Baylis-Hillman reaction of 1-formyl-β-carboline: One-step synthesis of the canthin-6-one framework by an unprecedented cascade cyclization reaction

Article abstract of DOI:10.1002/ejoc.200900962

A one-step access to the canthin-6-one architecture by the Baylis-Hillman reaction of methyl l-formyl-9H-β-carboline3-carboxylate or 1-formyl-9H-β-carboline involving an unprecedented cascade cyclization reaction is reported. Wiley-VCH Verlag GmbH & Co. K

Full text of DOI:10.1002/ejoc.200900962

FULL PAPER
DOI: 10.1002/ejoc.200900962
Baylis–Hillman Reaction of 1-Formyl-β-carboline: One-Step Synthesis of the
Canthin-6-one Framework by an Unprecedented Cascade Cyclization Reaction
Virender Singh,[a][‡] Samiran Hutait,[a][‡] and Sanjay Batra*[a]
Dedicated to Dr. A. P. Bhaduri
Keywords: Natural products / Cyclization / Synthetic methods / Nitrogen heterocycles / Polycycles
A one-step access to the canthin-6-one architecture by the
Baylis–Hillman reaction of methyl 1-formyl-9H-β-carboline-
3-carboxylate or 1-formyl-9H-β-carboline involving an un-
precedented cascade cyclization reaction is reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
ing anti-fungal, anti-HIV, anti-bacterial, anti-tumour and
anti-malarial activity.[6] As a result, several elegant strate-
gies involving Diels–Alder, Pictet–Spengler, intramolecular
Wittig or other reactions have been developed for their syn-
thesis.[7] We envisaged that the BH adduct of 1-formyl-9H-
β-carboline would be an obvious substrate for constructing
the canthine framework. The retrosynthetic analysis out-
lined in Figure 2 provides the basis for this work. Cleavage
of the D ring of the canthin-6-one skeleton I or the canthine
skeleton II leads to the BH adduct III, which can be gener-
ated from methyl 1-formyl-9H-β-carboline-3-carboxylate or
1-formyl-9H-β-carboline (IV).
Introduction
The Baylis–Hillman (BH) reaction is one of the most ef-
ficient and atom economic C–C bond-forming reactions
that has a propensity to afford adducts with high functional
diversity. These adducts or their derivatives have been dem-
onstrated to be viable precursors for a myriad of applica-
tions leading to the synthesis of heterocycles, drug interme-
diates and natural products.[1] Heterocyclic electrophiles,
which may undergo fast BH reactions, are a fruitful ad-
dition to the substrate base as their derivatives offer oppor-
tunities for intramolecular reactions leading to annulated
frameworks.[2] The β-carboline core is a key structural motif
of a variety of natural products and pharmaceutical
agents.[3] As a continuation of our interest in exploring the
use of new heterocyclic aldehydes for the BH reaction, we
disclose herein the interesting BH reactions of methyl 1-
formyl-9H-β-carboline-3-carboxylate and 1-formyl-9H-β-
carboline, which directly lead to the formation of the can-
thin-6-one skeleton in one step by an unprecedented cas-
cade cyclization reaction.
Figure 1. Canthine and canthin-6-one frameworks.
Canthin-6-ones are a subclass of β-carboline-based natu-
ral alkaloids in which an additional D ring is present (Fig-
ure 1). First isolated from Pentacerase australis in 1952 by
Nelson and co-workers,[4] more than 40 such alkaloids have
now been reported in the literature.[5] These alkaloids are
reported to have several pharmacological activities, includ-
[a] Medicinal and Process Chemistry Division, Central Drug Re-
search Institute, CSIR,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405
E-mail: batra_san@yahoo.co.uk
[‡] V. Singh and S. Hutait have contributed equally to the work:
CDRI Communication No. 7860
Figure 2. Retrosynthetic analysis of the canthine and canthin-6-one
frameworks.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900962.
Eur. J. Org. Chem. 2009, 6211–6216
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Singh, S. Hutait, S. Batra
FULL PAPER
tryptamine, each step in the reaction sequence was sluggish
and gave slightly lower yields.
Results and Discussion
The first objective of this study was to access methyl 1-
formyl-9H-β-carboline-3-carboxylate and 1-formyl-9H-β-
carboline. A search through the literature revealed that
these aldehydes have been synthesized by diverse strate-
gies.[8] In response to our requirement, however, we engine-
ered a modified protocol for obtaining this aldehyde on a
large scale. Our method commenced with the Pictet–Speng-
ler reaction of tryptophan methyl ester with dimethoxygly-
oxal (60% solution in water) to afford the tetrahydro-β-car-
boline derivative 3 in a yield of 96% and in good purity
(Scheme 1). Oxidation of 3 with KMnO4 at room tempera-
ture overnight resulted in acetal 5 (90%).[9] Deprotection of
the formyl group with aqueous AcOH gave the required
methyl 1-formyl-9H-β-carboline-3-carboxylate in 86%
yield. More importantly, in this three-step synthesis at no
stage was any purification required and reactions could be
scaled-up to obtain 10 g of the aldehyde. Subsequently, a
similar series of reactions employing tryptamine as the
starting material yielded the required aldehyde 8. Com-
pared with the reaction of tryptophan methyl ester, with
With aldehydes 7 and 8 in hand, we started to investigate
their BH reactions. The optimization studies were per-
formed with 7 as the test compound and methyl acrylate as
the alkene in the presence of DABCO. A mixture of alde-
hyde 7 (1.0 equiv.), methyl acrylate (20 equiv.) and DABCO
(1.5 equiv.) was stirred at room temperature. The reaction
was complete in 8 h, but the TLC analysis indicated the
presence of two products. Chromatographic purification af-
forded a polar compound as the major product in 55%
yield and a non-polar compound, which was isolated in
10% yield (Table 1). Spectroscopic analysis of the major
product indicated it to be the required adduct 9. However
1
the H NMR spectrum of the minor product displayed a
singlet signal arising from methyl protons along with sig-
nals from the methoxycarbonyl and the methylene groups,
but the signal from the hydroxy group was missing. The IR
spectrum indicated the presence of an amide group as well
as the ester moiety. Therefore, to establish the structure of
this product detailed 2D NMR experiments were con-
ducted. Based on HMBC and HSQC experiments coupled
with HRMS data, we assigned the structure of the minor
product to 10 (Scheme 2). The formation of 10, a canthin-
6-one derivative, indicated that during the BH reaction, a
side-reaction may occur leading to a cascade cyclization.
Following this observation 7 was subjected to the BH reac-
tion with ethyl acrylate Although this reaction was slow,
being completed in 13 h, here too derivative 12 was isolated
in 8% yield as a minor product in addition to the adduct
11 (54%).
Scheme 1. Synthesis of the 1-formyl-9H-β-carbolines 7 and 8. Rea-
gents and conditions: i. OHCCH(OMe)2, 5% TFA in CH2Cl2,
room temp., 15 h for 1, 3 d for 2; ii. KMnO4, dry THF, room temp., Scheme 2. Baylis–Hillman reaction of 7 and 8 with acrylates. Rea-
15 h for 3, 5 d for 4; iii. AcOH/H2O (2:3), 120 °C, 45 min. gents and conditions: i. DABCO, room temp. (see Table 1).
Table 1. Effect of the amount of DABCO on the BH reaction and isolated yields of the corresponding products.
Aldehyde
EWG
DABCO [equiv.]
Time [h]
Product
BH adduct (yield [%])
Canthin-6-one (yield [%])
7
7
7
7
7
7
7
8
8
8
8
8
8
CO2Me
CO2Et
CO2Me
CO2Et
CO2nBu
CO2nBu
CO2tBu
CO2Me
CO2Et
CO2Me
CO2Et
CO2nBu
CO2tBu
1.5
1.5
5
5
5
5
5
1.5
1.5
5
8
13
20
60
48
72
80
27
9 (55)
11 (54)
–
10 (10)
12 (13)
10 (59)
12 (60)
14 (30)
14 (67)
–
17 (10)
19 (13)
17 (57)
19 (59)
21 (64)
–
–
13 (38)
–
15 (72)
16 (60)
18 (55)
16 (8)
18 (10)
20 (10)
22 (88)
72
120
120
120
120
5
5
5
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6211–6216

Baylis–Hillman Reaction of 1-Formyl-β-carboline
Figure 3. Possible mechanism for the formation of canthin-6-one.
Encouraged by these results we investigated the BH reac-
tions of aldehyde 8 (Scheme 2) with methyl and ethyl acry-
late in the presence of 1.5 equiv. of DABCO. Compared
with the reaction of 7, the reactions of 8 proceeded slowly,
although it was pleasing to note that here too, besides the
BH adducts 16 and 18, canthin-6-one derivatives 17 and 19
were isolated in 10 and 13% yields, respectively.
These results encouraged us to seek experimental condi-
tions in which the canthin-6-one derivative was formed ex-
clusively. Consequently, in a representative study, several
combinations of 7, methyl acrylate and DABCO were
screened over different timescales. In the presence of
5.0 equiv. of DABCO the reaction between 7 and methyl
acrylate in neat conditions was complete in 20 h, yielding
10 (59%) as the sole product.
To assess the general application of this protocol, alde-
hydes 7 and 8 were treated with methyl, ethyl, n-butyl and
tert-butyl acrylates. We observed that, with the exception of
tert-butyl acrylate, the corresponding canthin-6-one deriva-
tives were isolated in good yields (Table 1). In the reactions
with tert-butyl acrylate only the corresponding BH adducts
(15 and 22) were obtained. Furthermore, the reactions of 8
were observed to be sluggish and were therefore allowed to
proceed for 5 d.
Scheme 3. Formation of canthine derivatives. Reagents and condi-
tions: i. DABCO, room temp., 3 h for 23, 5 h for 24; ii. K2CO3,
DMF, room temp., 30 min for 25, 3 h for 26.
reaction,[10a] reduction and Pictet–Spengler reaction
(Scheme 4). The BH reaction of 30 with acrylonitrile fol-
lowed by intramolecular reaction of the adduct 31 fur-
nished the new canthine analogue 32.[10b]
Based on these observations we have proposed a possible
mechanism for the formation of the canthin-6-one skeleton
(Figure 3). It is assumed that the formation of the amide
bond takes place ahead of the elimination of DABCO dur-
ing the first BH reaction. This is followed by a 1,3-hydrogen
shift and keto-enol rearrangement leading to an intermedi-
ate that undergoes a second BH reaction to produce the
isolated product. Furthermore, we believe this cyclization
to be highly concerted because once the adduct is isolated
it fails to react further with the alkene to form the canthin-
6-one framework.
Next we examined the BH reaction of 7 and 8 with acry-
lonitrile. This reaction was observed to be complete in 3–5 h
in the presence of 1.0 equiv. of DABCO, giving the desired
adducts 23 and 24 (Scheme 3). Extending the reaction time
led to polymerization. Treatment of 23 and 24 with K2CO3
in DMF at room temperature smoothly gave the canthine
products 25 and 26 by an intramolecular Michael reaction.
To produce more diverse products by this chemistry
Scheme 4. Reagents and conditions: i. Pd(OAc)2, K2CO3, 1,4-diox-
ane, N2, 110 °C, 24 h; ii. Fe/AcOH, N2, 80 °C, 1.5 h; iii. OHCCH-
(OMe)2, 2% TFA in CH2Cl2, room temp., 24 h; iv. TFA/H2O (1:1),
MeCN, 80 °C, 5 h; v. CH2=CHCN, DABCO, neat, room temp.,
we generated a new aldehyde (30) by sequential Heck 2 h; vi. K2CO3, DMF, room temp., 1 h.
