Morita-Baylis-Hillman reaction of indole-2-carboxaldehyde: New vistas for indole-annulated systems

Article abstract of DOI:10.1016/j.tet.2010.07.078

DABCO-mediated Morita-Baylis-Hillman reactions of several 1-substituted-indole-2-carboxaldehydes are disclosed. It was discovered that carboethoxy or tert-butoxycarbonyl groups installed at N-1 undergo cleavage under the reaction conditions to afford 2-su

Full text of DOI:10.1016/j.tet.2010.07.078

Tetrahedron 66 (2010) 7781e7786
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
MoritaeBayliseHillman reaction of indole-2-carboxaldehyde: new vistas
for indole-annulated systemsq
*
Subhasish Biswas, Virender Singh, Sanjay Batra
Medicinal and Process Chemistry Division, Central Drug Research Institute (CSIR), PO Box 173, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2010
Received in revised form 20 July 2010
Accepted 22 July 2010
Available online 3 August 2010
DABCO-mediated MoritaeBayliseHillman reactions of several 1-substituted-indole-2-carboxaldehydes
are disclosed. It was discovered that carboethoxy or tert-butoxycarbonyl groups installed at N-1 undergo
cleavage under the reaction conditions to afford 2-substituted indoles. Utility of the N-substituted
adducts for preparing a variety of annulated indoles has been exemplified.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
MoritaeBayliseHillman
Indole-2-carboxaldehyde
RCM
Heck-reaction
Reductive cyclization
1. Introduction
Following our interest to greatly expand the synthetic applica-
tions of the MBH chemistry for affording annulated heterocyclic
The MoritaeBayliseHillman (MBH) is a base-catalyzed carbone
carbon bond forming reaction between electrophiles generally
aldehyde and electron-deficient alkenes.1 It is a kind of domino
process where the nucleophilic bases, such as amines and phos-
phines essentially initiate a conjugate addition to the activated
alkene to afford an enolate, which reacts with aldehyde via an aldol
type process followed by elimination of the base. Remarkable
success in the ability of MBH products to afford diverse structural
motifs has led to significant increase in the substrate base both with
respect to aldehydes and alkenes.2 In spite of great advancement,
MBH reactions of indolecarboxaldehydes have not been reported
till date.
The influence of indole-based compounds on innumerable
biochemical processes in nature ensures that this heterocycle at-
tracts the attention of synthetic and medicinal chemists alike. It is
considered to be a privileged structure owing to its presence in
large number of pharmaceutical agents, natural products and drug
targets.3 Development of new protocols leading to this core unit or
strategies for introduction of substitution at different positions of
indole remains an active area of research.4
architecture,5 we now report the results of our study on MBH
reaction between indole-2-carboxaldehyde and activated alkenes
under the influence of DABCO. Our results suggest an essential role
of a substitution on the NH of indole to initiate MBH reaction. More
importantly, we have demonstrated that the MBH adduct with
naked NH can be even achieved in one-pot depending on the
nature of the substitution on N-1. Further the MBH adducts are
shown to be viable precursors to indole-annulated frameworks.
2. Results and discussions
The starting material, indole-2-carboxaldehyde 1 was efficiently
prepared in a two-step process from commercially available ethyl
indole-2-carboxylate.6 Initially MBH reaction of 1 was attempted
with methyl acrylate in the presence of DABCO. However even after
20 days of reaction time only a faint spot for the expected product
appeared in the TLC analysis. Arresting the reaction at this stage
followed by workup and purification yielded a trace amount of the
adduct 2 (ca. <1%) (Scheme 1). Unsuccessful with this initial
attempt, we decided to substitute the NH of indole and then
investigate the MBH reaction.
As a consequence compounds 3e5 were prepared via reaction of
1 with benzyl bromide, ethyl chloroformate and tert-butoxy-
carbonyl anhydride, respectively, as outlined in Scheme 1.7e9 The
viability of the MBH reaction of protected indoles was initially
tested by treating N-benzyl indole-2-carboxaldehyde 3 with methyl
q
CDRI communication no. 7947.
* Corresponding author. Tel.: þ91 522 2612411 18x4234/4368; fax: þ91 522
2623405/2623938; e-mail addresses: s_batra@cdri.res.in, batra_san@yahoo.co.uk.
