Asymmetrie organocatalytic N-alkylation of indole-2-carbaldehydes with α,β-unsaturated aldehydes: One-pot synthesis of chiral pyrrolo[1,2-α]indole-2-carbaldehydes

Article abstract of DOI:10.1002/chem.200902638

A highly useful method for the construction of pyrrolo[1,2-a]indole-2- carbaldehydes through a cascade aza-Michael/aldol reaction of indole-2- carbaldehydes with α, β-unsaturated aldehydes. Indole-2-carhaldehyde 1a was added to a solution of α, β-unsaturated aldehyde 2a in the presence of catalyst 3c and 4 A MS in toluene and the resulting solution was stirred for 72 h at room temperature. The reaction mixture was directly purified by silica gel chromatography without work up and fractions were collected and concentrated in vacuo to provide the pure desired product 4aa. The absolute configuration of the products was determined by X-ray analysis. Suitable crystals of compound 4ai that enabled assignment of the absolute configuration were obtained and single-crystal analysis revealed the configuration to be R.

Full text of DOI:10.1002/chem.200902638

DOI: 10.1002/chem.200902638
Asymmetric Organocatalytic N-Alkylation of Indole-2-carbaldehydes
with a,b-Unsaturated Aldehydes: One-Pot Synthesis of Chiral
PyrroloACTHNUGTRNEUNG[1,2-a]indole-2-carbaldehydes
Liang Hong,[a] Wangsheng Sun,[a] Chunxia Liu,[a] Lei Wang,[a] and Rui Wang*[a, b]
The pyrrolo
[1,2-a]indole tricyclic ring structures are
On the other hand, modifications of the indole structure
mainly focus on enantioselective alkylation at the C3-posi-
tion,[5] probably because of the privileged C3-chemoselectiv-
ity of indole compounds. Recently, the enantioselective syn-
thesis of C2-substituted indoles has also been realized
through the asymmetric alkylation of 4,7-dihydroindoles and
subsequent oxidation.[6] In sharp contrast, the enantioselec-
tive N-alkylation of indoles has rarely been explored, proba-
widely presented in a number of naturally occurring prod-
ucts and have attracted much attention due to the broad
scope of their biological activities.[1] Representative exam-
ples are mitomycins,[1b] some of the most effective antitumor
agents, and yuremamine,[1f] a new phytoindole recently iso-
lated from the stem bark of Mimosa hostilis, which shows
hallucinogenic and psychoactive effects. In addition to being
an important motif in many biologically and pharmaceuti-
cally interesting compounds, they are also useful intermedi-
ates for the synthesis of polyheterocycles.[2] Although several
approaches for the synthesis of this system have been ex-
plored, they usually require several steps and expensive re-
agents.[3] Thus, the exploration of novel, concise methodolo-
gies that allow the rapid establishment of these polycyclic
indole skeletons in a single operation is highly desired.[4]
À
bly due to the reduced nucleophilicity of the N H function-
ality of indoles.[7]
As noted above, the use of indoles in direct catalytic
À
asymmetric N-alkylation is challenging because the N H
proton of indoles, which must be removed to generate the
nucleophile, has a relatively high pKa value of 16.97 (Sche-
me 1).[8b] Direct organocatalytic methods based on amine
Scheme 1. N-Alkylation of indole or indole-2-carbaldehyde.
catalysis have a functional pKa barrier for nucleophile acti-
vation that lies between the pKa values of 16 and 17.[9]
Based on this concept, we sought to activate the removal of
[a] Dr. L. Hong, W. Sun, C. Liu, L. Wang, Prof. Dr. R. Wang
State Key Laboratory of Applied Organic Chemistry and
Institute of Biochemistry and Molecular Biology
Lanzhou University, Lanzhou, 730000 (China)
Fax : (+86)931-891-2567
À
the N H proton by introducing an electron-withdrawing
substituent at the C2-position; this may reduce the pKa
À
value of the N H proton. We attempted to introduce an al-
dehydic group because the indole-2-carbaldehyde has a re-
duced pKa value of 14.00,[8c] making it a candidate nucleo-
phile in catalytic direct asymmetric N-alkylation, and fur-
thermore, the aldehydic group allows many further transfor-
mations (Scheme 1).
E-mail: wangrui@lzu.edu.cn
[b] Prof. Dr. R. Wang
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Kowloon (Hong Kong)
As part of our continuing interest in asymmetric organo-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902638.
catalysis,[6g–h,10] we envisaged indole-2-carbaldehydes 1 and
440
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 440 – 444

