Convenient synthesis of tetrahydro-γ-carbolines and tetrahydroquinolines through a chemo- and regioselectivity switch by a broonsted acid catalyzed, one-pot, multicomponent reaction

Article abstract of DOI:10.1002/ejoc.201000853

An efficient, one-pot, multicomponent reaction of aldehydes 1, p-methoxyaniline (2a), and 2-vinylindoles 3 was developed. This approach provides a practical approach to synthetically and biologically significant tetrahydro-γ-carboline and tetrahydroquinol

Full text of DOI:10.1002/ejoc.201000853

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000853
Convenient Synthesis of Tetrahydro-γ-carbolines and Tetrahydroquinolines
through a Chemo- and Regioselectivity Switch by a Brønsted Acid Catalyzed,
One-Pot, Multicomponent Reaction
Hong-Gang Cheng,[a] Cai-Bao Chen,[a] Fen Tan,[a] Ning-Jie Chang,[a] Jia-Rong Chen,*[a]
and Wen-Jing Xiao*[a]
Keywords: Chemoselectivity / Multicomponent reactions / Nitrogen heterocycles / Fused-ring systems
An efficient, one-pot, multicomponent reaction of aldehydes
1, p-methoxyaniline (2a), and 2-vinylindoles 3 was devel-
oped. This approach provides a practical approach to syn-
thetically and biologically significant tetrahydro-γ-carboline
and tetrahydroquinoline derivatives in good yields through a
chemo- and regioselectivity switch, which can be tuned by
simply changing the substituent on the indole component
under identical reaction conditions.
Introduction
Heterocyclic chemistry is one of the most important dis-
ciplines in organic chemistry.[1] Among the various hetero-
cyclic systems discovered and developed, nitrogen-contain-
ing ones play a fundamental role in the context of both
chemistry and biology.[2] Tetrahydro-γ-carboline and tetra-
hydroquinoline are two especially outstanding fused hetero-
cyclic ring systems prevalent in natural and unnatural
heterocyclic compounds possessing significant biological
activities and pharmacophores of neuroleptic,[3a] antipsy-
chotic,[3c] antagonistic,[3f–3g] antimalarial,[3i–3j] and antitu-
moral[3d–3e] agents, among others.[3b,3h] Consequently, great
efforts have been devoted to the construction of tetrahydro-
γ-carboline[4] and tetrahydroquinoline[5] frameworks in the
area of organic/drug synthesis. Very recently, we developed
two distinct efficient approaches to tetrahydro-β-carbolines/
tetrahydroquinolines[6] and tetrahydrocarbazoles[7] based on
iminium catalysis and hydrogen-bonding catalysis, respec-
tively. As a continuation of this program, we document here
an unprecedented practical approach for the synthesis of
tetrahydro-γ-carboline and tetrahydroquinoline through a
chemo- and regioselectivity switch under identical reaction
conditions, specifically the Brønsted acid catalyzed, one-
pot, multicomponent reactions of aldehydes 1, aniline 2a,
and 2-vinylindoles 3 (Scheme 1).
Scheme 1. Chemo- and regioselectivity switch in the Brønsted acid
catalyzed, one-pot, multicomponent reactions of aldehydes 1, ani-
line 2a, and 2-vinylindoles 3.
Multicomponent reactions (MCRs),[8] which involve the
production of desired compounds by the reaction of three
or more simple and/or readily accessible starting reagents
in a one-pot fashion, provide significant advantages over
traditional stepwise strategies in terms of cost, waste, time,
and atom economy, and these reactions constitute an ex-
tremely popular research field in both academic and indus-
trial domains.[9] However, chemo- and stereoselectivities of
MCRs have been widely accepted as a significant challeng-
ing task for synthetic organic chemists.[10]
[a] Key Laboratory of Pesticide & Chemical Biology Ministry of
Education
Results and Discussion
College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079, China
Fax: +86-27-6786-2041
Initially, we investigated the three-component reaction of
benzaldehyde (1a) 2-aminophenol (2b), and 1-benzyl-2-
vinyl-1H-indole (3a) in the presence of common Brønsted
acid catalysts in the hope of gaining the designed cascade
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000853.
