Synthesis of substituted 1H- and 3H-1-benzazepines and rearrangement of alkyl 1H-1-benzazepine-2-carboxylates into isoquinolines

Article abstract of DOI:10.1002/ejoc.200700175

The SnCl₂-mediated reduction of nitro groups in 2-nitro-4-(2-nitrobenzylidene)alkanoates and 4-nitro-2-(2-nitroalkylidene) alkanoates allows the facile synthesis of substituted 1H-1-benzazepines and 3H-1-benzazepines. This reaction proceeds via

Full text of DOI:10.1002/ejoc.200700175

FULL PAPER
DOI: 10.1002/ejoc.200700175
Synthesis of Substituted 1H- and 3H-1-Benzazepines and Rearrangement of
Alkyl 1H-1-Benzazepine-2-carboxylates into Isoquinolines[‡]
Vijay Singh[a] and Sanjay Batra*[a]
Keywords: Baylis–Hillman reaction / Nitrogen heterocycles / Rearrangement
The SnCl2-mediated reduction of nitro groups in 2-nitro-4-
(2-nitrobenzylidene)alkanoates and 4-nitro-2-(2-nitroalkylid-
ene)alkanoates allows the facile synthesis of substituted 1H-
1-benzazepines and 3H-1-benzazepines. This reaction pro-
ceeds via SN2Ј reaction of ethyl nitroacetate and nitroethane
ing from 2-nitro-substituted benzaldehydes. During the
study, an unprecedented rearrangement of an alkyl 1H-
benzazepine-2-carboxylate to a substituted isoquinoline has
been observed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
with the acetyl derivatives of Baylis–Hillman adducts deriv- Germany, 2007)
we discovered that the 2-alkoxycarbonyl-1H-1-benzazepines
are highly unstable and rearrange easily to isoquinolines,
which is unprecedented.
Introduction
The products afforded by the Baylis–Hillman reaction
and their derivatives have served as an excellent source of
several heterocyclic motifs.[1–10] In this context, our research
group has successfully developed several simple, convenient,
and high-yielding protocols for the synthesis of a variety of
heterocyclic systems.[11–19] We have recently described syn-
theses of 3-methylene-2-pyrrolidinones and 3-(1-alkoxycar-
bonylvinyl)-1H-indole-2-carboxylates.[20] During this study,
we have discovered that a secondary nitro group attached
to the carbon bearing the alkoxycarbonyl group undergoes
a chemoselective reduction to an oxime in the presence of
SnCl2·2H2O. Mechanistic considerations generated interest
in extending the study to a similar reduction in the sub-
strates afforded by the SN2Ј reaction between acetyl deriva-
tives of the Baylis–Hillman adducts of 2-nitrobenzaldehyde
and ethyl nitroacetate or nitroethane. We reasoned that the
SnCl2·2H2O-mediated reduction of the nitro groups would
result in an aromatic amino group and an oxime in the case
of ethyl nitroacetate derivatives and an aliphatic amino
group in the case of nitroethane derivatives. Subsequently,
the intermediates in both cases would cyclize to yield
heterocyclic systems. In order to investigate the outcome of
this reaction, the acetyl derivatives of several Baylis–Hill-
man adducts were treated with ethyl nitroacetate or nitro-
ethane, and the resulting substrates were subjected to
SnCl2·2H2O-promoted reductions. We were pleased to note
that this reaction invariably led to the formation of 1H-1-
benzazepine or 3H-1-benzazepine derivatives. Interestingly,
1H-1-Benzazepine derivatives are a pharmacologically
important class of heterocycles. They are potent antagonists
of the glycine binding site associated with N-methyl--as-
partate (NMDA),[21] antagonists of the CC chemokine re-
ceptor-5, and therefore, useful against HIV-1 infec-
tion,[22–23] and show usefulness in illnesses related to the
melanocortin-4 receptor.[24] A survey of the literature re-
vealed that only a few methods for the synthesis of substi-
tuted 1H-benzazepines were known.[25–30] Our approach is
very simple and constitutes a practical route to this class of
heterocycle. The results of our study are being reported in
this paper.
Results and Discussion
The first part of our study deals with the substrates af-
forded from the reaction between acetyl derivatives of
Baylis–Hillman adducts and ethyl nitroacetate. The prepa-
ration of the starting materials 1a–d,2–3a in this synthetic
sequence was achieved by carrying out the Baylis–Hillman
reaction of 2-nitrobenzaldehyde or substituted 2-nitrobenz-
aldehydes with activated alkenes following the reported pro-
cedure.[20] The adducts 1a–d,2–3a were transformed into the
respective acetyl derivatives 4a–d,5–6a by reaction with ace-
tyl chloride in the presence of pyridine in dichloromethane
at room temperature in excellent yields. The SN2Ј reaction
of acetates 4a–d,5–6a with ethyl nitroacetate in the presence
of K2CO3 in DMF at room temperature stereoselectively
yielded the (E) isomer of the respective products 7a–d,8–9a
(Scheme 1) in good yields. Treatment of the nitroalkanoate
7a with SnCl2·2H2O in methanol at reflux for 2 h furnished
a product that was found to be less polar than the substrate.
[‡] CDRI communication no. 7149
[a] Medicinal and Process Chemistry Division, Central Drug Re-
search Institute,
P. O. Box 173, Lucknow 226001, India
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
2970
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2970–2976

Synthesis of Substituted Benzazepines
FULL PAPER
Scheme 1. Reagents and conditions: i) AcCl, pyridine, CH2Cl2, room temp., 3 h; ii) NO2CH2CO2Et, K2CO3, DMF, 3 h; iii) SnCl2·2H2O,
MeOH or EtOH, N2, reflux, 2 h; iv) R3COCl (R3 = Me, Ph), Et3N, CH2Cl2, room temp., 3 h; v) silica gel (60–120 mesh), room temp.,
24 h or silica gel (60–120 mesh), hν, room temp., 6 h.
On the basis of spectral analysis, the structure of this prod- that even the pure solid compounds changed to oils within
uct was established as the substituted 1H-1-benzazepine a short span of time (≈ 12–24 h) at room temperature.