Eur. J. Org. Chem. 2009, 6211–6216
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V. Singh, S. Hutait, S. Batra
FULL PAPER
8.70 (d, J = 8.2 Hz, 1 H, ArH), 8.78 (s, 1 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 14.3, 15.5, 53.0, 61.5, 117.5, 117.7, 123.0,
Conclusions
In this report we have disclosed a new application of the 124.8, 126.0, 130.6, 131.2, 131.6, 131.8, 135.2, 135.9, 136.7, 139.9,
143.6, 143.9, 160.3, 165.7, 166.1 ppm. MS (ES): m/z (%) = 391.2
(100) [M + 1]+. DART-HRMS (ES+): calcd. for C24H19N2O5
391.12607; found 391.12940.
BH reaction for the facile synthesis of canthin-6-one and
canthine frameworks bearing functional groups for further
derivatization.
Methyl 4-(3-Butoxy-3-oxoprop-1-en-2-yl)-5-methyl-6-oxo-6H-indolo-
[3,2,1-de][1,5]naphthyridine-2-carboxylate (14): The title compound
was prepared following the above-described general procedure and
after purification by silica gel (60–120 mesh) column chromatog-
raphy [hexane/EtOAc, 80:20, Rf = 0.70 (hexane/EtOAc, 70:30, v/v)]
14 was obtained as a white solid (0.33 g from 0.30 g, 67%), m.p.
Experimental Section
Melting points were determined in capillary tubes with a Precision
melting point apparatus containing silicon oil and are uncorrected.
IR spectra were recorded using a Perkin–Elmer RX I FTIR spec-
trometer. 1H and 13C NMR spectra were recorded with either a
Bruker DPX-200 FT or an Avance DRX-300 spectrometer using
TMS as the internal standard (chemical shifts in δ). ESMS were
recorded with a MICROMASS Quadro-II LCMS system. HRMS
were recorded as EI-HRMS with a JEOL spectrometer or as
DART-HRMS (recorded as ES+) with a JEOL-AccuTOF JMS-
T100LC spectrometer equipped with a DART (Direct Analysis in
Real Time) source. Elemental analyses were performed with a
Carlo Erba 108 or an Elementar Vario EL III microanalyser. Room
temperature varied between 21 and 35 °C.
159–161 °C. IR (KBr): ν
= 1674 (CON), 1716 (CO2Me) cm–1.
˜
max
1H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 7.3 Hz, 3 H,
OCH2CH2CH2CH3), 1.19–1.26 (m, 2 H, OCH2CH2CH2CH3),
1.53–1.60 (m, 2 H, OCH2CH2CH2CH3), 2.37 (s, 3 H, CH3), 4.01
(s, 3 H, CO2CH3), 4.20 (t, J = 6.5 Hz, 2 H, OCH2CH2CH2CH3),
6.00 (s, 1 H, =CHH), 6.94 (s, 1 H, =CHH), 7.54 (t, J = 7.5 Hz, 1
H, ArH), 7.54 (t, J = 8.0 Hz, 1 H, ArH), 8.10 (d, J = 7.6 Hz, 1 H,
ArH), 8.64 (d, J = 8.1 Hz, 1 H, ArH), 8.73 (s, 1 H, ArH) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 13.7, 15.4, 19.1, 30.6, 53.0, 65.4,
117.5, 117.7, 123.0, 124.7, 126.0, 130.5, 131.2, 131.7, 135.2, 135.9,
136.6, 139.9, 143.6, 143.9, 160.3, 165.7, 166.1 ppm. MS (ES): m/z
(%) = 419.2 (100) [M + 1]+. DART-HRMS (ES+): calcd. for
C24H23N2O5 419.16023; found 419.16070.
