Reductive-cyclization-mediated synthesis of fused polycyclic quinolines from Baylis-Hillman adducts of acrylonitrile: Scope and limitations

Article abstract of DOI:10.1002/ejoc.200900336

The synthesis of a variety of polycyclic quinolines is described. The target: molecules were obtained in two steps by an initial reductive cyclization followed by another intramolecular cyclization in the allylamines afforded from either the acetates or a

Full text of DOI:10.1002/ejoc.200900336

FULL PAPER
DOI: 10.1002/ejoc.200900336
Reductive-Cyclization-Mediated Synthesis of Fused Polycyclic Quinolines from
Baylis–Hillman Adducts of Acrylonitrile: Scope and Limitations[‡]
Virender Singh,[a] Samiran Hutait,[a] and Sanjay Batra*[a]
Dedicated to Professor Raymond C. F. Jones on his 60th birthday
Keywords: Cyclization / Nitrogen heterocycles / Annulation / Polycycles
The synthesis of a variety of polycyclic quinolines is de-
scribed. The target molecules were obtained in two steps by
an initial reductive cyclization followed by another intramo-
lecular cyclization in the allylamines afforded from either the
acetates or allyl bromides of Baylis–Hillman adducts of 2-ni-
trobenzaldehydes and acrylonitrile. The two steps proceeded
in one-pot for those substrates in which a formyl or hydroxy
group reacted with the amino group of the 2-aminoquinoline
in the second intramolecular cyclization. In contrast, a basic
medium was necessary for the second intramolecular cycliza-
tion reaction in substrates in which an alkoxycarbonyl group
and the amino group participated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
vantage of the participation of the aromatic amino group
and the carbonyl group originating from Baylis–Hillman
derivatives of 2-nitrobenzaldehyde and acrylates or (cyclo)-
alkenones. On the other hand, the participation of the aro-
matic amino group and the nitrile group in the Baylis–Hill-
man derivatives of 2-nitrobenzaldehyde and acrylonitrile,
respectively, remains unexplored. However, the literature
provides a precedence: Wang et al. accomplished the syn-
thesis of 2-aminoquinoline by Fe/AcOH-mediated intramo-
lecular reductive cyclization of a derivative of 2-nitrobenzal-
dehyde with participation of the nitrile functionality.[4] Ow-
ing to our continuing interest in developing general strate-
gies for furnishing aza-heterocycles by Baylis–Hillman
chemistry, we considered it worthwhile to investigate the
potential of the Baylis–Hillman derivatives of 2-nitrobenz-
aldehydes and acrylonitrile to afford polycyclic quinoline
systems by reductive cyclization as the key step.
A retrosynthetic analysis showed that quinoline-annu-
lated architecture containing at least three different ring
systems could easily be constructed from appropriate allyl-
amines afforded from the Baylis–Hillman adduct of 2-ni-
trobenzaldehyde and acrylonitrile (Figure 1). More import-
antly the Z stereochemistry of the allylamines generated
from these reactants would assist the envisaged cyclization
reactions. In principle, the SN2Ј reaction of a nucleophilic
species such as imidazole-2-carbaldehyde with the acetyl de-
rivative I or the SN2 reaction of the nucleophile with the
allyl bromide II of the aforementioned adduct would lead
to substrate III, which upon reduction of the aromatic nitro
group may trigger a domino process involving two success-
ive intramolecular cyclizations to furnish the polycyclic sys-
Introduction
Heterocyclic chemistry plays an important rôle in chemi-
cal research owing to the importance of a variety of hetero-
cycles in the pharmaceutical, agrochemical and electronic
industries. Amongst heterocyclic systems, the synthesis of
new polycyclic systems, especially those incorporating privi-
leged scaffolds, is of great interest owing to their resem-
blance to natural products. In this context, several elegant
synthetic protocols involving, for example, multicomponent
reactions, transition-metal-catalyzed cyclizations and ring-
closing metathesis have been developed. Nevertheless, new
alternative strategies to their access through cheap simpli-
fied routes are always desired and this has been reaffirmed
by Laird recently.[1]
Owing to their great biological properties, compounds
containing the quinoline system have been the subject of
several synthetic studies.[2] Reductive cyclization is an effec-
tive protocol for efficiently producing novel quinoline deriv-
atives.[2d] Recently, the application of this methodology to
the substrates afforded by Baylis–Hillman chemistry has re-
sulted in the disclosure of many new quinoline derivatives.[3]
Notably, however, the majority of these syntheses take ad-
[‡] CDRI Communication no. 7610.
[a] Medicinal and Process Chemistry Division, Central Drug Re-
search Institute,
P.O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405
+91-522-2623938
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900336.
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Synthesis of Fused Polycyclic Quinolines
tem V. Alternatively, using a proline ester as the nucleo-
philic partner in place of imidazole-2-carbaldehyde would
give VIII by a similar series of reactions. Consequently, we
have now carried out a detailed study with a view to under-
standing the scope and limitations of this strategy for the
synthesis of diverse polycyclic quinoline systems from dif-
ferently substituted allylamines. Herein, we report the re-
sults of this endeavour, which can now be treated as a gene-
ral and practical approach to such new polycyclic quino-
lines.
Scheme 1. Reagents and conditions: i) PBr3, CH2Cl2, 0 °C–room
temp., 3 h; ii) AcCl, pyridine, CH2Cl2, 0 °C–room temp., 30 min.
4a was observed to be Z with no trace of the E isomer.
Alternatively, substitution of imidazole-2-carbaldehyde
with allyl bromide 3a in the presence of K2CO3 in DMF
for 4 h resulted in isolation of the desired allylamine 4a in
33% yield. The relative stereochemistry of this product was
assigned as Z with minor amounts of the E isomer. In an
attempt to enhance the yield of 4a it was decided to initially
perform the SN2Ј–SN2Ј displacement reaction with imid-
azole-2-carbaldehyde in the presence of DABCO in an
aqueous medium and then subject the resulting product to
1,3-migration under suitable conditions to generate 4a. Ac-
cordingly, compound 2a was treated with imidazole-2-car-
baldehyde in the presence of DABCO in a mixture of THF/
H2O (1:1, v/v) at room temperature. The reaction was com-
plete in 4 h and normal work-up followed by purification
resulted in the product in 54% yield (Scheme 2). The spec-
troscopic data of the product was identical to that of 4a
formed only as the Z isomer. Next we screened several
metal-based reducing agents under different conditions to
carry out reduction of the aromatic nitro group that would
eventually trigger the intended domino process leading to
the polycyclic quinoline system (see the Supporting Infor-
mation). Heating the substrate 4a in the presence of Fe and
AcOH led to a clean reaction. The usual work-up followed
by triturating the afforded residue furnished a solid product
(57%), the structure of which was delineated as 5a. On the
Figure 1. Retrosynthetic strategy for the generation of polycyclic
quinolines.
