Enantioselective synthesis of 3H-Pyrrolo[1,2-α]indole-2-carbaldehydes via an organocatalytic domino aza-Michael/aldol Condensation reaction

Article abstract of DOI:10.1055/s-0029-1217069

A simple organocatalytic aza-Michael/aldol condensation domino reaction protocol opens an efficient and enantioselective entry to the tricyclic pyrrolo indole core, a characteristic structural unit of many bioactive natural products. Georg Thieme Verlag S

Full text of DOI:10.1055/s-0029-1217069

PAPER
4119
Enantioselective Synthesis of 3H-Pyrrolo[1,2-a]indole-2-carbaldehydes via an
Organocatalytic Domino Aza-Michael/Aldol Condensation Reaction
Organocatalytic
D
i
omino
e
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 27 August 2009
Dedicated to Professor Martin Jansen on the occasion of his 65th birthday
aldol
Abstract: A simple organocatalytic aza-Michael/aldol condensa-
tion domino reaction protocol opens an efficient and enantioselec-
tive entry to the tricyclic pyrrolo indole core, a characteristic
structural unit of many bioactive natural products.
condensation
O
O
O
+
N
N
*
R
H
Key words: pyrrolo[1,2-a]indole, organocatalysis, domino reac-
tion, aza-Michael reaction, asymmetric synthesis
R
aza-Michael
A
B
C
The indole subunit is a crucial structural feature in a large
number of naturally occurring and synthetic alkaloids
with various biological and pharmacological activities.1
The family of 3H-pyrrolo[1,2-a]indoles is of continuously
growing interest and a highly pursued synthetic target due
to its structural analogy to mitomycins, which are en-
dowed with an extraordinary ability of cross-linking DNA
and used as antitumor and chemotherapeutic agents.2,3
Despite many efforts to construct this structural motif in
the past decades, the efficient asymmetric synthesis of
3H-pyrrolo[1,2-a]indole derivatives has not been
achieved and still remains a great synthetic challenge.
Scheme 1 Secondary amine-catalyzed domino aza-Michael/aldol
condensation reaction – retrosynthetic analysis
screening indicated that the polar solvents such as DMF
and ethanol showed a detrimental effect to the level of the
asymmetric induction (Table 1, entries 2 and 3). Perform-
ing the reaction in dichloromethane provided a better
yield (60%) without improving the enantiomeric excess
(81% ee, Table 1, entry 4). In the case of MTBE, the dom-
ino product was obtained after a longer reaction time (4 d)
in a higher enantioselectivity (85% ee) and moderate yield
(53%).
After intense explorations in recent years, organocatalytic
domino reactions have been proven as a powerful tool for
the efficient and stereoselective synthesis of complex
molecules in a single process, which were difficult to ac-
cess by traditional methods.4–7 Domino reactions using
the aza-Michael addition provide a simple and direct way
for the synthesis of nitrogen containing heterocycles.8,9
We now wish to report a simple and efficient organocata-
lytic domino strategy for the asymmetric synthesis of 3H-
pyrrolo[1,2-a]indoles A starting from the commercially
available 1H-indole-2-carbaldehyde (B) and a,b-unsatur-
ated aldehydes C (Scheme 1). This novel domino reaction
consists of an aza-Michael addition/intramolecular aldol
condensation cascade following the iminium ion/enamine
activation sequence.
Next, three additional secondary amine catalysts were
evaluated with dichloromethane as solvent. Under the ca-
talysis of (S)-diphenylprolinol (5) or diarylprolinol silyl
ether 6 [Ar = 3,5-(CF3)2C6H3], no conversion of the start-
ing materials was observed after two days (Table 1, en-
tries 6 and 7), while (S)-proline (7) showed also a very low
catalytic activity in the domino reaction (Table 1, entry 8).
