Asymmetric substitutions of O-Boc-protected Morita-Baylis-Hillman adducts with pyrrole and indole derivatives

Article abstract of DOI:10.1039/c1ob06671d

An efficient asymmetric substitution process of O-Boc-protected Morita-Baylis-Hillman adducts with various pyrrole and indole derivatives has been developed in the presence of (DHQD)₂PYR in THF, affording the corresponding products in good to h

Full text of DOI:10.1039/c1ob06671d

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PAPER
Asymmetric substitutions of O-Boc-protected Morita–Baylis–Hillman
adducts with pyrrole and indole derivatives†
Long Huang,a Yin Weib and Min Shi*a,b
Received 3rd October 2011, Accepted 3rd November 2011
DOI: 10.1039/c1ob06671d
An efficient asymmetric substitution process of O-Boc-protected Morita–Baylis–Hillman adducts with
various pyrrole and indole derivatives has been developed in the presence of (DHQD)2PYR in THF,
affording the corresponding products in good to high yields (up to 99% yield) and moderate to high ee
values (up to 92 and 96% ee) under mild conditions.
(DHQD)2AQN (10 mol%) (eqn (1)).6f In this paper, we wish to
Introduction
disclose that if using 1H-pyrrole-2-carbonitrile instead of methyl
Recently, asymmetric substitutions of Morita–Baylis–Hillman
pyrrole-2-carboxylate in the asymmetric substitution of O-Boc-
(MBH) acetates or carbonates using cinchona alkaloid derived
protected Morita–Baylis–Hillman adducts, the corresponding
organocatalysts have attracted much attention because this
products can be obtained in good yields (up to 92% yield) and
asymmetric synthetic protocol can overcome the shortages in the
high ee values (up to 92% ee) in the presence of (DHQD)2PYR
direct catalytic asymmetric MBH reactions in terms of substrate
under mild conditions (10 mol%) (eqn (2)).
scope and catalytic efficiency as well as chiral induction.1–4 In
this respect, Lu5a and Hiemstra5b first independently reported
(4-(3-ethyl-4-oxa-1-azatricyclo[4,4,0,03,8]dec-5-yl)-quinolin-6-ol
(1)
(also called as b-isocupreidine) (b-ICD) catalyzed asymmetric
substitution of MBH carbonates with various nucleophiles,
affording the corresponding amination products in excellent yields
along with modest ee values, respectively. Moreover, Chen and
co-workers have recently used hydroquindine-(anthraquinone-1,4-
(2)
diyl) diether ((DHQD)2AQN), hydroquindine-1,4-phthalazinediyl
diether ((DHQD)2PHAL), hydroquinidine-2,5-diphenyl-4,6-
pyrimidinediyl diether ((DHQD)2PYR), and b-isocupreidine
(b-ICD) in asymmetric substitutions of MBH carbonates
to achieve C–C bond,6a–6d C–N bond6e,6f and C–O bond6g,6h
formation in good yields along with high enantioselectivities
under mild conditions. More recently, Wang’s group also
reported using cinchona alkaloids as catalysts to construct
chiral allylic phosphine oxides through substitution of MBH
carbonates in excellent yields along with high enantioselectivities.7
Previously, Chen and co-workers reported that the asymmetric
substitution of O-Boc-protected Morita–Baylis–Hillman adduct
with methyl pyrrole-2-carboxylate provided the desired N-allylic
alkylation product in 80% yield with 73% ee in the presence of
Results and discussion
Initially, we utilized multifunctional cinchona alkaloid b-
isocupreidine (b-ICD)1k,8 (10 mol%) as the chiral catalyst to
examine the reaction outcome of tert-butyl 2-methylene-1-(4-
chlorophenyl)-3-oxobutyl carbonate 2a (1.0 equiv) with 1H-
pyrrole-2-carbonitrile 1a (1.2 equiv) in tetrahydrofuran (THF)
and found that the corresponding substitution product 3a was
obtained in 68% yield along with 2% ee at room temperature
(25 ◦C) (Table 1, entry 1). We next turned our attention to
screening other multifunctional cinchona alkaloids, cat. 1a–1e and
cat. 2a–2c derived from b-ICD, in this reaction and found that the
desired product 3a was produced in 77–91% yields along with
low ee values (4–20%) (Table 1, entries 2–9). Then, we found 3a
could be obtained in higher ee values (31–41%) in good yields
(84–97%) in the presence of cat. 3a–3c (Table 1, entries 10–12).
Using (DHQ)2PHAL, (DHQ)2PYR and (DHQ)2PYDZ as the
catalysts afforded 3a in 70–99% yields along with 38–40% ee values
(Table 1, entries 13–15), while (DHQD)2PHAL, (DHQD)2PYR
and (DHQD)2PYDZ could afford 3a in 34–98% yields along with
aKey Laboratory for Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology, 130 Mei Long Road,
Shanghai, 200237, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai,
200032, China. E-mail: Mshi@mail.sioc.ac.cn; Fax: +86-21-64166128
† Electronic supplementary information (ESI) available: Experimental
procedures, NMR charts for all compounds and X-ray crystal data of
3h. CCDC reference numbers 812598. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1ob06671d
1396 | Org. Biomol. Chem., 2012, 10, 1396–1405
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Table 1 Screening of cinchona alkaloid organocatalysts for the asym-
metric substitution of O-Boc-protected Morita–Baylis–Hillman adduct 2a
with 1a
Table 2 Optimization of the reaction conditions using (DHQD)2PYR as
the catalyst
Entrya
Solvent
t [h]
T [◦C]
Yield [%]b
ee [%]c
Entrya
Catalyst
t [h]
Yield [%]b
ee [%]c
1
2
3
4
5
6
7
8
THF
DCM
DCE
toluene
CHCl3
dioxane
DMSO
EtOAc
THF
DCE
EtOAc
THF
THF
THF
48
48
48
48
72
96
48
72
168
144
168
96
72
96
rt
rt
rt
rt
rt
rt
rt
rt
0
0
0
0
0
98
89
92
99
97
82
89
92
92
91
80
93
95
81
96
80
82
82
75
74
67
81
85
92
90
89
90
90
92
83
1
2
3
4
5
6
7
8
b-ICD
48
48
48
48
48
48
48
48
48
1
68
78
82
87
91
93
77
87
91
85
84
97
70
89
99
62
98
34
-2
-10
-20
-17
-17
-15
-20
-5
cat. 1a
cat. 1b
cat. 1c
cat. 1d
cat. 1e
cat. 2a
cat. 2b
9
9
cat. 2c
-4
10
11
12d
13d,e
14d,e
15d,e
10
11
12
13
14
15
16
17
18
cat. 3a
-32
-31
-41
-38
-60
-44
39
cat. 3b
1
1
cat. 3c
(DHQ)2PHAL
(DHQ)2PYR
(DHQ)2PYDZ
(DHQD)2PHAL
(DHQD)2PYR
(DHQD)2PYDZ
48
48
48
48
48
48
-10
40
THF
24
a Unless otherwise noted, reactions were performed with 1a (0.12 mmol),
2a (0.10 mmol), and 10 mol% of catalyst in solvent (1.00 mL). b Yield
of isolated product. c Determined by HPLC on a chiral stationary
phase. d Reactions were performed with 1a (0.20 mmol), 2a (0.10 mmol)
and 10 mol% of catalyst in solvent (0.50 mL). e With 15 mol% catalyst.
80
41
a Reactions were performed with 1a (0.12 mmol), 2a (0.10 mmol) and
10 mol% of catalyst in solvent (1.00 mL) at room temperature. b Yield of
isolated product. c Determined by HPLC on a chiral stationary phase.
Table 3 Substrate scope in the (DHQD)2PYR-catalyzed asymmetric
substitution of O-Boc-protected Morita–Baylis–Hillman adducts 2 with
1a
Entrya
2
R1
Ar
t [h]
T [◦C] yield [%]b ee [%]c
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4-FC6H4
96
110
100
100
72
48
72
72
72
96
0
-10
-10
-10
0
0
0
0
0
-10
-10
-10
-10
0
3b, 78
3c, 91
3d, 88
3e, 95
3f, 91
3g, 90
3h, 82
3i, 97
3j, 95
3k, 99
82
88
85
89
90
91
91
84
83
92
4-CF3C6H4
3-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
2,3-Cl2C6H3
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-NO2C6H4
3-NO2C6H4 110
4-CNC6H4
C6H5
4-MeC6H4
2-MeOC6H4 100
39–80% ee values along with the opposite absolute configuration
as those of (DHQ)2PHAL, (DHQ)2PYR and (DHQ)2PYDZ since
they are pseudo-enantiomers (Table 1, entries 16–18). In brief,
(DHQD)2PYR gave the best result under identical conditions.
Examination of solvent effects using (DHQD)2PYR as the
catalyst revealed that THF, 1,2-dichloroethane (DCE) and ethyl
acetate (EtOAc) were the solvents of choice for this reaction (Table
2, entries 1–8). Lowering the reaction temperature to 0 ◦C in THF
afforded 3a in 92% yield along with 92% ee (Table 2, entry 9).
9
2j
2k
2l
10
11
12
13
14
15
16
17
18
19
3l, 84(89)d 78 (60)d
3m, 99 88
3n, 68(88)d 82 (79)d
2m
2n
2o
2p
2q
2r
2s
2t
72
110
100
◦
Carrying out the reaction at 0 C in DCE and EtOAc produced
3o, 80
3p, 93
3q, 89
3r, 75
76
88
39
62
-10
0
0
-10
rt
3a in 91% yield along with 90% ee and 80% yield along with
89% ee, respectively (Table 2, entries 10 and 11). Increasing the
employed amounts of (DHQD)2PYR to 15 mol% and 1a to 2.0
equiv provided 3a in 95% yield along with 90% ee within 72 h
in 0.5 mL of THF (Table 2, entry 13). Examination of reaction
temperatures under these reaction conditions indicated that the
2-furyl
2-thienyl
4-NO2C6H4 120
120
48
72
3s, 61(80)d 92 (90)d
OMe 4-ClC6H4
3t, 73
83
a Reactions were performed with 1 (0.20 mmol), 2(0.10 mmol) and 15 mol%
of catalyst in solvent (0.50 mL). b Yield of isolated product. c Determined
by HPLC on a chiral stationary phase. d Reactions were carried out at
◦
reaction should be carried out at 0 C and the ee of 3a could be
0
◦C.
improved at -10 ◦C (Table 2, entries 14–15).
