate =
1.0 mL/min, retention time: tmajor =11.2, tminor =16.1, 86% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(p-tolyl)methyl)-
acrylate (3l, Table 2, entry 12). The title compound (76.4 mg, 96%
yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1).
1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.20 (s,
1H), 7.17 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 8.1 Hz,
2H), 6.35 (d, J = 0.7 Hz, 1H), 5.98 (s, 1H), 5.68 (d, J = 1.5 Hz, 1H), 5.17
(ddt, J = 16.8, 10.0, 6.4 Hz, 1H), 4.79 (d, J = 8.1 Hz, 1H), 4.74 (s, 1H),
3.71 (d, J = 6.3 Hz, 2H), 3.52 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 166.3, 143.1, 139.3, 137.8, 137.7, 134.4,
133.8, 129.3, 129.2, 128.4, 127.5, 127.4, 117.5, 61.5, 51.9, 48.5, 21.4,
21.0; IR: 2952, 1723, 1437, 1342, 1159, 1035, 814 cmÀ1; [R]rtD = À114
(c = 1.11, CHCl3); HRMS (ESI): C22H25NO4S+H, Calcd: 400.1577,
Found: 400.1567; HPLC: DAICEL CHIRALCEL OD-H, hexane/
iPrOH = 80/20, flow rate = 1.0 mL/min, retention time: tmajor = 6.9,
tminor = 9.3, 90% ee.
(R)-Methyl 2-((N-Allyl-4-methylphenylsulfonamido)(4-methoxyphenyl)-
methyl)acrylate(3m, Table 2, entry 13). The title compound (82.0 mg,
99% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H),
6.92 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.41 (s, 1H), 6.04
(s, 1H), 5.76 (d, J = 1.5 Hz, 1H), 5.24 (m, 1H), 4.87 (d, J = 5.3 Hz, 1H),
4.82 (s, 1H), 3.79 (t, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.60 (s, 3H), 2.43
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.3, 159.2, 143.1, 139.3,
137.7, 134.4, 129.8, 129.4, 128.8, 127.4, 127.2, 117.5, 113.8, 61.2, 55.1,
51.9, 48.5, 21.4; IR: 2954, 1724, 1636, 1610, 1512, 1439, 1340, 1254,
1159, 1115, 1091, 1033, 928, 815, 778, 731, 664 cmÀ1; [R]rtD = À128
(c = 1.00, CHCl3); HRMS (ESI): C22H25NO5S+H, Calcd: 416.1526,
Found: 416.1533; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 80/
20, flow rate = 1.0 mL/min, retention time: tmajor = 9.6, tminor = 14.1,
86% ee.
(R)-Methyl 2-Phenyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate
(4a, Table 3, entry 1). The title compound (59.4 mg, 90% yield) was
prepared as a pale yellow oil by the general procedure and eluted from
1
silica gel with petroleum ether/AcOEt (2:1). H NMR (300 MHz,
CDCl3) δ 7.42 (d, J = 8.3 Hz, 2H), 7.23 (s, 5H), 7.14 (d, J = 8.1 Hz, 2H),
6.78 (dd, J = 3.8, 2.0 Hz, 1H), 5.73 (dt, J = 3.9, 1.8 Hz, 1H), 4.51 (dt, J =
17.1, 2.4 Hz, 1H), 4.38 (ddd, J = 17.1, 5.7, 1.8 Hz, 1H), 3.58 (s, 3H), 2.37
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 143.3, 139.3, 135.7,
135.6, 135.4, 129.4, 128.3, 128.0, 127.7, 127.0, 68.9, 54.9, 51.8, 21.4; IR:
1724, 1438, 1348, 1269, 1162, 1091, 817 cmÀ1; [R]rtD = À198 (c = 1.02,
CHCl3); HRMS (ESI): C19H19NO4S+H, Calcd: 358.1108, Found:
358.1107; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 70/30, flow
rate = 1.0 mL/min, retention time: tmajor = 11.3, tminor = 15.6, 86% ee.
(S)-Methyl 2-(2-Chlorophenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-
carboxylate (4b, Table 3, entry 2). The title compound (61.9 mg, 87%
yield) was prepared as a pale yellow oil by the general procedure and
eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR (300
MHz, CDCl3) δ 7.53 (d, J = 8.2 Hz, 2H), 7.26À7.20 (m, 1H),
7.17À7.07 (m, 5H), 6.72 (dd, J = 4.0, 2.0 Hz, 1H), 6.06 (ddd, J = 5.4,
3.5, 1.8 Hz, 1H), 4.43 (ddt, J = 17.1, 5.7, 2.1 Hz, 2H), 3.50 (s, 3H), 2.32
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 143.6, 137.2, 136.3,
134.7, 134.6, 133.6, 129.8, 129.7, 129.6, 129.0, 127.3, 126.9, 65.3, 55.4,
51.8, 21.5; IR: 1725, 1440, 1352, 1270, 1191, 1092, 911, 805 cmÀ1
;
[R]rtD = À206 (c = 0.98, CHCl3); HRMS (ESI): C19H18ClNO4S+H,
Calcd: 392.0718, Found: 392.0714; HPLC: CHIRALCEL OD-H,
(R)-Methyl 3-(N-Allyl-4-methylphenylsulfonamido)-2-methylene-5-
phenylpentanoate (3n, Table 2, entry 14). The title compound (49.8
mg, 60% yield) was prepared as a pale yellow oil by the general procedure
and eluted from silica gel with petroleum ether/AcOEt (4:1). 1H NMR
(300 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
6.9 Hz, 1H), 7.25 (d, J = 1.9 Hz, 2H), 7.23À7.16 (m, 2H), 7.12 (dd,
J = 8.1, 1.2 Hz, 2H), 6.36 (s, 1H), 5.90À5.78 (m, 1H), 5.77 (d, J = 0.7 Hz,
1H), 5.10 (dd, J = 26.7, 1.2 Hz, 1H), 5.08 (d, J = 1.2 Hz, 1H), 4.87 (t, J =
7.5 Hz, 1H), 3.85 (d, J = 6.4 Hz, 2H), 3.60 (s, 3H), 2.67À2.51 (m, 2H),
2.40 (s, 3H), 2.21À1.99 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 166.8,
hexane/iPrOH = 70/30, flow rate = 1.0 mL/min, retention time: tmajor
13.9 tminor = 24.2, 83% ee.