Subsequently, an additive screening was undertaken. Em-
ploying bases as additives led to a decrease both in yield
and enantioselectivity (Table 1, entries 9–11). Notably,
no desired product was formed when the reaction was car-
ried out under acidic conditions (Table 1, entries 12 and
13), probably due to the indole protonation. Performing
the reaction at a lower temperature resulted in a slightly
improved enantioselectivity (84% ee), but a drastically di-
minished yield (21%), (Table 1, entry 14)
Initially we performed the reaction with 1H-indole-2-
carbaldehyde (1) and (E)-3-(2-methoxyphenyl)acrylalde-
hyde (2a) in toluene at room temperature utilizing diphe-
nylprolinol silyl ether 410,11 as a catalyst. Encouragingly,
the domino reaction to form the pyrroloindole aldehyde
3a occurred in moderate yield (40%) and good enantiose-
lectivity (81% ee), (Table 1, entry 1). The brief solvent
The scope of the reaction was evaluated by varying the
structure of the enals 2 under the optimal conditions. In
the cases of cinnamaldehyde (2b) and the substituted aro-
matic enals 2a, 2c–g, the domino products 3a–g were ob-
tained in high enantiomeric excesses (85 to >99% ee) and
with moderate to good yields (40–71%, Table 2, entries
1–7). Notably, when 2b and 2c were used as the sub-
strates, the products 3b and 3c precipitated and could sim-
ply be isolated by suction. The aliphatic enals afforded
only traces of the product. Interestingly, utilizing the het-
SYNTHESIS 2009, No. 24, pp 4119–4124
x
x.
x
x
.
2
0
0
9
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217069; Art ID: Z18209SS
© Georg Thieme Verlag Stuttgart · New York

4120
D. Enders et al.
PAPER
Table 1 Solvent, Additive and Catalyst Screening for the Enantio-
Table 2 Organocatalytic Domino Reaction of Enals 2a–h and 1H-
Indole-2-carbaldehyde (1)a
selective Organocatalytic Domino Reactiona
O
O
O
O
catalyst
N
N
(20 mol%)
+
solvent
OMe
R
N
O
catalyst 4
O
H
(20 mol%)
3
+
OMe
solvent
N
+
H
1
2a
3a
R
1.0 equiv
1.2 equiv
1
2
O
N
1.0 equiv
1.2 equiv
Ph
Ph
OTMS
Ph
Ar
Ar
OTMS
R
Ph
CO2H
N
H
N
N
H
N
8
H
H
OH
Entry
R
Solvent
Time Yield ee
4
5
6
7
(d)
(%)b
53
55
51
71
60
58
40
30
(%)c
Ar = 3,5-(CF3)2C6H3
1
2-MeOC6H4 (3a)
Ph (3b)
MTBE
MTBE
MTBE
MTBE
MTBE
4
85
Entry Cat. Solvent
Additive
Time Yield ee
(d)
2
2
2
2
4
2
2
2
2
2
2
2
2
4
(%)b
40
47
52
60
53
0
(%)c
81
53
68
81
85
–
2d
3d
4e
5
3
>99
90
1
2
4
4
4
4
4
5
6
7
4
4
4
4
4
4
toluene
DMF
–
4-MeOC6H4 (3c)
4-ClC6H4 (3d)
p-tolyl (3e)
3
–
3
89
3
EtOH
–
1
87
f
4
CH2Cl2
MTBE
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
CH2Cl2
–
6
piperonyl (3f)
4-FC6H4 (3g)
furan-2-yl (8)
–
3
>99
>99
–
5
–
7
MTBE
CH2Cl2
4
8e
4
6
–
a Reactions were performed on a 1 mmol scale of 1 using 1.2 equiv of
enals 2, 20 mol% catalyst 4 at r.t. in 2.0 mL of solvent.
b Yield of the isolated product after flash chromatography.
c Determined by HPLC analysis on a chiral stationary phase.
d Workup procedure B (see experimental part).
7
–
0
–
8
–
traced n.d.e
9
Et3N
20
40
38
0
85
81
78
–
e Pyrrolidine (40 mol%) was utilized as catalyst. With the catalyst 4
the same product 8 was formed, but not analytically pure.
f Reactions were performed in a mixture of MTBE (2 mL) and CH2Cl2
(0.4 mL).