Having identified the optimal conditions, we next examined
the generality of this reaction with various O-Boc-protected
MBH adducts 2, and the results are summarized in Table 3.
For substrates 2b–2p bearing electron-withdrawing groups or
electron-donating groups on their aromatic rings, the asymmetric
substitution reactions with 1a proceeded smoothly to give the
corresponding products 3b–3p in 68–99% yields along with
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60–92% ee at 0 ◦C or -10 ◦C, suggesting that the electronic
property of substituents at the aromatic rings of 2 did not have a
significant impact on the reaction outcomes (Table 3, entries 1–15).
Only in the case of substrate 2l having a 3-nitrophenyl group, the
desired product 3l was formed in 89% yield along with 60% ee at
0 ◦C in THF (Table 3, entry 11). Furthermore, in the asymmetric
substitution reaction of O-Boc-protected MBH adducts 2q and 2r
having heteroaromatic groups, the corresponding products 3q and
3r were obtained in good yields along with moderate ee values
(39% ee and 62% ee), presumably due to the electronic property
of the heteroaromatic ring of MBH adducts (Table 3, entries 16
and 17). Using substrates 2s and 2t, in which R1 = Et and OMe, in
this reaction also afforded the desired products 3s and 3t in 61%
yield along with 92% ee at 0 ◦C and 73% yield along with 83%
ee at room temperature, respectively (Table 3, entries 18 and 19).
Carrying out the reaction of 2s with 1a at -10 ◦C could improve
the ee value of 3s but along with a sacrifice in yield, presumably
due to the steric effect of the ethyl group in MBH adduct 2 and
the electronic properties of the OMe group in MBH adduct 2,
respectively (Table 3, entry 18).
Table 5 (DHQD)2PYR-catalyzed asymmetric substitution of O-
Boc-protected Morita–Baylis–Hillman adducts
2 with 1H-indole-2-
carbonitrile 1h
Entrya
Ar
t [h]
Yield [%]b
ee [%]c
1
2
3
4
5
6
4-ClC6H4, 2a
4-FC6H4, 2b
4-CF3C6H4, 2c
4-BrC6H4, 2h
4-NO2C6H4, 2j
4-CNC6H4, 2l
72
96
96
96
96
72
5a, 99
5b, 91
5c, 67
5d, 98
5e, 93
5f, 98
95
96
92
96
95
92
a Reactions were performed with1 (0.20 mmol), 2 (0.10 mmol) and 15 mol%
of catalyst in THF (0.50 mL) at -10 ◦C. b Yield of isolated product.
c Determined by HPLC on a chiral stationary phase.
96%) under standard conditions (Table 4, entries 1–11), except
substrate 4c, bearing a p-CF3 group. The reason for its lower yield
may be due to the steric interaction between the CF3 substituent
and the BnC(O) substituent at the pyrrole ring (Table 4, entry
3). To be noted, when the R3 group was replaced by bromine
or a cyano group, the ee values of the corresponding products
decreased although their yields were still good, perhaps due to the
electronic effect of the pyrrole moiety (Table 4, entries 9 and 10).
1H-Indole-2-carbonitrile 1h is also a suitable substrate in this
asymmetric substitution reaction. As shown in Table 5, the
corresponding products 5a–5f were obtained in 67–99% yields
along with 92–96% ee in the reactions with 2a–2c, 2h, 2j and
2l under the standard conditions (Table 5, entries 1–6), further
suggesting the wide substrate scope in this asymmetric substitution
reaction. Notably, the main reason for the relatively low yield of
5c having a p-CF3 group may be also due to the steric interaction
between the CF3 substituent with the indole ring as mentioned
above (Table 5, entry 3).
We next attempted to use various pyrrole derivatives including
4-(2-phenylacetyl)-1H-pyrrole-2-carbonitrile 1b, 4-acetyl-1H-
pyrrole-2-carbonitrile 1c, 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-
ethanone
1d,
1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-
ethanone 1e, 1H-pyrrole-2,4-dicarbonitrile 1f and 1H-pyrrole-
2-carbaldehyde 1g in this reaction and the results of these
experiments are summarized in Table 4. Base on the relatively
better results obtained from Table 3, we focused on the use of
p-substituted substrates in this reaction. As can be seen from
Table 4, these reactions proceeded smoothly to give the desired
products 4a–4j in good yields with good to high ee values (up to
Table 4 (DHQD)2PYR-catalyzed asymmetric substitution of O-Boc-
protected Morita–Baylis–Hillman Adducts 2 with various pyrrole deriva-
tives 1
The absolute configuration of product 3 was unequivocally
assigned as (R)-configuration by X-ray diffraction of 3h bearing
a bromine atom on the benzene ring. Its ORTEP drawing is
shown in Fig. 1 and its CIF data are presented in the Supporting
Information.†9
Entrya
1
Ar
t [h]
Yield [%]b
ee [%]c
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1b
1c
1d
1e
1f
4-ClC6H4, 2a
4-FC6H4, 2b
4-CF3C6H4, 2c
4-BrC6H4, 2h
4-NO2C6H4, 2j
C6H5, 2m
4-ClC6H4, 2a
4-ClC6H4, 2a
4-ClC6H4, 2a
4-ClC6H4, 2a
4-ClC6H4, 2a
100
100
100
100
100
100
100
72
4a, 75
4b, 70
4c, 46
4d, 77
4e, 63
4f, 58
4g, 76
4h, 83
4i, 71
4j, 84
4k, 70
96
91
91
94
93
89
94
90
84
85
92
9
10
11
72
100
100
Fig. 1 ORTEP drawing of 3h.
1g
In light of the experimental results described above and recent
studies,10 we proposed a possible transition state for this asymmet-
ric substitution reaction although there are several possible confor-
mations of cinchona alkaloids in solution. The proposed possible
a Reactions were performed with 1 (0.20 mmol), 2 (0.10 mmol) and
15 mol% of catalyst in THF (0.50 mL) at 0 ◦C. b Yield of isolated product.
c Determined by HPLC on a chiral stationary phase.
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model to account for the high enantioselectivity is shown in Fig.
2. In the chiral pocket of the catalyst, the formed (DHQD)2PYR-
MBH adduct just above the 2,5-diphenylpyrimidine linker blocks
the rear face of this E isomer. While, on the other hand, the
aromatic ring of MBH substrate might be stabilized through
p–p stacking with the linker (we speculate that this may be
the main reason for the relatively low enantioselectivity for this
reaction catalyzed by the other bis(cinchona alkaloid) catalysts).
Subsequently the attack of the incoming nucleophile would
presumably take place on the re-face, which is consistent with
the experimental results.
tored by TLC with Huanghai GF254 silica gel coated plates. Flash
column chromatography was carried out using 300–400 mesh silica
gel at increased pressure. Cinchona alkaloids catalysts b-ICD8a
and catalysts cat. 1a–1e, cat. 2a–2c and cat. 3a were prepared
according to the literature procedure.4h Catalysts cat. 3b and cat.
3c were prepared based on Buchwald and Hartwig’s Pd-catalyzed
amination reaction.11 O-Boc-Protected Morita–Baylis–Hillman
products were prepared according to the literature procedure.4g
General procedure for the preparation of the catalysts
The reaction procedure for the preparation of the catalysts has
been summarized in the ESI† and the spectroscopic data of cat.
3b–3c are shown below.
4-((1S,5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl)-
N-phenylquinolin-6-amine cat. 3b: a yellow solid; [a]2D0 = +141.2
◦
1
(c 0.72, CHCl3); m.p. 166–168 C; H NMR (400 MHz, CDCl3,
TMS) d 1.03 (t, J = 7.5 Hz, 3H), 1.47 (dd, J = 12.8 Hz, 6.0 Hz,
1H), 1.69–1.80 (m, 4H), 1.94 (dd, J = 12.8 Hz, 6.0 Hz, 1H), 2.71
(d, J = 12.8 Hz, 1H), 3.40–3.46 (m, 2H), 4.15 (d, J = 12.8 Hz, 1H),
4.25 (d, J = 6.0 Hz, 1H), 5.28 (brs, 3H), 6.08 (s, 1H), 6.93 (t, J =
6.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 7.2 Hz, 2H), 7.45
(s,1H), 7.52 (d, J = 4.0 Hz, 1H), 7.72 (dd, J = 9.2 Hz, 2.0 Hz, 1H),
7.92–7.94 (m, 2H), 8.68 (d, J = 4.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 7.1, 21.5, 21.8, 27.1, 32.5, 45.7, 53.5, 58.0, 71.5, 76.1,
107.0, 118.6, 118.9, 120.1, 121.8, 126.2, 129.3, 130.8, 138.6, 142.2,
143.1, 143.4, 146.5; IR (neat) n 3445, 2935, 2360, 2342, 1601,1508,
1593, 1480, 1458, 1279, 1203. 1152, 1069, 822 cm-1; MS (%) m/z
385 (45), 328 (100), 346 (6), 285 (9), 233 (6), 166 (9); HRMS (EI)
for C25H26N3O: 385.2154; Found: 385.2158.
Fig. 2 Proposed model of the reaction transition state.
In summary, we have developed an interesting asymmetric
substitution process of O-Boc-protected Morita–Baylis–Hillman
adducts with various pyrrole and indole derivatives in the presence
of (DHQD)2PYR, affording the corresponding products in good
to high yields (up to 99% yield) and moderate to high ee values (up
to 92% ee and 96% ee) under mild conditions, which is applicable to
a wide range of substrates from MBH adducts. This new asymmet-
ric catalytic system can overcome the drawback in the asymmetric
substitution of Morita–Baylis–Hillman carbonates with methyl
pyrrole-2-carboxylate.6f Current efforts are in progress to use these
novel multifunctional quinidine derived organocatalysts for other
asymmetric catalysis.
