A multi-component domino reaction for the direct access to polyfunctionalized indoles via intermolecular allylic esterification and indolation

Article abstract of DOI:10.1039/c1cc15913e

A novel multi-component reaction for the synthesis of polyfunctionalized indoles and bis-indoles has been established. The reaction pathways were controlled by varying enamines with different substitution patterns to give polyfunctionalized indoles and bis-indoles selectively. The reaction proceeds at a fast speed within 15-30 min with water as the major byproduct, which makes work-up convenient.

Full text of DOI:10.1039/c1cc15913e

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Chemical Communications
www.rsc.org/chemcomm
Volume 48 | Number 6 | 21 January 2012 | Pages 773–920
ISSN 1359-7345
COMMUNICATION
Shu-Jiang Tu, Guigen Li et al.
A multi-component domino reaction for the direct access to
polyfunctionalized indoles via intermolecular allylic esterification
and indolation
1359-7345(2012)48:6;1-6

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COMMUNICATION
A multi-component domino reaction for the direct access to polyfunctionalized
indoles via intermolecular allylic esterification and indolationw
Bo Jiang,a Mian-Shuai Yi,a Feng Shi,a Shu-Jiang Tu,*a Suresh Pindi,b Patrick McDowellb
and Guigen Li*b
Received 23rd September 2011, Accepted 18th October 2011
DOI: 10.1039/c1cc15913e
A novel multi-component reaction for the synthesis of polyfunctio-
nalized indoles and bis-indoles has been established. The reaction
pathways were controlled by varying enamines with different
substitution patterns to give polyfunctionalized indoles and bis-
indoles selectively. The reaction proceeds at a fast speed within
15–30 min with water as the major byproduct, which makes work-up
convenient.
Scheme 1
leads to ‘‘benign by design’’.13 Therefore, the design of efficient
allylic functionalization without the use of metal catalysts is a
continuing challenge at the forefront of organic chemistry.
Over the past several years, our group has developed various
multicomponent domino reactions (MDRs) that can offer easy
access to useful multiple functionalized ring structures of
chemical and pharmaceutical interest.14 During our continuous
efforts on the development of useful multi-component domino
reactions,15,16 herein, we report the challenging annulation of
enamines with arylglyoxal monohydrate and the subsequent
allylic activation with aliphatic carboxylic acids as nucleophilic
reagents yielding multifunctionalized indoles (Scheme 1). The
great aspect of the present domino reaction is shown by the fact
that the formation of indole skeleton and its functionalization
were readily achieved via metal-free allylic activation in an
intermolecular manner and in a one-pot operation.
Indoles are probably the most ubiquitous heterocycles in nature
and have been referred to as ‘‘privileged structures’’ in drug
discovery because of their capacity to bind many receptors with
high affinity.1 Accordingly, many powerful methodologies for the
synthesis of these heterocycles have been developed,2 the majority
of these methods involve Fischer-type indole synthesis,3 reductive
cyclization,4 metal-catalyzed coupling/condensation cascades5
and electrophilic activation of N-aryl amides.6 Recently, the utility
of enamines in metal catalysis for the formation of valuable
indoles has also been reported.7,8 The development of concise
approaches to multi-functionalized indoles from readily available
and inexpensive starting material is of great importance and
challenging.
Meanwhile, the direct and selective functionalization of
allylic C–H bonds into C–C and/or C–X bonds (X = O, N,
halogen, etc.) has become an important topic because it
provides a powerful tool for the synthesis of numerous
complex molecules.9 In this regard, there has been enormous
interest in developing sp3-C–H bond functionalization,10 espe-
cially those of metal-free couplings.11 Among the various
known synthetic methodologies, the direct formations of
C–C and/or C–X bonds from allylic C–H bonds have attracted
great attention.12 These methodologies can provide a series of
intrinsic advantages, such as higher atom economy, shorter
synthetic routes, and less energy and manpower usage, which
To begin this study, we chose 3-(p-tolylamino)-5,5-dimethyl-
cyclohex-2-enone (1a), phenylglyoxal monohydrate (2a), and
acetic acid (3a) as the standard substrates to search for suitable
reaction conditions under microwave (MW) irradiation. Various
solvents including DMF, benzene, CHCl3, EtOH, and HOAc
were optimized. Non-protonic solvents, such as DMF, benzene,
CHCl3, resulted in poor to moderate yields under MW irradiation
for 10 min at 100 1C. In another case, when EtOH was selected
as the solvent, the reaction occurred and product 4a was obtained
in 54% isolated yield after purification is performed.z After
systematic screening was made, we found that, in the presence
of acetic acid, 1a was transformed into the desired product 4a in
an excellent yield (84%). It is anticipated that acetic acid serves as
nucleophile, reaction media and Bronsted acid promoter for the
allylic functionalization simultaneously.
a School of Chemistry and Chemical Engineering,
Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials, Xuzhou Normal University, P. R. China.
E-mail: laotu@xznu.edu.cn