10
11
12
13
14f
NaOAc
K2CO3
AcOH
4-O2NC6H4CO2H
–
0
–
21
84
a Unless otherwise specified, reactions were performed on a 1 mmol
scale of 1 using 1.2 equiv of (E)-3-(2-methoxyphenyl)acrylaldehyde
(2a), 20 mol% catalyst 4, 5, 6, or 7, and 20 mol% the corresponding
additive at r.t. in 2.0 mL of solvent.
b Yield of the isolated product after flash chromatography.
c Determined by HPLC analysis on a chiral stationary phase.
d Determined by GC analysis.
e Not determined.
f Reaction performed at 3 °C.
Figure 1 X-ray crystal structure of 3b12
eroaromtic furylacrolein 2h led to the formation of the
isomer 9H-pyrrolo[1,2-a]indole 8 instead of the expected
product (Table 2, entry 8).
A plausible catalytic cycle for the domino reaction is de-
scribed in Scheme 2. In the first step, the enal 2 is activat-
ed by the chiral amine through the formation of the
iminium ion 9, to which the 1H-indole-2-carbaldehyde (1)
performs an intermolecular aza-Michael addition. The re-
sulting enamine 10 subsequently undergoes an intramo-
lecular aldol reaction affording intermediate 11. Finally,
The absolute configuration of 3b was unambiguously de-
termined to be R by X-ray crystal structure analysis
(Figure 1), which is in agreement with the results of other
diphenylprolinol silyl ether catalyzed Michael additions
to enals.7,9
Synthesis 2009, No. 24, 4119–4124 © Thieme Stuttgart · New York

PAPER
Organocatalytic Domino Reactions
4121
Domino Aza-Michael/Aldol Condensation; General Procedure
Catalyst 4 (0.2 mmol, 20 mol%) was added to a solution of 1H-in-
dole-2-carbaldehyde (1; 1 mmol) and a,b-unsaturated aldehyde 2
(1.2 mol, 1.2 equiv) in MTBE or CH2Cl2 (2 mL) at r.t. The reaction
mixture was stirred for the time displayed in Table 2. Workup A:
Direct flash chromatography (silica gel, pentane–Et2O, 10:1 to 4:1)
of the reaction mixture afforded the pure 3H-pyrrolo[1,2-a]indoles
3. Workup B: The precipitated product was isolated by suction
through a funnel. The filtrate was concentrated in vacuum and the
resulting additional precipitate was suspended in MTBE (0.5 mL)
and suctioned again. The combined solids were dissolved in CH2Cl2
and passed through a short column (silica gel, CH2Cl2) affording the
pure 3H-pyrrolo[1,2-a]indoles 3.
O
N
O
R
3
Ph
Ph
OTMS
– H2O
H2O
R
N
2
H
catalyst (S)-4
Ph
Ph
Ph
Ph
OTMS
N
R
O
N
OTMS
N
catalytic
cycle
(R)-3-(2-Methoxyphenyl)-3H-pyrrolo[1,2-a]indole-2-carbalde-
OH
hyde (3a)
Yield: 153 mg (53%); bright yellow solid; mp 128 °C; [a]D20 –506
(c = 0.65, CHCl3).
R
9
11
Ph
Ph
OTMS
HN
HPLC: tR = 7.76 and 11.08 min [Chiralcel OD, n-heptane–i-PrOH
(8:2), 1.0 mL/min]; tR = 7.76 min; ee = 85%.
N
enamine activation
O
IR (KBr): 3306, 3120, 3056, 3013, 2975, 2940, 2840, 2817, 2716,
2472, 2325, 2185, 2107, 1999, 1926, 1811, 1778, 1722, 1659, 1600,
1562, 1493, 1463, 1335, 1330, 1308, 1292, 1246, 1212, 1189, 1166,
1150, 1112, 1094, 1051, 1023, 984, 933, 881, 819, 787, 749, 695,
668 cm–1.
O
H2O
1
R
N
iminium activation
1H NMR (300 MHz, CDCl3): d = 9.78 (s, 1 H), 7.63–7.66 (m, 2 H),
7.22–7.28 (m, 1 H), 6.98–7.11 (m, 4 H), 6.69–6.78 (m, 3 H), 6.56
(s, 1 H), 3.97 (s, 3 H).