N -(3,5-Dimethoxyphenyl)-4-((1S,5S)-3-ethyl-4-oxa-1-azatri-
cyclo[4.4.0.03,8]decan-5-yl)quinolin-6-amine ca◦t. 3c: a yellow solid;
1
[a]2D0 = +63.6 (c 0.31, CHCl3); m.p. 179–182 C; H NMR (400
MHz, CDCl3, TMS) d 1.06 (t, J = 7.2 Hz, 3H), 1.50 (dd, J = 13.2
Hz, 6.8 Hz, 1H), 1.73–1.86 (m, 4H), 1.98 (dd, J = 13.2 Hz, 6.8 Hz,
1H), 2.38 (s, 1H), 3.04 (d, J = 13.2 Hz, 1H), 3.41–3.43 (m, 2H), 3.75
(s, 6H), 4.16 (d, J = 13.2 Hz, 1H), 4.24 (d, J = 6.4 Hz, 1H), 5.00
(brs, 2H), 6.09 (s, 2H), 6.34 (s, 2H), 7.31 (s, 1H), 7.55 (d, J = 4.0 Hz,
1H), 7.78 (d, J = 9.2 Hz, 1H), 7.92–7.96 (m, 2H), 8.70 (d, J = 4.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) d 7.2, 23.2, 23.9, 27.2, 32.7,
46.3, 54.3, 55.2, 56.3, 72.8, 93.6, 96.2, 107.6, 119.1, 122.0, 126.6,
131.0, 141.4, 142.1, 143.8, 144.5, 147.3, 161.5; IR (neat) n 3396,
2928, 2359, 1608, 1508, 1480, 1463, 1279, 1204, 1152, 1069, 1014,
860, 823 cm-1; MS (%) m/z 445 (65), 388 (100), 346 (6), 223 (6),
166 (6); HRMS (EI) for C27H31N3O3: 445.2365; Found: 445.2371.
Experimental section
General remarks
1H NMR spectra were recorded on a Bruker AM-300 or AM-
400 spectrometer for solution in CDCl3 with tetramethylsilane
(TMS) as internal standard; J-values are in Hz. Mass spectra
were recorded with a HP-5989 instrument. All of the compounds
reported in this paper gave satisfactory HRMS analytic data.
Melting points were determined on a digital melting point
apparatus and temperatures were uncorrected. Optical rotations
were determined at 589 nm (sodium D line) using a Perkin-Elmer-
341 MC digital polarimeter; [a]D-values are given in units of 10
deg-1 cm2 g-1. Infrared spectra were recorded on a Perkin-Elmer
PE-983 spectrometer with absorption in cm-1. Chiral HPLC was
performed on a SHIMADZU SPD-10A vp series with chiral
columns (Chiralpak AD-H, IC-H columns 4.6 ¥ 250 mm, (Daicel
Chemical Ind., Ltd.)). THF, toluene and Et2O were distilled
from sodium (Na) under argon (Ar) atmosphere. CH3CN, 1,2-
dichloroethane and dichloromethane were distilled from CaH2
under argon (Ar) atmosphere. Commercially obtained reagents
were used without further purification. All reactions were moni-
Typical procedure for the preparation of Boc-protected
Morita–Baylis–Hillman adducts
The reaction procedure for the preparation of Boc-protected
Morita–Baylis–Hillman adducts has been summarized in the ESI†
and their spectroscopic data are shown below.
tert-Butyl (1-(4-fluorophenyl)-2-methylene-3-oxob◦utyl) carbon-
ate 2b: a white solid (2.99 g, 74% yield); m.p. 84–87 C; 1H NMR
(400 MHz, CDCl3, TMS) d 1.45 (s, 9H), 2.32 (s, 3H), 6.16 (d, J =
1.2 Hz, 1H), 6.24 (s, 1H), 6.52 (s, 1H), 7.00 (t, J = 8.4 Hz, 2H), 7.37
(dd, J = 5.2 Hz, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3) d 26.1, 27.7, 74.4, 82.7, 115.3
(d, JC-F = 21.5 Hz), 125.2, 129.3 (d, JC-F = 8.1 Hz), 133.8 (d,
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JC-F = 2.9 Hz), 147.6, 152.2, 162.5 (d, JC-F = 245.4 Hz), 197.2;
19F NMR (376 MHz, CDCl3): d -113.803– -113.728 (m, 1F); IR
(neat) n 2982, 2935, 1747, 1682, 1606, 1510, 1082, 973, 839 cm-1;
MS (ESI) m/z 317.2 M + Na); HRMS (ESI) for C16H19FNa1O4
(M + Na): 317.1160; Found: 317.1173.
tert-Butyl (1-(2,3-dichlorophenyl)-2-methylene-3-oxobutyl) car-
bonate 2g: a white solid (1.14 g, 33% yield); m.p. 114–117 ◦C; 1H
NMR (400 MHz, CDCl3, TMS) d 1.47 (s, 9H), 2.39 (s, 3H), 5.81
(d, J = 1.2 Hz, 1H), 6.31 (s, 1H), 6.94 (s, 1H), 7.22 (t, J = 8.0 Hz,
1H), 7.29 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.43 (dd, J = 1.6 Hz,
J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 26.0, 27.6, 72.0,
83.0, 126.0, 127.3, 128.2, 130.2, 131.6, 133.6, 138.1, 145.6, 152.0,
196.8; IR (neat) n 2979, 2920, 2351, 1744, 1670, 1566, 1414, 1279,
959, 847 cm-1; MS (ESI) m/z 367.1 (M + Na); HRMS (ESI) for
C16H18Cl2Na1O4 (M + Na): 367.0474; Found: 367.0492.
J = 1.6 Hz, 2.8 Hz, 1H), 6.72 (s, 1H), 6.88 (dd, J = 1.6 Hz, 4.0 Hz,
1H), 7.25 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H);13C NMR
(100 MHz, CDCl3): d 25.9, 60.5, 104.6, 109.8, 113.1, 121.1, 123.7
(q, JC-F = 270.7 Hz), 125.4, 126.0 (q, JC-F = 3.7 Hz), 128.2, 129.3,
130.5 (q, JC-F = 32.7 Hz), 140.6, 146.7, 196.4; 19F NMR (CDCl3,
376 MHz, CFCl3): d -62.759 (s, 3F); IR (neat) n 2925, 2218,
1740, 1682, 1621, 1523, 1418, 1323, 1264, 1166, 1114, 1068, 823,
738 cm-1; MS (%) m/z 318 (11), 115 (8), 89 (4), 57 (7), 43 (100);
HRMS (EI) for C17H13N2OF3: 318.0980; Found: 318.0981; [a]D20
-80.3 (c 1.50, CHCl3) (88% ee); Chiralcel OD-H, hexane/iPrOH =
80 : 20, 0.7 mL min-1, 230 nm, tmajor = 11.20 min, tminor = 8.56 min.
(R)-1-(1-(3-Chlorophenyl)-2-methylene-3-oxobutyl)-1H-pyrro-
le-2-carbonitrile 3d: a yellow oil (25 mg, 88% yield); 1H NMR (400
MHz, CDCl3, TMS) d 2.41 (s, 3H), 5.42 (s, 1H), 6.18 (t, J = 3.2 Hz,
1H), 6.45 (s, 1H), 6.61 (t, J = 2.0 Hz, 1H), 6.63 (s, 1H), 6.87 (dd, J =
1.6 Hz, 4.0 Hz, 1H), 7.03–7.05 (m, 1H), 7.11–7.12 (m, 1H), 7.30–
7.35 (m, 2H); 13C NMR (100 MHz, CDCl3) d 25.9, 60.5, 104.5,
109.6, 113.2, 121.0, 125.5, 126.2, 128.0, 128.9, 129.0, 130.3, 135.0,
138.5, 146.9, 196.4; IR (neat) n 2925, 2854, 2216, 1679, 1575, 1429,
1365, 1286, 1227, 1116, 1072, 977, 736 cm-1; MS (%) m/z 284 (34),
242 (4), 193 (5), 115 (19), 89 (7), 57 (6), 43 (100); HRMS (EI)
for C16H13N2OCl: 284.0716; Found: 284.0719; [a]2D0 -198.5 (c 0.80,
CHCl3) (85% ee); Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7
mL min-1, 230 nm, tmajor = 12.20 min, tminor = 10.92 min.
General procedure for the preparation of 3 from the reaction of 1a
with 2a using 3a as an example in the presence of (DHQD)2PYR
A solution of compound 1a (0.2 mmol, 17 mL) and compound 2a
(0.1 mmol, 31 mg) in THF (0.5 mL) was stirred at -10 ◦C for 96 h
in the presence of organocatalyst (DHQD)2PYR (0.015 mmol,
13 mg) under an argon atmosphere. The solvent was removed
under reduced pressure and the residue was chromatographed on
silica gel (elution with petroleum ether/EtOAc = 16 : 1–8 : 1) to
provide the corresponding product 3a.
(S)-1-(1-(2-Chlorophenyl)-2-methylene-3-oxobutyl)-1H-pyrrole-
1
2-carbonitrile 3e: a yellow oil (27 mg, 95% yield); H NMR (400
(R)-1-(1-(4-Chlorophenyl)-2-methylene-3-oxobutyl)-1H-pyrro-
le-2-carbonitrile 3a: a white solid (23 mg, 81% yield); m.p. 91–
MHz, CDCl3, TMS) d 2.42 (s, 3H), 5.36 (d, J = 0.8 Hz, 1H),
6.18 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.44 (s, 1H), 6.58 (dd, J = 1.6
Hz, 2.8 Hz, 1H), 6.87 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 6.88–6.91
(m, 1H), 6.96 (s, 1H), 7.23–7.34 (m, 2H), 7.43–7.45 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 26.0, 58.4, 104.8, 109.5, 113.1, 120.9,
125.5, 127.1 128.1, 128.7, 130.1, 130.4, 134.1, 134.7, 146.2, 196.2;
IR (neat) n 2924, 2854, 2216, 1679, 1469, 1409, 1365, 1290, 1116,
1052, 976, 855, 738 cm-1; MS (%) m/z 284 (4), 249 (36), 193 (5),
115 (15), 84 (9), 57 (7), 43 (100); HRMS (EI) for C16H13N2OCl:
284.0716; Found: 284.0715; [a]2D0 -72.9 (c 1.35, CHCl3) (90% ee);
Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm,
tmajor = 13.61 min, tminor = 12.34 min.