Results and Discussion
In the first instance the Baylis–Hillman reaction between basis of this result, the proposed mechanism for the forma-
differently substituted 2-nitrobenzaldehydes and acryloni- tion of 5a is presented in Figure 2. The isolation of 5a im-
trile was performed to obtain 1a–f.[5] These reactions were plies that initially the reductive cyclization takes place as
carried out neat and were extremely fast, being complete in expected followed by another intramolecular cyclization by
less than 2 h. Acetylation of 1a–f with acetyl chloride in the Schiff base formation between the generated 2-amino group
presence of pyridine provided the acetates 2a–f in 88–95% of the resulting quinoline unit and the formyl functionality
yields (Scheme 1). On the other hand, allyl bromides 3a,c– of the imidazole group. Subsequently, the reaction condi-
f were prepared from the reaction of 1a,c–f with PBr3 in tions induce reduction of the double bond of the intermedi-
CH2Cl2 in 76–91% yields.[6] Products 3a,c–f were obtained ate imine leading to the final product. Even the reaction in
as mixtures of the E and Z isomers, which were not sepa- the presence of Zn and AcOH was clean, but the isolated
rated due to their close proximity on the TLC plate.
yield (49%) of 5a was observed to be slightly lower. Inter-
Compounds 2a and 3a were simultaneously evaluated as estingly, the reaction of 4a with In and HCl yielded a mix-
the starting substrates for exploring the optimal conditions ture of two products, which were readily separated by col-
for the substitution of imidazole-2-carbaldehyde. The SN2Ј umn chromatography. One of the products isolated in 5%
reaction of imidazole-2-carbaldehyde in the presence of yield was identified as 5a whereas the major product af-
K2CO3 in DMF for 3 h resulted in a mixture of products forded in 35% yield was identified as 6. With standardized
from which 30% of 4a was isolated. The stereochemistry of conditions in hand, we investigated the reaction of sub-
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Scheme 2. Reagents and conditions: i) DABCO, THF/H2O (1:1, v/v), room temp., 4 h; ii) K2CO3, DMF, room temp., 1.5 h; iii) Fe, AcOH,
N2, 120 °C, 1.5 h; iv) In, HCl, THF/H2O (1:1, v/v), room temp., 45 min.
strates 4b–f with Fe and AcOH at 120 °C for 1.5 h to obtain simultaneously. The usual processing and purification of
the quinoline derivatives. We noted that all the compounds the reaction mixture from 2a resulted in the product 7a in
4b–f furnished the corresponding products 5b–f in moder- 55% yield as the Z isomer, whereas the reaction of 3a re-
ate-to-good yields.
sulted in the isolation of 7a in 60% yield as a mixture of
the Z (97%) and E (3%) isomers (Scheme 3). No attempt
to separate the isomeric mixture was made at this stage.
Compound 7a obtained by both routes was reduced with
Fe and AcOH at 100 °C for 1.5 h. However, purification of
the crude product by column chromatography was tedious
and furnished the pure product in around 30% yield in both
cases. The structure of the isolated product was established
as 8a, which implies that the anticipated second intramolec-
ular cyclization reaction did not occur during the reaction.
To assess the possibility of an intramolecular cyclization in
8a, it was treated with NaH in THF at room temperature;
this reaction was complete in 1 h.
Figure 2. Mechanism for the formation of 5.
Scheme 3. Reagents and conditions: i) K2CO3, DMF, room temp.,
1.5 h; ii) Et3N, DIEA, MeOH, 70 °C, 3 h; iii) Fe, AcOH, N2,
100 °C, 1.5 h; iv) NaH, THF, 0 °C–room temp., 1 h.
Because the formyl group of the imidazole readily par-
ticipated in the intramolecular cyclization with the amino
group, in the next stage of the study it was reasoned that an
analogous system bearing an alkoxycarbonyl functionality
instead of a formyl group could also undergo concomitant
Because the purification of 8a was found to be cumber-
intramolecular cyclizations upon reduction of the nitro some it was decided to subject the crude material contain-
group. To investigate this approach, it was decided to em- ing 8a, afforded after work-up, directly to the NaH-pro-
ploy -proline ester as the nucleophilic partner in the substi- moted cyclization. This strategy was found to successfully
tution reaction to obtain the required starting substrate.
furnish compound 9a in 43% yield. Significantly, no race-
Thus, 2a was treated with the proline methyl ester in the mization was observed during the formation of 9a. Owing
presence of K2CO3 in DMF, whereas 3a was treated with to the better yield of 7a achieved from 3a than from 2a,
the same nucleophile in the presence of Et3N in methanol different allyl bromides 3c–f were subjected to a similar set
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Synthesis of Fused Polycyclic Quinolines
of reactions to investigate the generality of the protocol. In THF furnished the product 17a (37% in two steps). The
all cases the polycyclic quinolines 9c–f were isolated, al- stereochemistry of the product was established to be trans
though in yields of only 47–51%.
on the basis of a NOESY experiment, which indicates that
Buoyed by this success, next we decided to investigate the ring-closure reaction was also stereoselective. During
the scope of this approach with an analogous allylamine this reaction sequence too we did not observe racemization
synthesized from the reaction between the ethyl ester deriv- in any of the products. This was substantiated by subjecting
ative of the β-carboline 10 obtained from -tryptophan fol- substrate 14d to similar reactions, which afforded 17d (46%)
lowing the reported procedure.[7] Here, too, 2a and 3a were stereoselectively.
simultaneously treated with 10 in the presence of K2CO3 in
Until now our attempts to synthesize polycyclic quino-
THF and yielded the desired allylamine 11a in 91 and 80% lines was restricted to the use of tertiary allylamines gener-
yields, respectively. Fortunately, both reactions were found ated by nucleophilic substitution of a secondary amine and
to stereoselectively yield only the Z isomer. Treatment of the Baylis–Hillman derivative. It was therefore considered
11a with Fe in AcOH at 120 °C resulted in the product 12a, important to examine the reactions of secondary allyl-
which was immediately subjected to NaH-promoted ring- amines generated by the SN2Ј reaction between a primary
closure to furnish the desired product 13a (68%) stereo- allylamine and the Baylis–Hillman derivative. To this end,
selectively without racemization (Scheme 4). This clearly in- acetate 2a was allowed to react with the glycine ethyl ester
dicates that the presence of the alkoxycarbonyl group does in the presence of Et3N in MeOH to yield 18 (85%) in 1 h
not facilitate the second intramolecular cyclization until the (Scheme 6). Reductive cyclization of 18 with Fe and AcOH
base has been added. The suitability of this strategy for the at 100 °C for 30 min resulted in the formation of the prod-
generation of polycyclic quinoline was further exemplified uct 19 (50%). Treatment of 19 with NaH in THF as solvent,
by using 2e. The SN2Ј reaction of 2e with 10 resulted in the however, resulted in the formation of an inseparable mix-
allylamine 11e (79%). Fe/AcOH-mediated reductive cycliza- ture of products. Unfortunately, several repetitions of this
tion followed by base-promoted intramolecular cyclization reaction failed to provide any isolable product. The failure
produced 13e (73%).
