Organocatalytic multiple cascade reactions: A new strategy for the construction of enantioenriched tetrahydrocarbazoles

Article abstract of DOI:10.1002/adsc.201000610

A novel cascade Friedel-Crafts alkylation/Michael addition/aromatization reaction of 2-vinylindoles with α,β-unsaturated aldehydes has been developed for the construction of functionalized tetrahydrocarbazoles. The products were obtained in up to 97% yiel

Full text of DOI:10.1002/adsc.201000610

FULL PAPERS
DOI: 10.1002/adsc.201000610
Organocatalytic Multiple Cascade Reactions: A New Strategy for
the Construction of Enantioenriched Tetrahydrocarbazoles
Yi-Ju Cao,a Hong-Gang Cheng,a Liang-Qiu Lu,a Ji-Ji Zhang,a Ying Cheng,a
Jia-Rong Chen,a,* and Wen-Jing Xiaoa,*
a
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, Hubei 430079, Peopleꢀs Republic of China
Fax : (+86) 27-6786-2041; e-mail: jiarongchen2003@yahoo.com.cn or wxiao@mail.ccnu.edu.cn
Received: July 29, 2010; Revised: December 12, 2010; Published online: March 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000610.
Abstract: A novel cascade Friedel–Crafts alkylation/ 97% yield and with excellent stereoselectivities (ee
Michael addition/aromatization reaction of 2-vinylin- up to>99%, dr up to>99:1).
doles with a,b-unsaturated aldehydes has been devel-
oped for the construction of functionalized tetrahy- Keywords: cascade reactions; enantioselectivity; or-
drocarbazoles. The products were obtained in up to ganocatalysis; tetrahydrocarbazoles
Introduction
Meanwhile, we developed a hydrogen bonding-cata-
lyzed double Michael addition-aromatization reaction
With its occurrence in various natural alkaloids and of 2-propenylindoles with nitroolefins, providing an
biologically active compounds, the tetrahydrocarba- efficient access to a variety of multisubstituted tetra-
zole unit has been receiving increasing attention as a hydrocarbazoles with high stereoselectivities.[3h] De-
valuable intermediate in organic synthesis and drug spite these contributions, the development of more ef-
discovery.[1] As a result, the development of efficient ficient and practical methods for the enantioselective
and elegant syntheses of this cyclic architecture with synthesis of novel multifunctionalized tetrahydrocar-
multiple stereogenic centres continues to be a chal- bazoles remains highly desirable.
lenge in both academic and industrial laboratories. In
Enantioselective cascade catalysis, due to its high
this context, the catalytic intramolecular alkylation of atom economy, remarkable efficiency and practicabili-
indoles using transition metal complexes has emerged ty, has been defined as the state of the art in organic
as a preeminent strategy in the last few years.[2] How- synthesis.[4] Recently, organocatalytic cascade reac-
ever, in contrast to lots of non-asymmetric protocols, tions[5] have been actively pursued and are booming
catalytic enantioselective approaches to tetrahydro- since pioneering works by the Barbas III,[5a–g] MacMil-
carbazoles are still rare.[3] Representative examples lan,[5h,i] List,[5j] and Jørgensen[5k] groups. In particular,
include the intramolecular hydroarylations of indole- using chiral secondary amines as catalysts, people
tethered alkenes or allenes catalyzed respectively by have designed many elegant cascade processes via
chiral scandiumACHTUNGTRENNUNG
(III),[3a] platinum(II),[3b,e] and gold(I) “iminium and then enamine” or reverse activation
complexes [Eq. (1)].[3c,f] More recently, MacMillan et modes.[5a,o,6] Despite these advances, the search for
al. have described a novel tandem Diels–Alder-cycli- new strategies that enable multiple cascade reactions
zation reaction of vinyltryptamine, which was success- and increase the diversity of starting materials is still
fully used in the total synthesis of (À)-Minfiensine.[3g] highly important. As part of our ongoing efforts to
develop novel cascade chemistry,[7] we herein disclose
a new triple cascade protocol of vinylindoles with
enals using an “iminium and then iminium/enamine”
activation strategy, resulting in one of the most
straightforward approaches to enantioenriched tetra-
hydrocarbazoles with two or more stereocentres.
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Yi-Ju Cao et al.
FULL PAPERS
Scheme 1. Designed cascade process to multifunctionalized tetrahydrocarbazoles.
The reaction sequence that we have designed is indole ring while avoiding its nucleophilic role.[10] In
outlined in Scheme 1. We presumed that the exposure consideration of these requirements, we decide to
of a,b-unsaturated aldehydes to chiral secondary carefully examine secondary amine catalysts to finely
amine catalysts would generate activated iminium tune the reactivity of the intermediates.
species A (single activation) which could then enan-
tioselectively intercept a nucleophilic indole through
a Friedel–Crafts type alkylation. By doing so, a new Results and Discussion
active intermediate B that contains both iminium and
enamine components (cooperative activation) will be An initial evaluation of the proposed cascade se-
produced to accomplish the intramolecular conjugate quence was performed with 2-vinylindole 1a, croto-
addition to form C. Subsequently, a rapid [1,3]-H mi- naldehyde 2a, and imidazolidinone catalyst I/TFA in
gration would regenerate the aromaticity of the CH2Cl2 at À408C [Eq. (2)]. Notably, the reaction was
indole ring, and the hydrolysis could release the cata-
lyst for further cycles and afford the corresponding
tetrahydrocarbazoles.
We recognized that two key chemoselectivity chal-
lenges must be addressed if this reaction sequence
were to be realized. Central to the design plan, we an-
ticipated that intermediate B would selectively partic-
ipate in the intramolecular Michael addition, yet
would be inert (or much slower) to re-aromatization
in order to preclude the simple alkylation product 4.[8]
Moreover, the cyclic enamine C would proceed [1,3]-
H migration[9] quickly to regenerate the aromatic
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Adv. Synth. Catal. 2011, 353, 617 – 623

Organocatalytic Multiple Cascade Reactions: A New Strategy
Table 1. Optimization of conditions: effect of catalyst and solvent.[a]
Entry
Cat./HX
Solvent
R
Yield [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
II/TFA
II/TFA
III/TFA
IV/TFA
V/THF
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
DCE
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
60
67
62
60
76
85
83
83
66
73
82
79
88
65:35
58:42
68:32
60:40
70:30
68:32
69:31
69:31
70:30
73:27
70:30
72:28
76:24
46
66
59
65
89
90
86
82
94
93
92
92
94
V/THF
V/CAN[d]
V/DNBA[e]
V/TfOH
V/HClO4
V/HClO4
V/HClO4
V/HClO4
9
10
11
12
13
CH3CN
[a]
All reactions were conducted with 0.25 mmol of 1, 20 mol% catalyst/HX, and 3 equiv. of 2a in 0.5 mL of solvent at
À158C.
[b]
[c]
[d]
[e]
Isolated yields.
Determined by chiral HPLC after reduction by NaBH4 in EtOH.
CNA=cyanoacetic acid.
DNBA=3,5-dinitrobenzoic acid.
completed within 10 min, but unfortunately afforded ation of a variety of catalyst salts (Table 1, entries 6–
the simple alkylation product 4 instead of the desired 10) demonstrated that diarylprolinol TMS ether V/
3a.
HClO4 exhibited superior reaction efficiency in terms
We speculated that the inherent steric interference of yield, diastereoselectivity, and enantioselectivity
of catalyst I might prevent the further intramolecular (Table 1, entry 10). Last, a survey of reaction media
addition process of intermediate B. With this in mind, (Table 1, entries 10–13) revealed that CH3CN was the
we next examined a number of diarylprolinol silyl optimal solvent (88% yield, 76:24 dr, 94% ee).
ethers II–V, sterically tunable secondary amines that
With the optimal conditions in hand, we then ex-
have previously enabled many enantioselective cas- plored the scope of the cascade reaction, representa-
cade reactions via an “iminium and enamine” activa- tive results of which are summarized in Table 2. As
tion platform.[6,11] To our delight, exposure of 1a to 2a depicted in entries 1–6, the current protocol is appli-
in the presence of catalyst II/TFA did indeed provide cable to a variety of commercially available enals
the desired cascade product 3a in moderate levels of bearing either alkyl or aryl groups with high yields
stereocontrol (Table 1, entry 1, 46% ee, 65:35 dr, 60% (up to 94%) and good stereoselectivities (up to 99:1
yield). Encouraged by these preliminary results, we dr, 94% ee). Moreover, the enantioselectivity can be
then performed structure-reaction efficiency relation- further improved by simply changing the N-substitu-
ship studies on the catalyst.[12] As revealed in Table 1, ents of indole from benzyl to a more sterically bulky
the steric and electronic contributions of the catalyst 3,4-dimethoxybenzyl group with excellent diastereose-
played an important role on this cascade reaction. lectivities being maintained (Table 2, entries 5 vs. 4).
Among the catalysts examined, diarylprolinol TMS This organocatalytic triple cascade reaction is also
ether V was identified as the best promoter (Table 1, general with respect to the indole moiety. Significant
entry 5 vs. entries 2–4). A dramatic improvement in structural variation in the indole ring can be well tol-
product yield was achieved using a benzyl instead of a erated. For example, incorporation of alkyl and
methyl group as the protection group without signifi- alkoxy substituents at C (5 or 7)-indole position re-
cant influence on the relative or absolute sense of the veals that electronic and steric variation of the indole
stereochemistry (Table 1, entry 6 vs. 5). Further evalu- component can be accomplished without compromis-
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Yi-Ju Cao et al.
Table 2. Organocatalytic multiple cascade reactions of 2-vinyl indoles 1 with enals 2 catalyzed by cat.V/HClO4.[a]
FULL PAPERS
Entry
R
R1
R2
Product 3
Yield [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Me
H
H
H
H
H
H
5-Me
5-MeO
7-Me
5-F
Me
Et
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
88
74
74
84
94
72
74
97
74
77
79
75
80
44
70
79
90
81
79
60
70
76:24
99:1
99:1
99:1
95:5
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
–
94
87
93
83
91
90
95
92
n-Pr
n-Bu
n-Bu
DCP
Et
Et
Et
n-Pr
Et
Et
9
90
89
10
11
12
13
14
15
16
17
18
19
20
21
5-Cl
5-Br
92
94[d]
91[e]
89
6-Cl, 7-Me
4-Cl, 7-Me
5-Me
5-MeO
5-F
Et
Et
DCP
DCP
H
TMS
TMS
TMS
TMS
92
90
56
98
99
97
>99
5-F
3s
3t
3u
3v
>99:1
>99:1
>99:1
>99:1
5-Me
5-MeO
6-Cl, 7-Me
[a]
See the Supporting Information for detailed reaction conditions.
Isolated yield.
[b]
[c]
[d]
[e]
Determined by chiral HPLC after reduction by NaBH4/EtOH.
Absolute configuration of 3m was determined by X-ray analysis (Figure 1).[16]
CH2Cl2 was used as solvent. DMB=3,4-dimethoxybenzyl. DCP=2,4-dichlorophenyl.
ing reaction efficiency (Table 2, entries 7–9). In partic- doing so structurally diverse and biological active tet-
ular, we have successfully employed electron-deficient rahydrocarbazoles with one single seterocentre could
reactants in the context of a 5-fluoro-substituted 2-vi- be generated.[15] To our delight, the reaction efficiency
nylindole (Table 2, entries 10, 17 and 18). Other halo- was remarkably improved in this case. The reaction
genated vinylindole substrates can also be utilized in afforded 4-trimethylsilyl-substituted tetrahydrocarba-
this cascade sequence (Table 2, entries 11 and 12, zoles in high yields with excellent diastereo- and
Figure 1) and, importantly, these products should be enantioselectivities regardless of electronic and steric
valuable intermediates for further functionaliza- effects of the indole moiety (Table 2, entries 18–21).
