Facile synthesis of 1,2,3,4-tetrahydro-carbolines by one-pot domino three-component indole formation and nucleophilic cyclization

Article abstract of DOI:10.1021/ol900460m

Two direct synthetic methods of 1,2,3,4-tetrahydro-/?-carboline derivatives have been developed. After initial indole formation by copper- catalyzed domino three-component coupling-cyclization using an appropriate ethynylaniline, aldehyde, and a secondary

Full text of DOI:10.1021/ol900460m

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1979-1982
Facile Synthesis of
1,2,3,4-Tetrahydro-ꢀ-carbolines by
One-Pot Domino Three-Component
Indole Formation and Nucleophilic
Cyclization
Yusuke Ohta, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received March 4, 2009
ABSTRACT
Two direct synthetic methods of 1,2,3,4-tetrahydro-ꢀ-carboline derivatives have been developed. After initial indole formation by copper-
catalyzed domino three-component coupling-cyclization using an appropriate ethynylaniline, aldehyde, and a secondary amine, treatment
with t-BuOK/hexane or MsOH afforded the desired tetrahydro-ꢀ-carboline derivatives in moderate to good yields.
Intense interest in modern organic chemistry has been
directed toward the development of simple methods which
produce structurally complex compounds in high yields under
mild and environmentally friendly conditions. In particular,
cascade1 or one-pot reactions which include a multicompo-
nent reaction2 using simple starting materials provide an
efficient and powerful tool for atom-economical synthesis.
A 1,2,3,4-tetrahydro-ꢀ-carboline, which consists of a
tricyclic indole, is an attractive drug template due to its
potential antioxidative activity.3 Carboline derivatives are
also useful as intermediates for natural product synthe-
sis.4,5 Because construction of tetrahydro-ꢀ-carbolines is
mostly dependent on the Pictet-Spengler4 and related
reactions,5 development of alternative synthetic methodolo-
(1) For recent reviews, see: (a) Malacria, M. Chem. ReV. 1996, 96, 289–
306. (b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 551–564. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134–7186. (d) Enders, D.; Grondal, C.; Hu¨ttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581.
(3) (a) Pless, G.; Frederiksen, T. J.; Garcia, J. J.; Reiter, R. J. J. Pineal
Res. 1999, 26, 236–246. (b) Herraiz, T.; Galisteo, J. Free Radic. Res. 2002,
36, 923–928. (c) Ichikawa, M.; Ryu, K.; Yoshica, J.; Ide, N.; Yoshida, S.;
Sasaoka, T.; Sumi, S. Biofactors 2002, 16, 57–72. (d) Herraiz, T.; Galisteo,
J.; Chamorro, C. J. Agric. Food Chem. 2003, 51, 2168–2173. (e) Herraiz,
T.; Galisteo, J. J. Agric. Food Chem. 2003, 51, 7156–7161. (f) Bi, W.;
Bai, L.; Cai, J.; Liu, S.; Peng, S.; Fischer, N. O.; Tok, J. B.-H.; Wang, G.
Bioorg. Med. Chem. Lett. 2006, 16, 4523–4527. (g) Bi, W.; Cai, J.; Liu,
S.; Baudy-Floc’h, M.; Bi, L. Bioorg. Med. Chem. 2007, 15, 6906–6919.
(2) For recent reviews, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168–3210. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17–
89. (c) Tejedor, D.; Garc´ıa-Tellado, F. Chem. Soc. ReV. 2007, 36, 484–
491. (d) D’Souza, D. M.; Mu¨ller, T. J. J. Chem. Soc. ReV. 2007, 36, 1095–
1108.