View this journal online at
wileyonlinelibrary.com
4976
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Eur. J. Org. Chem. 2010, 4976–4980

Synthesis of Tetrahydro-γ-carbolines and Tetrahydroquinolines
tetrahydro-γ-carboline product 4a (Table 1). To our delight,
We obtained the crystal of novel tetrahydro-γ-carboline
with 30 mol-% of these Brønsted acids in dichloromethane, product 4b from a mixture of hexane and ethyl acetate, and
all reactions proceeded smoothly and cleanly to give 4a in its structure was further confirmed by X-ray crystallo-
moderate to good yields (45–69% yield; Table 1, Entries 1– graphic analysis (Figure 1).[13]
6) together with some double Friedel–Crafts alkylation side
product 4aЈ;[11] 3,5-dinitrobenzoic acid (DNBA) was found
to be the best acid (69% yield; Table 1, Entry 6). Further
efforts were then directed toward improving the yield of cas-
cade product 4a[7] while suppressing the double Friedel–
Crafts alkylation side reaction. Our studies on the solvents
with DNBA as the catalyst showed that this one-pot, three-
component reaction was general with a wide range of sol-
vents (Table 1, Entries 6–12).[12] However, the reaction pro-
ceeded better in halogenated solvents (Table 1, Entries 6–8)
than in other solvents, such as diethyl ether, toluene, aceto-
nitrile, and ethanol (Table 1, Entries 9–12), and 1,2-dichlor-
oethane proved to be the best solvent choice. Moreover, a
brief survey of aniline substrates 2 disclosed that p-meth-
oxyaniline (2a) was the most suitable amine component.[12]
With 30 mol-% DNBA in 1,2-dichloroethane, the reaction
of benzaldehyde (1a), p-methoxyaniline (2a), and 1-benzyl-
2-vinyl-1H-indole (3a) efficiently provided desired product
4b in high yield and with only a trace amount of side prod-
uct (Table 1, Entry 13).
Figure 1. X-ray crystal structure of tetrahydro-γ-carboline 4b.
Next, investigation of the substitution effects on the ni-
trogen group of 2-vinylindole 3 led us to the discovery of
an unprecedented chemo- and regioselectivity switch in this
Brønsted acid catalyzed, one-pot, multicomponent reac-
tion. Only unexpected tetrahydroquinoline product 5a was
obtained in high yield (87%; Table 2, Entry 2) with excel-
lent diastereoselectivity (Ͼ95:5) when N-free 2-vinylindole
3b was employed in the reaction.[14,15] Meanwhile, all of the
other N-substituted (R = Me, allyl, or Ts) 2-vinylindoles
3c–e were compatible in the reaction to provide tetrahydro-
γ-carboline products 4c–e without formation of tetra-
hydroquinoline products. Although complete understand-
ing of the chemo- and regioselectivity switch in this
Brønsted acid catalyzed reaction has not yet been reached,
we believe that tetrahydroquinoline product 5a was the re-
Table 1. Optimization conditions for the one-pot, multicomponent
synthesis of tetrahydro-γ-carboline 4a.[a]
Table 2. Significant chemo- and regioselectivity switch in the
Brønsted acid catalyzed, one-pot, multicomponent reaction.[a]
Entry
Catalyst
Solvent
t [h]
% Yield of 4a[b]
1
2
3
4
5
6
7
8
HOAc
PhCO2H
pTSA·H2O
(Ϯ)-CSA
MeSO3H
DNBA
DNBA
DNBA
DNBA
DNBA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
96
112
96
96
96
96
64
48
84
70
69
66
24
54
62
55
40
45
69
74
76
45
9
Et2O
10
11
12
13
toluene
CH3CN
EtOH
60
56
DNBA
DNBA
DNBA
Entry
3a–e
t [h]
Product, % Yield[b]
57
DCE
83[c,d]
1
2
3
4
5
3a: R = Bn
3b: R = H
3c: R = Me
3d: R = allyl
3e: R = Ts
24
24
24
48
48
4b, 83
5a, 87[c]
4c, 85
4d, 82
4e, 79
[a] Unless otherwise noted, reactions were carried out with 1a
(0.30 mmol), 2b (0.30 mmol), 3a (0.45 mmol), 4 Å MS (100 mg),
and catalyst (0.090 mmol) in solvent (1.5 mL) at room temperature.