to produce 20 indicates that our protocol is probably lim-
ited to allylamines with a tertiary nitrogen atom. On this
basis we decided to install a tosyl group onto the NH group
in compound 18 and investigate this strategy.
Thus, compound 21 was prepared by the reaction of 18
with TsCl in the presence of Et3N in CH2Cl2 in 84% yield.
Heating 21 with Fe and AcOH at 100 °C for 30 min yielded
a product that was characterized as 22 (82%). Compound
22 underwent the desired cyclization in the presence of
NaH within 1 h to afford 23 albeit in a low yield (30%).
Encouraged by this outcome it was proposed to introduce
functional groups onto the NH of 18 that could participate
in intramolecular cyclization reactions with the generated
amino group. Hence, it was decided to substitute the amino
hydrogen atom with ethoxycarbonyl and nitrile groups
using ethyl chloroformate and cyanogen bromide, respec-
tively. The reaction of compound 18 with ethyl chloro-
Scheme 4. Reagents and conditions: i) K2CO3, DMF, room temp.,
4 h; ii) Fe, AcOH, N2, 120 °C, 1.5 h; iii) NaH, THF, 0 °C–reflux,
1 h.
Encouraged by the successful formation of 13, we de- formate furnished 24 (93%), whereas with cyanogen bro-
cided to evaluate the feasibility of similar products by ini- mide it produced 25 (87%). The reductive cyclization of 24
tiating the reaction with tetrahydro-β-carboline substituted in the presence of Fe and AcOH at 100 °C gave the product
at the 1-position. It is widely reported that tetrahydro-β- 26 (75%). Further treatment of 26 with NaH in THF at
carbolines substituted at the 1-position synthesized by the room temperature for 1 h, followed by work-up and purifi-
Pictet–Spengler reaction are obtained as a mixture of cis cation resulted in the isolation of the product in 90% yield,
and trans products.[8] It is also reported that if the trypto- identified as 27 on of the basis of its spectroscopic data.
phan ester is first N-alkylated and then subjected to the This indicates that the second intramolecular cyclization in
Pictet–Spengler reaction it leads to the formation of the 26 was regioselective, with the alkoxycarbonyl group di-
trans isomer exclusively.[8b] On the basis of these reports, we rectly attached to the nitrogen participating in the cycliza-
first treated 2a with the tryptophan methyl ester in MeOH, tion. However, unlike other substrates in which alkoxycar-
which stereoselectively gave the Z isomer of 14a (77%) in bonyls participate in the second cyclization, the reduction
1 h (Scheme 5). Pictet–Spengler reaction of 14a with benz- of 25 with Fe and AcOH by heating at reflux for 1.5 h af-
aldehyde in 2% TFA in DCM smoothly afforded the trans forded a product that was delineated to be 28 (88%). This
isomer of 15a. The stereochemistry of 15a was ascertained implies that the reduction of the aromatic nitro group in 25
by NOESY spectroscopy. Heating 15a in the presence of initiated a domino process. The transformation of the nitrile
Fe and AcOH at 120 °C resulted in the formation of 2- group into an amide functionality in 28 was attributed to
aminoquinoline 16a, which upon treatment with NaH in the acidic medium of the reaction mixture. Thus, it seems
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Scheme 5. Reagents and conditions: i) -tryptophan methyl ester, MeOH, room temp., 1 h; ii) PhCHO, 2% TFA in CH2Cl2, room temp.,
8 h; iii) NaH, THF, 0 °C–reflux, 1.0 h.
Scheme 6. Reagents and conditions: i) Et3N, MeOH, room temp., 1 h; ii) Fe, AcOH, N2, 100 °C, 30 min; iii) NaH, THF, 0 °C–reflux,
1 h; iv) TsCl, Et3N, DMAP, CH2Cl2, room temp., 15 h; v) ClCO2Et, Et3N, CH2Cl2, 0 °C–room temp., 1 h; vi) CNBr, K2CO3, dry THF,
room temp., 3 h; vii) Fe, AcOH, 120 °C, 1.5 h; viii) 2-nitrobenzaldehyde, H2O2, CAN, 50 °C, 15 h.
that the tertiary nature of allylamines is necessary to effect
Continuing with our studies, we tested the protocol with
the second intramolecular cyclization to obtain the annu- 30, which could be easily synthesized by a SN2Ј reaction
lated derivatives. In our attempt to demonstrate the use of between amino acetaldehyde dimethyl acetal and 2a, as re-
diamine 19 for providing a quinoline-annulated system, we ported previously.[10] It was expected that the amino group
performed the reaction between 19 and 2-nitrobenzalde- of 2-aminoquinoline would react with the protected alde-
hyde in the presence of CAN and H2O2, which led to 29 hyde in the presence of acetic acid to afford another quino-
(30%).[9]
line-annulated system. Hence 30 was prepared and sub-
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Synthesis of Fused Polycyclic Quinolines
Scheme 7. Reagents and conditions: i) MeOH, room temp., 1.0 h; ii) Fe, AcOH, N2, 100 °C, 1.5 h; iii) TsCl, Et3N, CH2Cl2, room temp.,
15 h; iv) Fe, AcOH, N2, 100 °C, 30 min; v) CHCl3, TFA/H2O (1:1), room temp., 5 d; vi) Fe, AcOH, N2, 100 °C, 30 min, then H2O, 100 °C,
15 h.
jected to the reduction in the presence of Fe and AcOH at reaction mixture led to isolation of the product in 49%
100 °C for 1.5 h. This reaction led to the formation of a yield. Spectroscopic evidence led to its assignment as 38a
mixture of products from which compound 31 was isolated without any racemization. The successful isolation of 38a
in only 15% yield (Scheme 7). Isomerization to yield the prompted us to repeat the sequence with substrate 2e. Un-
double bond between the C-2 and C-3 atoms was evident der identical reaction conditions, 2e afforded the annulated
1
from the H and 13C NMR spectra. Acetylation of the NH quinoline 38e (41%).
group would have occurred owing to the presence of AcOH.
