Enantioselective intermolecular formal [3 + 3] cycloaddition of 2,3-disubstituted indoles with acrolein

Article abstract of DOI:10.1021/ol401809d

An expedient enantioselective synthesis of highly substituted hydrocarbazoles has been realized by an organocatalyzed formal [3 + 3] cycloaddition between acrolein and 2,3-disubstituted indoles. Tricyclic hydrocarbazoles were obtained from a broad range of 2,3-disubstituted indoles and acrolein in good to excellent yields and excellent enantioselectivites.

Full text of DOI:10.1021/ol401809d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Intermolecular Formal
[3 þ 3] Cycloaddition of 2,3-Disubstituted
Indoles with Acrolein
Jianbiao Huang, Long Zhao, Yong Liu, Weiguo Cao, and Xiaoyu Wu*
Department of Chemistry, Shanghai University, 99 Shangda Road,
Shanghai 200444, China
wuxy@shu.edu.cn
Received June 27, 2013
ABSTRACT
An expedient enantioselective synthesis of highly substituted hydrocarbazoles has been realized by an organocatalyzed formal [3 þ 3]
cycloaddition between acrolein and 2,3-disubstituted indoles. Tricyclic hydrocarbazoles were obtained from a broad range of 2,3-disubstituted
indoles and acrolein in good to excellent yields and excellent enantioselectivites.
Chiral hydrocarbazoles bearing a quaternary stereocen-
ter at C3 in the indoline substructure constitute the frame-
work of quite a number of alkaloids. The stereochemical
diversity and structural complexity as well as biological
activities of such alkaloids have rendered them highly
attractive synthetic targets.1 In the past few decades,
tremendous synthetic efforts have been devoted to the
construction of these structural frameworks both in race-
mic and in optically pure form (Figure 1).2,3
From the point of biogenesis, this type of alkaloid is
presumed to arise from the conjunction of tryptamine and
secologanin, followed by skeleton rearrangements and
functional transformations.4 Thus, it is not surprising that
tryptamine and other indole derivatives have been fre-
quently chosen as starting materials for the chemical
Figure 1. Examples of alkaloids bearing hydrocarbazole unit.
synthesis of such alkaloids. A survey of the synthetic work
on this class of alkaloids reveals that the most challeng-
ing task, assembling the densely substituted cyclohexane
(1) (a) Saxton, J. E. In The Alkaloids; Cordell, G. A. Ed.; Academic
Press: New York, 1998; Vol. 50, Chapter 9. (b) Saxton, J. E. In The
Alkaloids; Cordell, G. A. Ed.; Academic Press: New York, 1998; Vol. 51,
Chapter 1. (c) Ramirez, A.; Garcia-Rubio, S. Curr. Med. Chem. 2003, 10,
1891. (d) Jordan, M. A.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253.
metric by organocatalysis.6 Recent examples include
(2) (a) For reviews see: Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res.
moiety embedded in the hydrocarbazoles, has been solved
by means of DielsꢀAlder reactions and related formal [4 þ
2] cycloadditions.5 This process has been rendered asym-
the following: (1) MacMillan and co-workers reported
an asymmetric intermolecular DielsꢀAlder/elimination/
conjugate addition cascade sequence for the synthesis of
a key intermediate, which greatly facilitated the synthesis
of a number of complex alkaloids;3h,j (2) You et al. em-
ployed an intramolecular Michael/Mannich organocascade
2011, 44, 447. (b) Attorusso, E.; Taglialatela-Scafati, O. Modern Alka-
loids: Structure, Isolation, Synthesis and Biology, Wiley-VCH: Weinheim,
Germany, 2008. (c) Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.;
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Brossi, A. Med. Res. Rev. 1995, 15, 3. (d) Bonjoch, J.; Sole, D. Chem. Rev.