10a. The formation of 1H-1-benzazepine 10a indicates that Furthermore, this phenomenon was accelerated if com-
the aromatic amino group attacks the carbon bearing the pounds were left on a silica gel column. As compared to
oxime as observed earlier.[20] The presence of the meth- the starting 1H-1-benzazepine, the new product was more
oxycarbonyl group instead of the ethoxycarbonyl group at polar by TLC analysis. Purification, isolation, and charac-
the 3-position of the 1H-1-benzazepine ring was attributed terization by detailed NMR spectroscopy led to the elucida-
to the transesterification of the ethoxycarbonyl moiety due tion of the structure of these products as substituted isoqui-
to the use of methanol as the solvent in the reaction. In nolines 17a–b,18–20a. Although the oxidation of N-methyl-
order to examine the general applicability of this reaction, benzazepines to naphthyl-1-amine[32] and the acid-pro-
other substrates 7b–d,8–9a were also subjected to moted rearrangement of 1H-1-benzazepine-2,5-dione to
SnCl2·2H2O-promoted reductions in methanol or ethanol. 2,4-dihydroxyquinoline[33] have been previously reported,
Interestingly, similar to 7a, compounds 7b,8–9a afforded the ring contraction of 1H-1-benzazepines to isoquinoline
the corresponding 1H-1-benzazepines 10b,11–12a, but com- derivatives is unprecedented. However, we are unable to
pounds 7c–d yielded 3H-benzazepines 14c–d instead of the propose a mechanism for this unusual observation at the
expected products. At this stage of the study, we reasoned present time. Nevertheless, with the objective to understand
that the substitution of the phenyl ring could have some the possible reason behind such an unusual rearrangement,
role in the outcome of the reactions, since compounds 7c– we carried out a set of experiments with 10a. Table 1 sum-
d had electron-donating substituents on the phenyl ring. Re- marizes the results of these experiments. It is evident from
markably, we found that the transesterification was chemo- this study that the 1H-benzazepines are stable only when
selective, since only the ethoxycarbonyl group originating stored at a temperature below 0 °C in the dark. Since the
from the ethyl nitroacetate was affected, whereas no such transformation of a 1H-1-benzazepine to an isoquinoline
phenomenon was observed with the other ester moiety pres- proceeded smoothly on silica gel, compounds 10a–b,11–13a
ent in the substrate. The reduction of 8a indeed resulted in were treated with silica gel at room temperature under UV
the formation of the product 13a when the reaction was light for 6 h or normal light for 24 h to furnish the corre-
performed in ethanol. In our efforts to provide chemical sponding isoquinoline derivatives 17a–b,18–20a in excellent
evidence of the formation of a substituted 1H-1-benzazep- yields. In contrast to the behavior of 1H-1-benzazepine de-
ine, 10a was treated with acetyl chloride and benzoyl chlo- rivatives, the 3H-1-benzazepine derivatives were stable at
ride separately to furnish the N-substituted products 15 and room temperature.
16, respectively. It was interesting to note that both of these
The second phase of our study relates to the similar re-
products were obtained as a mixture of rotational isomers duction of a nitro group in substrates resulting from the
(endo and exo forms). This observation has literature prece- SN2Ј reaction of nitroethane with the acetyl derivatives of
dence since it has been reported that the hindered rotation Baylis–Hillman adducts 4a,c–d,5a. Compounds 21a,c–d,22a
about the N–C, owing to its partial double bond character, were prepared following the literature procedure. In con-
leads to steric interactions in amides where the nitrogen is trast to the reactions with ethyl nitroacetate, all reactions
disubstituted.[31]
with nitromethane led to the isolation of unexpected prod-
During the course of this work, we observed that the 1H- ucts along with the expected nitro derivatives (Scheme 2).
1-benzazepine derivatives 10a–b,11–13a were unstable, and The spectroscopic analysis led us to elucidate the structure
Eur. J. Org. Chem. 2007, 2970–2976
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2971

V. Singh, S. Batra
FULL PAPER
Table 1. Results of the transformation of 1H-1-benzazepine 10a to ter 3 h, as exemplified in a model reaction with compound
isoquinoline 17a under various conditions, monitored for 12 h by
22a, we could isolate 27 in addition to the usual product
26a.
HPLC.[a]
Entry Conditions for reactions of 10a % Yield of 10a % Yield of 17a
1
2
3
4
5
6
7
8
9
10
CCl4, dark, r.t.
CCl4, AIBN, hν, r.t.
CCl4, hν, r.t.
CCl4, silica gel, hν, r.t.
silica gel, open flask, r.t.
silica gel, hν, r.t.
silica gel, darkness, r.t.
AIBN, toluene, reflux
left at 0 °C under nitrogen
left at 0 °C
100
3
80
0
30
0
30
5
–
28
4
31
37
100
70
45
–
Conclusion
In summary, we have demonstrated a facile approach for
the synthesis of substituted 1H-1-benzazepines and 3H-1-
benzazepines by the SnCl2-mediated reduction of nitro
groups in the 2-nitro-4-(2-nitrobenzylidene)alkanoates and
4-nitro-2-(2-nitroalkylidene)alkanoates afforded by the
SN2Ј reaction of ethyl nitroacetate and nitroethane with the
acetyl derivatives of Baylis–Hillman adducts deriving from
2-nitro-substituted benzaldehydes. The protocol described
herein is impressive due to the easy availability of starting
materials and simple reaction conditions. We have, for the
first time, discovered the unusual rearrangement of an alkyl
1H-1-benzazepine-2-carboxylate to an isoquinoline deriva-
tive.
100
100
–
[a] HPLC was performed with an RP C-18 column (250ϫ4.5 mm,
5 µ) with a gradient of 10–100% methanol in 0.1% TFA/H2O over
25 min at a flow rate of 1 mL/min.
of these unexpected products as naphthalenes 23a,c–d,24a.
The formation of naphthalenes by the SNAr reaction of ni-
tro derivatives of Baylis–Hillman derivatives is known in
the literature.[34–35] Subsequent reduction of nitro groups in
compounds 21a,c–d,22a with SnCl2·2H2O at reflux was
complete in 24 h and furnished the corresponding products,
which were determined to be 3H-1-benzazepine derivatives
25a,c–d,26a. In contrast to the observation made with the
derivatives of ethyl nitroacetate, the substitution pattern of
the phenyl ring played no role in the outcome of these reac-
tions. The long reaction time was in line with our earlier
observation, where we found that the reduction of the ali-
Experimental Section
General: Melting points were recorded with a hot-stage melting
point apparatus and are uncorrected. IR spectra were recorded
with an FTIR spectrophotometer. H and 13C NMR spectra were
1
recorded with a 200 MHz, 300 MHz, or 600 MHz spectrometer
with TMS as an internal standard. Mass spectra were recorded
with FAB or LCMS and an ES probe. HRMS spectra were re-
corded as EI-HRMS. All the solvents and chemicals were used as
procured from the suppliers. Compounds 23–24a were previously
phatic nitro group was slower than the reduction of the aro- reported in the literature.[35] Due to their unstable behavior, 10a–
matic nitro group.[20] Indeed, if the reduction is arrested af-
b,11–13a were not subjected to chemical analyses or HR-EIMS.
HPLC was performed with an RP C-18 column (250ϫ4.5 mm, 5 µ)
with a gradient of 10–100% methanol in 0.1% TFA/H2O over
25 min at a flow rate of 1 mL/min.
General Procedure for the Preparation of Compounds 7a–d, 8–9a,
21,23a,c–d, 22,24a, as Exemplified for Compound 7a: To a stirred
solution of compound 4a (1.5 g, 5.38 mmol) in DMF (10 mL) was
added ethyl nitroacetate (0.73 mL, 6.56 mmol) and K2CO3 (1.11 g,
8.06 mmol) at room temperature, and the reaction was allowed to
proceed for 4 h. The reaction mixture was acidified to pH5 with
concentrated aqueous HCl and extracted with EtOAc (3ϫ40 mL).