COMMUNICATION
a,b-unsaturated aldehydes 2 as potential substrates for a
cascade reaction made up of a Michael addition and an
aldol reaction.[12] In planning our investigation of the reac-
tion, the question arose as to whether the reaction of an
indole-2-carbaldehyde with an a,b-unsaturated aldehyde
leads to the classical Friedel–Crafts/aldol/dehydration prod-
ucts (Scheme 2, path a) or whether, after the aza-Michael
addition, an intramolecular aldol reaction would occur, lead-
phenyl ring or the substitution pattern, participated in this
process in high efficiency (Table 2, entries 1–9). Unfortu-
nately, when 2-furyl enal (2j) was used, the major product
was the isomeric product 5aj (Table 2, entry 10 and Sche-
me 3a).[15] For less reactive alkyl a,b-unsaturated aldehydes,
the reaction showed much lower reactivity. This phenomen-
on was observed in the asymmetric N-allylic alkylation of in-
doles with Morita–Baylis–Hillman carbonates.[7c] The indole-
2-carbaldehydes with electron-donating or -withdrawing sub-
stituents at the C5-position underwent the reaction with
good yields and stereocontrol
ing to pyrrolo
b).
ACHTUNGTRENNUNG[1,2-a]indole-2-carbaldehydes (Scheme 2, path
(Table 2, entries 11–13). Re-
markably, nearly enantiomeri-
cally pure compounds can be
readily obtained by a single re-
crystallization (Table 2, en-
tries 1 and 9).
Furthermore, we found that
all
pyrroloACTHUNGTERNNU[G 1,2-a]indole-2-car-
Scheme 2. Proposed C3- or N-selective alkylation of indole-2-carbaldehydes with a,b-unsaturated aldehydes.
baldehyde derivatives 4 were
stable in the air at room tem-
To test our hypothesis, our experiments began with the
addition of indole-2-carbaldehyde (1a) to cinnamaldehyde
(2a) by the readily available diphenylprolinol TMS ether 3c
(TMS=trimethylsilyl). Indeed, the initial experiments
showed that the use of catalytic amounts of a secondary
amine enabled a reaction that resulted in the formation of
perature. However, conversion of compound 4aa into the
tautomeric form 5aa took place spontaneously and was
complete within 24 h in a solution in CDCl3 at room temper-
Table 1. Catalyst screening and reaction optimization.[a]
the pyrroloACHTUNGTRENNUNG[1,2-a]indole-2-carbaldehyde 4aa. On the basis of
these observations, we decided to develop an asymmetric
version of this domino reaction. Next, chiral pyrrolidines
3a–d were screened for promoting the cascade reactions be-
cause they can activate a,b-unsaturated aldehydes by the
formation of active iminium species.[13] The results showed
that the catalysts probed exhibited significantly different
catalytic activity toward the process. Poor catalytic activities
were observed for l-proline (3a) and the MacMillan cata-
lyst, 3b[14] (Table 1, entries 1 and 2). Fortunately, the diphe-
nylprolinol ether 3c catalyzed the reaction efficiently to
afford 4aa in moderate yield and promising enantiomeric
excess (ee) (Table 1, entry 3). To our surprise, catalyst 3d, a
general catalyst for the Michael addition of a,b-unsaturated
aldehydes, was not active in this reaction (Table 1, entry 4).
To optimize the reaction conditions further, the additives
and solvents were varied. We found that the use of 4 ꢁ mo-
lecular sieves (MS) as an additive and toluene as the solvent
gave the best results (Table 1, entry 11). Experiments run at
08C showed similar results to those conducted at room tem-
perature; however, a longer reaction time was required
(Table 1, entry 16).
Entry
Catalyst
Solvent
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
THF
THF
THF
THF
THF
THF
THF
THF
none
none
none
none
<10
<10
47
<10
38
40
<10
48
45
62
67
81
n.d.[d]
n.d.[d]
83
n.d.[d]
84
PhCO2H
CH3CO2H
CF3CO2H
Et3N
CH3CO2Na
4 ꢁ MS[e]
4 ꢁ MS[e]
4 ꢁ MS[e]
4 ꢁ MS[e]
4 ꢁ MS[e]
4 ꢁ MS[e]
4 ꢁ MS[e]
76
n.d.[d]
66
9
THF
THF
83
83
92
53
42
35
60
93
10
11
12
13
14
15
16[f]
toluene
CHCl3
CH2Cl2
ether
MTBE
toluene
77
43
71
58
Having established optimal reaction conditions, we next
examined the scope and limitations of this methodology
with regard to the a,b-unsaturated aldehyde and indole-2-
carbaldehyde substrates. The results showed that, in general,
the reactions took place efficiently in moderate to good
yields with good to excellent levels of enantioselectivity
(Table 2). Aromatic a,b-unsaturated aldehydes, regardless of
electron-donating or -withdrawing substituents on the
[a] Unless otherwise specified, the reaction was carried out with 1a
(0.24 mmol) and 2a (0.20 mmol) in the presence of an organocatalyst 3
(0.04 mmol), additive (0.04 mmol), and solvent (1.0 mL) for 72 h.
[b] Yield of the isolated product. [c] Determined by chiral HPLC on a
Chiralpak AD column. [d] Not determined. [e] 4 ꢁ MS (100 mg) were
used. [f] The reaction was performed at 08C for 120 h. MTBE=methyl
tert-butyl ether.
Chem. Eur. J. 2010, 16, 440 – 444
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
441