10
Scheme 2 Proposed catalytic cycle of the domino reaction
13C NMR (101 MHz, CDCl3): d = 185.5, 157.5, 149.0, 142.5, 136.2,
134.2, 132.8, 129.8, 127.6, 124.1, 123.7, 122.4, 121.2, 120.0, 111.6,
110.2, 98.8, 57.3, 56.0.
MS (EI, 70 eV): m/z (%) = 289 (11, [M+]), 260 (6.5), 244 (11), 228
(20), 216 (50), 202 (11), 189 (32), 178 (26), 163 (17), 153 (72), 140
(21), 126 (62), 115 (26), 102 (26), 89 (55), 77 (98), 63 (93), 51
(100).
the catalyst is regenerated for the next catalytic cycle
through hydrolysis of the intermediate 11 and dehydration
to form the 3H-pyrrolo[1,2-a]indole products 3.
In summary, we have developed a novel organocatalytic
domino reaction between 1H-indole-2-carbaldehyde and
a,b-unsaturated aldehydes under diphenylprolinol silyl
ether catalysis following an iminium/enamine activation
mode. The new asymmetric synthesis provides an effi-
cient entry to synthetically useful and potentially bioac-
tive 3-substituted 3H-pyrrolo[1,2-a]indoles in moderate
to good yields (40–71%) and high to excellent enantio-
meric excesses (85 to >99% ee).
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.87; H, 5.14; N, 4.83.
(R)-3-Phenyl-3H-pyrrolo[1,2-a]indole-2-carbaldehyde (3b)
Yield: 143 mg (55%); bright yellow solid; mp 183 °C; [a]D20 –959
(c = 1.0, CHCl3).
HPLC: tR = 8.85 and 13.84 min [Chiralcel OD, n-heptane–i-PrOH
(8:2), 1.0 mL/min]; tR = 8.85 min; ee = >99%.
IR (KBr): 3285, 3120, 3057, 3032, 2909, 2834, 2657, 2464, 2323,
2090, 1981, 1931, 1895, 1811, 1710, 1646, 1549, 1491, 1450, 1381,
1356, 1311, 1234, 1206, 1158, 1101, 1029, 1005, 982, 933, 879,
856, 820, 800, 740, 691, 672 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.76 (s, 1 H), 7.67–7.70 (m, 1 H),
7.59 (m, 1 H), 7.25–7.29 (m, 3 H), 7.05–7.14 (m, 4 H), 6.89–6.92
(m, 1 H), 6.79 (s, 1 H), 6.03 (s, 1 H).
13C NMR (101 MHz, CDCl3): d = 185.0, 148.8, 142.2, 136.0, 135.9,
134.1, 132.6, 128.6, 128.3, 127.1, 123.8, 122.4, 120.1, 110.1, 99.1,
63.7.
MS (EI, 70 eV): m/z (%) = 259 (22, [M+]), 230 (100), 202 (5.9), 176
(1.1), 154 (4.2), 127 (2.6), 114 (4.8), 101 (2.6), 89 (1.4), 77 (3.2), 63
(1.1), 51 (2.9).
Unless otherwise noted, all commercially available compounds
were used without further purification. Cinnamaldehyde was fresh-
ly distilled. Racemic samples of 3H-pyrrolo[1,2-a]indoles 3a–g
were prepared using pyrrolidine (40 mol%) as a catalyst in MTBE
at r.t. Preparative column chromatography: Merck silica gel 60, par-
ticle size 0.040–0.063 mm (230–240 mesh, flash). Analytical TLC:
silica gel 60 F254 plates from Merck, Darmstadt. Visualization of the
developed TLC plates was performed with ultraviolet irradiation
(254 nm) or by staining with anisaldehyde. Optical rotation values
were measured on a PerkinElmer 241 polarimeter. Microanalyses
were performed with a Vario EL element analyzer. Mass spectra
were acquired on a Finnigan SSQ7000 (EI 70 eV) spectrometer and
high-resolution mass spectra on a Finnigan MAT 95. IR spectra
were taken on a PerkinElmer FT-IR 1760 spectrometer. 1H and 13
C
NMR spectra were recorded at r.t. on Gemini 300, Varian Mercury
300, or Inova 400 instruments with TMS as an internal standard.