b Department of Chemistry and Biochemistry, Texas Tech University,
Lubbock, TX 79409-1061, USA. E-mail: guigen.li@ttu.edu
w Electronic supplementary information (ESI) available: Experimental,
full analytic and X-ray data. CCDC [846865, 846866]. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c1cc15913e
With these optimized conditions in hand, we examined the
scope of this new multicomponent domino process by using
various easily available starting materials. As revealed in
Table 1, a range of invaluable polysubstituted indole derivatives
c
808 Chem. Commun., 2012, 48, 808–810
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Table 1 Domino synthesis of indoles 4 under MWa
Entry
Product
R or R0
Time/min
Yieldb/%
1
2
3
4
4a, H (1a)
18
20
22
16
85
81
82
88
4b, 4-Fluoro (1b)
4c, 4-Bromo (1d)
4d, 4-Methyl (1e)
Scheme 2
5
6
7
8
4e, H (1a)
18
24
20
18
16
15
22
20
18
18
86
82
84
85
87
89
79
75
81
84
4f, 4-Fluoro (1b)
4g, 4-Chloro (1c)
4h, 4-Bromo (1d)
4i, 4-Methyl (1e)
4j, 4-Methoxy (1f)
4k, 4-Chloro (1b)
4l, 4-Bromo (1d)
4m, 4-Methyl (1e)
4n, 4-Ethoxy (1f)
very good chemical yields (5a–5l). Furthermore, functional
groups like bromide and chloride were well tolerated. These
functional groups provide ample opportunity for further
functional group manipulations, for example, by modern
cross-coupling reactions.
9
10
11
12
13
14
In all cases, the complexity of resulting products from this
new reaction illustrates the remarkable chemo-, and regio-
selectivity of the sequence starting from very common and
easily accessible inexpensive starting materials. The structural
elucidation and the attribution of regioselectivity were unequivo-
cally determined by NMR spectroscopic analysis and X-ray
diffraction of single crystals that were obtained by slow evapora-
tion of the solvent, as in the case of bis-indoles 5a (Fig. 1).
During these domino processes, up to two indole rings and five
sigma-bonds were formed accompanied by cleavage of two
C=O and four C–O bonds of the aryl glyoxal, and direct
indolation of hydroindoles B was simultaneously achieved via
intermolecular coupling between sp2-C–H and sp3-C–H bonds
(Scheme 3). This observation is truly rare, very interesting and
important in organic chemistry. Only microwave irradiation
15
16
17
18
19
4o, 4-Fluoro (1b)
4p, 4-Chloro (1c)
4q, 4-Bromo (1d)
4r, 4-Methyl (1e)
4s, 4-Methoxy (1f)
26
22
22
18
18
82
77
79
84
85
20
21
22
23
4t, Methyl (3a)
4u, Ethyl (3b)
4w, Propyl (3c)
4v, Isopropyl (3d)
20
22
22
20
79
76
78
80
a
b
Reagents and conditions: 120 1C, microwave heating. Isolated yield.
can be synthesized in good to excellent yields. The reaction is
easy to perform simply by subjecting a mixture of enamine 1
and arylglyoxal monohydrate 2 in various carboxylic acids to
microwave heating. Subsequently, the enamine scope of this
interesting transformation was investigated (Table 1). Several
different N-substituents were compared and substituents bearing
electron-withdrawing or electron-donating groups were found
to be suitable for this domino reaction. Furthermore, using
various carboxylic acids, such as propionic acid (3b), butyric
acid (3c), and isobutyric acid (3d), together with different
N-substituted enamines 1a–f resulted in the cyclization to
corresponding substituted indoles 4e–4s smoothly. The
benzo[d][1,3]dioxol-6-ylglyoxal monohydrate 2b was subjected
to the reaction with various carboxylic acids, providing the
corresponding benzo[d][1,3]dioxol-6-yl substituted indoles
4t–4v. The results exhibit the scope and generality of the novel
allylic activation-based multicomponent domino reaction with
respect to a range of enamine and carboxylic acid substrates.
Indeed, the protocol provides a straightforward pathway to
construct highly substituted indoles, which are generally prepared
via metal-catalyzed coupling reactions.10
Table 2 Domino synthesis of bis-indoles 5 under MWa
Time/ Yieldb/
Entry 5 Ar
Ar0
min
%
1
2
3
4
5
6
7
8
9
5a 4-Tolyl (1g)
Phenyl (2a)
30
51
54
50
52
48
45
43
40
52
5b 4-Tolyl (1g)
5c 4-Tolyl (1g)
5d 4-Tolyl (1g)
5e 4-Tolyl (1g)
5f 4-Tolyl (1g)
5g 4-Chlorophenyl (1h) 4-Fluorophenyl (2c) 28
5h 4-Chlorophenyl (1h) 4-Tolyl (2h) 30
5i 4-Chlorophenyl (1h) Benzo[d][1,3]dioxol- 30
6-yl (2b)
4-Fluorophenyl (2c) 28
4-Chlorophenyl (2d) 26
4-Bromophenyl (2e) 26
4-Methoxyphenyl (2f) 30
3-Methoxyphenyl (2g) 30
10
11
5j 4-Fluorophenyl (1i) Phenyl (2a)
5k 4-Fluorophenyl (1i) Benzo[d][1,3]dioxol- 30
6-yl (2b)
28
49
47
12
5l 4-Methoxyphenyl (1j) Phenyl (2a)
30
53
a
Reagents and conditions: HOAc (2.0 mL), 100 1C, microwave
heating. Isolated yield.
b
In view of these results, we turned our attention to investigate
several differently substituted enamines. The reactions of
arylglyoxal monohydrate (2a–2h) with N-substituted 3-amino-
cyclohex-2-enones (1g–1j) in acetic acid were performed under
the conditions described above for a short period (26–30 min).
Interestingly, acetic acid was found to be the only efficient
solvent and Bronsted acid catalyst, not as a nucleophile. Two
molecules of arylglyoxal monohydrate and N-substituted
3-aminocyclohex-2-enones were introduced into the final poly-
substituted bis-indoles (Scheme 2). The results are summarized
in Table 2. Both electron-deficient and electron-rich aromatic
groups on the N-substituted 3-aminocyclohex-2-enones gave
Fig. 1 X-Ray structure of 5a.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 808–810 809