General Procedure for the Synthesis of Compounds 10, 12, 14, 17, 19
and 21, as Exemplified for Compound 10: Methyl acrylate (2.66 mL,
29.5 mmol) was added to a mixture of 7 (0.40 g, 1.57 mmol) and
DABCO (0.88 g, 7.87 mmol), and the mixture was stirred at room
temperature for 20 h. After completion of the reaction, as moni-
tored by TLC, the mixture was poured into water (35 mL) and
EtOAc (50 mL) was added and the organic layer was partitioned.
The aqueous layer was further extracted with EtOAc (3ϫ25 mL).
The combined organic layers were washed with brine (70 mL),
dried with anhydrous Na2SO4 and evaporated to yield a solid resi-
due which was further purified by silica gel (60–120 mesh) column
chromatography using hexane/EtOAc as eluent [80:20, Rf = 0.38
(hexane/ethyl acetate, 70:30, v/v)] to afford 10 (0.35 g from 0.40 g,
59%) as a light-yellow solid.
Methyl 2-(5-Methyl-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridin-4-
yl)acrylate (17): The title compound was prepared following the
above-described general procedure (5 equiv. DABCO, 120 h) and
after purification by silica gel (60–120 mesh) column chromatog-
raphy [hexane/EtOAc, 80:20, Rf = 0.50 (hexane/EtOAc, 70:30, v/v)]
17 was obtained as a light-yellow solid (0.19 g from 0.20 g, 57%)
followed by 16 (0.023 g from 0.20 g, 8%). Data for 17: m.p. 193–
195 °C. IR (KBr): ν
= 1664 (CON), 1720 (CO2CH3) cm–1. 1H
˜
max
NMR (300 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 3.78 (s, 3 H,
CO2CH3), 5.95 (s, 1 H, =CHH), 6.94 (s, 1 H, =CHH), 7.51 (d, J
= 7.31 Hz, 1 H, ArH), 7.69 (d, J = 7.7 Hz, 1 H, ArH), 7.88 (d, J
= 5.0 Hz, 1 H, ArH), 8.08 (d, J = 7.7 Hz, 1 H, ArH), 8.68 (d, J =
8.2 Hz, 1 H, ArH), 8.76 (d, J = 5.0 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 15.2, 52.6, 115.7, 117.4, 122.8, 124.9, 125.7,
130.1, 130.5, 130.8, 131.4, 135.3, 135.7, 136.5, 139.5, 143.4, 145.6,
160.2, 165.9 ppm. MS (ES): m/z (%) = 319.2 (100) [M + 1]+.
DART-HRMS (ES+): calcd. for C19H15N2O3 319.10600; found
319.10827.
Methyl 4-(3-Methoxy-3-oxoprop-1-en-2-yl)-5-methyl-6-oxo-6H-ind-
olo[3,2,1-de][1,5]naphthyridine-2-carboxylate (10): Yield: 59%
(0.35 g from 0.40 g), m.p. 203–205 °C. IR (KBr): ν
= 1679
˜
max
(CON), 1714 (CO2CH3) cm–1. 1H NMR (200 MHz, CDCl3): δ =
2.39 (s, 3 H, CH3), 3.80 (s, 3 H, CO2CH3), 4.03 (s, 3 H, CO2CH3),
6.01 (d, J = 0.8 Hz, 1 H, =CHH), 6.95 (d, J = 0.8 Hz, 1 H, =CHH),
7.53–7.61 (m, 1 H, ArH), 7.70–7.79 (m, 1 H, ArH), 8.16 (d, J =
7.8 Hz, 1 H, ArH), 8.70 (d, J = 8.2 Hz, 1 H, ArH), 8.79 (s, 1 H,
ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.5, 29.8, 52.6, 53.1,
73.0, 117.5, 117.7, 123.1, 126.1, 131.2, 132.0, 136.8, 139.9, 144.0,
160.2, 166.1, 166.3 ppm. MS (ES): m/z (%) = 377.2 (100) [M +
1]+. DART-HRMS (ES+): calcd. for C21H17N2O5 377.11028; found
377.11375.
Ethyl 2-(5-Methyl-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridin-4-yl)-
acrylate (19): The title compound was prepared following the
above-described general procedure and after purification by silica
gel (60–120 mesh) column chromatography [hexane/EtOAc, 80:20,
Rf = 0.54 (hexane/EtOAc, 70:30, v/v)] 19 was obtained as a light-
yellow solid (0.31 g from 0.31 g, 59%) followed by 18 (0.05 g from
0.31 g, 10%). Data for 19: m.p. 122–123 °C. IR (KBr): νmax = 1660
˜
(CON), 1723 (CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.23 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.36 (s, 3 H, CH3), 4.25 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 5.94 (d, J = 0.8 Hz, 1 H, =CHH),
6.94 (s, 1 H, =CHH), 7.53 (d, J = 7.6 Hz, 1 H, ArH), 7.68–7.74
(m, 1 H, ArH), 7.90 (d, J = 5.0 Hz, 1 H, ArH), 8.11 (d, J = 7.7 Hz,
1 H, ArH), 8.71 (d, J = 8.2 Hz, 1 H, ArH), 8.78 (d, J = 5.0 Hz, 1
H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 15.1, 61.5,
115.6, 117.3, 122.7, 124.8, 125.6, 130.0, 130.4, 130.7, 131.1, 135.6,
136.4, 139.4, 143.5, 145.5, 160.1, 165.4 ppm. MS (ES): m/z (%) =
333.2 (100) [M + 1]+. DART-HRMS (ES+): calcd. for C20H17N2O3
333.12097; found 333.12392.
Methyl 4-(3-Ethoxy-3-oxoprop-1-en-2-yl)-5-methyl-6-oxo-6H-indolo-
[3,2,1-de][1,5]naphthyridine-2-carboxylate (12): The title compound
was prepared following the above-described general procedure and
after purification by silica gel (60–120 mesh) column chromatog-
raphy [hexane/EtOAc, 80:20, Rf = 0.60 (hexane/EtOAc, 70:30, v/v)]
12 was obtained as a light-yellow solid (0.37 g from 0.40 g, 60%),
m.p. 176–178 °C. IR (KBr):
ν
= 1671 (CON), 1716
˜
max
(CO2Et) cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.25 (t, J =
7.1 Hz, 3 H, OCH2CH3), 2.39 (s, 3 H, CH3), 4.02 (s, 3 H, CO2CH3),
4.28 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.00 (d, J = 0.8 Hz, 1 H,
=CHH), 6.95 (d, J = 0.8 Hz, 1 H, =CHH), 7.52–7.60 (m, 1 H,
Butyl 2-(5-Methyl-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridin-4-yl)-
ArH), 7.70–7.78 (m, 1 H, ArH), 8.16 (d, J = 7.6 Hz, 1 H, ArH), acrylate (21): The title compound was prepared following the
6214 Eur. J. Org. Chem. 2009, 6211–6216
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Baylis–Hillman Reaction of 1-Formyl-β-carboline
above-described general procedure and after purification by silica
gel (100–200 mesh) column chromatography [hexane/EtOAc, 80:20,
Rf = 0.57 (hexane/EtOAc, 70:30, v/v)] compound 21 was obtained
(0.24 g from 0.20 g, 64%) as a white solid followed by 20 (0.04 g
6-Hydroxy-7,8-dihydro-6H-benzo[b]indolo[3,2,1-de][1,5]naphthyrid-
ine-7-carbonitrile (32; Mixture of Diastereomers, 1:1): The title
compound was prepared following the above-described general