[b] Isolated yield of 4a. [c] p-Methoxyaniline (2a) was used instead
of 2b, and product 4b was obtained. [d] The structure of corre-
sponding product 4b was confirmed by X-ray analysis. pTSA·H2O
= p-toluenesulfonic acid monohydrate, (Ϯ)-CSA = (Ϯ)-cam-
phorsulfonic acid, DNBA = 3,5-dinitrobenzoic acid, DCE = 1,2-
dichloroethane.
[a] Reactions were carried out with 1a (0.30 mmol), 2a (0.30 mmol),
3a–e (0.45 mmol), 4 Å MS (100 mg), and DNBA (0.090 mmol) in
DCE (1.5 mL) at room temperature. [b] Isolated yield. [c] dr Ͼ 95:5,
determined by NMR spectroscopic analysis of the crude reaction
mixture.
Eur. J. Org. Chem. 2010, 4976–4980
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4977

J.-R. Chen, W.-J. Xiao et al.
SHORT COMMUNICATION
sult of a formal inverse-electron-demand aza-Diels–Alder Table 3, Entries 1–9). The electronic properties and the ste-
process due to the hydrogen bonding between the Brønsted ric hindrance of the substituent at the aromatic ring had
acid DNBA and the N-free 2-vinylindole 3b (Scheme 2).
little influence on the reaction outcome. Aromatic alde-
hydes possessing electron-donating groups gave good yields
(Table 3, Entries 1 and 2), whereas aldehydes with electron-
withdrawing substituents at the para and meta positions
underwent the sequential process more efficiently and gave
higher yields (Table 3, Entries 3–7). Moreover, multisubsti-
tuted aromatic aldehydes were also successfully engaged in
the reaction (87% yield; Table 3, Entry 9). Furthermore,
this protocol was satisfactorily tolerated by the 2-vinylin-
dole component (Table 3, Entries 10–14). Vinylindoles with
either electron-donating or electron-withdrawing substitu-
ents at the C-5 position smoothly participated in the reac-
tion, providing the desired products in high yields (70–
85%).
Finally, we explored the synthesis of tetrahydroquino-
lines by using the reaction of N-free 2-vinylindoles 3 with
aldehydes 1 and aniline 2 in the presence of 30 mol-%
DNBA (55–88%, Table 4). As shown, this switch approach
to tetrahydroquinoline synthesis was well tolerant by the
aldehyde and 2-vinylindole components, as significant
changes in both were achieved with no detrimental effects
on the yields; these results are comparable to the corre-
sponding tetrahydro-γ-carboline synthesis (Table 4, En-
tries 1–7). Meanwhile, anilines 2c and 2d can also partici-
pate in this process, providing the desired products in good
yields (Table 4, Entries 8 and 9). We obtained the crystal of
tetrahydroquinoline product 5b and its relative configura-
tion was further confirmed by X-ray crystallographic analy-
sis (Figure 2).[13]
Scheme 2. Proposed transition states in this Brønsted acid cata-
lyzed, one-pot, multicomponent reaction.
With optimal conditions in hand, we subsequently ex-
plored the scope of this chemo- and regioselectivity switch
protocol in the synthesis of tetrahydro-γ-carbolines and
tetrahydroquinolines. As seen from Table 3, a variety of
tetrahydro-γ-carbolines were obtained in high yields when
N-benzyl 2-vinylindoles 3 were employed with aldehydes 1
and aniline 2a in the presence of 30 mol-% DNBA. A wide
range of aromatic aldehydes were well tolerated and fur-
nished the corresponding products in good yields (67–88%;
Table 3. Scope of the one-pot, multicomponent synthesis of tetra-
hydro-γ-carbolines.[a]
Table 4. Scope of the one-pot, multicomponent synthesis of tetra-
hydroquinolines.[a]
Entry
R1
R2
t [h]
Product,
% Yield[b]
1
2
3
4
5
6
7
8
4-MeOPh (1b)
4-MePh (1c)
4-FPh (1d)
H (3a)
H (3a)
72
72
48
42
42
18
22
70
48
42
48
18
22
48
4f, 68
4g, 70
4h, 78
4i, 88
4j, 75
4k, 85
4l, 84
4m, 67
4n, 87
4o, 85
4p, 81
4q, 78
4r, 70
4s, 75
Entry
R1
R2
R3
t [h]
Product,
% Yield[b,c]
H (3a)
4-ClPh (1e)
4-BrPh (1f)
4-NO2Ph (1g)
3-NO2Ph (1h)
2-BrPh (1i)
3,4-F2-Ph (1j)
4-ClPh (1e)
4-ClPh (1e)
4-ClPh (1e)
4-ClPh (1e)
4-ClPh (1e)
H (3a)
1
2
3
4
5
6
7
8
9
Ph (1a)
4-NO2Ph (1g)
4-MePh (1c)
Ph (1a)
H (3b)
H (3b)
H (3b)
OMe (2a)
OMe (2a)
OMe (2a)
24
24
36
24
24
48
48
48
48
5a, 87
5b, 65
5c, 72
5d, 71
5e, 82
5f, 84
5g, 88
5h, 64
5i, 55
H (3a)
H (3a)
H (3a)
5-MeO (3k) OMe (2a)
H (3a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
5-Me (3l)
5-F (3m)
5-Cl (3n)
H (3b)
OMe (2a)
OMe (2a)
OMe (2a)
H (2c)
9
H (3a)
10
11
12
13
14
5-MeO (3f)
5-Me (3g)
5-F (3h)
5-Cl (3i)
5-Br (3j)
Ph (1a)
H (3b)
Cl (2d)
[a] Reactions were carried out with 1 (0.30 mmol), 2 (0.30 mmol),
3 (0.45 mmol), 4 Å MS (100 mg), and DNBA (0.090 mmol) in DCE
(1.5 mL) at room temperature. [b] Isolated yield. [c] dr Ͼ 95:5, de-
termined by NMR spectroscopic analysis of the crude reaction
mixture.
[a] Reactions were carried out with 1 (0.30 mmol), 2a (0.30 mmol),
3 (0.45 mmol), 4 Å MS (100 mg), and DNBA (0.090 mmol) in DCE
(1.5 mL) at room temperature. [b] Isolated yield.
4978
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Synthesis of Tetrahydro-γ-carbolines and Tetrahydroquinolines
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Figure 2. X-ray crystal structure of tetrahydroquinoline 5b.
Conclusions
In summary, we have developed an efficient one-pot,
three-component reaction of aldehydes 1, p-methoxyaniline
(2a), and 2-vinylindoles 3. The chemo- and regioselectivity
of the reaction can easily be tuned by changing the protect-
ing group of the indole component; two kinds of structur-
ally different products can be obtained in good yields, pro-
viding a practical approach to obtain synthetically and bio-
logically important tetrahydro-γ-carboline and tetra-
hydroquinoline derivatives. Further studies on the mecha-
nism and the asymmetric version of this reaction are ac-
tively underway in this laboratory.
[4]
[5]
Experimental Section
Typical Procedure: A reaction vial equipped with a magnetic stir-
ring bar was sequentially charged with 1a (32 mg, 0.30 mmol), 2a
(37 mg, 0.30 mmol), 4 Å MS (100 mg), DCE (1.5 mL), and DNBA
(19 mg, 0.090 mmol). The mixture was stirred at room temperature
for 15 min and 3a (105 mg, 0.45 mmol) was then added. The re-
sulting solution was stirred at the same temperature until the reac-
tion was complete (TLC). The crude reaction mixture was directly
subjected to column chromatography (petroleum ether/ethyl acet-
ate, 15:1) to afford 4b as a white solid in 83% yield. Rf = 0.40
(petroleum ether/ethyl acetate, 8:1).
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Supporting Information (see footnote on the first page of this arti-
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[7]
[8]
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Received: June 15, 2010
Published Online: August 16, 2010
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