(R)-1-(1-(3,4-Dichlorophenyl)-2-methylene-3-oxobutyl)-1H-
pyrrole-2-carbonitrile 3f: a yellow oil (29 mg, 91% yield); 1H NMR
(400 MHz, CDCl3, TMS) d 2.42 (s, 3H), 5.44(s, 1H), 6.20 (dd,
J = 2.4 Hz, 4.0 Hz, 1H), 6.47 (s, 1H), 6.60–6.61 (m, 2H), 6.88
(dd, J = 1.6 Hz, 4.0 Hz, 1H), 6.99 (dd, J = 2.4 Hz, 8.0 Hz, 1H),
7.21 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) d 26.0, 60.1, 104.6, 109.8, 113.1, 121.2, 125.4, 127.3,
129.1, 129.8, 131.0, 133.1, 133.4, 136.7, 146.7, 196.3; IR (neat) n
2925, 2855, 2216, 1677, 1523, 1470, 1365, 1285, 1115, 1073, 961,
879, 817, 737 cm-1; MS (%) m/z 318 (17), 227 (4), 149 (10), 57
(3), 43 (100); HRMS (EI) for C16H12N2OCl2: 318.0327; Found:
318.0323; [a]2D0 -154.5 (c 1.20, CHCl3) (90% ee); Chiralcel OD-H,
hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm, tmajor = 13.01 min,
tminor = 9.69 min.
◦
1
92 C; H NMR (400 MHz, CDCl3, TMS) d 2.40 (s, 3H), 5.40
(s, 1H), 6.17 (dd, J = 2.4 Hz, 4.0 Hz, 1H), 6.44 (s, 1H), 6.60 (dd,
J = 1.6 Hz, 2.4 Hz, 1H), 6.63 (s, 1H), 6.86 (dd, J = 1.6 Hz, 4.0
Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 26.0, 60.4, 104.4, 109.5, 113.2, 121.0,
125.5, 128.7, 129.2, 129.3, 134.7, 134.9, 147.0, 196.4; IR (neat) n
2924, 2854, 2215, 1678, 1490, 1367, 1225, 1088, 1070, 969, 861,
815, 735 cm-1; MS (%) m/z 284 (35), 242 (4), 193 (11), 149 (4),
115 (22), 89 (4), 57 (6), 43 (100); HRMS (EI) for C16H13N2OCl:
284.0716; Found: 284.0718; [a]2D0 -116.6 (c 0.35, CHCl3) (92% ee);
Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm,
tmajor = 12.10 min, tminor = 9.65 min.
(R)-1-(1-(4-Fluorophenyl)-2-methylene-3-oxobutyl)-1H-pyrrole-
1
2-carbonitrile 3b: a yellow oil (21 mg, 78% yield); H NMR (400
MHz, CDCl3, TMS) d 2.40 (s, 3H), 5.38 (s, 1H), 6.16 (dd, J = 3.2
Hz, 4.0 Hz, 1H), 6.43 (s, 1H), 6.59 (t, J = 2.0 Hz, 1H), 6.64 (s, 1H),
6.86 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.07 (t, J = 8.8 Hz, 2H), 7.15 (dd,
J = 5.2 Hz, 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 26.0, 60.4,
104.4, 109.4, 113.2, 116.0 (d, JC-F = 21.5 Hz), 121.0, 125.5, 128.3,
129.8 (d, JC-F = 8.2 Hz), 132.1 (d, JC-F = 3.0 Hz), 147.3, 162.7 (d,
JC-F = 246.9 Hz), 196.5; 19F NMR (376 MHz, CDCl3): d -112.674
(s, 1F); IR (neat) n 2925, 2853, 2216, 1681, 1509, 1410, 1366, 1293,
1226, 1172, 977, 823, 739 cm-1; MS (ESI) m/z 291.2 (M + Na);
HRMS (ESI) for C16H13FN2NaO (M + Na): 291.0904; Found:
291.0914; [a]2D0 -197.9 (c 0.60, CHCl3) (82% ee); Chiralcel AD-H,
hexane/iPrOH = 70 : 30, 0.6 mL min-1, 214 nm, tmajor = 7.62 min,
tminor = 8.42 min.
(S)-1-(1-(2,3-Dichlorophenyl)-2-methylene-3-oxobutyl)-1H-py-
rrole-2-carbonitrile 3g: a white solid (29 mg, 91% yield); m.p. 124–
126 ◦C 1H NMR (300 MHz, CDCl3, TMS) d 2.43 (s, 3H), 5.40 (s,
1H), 6.20 (s, 1H), 6.46 (s, 1H), 6.60 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H),
6.88 (s, 1H), 6.97 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) d 25.9, 58.9, 104.8, 109.7,
113.0, 121.1, 125.4, 126.2, 127.5, 129.1, 130.8, 132.4, 134.4, 137.2,
(R)-1-(2-Methylene-3-oxo-1-(4-(trifluoromethyl)phenyl)butyl)-
1H-pyrrole-2-carbonitrile 3c: a colorless oil (29 mg, 91% yield); 1H
NMR (400 MHz, CDCl3, TMS) d 2.42 (s, 3H), 5.45 (d, J = 1.2
Hz, 1H), 6.20 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.49 (s, 1H), 6.63 (dd,
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145.9, 196.1; IR (neat) n 2923, 2850, 2214, 1676, 1447, 1411, 1365,
1290, 1177, 1121, 1047, 963, 876, 745 cm-1; MS (%) m/z 318 (4),
283 (37), 149 (11), 113 (5), 43 (100); HRMS (EI) for C16H12N2OCl2:
318.0327; Found: 318.0325; [a]2D0 -119.5 (c 0.90, CHCl3) (91% ee);
Chiralcel AD-H, hexane/iPrOH = 90 : 10, 0.7 mL min-1, 230 nm,
tmajor = 11.88 min, tminor = 10.92 min.
(R) - 1 - (1 - (4 - Bromophenyl) - 2 - methylene - 3 - oxobutyl)-
1H-pyrrole-2-carbonitrile 3h: a white solid (27 mg, 82% yield); m.p.
87–89 ◦C 1H NMR (400 MHz, CDCl3, TMS) d 2.40 (s, 3H), 5.41
(s, 1H), 6.17 (dd, J = 2.4 Hz, 3.6 Hz, 1H), 6.44 (s, 1H), 6.60–6.62
(m, 1H), 6.85 (dd, J = 1.6 Hz, 3.6 Hz, 1H), 7.01 (d, J = 8.4 Hz,
2H), 7.50 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 26.0,
60.5, 104.5, 109.6, 113.2, 121.0, 122.9, 125.5, 128.9, 129.6, 132.2,
135.6, 146.9, 196.5; IR (neat) n 2925, 2215, 1940, 1680, 1521, 1367,
1440, 1350, 1224, 1170, 1069, 818, 737 cm-1; MS (%) m/z 328 (8),
237 (4), 158 (13), 115 (17), 89 (4), 84 (4), 63 (4), 43 (100); HRMS
(EI) for C16H13N2OBr: 328.0211; Found: 328.0209; [a]2D0 -177.0 (c
0.25, CHCl3) (91% ee); Chiralcel OD-H, hexane/iPrOH = 80 : 20,
0.7 mL min-1, 230 nm, tmajor = 12.42 min, tminor = 9.91 min.
(R)-1-(2-Methylene-1-(3-nitrophenyl)-3-oxobutyl)-1H-pyrrole-
2-carbonitrile 3l: a yellow oil (25 mg, 84% yield); H NMR (400
1
MHz, CDCl3, TMS) d 2.45 (s, 3H), 5.51 (t, J = 1.2 Hz, 1H), 6.24
(dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.55 (s, 1H), 6.64 (dd, J = 1.6 Hz,
2.8 Hz, 1H), 6.76 (s, 1H), 6.90 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.49–
7.51 (m, 1H), 7.59–7.63 (m, 1H), 7.96–7.97 (m, 1H), 8.22–8.25 (m,
1H); 13C NMR (100 MHz, CDCl3) d 26.0, 60.3, 104.6, 110.1, 113.0,
121.3, 122.5, 123.7, 125.4, 129.7, 130.2, 134.1, 138.9, 146.3, 148.6,
196.4; IR (neat) n 2926, 2855, 2216, 1679, 1529, 1456, 1409, 1349,
1291, 1073, 967, 808, 730 cm-1; MS (%) m/z 295 (14), 278 (32),
162 (6), 115 (14), 92 (11), 43 (100); HRMS (EI) for C16H13N3O3:
295.0957; Found: 295.0953; [a]2D0 -122.5 (c 1.10, CHCl3) (78% ee);
Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm,
tmajor = 23.20 min, tminor = 18.43 min.
(R)-1-(1-(4-Cyanophenyl)-2-methylene-3-oxobutyl)-1H-pyrrole-
1
2-carbonitrile 3m: a colorless oil (27.3 mg, 99% yield); H NMR
(400 MHz, CDCl3, TMS) d 2.43 (s, 3H), 5.49 (s, 1H), 6.22 (dd,
J = 2.8 Hz, 4.0 Hz, 1H), 6.52 (s, 1H), 6.64 (dd, J = 1.6 Hz, 2.8
Hz, 1H), 6.71 (s, 1H), 6.88 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.23 (d,
J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 25.9, 60.4, 104.6, 110.0, 112.6, 113.0, 118.0, 121.1,
125.3, 128.4, 129.8, 132.7, 141.9, 146.3, 196.3; IR (neat) n 2925,
2854, 2216, 1678, 1454, 1410, 1366, 1295, 1115, 1073, 976, 818,
740 cm-1; MS (%) m/z 275 (85), 260 (12), 232 (11), 184 (15), 142
(51), 92 (11), 43 (100); HRMS (EI) for C17H13N3O: 275.1059;
Found: 275.1055; [a]2D0 -121.1 (c 1.50, CHCl3) (88% ee); Chiralcel
(R)-1-(1-(3-Bromophenyl)-2-methylene-3-oxobutyl)-1H-pyrrole-
1
2-carbonitrile 3i: a yellow oil (32 mg, 97% yield); H NMR (400
MHz, CDCl3, TMS) d 2.41 (s, 3H), 5.42 (s, 1H), 6.18 (t, J = 2.8
Hz, 1H), 6.45 (s, 1H), 6.62 (s, 2H), 6.86 (d, J = 2.8 Hz, 1H), 7.08
(d, J = 8.0 Hz, 1H), 7.23–7.27 (m, 2H), 7.49 (d, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3) d 26.0, 60.5, 104.6, 109.7, 113.2, 121.0,
123.1, 125.6, 126.7, 129.0, 130.6, 130.9, 132.0, 138.7, 146.9, 196.4;
IR (neat) n 2925, 2853, 2216, 1679, 1570, 1456, 1409, 1365, 1286,
1226, 1116, 1072, 976, 738, 688 cm-1; MS (%) m/z 328 (6), 253
(4), 207 (1), 158 (8), 115 (15), 84 (8), 57 (5), 43 (100); HRMS
(EI) for C16H13N2OBr: 328.0211; Found: 328.0215; [a]2D0 -107.1
(c 1.50, CHCl3) (84% ee); Chiralcel OD-H, hexane/iPrOH =
OD-H, hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm, tmajor
26.84 min, tminor = 19.98 min.