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c = 15.2089(16) A, U = 1594.8(3) A3, T = 298(2) K, space group
%
P1, Z = 2, 8283 reflections measured, 5520 unique (Rint = 0.1165) which
were used in all calculations. The final wR(F2) was 0.2184 (all data).
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Scheme 3
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can make the present multi-component domino reaction to
occur rapidly and efficiently, while normal heating diminished
both yield and speed.
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Complete regioselectivity and excellent yields (particularly
for multicomponent reactions) were achieved for all cases that
were examined. Furthermore, the reaction occurred at a very fast
speed; in fact, all cases can be finished within 15–30 minutes.
Water is nearly a sole by-product, which makes work-up
convenient. In most cases, the products can precipitate out
after cold water was poured into the reaction mixture. The
continuing work on this reaction will be focused on the
development of its asymmetric version in our lab.
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The mechanism of this domino reaction is proposed in
Scheme 3. An initial condensation generated imine-isomeric
enamines A, which successively underwent intramolecular
cyclization to give hydroindoles B. The key step of a diver-
gence in reaction paths depends on the aromatization of
hydroindoles B. With two methyl groups on the 5-position
of cyclohex-2-enones, the 6-position of the hydroindoles B
was activated to an electrophilic center and coupled with
carboxylic acid, leading to multifunctionalized indoles 4. The
hydroindoles B without methyl groups (R1 = H) were easily
converted into the aromatic indoles D with a nucleophilic
center at the 3-position, which through intermolecular coupling
reaction with activated hydroindoles B resulted in the final
polysubstituted bis-indoles.
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In conclusion, a novel multicomponent domino reaction for the
divergent synthesis of polyfunctionalized indoles and bis-indoles
has been discovered. The reaction is easy to perform simply by
mixing common reactants under microwave irradiation. The
reaction is very fast and can be finished within 15–30 min with
water as the major byproduct, making workup convenient.
We are grateful for financial support from the NSFC
(No. 20928001, 21072163, 21002083, and 21102124), and Sci.
Foundation in Interdisciplinary Major Res. Project of XZNU
(No. 09XKXK01), PADA of Jiangsu Higher Education
Institutions, Robert A. Welch Foundation (D-1361) and
NIH (R21DA031860-01).
Notes and references
z Crystal data for 4a: C25H25NO3, Mr = 387.46, monoclinic, a =
8.6760(8) A, b = 12.8793(13) A, c = 9.4794(11) A, U = 1045.73(19) A3,
T = 298(2) K, space group P21, Z = 2, 5349 reflections measured,
1936 unique (Rint = 0.0428) which were used in all calculations. The
final wR(F2) was 0.0638 (all data). Crystal data for 5a: C42H34N2O2,
Mr = 598.71, triclinic, a = 10.0878(13) A, b = 11.1881(13) A,
c
810 Chem. Commun., 2012, 48, 808–810
This journal is The Royal Society of Chemistry 2012