Considering our preceding experience with secondary allyl-
amines, compound 30 was readily tosylated to generate 32
(85%). Further reaction of 32 with Fe and AcOH under
heating resulted in a product that was established as 33.
Thus it is apparent that the acidity of the medium was not
suited to unmasking the protected formyl group for further
reaction. Nevertheless treatment of 33 with a mixture of
CHCl3, TFA and water for 5 d showed the complete disap-
pearance of the starting material. Purification of the mix-
ture furnished a product that was established as 34 (35%).
Unlike 31, no isomerization of the double bond was ob-
served in this case. During the optimization of the reaction
we discovered another set of conditions for obtaining 34
directly from 32 in a shorter period of time. In this method,
after the treatment of 32 with Fe and AcOH for 30 min,
water was added to the reaction mixture and heating was Scheme 8. Reagents and conditions: i) MeOH, room temp., 1 h (for
tryptophan ester); K2CO3, DMF, room temp., 2 h (for phenylala-
continued for 15 h to give 34 in an isolable yield of 25%.
nine ester); ii) Fe, AcOH, N2, 100 °C, 1 h; iii) NaH, THF, 0 °C–
A critical analysis of the reactions studied up to this
reflux, 1 h.
point revealed that we had failed to achieve the quinoline-
annulated product whenever the amine group of the allyla-
To achieve greater variety, the tryptophan methyl ester
mine was secondary because the expected second intramo- was replaced by the phenylalanine ethyl ester as the nucleo-
lecular cyclization did not take place. Interestingly, it was phile for generating the allylamine. Hence 2a was treated
observed that for both substrates 18 and 30, the carbon with phenylalanine ethyl ester in the presence of K2CO3 in
adjacent to the nitrogen of the introduced nucleophile did DMF to afford 35 (47%; Scheme 8). Fe/AcOH-mediated re-
not carry any substitution. Therefore we decided to probe ductive cyclization at 100 °C was complete in 30 min to fur-
the scope of the protocol by installing a substituent on this nish 96% of 37. Treatment of 37 with NaH in THF at reflux
carbon atom. This could be readily accomplished by gener- gave 39 (66%). These results make it apparent that the sec-
ating allylamines from the esters of amino acids other than ond step of the protocol for the synthesis of annulated quin-
glycine. For this endeavour compound 14a synthesized ear- olines developed by us works better for secondary allyl-
lier was selected as the substrate. As expected, reductive cy- amines in which the carbon adjacent to the nitrogen of the
clization with Fe and AcOH at 100 °C for 1 h resulted in introduced nucleophile carry a substitution.
the formation of 36a (85%; Scheme 8). The subsequent re-
To further enhance the scope of our protocol, we investi-
action of 36a under optimized conditions was completed gated the participation of the hydroxy group in the second
with 10.0 equiv. of NaH under heating. Purification of the intramolecular cyclization. In principle, treatment of the
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Baylis–Hillman acetate with phthalimide would yield an al- was established to be 44 (86%). Unfortunately, attempts to
lylamine in which one of the amide carbonyl groups can be perform the intramolecular cyclization in the presence of p-
reduced to a secondary hydroxy group that may participate toluenesulfonic acid (pTSA) to afford 45 failed and the
in the second intramolecular cyclization.[11] It can be specu- starting was recovered.
lated that in the presence of AcOH the partially reduced
phthalimide can dehydrate to produce the N-acylinium ion,
Conclusions
which can be attacked by the amino group to produce the
desired polycyclic scaffold. Thus, 2a was treated with
phthalimide in the presence of K2CO3 in DMF to obtain
40 (85%) as a mixture of Z and E isomers (10:1; Scheme 9).
Reduction of 40 in the presence of NaBH4 resulted in the
formation of product 41 (60%) within 10 min. Treatment of
41 with Fe and AcOH at 120 °C resulted in the completion
of the reaction in 2 h and yielded a product that was delin-
eated to be 42 (70%). The formation of 42 established that
here too reduction of the aromatic nitro group triggered the
domino process.
We have disclosed the potential of allylamines originating
from the Baylis–Hillman adducts of 2-nitrobenzaldehydes
and acrylonitrile for the preparation of polycyclic quinoline
frameworks employing reductive cyclization as the key step.
The two-step synthetic protocol was found to be a domino
process involving two successive intramolecular cyclizations
triggered by the reduction of the aromatic nitro group in
the case of substrates bearing a formyl or hydroxy group.
In contrast, a similar two-step sequence for substrates bear-
ing an alkoxycarbonyl group was found to proceed through
an initial reductive cyclization followed by a base-promoted
second intramolecular cyclization. A study of the scope of
the approach indicates that tertiary allylic amines readily
follow the protocol to furnish the desired annulated quino-
lines. On the other hand, secondary allylamines bearing an
unsubstituted carbon adjacent to the nitrogen atom are un-
likely to undergo the second intramolecular cyclization in
contrast to secondary amines with a substituted carbon
atom adjacent to the nitrogen atom. Rapid access to the
starting substrates, simple reaction conditions and the di-
verse nature of nucleophiles that could be installed onto the
Baylis–Hillman derivatives makes this an attractive ap-
proach that could be exploited further to generate more di-
verse polycyclic quinolines.
Scheme 9. Reagents and conditions: i) K2CO3, DMF, room temp.,
2 h; ii) NaBH4, MeOH, room temp., 10 min; iii) Fe, AcOH, N2,
120 °C, 2 h.
Finally, we examined the suitability of this approach for
a substrate originating from the SN2Ј reaction of an oxygen
nucleophile bearing a suitable group for intramolecular cy-
clization. For example, the reaction of salicylaldehyde with
2a would yield a substrate that has the potential to partici-
pate in the intramolecular cyclization through the formyl
group. Accordingly, compound 43 (63%) was readily gener-
ated by the reaction between 2a and salicylaldehyde in the
presence of K2CO3 in DMF (Scheme 10). Reductive cycli-
zation with Fe and AcOH at 120 °C yielded a product that
Experimental Section
General: 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 Spec-
trum RX I FTIR spectrometer. 1H and 13C NMR spectra were
recorded with either a Bruker DPX-200 FT or an Avance DRX-
300 spectrometer using TMS as an internal standard (chemical
shifts are given as δ values). The ESMS were recorded with the
MICROMASS Quadro-II LCMS system. The HRMS spectra were
recorded as EI-HRMS spectra with a JEOL system or as DART-
HRMS spectra (recorded as ES+) with a JEOL-AccuTOF JMS-
T100LC mass spectrometer with a DART (Direct Analysis in Real
Time) source. The optical rotations were measured with an Autopol
III instrument, serial no 30166 from Rudolph. Elemental analyses
were performed with a Carlo–Erba 108 or an Elementar Vario EL
III microanalyzer.