=
(R)-1-(2-Methylene-3-oxo-1-phenylbutyl)-1H-pyrrole-2-carbo-
1
nitrile 3n: a yellow oil (17 mg, 68% yield); H NMR (400 MHz,
CDCl3, TMS) d 2.39 (s, 3H), 5.38 (t, J = 0.8 Hz, 1H), 6.15 (t, J =
3.2 Hz, 1H), 6.41 (s, 1H), 6.60–6.61 (m, 1H), 6.66 (s, 1H), 6.85 (dd,
J = 1.2 Hz, 3.2 Hz, 1H), 7.14–7.16 (m, 2H), 7.34–7.39 (m, 3H); 13
C
80 : 20, 0.7 mL min-1, 230 nm, tmajor = 16.58 min, tminor
=
15.28 min.
(S)-1-(1-(2-Bromophenyl)-2-methylene-3-oxobutyl)-1H-pyrrole-
2-carbonitrile 3j: a yellow oil (31 mg, 94% yield); H NMR (400
NMR (100 MHz, CDCl3) d 26.1, 61.2, 104.4, 109.3, 113.4, 120.9,
125.7, 128.0, 128.3, 128.8, 129.0, 136.3, 147.4, 196.6; IR (neat) n
3124, 2216, 1740, 1680, 1598, 1451, 1365, 1292, 1171, 976, 734, 699
cm-1; MS (%) m/z 250 (18), 235 (4), 207 (3), 159 (7), 115 (14), 91
(4), 57 (8), 43 (100); HRMS (EI) for C16H14N2O: 250.1106; Found:
250.1103; [a]2D0 -165.6 (c 0.75, CHCl3) (82% ee); Chiralcel OD-H,
hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm, tmajor = 16.49 min,
tminor = 14.90 min.
1
MHz, CDCl3, TMS) d 2.42 (s, 3H), 5.35 (s, 1H), 6.18 (dd, J =
2.8 Hz, 4.0 Hz, 1H), 6.45 (s, 1H), 6.57 (dd, J = 1.6 Hz, 2.8 Hz,
1H), 6.87 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 6.88–6.91 (m, 1H), 6.92
(s, 1H), 7.21–7.32 (m, 2H), 7.62–7.64 (m, 1H); 13C NMR (100
MHz, CDCl3) d 26.0, 60.8, 104.9, 109.5, 113.0, 120.9, 124.5,
125.5, 127.7, 128.3, 128.8, 130.2, 133.8, 136.3, 146.4, 196.2; IR
(neat) n 2367, 2218, 1678, 1521, 1406, 1281, 1220, 1111, 1074,
978, 751 cm-1; MS (ESI) m/z 351.2 (M + Na); HRMS (ESI) for
C16H13BrN2NaO (M + Na): 351.0104; Found: 351.0116; [a]D20
-84.2 (c 0.67, CHCl3) (84% ee); Chiralcel OD-H, hexane/iPrOH =
80 : 20, 0.7 mL min-1, 230 nm, tmajor = 11.07 min, tminor = 9.88 min.
(R)-1-(2-Methylene-1-(4-nitrophenyl)-3-oxobutyl)-1H-pyrrole-
2-carbonitrile 3k: a yellow oil (30 mg, 99% yield); 1H NMR (400
MHz, CDCl3, TMS) d 2.45 (s, 3H), 5.52 (s, 1H), 6.24 (t, J = 2.8
Hz, 3.6 Hz, 1H), 6.54 (s, 1H), 6.66 (d, J = 1.2 Hz, 1H), 6.75 (s, 1H),
6.90 (dd, J = 1.2 Hz, 4.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 8.24
(d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 26.0, 60.3,
104.7, 110.1, 113.0, 121.3, 124.2, 125.3, 128.7, 129.8, 143.8, 146.3,
147.9, 196.3; IR (neat) n 2923, 2853, 2216, 1679, 1605, 1520, 1440,
1346, 1227, 1173, 976, 856, 735 cm-1; MS (%) m/z 295 (465), 278
(49), 236 (15), 162 (18), 115 (9), 92 (11), 43 (100); HRMS (EI)
for C16H13N3O3: 295.0957; Found: 295.0956; [a]2D0 -87.9 (c 1.50,
CHCl3) (93% ee); Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7
mL min-1, 230 nm, tmajor = 31.61 min, tminor = 22.63 min.
(R)-1-(2-Methylene-3-oxo-1-(p-tolyl)butyl)-1H-pyrrole-2-
◦
carbonitrile 3o: a white solid (21 mg, 80% yield); m.p. 63–65 C
1H NMR (400 MHz, CDCl3, TMS) d 2.34 (s, 3H), 2.38 (s, 3H),
5.34 (d, J = 1.2 Hz, 1H), 6.13 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.39 (s,
1H), 6.59 (dd, J = 1.6 Hz, 2.8 Hz, 1H), 6.61 (s, 1H), 6.84 (dd, J =
1.6 Hz, 4.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 21.1, 26.1, 61.0, 104.3, 109.1,
113.4, 120.8, 125.8, 127.9, 128.0, 129.7, 133.2, 138.7, 147.6, 196.6;
IR (neat) n 2925, 2854, 1718, 1622, 1560, 1467, 1380, 1259, 1186,
1082, 965, 763 cm-1; MS (%) m/z 264 (20), 249 (7), 173 (10), 131
(7), 115 (7), 91 (3), 84 (3), 43 (100); HRMS (EI) for C17H16N2O:
264.1263; Found: 264.1267; [a]2D0 -142.1 (c 1.00, CHCl3) (76% ee);
Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm,
tmajor = 13.81 min, tminor = 10.92 min.
(R)-1-(1-(2-Methoxyphenyl)-2-methylene-3-oxobutyl)-1H-
pyrrole-2-carbonitrile 3p: a white solid (26 mg, 93% yield); m.p.
95–97 ◦C; 1H NMR (400 MHz, CDCl3, TMS) d 2.38 (s, 3H), 3.80
(s, 3H), 5.31 (d, J = 1.2 Hz, 1H), 6.12 (dd, J = 2.8 Hz, 4.0 Hz, 1H),
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6.35 (s, 1H), 6.60 (dd, J = 1.6 Hz, 2.8 Hz, 1H), 6.83 (dd, J = 1.6
Hz, 4.0 Hz, 1H), 6.85–6.87 (m, 1H), 6.90–6.93 (m, 2H), 6.96 (s,
1H), 7.31–7.35 (m, 1H); 13C NMR (100 MHz, CDCl3) d 26.1, 55.6,
104.4, 108.8, 113.4, 120.4, 120.5, 125.0, 125.5, 127.3, 127.5, 130.1,
147.1, 156.7, 196.5; IR (neat) n 2924, 2854, 1713, 1671, 1598, 1490,
1463, 1361, 1250, 1111, 1022, 970, 745 cm-1; MS (%) m/z 280 (19),
189 (12), 147 (14), 115 (7), 91 (7), 71 (13), 57 (17), 43 (100); HRMS
(EI) for C17H16N2O2: 280.1212; Found: 280.1210; [a]2D0 -183.1 (c
0.50, CHCl3) (89% ee); Chiralcel OD-H, hexane/iPrOH = 80 : 20,
0.7 mL min-1, 230 nm, tmajor = 12.91 min, tminor = 11.29 min.
2853, 2216, 1679, 1605, 1520, 1440, 1346, 1227, 1173, 976, 856, 735
cm-1; MS (%) m/z 300 (58), 209 (47), 177 (16), 149 (69), 130 (27),
115 (100), 91 (15), 59 (50), 49 (15); HRMS (EI) for C16H13N2O2Cl:
300.0666; Found: 300.0663; [a]2D0 -110.0 (c 1.00, CHCl3) (83% ee);
Chiralcel AD, hexane/iPrOH = 70 : 30, 0.6 mL min-1, 214 nm,
tmajor = 7.37 min, tminor = 8.31 min.
General procedure for the preparation of 4 from the reaction of 1b
with 2a using 4a as an example in the presence of (DHQD)2PYR
(S)-1-(1-(Furan-2-yl)-2-methylene-3-oxobutyl)-1H-pyrrole-2-
A solution of compound 1b (0.2 mmol, 42 mg) and compound
2a (0.1 mmol, 31 mg) in THF (0.5 mL) was stirred at 0 ◦C in the
presence of organocatalyst (DHQD)2PYR (0.015 mmol, 13 mg)
under argon atmosphere. The reaction solution was monitored by
TLC. After the reaction complete, the solvent was removed under
reduced pressure and the residue was chromatographed on silica
gel (elution with petroleum ether/EtOAc = 4 : 1–2 : 1) to provide
the corresponding product 4a.