procedure and after purification by crystallization using EtOAc [Rf
= 0.48 (hexane/EtOAc, 60:40, v/v)] 32 was obtained as a brown
solid (0.04 g from 0.05 g). Yield: 80%, m.p. Ͼ240 °C. IR (KBr):
from 0.20 g, 10%). Data for 21: m.p. 107–109 °C. IR (KBr): ν
˜
max
= 1670 (CON), 1711 (CO2Me) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 0.84 (t, J = 7.3 Hz, 3 H, OCH2CH2CH2CH3), 1.20–1.28 (m, 2
ν
max
= 2242 (CN), 3426 (OH) cm–1. 1H NMR (300 MHz, [D6]-
˜
H, OCH2CH2CH2CH3), 1.52–1.60 (m, 2 H, OCH2CH2CH2CH3), DMSO): δ = 4.10 (d, J = 4.2 Hz, 2 H, 2 CHH), 4.71 (dd, J1 = 3.5,
2.36 (s, 3 H, CH3), 4.19 (t, J = 6.6 Hz, 2 H, OCH2CH2CH2CH3), J2 = 11.5 Hz, 2 H, 2 CHH), 4.94 (dd, J1 = 4.7, J2 = 12.5 Hz, 2 H,
5.94 (s, 1 H, =CHH), 6.94 (s, 1 H, =CHH), 7.53 (t, J = 7.5 Hz, 1 2 CHCN), 5.37 (br. s, 2 H, 2 CHOH), 6.78 (d, J = 5.0 Hz, 2 H, 2
H, ArH), 7.72 (t, J = 7.7 Hz, 1 H, ArH), 7.90 (d, J = 4.9 Hz, 1 H,
ArH), 8.11 (d, J = 7.8 Hz, 1 H, ArH), 8.72 (d, J = 8.2 Hz, 1 H,
CHOH), 7.48 (t, J = 7.7 Hz, 2 H, ArH), 7.71–7.82 (m, 7 H, ArH),
7.93 (d, J = 8.0 Hz, 2 H, ArH), 8.25 (d, J = 8.0 Hz, 1 H, ArH),
ArH), 8.78 (d, J = 4.9 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, 8.72 (d, J = 8.1 Hz, 2 H, ArH), 8.79 (d, J = 8.1 Hz, 2 H, ArH) ppm.
CDCl3): δ = 13.7, 15.1, 19.1, 30.6, 65.4, 115.6, 117.4, 122.7, 124.9,
13C NMR (50 MHz, [D6]DMSO): δ = 33.4, 66.1, 67.1, 111.1, 118.4,
125.6, 130.0, 130.4, 130.7, 131.0, 135.5, 135.7, 139.5, 143.6, 145.5,
119.2, 121.1, 121.4, 123.4, 124.4, 125.8, 127.1, 127.3, 128.8, 130.1,
160.2, 165.5 ppm. MS (ES): m/z (%) = 361.2 (100) [M + 1]+. EI- 139.0, 142.6, 145.4, 146.0 ppm. MS (ES): m/z (%) = 300.2 (100) [M
HRMS: calcd. for C22H20N2O3 360.1474; found 360.1487.
+ 1]+. C19H13N3O (299.1059): calcd. C 76.24, H 4.38, N 14.04;
found C 76.40, H 4.27, N 14.25.
General Procedure for the Synthesis of Compounds 25, 26 and 32,
as Exemplified for Compound 25: K2CO3 (1.23 g, 11.79 mmol) was
added to a solution of 23 (1.00 g, 3.93 mmol) in dry DMF (6 mL),
and the reaction was stirred at room temperature for 30 min. After
completion, water (50 mL) was added followed by EtOAc (60 mL)
and the mixture was taken up in a separating funnel. The organic
layer was separated and the aqueous layer was further extracted
with EtOAc (4ϫ25 mL). The organic layers were combined and
washed with brine (50 mL), dried with anhydrous Na2SO4 and con-
centrated to yield a crude product which was further purified by
crystallization using EtOAC [Rf = 0.48 (CHCl3/MeOH, 95:05,
v/v)] to afford 25 as a yellow solid (0.63 g from 1.00 g, 63%).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, spectroscopic data for remaining com-
1
pounds and H and 13C NMR spectra for all new compounds are
provided.
Acknowledgments
Two of the authors (V. S. and S. H.) gratefully acknowledge the
financial support from the Council of Scientific and Industrial Re-
search, New Delhi. This work was carried out under a grant from
the Department of Science and Technology, New Delhi.
Methyl
naphthyridine-2-carboxylate (25; Mixture of Diastereomers, 10:1):
Yield: 63%, m.p. 233–235 °C. IR (KBr): ν = 1715 (CO2CH3),
5-Cyano-4-hydroxy-5,6-dihydro-4H-indolo[3,2,1-de][1,5]-
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max
1
2239 (CN), 3188 (OH) cm–1. H NMR (300 MHz, [D6]DMSO): δ
= 3.93 (s, 6 H, 2 CO2CH3), 4.01–4.06 (m, 2 H, 2 CHOH), 4.40–
4.57 (m, 2 H, 2 CHH), 4.87–4.96 (m, 2 H, 2 CHH), 5.28 (t, J =
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2 H, ArH), 7.84 (t, J = 6.5 Hz, 2 H, ArH), 8.46 (t, J = 7.4 Hz, 2
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(75 MHz, [D6]DMSO): δ = 33.0, 33.3, 52.1, 65.2, 66.4, 111.0, 118.2,
118.4, 119.1, 120.9, 121.0, 121.1, 123.2, 126.0, 129.0, 129.1, 133.3,
137.2, 140.5, 140.7, 140.9, 141.6, 166.1 ppm. MS (ES): m/z (%) =
308.1 (100) [M + 1]+. C17H13N3O3 (307.0957): calcd. C 66.44, H
4.26, N 13.67; found C 66.57, H 4.35, N 13.76.
4-Hydroxy-5,6-dihydro-4H-indolo[3,2,1-de][1,5]naphthyridine-5-car-
bonitrile (26; Mixture of Diastereomers, 1:1): The title compound
was prepared following the above-described general procedure and
after purification by column chromatography [CHCl3/MeOH,
98:02, Rf = 0.51 (CHCl3/MeOH, 95:05, v/v)] 26 was obtained as a
grey solid (0.114 g from 0.20 g). Yield: 57%, m.p. 155–157 °C. IR
(KBr): ν
= 2230 (CN), 3178 (OH) cm–1. 1H NMR (300 MHz,
˜
max
[D6]DMSO): δ = 3.94–4.02 (m, 2 H, 2 CHOH), 4.36–4.50 (m, 2 H,
CH2), 4.80–4.89 (m, 2 H, CH2), 5.21 (q, J = 5.3 Hz, 2 H, 2 CHCN),
6.50 (d, J = 5.8 Hz, 1 H, CHOH), 6.58 (d, J = 5.8 Hz, 1 H,
CHOH), 7.33 (q, J = 7.4 Hz, 2 H, ArH), 7.62–7.69 (m, 2 H, ArH),
7.76–7.80 (m, 2 H, ArH), 8.08 (q, J = 5.3 Hz, 2 H, ArH), 8.29 (t,
J = 5.8 Hz, 2 H, ArH), 8.38 (q, J = 5.3 Hz, 2 H, ArH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 33.1, 33.4, 65.5, 66.7, 110.5,
115.1, 119.4, 120.0, 120.1, 120.8, 120.9, 122.6, 122.7, 125.7, 126.0,
128.5, 128.6, 131.6, 131.8, 138.6, 138.8, 140.0, 140.2, 141.0,
141.7 ppm. MS (ES): m/z (%) = 250.2 (100) [M + 1]+. C15H11N3O
(249.0902): calcd. C 72.28, H 4.45, N 16.86; found C 72.33, H 4.17,
N 16.73.
Eur. J. Org. Chem. 2009, 6211–6216
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6215

V. Singh, S. Hutait, S. Batra
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Received: August 24, 2009
Published Online: October 26, 2009
6216
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