(S. Batra)
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.078

7782
S. Biswas et al. / Tetrahedron 66 (2010) 7781e7786
adduct (entry 10 and 13, Table 1). Although deprotection of the
N-Boc of indole is reported under the basic medium,10 this is the
first observation of DABCO-promoted Boc-deprotection of the in-
dole nucleus. In order to examine whether this observation is
general for N-Boc indoles, 5 was treated with DABCO under similar
conditions. For this reaction, we did not observe cleavage of the
Boc-group and the starting material was recovered unreacted even
after 10 days. Unlike, when compounds 13 and 14 were treated
with DABCO in THF they smoothly undergo cleavage of the Boc-
group in 24 h to afford 2 and 11, respectively (Scheme 2). Use of
other bases instead of DABCO, including Et3N or DMAP failed to
effect this reaction. It is presumed that during the reaction DABCO
act as nucleophile to attack at the carbonyl of the carbamate group
leading to elimination of the Boc-group.10a Such an attack occurs
only after the MBH adduct is formed and the hydroxy acrylate
chain placed at 2-position of the indole may have a role in facili-
tating this event. In an effort to provide chemical evidence to this,
reaction between 5 and acrylonitrile was performed at 0 ꢀC with
continuous monitoring to a stage when deprotected product 11
starts appearing (ca. 2.5 h). Reaction was arrested at this stage and
subjected to purification to afford 14 in 79% (based on amount of
reacted 5) and unreacted 5 in 40% yields. Success with DABCO
prompted us to examine DBU for similar deprotection of the Boc-
group in 13 and 14, which smoothly afforded the corresponding
unprotected products 2 and 11.
ii
CHO
CHO
N
R
N
H
1
3 R= Bn (94%)
R= CO2Et (90%)
R= CO2 Bu (92%)
4
iii
t
5
i
(trace)
iv
CO2Me
N
H
N
R
OH
OH
O
12
2,6-11,13-14
Scheme 1. Reagents and conditions: (i) CH2]CHCO2Me, DABCO, rt, 20 d; (ii) NaH,
BnBr, DMF, rt, 1 h (for 3), ClCO2Et, NaH, THF, rt, 3 h (for 4), (Boc)2O, Et3N, DMAP, CH2Cl2,
rt, 10 h (for 5); (iii) CH2]CHEWG, DABCO, rt or 0 ꢀC, 3 h to 4 days; (iv) 2-cyclohexen-1-
one, DABCO, rt, 2 days.
acrylate in the presence of DABCO under neat conditions at room
temperature. It was satisfying to observe that the reaction was
completed in 3 days to yield the MBH adduct 6 in good yields (Table
1). Next 3 was treated with other alkenes to successfully afford the
required adducts. As illustrated by the results in Table 1, acryloni-
trile reacted faster as compared to acrylates. Following, aldehyde 4
was subjected to MBH reactions with various alkenes under similar
conditions. Except acrylonitrile, all alkenes yielded the corre-
sponding MBH adducts wherein the carboethoxy group on the
nitrogen of indole was cleaved under the reaction condition
(Table 1). Under basic conditions such deprotection of carboethoxy
group in indole has been reported earlier.10 Importantly for us, this
in situ deprotection complimented our efforts to generate depro-
tected or protected MBH adduct depending on the substitution
placed on the NH of the indole unit. For acrylonitrile it was dis-
covered that the reaction has to be performed at 0 ꢀC instead of the
room temperature to obtain the MBH in 3 h.
i
CHO
No reaction
N
t
CO2 Bu
5
EWG
OH
EWG
ii
N
H
N
OH
CO2 Bu
13-14
t
2,11
Scheme 2. Reagents and conditions: (i) DABCO, rt, 10 days; (ii) DABCO, THF, rt, 1 day.
Table 1
Results of the MBH reactions of 1,3e5 via Scheme 1
Entry
Aldehyde
R
Alkene
Conditions
N-Protected MBH
N-Deprotected MBH
adduct (Yield %)
adduct (Yield %)
1
1
3
3
3
4
4
4
4
4
5
5
5
5
5
H
Bn
Bn
Bn
Methyl acrylate
Methyl acrylate
Ethyl acrylate
Acrylonitrile
Methyl acrylate
Ethyl acrylate
tert-Butyl acrylate
Acrylonitrile
Cyclohex-1-ene-2-one
Methyl acrylate
Ethyl acrylate
tert-Butyl acrylate
Acrylonitrile
Cyclohex-1-ene-2-one
Neat, rt, 20 days
Neat, rt, 3 days
Neat, rt, 4 days
Neat, rt, 2 days
Neat, rt, 24 h
Neat, rt, 2 days
Neat, rt, 4 days
Neat, 0 ꢀC, 3 h
Neat, rt, 2 days
Neat, rt, 24 h
d
2 (<1)
d
2
6 (70)
7 (65)
8 (72)
d
3b
4
d
d
5
6
7
8
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
2 (68)
9 (67)
10 (66)
11 (69)
12 (69)
2 (45)
9 (65)
10 (66)
11 (47)
12 (68)
d
d
d
9
d
10
11
12
13
14
13 (24)
d
Neat, rt, 2 days
Neat, rt, 4 days
Neat, 0 ꢀC, 3 h
Neat, rt, 2 days
d
14 (23)
d
Subsequently MBH reactions of 5 with different activated