1
carbonitrile 3q: a yellow oil (18 mg, 75% yield); H NMR (400
MHz, CDCl3, TMS) d 2.40 (s, 3H), 5.50 (t, J = 1.2 Hz, 1H), 6.17
(dd, J = 2.8 Hz, J = 4.0 Hz, 1H), 6.28 (dd, J = 0.8 Hz, J = 4.0 Hz,
1H), 6.36 (s, 1H), 6.38 (dd, J = 1.6 Hz, J = 4.0 Hz, 1H), 6.67 (s,
1H), 6.69 (dd, J = 1.6 Hz, J = 2.8 Hz, 1H), 6.85 (dd, J = 1.6 Hz,
J = 4.0 Hz, 1H), 7.44 (dd, J = 0.8 Hz, J = 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 25.9, 55.0, 103.8, 109.4, 110.6, 110.7, 113.1,
121.0, 125.8, 127.6, 143.6, 145.5, 149.0, 196.2; IR (neat) n 2924,
2855, 2217, 1680, 1454, 1409, 1366, 1286, 1142, 1116, 1071, 1015,
961, 808, 815 cm-1; MS (ESI) m/z 263.1 (M + Na); HRMS (ESI)
(R)-1-(1-(4-Chlorophenyl)-2-methylene-3-oxobutyl)-4-(2-phe-
nylacetyl)-1H-pyrrole-2-carbonitrile 4a: a white oil (30 mg, 75%
yield); 1H NMR (400 MHz, CDCl3, TMS) d 2.40 (s, 3H), 3.97 (s,
2H), 5.44 (t, J = 1.2 Hz, 1H), 6.47 (s, 1H), 6.59 (s, 1H), 7.03 (d, J =
8.4 Hz, 2H), 7.11 (d, J = 1.6 Hz, 1H), 7.18–7.20 (m, 2H), 7.25–7.32
(m, 4H), 7.37 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 25.9, 47.0, 60.9, 106.3, 111.8, 121.1, 124.8, 127.0, 128.7, 129.2,
129.3, 129.6, 133.6, 134.2, 135.3, 146.1, 191.8, 196.1; IR (neat) n
2925, 2855, 2222, 1674, 1538, 1491, 1367, 1277, 1216, 1157, 1068,
977, 931, 863, 835, 724, 637 cm-1; MS (%) m/z 311 (48), 193 (28),
115 (13), 91 (31), 65 (8), 43 (100); HRMS (EI) for C24H19N2O2Cl:
402.1135; Found: 402.1138; [a]2D0 -10.1 (c 0.60, CHCl3) (96% ee);
for C20H20N2NaO7S (M + Na): 263.0791; Found: 263.0801; [a]D20
=
+134 (c 0.17, CHCl3) (62% ee); Chiralcel OD-H, hexane/iPrOH =
80 : 20, 0.7 mL min-1, 230 nm, tmajor = 17.58 min, tminor = 24.15 min.
(S)-1-(2-Methylene-3-oxo-1-(thiophen-2-yl)butyl)-1H-pyrrole-
1
2-carbonitrile 3r: a yellow oil (23 mg, 89% yield); H NMR (400
MHz, CDCl3, TMS) d 2.40 (s, 3H), 5.48 (s, 1H), 6.16 (t, J = 3.2 Hz,
1H), 6.37 (s, 1H), 6.71 (d, J = 1.6 Hz, 1H), 6.85 (dd, J = 1.6 Hz, 4.0
Hz, 1H), 6.87 (s, 1H), 6.95–6.96 (m, 1H), 7.00–7.02 (m, 1H), 7.34–
7.35 (m, 1H); 13C NMR (100 MHz, CDCl3) d 26.0, 56.3, 104.0,
109.4, 113.2, 121.1, 125.7, 127.0, 127.2, 127.3, 128.0, 138.9, 147.7,
196.2; IR (neat) n 2925, 2854, 2216, 1669, 1574, 1468, 1359, 1254,
1082, 1065, 972, 851, 760 cm-1; MS (ESI) m/z 279.1 (M + Na);
HRMS (ESI) for C20H20N2NaO7S (M + Na): 279.0563; Found:
279.0576; [a]2D0 = +84.4 (c 1.1, CHCl3) (39% ee); Chiralcel OD-H,
hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm, tmajor = 10.47 min,
tminor = 12.70 min.
Chiralcel IC, hexane/iPrOH = 70 : 30, 0.7 mL min-1, 214 nm, tmajor
36.70 min, tminor = 32.15 min.
=
(R)-1-(1-(4-Fluorophenyl)-2-methylene-3-oxobutyl)-4-(2-phenyl-
acetyl)-1H-pyrrole-2-carbonitrile 4b: a white oil (27 mg, 70%
1
yield); H NMR (400 MHz, CDCl3, TMS) d 2.40 (s, 3H), 3.97
(s, 2H), 5.42 (s, 1H), 6.46 (s, 1H), 6.60 (s, 1H) 7.08–7.32 (m, 11H);
13C NMR (100 MHz, CDCl3) d 25.9, 47.0, 61.0, 106.2, 111.9, 116.4
(d, JC-F = 21.6 Hz), 121.1, 124.8, 127.0, 128.7, 128.8, 129.2, 129.8 (d,
(R)-1-(2-Methylene-1-(4-nitrophenyl)-3-oxobutyl)-1H-pyrrole-
1
2-carbonitrile 3s: a yellow oil (19 mg, 61% yield); H NMR (400
JC-F = 8.1 Hz), 130.8 (d, JC-F = 3.0 Hz), 145.2, 146.3, 162.9 (d, JC-F =
MHz, CDCl3, TMS) d 1.11 (t, J = 7.2 Hz, 3H), 2.81 (q, J = 7.2
Hz, 2H), 5.46 (dd, J = 0.8 Hz, 1.2 Hz, 1H), 6.23 (dd, J = 2.8 Hz,
4.0 Hz, 1H), 6.52 (s, 1H), 6.65 (dd, J = 1.6 Hz, 2.8 Hz, 1H), 6.76
(s, 1H), 6.90 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H),
8.24 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 7.9, 31.2,
60.6, 104.8, 110.1, 113.0, 121.3, 124.2, 125.3, 128.5, 128.7, 143.9,
146.0, 147.9, 199.1; IR (neat) n 2981, 2940, 2218, 1682, 1607, 1522,
1456, 1345, 1225, 1073, 979, 839, 739 cm-1; MS (ESI) m/z 332.3
(M + Na); HRMS (ESI) for C17H15N3NaO3S (M + Na): 332.1006;
Found: 332.1015; [a]2D0 -116.3 (c 1.00, CHCl3) (93% ee); Chiralcel
248.4 Hz), 191.8, 196.2;19F NMR (376 MHz, CDCl3): d -111.681–
-111.610 (m, 1F); IR (neat) n 2925, 2854, 2222, 1674, 1538, 1510,
1367, 1319, 1224, 1158, 978, 931, 868, 832, 764, 724, 637 cm-1;
MS (ESI) m/z 409.3 (M + Na); HRMS (ESI) for C24H19FN2NaO2
(M + Na): 409.1323; Found: 409.1341; [a]2D0 -11.1 (c 0.50, CHCl3)
(91% ee); Chiralcel IC, hexane/iPrOH = 70 : 30, 0.7 mL min-1, 214
nm, tmajor = 33.90 min, tminor = 33.29 min.
(R)-1-(2-Methylene-3-oxo-1-(4-(trifluoromethyl)phenyl)butyl)-
4-(2-phenylacetyl)-1H-pyrrole-2-carbonitrile 4c: a white oil (27 mg,
46% yield); 1H NMR (400 MHz, CDCl3, TMS) d 2.41 (s, 3H), 3.98
(s, 2H), 5.49 (t, J = 1.2 Hz, 1H), 6.52 (s, 1H), 6.68 (s, 1H), 7.14 (d,
OD-H, hexane/iPrOH = 90 : 10, 0.7 mL min-1, 230 nm, tmajor
32.22 min, tminor = 29.03min.
=
J = 1.6 Hz, 1H), 7.14–7.31 (m, 8H), 7.64 (d, J = 8.4 Hz, 2H); 13
C
(R)-Methyl 2-((4-chlorophenyl)(2-cyano-1H-pyrrol-1-yl)meth-
yl)acrylate 3t: a colorless oil (22 mg, 73% yield); H NMR (400
NMR (100 MHz, CDCl3) d 25.8, 47.0, 60.9, 106.3, 111.7, 119.5,
123.1 (q, JC-F = 270.7 Hz), 125.0, 126.2 (q, JC-F = 3.7 Hz), 127.0,
128.1, 128.6, 128.7, 129.2, 130.3, 131.3 (q, JC-F = 32.7 Hz), 134.2,
139.2, 145.7, 191.7, 196.1; 19F NMR (376 MHz, CDCl3): d -62.797
(s, 3F); IR (neat) n 3121, 2223, 1676, 1539, 1510, 1367, 1319, 1224,
1161, 1112, 1068, 978, 931, 863, 827, 722, 637 cm-1; MS (ESI) m/z
459.3 (M + Na); HRMS (ESI) for C25H19F3N2NaO2 (M + Na):
459.1291; Found: 459.1307; [a]2D0 = +21.1 (c 0.90, CHCl3) (91%
1
MHz, CDCl3, TMS) d 3.73 (s, 3H), 5.22 (d, J = 1.2 Hz, 1H),
6.19 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.56 (s, 1H), 6.59 (s, 1H), 6.65
(dd, J = 1.6 Hz, 2.8 Hz, 1H), 6.87 (dd, J = 1.6 Hz, 4.0 Hz, 1H),
7.11 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 52.4, 61.3, 104.5, 109.6, 113.1, 120.9, 125.2,
129.1, 129.2, 129.3, 134.7, 134.8, 139.1, 164.9; IR (neat) n 2923,
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ee); Chiralcel IC, hexane/iPrOH = 70 : 30, 0.7 mL min-1, 214 nm,
tmajor = 16.26 min, tminor = 14.73 min.
(R)-1-(1-(4-Bromophenyl)-2-methylene-3-oxobutyl)-4-(2-phenyl-
3H), 5.17 (d, J = 1.2 Hz, 1H), 6.23 (dd, J = 2.8 Hz, 4.4 Hz, 1H),
6.29 (s, 1H), 6.73 (dd, J = 1.6 Hz, 2.8 Hz, 1H), 7.15 (d, J = 8.4 Hz,
2H), 7.33 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 1.6 Hz, 4.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.1, 61.2, 96.3, 109.2,
121.5, 125.4, 126.4, 129.2, 129.5, 130.1, 131.2, 134.6, 135.5, 148.5,
172.3, 196.6; IR (neat) n 2925, 2855, 2224, 1677, 1538, 1489, 1408,
1373, 1326, 1230, 1168, 1132, 1068, 979, 946, 865, 851, 765, 726,
689 cm-1; MS (%) m/z 286 (24), 258 (9), 244 (9), 193 (5), 115 (10),
84 (11), 71 (13), 57 (5), 43 (100); HRMS (EI) for C17H13NO2Cl4:
402.9700; Found: 402.9705; [a]2D0 -216.4 (c 0.65, CHCl3) (90% ee);
acetyl)-1H-pyrrole-2-carbonitrile 4d: a white oil (34 mg, 76%
1
yield); H NMR (400 MHz, CDCl3, TMS) d 2.40 (s, 3H), 3.97
(s, 2H), 5.45 (s, 1H), 6.47 (s, 1H), 6.57 (s, 1H), 6.96 (d, J = 8.4
Hz, 2H), 7.11 (d, J = 1.6 Hz, 1H), 7.18–7.32 (m, 6H), 7.52 (d,
J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 25.9, 47.1, 61.0,
106.3, 111.8, 121.1, 123.5, 124.9, 127.0, 128.7, 129.2, 129.5, 129.6,
132.5, 134.2, 134.3, 146.1, 191.8, 196.1; IR (neat) n 2925, 2855,
2222, 1673, 1538, 1489, 1387, 1367, 1217, 1158, 1072, 1011, 978,
931, 859, 723, 637 cm-1; MS (%) m/z 355 (27), 237 (14), 158 (17),
115 (12), 91 (21), 65 (8), 43 (100); HRMS (EI) for C24H19N2O2Br:
446.0630; Found: 446.0633; [a]2D0 -4.8 (c 0.90, CHCl3) (94% ee);
Chiralcel IC, hexane/iPrOH = 70 : 30, 0.5 mL min-1, 214 nm, tmajor
11.17 min, tminor = 14.50 min.