2000, 100, 3455. (e) Mori, M. Heterocycles 2010, 81, 259. (f) Jeffrey,
S. C.; Overman., L. E. Angew. Chem., Int. Ed. 2012, 51, 4288. (g)
Shibasaki, M.; Ohshima, T. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 2007; Vol. 64, Chapter 3.
r
10.1021/ol401809d
XXXX American Chemical Society

catalyzed by a quinine-derived primary amine for the
enantioselective synthesis of tetracyclic indolines.5d De-
spite these achievements, the development of new strate-
gies for efficient and asymmetric construction of such
hydrocarbazoles that can serve as suitable precursors for
the synthesis of alkaloids and their analogues is still
highly desirable.7
In our ongoing search for a new efficient one-pot
cascade sequence for the asymmetric synthesis of hydro-
carbazoles (Scheme 1), we envisioned that 2,3-disubsti-
tuted indole 1 would be a suitable nucleophile for the
conjugate addition to acrolein 2, providing an asymmetric
access to hydrocarbazoles. As outlined in Scheme 1, con-
densation of indole derivative 1 with acrolein2 ispromoted
through the activation of the enal by formation of an
imminium intermediate to afford indolenine intermediate
4 after release of the catalyst.8 Intermediate 4 undergoes
isomerization to afford enamino-ester 5, which after an
intramolecular cyclization and following dehydration af-
fords highly functionalized hydrocarbazole 3.
Of concern are two major issues inherent in this se-
quence: the first is the possible competitive reaction be-
tween N(1) and C(3), although the latter is the most
reactive site toward electrophilic substitution;9ꢀ11 while
the second is the further conjugate addition(s) of cyclized
Scheme 1. Conceptual Cascade Sequence to Chiral Hydrocar-
bazoles
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Marko, I. E. Org. Biomol. Chem. 2006, 4, 3898. (b) Heureux, N.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

functionality at the β-position to reduce the nucleophilicity
of the dienamine.
Table 1. Screening of Reaction Conditionsa
To test the feasibility of the above-mentioned working
hypothesis, our study was carried out with 2,3-disubsti-
tuted indole 1a and acrolein 2 as model substrates for
screening reaction conditions (Scheme 2). At the begin-
ning, L-proline derived secondary amine13 7aand L-phenyl-
alanine derived imidazolidinone 8a were evaluated using
reaction conditions similar to those reported by MacMil-
lan and co-workers.3h Although the reactions proceeded
smoothly and 1a was consumed quickly, to our dismay,
7a resulted in a mixture of unidentified products besides a
trace amount of 3a, while 8a led to the formation of 3a in
17% yield with 81% ee and a mixture of 9 and its
diastereoisomers. The relative configuration of 9 was
determined by X-ray diffraction.14
The initial frustrations caused by secondary amine
catalysts prompted us to turn our attention to chiral
primary amines15 as alternative catalysts for this cascade.
To our delight, with quinine-derived primary amine16 10a
(15 mol %) as the catalyst and perfluorobenzoic acid
(PFBA, 30 mol %) as the cocatalyst, the cascade reaction
proceeded smoothly in dioxane at 15 °C to afford the
cyclized product 3a in 88% yield and 90% ee (Table 1,
entry 1). Attempts to improve the performance of this
reaction by screening of the acid cocatalysts (Table 1,
entries2ꢀ6) revealedthatortho-nitrobenzoicacid(2-NBA)
entry cat.