General Procedure for the Synthesis of Compounds 4a–f as Exem-
plified for Compound 4a: DABCO (1.02 g, 9.14 mmol) was added
to a stirred solution of acetate 2a (1.5 g, 6.09 mmol) in a mixture
of THF/water (12 mL, 1:1, v/v) and stirring was continued for
15 min at room temperature. Thereafter, imidazole-2-carbaldehyde
(0.64 g, 6.7 mmol) was added and the reaction was allowed to pro-
ceed for 4 h. After completion of the reaction, as monitored by
TLC, THF was evaporated in vacuo and the residue was extracted
with EtOAc (8ϫ30 mL) and water (70 mL). The organic layers
were combined and washed with brine (50 mL), dried with Na2SO4
Scheme 10. Reagents and conditions: i) K2CO3, DMF, room temp.,
2 h; ii) Fe, AcOH, N2, 120 °C, 1 h; iii) pTSA, PhMe, reflux, 3 d.
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Eur. J. Org. Chem. 2009, 3454–3466

Synthesis of Fused Polycyclic Quinolines
and concentrated to yield the crude product. Purification by short
column chromatography using hexane/EtOAc (1:1, v/v) afforded
0.93 g (54%) of pure 4a as a yellowish brown solid.
(75 MHz, [D6]DMSO): δ = 38.7, 47.3, 118.5, 120.0, 123.2, 125.5,
125.9, 126.0, 126.7, 130.0, 136.0, 145.5, 146.1, 156.8 ppm. MS (ES):
m/z (%) = 271.2 (100) [M + 1]+, 273.2 (33) [M + 3]+. DART-HRMS
(ES+): calcd. for C14H11ClN4 271.0751; found 271.0744.
(Z)-2-[(2-Formyl-1H-imidazol-1-yl)methyl]-3-(2-nitrophenyl)prop-2-
enenitrile (4a): M.p. 153–155 °C; Rf = 0.68 (hexane/EtOAc, 30:70).
8,9-Dimethoxy-12,13-dihydro-5H-imidazo[1Ј,2Ј:1,2][1,4]diazepino-
[5,6-b]quinoline (5d): The title compound was prepared following
the above-described general procedure and after purification by
column chromatography [hexane/EtOAc, 1:1; Rf = 0.25 (MeOH/
CHCl3, 05:95)] was obtained as a yellowish brown solid (0.13 g
IR (KBr): ν
= 1678 (CHO), 2227 (CN) cm–1 1H NMR
.
˜
max
(300 MHz, CDCl3): δ = 5.42 (s, 2 H, CH2), 7.40 (d, J = 7.9 Hz, 2
H, ArHimid.), 7.61–7.78 (m, 4 H, ArH), 8.24 (d, J = 8.0 Hz, 1 H,
ArH), 9.87 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 48.4, 111.3, 115.9, 125.0, 127.5, 128.9, 130.7, 131.2, 131.6,
134.5, 142.8, 144.3, 147.0, 181.8 ppm. MS (ES+): m/z (%) = 283.1
(%) [M + 1]+, 315.0 (100) [M + 32]+. C14H10N4O3 (282.0753): calcd.
C 59.57, H 3.57, N 19.85; found C 59.73, H 3.46, N 19.97.
from 0.30 g); yield 49 %; m.p. Ͼ240 °C. IR (KBr): ν
= 3393
˜
max
(NH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 3.80 (s, 3 H,
OCH3), 3.82 (s, 3 H, OCH3), 4.55 (d, J = 4.8 Hz, 2 H, CH2NH),
5.38 (s, 2 H, CH2N), 6.76 (s, 1 H, ArHimid.), 6.84 (s, 1 H, ArHimid.),
7.05 (s, 1 H, ArH), 7.24 (s, 1 H, ArH), 7.75 (s, 1 H, ArH) ppm. 13
C
General Procedure for the Synthesis of Compounds 5b–f, 8a, 12a,
16a, 19, 22, 26, 28, 31, 33, 36a,e, 37, 42 and 44 as Exemplified for
the Compound 5a: Iron powder (0.54 g, 9.57 mmol) was added to a
solution of 4a (0.45 g, 1.60 mmol) in glacial acetic acid (10 mL)
and the reaction was heated at reflux at 120 °C whilst stirring under
nitrogen for 1.5 h. On completion, excess acetic acid was evapo-
rated in vacuo and the reaction mixture was poured into a 10%
aq. NaHCO3 solution whilst stirring with a glass rod. Then EtOAc
(50 mL) was added and the contents were passed through a bed of
Celite. The organic layer was separated and the aqueous layer was
extracted with EtOAc (5 ϫ 15 mL).The combined organic layers
were evaporated in vacuo and the residue was recrystallized from
EtOAc to furnish 0.21 g (57%) of 5a as a yellow solid.
NMR (75 MHz, [D6]DMSO): δ = 38.9, 47.5, 55.4, 55.5, 104.8,
106.2, 114.5, 116.8, 119.7, 125.7, 135.4, 144.0, 145.7, 146.1, 152.3,
155.2 ppm. MS (ES): m/z (%) = 297.2 (100) [M + 1]+. DART-
HRMS (ES+): calcd. for C16H16N4O2 297.1352; found 297.1330.
6,12-Dihydro-7H-[1,3]dioxolo[4,5-g]imidazo[1Ј,2Ј:1,2][1,4]diazepino-
[5,6-b]quinoline (5e): The title compound was prepared following
the above-described general procedure and after purification by
column chromatography [hexane/EtOAc, 1:1; Rf = 0.27 (MeOH/
CHCl3, 05:95)] was obtained as a yellowish brown solid (0.12 g
from 0.30 g); yield 47 %; m.p. Ͼ240 °C. IR (KBr): ν
= 3411
˜
max
(NH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 4.53 (d, J =
4.7 Hz, 2 H, CH2NH), 5.37 (s, 2 H, CH2N), 6.06 (s, 2 H, OCH2O),
6.76 (s, 1 H, ArHimid.), 6.82 (s, 1 H, ArHimid.), 7.08 (s, 1 H, ArH),
7.16 (t, J = 4.4 Hz, 1 H, NH), 7.23 (s, 1 H, ArH), 7.73 (s, 1 H,
ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 40.4, 47.3, 79.2,
101.2, 102.1, 103.0, 114.5, 117.8, 119.7, 125.7, 135.9, 143.9, 145.2,
145.6, 150.3, 155.3 ppm. MS (ES): m/z (%) = 281.2 (100) [M +
1]+. DART-HRMS (ES+): calcd. for C15H12N4O2 281.1039; found
281.1022.