Analytical HPLC was performed on a Hewlett-Packard 1100 Series
instrument using chiral stationary phases (Chiralcel OD).
Anal. Calcd for C18H13NO: C, 83.37; H, 5.05; N, 5.40. Found: C,
83.00; H, 5.01; N, 5.35.
(R)-3-(4-Methoxyphenyl)-3H-pyrrolo[1,2-a]indole-2-carbalde-
hyde (3c)
Yield: 147 mg (51%); bright yellow solid; mp 180 °C; [a]D20 –1130
(c = 0.7, CHCl3).
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D. Enders et al.
PAPER
(R)-3-(Benzo[d][1,3]dioxol-5-yl)-3H-pyrrolo[1,2-a]indole-2-
HPLC: tR = 9.99 and 17.05 min [Chiralcel OD, n-heptane–i-PrOH
(8:2), 1.0 mL/min]; tR = 9.99 min; ee = 90%.
carbaldehyde (3f)
Yield: 176 mg (58%); bright yellow solid; mp 178 °C; [a]D20 –790
(c = 0.25, CHCl3).
IR (KBr): 3307, 3051, 2962, 2909, 2837, 2728, 2285, 2077, 1931,
1900, 1783, 1660, 1612, 1557, 1514, 1459, 1447, 1424, 1354, 1328,
1308, 1254, 1210, 1175, 1149, 1027, 1105, 984, 932, 882, 838, 780,
742, 692, 667 cm–1.
HPLC: tR = 10.16 and 14.04 min [Chiralcel OD, n-heptane–i-PrOH
(7:3), 1.0 mL/min]; tR = 10.16 min; ee = >99%.
1H NMR (300 MHz, CDCl3): d = 9.75 (s, 1 H), 7.66–7.69 (m, 1 H),
7.56 (s, 1 H), 7.03–7.08 (m, 4 H), 6.91–6.93 (m, 1H), 6.76–6.81 (m,
3 H), 5.98 (s, 1 H), 3.50 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 185.5, 159.6, 149.2, 142.3, 136.1,
134.3, 132.8, 128.5, 128.0, 123.9, 122.6, 120.3, 114.2, 110.3, 99.2,
63.3, 55.2.
MS (EI, 70 eV): m/z (%) = 289 (20, [M+]), 260 (85), 245 (10), 228
(9.3), 216 (100), 204 (7.5), 189 (26), 182 (15), 163 (14), 153 (62),
140 (12), 126 (50), 115 (16), 102 (28), 92 (35), 89 (44), 77 (47), 63
(78), 51 (51).
IR (KBr): 3303, 3045, 3005, 2915, 2832, 2726, 2681, 2456, 2323,
2074, 2019, 1997, 1933, 1901, 1832, 1782, 1753, 1715, 1657, 1555,
1482, 1443, 1375, 1352, 1324, 1308, 1241, 1152, 1102, 1033, 983,
933, 909, 877, 827, 779, 742, 693, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.76 (s, 1 H), 7.66–7.68 (m, 1 H),
7.57 (s, 1 H), 7.05–7.12 (m, 2 H), 6.96–6.98 (m, 1 H), 6.75 (m, 3 H),
6.45 (s, 1 H), 5.88–6.02 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 185.4, 150.0, 148.1, 147.8, 142.2,
132.8, 136.2, 132.9, 129.9, 124.0, 122.6, 121.4, 120.4, 110.3, 108.5,
107.2, 101.2, 99.4, 63.5.
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.91; H, 5.28; N, 4.80.
MS (EI, 70 eV): m/z (%) = 303 (30, [M+]), 274 (100), 244 (2.6), 215
(22), 202 (9.8), 189 (3.0), 178 (1.5), 163 (231.2), 154 (3.4), 136
(11), 126 (3.2), 123 (7.1), 109 (13), 95 (7.8), 82 (3.4), 75 (5.3), 63
(11), 51 (7.6).