alkenes were investigated. Interestingly similar to earlier results,
reaction of 5 with higher acrylates and 2-cyclohexene-1-one
afforded the N-deprotected MBH adducts in good yields (entry 11,
12 and 14, Table 1). But the MBH reaction of 5 with methyl acrylate
and acrylonitrile afforded two products out of which the major
product was identified as the N-deprotected adduct, whereas the
minor product was spectrally characterized to be N-Boc protected
Having established the MBH reactions of indole-2-carbox-
aldehyde, we turned our attention to develop protocols for annu-
lated indoles via use of N-substituted MBH adducts. Towards this
objective, in one of the approaches N-allyl protected indole-2-car-
baldehyde 15 was prepared11 and subjected to MBH reaction with
different alkenes. It was found that this substrate took longer times
to react and yields of the afforded adducts 16e18 were moderate
(54e58%) (Scheme 3). Compounds 16e18 were ideally suited for

S. Biswas et al. / Tetrahedron 66 (2010) 7781e7786
7783
OH
OH
EWG
i
ii
1
CHO
80%
N
N
CHO
I
EWG
N
ii
i
N
1
82%
15
I
24
16 EWG= CO2Me (56%)
17
EWG= CO2Et (54%)
EWG= CN (58%)
25
EWG= CO2Me (68%)
26 EWG= CO2Et (65%)
18
OH
iii
iii
EWG
N
EWG= CO2Me
CO2Et
EWG= CN
N
OH
N
EWG
27
EWG= CO2Me (58%)
CN
28 EWG= CO2Et (57%)
19 EWG= CO2Me (70%)
21 (72%)
20
EWG= CO2Et (68%)
Scheme 5. Reagents and conditions: (i) 2-Iodobenzyl chloride, NaH, DMF, 0 ꢀC, 4.5 h;
(ii) CH2]CHeEWG, DABCO, rt, 2e4 days; (iii) PdCl2(PPh3)2, Et3N, DMF, MW, 150 ꢀC,
30 min.
Scheme 3. Reagents and conditions: (i) CH2]CHCH2Br, NaH, DMF, 0 ꢀC- rt, 4 h;
(ii) CH2]CHeEWG, DABCO, rt, 2e4 days; (iii) Grubb’s second Cat., CH2Cl2, reflux, 1.5 h.
intramolecular ring-closure via metathesis reaction.12,2h Reacting
16e18 with Grubbs II generation catalyst in dichloromethane
yielded the corresponding ring-closed products 19e21 in 68e72%
yields. It was observed that for acrylates the dehydration did not
occur and the isolated product (19,20) bear the hydroxyl group
whereas for acrylonitrile derived substrate 18 the dehydration oc-
curs to afford a fully aromatized product 21. Such dehydration for
acrylonitrile derived substrate during metathesis reaction has lit-
erature precedence.13
EWG
CHO
NO2
ii
i
N
N
OH
1
82%
O2N
29
30
EWG= CO2Me (64%)
31 EWG= CO2Et (62%)
In an extension to the protocol it was envisaged that reaction
between ethyl 2-(bromomethyl)acrylate (prepared from MBH
adduct of formaldehyde) and 1 will lead to a new aldehyde 22.
Sequential MBH and metathesis reactions of 22 would result in
another novel indole-annulated system. Unfortunately we disco-
vered that reaction between ethyl 2-(bromomethyl)acrylate and 1
resulted in a mixture of products, which could not be characterized
(Scheme 4). Alternatively, another substituted allyl bromide was
screened for reaction with 1. Interestingly the reaction of 1 with
trans methyl 4-bromobut-2-enoate in the presence of NaH in DMF
at room temperature resulted in a product in 72% yields, which was
spectrally characterized to be methyl pyrido[1,2-a]indole-8-car-
boxylate 23.14
EWG
iii
N
NH
32
EWG= CO2Me (70%)
33 EWG= CO2Et (68%)
Scheme 6. Reagents and conditions: (i) 2-Fluoronitrobenzene, K2CO3, DMF, 100 ꢀC,
1.5 h; (ii) CH2]CHeEWG, DABCO, rt, 2e4 days; (iii) FeeAcOH, 100 ꢀC, 2 h.
group. Unexpectedly, however, FeeAcOH-promoted reductive
cyclization in 30 and 31 resulted in the formation of a new indole-
fused quinoxaline framework 32 and 33, respectively.
CHO
i
ii
1
3. Conclusions
N
N
CO2Et
CO2Me
72%
In conclusion we have successfully achieved the MBH reaction of
several N-substituted indole-2-carboxaldehydes. We have demon-
strated that placing a suitable substitution at the NH makes the
MBH adducts viable precursors to several new indole-annulated
systems using robust reactions. The deprotection of the carbo-
ethoxy and tert-butoxycarbonyl protected indole-2-carbox-
aldehydes to afford the MBH adduct possessing no substitution on
indole nucleus opens up new opportunities to make substitution at
3-position of indole and extend the chemistry further especially for
indole-annulated architectures. Exploration of chemistry in this
direction is underway.
22 (not isolated)
23
Scheme 4. Reagents and conditions: (i) BrCH2C(]CH2)CO2Et, NaH, DMF, 0 ꢀC to rt,
48 h; (ii) BrCH2CH]CHCO2Me, NaH, DMF, 0 ꢀC to rt, 8 h.