10.1021/ol900460m CCC: $40.75
Published on Web 04/08/2009
 2009 American Chemical Society

gies is extremely important to ensure diversity-oriented
synthesis.6
Table 1. One-Pot, Three-Component Synthesis of
Tetrahydro-ꢀ-carbolines Using t-BuOKa
We recently reported the copper-catalyzed synthesis of
2-(aminomethyl)indoles via a domino three-component
coupling-cyclization reaction of a 2-ethynylaniline, paraform-
aldehyde, and a secondary amine.7,8 Bosch and co-workers
previously reported that treatment of a 2-[N-(benzenesulfo-
nyl)indol-2-yl]piperidin-4-one derivative having an N-hy-
droxylethyl group with t-BuOK brought about the formation
of the corresponding indolo[2,3-a]quinolizine, although this
was an isolated example.9 On the other hand, it is well
established that cyclization at the 3-position of N-alkylindoles
containing an ester group is efficiently promoted by a strong
acid to afford 4-oxotetrahydro-ꢀ-carbolines.10 Based on this
chemistry, we expected that 2-(aminomethyl)indole 5, gener-
ated by copper-catalyzed indole formation using ethynyla-
nilines 1, aldehydes 2, and secondary amines 3 bearing an
appropriate functionality (R3 ) CH2OH or CO2R), could be
converted into ꢀ-carboline derivatives 6 or 7 by a second
cyclization at the C-3 position (Scheme 1). This sequential
yieldb (%)
entry
R1
conditions cosolvent 6a
8a
1
2
3
4
5
Ts (1a)
Ts (1a)
Ts (1a)
Ms (1b)
Mts (1c)
80 °C, 1 h
80 °C, 1 h
80 °C, 1 h
80 °C, 2 h
80 °C, 2 h
31
23
53
29
19
63
58
65
48
23
75
69
20
33
35
43
25
14
18
20
10
25
Et2O
hexane
hexane
hexane
6
7
8
9
SO2Ph (1d)
80 °C, 1.5 h hexane
80 °C, 0.5 h hexane
80 °C, 0.5 h hexane
80 °C, 0.5 h hexane
Scheme 1
.
Two Direct Routes to 1,2,3,4-Tetrahydro-ꢀ-carboline
SO2C6H4(4-Br) (1e)
SO2C6H4(4-Cl) (1f)
SO2C6H4(4-F) (1g)
Derivatives
10
11
SO2C6H4(4-NO2) (1h) 80 °C, 0.5 h hexane
SO2C6H4(4-Cl) (1f) 50 °C, 1.5 h hexane
a Ethynylaniline 1 (0.18 mmol), n-PrCHO 2a (2 equiv), and 2-(N-
methylamino)ethanol 3a (1.1 equiv) in dioxane (2 mL) were treated with
CuBr (5 mol %) under the conditions shown. After the indole formation
was complete (monitored by TLC), cosolvent (2 mL) and t-BuOK (3 equiv)
were added at 0 °C and the reaction mixture was stirred at 0 °C for 5 min
and rt for an additional 30 min. b Isolated yields.
in dioxane was complete as monitored by TLC (1 h at 80
°C), t-BuOK (3 equiv) was added to the reaction mixture.
Although the desired bis-cyclization product 1,2,3,4-tetrahy-
dro-ꢀ-carboline derivative 6a was obtained in 31% yield,
the N-cyclization product 8a was formed as the major product
(69% yield, entry 1).12 To improve the selectivity of the
second cyclization, we optimized the reaction conditions for
deprotection-cyclization as well as the nitrogen protecting
group.13 Addition of Et2O as the cosolvent slightly improved
(4) (a) Yu, P.; Wang, T.; Li, J.; Cook, J. M. J. Org. Chem. 2000, 65,
3173–3191. (b) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249–
252. (c) Liu, C.; Masuno, M. N.; MacMillan, J. B.; Molinski, T. F. Angew.
Chem., Int. Ed. 2004, 43, 5951–5954. (d) Yamashita, T.; Kawai, N.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127, 15038–15039.
(e) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Org. Chem. 2005, 70, 3963–
3979. (f) Zhou, H.; Han, D.; Liao, X.; Cook, J. M. Tetrahedron Lett. 2005,
46, 4219–4224. (g) Zhou, H.; Liao, X.; Yin, W.; Ma, J.; Cook, J. M. J.
Org. Chem. 2006, 71, 251–259. (h) Ma, J.; Yin, W.; Zhou, H.; Cook, J. M.
Org. Lett. 2007, 9, 3491–3494. (i) Volz, F.; Krause, N. Org. Biomol. Chem.
2007, 5, 1519–1521. (j) Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org.