=
(R)-3-((2-Bromo-4-(2,2,2-trichloroacetyl)-1H -pyrrol-1-yl)(4-
chlorophenyl)methyl)bu◦t-3-en-2-one 4i: a white solid (34.0 mg, 71%
yield); m.p. = 168–170 C; 1H NMR (400 MHz, CDCl3, TMS) d
2.40 (s, 3H), 5.26 (t, J = 0.8 Hz, 1H), 6.32 (s, 1H), 6.69 (d, J = 1.6
Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 7.37 (d, J = 8.4 Hz,
2H), 7.59 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.1,
61.5, 96.8, 121.9, 126.0, 126.8, 129.4, 130.0, 130.4, 134.8, 134.9,
148.0, 171.7, 196.3; IR (neat) n 2925, 2855, 2224, 1679, 1366, 1326,
1191, 1169, 1068, 979, 955, 922, 861, 836, 765, 732, 683 cm-1; MS
(%) m/z 364 (5), 193 (5), 115 (8), 84 (12), 43 (100); HRMS (EI)
for C17H12NO2Cl4Br: 480.8806; Found: 480.8802; [a]2D0 -111.3 (c
0.50, CHCl3) (84% ee); Chiralcel IC, hexane/iPrOH = 70 : 30, 0.5
mL min-1, 214 nm, tmajor = 9.07 min, tminor = 10.65 min.
Chiralcel IC, hexane/iPrOH = 70 : 30, 0.7 mL min-1, 214 nm, tmajor
38.74 min, tminor = 33.76 min.
=
(R)-1-(2-Methylene-1-(4-nitrophenyl)-3-oxobutyl)-4-(2-phenyl-
acetyl)-1H-pyrrole-2-carbonitrile 4e: a white solid (26 mg, 63%
◦
1
yield); m.p. 150–152 C; H NMR (400 MHz, CDCl3, TMS) d
2.43 (s, 3H), 3.99 (s, 2H), 5.54 (s, 1H), 6.56 (s, 1H), 6.72 (s, 1H),
7.17–7.33 (m, 9H), 8.24 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 25.8, 47.1, 60.7, 106.4, 111.6, 124.4, 125.3, 127.1, 128.5,
128.6, 128.7, 129.3, 130.8, 134.1, 142.4, 145.4, 148.2, 191.7, 196.0;
IR (neat) n 2925, 2855, 2221, 1679, 1538, 1493, 1462, 1376, 1325,
1278, 1197, 1161, 979, 932, 853, 764,750, 637 cm-1; MS (%) m/z 322
(72), 158 (13), 119 (42), 115 (9), 91 (46), 71 (14), 57 (20), 43 (100);
(R)-1-(1-(4-Chlorophenyl)-2-methylene-3-oxobutyl)-1H-pyrro-
HRMS (EI) for C24H19N3O4: 413.1376; Found: 413.1371; [a]D20
=
le-2,4-dic◦arbonitrile 4j: a white solid (26 mg, 84% yield); m.p. =
+22.4 (c 0.55, CHCl3) (93% ee); Chiralcel OD-H, hexane/iPrOH =
70 : 30, 0.7 mL min-1, 214 nm, tmajor = 47.40 min, tminor = 35.17 min.
(R)-1-(2-Methylene-3-oxo-1-phenylbutyl)-4-(2-phenylacetyl)-
117–119 C; H NMR (400 MHz, CDCl3, TMS) d 2.44 (s, 3H),
1
5.51 (t, J = 0.8 Hz, 1H), 6.54 (s, 1H), 6.64 (s, 1H), 7.05 (d, J =
1.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 1.6 Hz, 1H),
7.41 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.0,
61.5, 94.8, 106.7, 110.8, 113.8, 123.2, 129.2, 129.7, 129.8, 130.7,
133.1, 135.7, 145.9, 196.0; IR (neat) n 2930, 2859, 2222, 1669,
1263, 1112, 1022, 910, 803, 662 cm-1; MS (%) m/z 309 (36), 274
(8), 193 (11), 115 (18), 85 (11), 71 (14), 57 (25), 43 (100); HRMS
(EI) for C17H12N3OCl: 309.0669; Found: 309.0668; [a]2D0 -1.3 (c
0.50, CHCl3) (85% ee); Chiralcel IC, hexane/iPrOH = 70 : 30, 0.7
mL min-1, 214 nm, tmajor = 30.62 min, tminor = 25.64 min.
1
1H-pyrrole-2-carbonitrile 4f: a yellow oil (23 mg, 58% yield); H
NMR (400 MHz, CDCl3, TMS) d 2.40 (s, 3H), 3.97 (s, 2H), 5.43
(s, 1H), 6.46 (s, 1H), 6.63 (s, 1H), 7.09–7.30 (m, 9H), 7.38–7.40 (m,
3H); 13C NMR (100 MHz, CDCl3) d 26.0, 46.9, 61.6, 106.3, 112.0,
121.0, 124.6, 127.0, 127.9, 128.7, 129.0, 129.2, 129.3, 130.8, 134.3,
134.9, 146.4, 191.8, 196.2; IR (neat) n 2924, 2854, 2223, 1666, 1537,
1455, 1379, 1276, 1215, 1158, 978, 955, 931, 859, 749, 696 cm-1;
MS (%) m/z 277 (84), 159 (46), 119 (15), 115 (14), 91 (18), 71 (4),
57 (7), 43 (100); HRMS (EI) for C24H20N2O2: 368.1525; Found:
368.1523; [a]2D0 -4.1 (c 1.00, CHCl3) (89% ee); Chiralcel OD-H,
hexane/iPrOH = 70 : 30, 0.6 mL min-1, 214 nm, tmajor = 27.99 min,
tminor = 24.04 min.
(R)-4-Acetyl-1-(1-(4-chlorophenyl)-2-methylene-3-oxobutyl)-
1H-pyrrole-2-ca◦rbonitrile 4g: a white solid (25 mg, 76% yield);
m.p. = 122–124 C; 1H NMR (400 MHz, CDCl3, TMS) d 2.38 (s,
3H), 2.43 (s, 3H), 5.51 (s, 1H), 6.52 (s, 1H), 6.63 (s, 1H), 7.08 (d,
J = 8.4 Hz, 2H), 7.18 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H),
7.39 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 25.9,
27.2, 60.9, 106.3, 111.8, 121.0, 125.8, 128.0, 129.2, 129.5, 129.7,
133.6, 135.3, 146.1, 192.1, 196.2; IR (neat) n 3114, 2924, 2223,
1669, 1538, 1489, 1391, 1372, 1205, 1118, 1092, 1014, 974, 936,
809, 780, 659, 643 cm-1; MS (%) m/z 326 (45), 193 (16), 115 (8),
85 (13), 71 (13), 57 (14), 43 (100); HRMS (EI) for C18H15N2O2Cl:
326.0822; Found: 326.0820; [a]2D0 -2.1 (c 1.00, CHCl3) (94% ee);
Chiralcel AD-H, hexane/iPrOH = 70 : 30, 0.6 mL min-1, 214 nm,
tmajor = 10.39 min, tminor = 14.88 min.
(R)-1-(1-(4-Chlorophenyl)-2-methylene-3-oxobutyl)-1H-pyrro-
le-2-carbaldehyde 4k: a white solid (20.0 mg, 70% yield); m.p. =
◦
1
140–143 C; H NMR (400 MHz, CDCl3, TMS) d 2.36 (s, 3H),
5.19 (d, J = 1.2 Hz, 1H), 6.22 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.29
(s, 1H), 6.71 (t, J = 0.8 Hz, 1H), 7.01 (dd, J = 1.6 Hz, 4.0 Hz, 1H),
7.12 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H),
9.52 (s, 1H); 13C NMR (100 MHz, CDCl3) d 26.1, 60.1, 109.8,
125.5, 126.8, 129.0, 129.4, 129.8, 131.4, 134.3, 135.7, 148.3, 179.1,
196.7; IR (neat) n 2803, 2346, 1675, 1651, 1460, 1327, 1220, 1058,
956, 861, 741 cm-1; MS (%) m/z 287 (6), 258 (9), 244 (25), 115
(15), 43 (100); HRMS (EI) for C16H14NO2Cl: 287.0713; Found:
287.0716; [a]2D0 -193.1 (c 0.75, CHCl3) (92% ee); Chiralcel OD,
hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm, tmajor = 30.62 min,
tminor = 25.64 min.
General procedure for the preparation of 5 from the reaction of 1h
with 2a using 5a as an example in the presence of (DHQD)2PYR
(R)-3-((4-Chlorophenyl)(3-(2,2,2-trichloroacetyl)-1H -pyrrol-
1-yl)methyl)but-◦3-en-2-one 4h: a white solid (33.6 mg, 83% yield);
m.p. = 152–124 C; 1H NMR (400 MHz, CDCl3, TMS) d 2.39 (s,
A solution of compound 1h (0.2 mmol, 14 mg) and compound 2a
(0.1 mmol, 31 mg) in THF (0.5 mL) was stirred at -10 ◦C for 96 h
in the presence of organocatalyst (DHQD)2PYR (0.015 mmol,
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13 mg) under argon atmosphere. The solvent was removed under
reduced pressure and the residue was chromatographed on silica
gel (elution with petroleum ether/EtOAc = 16 : 1–8 : 1) to provide
the corresponding product 5a.