acidb
solvent time (h) yield (%)c ee (%)d
1
2
3
4
5
6
7
8
9
10a PFBA
10a 2-NBA
10a 4-NBA
dioxane
dioxane
dioxane
4
6
88
95
90
90
90
20
98
60
60
99
86
98
49
73
90
98
10
62
69
90
95
12
12
15
20
2
92
10a 3,5-(CF3)2-BA dioxane
88
10a 4-CF3ꢀBA
10a BA
dioxane
dioxane
toluene
Et2O
THF
DCM
DCE
EA
89
NDe
53
10a 2-NBA
10a 2-NBA
10a 2-NBA
15
15
2
75
97
10 10a 2-NBA
11 10a 2-NBA
86
3
90
Scheme 2. Reaction between 1a and 2 Catalyzed by a Chiral
Secondary Amine
12 10a 2-NBA
13 10a 2-NBA
14 10a 2-NBA
15 10b 2-NBA
16 10c 2-NBA
17 10d 2-NBA
18 11a 2-NBA
19 11b 2-NBA
4
95
DMF
MeOH
EA
48
6
75
90
12
18
20
6
ꢀ60
EA
87
EA
NDe
ꢀ9
ꢀ9
EA
EA
6
a General conditions: 1a (0.2 mmol), 2 (0.40 mmol), cat. (15 mol %)
and acid additive (30 mol %) in solvent (1 mL) at 15 °C. b PFBA,
perfluorobenzoic acid; 2-NBA, 2-NO2ꢀC6H4CO2H; 4-NBA, 4-NO2ꢀ
C6H4CO2H; 3,5-(CF3)2-BA, 3,5-(CF3)2-C6H3CO2H; 4-CF3ꢀBA, 4-(CF3)-
C6H4CO2H; BA, benzoic acid. c Yield referred to isolated pure 3a. d En-
antiomeric excess of 3a was determined by chiral HPLC analysis.
e Enantiomeric excess not determined.
was the best, providing 3a in 95% yield and 95% ee
(Table 1, entry 2).
A brief screening of solvents indicated that the reac-
tion was quite solvent-dependent (Table 1, entries 7ꢀ14).
EA proved to be the best in terms of both yield and ee
(entry 12). Solvents such as THF, DCE, and MeOH
provided the product in excellent enantioselectivity albeit
in lower yields (entries 9, 11, and 14). With the use of
toluene orDCM asa solvent, significant acceleration in the
reaction rate was observed and high yield was attained,
whereas the enantioselectivity was inferior as compared to
(13) For reviews on chiral secondary amine catalysis, see: (a)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471. (b) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922. (c)
Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K. A.
Acc. Chem. Res. 2012, 45, 248.
(14) CCDC-937785 (9) and CCDC-937778 (13) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(15) For reviews on chiral primary amine catalysis, see: (a) Bartoli,
G.; Melchiorre, P. Synlett 2008, 1759. (b) Chen, Y. C. Synlett 2008, 1919.
(c) Peng, F.; Shao, Z. J. Mol. Catal. A 2008, 285, 1. (d) Xu, L. W.; Lu, Y.
Org. Biomol. Chem. 2008, 6, 2047. (e) Xu, L. W.; Luo, J.; Lu, Y. Chem.
Commun. 2009, 1807.
(16) For a review on cinchona-based primary amine catalysis:
Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
Org. Lett., Vol. XX, No. XX, XXXX
C

the use of EA (entries 7, 10). The catalytic performance of
the other three primary amines (10bꢀd) derived from
cinchona alkaloids and two amino acid-based primary
amines (11a, 11b) were also evaluated; however, the results
were not as good as that of 10a (entries 15ꢀ19).
Table 2. Cascade Reaction between 2,3-Disubstituted Indoles
and Acroleina
With the optimized reaction conditions established
(Table 1, entry 12), the substrate scope of this cascade
reaction was then extended to other 2,3-disubstituted
indoles. As shown in Table 2, a broad range of 2,3-
disubstituted indoles reacted to afford the corresponding
hydrocarbazoles in good to excellent yields and high ee
values. It should be noted that the size of the alkoxy group
ofthe ester moiety in the substrate did not exhibita marked
influence on the outcome of this reaction, since 1b with an
ethoxy group and 1c with a benzyloxy group furnished the
corresponding cyclized products 3b and 3c in comparable
yields and ees as 1a (entries 1ꢀ3). A comparative study
revealed that bulkiness of the substituent on the indolic
C(3) did not affect the enantioselectivity of this reac-
tion, while longer reaction time was needed for a substrate
with a larger substituent on C(3) than methyl group
(entries 4ꢀ9). Furthermore, the electronic nature of the
substituent on indolic C(5) was found to have no influence
on the results of this cascade (entries 10ꢀ15).