The organic layers were pooled, washed with brine (50 mL), dried
(anhydrous Na2SO4), and evaporated to yield a residue, which was
purified by silica gel column chromatography employing hexane/
EtOAc (80:20, v/v) to afford 1.14 g (83% yield) of product 7a as a
yellow oil.
1-Ethyl 5-Methyl 2-Nitro-4-[(E)-(2-nitrophenyl)methylidene]pen-
tanedioate (7a): IR (neat): ν = 1716 (CO Et), 1740 (CO Me) cm–1.
˜
2
2
1H NMR (200 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 3 H,
CH3CH2), 3.18 (d, J = 7.5 Hz, 2 H, CH2CH), 3.89 (s, 3 H,
CO2CH3), 4.19 (q, J = 7.2 Hz, 2 H, CH2CH3), 5.60 (t, J = 7.5 Hz,
1 H, CHNO2), 7.24–7.28 (m, 1 H, ArH), 7.59–7.63 (m, 1 H, ArH),
7.68–7. 73 (m, 1 H, ArH), 8.19 (s, 1 H, =CH), 8.24–8.28 (m, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 29.2, 51.3, 86.4,
125.6, 127.9, 130.1, 130.9, 131.4, 134.3, 141.9, 147.6, 164.3, 165.7
ppm. FAB-MS: m/z = 353 [M + 1]+. C15H16N2O8 (352.29): calcd.
C 51.14, H 4.58, N 7.95; found C 51.06, H 4.64, N 7.76.
Scheme 2. Reagents and conditions: i. EtNO2, K2CO3, DMF, room
temp., 3 h; ii. SnCl2·2H2O, MeOH or EtOH, N2, reflux, 24 h; iii.
SnCl2·2H2O, MeOH, N2, reflux, 4 h.
5-Ethyl 1-Methyl 2-[(E)-(5-Chloro-2-nitrophenyl)methylidene]-4-ni-
tropentanedioate (7b): 1.5 g (78% yield) as a yellow oil. IR (neat):
2972
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2970–2976

Synthesis of Substituted Benzazepines
ν = 1719 (CO Et), 1750 (CO Me) cm–1. 1H NMR (300 MHz, (m, 1 H, CHNO2), 7.23–7.28 (m, 1 H, ArH), 7.56–7.61 (m, 1 H,
FULL PAPER
˜
2
2
CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H, CH3CH2), 3.17–3.20 (m, 1
ArH), 7.69–7.74 (m, 1 H, ArH), 8.12 (s, 1 H, =CH), 8.20–8.24 (m,
H, 1H of CH2CH), 3.86–3.89 (m, 1 H, 1H of CH2CH), 3.90 (s, 3 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.6, 31.9, 51.2,
H, CO2CH3), 4.22 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.58–5.61 (m, 1 80.3, 123.8, 126.7, 128.4, 129.3, 132.0, 132.6, 139.8, 146.0, 165.4
H, CHNO2), 7.25–7.33 (m, 1 H, ArH), 7.55–7.59 (m, 1 H, ArH), ppm. FAB-MS: m/z = 295 [M + 1]+. C13H14N2O6 (294.26): calcd.
8.12 (s, 1 H, ArH), 8.23 (s, 1 H, =CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.5, 27.5, 33.7, 51.5, 62.0, 84.5, 124.6, 125.4, 128.6,
129.0, 131.2, 140.0, 144.2, 162.4, 164.9 ppm. FAB-MS: m/z = 387
[M + 1]+. C15H15ClN2O8 (386.74): calcd. C 46.58, H 3.91, N 7.24;
found C 46.63, H 3.67, N 7.13.
C 53.06, H 4.80, N 9.52; found C 53.67, H 4.41, N 9.49.
Methyl (E)-3-(6-Nitro-1,3-benzodioxol-5-yl)-2-(2-nitropropyl)prop-
2-enoate (21c): 1.8 g (60% yield) as a yellow oil. IR (neat): ν = 1715
˜
(CO2Me) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.40 (d, J =
6.6 Hz, 3 H, CH3CH), 2.69–2.77 (m, 1 H, 1H of CH2CH), 2.92–
2.3.00 (m, 1 H, 1H of CH2CH), 3.87 (s, 3 H, CO2CH3), 4.86–4.93
(m, 1 H, CHNO2), 6.02 (s, 2 H, OCH2O), 6.59 (s, 1 H, ArH), 7.71
(s, 1 H, ArH), 8.04 (s, 1 H, =CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.5, 31.9, 51.2, 80.3, 102.3, 104.5, 107.7, 125.9, 126.2,
139.6, 140.3, 147.2, 151.1, 165.5 ppm. FAB-MS: m/z = 339 [M +
1]+. C14H14N2O8 (338.26): calcd. C 49.71, H 4.17, N 8.28; found C
49.98, H 3.94, N 8.05.
1-Ethyl 5-methyl 2-nitro-4-[(E)-(6-nitro-1,3-benzodioxol-5-yl)methyl-
idene]pentanedioate (7c): 1.68 g (72% yield) as a yellow oil. IR
(neat):
ν =
˜
1709 (CO2Et), 1739 (CO2Me) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.18–
3.22 (m, 2 H, CH2CH), 3.89 (s, 3 H, CO2CH3), 4.22 (q, J = 7.2 Hz,
2 H, CH2CH3), 5.59–5.64 (m, 1 H, CHNO2), 6.21 (s, 2 H, OCH2O),
6.62 (s, 1 H, ArH), 7.75 (s, 1 H, ArH), 8.11 (s, 1 H, =CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.5, 27.5, 51.4, 61.9, 84.5, 102.3,
104.6, 107.6, 123.8, 125.9, 140.3, 141.9, 147.3, 151.1, 162.7, 165.3
ppm. FAB-MS: m/z = 397 [M + 1]+. C16H16N2O10 (396.30): calcd.
C 48.49, H 4.07, N 7.07; found C 48.61, H 3.89, N 7.31.
Methyl (E)-3-(4,5-Dimethoxy-2-nitrophenyl)-2-(2-nitropropyl)prop-
2-enoate (21d): 1.8 g (61% yield) as a yellow solid, m.p. 130–132 °C.
1
IR (KBr): ν = 1715 (CO Me) cm–1. H NMR (300 MHz, CDCl ):
˜
2
3
δ = 1.42 (d, J = 6.6 Hz, 3 H, CH3CH), 2.67–2.85 (m, 2 H, CH2CH),
3.87 (s, 3 H, CO2CH3), 3.98 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3),
4.94–5.01 (m, 1 H, CHNO2), 6.54 (s, 1 H, ArH), 7.75 (s, 1 H, ArH),
8.07 (s, 1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.6,
32.6, 51.2, 55.2, 55.4, 80.3, 106.5, 110.3, 124.0, 125.9, 138.5, 140.5,
147.7, 152.3, 165.6 ppm. FAB-MS: m/z = 355 [M + 1]+.
5-Ethyl 1-Methyl 2-[(E)-(4,5-Dimethoxy-2-nitrophenyl)methylidene]-
4-nitropentanedioate (7d): 1.1 g (75% yield) as a yellow oil. IR
(neat):
ν =
˜
1706 (CO2Et), 1755 (CO2Me) cm–1. 1H NMR
(200 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.18
(d, J = 7.9 Hz, 2 H, CH2CH), 3.89 (s, 3 H, CO2CH3), 3.99 (s, 3 H,
OCH3), 4.00 (s, 3 H, OCH3), 4.22 (q, J = 7.2 Hz, 2 H, CH2CH3),
5.71 (t, J = 7.9 Hz, 1 H, CHNO2), 6.63 (s, 1 H, ArH), 7.79 (s, 1 H,
ArH), 8.15 (s, 1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
12.5, 27.8, 51.3, 55.2, 55.5, 61.9, 84.6, 106.6, 110.1, 123.7, 123.8,
138.5, 141.9, 147.8, 152.3, 162.6, 165.4 ppm. FAB-MS: m/z = 413
[M + 1]+. C17H20N2O10 (412.34): calcd. C 49.52, H 4.89, N 6.79;
found C 49.73, H 5.66, N 6.89.
C
15H18N2O8 (354.31): calcd. C 50.85, H 5.12, N 7.91; found C
50.88, H 5.29, N 8.06.
Ethyl (E)-3-(2-Nitrophenyl)-2-(2-nitropropyl)prop-2-enoate (22a):
1.6 g (73% yield) as a yellow oil. IR (neat): ν = 1709 (CO Et) cm–1.
˜
2
1H NMR (300 MHz, CDCl3): δ = 1.36–1.41 (m, 6 H, CH3CH and
CH3CH2), 2.73 (dd, J = 5.7 Hz, J = 5.8 Hz, 1 H, 1H of CH2CH),
2.93 (dd, J = 8.3 Hz, J = 7.9 Hz, 1 H, 1H of CH2CH), 4.34 (q, J
= 7.2 Hz, 2 H, CH2CH3), 4.89–4.92 (m, 1 H, CHNO2), 7.24–7.28
(m, 1 H, ArH), 7.56–7.61 (m, 1 H, ArH), 7.69–7.72 (m, 1 H, ArH),
8.12 (s, 1 H, =CH), 8.21–8.24 (m, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.6, 19.3, 33.6, 62.0, 82.0, 125.5, 129.1,
130.0, 131.1, 134.3, 141.1, 147.8, 166.7 ppm. FAB-MS: m/z = 309
[M + 1]+. C14H16N2O6 (308.28): calcd. C 54.54, H 5.23, N 9.09;
found C 54.37, H 5.26, N 8.91.
Diethyl
2-Nitro-4-[(E)-(2-nitrophenyl)methylidene]pentanedioate
(8a): 1.34 g (80% yield) as a yellow oil. IR (neat): ν = 1709 (CO Et)
˜
2
cm–1. H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H,
1
CH3CH2), 1.38 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.18–3.21 (m, 2 H,
CH2CH), 4.20 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.37 (q, J = 7.2 Hz,
2 H, CH2CH3), 5.60–5.65 (m, 1 H, CHNO2), 7.27–7.30 (m, 1 H,
ArH), 7.60–7.63 (m, 1 H, ArH), 7.71–7.73 (m, 1 H, ArH), 8.19 (s,
1 H, =CH), 8.26–8.28 (m, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.2, 14.6, 62.1, 63.5, 86.3, 125.6, 126.6, 130.2, 130.9,
131.2, 134.3, 142.5, 147.6, 164.3, 166.4 ppm. FAB-MS: m/z = 367
[M + 1]+. C16H18N2O8 (366.32): calcd. C 52.46, H 4.95, N 7.65;
found C 52.33, H 5.11, N 7.74.
Methyl 8-Methylnaphtho[2,3-d][1,3]dioxole-6-carboxylate (23c):
Column chromatography with hexane/EtOAc, 90:10, v/v; 0.54 g
(25% yield) as a pale yellow solid, m.p. 152–154 °C. IR (KBr): ν =
˜
1
1722 (CO2Me) cm–1. H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3
H, CH3), 3.96 (s, 3 H, CO2CH3), 6.07 (s, 2 H, OCH2O), 7.17 (s, 1
H, ArH), 7.24 (s, 1 H, ArH), 7.77 (s, 1 H, ArH), 8.24 (s, 1 H, ArH)
ppm. 13C NMR (75 MHz, CDCl3): δ = = 18.5, 50.8, 99.4, 100.2,
104.2, 123.5, 124.2, 126.9, 128.4, 131.2, 132.2, 146.4, 148.3, 166.2
ppm. FAB-MS: m/z = 245 [M + 1]+. C14H12O4 (244.24): calcd. C
68.85, H 4.95; found C 68.86, H 4.99.
5-(tert-Butyl) 1-Ethyl 2-Nitro-4-[(E)-(2-nitrophenyl)methylidene]pen-
tanedioate (9a): 1.9 g (77% yield) as a yellow oil. IR (neat): ν =
˜
1
1706 (CO2tBu), 1713 (CO2Et) cm–1. H NMR (200 MHz, CDCl3):
δ = 1.25 (t, J = 7.2 Hz, 3 H, CH3CH2), 1.57 [s, 9 H, CO2-
C(CH3)3], 3.13 (d, J = 7.6 Hz, 2 H, CH2CH), 4.19 (q, J = 7.2 Hz,
2 H, CH2CH3), 5.54 (t, J = 7.6 Hz, 1 H, CHNO2), 7.20–7.31 (m,
1 H, ArH), 7.51–7.78 (m, 2 H, ArH), 8.07 (s, 1 H, =CH), 8.26 (d,
J = 8.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 28.5,
29.2, 63.5, 82.8, 86.4, 87.4, 125.5, 127.9, 130.0, 131.5, 134.3, 141.7,
147.7, 164.4, 165.5 ppm. FAB-MS: m/z = 395 [M + 1]+.
C18H22N2O8 (394.37): calcd. C 54.82, H 5.62, N 7.10; found C
65.71, H 5.84, N 6.82.
Methyl 6,7-Dimethoxy-4-methyl-2-naphthoate (23d): 0.61 g (28%
yield) as a brown solid, m.p. 114–116 °C. IR (KBr): ν = 1728
˜
(CO2Me) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.63 (s, 3 H,
CH3), 3.94 (s, 3 H, CO2CH3), 3.99 (s, 3 H, OCH3), 4.02 (s, 3 H,
OCH3), 7.15 (s, 1 H, ArH), 7.19 (s, 1 H, ArH), 7.77 (s, 1 H, ArH),
8.29 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.3,
50.7, 54.6, 101.5, 106.7, 123.1, 124.0, 126.5, 127.1, 129.7, 131.6,
148.2, 149.8, 166.4 ppm. FAB-MS: m/z = 261 [M + 1]+. C15H16O4
(260.28): calcd. C 69.22, H 6.20; found C 69.41, H 6.17.
Methyl (E)-3-(2-Nitrophenyl)-2-(2-nitropropyl)prop-2-enoate (21a):
1.92 g (69% yield) as a yellow solid, m.p. 92–94 °C. IR (KBr): ν =
˜
1
1742 (CO2Me) cm–1. H NMR (300 MHz, CDCl3): δ = 1.39 (d, J
= 6.7 Hz, 3 H, CH3CH), 2.68–2.75 (m, 1 H, 1H of CH2CH), 2.89– General Procedure for the Preparation of Compounds 10a–b,11–
2.96 (m, 1 H, 1H of CH2CH), 3.88 (s, 3 H, CO2CH3), 4.88–4.91 13a,14c–d, Exemplified for Compound 10a: To a solution of com-
Eur. J. Org. Chem. 2007, 2970–2976
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2973

V. Singh, S. Batra
FULL PAPER
pound 7a (0.8 g, 2.27 mmol) in methanol (10 mL) was added
SnCl2·2H2O (2.56 g, 11.36 mmol), and the reaction mixture was
heated at reflux with stirring at 80 °C for 2 h under a nitrogen at-
mosphere. Upon completion, methanol was evaporated, and the
residue was made alkaline with saturated aqueous NaHCO3, and
then EtOAc (100 mL) was added. The suspension was passed
through a bed of Celite, and the filtrate was partitioned in a separa-
tory funnel. The organic layer was separated, dried (anhydrous
Na2SO4), and concentrated to afford a residue, which was purified
by silica gel column chromatography with hexane/EtOAc (90:10,
v/v or 80:20, v/v) as the eluent to yield 0.32 g (55%) of product 10a
as a black solid.
OCH2O), 6.91 (s, 1 H, ArH), 7.06 (s, 1 H, ArH), 7.73 (s, 1 H, =CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 28.4, 51.1, 51.4, 82.3, 91.7,
99.3, 99.8, 104.8, 118.9, 128.5, 137.2, 142.2, 145.2, 163.5, 164.1
ppm. ESI-MS: m/z = 304.0 [M + 1]+. C15H13NO6 (303.26): calcd.
C 59.41, H 4.32, N 4.62; found C 59.21, H 4.59, N 4.48.
Dimethyl 7,8-Dimethoxy-3H-1-benzazepine-2,4-dicarboxylate (14d):
0.41 (7% yield) as a yellow oil. IR (neat): ν = 1732 (CO Me) cm–1.
˜
2
1H NMR (300 MHz, CDCl3): δ = 3.26 (s, 2 H, CH2), 3.87 (s, 3 H,
CO2CH3), 3.95 (s, 3 H, CO2CH3), 3.96 (s, 6 H, 2ϫOCH3), 4.05 (s,
2 H, CH2), 6.91 (s, 1 H, ArH), 7.11 (s, 1 H, ArH), 7.79 (s, 1 H,
=CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.6, 51.1, 52.1, 54.8,
54.9, 109.6, 110.2, 120.2, 135.7, 140.1, 145.9, 146.5, 148.9, 162.2,
164.2 ppm. ESI-MS: m/z = 320.0 [M + 1]+. C16H17NO6 (319.30):
calcd. C 60.18, H 5.37, N 4.39; found C 60.03, H 5.49, N 4.50.
Dimethyl 1H-1-Benzazepine-2,4-dicarboxylate (10a): M.p. 110–
1
112 °C. IR (KBr): ν = 1731 (CO Me), 3350 (NH) cm–1. H NMR
˜
2
(300 MHz, CDCl3): δ = 3.80 (s, 3 H, CO2CH3), 3.81 (s, 3 H,
CO2CH3), 5.35 (s, 1 H, NH), 6.23 (d, J = 7.9 Hz, 1 H, ArH), 6.42
(s, 1 H, ArH), 6.78–6.80 (m, 2 H, ArH), 7.05–7.08 (m, 1 H, ArH),
7.32 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 51.0,
51.6, 114.2, 118.7, 122.6, 126.9, 128.7, 131.7, 131.8, 136.2, 144.5,
148.2, 162.1, 164.4; ESI-MS: m/z = 260.1 [M + 1]+.
General Procedure for the Preparation of Compounds 25a,c–d,26a:
These compounds were prepared following the experimental pro-
cedure described for compound 10a except that heating was contin-
ued for 12 h.
Methyl 2-Methyl-3H-1-benzazepine-4-carboxylate (25a): 0.63 g
(58% yield) as a brown oil. IR (neat): ν = 1733 (CO Me) cm–1. 1H
˜
2
Dimethyl 7-Chloro-1H-1-benzazepine-2,4-dicarboxylate (10b):
NMR (300 MHz, CDCl3): δ = 2.36 (s, 3 H, CH3), 2.87 (s, 2 H,
CH2), 3.88 (s, 3 H, CO2CH3), 7.22–7.25 (m, 1 H, ArH), 7.41–7.48
(m, 3 H, ArH), 7.79 (s, 1 H, =CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.1, 32.2, 51.0, 116.2, 117.2, 122.8, 125.9, 127.6,
129.7, 135.7, 146.8, 162.1, 164.9 ppm. ESI-MS: m/z = 216.1 [M +
1]+. C13H13NO2 (215.24): calcd. C 72.54, H 6.09, N 6.51; found C
72.47, H 5.97, N 6.66.
0.44 g (58% yield) as a black solid, m.p. 103–105 °C. IR (KBr): ν
˜
1
= 1709 (CO2Me), 3329 (NH) cm–1. H NMR (300 MHz, CDCl3):
δ = 3.80 (s, 6 H, 2ϫCO2CH3), 5.35 (s, 1 H, NH), 6.24 (d, J =
7.8 Hz, 1 H, ArH), 6.40 (s, 1 H, ArH), 6.74 (s, 1 H, ArH), 7.02 (d,
J = 7.8 Hz, 1 H, ArH), 7.20 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 51.1, 51.7, 114.0, 119.8, 127.7, 128.5, 130.0,
130.9, 136.5, 142.7, 146.8, 162.0, 164.1; ESI-MS: m/z = 294.1 [M
+ 1]+, 296.1 [M+3]+.
Methyl 6-Methyl-7H-[1,3]dioxolo[4,5-h][1]benzazepine-8-carboxyl-
ate (25c): 0.66 (51% yield) as a yellow oil. IR (neat): ν = 1723
˜
(CO2Me) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.34 (s, 3 H,
CH3), 2.84 (s, 2 H, CH2), 3.93 (s, 3 H, CO2CH3), 6.00 (s, 2 H,
OCH2O), 6.76 (s, 1 H, ArH), 6.84 (s, 1 H, ArH), 7.48 (s, 1 H, =CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 26.0, 31.6, 49.7, 81.9, 90.7,
99.2, 99.7, 104.5, 119.3, 128.2, 138.0, 143.4, 144.2, 164.8 ppm. ESI-
MS: m/z = 260.3 [M + 1]+. C14H13NO4 (259.25): calcd. C 64.86, H
5.05, N 5.40; found C 64.70, H 4.98, N 5.42.
4-Ethyl 2-Methyl 1H-1-Benzazepine-2,4-dicarboxylate (11a): 0.56 g
(54% yield) as a black solid, m.p. 98–100 °C. IR (KBr): ν = 1711
˜
(CO2Et), 1731 (CO2Me), 3350 (NH) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.36 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.81 (s, 3 H,
CO2CH3), 4.26 (s, 2 H, CH2CH3), 5.35 (s, 1 H, NH), 6.32 (d, J =
7.9 Hz, 1 H, ArH), 6.44 (s, 1 H, ArH), 6.79–6.80 (m, 2 H, ArH),
7.05–7.10 (m, 1 H, ArH), 7.32 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.6, 53.2, 61.6, 116.1, 120.3, 124.2, 128.7,
130.7, 133.3, 133.4, 137.8, 145.9, 149.9, 164.4, 166.2 ppm. ESI-MS:
m/z = 274.1 [M + 1]+.
Methyl 7,8-Dimethoxy-2-methyl-3H-1-benzazepine-4-carboxylate
(25d): 0.61 (53% yield) as a brown oil. IR (neat): ν = 1728 (CO Me)
˜
2
cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.33 (s, 3 H, CH3), 2.84
(s, 2 H, CH2), 3.85 (s, 3 H, CO2CH3), 3.91 (s, 3 H, OCH3), 3.93 (s,
3 H, OCH3), 6.84 (s, 1 H, ArH), 6.92 (s, 1 H, ArH), 7.70 (s, 1 H,
=CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.8, 32.3, 50.9, 54.6,
54.7, 108.1, 110.1, 118.9, 119.2, 135.2, 142.0, 148.7, 151.8, 159.5
ppm. ESI-MS: m/z = 276.2 [M + 1]+. C15H17NO4 (275.29): calcd.
C 65.44, H 6.22, N 5.09; found C 65.66, H 6.25, N 4.90.
4-(tert-Butyl) 2-Methyl 1H-1-Benzazepine-2,4-dicarboxylate (12a):
0.48 g (45% yield) as a black oil. IR (neat): ν = 1706 (CO tBu),
˜
2
1
1722 (CO2Me), 3424 (NH) cm–1. H NMR (300 MHz, CDCl3): δ
= 1.55 [s, 9 H, C(CH3)3], 3.79 (s, 3 H, CO2CH3), 5.36 (s, 1 H, NH),
6.33 (d, J = 7.8 Hz, 1 H, ArH), 6.45 (s, 1 H, ArH), 6.74 (s, 1 H,
ArH), 6.79–6.81 (m, 2 H, ArH), 7.05–7.09 (m, 1 H, ArH), 7.26 (s,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.8, 51.5, 115.0,
118.6, 122.5, 127.1,130.4, 131.4, 1315, 135.8, 143.4, 148.2, 163.1
ppm. ESI-MS: m/z = 302.0 [M + 1]+.
Ethyl 2-Methyl-3H-1-benzazepine-4-carboxylate (26a): 0.62 g (56%
1
yield) as a yellow oil. IR (neat): ν = 1703 (CO Et) cm–1. H NMR
˜
2
(300 MHz, CDCl3): δ = 1.39 (t, J = 7.2 Hz, 3 H, CH3CH2), 2.35
(s, 3 H, CH3), 2.85 (s, 2 H, CH2), 4.33 (q, J = 7.2 Hz, 2 H,
CH2CH3), 7.19–7.24 (m, 1 H, ArH), 7.41–7.48 (m, 3 H, ArH), 7.78
(s, 1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.0, 26.0,
32.1, 60.0, 122.6, 123.2, 125.9, 126.0, 127.5, 129.6, 135.4, 148.6,
162.2, 164.4 ppm. ESI-MS: m/z = 230.1 [M + 1]+. C14H15NO2
(229.27): calcd. C 73.34, H 6.59, N 6.11; found C 73.19, H 6.41, N
5.88.
Diethyl 1H-1-Benzazepine-2,4-dicarboxylate (13a): 0.38 g (62%
yield) as a black oil. IR (neat): ν = 1714 (CO Et), 3352 (NH) cm–1.
˜
2
1H NMR (300 MHz, CDCl3): δ = 1.28–1.36 (m, 6 H, 2ϫCH3CH2),
4.22–4.29 (m, 4 H, 2ϫCH2CH3), 5.38 (s, 1 H, NH), 6.32 (d, J =
7.9 Hz, 1 H, ArH), 6.44 (s, 1 H, ArH), 6.78–6.80 (m, 2 H, ArH),
7.05–7.10 (m, 1 H, ArH), 7.35 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.9, 13.0, 59.9, 60.8, 114.2, 118.7, 122.5,
127.0, 129.5, 131.6, 131.7, 136.4, 144.1, 148.3, 161.7, 164.4 ppm.
ESI-MS: m/z = 288.0 [M + 1]+.
Ethyl (E)-3-(2-Aminophenyl)-2-(2-nitropropyl)prop-2-enoate (27):
0.50 g (37% yield) as a yellow oil. IR (neat): ν = 1713 (CO Et)
˜
2
Dimethyl 7H-[1,3]Dioxolo[4,5-h][1]benzazepine-6,8-dicarboxylate cm–1. H NMR (300 MHz, CDCl3): δ = 1.44 (d, J = 6.7 Hz, 3 H,
1
(14c): 0.58 g (54 % yield) as a black oil. IR (neat): ν = 1738 CH3CH), 2.86 (dd, J = 5.7 Hz, J = 5.8 Hz, 1 H, 1H of CH2CH),
˜
(CO2Me) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.24 (s, 2 H, 3.21 (dd, J = 8.3 Hz, J = 7.9 Hz, 1 H, 1H of CH2CH), 4.31 (q, J
CH2), 3.88 (s, 3 H, CO2CH3), 3.95 (s, 3 H, CO2CH3), 6.10 (s, 2 H,
2974
= 7.2 Hz, 2 H, CH2CH3), 4.85–4.92 (m, 1 H, CHNO2), 6.72–6.81
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2970–2976

Synthesis of Substituted Benzazepines
FULL PAPER
(m, 2 H, ArH), 6.98 (d, J = 7.5 Hz, 1 H, ArH), 7.14–7.20 (m, 1 H,
Dimethyl 6-Chloroisoquinoline-1,3-dicarboxylate (17b): 0.14 g (75%
ArH), 7.78 (s, 1 H, =CH) ppm. 13C NMR (75 MHz, CDCl3): δ = yield) as a yellow oil. IR (neat): ν = 1732 (CO Me) cm–1. 1H NMR
˜
2
12.9, 17.5, 32.0, 60.0, 80.7, 114.5, 117.2, 119.1, 127.5, 128.2, 128.7,
138.8, 143.1, 165.6 ppm. ESI-MS: m/z = 279.2 [M + 1]+.
C14H18N2O4 (278.30): calcd. C 60.42, H 6.52, N 10.07; found C
60.31, H 6.66, N 9.84.
(300 MHz, CDCl3): δ = 0.96 (s, 3 H, CO2CH3), 4.06 (s, 3 H,
CO2CH3), 7.78 (d, J = 8.0 Hz, 1 H, ArH), 8.02 (s, 1 H, ArH), 8.70
(s, 1 H, ArH), 8.89 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 51.1, 51.7, 119.8, 124.3, 126.9, 128.5, 131.0,
131.8, 136.5, 144.2, 147.3, 162.0, 164.2 ppm. ESI-MS: m/z = 280.1
[M + 1]+. HRMS (EI): Calcd. for C13H10ClNO4 279.0298; found
279.0296.
General Procedure for the Preparation of Compounds 15–16, Exem-
plified for Compound 15: To a stirred solution of compound 10a
(0.15 g, 0.58 mmol) in dry dichloromethane (5 mL) was added
Et3N (0.121 mL, 0.87 mmol), and the reaction was allowed to con-
tinue for 20 min at 0 °C. Thereafter, acetyl chloride (1.16 g,
1.0 mmol) was added to the reaction mixture at the same tempera-
ture, and the stirring was continued for another 2 h at room tem-
perature. Upon completion (monitored by TLC), the mixture was
extracted with water and dichloromethane. The organic layer was
separated and dried (Na2SO4), and the solvents were evaporated to
dryness to yield the crude product, which was purified by silica gel
column chromatography with hexane/EtOAc (70:30, v/v) to yield
0.16 g (92%) of pure product 15 as a pale yellow solid.
3-Ethyl 1-Methyl Isoquinoline-1,3-dicarboxylate (18a): 0.212 (78%
yield) as a pale yellow solid, m.p. 85–87 °C, IR (KBr): ν = 1712
˜
(CO2Et), 1740 (CO2Me) cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.51 (t, J = 7.2 Hz, 3 H, CH3CH2), 4.13 (s, 3 H, CO2CH3), 4.56
(q, J = 7.2 Hz, 2 H, CH2CH3), 7.78–7.87 (m, 2 H, ArH), 8.37–8.40
(m, 1 H, ArH), 8.69 (s, 1 H, ArH), 8.83 (d, J = 1.2 Hz, 1 H, ArH)
ppm. 13C NMR (150 MHz, CDCl3): δ = 14.3, 53.4, 62.2, 122.1,
125.5, 126.3, 130.3, 130.5, 131.2, 136.6, 147.5, 148.6, 165.4, 165.6
ppm. ESI-MS: m/z = 260.0 [M + 1]+. HRMS (EI): Calcd. for
C14H13NO4 259.0845; found 259.0847.
Dimethyl 1-Acetyl-1H-1-benzazepine-2,4-dicarboxylate (15, rotamer
ratio of 1:2, as evident from 1H NMR): M.p. 144–146 °C. IR (KBr):
Diethyl Isoquinoline-1,3-dicarboxylate (19a): 0.29 (82% yield) as a
pale yellow oil, IR (neat): ν = 1723 (CO Et) cm–1 1H NMR
.
˜
2
ν = 1710 (COMe), 1735 (CO Me) cm–1 1H NMR (300 MHz,
.
˜
2
(300 MHz, CDCl3): δ = 1.46–1.55 (m, 6 H, 2ϫCH3CH2), 4.49–
4.64 (m, 4 H, 2ϫCH2CH3), 7.74–7.88 (m, 2 H, ArH), 8.39 (d, J =
8.2 Hz, 1 H, ArH), 8.66 (s, 1 H, ArH), 8.84 (d, J = 8.2 Hz, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.0, 13.1, 60.9, 61.2,
120.8, 124.2, 125.0, 128.9, 129.1, 130.1, 135.2, 146.6, 147.4, 163.6,
164.4 ppm. ESI-MS: m/z = 274.1 [M + 1]+. HRMS (EI): Calcd.
for C15H15NO4 273.1001; found 273.1002.
CDCl3): δ = 1.85 (s, 3 H, OCOCH3), 2.05 (s, 3 H, OCOCH3), 3.85
(s, 3 H, CO2CH3), 3.89 (s, 3 H, CO2CH3), 3.90 (s, 3 H, CO2CH3),
3.92 (s, 3 H, CO2CH3), 7.39–7.57 (m, 6 H, 2ϫ3ArH), 7.62–7.68
(m, 2 H, 2ϫ1ArH), 7.68 (s, 1 H, ArH), 7.78 (s, 1 H, ArH), 8.21 (s,
1 H, ArH), 8.30 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 19.7, 19.9, 51.3, 51.4, 51.5, 51.6, 126.1, 126.5, 126.6, 127.0, 127.3,
127.7, 127.8, 129.4, 129.9, 130.0, 130.4, 131.0, 131.6, 131.7, 131.8,
138.5, 138.8, 140.7, 143.6, 161.5, 161.8, 164.6, 164.7, 168.3, 168.6
ppm. ESI-MS: m/z = 302.0 [M + 1]+. HRMS (EI): Calcd. for
C16H15NO5 301.0950; found 301.0954.
3-(tert-Butyl) 1-Methyl Isoquinoline-1,3-dicarboxylate (20a): 0.40 g
(77% yield) as a pale yellow oil, IR (neat): ν = 1703 (CO tBu),
˜
2
1733 (CO2Me) cm–1. H NMR (300 MHz, CDCl3): δ = 1.71 [s, 9
1
H, C(CH3)3], 4.12 (s, 3 H, CO2CH3), 7.34–7.87 (m, 2 H, ArH), 8.36
(d, J = 8.1 Hz, 1 H, ArH), 8.56 (s, 1 H, ArH), 8.73 (d, J = 8.1 Hz,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.8, 52.0, 82.3,
120.4, 124.2, 125.0, 128.7, 129.1, 129.9, 137.2, 147.2, 163.7, 164.2
ppm. ESI-MS: m/z = 287.9 [M + 1]+. HRMS (EI): Calcd. for
C16H17NO4 287.0058; found 287.0059.
Dimethyl 1-Benzoyl-1H-1-benzazepine-2,4-dicarboxylate (16, rot-
amer ratio of 1:2, as evident from H NMR): 0.13 g (96% yield) as
1
an off-white solid, m.p. 164–166 °C. IR (KBr): ν = 1707 (COPh),
˜
1
1738 (CO2Me) cm–1. H NMR (300 MHz, CDCl3): δ = 3.93 (s, 3
H, CO2CH3), 3.96 (s, 3 H, CO2CH3), 4.11 (s, 3 H, CO2CH3), 4.14
(s, 3 H, CO2CH3), 7.11–7.26 (m, 8 H, 2ϫ4ArH), 7.27–7.38 (m, 8
H, 2ϫ4ArH), 7.44–7.46 (m, 1 H, ArH), 7.52–7.55 (m, 1 H, ArH),
7.68 (s, 1 H, ArH), 7.73 (s, 1 H, ArH), 8.35 (s, 1 H, ArH), 8.40 (s,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 51.2, 51.4, 51.5,
51.6, 126.3, 126.4, 126.6, 126.8, 126.9, 127.2, 127.3, 127.6, 128.1,
128.5, 129.1, 129.4, 129.8, 131.1, 131.2, 131.3, 131.5, 132.5, 133.5,
138.1, 140.1, 141.0, 143.9, 161.5, 161.6, 164.7, 164.9, 168.3, 168.6
ppm. FAB-MS: m/z = 364 [M + 1]+. HRMS (EI): Calcd. for
C21H17NO5 363.1107; found 363.1105.
Supporting Information (see also the footnote on the first page of
1
this article): Copies of H NMR, 13C NMR, and mass spectra of
several new compounds are being provided. Copies of HSQC and
HMBC spectra for compound 18a is also provided.
Acknowledgments
One of the authors (V. S.) acknowledges the financial support from
the Department of Science and Technology (DST), New Delhi, in
the form of a fellowship. This work was supported by a financial
grant from DST. The authors acknowledge Dr. R. Roy and Dr. A.
Arora for carrying out the NOESY, HMBC, and HSQC experi-
ments.
General Procedure for the Preparation of Compounds 17a–b,18–20a,
Exemplified for 17a: To a solution of compound 10a (0.2 g,
0.77 mmol) in dichloromethane (1.0 mL) was added silica gel (60–
120 mesh, 0.1 g), and the mixture was evaporated to dryness. The
flask was exposed to a UV lamp (Philips, 500 W flash light) for
6 h. The silica gel was transferred to a column, and elution with
hexane/EtOAc (80:20, v/v) yielded 0.15 g (80%) of pure 17a as an
off-white solid.
[1] D. Basavaiah, A. Jaganmohan Rao, T. Satyanarayana, Chem.
Rev. 2003, 103, 811–890.
[2] T. P. Majhi, A. Neogi, S. Ghosh, A. K. Mukherjee, P. Chatto-
padhyay, Tetrahedron 2006, 62, 12003–12010.
[3] R. Rios, H. Sunden, I. Ibrahem, G.-L. Zhao, A. Cordova, Tet-
rahedron Lett. 2006, 47, 8679–8682.
[4] F. Coelho, D. Veronese, C. H. Pavam, V. I. de Paula, R. Buffon,
Tetrahedron 2006, 62, 4563–4572.
[5] S. Chandrasekhar, D. Basu, Ch. Rambabu, Tetrahedron Lett.
2006, 47, 3059–3063.
Dimethyl Isoquinoline-1,3-dicarboxylate (17a): Mp 118–120 °C. IR
1
(KBr): ν = 1742 (CO Me) cm–1. H NMR (300 MHz, CDCl ): δ =
˜
2
3
4.09 (s, 3 H, CO2CH3), 4.13 (s, 3 H, CO2CH3), 7.79–7.89 (m, 2 H,
ArH), 8.39 (d, J = 8.4 Hz, 1 H, ArH), 8.71 (s, 1 H, ArH), 8.87 (d,
J = 8.4 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 51.1,
51.9, 119.0, 122.6, 126.9, 128.8, 131.7, 131.8, 136.3, 144.5, 148.3,
162.2, 164.5 ppm. ESI-MS: m/z = 246.0 [M + 1]+. HRMS (EI):
Calcd. for C13H11NO4 245.0688; found 245.0687.
Eur. J. Org. Chem. 2007, 2970–2976
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2975

V. Singh, S. Batra
FULL PAPER
[6]
[22] Y. Aramaki, M. Seto, T. Okawa, T. Oda, N. Kanazaki, M. Shi-
raishi, Chem. Pharm. Bull. 2004, 52, 254–258.
[23] M. Seto, N. Miyamoto, K. Aikawa, Y. Aramaki, N. Kanazaki,
Y. Iizawa, M. Baba, M. Shiraishi, Bioorg. Med. Chem. 2005,
13, 363–368.
G. W. Kabalka, B. Venkataiah, C. Chen, Tetrahedron Lett.
2006, 47, 4187–4189.
L. Jean, A. Marinetti, Tetrahedron Lett. 2006, 47, 2141–2145.
P. Wasnaire, M. Wiaux, R. Touillaux, I. E. Marko, Tetrahedron
Lett. 2006, 47, 985–989.
J. Jayashankaran, R. Durga, R. S. Manian, M. Sivaguru, R.
Raghunathan, Tetrahedron Lett. 2006, 47, 5535–5538.
D. Basavaiah, R. J. Reddy, J. S. Rao, Tetrahedron Lett. 2006,
47, 73–77.
V. Singh, R. Saxena, S. Batra, J. Org. Chem. 2005, 70, 353–356.
R. Pathak, A. K. Roy, S. Batra, Synlett 2005, 848–850.
V. Singh, S. Batra, Synthesis 2006, 63–72.
[7]
[8]
[24] J. R. Szewczyk, K. H. Donaldson, US Patent 2006003991,
2006.
[9]
[25] H. J. Teuber, G. Emmerich, Tetrahedron Lett. 1970, 11, 4069–
[10]
4070.
[26] V. N. Gogte, K. M. More, B. D. Tilak, Ind. J. Chem. 1974, 12,
1238–1241.
[27] E. Gonzalez, Bull. Chem. Soc. Fr. 1993, 130, 143–145.
[28] J. S. Yadav, B. V. Subba Reddy, M. K. Gupta, A. Prabhakar, B.
Jagadeesh, Chem. Commun. 2004, 2124–2125.
[29] W. M. Abdou, A. A. Kamel, M. D. Khidre, Synth. Commun.
2004, 34, 4119–4134.
[30] W. M. Abdou, N. A. Ganoub, A. F. Fahmy, A. M. Shaddy,
Heteroat. Chem. 2005, 16, 56–64.
[31] G. V. Garner, O. Meth-Cohn, H. Suschitzky, J. Chem. Soc., C
1971, 1234–1236.
[11]
[12]
[13]
[14] S. Nag, R. Pathak, M. Kumar, P. K. Shukla, S. Batra, Bioorg.
Med. Chem. Lett. 2006, 16, 3824–3828.
[15] V. Singh, G. P. Yadav, P. R. Maulik, S. Batra, Tetrahedron 2006,
62, 8731–8739.
[16] R. Pathak, S. Nag, S. Batra, Synthesis 2006, 4205–4211.
[17] R. Pathak, S. Madapa, S. Batra, Tetrahedron 2007, 63, 451–
460.
[18] S. Madapa, V. Singh, S. Batra, Tetrahedron 2006, 62, 8740–
[32] B. Kharraz, P. Uriac, S. Sinbandhit, L. Toupet, Tetrahedron
1996, 52, 4423–4434.
8747.
[19] V. Singh, S. Batra, Tetrahedron Lett. 2006, 47, 7043–7045.
[20] V. Singh, S. Kanojiya, S. Batra, Tetrahedron 2006, 62, 10100–
10110.
[21] R. D. Fabio, F. Micheli, D. Baraldi, B. Bertani, N. Conti, G. D.
Forno, A. Feriani, D. Donati, C. Marchioro, T. Messeri, A.
Missio, A. Pasquarello, G. Pentassuglia, D. A. Pizzi, S. Provera,
A. M. Quaglia, F. M. Sabbatini, Il Farmaco 2003, 58, 723–738.
[33] T. A. Geissman, A. K. Cho, J. Org. Chem. 1959, 24, 41–43.
[34] K. Y. Lee, S. Gowrisankar, Y. J. Lee, J. N. Kim, Tetrahedron
2006, 62, 8798–8804 and references cited therein.
[35] J. N. Kim, Y. J. Im, J. H. Gong, K. Y. Lee, Tetrahedron Lett.
2001, 42, 4195–4197.
Received: February 25, 2007
Published Online: April 23, 2007
2976
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2970–2976