In another strategy the NH of the indole-2-carboxaldehyde was
protectedwith2-iodobenzylgroupand theresultingsubstrate 24 was
subjected to MBH reaction with acrylates (Scheme 5).15 This reaction
yielded adducts 25 and 26, which upon Heck coupling reaction in the
presence of palladium complex under microwave condition afforded
indole-fused benzoazocines (27e28) in moderate yields.16
Prompted by the success of the chemistry, we next embarked on
protection of the NH of indole by 2-fluoronitrobenzene in the
presence of K2CO3 to afford the aldehyde 29.17 MBH reaction of 29
with methyl and ethyl acrylate furnished adducts 30 and 31 in 64%
and 62% yields, respectively (Scheme 6). It was assumed that
reductive cyclization of the substrate would take place via attack of
the aromatic amino group either on the double bond or the ester
4. Experimental
4.1. General
Melting points are uncorrected and were determined in capil-
lary tubes on an apparatus containing silicon oil. IR spectra were

7784
S. Biswas et al. / Tetrahedron 66 (2010) 7781e7786
recorded using a PerkineElmer’s RX I FTIR spectrophotometer. 1H
NMR and 13C NMR spectra were recorded either on a Bruker DPX-
200 FT or Bruker Avance DRX-300 spectrometer, using TMS as an
v/v), Rf¼0.24 (EtOAc/hexane 20:80, v/v) as eluent was obtained as
yellow solid in 65% yield (0.029 g from 0.05 g); mp 118e120 ꢀC. IR
(KBr) 1701 (CO2Et), 3509 (OH) cmꢂ1 1H NMR (200 MHz, CDCl3)
;
internal standard (chemical shifts in
d
). The ESMS were recorded on
d
1.40 (3H, t, J¼7.1 Hz, CO2CH2CH3), 3.30 (1H, d, J¼3.6 Hz, CHOH),
MICROMASS Quadro-II LCMS system, respectively. Elemental
analyses were performed on a Carlo Erba’s 108 or an Elementar’s
Vario EL III microanalyzer. The reactions under microwave heating
were carried out in a Biotage initiator 2.5 microwave system. All
yields described herein are the isolated yields after column
chromatography.
4.36 (2H, q, J¼7.1 Hz, CO2CH2CH3), 4.82e4.88 (2H, m, NCH2), 5.86
(1H, s, CHOH), 6.71 (1H, s, ]CH), 7.12e7.21 (1H, m, ArH), 7.24e7.28
(1H, m, ArH), 7.31e7.38 (2H, m, ArH), 7.66 (1H, d, J¼7.2 Hz, ArH); 13C
NMR (75 MHz, CDCl3)
d 14.4, 42.4, 60.0, 61.6, 100.4, 109.2, 120.5,
121.1, 121.9, 128.4, 129.9, 134.2, 134.8, 135.4, 165.9; MS (ESI) m/z
258.2 (MþþH). Anal. Calcd for C15H15NO3 (257.1052) C 70.02, H
5.88, N 5.44; found C 70.31, H 5.97, N 5.23.
4.2. General procedure for the preparation of 2, 6e14, 16e18,
25, 26, 30,31 as exemplified for compound 2
4.3.3. Pyrido[1,2-a]indole-8-carbonitrile (21). The title compound
was prepared from 18 following the above described procedure and
after purification by column chromatography over silica gel with
EtOAc/hexane(20:80, v/v), Rf¼0.55 (EtOAc/hexane 10:90, v/v) as
eluent was obtained as yellow solid in 72% yield (0.031 g from
To
a well stirred solution of methyl acrylate (0.74 mL,
9.21 mmol) and DABCO (0.10 g, 0.92 mmol), compound 4 (0.2 g,
0.92 mmol) was added and the reaction was allowed to proceed
for 24 h. On completion as monitored by the TLC the mixture was
extracted with EtOAc (3ꢁ20 mL) and water (20 mL). The com-
bined organic layer was washed with brine (2ꢁ20 mL), dried
(Na2SO4) and concentrated to yield a crude residue. Purification by
column chromatography over silica gel with EtOAc/hexane (30:70,
v/v), Rf¼0.15 (EtOAc/hexane 20:80, v/v) as eluent furnished the
desired compound as a white solid in 68% yield (0.14 g). Following
the similar procedure compound 5 afforded 2 in 45% yields (0.8 g
from 0.2 g).
0.05 g); mp 105e107 ꢀC. IR (neat) 2227 (CN) cmꢂ1
;
1H NMR
6.53 (1H, dd, J1¼1.6 Hz, J2¼7.3 Hz, ArH), 6.94
(300 MHz, CDCl3)
d
(1H, s, ArH), 7.39e7.46 (2H, m, ArH), 7.85e7.91 (3H, m, ArH), 8.33
(1H, d, J¼7.3 Hz, ArH); 13C NMR (75 MHz, CDCl3)
d 97.1, 104.6, 106.5,
110.7, 118.7, 121.8, 122.6, 124.0, 125.1, 127.6, 129.5, 130.5, 133.4; MS
(ESI) m/z 193.4 (MþþH). Anal. Calcd for C13H8N2 (192.0687) C 81.23,
H 4.20, N 14.57; found C 81.42, H 4.46, N 14.30.