12,13-Dihydro-5H-imidazo[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]quinoline
(5a): M.p. Ͼ240 °C; Rf = 0.27 (MeOH/CHCl3, 05:95). IR (KBr):
1
ν
= 3187 (NH) cm–1. H NMR (300 MHz, CDCl3): δ = 4.75 (s,
˜
max
2 H, CH2NH), 5.27 (s, 2H, CH2N), 5.81 (br. s, 1 H, NH), 6.95 (d,
J = 1.0 Hz, 1 H, ArHimid.), 6.99 (d, J = 1.0 Hz, 1 H, ArHimid.),
7.20–7.26 (m, 1 H, ArH), 7.57 (t, J = 8.5 Hz, 3 H, ArH), 7.76 (s,
1 H, ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 38.7, 47.4,
117.4, 119.8, 121.7, 122.5, 124.7, 125.9, 127.3, 129.6, 136.7, 145.6,
147.5, 156.4 ppm. MS (ES+): m/z (%) = 237.2 (100) [M + 1]+;
DART-HRMS (ES+): calcd. for C14H13N4 237.1140; found
237.1141.
13,14-Dihydro-8H-benzo[h]imidazo[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]-
quinoline (5f): The title compound was prepared following the
above-described general procedure and after purification by
crystallization using EtOAc [Rf = 0.41 (MeOH/CHCl3, 05:95)] was
obtained as a yellowish brown solid (0.10 g from 0.15 g); yield 74%;
10-Methoxy-12,13-dihydro-5H-imidazo[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]-
quinoline (5b): The title compound was prepared following the
above-described general procedure and after purification by
crystallization using EtOAc [Rf = 0.23 (MeOH/CHCl3, 05:95)] was
obtained as a yellowish brown solid (0.21 g from 0.50 g); yield 48%;
m.p. 240–242 °C. IR (KBr): ν
= 3244 (NH) cm–1 1H NMR
.
˜
max
(300 MHz, [D6]DMSO): δ = 4.66 (d, J = 4.8 Hz, 2 H, CH2NH),
5.50 (s, 2 H, CH2N), 6.79 (s, 1 H, ArHimid.), 7.27 (s, 1 H, ArHimid.),
7.52–7.62 (m, 5 H, ArH), 7.88 (t, J = 4.5 Hz, 1 H, ArH), 7.99 (s,
1 H, ArH), 8.87 (t, J = 4.5 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 38.7, 47.3, 116.1, 118.8, 119.9, 122.1,
123.7, 125.2, 125.8, 127.6, 129.2, 133.8, 137.1, 144.9, 145.6,
156.2 ppm. MS (ES): m/z (%) = 287.3 (100) [M + 1]+. EI-HRMS:
calcd. for C18H14N4 286.1218; found 286.1218.
m.p. Ͼ240 °C. IR (KBr): ν
= 3425 (NH) cm–1 1H NMR
.
˜
max
(300 MHz, [D6]DMSO): δ = 3.84 (s, 3 H, OCH3), 4.56 (d, J =
4.2 Hz, 2 H, CH2NH), 5.43 (s, 2 H, CH2N), 6.77 (s, 1 H, ArHimid.),
6.96 (t, J = 7.6 Hz, 1 H, ArH), 7.07 (t, J = 7.6 Hz, 1 H, ArH), 7.19
(d, J = 7.6 Hz, 1 H, ArH), 7.24 (s, 1 H, ArHimid.), 7.59 (br. s, 1 H,
NH), 7.88 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 38.7, 47.4, 55.3, 108.9, 117.5, 119.1, 119.8, 121.6, 123.3, 125.8,
136.8, 139.0, 145.7, 152.7, 155.7 ppm. MS (ES+): m/z (%) = 267.2
(100) [M + 1]+. EI-HRMS: calcd. for C15H14N4O 266.1168; found
266.1158.
2-Oxo-1,2,3,5-tetrahydro-4H-[1,4]diazepino[5,6-b]quinoline-4-car-
boxamide (28): The title compound was prepared following the
above-described general procedure and after purification by
crystallization with EtOAc [Rf = 0.35 (MeOH/CHCl3, 05:95)] was
obtained as a white solid (0.32 g from 0.45 g); yield 88%; m.p. 180–
8-Chloro-12,13-dihydro-5H-imidazo[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]-
quinoline (5c): The title compound was prepared following the
above-described general procedure and after purification by col-
umn chromatography [hexane/EtOAc, 45:55; Rf = 0.25 (MeOH/
182 °C. IR (KBr): νmax = 1696 (CONH) cm–1. 1H NMR (300 MHz,
˜
[D6]DMSO): δ = 3.97 (s, 2 H, CH2), 4.42 (s, 2 H, CH2), 6.35 (br.
s, 2 H, NH2), 7.16–7.20 (m, 1 H, ArH), 7.47 (d, J = 3.8 Hz, 2 H,
CHCl3, 05:95)] was obtained as a yellowish brown solid (0.19 g ArH), 7.68 (d, J = 8.1 Hz, 1 H, ArH), 7.85 (s, 1 H, ArH), 10.99 (s,
from 0.24 g); yield 78 %; m.p. Ͼ240 °C. IR (KBr): ν
= 3184
1 H, CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 42.3,
51.1, 118.4, 121.6, 123.1, 124.8, 127.6, 129.1, 135.3, 147.3, 156.3,
157.8, 171.8, 172.2 ppm. MS (ES): m/z (%) = 257.2 (100) [M +
1]+. C13H12N4O2 (256.0960): calcd. for C 60.93, H 4.72, N 21.86;
˜
max
(NH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 4.58 (d, J =
4.3 Hz, 2 H, CH2NH), 5.45 (s, 2 H, CH2N), 6.78 (s, 1 H, ArHimid.),
7.26 (s, 1 H, ArHimid.), 7.39–7.47 (m, 2 H, ArH), 7.62 (br. s, 1 H,
NH), 7.74 (s, 1 H, ArH), 7.90 (s, 1 H, ArH) ppm. 13C NMR found C 60.78, H 4.89, N 21.73.