(R)-3-(4-Chlorophenyl)-3H-pyrrolo[1,2-a]indole-2-carbalde-
hyde (3d)
HRMS (ESI-TOF): m/z calcd for C19H13NO3: 303.0895; found:
153.0890.
Yield: 208 mg (71%); bright yellow solid; mp 154 °C; [a]D20 –937
(c = 0.45, CHCl3).
HPLC: tR = 14.21 and 25.18 min [Chiralcel OD, n-heptane–i-PrOH
(9:1), 1.0 mL/min]; tR = 14.21 min; ee = 89%.
(R)-3-(4-Fluorophenyl)-3H-pyrrolo[1,2-a]indole-2-carbalde-
hyde (3g)
Yield: 111 mg (40%); bright yellow solid; mp 132 °C; [a]D20 –1073
(c = 0.3, CHCl3).
IR (KBr): 3316, 3122, 3062, 2902, 2828, 2724, 2681, 2459, 2325,
2216, 2112, 1982, 1942, 1908, 1789, 1722, 1662, 1596, 1557, 1490,
1445, 1410, 1354, 1323, 1309, 1255, 1235, 1207, 1186, 1165, 1152,
1100, 1014, 982, 935, 878, 857, 840, 796, 779, 736, 692, 668 cm–1.
HPLC: tR = 10.16 and 14.04 min [Chiralcel OD, n-heptane–i-PrOH
(7:3), 0.7 mL/min]; tR = 10.16 min; ee = >99%.
1H NMR (400 MHz, CDCl3): d = 9.76 (s, 1 H), 7.68–7.70 (m, 1 H),
7.59–7.60 (m, 1 H), 7.24–7.27 (m, 2 H), 7.04–7.14 (m, 4 H), 6.87–
6.90 (m, 1 H), 6.80 (s, 1 H), 6.00 (s, 1 H).
IR (KBr): 3293, 3121, 3059, 2925, 2848, 2328, 2083, 1935, 1897,
1777, 1652, 1605, 1554, 1505, 1449, 1417, 1357, 1318, 1260, 1226,
1156, 1103, 1109, 983, 936, 883, 835, 787, 739, 692, 671 cm–1.
13C NMR (101 MHz, CDCl3): d = 185.2, 148.6, 142.2, 136.3, 134.8,
134.2 (2 C), 132.8, 129.0, 128.7, 124.2, 122.7, 120.5, 110.2, 99.7,
63.1.
1H NMR (400 MHz, C6D6): d = 9.17 (s, 1 H), 7.59 (d, J = 8.0 Hz,
1 H), 6.92–7.02 (m, 2 H), 6.64–6.71 (m, 3 H), 6.53 (t, J = 8.8 Hz,
2 H), 6.46 (s, 1 H), 6.37 (m, 1 H), 5.28 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 293 (48, [M+]), 264 (100), 228 (55), 202
(9.8), 189 (0.9), 176 (3.3), 149 (3.7), 128 (23), 114 (22), 101 (8.0),
89 (11), 75 (8.5), 63 (9.9), 51 (8.4).
13C NMR (101 MHz, C6D6): d = 183.9, 162.4 (d, JC,F = 247 Hz, 1
C), 148.9, 142.3, 134.6, 134.2, 133.0, 132.1, 123.8, 122.5, 120.4,
115.5, 115.3, 110.3, 98.7, 62.7.
Anal. Calcd for C18H12ClNO: C, 73.60; H, 4.12; N, 4.77. Found: C,
73.36; H, 4.30; N, 4.83.
MS (EI, 70 eV): m/z (%) = 277 (98, [M+]), 248 (100), 227 (2.3), 220
(10), 194 (2.7), 182 (3.7), 158 (2.1), 154 (18), 133 (5.0), 127 (8.0),
114 (9.2), 102 (11), 95 (9.4), 89 (5.7), 77 (12), 75 (15), 63 (13), 51
(12).
(R)-3-p-Tolyl-3H-pyrrolo[1,2-a]indole-2-carbaldehyde (3e)
Yield: 164 mg (60%); bright yellow solid; mp 168 °C; [a]D20 –1604
(c = 0.25, CHCl3).
HRMS (ESI-TOF): m/z calcd for C18H12FNO: 277.0903; found:
277.0891.
HPLC: tR = 7.90 and 11.79 min [Chiralcel OD, n-heptane–i-PrOH
(8:2), 1.0 mL/min]; tR = 7.90 min; ee = 87%.
3-(Furan-2-yl)-9H-pyrrolo[1,2-a]indole-2-carbaldehyde (8)
Yield: 75 mg (30%); bright yellow solid; mp 147 °C.
IR (KBr): 3313, 3120, 3047, 2922, 2827, 2803, 2728, 2461, 2323,
2112, 1989, 1928, 1899, 1810, 1721, 1661, 1555, 1512, 1478, 1448,
1354, 1321, 1235, 1206, 1147, 1103, 1007, 982, 879, 834, 778, 739,
692, 671 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.78 (s, 1 H), 7.67 (m, 1 H), 7.58
(s, 1 H), 6.92–7.07 (m, 7 H), 6.77 (s, 1 H), 6.00 (s, 1 H), 2.29 (s,
3 H).
13C NMR (101 MHz, CDCl3): d = 185.2, 149.0, 142.2, 138.0, 135.9,
134.1, 132.9, 132.6, 129.4, 127.0, 123.7, 122.4, 120.1, 110.1, 99.0,
63.5, 21.2.
MS (EI, 70 eV): m/z (%) = 273 (21, [M+]), 244 (100), 228 (9.5), 215
(2.0), 202 (2.7), 189 (1.4), 182 (1.2), 167 (1.0), 153 (4.3), 127 (4.9),
121 (10), 114 (5.6), 91 (3.2), 89 (3.8), 77 (2.8), 63 (4.6), 51 (4.3).
IR (KBr): 3147, 3119, 3066, 2912, 2821, 2747, 2323, 2190, 2083,
2024, 1958, 1900, 1831, 1759, 1658, 1605, 1563, 1515, 1477, 1409,
1390, 1369, 1329, 1309, 1280, 1249, 1219, 1182, 1163, 1134, 1094,
1068, 1028, 995, 950, 912, 882, 846, 790, 744, 710, 691, 663 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.79 (s, 1 H), 7.72 (m, 1 H), 7.44
(d, J = 7.4 Hz, 1 H), 7.19–7.28 (m, 2 H), 7.10 (d, J = 8.0 Hz, 1 H),
6.65–6.74 m, (m, 3 H), 3.94 (s, 2 H).
13C NMR (101 MHz, CDCl3): d = 186.0, 143.5, 141.9, 139.6, 138.0,
135.2, 129.3, 127.6, 125.8, 125.0, 123.8, 113.8, 112.7, 111.7, 100.8,
28.8.
MS (EI, 70 eV): m/z (%) = 249 (28, [M+]), 220 (65), 204 (4.5), 191
(100), 178 (4.9), 165 (22), 152 (39.6), 140 (17.4), 126 (10), 117
(8.6), 102 (5.8), 89 (45), 75 (18), 63 (934), 51 (31).
HRMS (ESI-TOF): m/z calcd for C19H15NO: 273.1154; found:
273.1148.
Synthesis 2009, No. 24, 4119–4124 © Thieme Stuttgart · New York

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Organocatalytic Domino Reactions
4123
HRMS (ESI-TOF): m/z calcd for C16H11NO2: 249.0790; found:
(6) For reviews on organocatalytic domino reactions, see:
249.0782.
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Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(priority program Organocatalysis) and the Fonds der Chemischen
Industrie. We thank the former Degussa AG and BASF AG for the
donation of chemicals.
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(12) CCDC-737780 contains the supplementary crystallographic
data for the compound 3b reported in this paper. These data
can be obtained free of charge from The Cambridge
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data_request/cif.
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Synthesis 2009, No. 24, 4119–4124 © Thieme Stuttgart · New York