4.4. General procedure for the preparation of 27,28 as
exemplified for compound 27
4.2.1. Methyl 2-[hydroxy(1H-indol-2-yl)methyl]acrylate (2). Mp
110e112 ꢀC. IR (KBr) 1705 (CO2Me), 3022 (]CH), 3459 (OH) cmꢂ1
;
An oven dried microwave vial charged with 25 (0.05 g,
0.11 mmol), Et3N (0.03 ml, 0.22 mmol), PdCl2(PPh3)2 (0.001 g,
0.001 mmol) in dry DMF (2 mL) was heated at 150 ꢀC with stirring
under microwave for 0.5 h. The reaction was diluted with a 5 mL of
ether and washed with saturated aqueous NH4Cl solution (2ꢁ2 ml).
The aqueous part was extracted with ether (2ꢁ5 ml). The combined
organic part was washed with brine and dried over Na2SO4. The
solvent was evaporated to yield a crude residue, which upon pu-
rification via silica gel column chromatography using EtOAc/hexane
(18:82, v/v), Rf¼0.35 (EtOAc/hexane 20:80, v/v) as eluent yielded 25
as a pink solid in 58% (0.021 g) yield.
1H NMR (300 MHz, CDCl3)
d
3.41 (1H, d, J¼6.3 Hz, CHOH), 3.79 (3H,
s, CO2CH3), 5.72 (1H, d, J¼6.4 Hz, CHOH), 5.93 (1H, s, ]CHH), 6.34
(1H, s, ]CHH), 6.37 (1H, s, ArH), 7.08 (1H, t, J¼7.2 Hz, ArH), 7.17 (1H,
t, J¼7.2 Hz, ArH), 7.35 (1H, d, J¼7.8 Hz, ArH), 7.55 (1H, d, J¼7.7 Hz,
ArH), 8.55 (1H, br s, NH); 13C NMR (75 MHz, CDCl3)
d 52.4, 68.9,
100.1,111.2,120.0,120.7,122.2, 127.2,128.3, 136.1,138.4, 140.0, 167.2;
MS (ESI) m/z 232.1 (MþþH). Anal. Calcd for C13H13NO3 (231.0895) C
67.52, H 5.67, N 6.06; found C 67.78, H 5.85, N 5.84.
4.3. General procedure for the preparation of 19e21 as
exemplified for compound 19
4.4.1. Methyl 7-hydroxy-7,14-dihydroindolo[1,2-b][2]benzazocine-6-
To a well stirred suspension of Grubbs second Generation cat-
alyst (0.016 g, 0.018 mmol) in dry CH2Cl2 (10 ml) at room temper-
ature, compound 16 (0.05 g, 0.18 mmol) was added. The reaction
mixture was heated at 40 ꢀC for 1.5 h under nitrogen atmosphere.
Thereafter, the solvent was evaporated to obtain the crude residue,
whose purification by column chromatography over silica gel with
EtOAc/hexane (12:88, v/v), Rf¼0.23 (EtOAc/hexane 20:80, v/v) as
eluent furnished the desired compound 19 as a yellow solid in 70%
yield (0.03 g).
carboxylate (27). Mp 119e121 ꢀC. IR (KBr) 1682 (CO2Me), 3499
(OH) cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 3.85 (3H, s, CO2CH3), 4.40
(1H, d, J¼9.9 Hz, CHOH), 4.86 (1H, d, J¼14.0 Hz, NCHH), 5.30 (1H, d,
J¼14.0 Hz, NCHH), 5.39 (1H, d, J¼9.0 Hz, CHOH), 6.66 (1H, s, ArH),
7.11 (1H, t, J¼7.1 Hz, ArH), 7.23e7.27 (1H, m, ArH), 7.37e7.41 (3H, m,
ArH), 7.53 (2H, d, J¼8.0 Hz, ArH), 7.61 (1H, d, J¼8.0 Hz, ArH), 8.08
(1H, s, ]CH); 13C NMR (75 MHz, CDCl3)
d 47.4, 52.5, 66.8, 100.5,
109.2,119.9,121.2,121.7,128.4,128.6,128.7,130.0,131.3,132.9,134.5,
136.1, 138.3, 139.2, 140.3, 166.9; MS (ESI) m/z 320.2 (MþþH). Anal.
Calcd for C20H17NO3 (319.1208) C 75.22, H 5.37, N 4.39; found C
75.36, H, 5.53, N 4.15.
4.3.1. Methyl 9-hydroxy-6,9-dihydropyrido[1,2-a]indole-8-carboxꢂy1l-
ate (19). Mp 110e112 ꢀC. IR (KBr) 1703 (CO2Me), 3505 (OH) cm
;
1H NMR (300 MHz, CDCl3)
d
3.19 (1H, d, J¼3.5 Hz, CHOH), 3.90 (3H,
4.4.2. Ethyl 7-hydroxy-7,14-dihydroindolo[1,2-b][2]benzazocine-6-
carboxylate (28). The title compound was prepared from 26
following the above described general procedure and after purifi-
cation by column chromatography over silica gel with EtOAc/hex-
ane (15:85, v/v), Rf¼0.40 (EtOAc/hexane 20:80, v/v) as eluent was
obtained as a pink solid in 57% yield (0.02 g fromꢂ01 .05 g); mp
s, CO2CH3), 4.74e4.94 (2H, m, NCH2), 5.85 (1H, s, CHOH), 6.71 (1H, s,
]CH), 7.14e7.21 (1H, m, ArH), 7.24e7.26 (1H, m, ArH), 7.31e7.36
(2H, m, ArH), 7.65 (1H, d, J¼7.7 Hz, ArH); 13C NMR (75 MHz, CDCl3)
d
42.6, 52.5, 60.1, 100.5, 109.2, 120.6, 121.2, 122.0, 128.5, 129.9, 134.5,
134.8, 135.5, 166.4; Mass (ESI) m/z 244.1 (MþþH). Anal. Calcd for
C14H13NO3 (243.0895) C 69.12, H 5.39, N 5.76; found C 69.28, H 5.62,
N 5.51.
139e141 ꢀC. IR (KBr) 1709 (CO2Et), 3462 (OH) cm
;
1H NMR
(200 MHz, CDCl3)
d
1.36 (3H, t, J¼7.1 Hz, CO2CH2CH3), 4.24e4.35
(2H, m, CO2CH2CH3), 4.46 (1H, d, J¼9.7 Hz, CHOH), 4.85 (1H, d,
J¼14.0 Hz, NCHH), 5.29 (1H, d, J¼14.0 Hz, NCHH). 5.39 (1H, d,
J¼9.6 Hz, CHOH), 6.65 (1H, s, ArH), 7.06e7.28 (1H, m, ArH),
7.20e7.28 (1H, m, ArH), 7.35e7.40 (3H, m, ArH), 7.49e7.54 (2H, m,
ArH), 7.60 (1H, d, J¼7.7 Hz, ArH), 8.07 (1H, s, ]CH); 13C NMR
4.3.2. Ethyl 9-hydroxy-6,9-dihydropyrido[1,2-a]indole-8-carboxylate
(20). The title compound was prepared from 17 following the
general procedure described above and after purification by col-
umn chromatography over silica gel with EtOAc/hexane(20:80,

S. Biswas et al. / Tetrahedron 66 (2010) 7781e7786
7785
(75 MHz, CDCl3)
d
14.3, 47.4, 61.7, 66.9, 100.4, 109.2, 119.9, 121.1,
References and notes
121.7, 128.4, 128.5, 128.7, 129.9, 131.3, 133.1, 134.5, 136.2, 140.0,
166.4; MS (ESI) m/z 334.2 (MþþH). Anal. Calcd for C21H19NO3
(333.1365) C 75.66, H 5.74, N 4.20; found C 75.82, H 5.91, N 4.03.
1. (a) Morita, K. Japan Patent 6,803,364, 1968; Chem. Abstr. 1968, 69, 58828s;
(b) Baylis, A.B.; Hillman, M.E.D. German Patent 2,155,113,1972; Chem. Abstr.1972,
77, 34174q.
2. Only a few citations (a) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,
109, 1e48 and references cited therein; (b) Gowrisankar, S.; Lee, H. S.; Kim, S.
H.; Lee, K. Y.; Kim, J. N. Tetrahedron 2009, 65, 8769e8780; (c) Singh, V.; Batra, S.
Tetrahedron 2008, 64, 4511e4574 and references cited therein; (d) Basavaiah,
D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581e1588 and references
cited therein; (e) Basavaiah, D.; Rao, J. R.; Satyanarayana, T. Chem. Rev. 2003,
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Chem.dEur. J. 2010, 16, 2031e2035; (g) Amarante, G. W.; Benassi, M.; Pascoal,
R. N.; Eberlin, M. N.; Coelho, F. Tetrahedron 2010, 66, 4370e4376; (h) Barth, R.;
Roush, W. R. Org. Lett. 2010, 12, 2342e2345; (i) Krishna, P. R.; Kadiyala, R. R.
Tetrahedron Lett. 2010, 51, 2586e2588; (j) Amarante, G. W.; Cavallaro, M.;
Coelho, F. Tetrahedron Lett. 2010, 51, 2597e2599; (k) Basavaiah, D.; Reddy, K. R.
Tetrahedron 2010, 66, 1215e1219; (l) Singh, V.; Hutait, S.; Batra, S. Eur. J. Org.
Chem. 2010, 19, 3684e3691.