Eur. J. Org. Chem. 2009, 3454–3466
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3461

V. Singh, S. Hutait, S. Batra
FULL PAPER
1-(1,5-Dihydro-4H-[1,4]diazepino[5,6-b]quinolin-4-yl)ethan-1-one
(31): The title compound was prepared following the above-de-
scribed general procedure and after purification by column
chromatography [MeOH/CHCl3, 03:97; Rf = 0.60 (MeOH/CHCl3,
NMR (300 MHz, [D6]DMSO): δ = 4.51 (d, J = 4.2 Hz, 2 H,
CH2OH), 5.22 (s, 2 H, CH2), 5.58 (br. s, 1 H, OH), 6.49 (br. s, 2
H, NH2), 6.88 (s, 1 H, ArHimid. and ArH), 7.11–7.17 (m, 2 H,
ArHimid.), 7.31 (s, 1 H, ArH), 7.49–7.56 (m, 3 H, ArH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 45.5, 55.9, 119.7, 121.1, 121.6,
122.8, 124.9, 127.0, 127.5, 129.2, 134.6, 147.2, 147.3, 155.8 ppm.
MS (ES): m/z (%) = 255.1 (100) [M + 1]+. C14H14N4O (254.1168):
calcd. C 66.13, H 5.55, N 22.03; found C 66.34, H 5.77, N 21.86.
10:90)] was obtained as a yellow solid (0.04 g from 0.30 g); yield
1
15%; m.p. Ͼ250 °C °C. IR (KBr): ν
= 1718 (COMe) cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 2.16 (s, 3 H, COCH3), 4.82 (s, 2 H,
CH2N), 5.66 (d, J = 7.0 Hz, 1 H, =CH), 5.85 (d, J = 7.0 Hz, 1 H,
=CH), 7.26–7.34 (m, 2 H, ArH and NH), 7.55–7.60 (m, J = 7.8 Hz,
1 H, ArH), 7.66 (d, J = 8.2 Hz, 2 H, ArH), 7.96 (s, 1 H, ArH) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 22.5, 47.5, 109.7, 116.8,
121.9, 123.9, 124.5, 125.7, 127.7, 130.3, 138.0, 146.8, 156.6,
168.8 ppm. MS (ES): m/z (%) = 240.2 (100) [M + 1]+. C14H13N3O
(239.1059): calcd. C 70.28, H 5.48, N 17.56; found C 70.17, H 5.39,
N 17.67.
General Procedure for the Synthesis of Compounds 7a,c,e–g as Ex-
emplified for Compound 7a: Et3N (0.53 mL, 3.77 mmol) was added
to a stirred solution of the proline methyl ester hydrochloride
(0.25 g, 1.51 mmol) in dry MeOH (6 mL) and the mixture was
stirred for 15 min at room temperature. Thereafter, DIEA
(0.13 mL, 0.83 mmol) was added followed by 3a (0.25 g,
1.51 mmol) and the reaction was heated at 70 °C whilst stirring for
3 h. After completion of the reaction, MeOH was evaporated in
vacuo and the residue was dissolved in CH2Cl2 and the slurry pre-
pared with silica-gel. Purification on a short column of silica gel
using hexane/ EtOAc (85:15, v/v) afforded 0.14 g (60%) of pure 7a
as a yellow oil.
6,13-Dihydroisoindolo[2Ј,1Ј:1,2]pyrimido[4,5-b]quinolin-11(6aH)-one
(42): The title compound was prepared following the above-de-
scribed general procedure and after purification by crystallization
with EtOAc [Rf = 0.50 (MeOH/CHCl3, 05:95)] was obtained as a
white solid (0.36 g from 0.60 g); yield 70%; m.p. Ͼ250 °C; [α]2D9
=
216 (c = 0.600, DMSO). IR (KBr): ν
= 1689 (CO) cm–1. 1H
˜
max
Methyl 1-[(Z)-2-Vyano-3-(2-nitrophenyl)prop-2-enyl]pyrrolidine-2-
carboxylate (7a): Yield: 60% (0.14 g from 0.20 g) as a yellow oil;
Rf = 0.62 (hexane/EtOAc, 70:30); [α]2D9 = –49 (c = 0.274, CHCl3).
NMR (300 MHz, [D6]DMSO): δ = 4.65 (d, J = 17.1 Hz, 1 H,
CHH), 5.26 (d, J = 17.1 Hz, 1 H, CHH), 5.97 (s, 1 H, CH), 7.22–
7.27 (m, 1 H, ArH), 7.49–7.58 (m, 2 H, ArH), 7.62 (d, J = 7.4 Hz,
1 H, ArH), 7.69–7.72 (m, 2 H, ArH), 7.76 (d, J = 7.8 Hz, 1 H,
ArH), 7.97 (d, J = 7.4 Hz, 1 H, ArH), 8.03 (s, 1 H, ArH), 8.29 (br.
s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 65.3,
115.5, 122.4, 123.1, 123.4, 124.0, 125.2, 127.4, 129.3, 129.6, 131.3,
132.2, 133.8, 143.1, 146.6, 153.5, 165.6 ppm. MS (ES): m/z (%) =
288.0 (100) [M + 1]+. C18H13N3O (287.1059): calcd. C 75.25, H
4.56, N 14.63; found C 75.40, H 4.67, N 14.45.
IR (neat): ν
= 1737 (CO2Me), 2221 (CN) cm–1 1H NMR
.
˜
max
(300 MHz, CDCl3): δ = 1.86–2.07 (m, 3 H, CH2 and CHH), 2.16–
2.22 (m, 1 H, CHH), 2.71 (q, J = 7.3 Hz, 1 H, CHH), 3.21–3.28
(m, 1 H, CHH), 3.50–3.57 (m, 2 H, CH2), 3.74 (s, 3 H, CO2CH3),
3.76–3.81 (m, 1 H, CH), 7.56–7.62 (m, 1 H, ArH), 7.66 (s, 1 H,
ArCH), 7.70–7.81 (m, 2 H, ArH), 8.18 (dd, J1 = 1.0, J2 = 8.1 Hz,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.6, 29.5, 52.0,
53.0, 57.0, 64.5, 114.5, 117.5, 125.2, 130.0, 130.5, 131.1, 134.3,
142.0, 147.3, 174.2 ppm. MS (ES): m/z (%) = 316.1 (100) [M +
1]+. C16H17N3O4 (315.1219): calcd. C 60.94, H 5.43, N 13.33; found
C 60.83, H 5.59, N 13.50.