-38.6 (c 1.10, CHCl3) (96% ee); Chiralcel OD-H, hexane/iPrOH =
80 : 20, 0.7 mL min-1, 230 nm, tmajor = 10.20 min, tminor = 12.25 min.
1-(2-Methylene-1-(4-nitrophenyl)-3-oxobutyl)-1H -indole-2-
carbonitrile 5e: a yellow solid (32 mg, 93% yield); m.p. 90–93 ◦C;
1H NMR (400 MHz, CDCl3, TMS) d 2.47 (s, 3H), 5.84 (s, 1H),
6.60 (s, 1H), 7.15 (s, 1H), 7.20–7.35 (m, 6H), 7.68 (d, J = 7.6 Hz,
2H), 8.20 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 25.9,
58.3, 109.4, 111.1, 113.5, 116.1, 122.0, 122.6, 124.0, 126.5, 128.9,
130.8, 137.5, 143.8, 145.2, 147.7, 197.2; IR (neat) n 2925, 2855,
2221, 1680, 1517, 1446, 1344, 1318, 1279, 1228, 1192, 1165, 964,
850, 750 cm-1; MS (%) m/z 345 (56), 328 (15), 299 (5), 256 (8),
162 (15), 142 (31), 115 (28), 89 (7), 63 (8), 43 (100); HRMS (EI)
for C20H15N3O3: 345.1113; Found: 345.1111; [a]2D0 -69.5 (c 1.40,
CHCl3) (95% ee); Chiralcel AD-H, hexane/iPrOH = 70 : 30, 0.6
mL min-1, 214 nm, tmajor = 13.69 min, tminor = 18.09 min.
1-(1-(4-Chlorophenyl)-2-methylene-3-oxobutyl)-1H -indole-2-
carbonitrile 5a: a white solid (33 mg, 99% yield); m.p. 144–146 ◦C;
1H NMR (400 MHz, CDCl3, TMS) d 2.43 (s, 3H), 5.78 (dd, J =
0.8 Hz, 1.2 Hz, 1H), 6.51 (t, J = 0.8 Hz, 1H), 7.02 (s, 1H), 7.07 (d,
J = 8.0 Hz, 2H), 7.17–7.21 (m, 1H), 7.24–7.32 (m, 5H), 7.64–7.66
(m, 1H); 13C NMR (100 MHz, CDCl3) d 26.0, 58.5, 109.6, 111.4,
113.6, 115.6, 121.7, 122.4, 126.1, 126.4, 129.0, 129.2, 130.2, 134.4,
135.0, 137.6, 145.9, 197.3; IR (neat) n 2925, 2855, 2221, 1680,
1444, 1406, 1343, 1320, 1277, 1226, 1164, 948, 853, 750 cm-1; MS
(%) m/z 334 (50), 299 (4), 193 (13), 142 (8), 115 (13), 84 (5), 71 (2),
57 (3), 43 (100); HRMS (EI) for C20H15N2OCl: 334.0873; Found:
334.0874; [a]2D0 -49.6 (c 1.10, CHCl3) (95% ee); Chiralcel AD-H,
hexane/iPrOH = 70 : 30, 0.6 mL min-1, 214 nm, tmajor = 9.10 min,
tminor = 10.07 min.
1-(2-Methylene-1-(4-nitrophenyl)-3-oxobutyl)-1H -indole-2-
1
carbonitrile 5f: a colorless oil (32 mg, 98% yield); H NMR (400
MHz, CDCl3, TMS) d 2.45 (s, 3H), 5.81 (t, J = 1.2 Hz, 1H), 6.58
(s, 1H), 7.10 (s, 1H), 7.20–7.35 (m, 7H), 7.63–7.68 (m, 3H), 13C
NMR (100 MHz, CDCl3) d 25.9, 58.4, 109.5, 111.1, 112.4, 113.5,
116.0, 118.1, 122.0, 122.6, 126.3, 126.4, 128.6, 130.7, 132.6, 137.5,
141.8, 145.2, 197.2; IR (neat) n 2924, 2854, 2221, 1680, 1446, 1401,
1363, 1345, 1317, 1278, 1229, 1194, 967, 851, 750 cm-1; MS (%)
m/z 325 (40), 310 (5), 282 (7), 184 (6), 142 (51), 115 (9), 84 (4),
63 (4), 43 (100); HRMS (EI) for C21H15N3O: 325.1215; Found:
325.1214; [a]2D0 -51.8 (c 1.60, CHCl3) (93% ee); Chiralcel AD-H,
hexane/iPrOH = 70 : 30, 0.6 mL min-1, 214 nm, tmajor = 12.94 min,
tminor = 15.17 min.
1-(1-(4-Fluorophenyl)-2-methylene-3-oxobutyl)-1H -indole-2-
1
carbonitrile 5b: a white foam (32 mg, 99% yield); H NMR (400
MHz, CDCl3, TMS) d 2.43 (s, 3H), 5.74 (s, 1H), 6.49 (s, 1H),
7.01–7.05 (m, 3H), 7.11–7.18 (m, 3H), 7.20–7.32 (m, 3H), 7.65
(d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 26.0, 58.5,
109.5, 111.4, 113.5, 115.6 (d, JC-F = 3.7 Hz), 115.9, 121.7, 122.4,
126.1, 126.4, 129.7 (d, JC-F = 8.3 Hz), 129.9, 132.2 (d, JC-F = 3.8
Hz), 137.6, 146.2, 162.5 (d, JC-F = 246.5 Hz), 197.4; 19F NMR (376
MHz, CDCl3): d -113.075– -113.003 (m, 1F); IR (neat) n 2923,
2855, 2219, 1675, 1510, 1365, 1319, 1226, 1160, 972, 846, 750 cm-1;
MS (%) m/z 318 (35), 275 (4), 177 (21), 142 (8), 133 (13), 115 (5),
84 (5), 57 (3), 43 (100); HRMS (EI) for C20H15N2OF: 318.1168;
Found: 318.1171; [a]2D0 -82.0 (c 0.50, CHCl3) (96% ee); Chiralcel
Acknowledgements
OD-H, hexane/iPrOH = 80 : 20, 0.7 mL min-1, 230 nm, tmajor
13.97 min, tminor = 9.40 min.
=
Financial support from the Shanghai Municipal Committee of
Science and Technology (08dj1400100-2), National Basic Re-
search Program of China (973)-2010CB833302, the Fundamental
Research Funds for the Central Universities and the National Nat-
ural Science Foundation of China (21072206, 20472096, 20902019,
20872162, 20672127, 20821002, 20732008 and 20702059) and
Professor Jie Sun for performing X-ray diffraction are greatly
acknowledged.
1-(2-methylene-3-oxo-1-(4-(trifluoromethyl)phenyl)butyl)-1H-
indole-2-carbonitrile 5c: a white foam (25 mg, 68% yield); 1H NMR
(400 MHz, CDCl3, TMS) d 2.44 (s, 3H), 5.82 (s, 1H), 6.56 (s, 1H),
7.11 (s, 1H), 7.18–7.22 (m, 1H), 7.24–7.31 (m, 5H), 7.60 (d, J = 8.4
Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
25.9, 58.6, 109.6, 111.3, 113.6, 115.7, 121.8, 122.5, 123.8 (q, JC-F
=
270.7 Hz), 125.8 (q, JC-F = 2.9 Hz), 126.2, 126.4, 128.2, 130.6 (q,
JC-F = 32.6 Hz), 130.7, 137.6, 140.6, 145.6, 197.2; 19F NMR (376
MHz, CDCl3): d -62.692– -62.680 (m, 3F); IR (neat) n 2925,
2854, 2221, 1681, 1618, 1445, 1321, 1247, 1165, 1120, 1168, 977,
877, 750 cm-1; MS (%) m/z 368 (44), 349 (3), 325 (7), 299 (3), 227
(8), 142 (20), 133 (2), 115 (14), 84 (2), 63 (3), 43 (100); HRMS (EI)
for C21H15N2OF3: 368.1136; Found: 368.1141; [a]2D0 -36.4 (c 0.50,
CHCl3) (92% ee); Chiralcel OD-H, hexane/iPrOH = 80 : 20, 0.7
mL min-1, 230 nm, tmajor = 9.75 min, tminor = 8.35 min.
1-(1-(4-Bromophenyl)-2-methylene-3-oxobutyl)-1H-indole-2-
carbonitrile 5d: a white solid (38 mg, 99% yield); m.p. 151–153 ◦C;
1H NMR (400 MHz, CDCl3, TMS) d 2.43 (s, 3H), 5.79 (s, 1H),
6.52 (s, 1H), 7.00–7.02 (m, 3H), 7.17–7.21 (m, 1H), 7.25–7.32 (m,
3H), 7.47 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 26.0, 58.5, 109.6, 111.4, 113.6, 115.7, 121.8,
122.5, 122.6, 126.1, 126.4, 129.6, 130.3, 132.0, 135.6, 137.6, 145.9,
197.3; IR (neat) n 2925, 2854, 2221, 1680, 1444, 1402, 1346, 1319,
1278, 1225, 1163, 1070, 948, 852, 749 cm-1; MS (%) m/z 378 (28),
299 (5), 237 (8), 158 (22), 142 (9), 115 (47), 89 (6), 63 (7), 43 (100);
HRMS (EI) for C20H15N2OBr: 378.0368; Found: 378.0363; [a]D20
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9 The crystal data of 3h have been deposited to the CCDC with reference
number 812598.† Empirical formula: C16H13BrN2O; Formula weight:
329.19; Crystal color, habit: colorless, Crystal dimensions: 0.26 ¥ 0.18
¥ 0.13 mm; Crystal system: Orthorhombic; Lattice parameters: a ◦=
◦
˚
˚
˚
8.5810(18) A, b = 9.4511(19) A, c = 18.265(4) A, a = 90 , b = 90 ,
◦
3
˚
g = 90 , V = 1481.3(5) A ; Space group: P2(1)2(1)2(1); Z = 4; Dc =
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1.476 g cm-3; F000 = 664; Final R induces [I > 2s(I)]: R1 = 0.0407; w
R2 = 0.1105.
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The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1396–1405 | 1405
©