3. (a) Trofimov, B. A.; Nedolya, N. A. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2008; 3, pp 88e167; (b) Kochanowska-Karamyan, A. J.; Hamann, M. T.
Chem. Rev. 2010, 110, 4489e4497; (c) Sundberg, R. J.; Smith, S. Q. Alkaloids 2002,
59, 281e376; (d) Menendez, J. C. Top. Heterocycl. Chem. 2007, 11, 63e101; (e)
Suezen, S. Top. Heterocycl. Chem. 2007, 11, 145e178; (f) Newhouse, T.; Lewis, C. A.;
Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119e7137; (g) Li, S.-M.
Nat. Prod. Rep. 2010, 27, 57e78.
4.5. General procedure for preparation of 32,33 as
exemplified for 33
Iron powder (0.08 g, 1.56 mmol) was added to a solution of 30
(0.10 g, 0.30 mmol) in glacial AcOH (2 mL) and the reaction was
heated at 100 ꢀC with stirring under nitrogen for 1.5 h. On com-
pletion, the reaction mixture was poured into 10% aqueous NaHCO3
solution with stirring by a glass rod. EtOAc (30 ml) was added to
this mixture and the contents were passed through a bed of Celite.
The organic layer was separated and the aqueous layer was
extracted with EtOAc (3ꢁ10 ml). The organic layers were pooled,
dried (Na2SO4) and evaporated in vacuo to afford a residue that was
purified by column chromatography over silica gel with EtOAc/
hexane (5:95, v/v), Rf¼0.80 (EtOAc/hexane 20:80, v/v) as eluent to
obtain 32 as brown oil in 70% (0.07 g) yield.
4. A few citations only (a) Gribble, G. W.; Saulnier, M. G.; Pelkey, E. T.; Kishbaugh,
T. L. S.; Liu, Y. B.; Jiang, J.; Trujillo, H. A.; Keavy, D. J.; Davis, D. A.; Conway, S. C.;
Switzer, F. L.; Roy, S.; Silva, R. A.; Obaza-Nutaitis, J. A.; Sibi, M. P.; Moskalev, N. V.;
Barden, T. C.; Chang, L.; Habeski, W. M.; Pelcman, B.; Sponholtz, W. R.; Chau, R.
W.; Allison, B. D.; Garaas, S. D.; Sinha, M. S.; McGowan, M. A.; Reese, M. R.;
Harpp, K. S. Curr. Org. Chem. 2005, 9, 1493e1519; (b) Humphrey, G. R.; Kuethe, J.
T. Chem. Rev. 2006, 106, 2875e2911; (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005,
105, 2873e2920; (d) Thansandote, P.; Lautens, M. Chem.dEur. J. 2009, 15,
5874e5883; (e) Baxter, C. A.; Cleator, E.; Alam, M.; Davies, A. J.; Goodyear, A.;
O’Hagan, M. Org. Lett. 2010, 12, 668e671; (f) Wahab, B.; Ellames, G.; Passey, S.;
Watts, P. Tetrahedron 2010, 66, 3861e3865; (g) Sanz, R.; Guilarte, V.; Perez, A.
Tetrahedron Lett. 2009, 50, 4423e4426; (h) Sasaki, S.; Yamauchi, T.; Higa-
shiyama, K. Tetrahedron Lett. 2010, 51, 2326e2328 and references cited therein;
(i) Wang, W.; Herdtweckb, E.; Domling, A. Chem. Commun. 2010, 46, 770e772;
(j) Guan, Z. H.; Yan, Z. Y.; Ren, Z. H.; Liua, X. Y.; Liang, Y. M. Chem. Commun. 2010,
46, 2823e2825; (k) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.;
Trindade, A. F. Chem. Rev. 2009, 109, 2703e2802; (l) Donohoe, T. J.; Fishlock, L.
P.; Procopiou, P. A. Chem.dEur. J. 2008, 14, 5716e5726; (m) Cui, H.-L.; Feng, X.;
Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5737e5740;
(n) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int. Ed. 2008, 47, 346e349.
5. A few recent citations for annulated heterocycles using MBH chemistry from
this lab (a) Mishra, A.; Batra, S. Eur. J. Org. Chem. 2010. doi:10.1002/ejoc.
201000355; (b) Nag, S; Bhowmik, S.; Gauniyal, H. M.; Batra, S. Eur. J. Org. Chem.
2010. doi:10.1002/ejoc.201000586; (c) Mishra, A; Hutait, S.; Bhowmik, S.;
Rastogi, N.; Roy, R.; Batra, S. Synthesis 2010, 2731e2748; (d) Nayak, M.; Batra, S.
Tetrahedron Lett. 2010, 51, 510e516; (e) Singh, V.; Hutait, S.; Batra, S. Eur. J. Org.
Chem. 2009, 6211e6216; (f) Nag, S.; Nayak, M.; Batra, S. Adv. Synth. Catal. 2009,
351, 2715e2723; (g) Singh, V.; Hutait, S.; Batra, S. Eur. J. Org. Chem. 2009,
3454e3466.
4.5.1. Methyl 2-(5,6-dihydroindolo[1,2-a]quinoxalin-6-yl)acrylate
(32). IR (neat) 1721 (CO2Me), 3376 (NH) cmꢂ1; 1H NMR (300 MHz,
CDCl3)
d 3.82 (3H, s, CO2CH3), 4.77 (1H, br s, NH), 5.31 (1H, s,
]CHH), 5.60 (1H, s, CHNH), 6.21 (1H, s, ]CHH), 6.41 (1H, s, ArH),
6.81 (1H, dd, J1¼2.4 Hz, J2¼7.5 Hz, ArH), 6.94e7.03 (2H, m, ArH),
7.17e7.31 (2H, m, ArH), 7.64 (1H, d, J¼7.6 Hz, ArH), 7.88 (1H, d,
J¼6.7 Hz, ArH), 8.01 (1H, d, J¼8.4 Hz, ArH); 13C NMR (75 MHz,
CDCl3)
d 51.9, 52.3, 100.3, 111.9, 116.7, 116.8, 120.1, 121.1, 121.3,
122.7, 124.4, 127.0, 128.0, 129.7, 134.0, 134.5, 135.5, 138.8, 166.9; MS
(ESI) m/z 305.1 (MþþH). Anal. Calcd for C19H16N2O2 (304.1212) C
74.98, H 5.30, N 9.20; found C 75.21, H 5.56, N 8.97.
4.5.2. Ethyl 2-(5,6-dihydroindolo[1,2-a]quinoxalin-6-yl)acrylate (33).
The title compound was prepared from 31 following the general
procedure described above and after purification by column chro-
matography over silica gel with EtOAc/hexane(5:95, v/v), Rf¼0.82
(EtOAc/hexane 20:80, v/v) as eluent was obtained as red oil in 68%
yield (0.06 g from 0.10 g). IR (neat) 1716 (CO2Et), 3415 (NH) cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
1.32 (3H, t, J¼7.1 Hz, CO2CH2CH3),
4.21e4.33 (2H, m, CO2CH2CH3), 4.79 (1H, br s, NH), 5.28 (1H, s, ]
CHH), 5.59 (1H, s, CHNH), 6.21 (1H, s, ]CHH), 6.41 (1H, s, ArH),
6.78e6.83 (1H, m, ArH), 6.92e7.04 (2H, m, ArH), 7.15e7.33 (2H, m,
ArH), 7.67 (1H, m, ArH), 7.85e7.90 (1H, m, ArH), 8.01 (1H, d,
6. Friary, R.J.; Kozlowski, J.A.; Shankar, B.B.; Wong, M.K.C.; Zhou, G.; Lavey, B.J.;
Shih, N.-Y.; Tong, L.; Chen, L.; Shu, Y. World Patent WO 2,003,042,174, 2003;
Chem. Abstr. 2003, 138, 401607g.
7. McKew, J. C.; Lee, K. L.; Shen, M. W. H.; Thakker, P.; Foley, M. A.; Behnke, M. L.; Hu,
B.; Sum, F.-W.; Tam, S.; Hu, Y.; Chen, L.; Kirincich, S. J.; Michalak, R.; Thomason, J.;
Ipek, M.; Wu, K.; Wooder, L.; Ramarao, M. K.; Murphy, E. A.; Goodwin, D. G.; Al-
bert, L.; Xu, X.; Donahue, F.; Ku, M. S.; Keith, J.; Nickerson-Nutter, C. L.; Abraham,
W. M.; Williams, C.; Hegen, M.; Clark, J. D. J. Med. Chem. 2008, 51, 3388e3413.
8. Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour, J.-Y.; Coudert, G.
Tetrahedron 2004, 60, 10039e10047.
J¼8.0 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d 14.3, 52.0, 61.3, 100.3,
111.9, 116.7, 120.1, 121.1, 121.2, 122.7, 124.4, 127.0, 127.8, 129.7, 134.0,
134.6, 135.5, 139.0, 166.4; MS (ESI) m/z 319.2 (MþþH). Anal. Calcd
for C20H18N2O2 (318.1368) C 75.45, H 5.70, N 8.80; found C 75.71, H
5.43, N 9.03.
Acknowledgements
9. (a) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70,
5840e5851; (b) Wang, W.; Xiong, C.; Zhang, J.; Hruby, V. J. Tetrahedron 2002,
58, 3101e3110.
Two of the authors (S.B. and V.S.) gratefully acknowledge the
financial support in the form of fellowships from CSIR, New Delhi.
This work was supported by a grant from DST, New Delhi. Authors
acknowledge the SAIF Division for providing the spectroscopic and
analytical data.
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Supplementary data
Remaining experimental procedures and spectroscopic data and
copies of NMR spectra of all compounds are included. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2010.07.078. These data include MOL
files and InChIKeys of the most important compounds described in
this article.

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