=
(R)-Methyl 2-m-Tolyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate
(4c, Table 3, entry 3). The title compound (54.8 mg, 90% yield) was
prepared as a pale yellow oil by the general procedure and eluted from
1
silica gel with petroleum ether/AcOEt (2:1). H NMR (300 MHz,
CDCl3) δ 7.40 (d, J = 8.3 Hz, 2H), 7.12 (dd, J = 7.8, 2.7 Hz, 3H), 7.03
(dd, J = 7.2, 0.9 Hz, 2H), 6.91 (s, 1H), 6.77 (dd, J = 3.9, 1.8 Hz, 1H), 5.69
(dd, J = 3.7, 1.8 Hz, 1H), 4.52 (dt, J = 17.1, 2.4 Hz, 1H), 4.38 (ddd, J =
17.1, 5.7, 1.8 Hz, 1H), 3.59 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H); 13C NMR
7831
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ARTICLE
(75 MHz, CDCl3) δ 162.2, 143.1, 139.0, 137.8, 135.7, 135.5, 129.3,
128.8, 128.2,128.1, 127.0, 125.0, 68.9, 54.9, 51.8, 21.4, 21.3; IR: 2952,
1724, 1457, 1348, 1268, 1162, 1091, 776 cmÀ1; [R]rtD = À157 (c = 1.02,
CHCl3); HRMS (ESI): C20H21NO4S+H, Calcd: 372.1264, Found:
372.1258; HPLC: CHIRALCEL AD, hexane/iPrOH = 70/30, flow rate =
1.0 mL/min, retention time: tmajor = 9.9, tminor = 12.6, 87% ee.
(5) Lange, U. E. W.; Baucke, D.; Hornberger, W.; Mack, H.; Seitz,
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115976, 2005.
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2009, 146.
(R)-Methyl 2-(4-Bromophenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-
carboxylate (4d, Table 3, entry 4). The title compound (67.3 mg, 86%
yield) was prepared as a pale yellow oil by the general procedure and
eluted from silica gel with petroleum ether/AcOEt (2:1). 1H NMR (300
MHz, CDCl3) δ 7.38 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.11
(d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 1.8 Hz, 1H), 5.59
(dt, J = 5.4, 1.8 Hz,1H), 4.44 (dt, J = 17.2, 2.5 Hz, 1H), 4.33 (ddd, J =
17.2, 5.7, 2.0 Hz, 1H), 3.52 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 162.0, 143.6, 138.5, 136.0, 135.3, 135.2, 131.4, 129.6, 129.4,
127.0, 122.1, 68.3, 55.0, 51.9, 21.5; IR: 2953, 1724, 1595, 1487, 1439,
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64, 9471.
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1350, 1268, 1162, 1091, 813, 732 cmÀ1; [R]rt = À210 (c = 0.97,
D
CHCl3); HRMS (ESI): C19H18BrNO4S+H, Calcd: 436.0213, Found:
436.0201; HPLC: CHIRALCEL OD-H, hexane/iPrOH = 70/30, flow
rate = 1.0 mL/min, retention time: tmajor = 11.1, tminor = 13.0, 86% ee.
(R)-Methyl 2-p-Tolyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate
(4e, Table 3, entry 5). The title compound (65.2 mg, 90% yield) was
prepared as a pale yellow oil by the general procedure and eluted from
silica gel with petroleum ether/AcOEt (2:1). 1H NMR (300 MHz,
CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.13 (dd, J = 10.5, 8.4 Hz, 3H), 7.10
(s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 1.8 Hz, 1H), 5.68 (dt, J =
5.1, 1.8 Hz, 1H), 4.48 (dt, J = 17.1, 2.5 Hz, 1H), 4.37 (ddd, J = 17.1, 5.5,
2.0 Hz, 1H), 3.58 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 162.2, 143.2, 137.7, 136.4, 135.6, 135.5, 135.4, 129.4,
128.9, 127.5, 127.1, 68.7, 54.8, 51.8, 21.4, 21.1; IR: 2952, 1724, 1645,
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1439, 1349, 1269, 1162, 1090, 813 cmÀ1; [R]rt = À156 (c = 1.13,
D
CHCl3); HRMS (ESI): C20H21NO4S+H, Calcd: 372.1264, Found:
372.1271; HPLC: CHIRALCEL AD, hexane/iPrOH = 70/30, flow rate
= 1.0 mL/min, retention time: tmajor = 11.0, tminor = 15.8, 87% ee.
Angew. Chem., Int. Ed. 2009, 48, 5737.
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’ ASSOCIATED CONTENT
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S
Supporting Information. General methods, HPLC con-
b
ditions and chromatograms, and copies of NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: hongl@lzu.edu.cn; wangrui@lzu.edu.cn.
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