R. Wang et al.
Table 2. Scope of domino aza-Michael/aldol reaction.[a]
Entry 1, R1
2, R2
Product Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
1a, H
2a, Ph
2b, 2-MeOPh 4ab
2c, 2-FPh
2d, 2-ClPh
2e, 3-MeOPh 4ae
2 f, 4-MeOPh 4af
2g, 4-FPh
2h, 4-ClPh
2i, 4-BrPh
2j, 2-furyl
4aa
67
61
75
70
66
63
81
75
74
trace
71
84
57
92 (>99)[d]
88
90
96
4ac
4ad
86
81
90
90
Figure 1. X-ray structure of (R)-4ai. Thermal ellipsoids are given at the
20 % probability level.
4ag
4ah
4ai
4aj
4ba
4ca
4da
9
91 (>99)[d]
10
11
12
13
71
89
83
86
1b, 5-MeO 2a, Ph
1c, 5-F
1d, 5-Cl
2a, Ph
2a, Ph
[a] Unless otherwise specified, the reactions were carried out with 2
(0.20 mmol) and 1 (1.2 equiv) in toluene at room temperature for 72 h in
the presence of 3c (20 mol%) and 4 ꢁ MS (100 mg). [b] Yield of the iso-
lated product. [c] For analysis of the ee values of the products, see the
Supporting Information. [d] After a single recrystallization.
Scheme 4. Iminium/enamine activation: a proposed catalytic cycle for the
asymmetric cascade aza-Michael/aldol reaction.
Scheme 3. Synthesis of 9H-pyrroloACTHNUTRGENUGN[1,2-a]indole-2-carbaldehydes 5.
from the catalytic cycle and the catalyst 3c is regenerated.
Finally, the elimination of water results in the formation of
product 4.
In summary, we have developed a highly useful method
for the construction of pyrroloACTHNUTRGENUGN[1,2-a]indole-2-carbaldehydes
ature in the NMR tube.[3b,6c] The same result was obtained
by stirring a solution of 4aa in toluene for 1 h in the pres-
ence of a catalytic amount of p-toluenesulfonic acid (p-
TSA; Scheme 3b).
through a cascade aza-Michael/aldol reaction of indole-2-
Finally, the absolute configuration of the products was de-
termined by X-ray analysis. Suitable crystals of compound
4ai that enabled assignment of the absolute configuration
were obtained and single-crystal analysis revealed the con-
figuration to be R (Figure 1).[16]
With regard to the reaction mechanism, we assume that
the diphenylprolinol ether 3c forms the intermediate imini-
um ion A (Scheme 4) from reaction with the a,b-unsaturat-
ed aldehyde 2.[17] The efficient shielding of the Si face of the
chiral iminium intermediate by the bulky aryl groups results
in a stereoselective Re-facial nucleophilic conjugate attack
on the b-carbon by the indole-2-carbaldehyde 1, resulting in
a chiral enamine intermediate B (Scheme 4). Next, the acti-
vated enamine undergoes an intramolecular aldol reaction.
Hydrolysis then releases the intermediate D (Scheme 4)
carbaldehydes with a,b-unsaturated aldehydes. This method
provides easy access to pyrroloACTHNUGRTNEUNG[1,2-a]indole-2-carbalde-
hydes, which are generally difficult to access synthetically
and can be used in the future synthesis of natural products,
in a single operation with moderate to excellent enantiose-
lectivities. The notable features of the process include 1) the
use of easily accessible building blocks; 2) the cheapness of
the reagents involved; 3) the capability to obtain optically
active pyrroloACTHNUGTRNEUNG[1,2-a]indole tricyclic ring structures in a single
step that are otherwise difficult to prepare by asymmetric
catalysis; and 4) the generation of chiral products possessing
different substituents and containing a synthetically useful
aldehyde functionality, which is susceptible to further trans-
formations. Further applications of the current methodology
are ongoing in our laboratory.
442
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 440 – 444

Asymmetric Organocatalytic N-Alkylation of Indole-2-carbaldehydes
COMMUNICATION
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Experimental Section
General procedure: Indole-2-carbaldehyde 1a (0.24 mmol) was added to
a solution of a,b-unsaturated aldehyde 2a (0.20 mmol) in the presence of
catalyst 3c (20 mol%) and 4 ꢁ MS (100 mg) in toluene (1.0 mL) and the
resulting solution was stirred for 72 h at room temperature. The reaction
mixture was directly purified by silica gel chromatography without work
up and fractions were collected and concentrated in vacuo to provide the
pure desired product 4aa.
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We gratefully acknowledge financial support from NSFC (20525206,
20932003, 90813012, and 20621091) and the National S&T Major Project
of China (2009ZX09503-017).
Keywords: aldehydes · alkylation · domino reactions ·
indoles · organocatalysis
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[15] The same phenomenon was observed in reference [3b]. In this
study, when a heteroaryl substituent such as thiophen-2-yl or furan-
2-yl was used, only the isomeric 9H-pyrrolo
G
Received: September 25, 2009
hydes were obtained.
Published online: November 24, 2009
444
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