tions.[13] Moreover, multi-substituted vinylindole de-
It is worth to note that when 4-methyl-2-pentenal
rivatives can readily participate in this reaction and was subjected to the optimal conditions, a quaternary
afford various substituted enantioenriched tetrahydro- cascade sequence occurred along with the triple cas-
carbazoles in high yields and excellent stereoselectivi- cade. A representative example is highlighted in Eq.
ties (Table 2, entries 13, 14 and 21). When acrolein (3). Highly functionalized tetrahydrocarbazole 5 with
was employed, the reaction proceeded smoothly to four stereocentres was isolated in excellent stereose-
give the desired product in 90% yield but with only lectivity (>99:1 dr,>99% ee) and its absolute config-
moderate enantiomeric excess (Table 2, entry 17) uration was unambiguously confirmed by X-ray anal-
which might be due to racemization. However, a b-tri- ysis (Figure 2).[16]
methylsilyl-substituted enal could be engaged as an
In order to classify the mechanism of this transfor-
invaluable surrogate because the trimethylsilyl group mation, we carried out the reaction of (Z)-hex-2-enal
can be easily removed by known procedures[14] and in 2c’ and (E)-hex-2-enal 2c with 2-vinyl indole 1a, re-
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Organocatalytic Multiple Cascade Reactions: A New Strategy
Figure 1. X-ray crystal structure of 3m.
spectively [Eq. (4) and Eq. (5)]. It was found that
both reactions gave the desired product 3d with the
same configuration. These results indicated that the
designed pathway in Scheme 1 is more favourable
than the alternative Diels–Alder cycloaddition route.
Conclusions
In summary, we have developed an intermolecular or-
ganocascade approach to highly functionalized tetra-
hydrocarbazoles with excellent selectivities by means
of readily accessible substrates and amine catalyst.[17]
Further investigations toward the synthetic utilities of
the current protocol, the four-step sequential reaction
and other novel organocascade approaches are active-
ly underway in this laboratory.
Figure 2. X-ray crystal structure of 5.
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Experimental Section
Acknowledgements
We are grateful to the National Science Foundation of China
(20872043) and the Program for Academic Leader in Wuhan
Municipality (200851430486) for support of this research.
General Procedure for the Organocatalytic Multiple
Cascade Reactions
HClO4 (8 mL, 20 mol%) was added to the solution of cata-
lyst V (59.8 mg, 20 mol%) in CH3CN (1 mL) at À158C, and
the mixture was stirred for 30 min. Aldehyde 2 (1.5 mmol,
3.0 equiv.) was then added via syringe at the same tempera-
ture. The resulting solution was stirred further for 15 min
before the addition of 2-vinylindole 1 (0.5 mmol). After
completion of the reaction as indicated by TLC, the reaction
mixture was purified by column chromatography (petroleum
ether/ethyl acetate, 20:1) to give the desired product 3. A
part of the product (ca. 10 mg) was reduced by NaBH4 in
EtOH, and the reduction product was directly analyzed by
chiral HPLC to determine the dr and ee.
Data for (3S,4R)-9-benzyl-4-methyl-2,3,4,9-tetrahydro-
1H-carbazole-3-carbaldehyde (3b): 1H NMR (CDCl3,
600 MHz): d=1.62 (d, J=6.6 Hz, 3H), 2.23–2.28 (m, 2H),
2.56 (s, 1H) 2.69–2.83 (m, 3H), 3.74 (s, 1H), 5.28 (s, 2H),
7.06 (d, J=6.6 Hz, 2H), 7.25–7.37 (m, 6H), 7.77 (s, 1H),
9.80 (s, 1H); 13C NMR (CDCl3, 150 MHz): d=204.44,
137.66, 136.84, 134.37, 128.59, 127.12, 126.48, 125.88, 120.98,
118.95, 118.32, 112.41, 109.15, 53.15, 53.10, 27.18, 21.06,
20.98, 19.61, 19.46, 17.21; MS (EI): m/z=303 [M]+; [a]D19:
+15.21 (c 1.06, CH2Cl2); anal. calcd. for C21H21NO: C 83.13,
H 6.98, N 4.62; found: C 83.09, H 6.95, N 4.60.
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column,
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