Lett. 2008, 10, 745–748.
reaction is challenging in that various reactive components
exist in the reaction mixture, including unprotected amine(s),
an aldehyde, and an ester/alcohol, especially when N-
alkylanilines are employed. Herein we report two direct
routes to 1,2,3,4-tetrahydro-ꢀ-carboline derivatives by a
copper-catalyzed three-component coupling-indole forma-
tion-nucleophilic cyclization at the 3-position. To the best
of our knowledge, there is no precedent for multicomponent
synthesis of tetrahydro-ꢀ-carbolines, except for those using
the Pictet-Spengler-type reaction.2a,11
(5) (a) Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79–
81. (b) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867–8878. (c)
Ohba, M.; Natsutani, I.; Sakuma, T. Tetrahedron Lett. 2004, 45, 6471–
6474. (d) Ohba, M.; Natsutani, I.; Sakuma, T. Tetrahedron 2007, 63, 10337–
10344. (e) Czarnocki, S. J.; Wojtasiewicz, K.; Jo´z´wiak, A. P.; Maurin, J. K.;
Czarnocki, Z.; Drabowicz, J. Tetrahedron 2008, 64, 3176–3182. (f)
Shankaraiah, N.; da Silva, W. A.; Andrade, C. K. Z.; Santos, L. S.
Tetrahedron Lett. 2008, 49, 4289–4291.
The initial attempt was carried out with N-tosyl-2-
ethynylaniline 1a, butanal 2a (2 equiv), and 2-(N-methyl-
amino)ethanol 3a (1.1 equiv) in the presence of 5 mol % of
CuBr (Table 1). After the three-component indole formation
1980
Org. Lett., Vol. 11, No. 9, 2009

the selectivity but decreased the combined yield to 43% (entry
2). In contrast, use of hexane led to the formation of 6a as the
major product (53% yield, entry 3). These results are in good
agreement with Bosch’s observation, in which carrying out the
reaction in a less polar solvent improved the selectivity of the
C-3 cyclization over the N-cyclization.9 The N-protecting groups
of 2-ethynylaniline, mesyl, and mesitylenesulfonyl (Mts) groups
were less effective for selective formation of 6a (entries 4 and
5). The reaction of 1d bearing an N-benzenesulfonyl group gave
a better result (entry 6) than that of the N-tosyl derivative 1a
(entry 2). This result promoted us to utilize more electron-
deficient benzenesulfonamides 1e-h bearing an electron-
withdrawing atom on the benzene ring (entries 7-10). The
results indicated that the 4-chlorophenylsulfonyl group was the
best protecting group of the aniline nitrogen of 1 (entry 8). In
this case, the 2,3-unsubstituted N-arylsulfonylindole, formed by
intramolecular hydroamination of 1 without resulting in a
Mannich-type reaction, was observed as a byproduct. We also
tested the reaction at a lower temperature (50 °C) for the three-
component indole formation and obtained 6a in 75% yield
(entry 11).14
and 8c, respectively. In these reactions, a prolonged reaction
time and elevated temperature were necessary for completion
of the initial indole formation, presumably because of the
steric bulkiness of the functional groups. The reaction with
paraformaldehyde 2d gave 6d in 45% yield (entry 3).15
We next investigated the acid-induced direct construction of
a 4-oxotetrahydro-ꢀ-carboline scaffold using amino esters 3b-j
(Table 3). In this reaction, use of anilines without an electron-
Table 3. Preparation of 4-Oxotetrahydro-ꢀ-carboline by Domino
Three-Component Coupling-Indole Formation and Successive
MsOH-Induced Cyclizationa
Under the optimized conditions (Table 1, entry 11), the
scope of this one-pot tetrahydro-ꢀ-carboline synthesis was
explored using ethynylaniline derivative 1f and several
aldehydes (Table 2). Reaction with aldehyde 2b or 2c
containing a (trimethylsilyl)vinyl or benzyloxymethyl group
afforded 6b and 6c in moderate yields (entries 1 and 2, 48%
and 55%, respectively), accompanied by the byproduct 8b
Table 2. Synthesis of Tetrahydro-ꢀ-carbolines Using Several
Aldehydesa
a Ethynylaniline 1f (0.18 mmol), aldehyde 2 (2 equiv), and 2-(N-
methylamino)ethanol 3a in dioxane were treated with CuBr (5 mol %)
under the conditions shown. Hexane (2 mL) and t-BuOK were then added
at 0 °C, and the reaction mixture was stirred at 0 °C for 5 min and rt for
an additional 30 min. b Conditions for the initial indole formation.