entry
R1, R2, R3, 1
3
time (h) yield (%)b ee (%)c
1
Me, Me, H, 1a
Et, Me, H, 1b
Bn, Me, H, 1c
Me, n-Pr, H, 1d
Me, allyl, H, 1e
Me, Bn, H, 1f
Me, BnCH2, H, 1g
1hd
3a
3b
3c
3d
3e
3f
4
6
98
86
93
93
99
63
92
67
73
99
94
87
85
99
93
95
91
90
95
90
89
96
99
92
94
92
96
98
94
90
2
3
6
4
12
6
5
6
24
12
18
18
7
3g
3h
3i
8
9
1id
10
11
12
13
14
15
Me, Me, Me, 1j
Me, Me, MeO, 1k
1ld
3j
1.5
3k
3l
3
8
Et, BnCH2, MeO, 1m 3m
4
Me, Me, F, 1n
Me, Me, Br, 1o
3n
3o
2.5
18
Attempts to extend the scope of R,β-unsaturated enal to
substituted ones such as cinnaldehyde, crotonaldehyde,
and methyl acrolein were unsuccessful, providing no de-
sired cyclized products even at elevated temperatures in
prolonged reaction times. The proton on the indolic nitro-
gen is necessary in the current research, as N-methyl
protected 1a is inactive for this transformation.
a Genreal conditions: 1a (0.2 mmol), 2 (0.40 mmol), cat. (15 mol %)
and acid additive (30 mol %) in solvent (1 mL) at 15 °C. b Yield referred
to isolated pure 3. c Enantiomeric excess of 3 was determined by chiral
HPLC analysis. d R1 = Et, R2 = CH2CH2NHBoc, R3 = H, 1h; R1 =
Me, R2 = CH2CH2NHCO2Et, R3 = H, 1i; R1 = Me, R2
CH2CH2NHCO2Et, R3 = Me, 1l.
=
The synthetic utility of chiral hydrocarbazoles thus
prepared was explored in a DielsꢀAlder reaction17 and
in electrophilic substitution, and satisfactory results were
obtained. Treatment of 3a with N-(4-bromophenyl)-
maleimide 12 in toluene at 110 °C for 1.5 h gave the endo
product 13 in 95% yield;14 when exposed to a mixture of
DMF and POCl3 (VilsmeierꢀHaack reaction),18 3a was
converted into aldehyde 14 quantitatively (Scheme 3).
The absolute configuration of hydrocarbazole 3a was
unambiguously determined to be 4aR by single-crystal
X-ray diffraction analysis of its DielsꢀAlder adduct
13 (see Supporting Information). The absolute configu-
ration of other tricyclic products could be assigned by
analogy.
Scheme 3. Additional Derivatization of 3
by further derivatization via a DielsꢀAlder reaction and
VilsmeierꢀHaack reaction.
In summary, we have developed formal [3 þ 3] organo-
catalytic cascade sequences for the asymmetric prepara-
tion of tricyclic hydrocarbazoles 3 from a broad range of
2,3-disubstituted indoles and acrolein in good to excel-
lent yields and excellent enantioselectivites. The synthetic
potential of these advanced structures was demonstrated
Acknowledgment. The generous financial support from
the National Natural Science Foundation of China (No.
21072125 and No. 21272150) is acknowledged. Dr Hanwei
Hu at Shanghai Medicilon is also gratefully acknowledged
for helpful discussions.
(17) (a) Kuehne, M. E.; Seaton, P. J. J. Org. Chem. 1985, 50, 4790. (b)
Wenkert, E.; Pestchanker, M. J. J. Org. Chem. 1988, 53, 4875. (c)
Magnus, P.; Payne, A. H.; Hobson, L. Tetrahedron Lett. 2000, 41,
2077. (d) Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Rainey,
T. J.; Westlund, N.; Lynch, V. Tetrahedron 2002, 58, 3423.
(18) ForselectedreviewsonVilsmeierꢀHacck reaction: (a) Kantlehner,
W. Eur. J. Org. Chem. 2003, 2530. (b) Jones, G.; Stanforth, S. P. Org. React.
2000, 56, 355.
Supporting Information Available. General experimen-
tal conditions, NMR spectra, and HPLC analysis of the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX