Facile synthesis of fully substituted dihydro-β-carbolines via Bronsted acid promoted cascade reactions of α-indolyl propargylic alcohols with nitrones

Article abstract of DOI:10.1021/ol302695p

A straightforward synthesis of fully substituted β-carbolines via Bronsted acid promoted cyclizations of α-indolyl propargylic alcohols with nitrones is described. The use of nitrones bearing alkenyl or electron-rich aryl groups as the R⁴ substituent dramatically switches the reaction pathway to afford tetrasubstituted alkenes and amines, which is assumed to proceed through a rearrangement reaction involving N-O bond cleavage and 1,2-migration of the R⁴ group to an adjacent nitrogen atom.

Full text of DOI:10.1021/ol302695p

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5848–5851
Facile Synthesis of Fully Substituted
Dihydro-β-carbolines via Brønsted Acid
Promoted Cascade Reactions of r‑Indolyl
Propargylic Alcohols with Nitrones
Lu Wang, Xin Xie, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
People’s Republic of China
yhliu@mail.sioc.ac.cn
Received September 28, 2012
ABSTRACT
A straightforward synthesis of fully substituted β-carbolines via Brønsted acid promoted cyclizations of r-indolyl propargylic alcohols with
nitrones is described. The use of nitrones bearing alkenyl or electron-rich aryl groups as the R4 substituent dramatically switches the reaction
pathway to afford tetrasubstituted alkenes and amines, which is assumed to proceed through a rearrangement reaction involving NꢀO bond
cleavage and 1,2-migration of the R4 group to an adjacent nitrogen atom.
β-Carbolines, including its reduced derivatives, repre-
sent a large group of biologically active indole alkaloids wide-
spread in nature.1 For example, Jadiffine2 and Neonaucleo-
side C3 were isolated from Vinca difformis and Neonauclea
sessilifolia, respectively. Lavendamycin is a naturally oc-
curring antitumor antibiotic, which possesses cytotoxic
properties and exhibits significant activity against topo-
isomerases (Figure 1).4 β-Carbolines also act as useful
intermediates for natural product synthesis.5 As a con-
sequence, much attention has been paid to the synthesis
of β-carboline derivatives.6 The most common strategy is
through the PictetꢀSpengler reaction.7 Others include,
for examples, ring derivatizations,8 metal or Lewis acid
catalyzed intramolecular nucleophilic cyclization at the
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r
10.1021/ol302695p
Published on Web 11/12/2012
2012 American Chemical Society

Table 1. Optimization of Reaction Conditions
Figure 1. Representative examples of highly substituted
β-carboline alkaloids.
C-3 position of indole,9 copper-catalyzed CꢀN bond
coupling reactions,10 Ru-catalyzed [2 þ 2 þ 2] cycloaddi-
tion of an electron-deficient nitrile to an alkynylynamide,11
etc. Nevertheless, the development of straightforward
methodology that allows the formation of densely sub-
stituted β-carbolines still remains an important objective.
We have recently reported a series of gold-catalyzed
cascade transformations of indolyl tethered alkynes,12
such as cascade FriedelꢀCrafts/hydroarylation of indoles
with (Z)-enynols,12a 1,5-indole migration reactions,12b and
deacylative cycloisomerization of 3-acylindole/ynes12c into
carbazole derivatives. On the other hand, recent research
demonstrated that nitrones could serve as a satisfactory
oxidant for redox reactions with cleavage of a weak NꢀO
bond in gold-catalyzed reactions, leading to an oxygen-
atom transfer to alkynes.13 We envisioned that the use of
nitrone as a nucleophile to attack the alkyne moiety of
indole/ynes might initialize new types of cascade reac-
tions. Along this line, we discovered that fully substituted
dihydro-β-carbolines could be constructed conveniently
via tandem reactions of R-indolyl propargylic alcohols
with nitrones promoted by Lewis or Brønsted acids
(Scheme 1). Herein we’d like to describe this new protocol
to β-carbolines.
a Isolated yields. b Compound 4 was also isolated in 18% yield as a
mixture of two isomers in the ratio of 2.4:1. c 4 was isolated in 15% yield
as a mixture of two isomers in the ratio of 2.4:1. d In the absence of
molecular sieve. e Complicated reaction mixture.
In light of the efficient activation of alkynes by gold
catalysts, we first investigated the model reaction of the
propargylic alcohol 1a with nitrone 2a in the presence of
5 mol % of PPh3AuNTf2 (Table 1).14,15 It was found that
β-carboline 3a could be obtained in 40% yield at 100 °C in
CH3NO2 (Table 1, entry 1). Elevating the reaction tem-
perature to 150 °C did not improve the reaction, and 3a
was isolated in 24% yield (entry 2). Advantageously, the
use of 30 mol % of Sc(OTf)3 could enable the reaction
to proceed at 0 °C and improve the yield of 3a to 62%
(entry 4). Decreasing or increasing the amounts of the
Scheme 1. A New Strategy for the Synthesis of Dihydro-β-
carbolines
(12) (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351,
1517. (b) Li, G.; Liu, Y. J. Org. Chem. 2010, 75, 3526. (c) Wang, L.; Li,
G.; Liu, Y. Org. Lett. 2011, 13, 3786. (d) Xie, X.; Du, X.; Chen, Y.; Liu,
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4744. (d) Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.;
Karad, S. N.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 15372.
(14) For a review on transition-metal-catalyzed functionalization of
propargylic alcohols, see: Bauer, E. B. Synthesis 2012, 44, 1131.
(15) Forgold-catalyzed cyclization of2-(propargylicalcohol)-anilines,
see: Cera, G.; Piscitelli, S.; Chiarucci, M.; Fabrizi, G.; Goggiamani, A.;
(9) (a) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A.
J. Org. Chem. 2003, 68, 7126. (b) Bandini, M.; Melloni, A.; Piccinelli, F.;
Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128,
1424. (c) England, D. B.; Padwa, A. Org. Lett. 2008, 10, 3631. (d) Ohta,
Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 7052.
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Org. Lett., Vol. 14, No. 23, 2012
5849

Scheme 2. Scope of Propargylic Alcoholsa
Scheme 3. Scope of Nitronesa
a Isolated yields. bRoom temperature, 3 h.
However, an N-Boc-protected substrate gave the product
3c in a low yield of 28%, possibly due to the instability of
the starting alcohol 1c under the acidic conditions. The
use of Sc(OTf)3 as a catalyst could improve the yield of 3c
to 45%. A heteroaryl group such as 2-furanyl as the R2
substituent afforded 51% of 3d. Alkyl substitution as R2
as in the case of tBu-substituted substrate 1e also worked
smoothly to give 3e in 46% yield. Next, we investigated the
substituent effects on the alkyne terminus (R3 group). Both
electron-rich (p-MeOC6H4) and electron-poor (p-NO2C6H4)
aryl substituents were tolerated, furnishing the corresponding
β-carbolines 3f and 3g in 75% and 42% yields, respectively.
The results indicated that the electron-withdrawing substitu-
ent on the aryl ring led to a lower yield of the product, which
might be due to the lower stability of the allenyl cation
intermediate formed in the initial step. A cyclopropyl-group
as R3 was also suitable in this domino reaction, producing 3h
in 64% yield. However, a terminal alkyne only led to a 22%
yield of 3i. 5-MeO or 5-Br-substituted indole substrates were
also compatible for this transformation to deliver 3jꢀ3k in
52ꢀ64% yields. The structure of 3 was unambiguously
confirmed by X-ray single-crystal analysis of 3b and 3c.16
The scope of nitrones was also tested using 1a as a
reaction partner (Scheme 3). It was found that, for nitrones
bearing electron-deficient C-aryl groups (R4), such as the
p-BrC6H4 or p-CF3C6H4 group, the desired carbolines
3lꢀ3m could be obtained in 67ꢀ70% yields. However,
when R4 is an electron-rich aryl group, product 4 was
isolated as a major product (vide infra). The N-aryl rings
bearing p-MeO, p-Me, p-Cl, and p-CO2Me substituents
reacted smoothly with 1a to afford 3nꢀ3q in 48ꢀ86% yields.
The use of N-Bn-substituted nitrone gave a low yield of 3r.
a
b
Isolated yields. 30% Sc(OTf)3, 4A MS, in CH3NO3, rt, 15 min. 1 h.
c
˚
catalyst did not change the product yields significantly
(entries 3 and 5). Further studies revealed that the con-
jugate acid of the metal triflates, TfOH, also showed good
activities to afford 61% of 3a in CH3NO2 or 66% of 3a in
DCM (entries 6ꢀ7). In the latter case, a tetrasubstituted
alkene with two electron-withdrawing groups 4 was also
isolated in 18% yield. A catalytic amount (50 mol %) of
TfOH afforded a lower yield of 3a (57%, entry 8). In
the absence of molecular sieve, 3a was obtained in a lower
yield of 55% (entry 9). Other Brønsted acids, such as
TsOH H2O, MsOH, or CF3COOH, were less or not effec-
3
tive (entries 10ꢀ12). We chose Table 1, entry 7 as the
optimum conditions due to the lower cost of TfOH.
Having the optimized reaction conditions in hand,
we next examined the substrate scope with a range of
R-indolyl-bearing propargylic alcohols. As shown in
Scheme 2, a wide range of propargylic alcohols could be
converted into the desired β-carbolines in the presence of
1.0 equiv of TfOH. The use of N-methyl-substituted indole
afforded the corresponding carboline 3b in 56% yield.
(16) See Supporting Information.
5850
Org. Lett., Vol. 14, No. 23, 2012

cleavage of the NꢀO bond from 7 is accompanied by
the migration of the R4 group to the nitrogen atom20 to
give iminium ion 11. Hydrolysis of 11 affords the
alkene product 4 and releases the amine 5. The results
also demonstrate that the electron-rich π-system tends
toward migration.20
Scheme 4. 1,2-Migration Reactions
Scheme 5. Possible Reaction Mechanism
As mentioned above, when nitrones bearing an electron-
rich C-aryl group was employed, product 4 was isolated as
a major product. For example, when 1a was reacted with
nitrone 2i substituted with a strong electron-donating
methylenedioxy group on the C-aryl ring, 4 was formed
in 87% yield, and an unexpected liberation of N- phenylbenzo-
[d][1,3]dioxol-5-amine 5 was alsoobserved(Scheme4). The
results indicated that the migration of a C-aryl group to
the nitrogen atom occurred during the reaction. Similarly,
the use of nitrone 2j (R4 = p-tBuC6H4) and 2k (R4 =
;CHdCH;Ph) resulted in the formation of 4 in 83%
and 86% yields, respectively. The structure of 4 was con-
firmed by X-ray single-crystal analysis.16
Based on the above observations and the known pre-
cedents in literature, we propose the following reaction
mechanism for this reaction (Scheme 5). Initially, allenyl
cation 6 is generated via a MeyerꢀSchuster rearrange-
ment,17,18 which is attacked by nitrone 2 to give inter-
mediate 7. 7 undergoes cyclization via attack of the indolyl
moiety to the iminium cation leading to eight-membered
NꢀO heterocycle 9. 1,3-Rearrangement of 9 with cleavage
of the NꢀO bond, similar to Baldwin rearrangement and
related reactions,19 delivers highly substituted β-carboline
3. When R4 is an alkenyl or electron-donating aryl group,
In summary, we have developed a new procedure for the
synthesis of fully substituted 1,2-dihydro-β-carbolines via
Brønsted acid mediated cyclization of R-indolyl pro-
pargylicalcoholswithnitrones. The use of nitrones bearing
an electron-rich C-aryl ring or C-alkenyl group dramati-
cally switches the reaction pathway to afford tetrasubsti-
tuted alkenes and amines, which is assumed to proceed
through a rearrangement reaction involving NꢀO bond
cleavage and 1,2-migration. These results will be of im-
portance for the development of new reactions with the use
of nitrones. Clarification of the reaction mechanism and
further application of this chemistry are in progress.
(17) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.
(18) For recent papers, see: (a) Yao, L.-F.; Shi, M. Chem.;Eur. J.
2009, 15, 3875. (b) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shu, X.-Z.; Zhao,
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Lett. 2011, 13, 3553.
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 21125210,
21121062), Chinese Academy of Science and the Major
State Basic Research Development Program (Grant No.
2011CB808700) for financial support.
(19) (a) Baldwin, J. A.; Pudussery, R. G.; Qureshi, A. K.; Sklarz, B.
J. Am. Chem. Soc. 1968, 90, 5325. (b) Gree, R.; Carrie, R. J. Am. Chem.
Soc. 1977, 99, 6667. (c) Gayon, E.; Debleds, O.; Nicouleau, M.; Lamaty,
F.; van der Lee, A.; Vrancken, E.; Campagne, J.-M. J. Org. Chem. 2010,
75, 6050. (d) Ishikawa, T.; Kudoh, T.; Yoshida, J.; Yasuhara, A.;
Manabe, S.; Saito, S. Org. Lett. 2002, 4, 1907. (e) Wang, H.-Y.; Mueller,
D. S.; Sachwani, R. M.; Kapadia, R.; Londino, H. N.; Anderson, L. L.
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16, 1149.
Supporting Information Available. Experimental de-
tails, spectroscopic characterization of all new com-
pounds, and X-ray crystallography of compounds 3b,
3c and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Chukanov, N. V.; Popov, S. A.; Romanenko, G. V.; Reznikov,
V. A. Tetrahedron 2008, 64, 7432.
The authors declare no competing financial interest.
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