c Isolated yields. d Structures of 8b-d are shown below. e Not isolated.
a The mixture of ethynylaniline 1g (0.19 mmol), paraformaldehyde 2d
(2 equiv), and amino ester 3 (1.2 equiv) in dioxane was stirred with CuX
(5 mol %) under microwave irradiation (300 W). After indole formation
was complete on TLC, the reaction mixture was treated with MsOH at 80
°C for 30 min. b Conditions A: CuI, 170 °C, 1 h. Conditions B: CuBr, 120
°C, 15 min, then 140 °C, 15 min. Conditions C: CuBr, 120 °C, 15 min.
c Isolated yields.
Org. Lett., Vol. 11, No. 9, 2009
1981

withdrawing group on the nitrogen atom is essential to secure
the nucleophilicity of the intermediate indoles of type 5 (Scheme
1). A mixture of N-methyl-2-ethynylaniline 1i, paraformalde-
hyde 2d, and N-methylglycine ethyl ester 3b was treated with
5 mol % of CuBr in dioxane at 170 °C under microwave
irradiation (conditions A) followed by the reaction with MsOH16
to give the desired 4-oxo-1,2,3,4-tetrahydro-ꢀ-carboline 7a in
72% yield (entry 1). The N-allyl- or N-butylglycine derivatives
3c and 3d showed clean conversion to 7b and 7c, respectively
(entries 2 and 3). Methyl ester 3e was also a good component
for this one-pot reaction (entry 4). Whereas 3f having an
N-benzyl group resulted in sluggish conversion in the indole
formation step using conditions A (entry 5), use of CuBr, a
more reactive catalyst for the initial three-component indole
formation than CuI, led to 57% of 7d after treatment with
MsOH (conditions B, entry 6). This one-pot construction of
ꢀ-carboline derivatives also tolerated such chiral amino acid
derivatives as 3g-i (entries 7-9).17 The tetracyclic compound
7h can be easily obtained from racemic pipecolinate 3j, although
in relatively low yield (29%, entry 10).18
(6) For other representative synthetic routes, see: (a) Abramovitch, R. A.;
Shapiro, D. J. Chem. Soc. 1956, 4589–4592. (b) Pelchobicz, Z.; Bergmann,
E. D. J. Chem. Soc. 1959, 847. (c) Frangatos, G.; Kohan, G.; Chubb, F. L.
Can. J. Chem. 1960, 38, 1082–1086. (d) Wender, P. A.; White, A. W.
Tetrahedron 1983, 39, 3767–3776. (e) Luis, S. V.; Burguete, M. I.
Tetrahedron 1991, 47, 1737–1744. (f) Dantale, S. W.; So¨derberg, B. C. G.
Tetrahedron 2003, 59, 5507–5514. (g) Baruah, B.; Dasu, K.; Vaitilingam,
B.; Mamnoor, P.; Venkata, P. P.; Rajagopal, S.; Yeleswarapu, K. R. Bioorg.
Med. Chem. 2004, 12, 1991–1994. (h) Iwadate, M.; Yamashita, T.;
Tokuyama, H.; Fukuyama, T. Heterocycles 2005, 66, 241–249.
(7) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007,
46, 2295–2298.
(8) For related heterocycle syntheses, see: (a) Ohta, Y.; Oishi, S.; Fujii,
N.; Ohno, H. Chem. Commun. 2008, 835–837. (b) Ohta, Y.; Chiba, H.;
Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 3535–3838.
(9) Rubiralta, M.; Diez, A.; Bosch, J.; Solans, X. J. Org. Chem. 1989,
54, 5591–5597.
In conclusion, we have developed two direct synthetic
routes to 1,2,3,4-tetrahydro-ꢀ-carboline derivatives by cop-
per-catalyzed three-component indole formation followed by
successive cyclization at the 3-position of indole. When an
aminoethanol was used as the amine component, the 4-chlo-
rophenylsulfonyl group is the protecting/activating group of
choice for the second cyclization induced by t-BuOK. On
the other hand, N-methyl-2-ethynylaniline and R-amino esters
were good components for MsOH-induced cyclization at C-3
to produce various 4-oxo-1,2,3,4-tetrahydro-ꢀ-carbolines,
including optically active ones. These two methodologies
using three-component coupling of readily available sub-
strates should contribute to diversity-oriented synthesis of
tetrahydro-ꢀ-carbolines as a druglike scaffold.
(10) (a) Murakami, Y.; Yokoyama, Y.; Aoki, C.; Miyagi, C.; Watanabe,
T.; Ohmoto, T. Heterocycles 1987, 26, 875–878. (b) Suzuki, H.; Yokoyama,
Y.; Miyagi, C.; Murakami, Y. Chem. Pharm. Bull. 1991, 39, 2170–2172.
(c) Murakami, Y.; Yokoyama, Y.; Aoki, C.; Suzuki, H.; Sakurai, K.;
Shinohara, T.; Miyagi, C.; Kimura, Y.; Takahashi, T.; Watanabe, T.;
Ohmoto, T. Chem. Pharm. Bull. 1991, 39, 2189–2195. (d) Suzuki, H.; Iwata,
C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama,
Y.; Murakami, Y. Tetrahedron 1997, 53, 1593–1606. (e) Suzuki, H.;
Umemoto, M.; Hagiwara, M.; Ohyama, T.; Yokoyama, Y.; Murakami, Y.
J. Chem. Soc., Perkin Trans. 1 1999, 1717–1723. (f) Jennings, L. D.;
Foreman, K. W.; Rush, T. S., III.; Tsao, D. H. H.; Mosyak, L.; Li, Y.;
Sukhdeo, M. N.; Ding, W.; Dushin, E. G.; Kenny, C. H.; Moghazeh, S. L.;
Petersen, P. J.; Ruzin, A. V.; Tuckman, M.; Sutherland, A. G. Bioorg. Med.
Chem. Lett. 2004, 14, 1427–1431.
(11) (a) Karpov, A. S.; Oeser, T.; Mu¨ller, T. J. J. Chem. Commun. 2004,
1502–1503. (b) Karpov, A. S.; Rominger, F.; Mu¨ller, T. J. J. Org. Biomol.
Chem. 2005, 3, 4382–4391.
(12) Recently, we reported a selective N-cyclization with an aryl bromide
moiety; see ref 8b.
(13) Bosch proposed that the arylsulfonyl group on the indole nitrogen
would be transferred to the primary hydroxy group by the action of in situ
generated t-BuOTs, and nucleophilic attack of the C-3 position of the
resulting NH-indole furnishes the corresponding cyclization product; see
ref 9.
(14) When NaH was used instead of t-BuOK, the desired product 6a
was not obtained. This suggests that the C-3 cyclization proceeds through
rearrangement of the arylsulfonyl group from the nitrogen atom of the indole
to the hydroxyl group, as proposed by Bosch et al.
(15) The high polarity of 6d considerably lowered the chemical yield
during purification with column chromatography over silica gel. Use of
alumina column partly improved the yield of 6d (45%).
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists (A) (H.O.)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan and Targeted Proteins Research Pro-
gram. Y.O. is grateful for a Research Fellowship from the
Japan Society for the Promotion of Science (JSPS) for Young
Scientists.
(16) Other acids were less effective. For example, after indole formation
with 1g, 2d, and 3d was completed, the reaction mixture was treated with
polyphosphoric acid (PPA) to give 7c in only 19% yield.
(17) The product 7e was obtained in 95% ee [Chiralcel OD-H, with a
linear gradient of i-PrOH (20-40% over 45 min) in hexane in the presence
of 0.1% Et2NH]. HPLC charts (7e and an enantiomeric mixture 7e/ent-7e)
were given in the Suppoting Information.
(18) It should be noted that the indole formation of Mannich adducts
derived from 1g did not proceed when using aldehydes other than
paraformaldehyde and amino esters.
Supporting Information Available: General experimental
1
procedure and H and 13C NMR spectra for all of the
synthesized tetrahydro-ꢀ-carbolines (6a-d and 7a-h) as
well as N-cyclization products (8a-c). This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900460M
1982
Org. Lett., Vol. 11, No. 9, 2009