2-[(2-Aminoquinolin-3-yl)methoxy]benzaldehyde (44): The title com-
pound was prepared following the above-described general pro-
cedure and after purification by column chromatography [MeOH/
CHCl3, 02:98; Rf = 0.43 (MeOH/CHCl3, 05:95)] was obtained as a
white solid (0.39 g from 0.50 g); yield 86%; m.p. 169–171 °C. IR
General Procedure for the Synthesis of Compounds 9a,c–f from
7a,c–f as Exemplified for Compound 9c: Iron powder (0.116 g,
2.06 mmol) was added to a solution of 7c (0.12 g, 0.34 mmol) in
glacial acetic acid (5 mL) and the reaction was heated at reflux at
120 °C whilst stirring under nitrogen for 1.5 h. On completion, ex-
cess acetic acid was evaporated in vacuo and the reaction mixture
was poured into a 10% NaHCO3 aq. solution whilst stirring with a
glass rod. EtOAc (15 mL) was added and the contents were passed
through a bed of Celite. The organic layer was partitioned and
separated and the aqueous layer was further extracted with EtOAc
(5ϫ15 mL). The combined organic layers were washed with brine,
dried with Na2SO4 and the solvents evaporated in vacuo to furnish
0.072 g of a yellow solid residue (8c). This residue was dissolved in
dry THF (3 mL) and NaH (0.016 g, 0.677 mmol) was added at 0 °C
and the reaction was stirred at room temp. for 1 h. On completion
of the reaction, as monitored by TLC, excess THF was evaporated
in vacuo and EtOAc (20 mL) was added. The reaction mixture was
poured into water (20 mL) and extracted further (5ϫ10 mL) with
EtOAc. The organic layers were combined and washed with brine
(20 mL), dried with Na2SO4 and concentrated in vacuo. The prod-
(KBr): νmax = 1659 (CHO), 3167 (NH2) cm–1. 1H NMR (300 MHz,
˜
[D6]DMSO): δ = 5.27 (s, 2 H, OCH2), 6.51 (s, 2 H, NH2), 7.09–
7.21 (m, 2 H, ArH), 7.43 (d, J = 8.3 Hz, 1 H, ArH), 7.50 (d, J =
8.3 Hz, 2 H, ArH), 7.67–7.76 (m, 3 H, ArH), 8.17 (s, 1 H, ArH),
10.50 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
67.0, 114.3, 118.3, 121.1, 121.6, 122.8, 124.8, 124.9, 127.8, 128.1,
129.4, 135.9, 136.3, 147.6, 156.2, 160.4, 189.7 ppm. MS (ES): m/z
(%) = 279.1 (100) [M + 1]+. C17H14N2O2 (278.1055): calcd. C 73.37,
H 5.07, N 10.07; found C 73.53, H 5.10, N 9.95.
Typical Procedure for the Synthesis of Compound 6: Water was
added (3 mL) to a solution of 2a (0.21 g, 0.85 mmol) in THF
(3 mL) followed by indium powder (0.39 g, 3.41 mmol) and the
mixture was stirred for 10 min at room temperature. Thereafter
HCl (0.56 mL, 5.12 mmol) was added dropwise and stirring was
continued for another 45 min. On completion, the reaction mixture
was poured into a 10% aq. NaHCO3 solution whilst stirring with a
glass rod. EtOAc (50 mL) was added and the contents were passed
through a bed of Celite. The organic layer was separated and the
aqueous layer was further extracted with EtOAc (5ϫ15 mL).The uct was further recrystallized from EtOAc to furnish 0.05 g (47%)
combined organic layers were evaporated in vacuo to obtain the
crude material, which was purified by column chromatography.
Elution with MeOH/CHCl3 [3:97; Rf = 0.48 (MeOH/CHCl3,
10:90)] first furnished 0.01 g (5%) of 5a as a yellow solid followed
by 0.07 g (35%) of 6 as a yellowish brown solid.
of 9c as a yellowish brown solid.
8-Chloro-1,2,3,5,12,13a-hexahydro-13H-pyrrolo[1Ј,2Ј:1,2][1,4]dia-
zepino[5,6-b]quinolin-13-one (9c): Rf = 0.72 (MeOH/CHCl3, 05:95);
m.p. 171–173 °C; [α]2D7 = 264 (c = 0.100, DMSO). IR (KBr): ν
˜
max
= 1673 (CONH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 1.70–
{1-[(2-Aminoquinolin-3-yl)methyl]-1H-imidazol-2-yl}methanol (6): 1.91 (m, 3 H, CH2 and CHH), 2.21–2.30 (m, 1 H, CHH), 2.50 (br.
M.p. Ͼ240 °C. IR (KBr): ν s, 1 H, CHH), 2.99–3.01 (m, 1 H, CHH), 3.51–3.58 (m, 2 H, CH2),
= 3239 (NH2 and OH) cm–1. 1H
˜
max
3462
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3454–3466

Synthesis of Fused Polycyclic Quinolines
4.12 (d, J = 12.2 Hz, 1 H, CH), 7.69–7.73 (m, 1 H, ArH), 7.83 (d,
(300 MHz, [D6]DMSO): δ = 1.78–1.87 (m, 3 H, CH2 and CHH),
J = 8.9 Hz, 1 H, ArH), 8.04 (d, J = 2.0 Hz, 1 H, ArH), 8.30 (s, 1 2.31 (br. s, 1 H, CHH), 2.50–2.59 (m, 1 H, CHH), 3.00 (br. s, 1 H,
H, ArH), 10.62 (s, 1 H, CONH) ppm. 13C NMR (75 MHz, [D6] CHH), 3.62–3.66 (m, 2 H, CH2), 4.17 (d, J = 12.3 Hz, 1 H, CH),
DMSO): δ = 23.2, 24.7, 53.3, 62.0, 126.0, 126.2, 126.5, 129.2, 129.5,
130.3, 136.9, 144.6, 152.5, 171.5 ppm. MS (ES): m/z (%) = 288.1
(100) [M + 1]+. EI-HRMS: calcd. for C15H14ClN3O 287.0825;
found 287.0368.
7.73 (t, J = 3.2 Hz, 2 H, ArH), 7.85 (dd, J1 = 4.7, J2 = 8.3 Hz, 2
H, ArH), 8.01, (s, 1 H, ArH), 8.37 (s, 1 H, ArH), 9.04 (d, J =
3.6 Hz, 1 H, ArH), 10.59 (s, 1 H, CONH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 23.3, 24.8, 53.5, 62.3, 123.3, 123.8,
124.8, 125.0, 126.2, 126.7, 128.0, 128.2, 129.9, 133.5, 137.9, 143.9,
151.0, 171.8 ppm. MS (ES): m/z (%) = 304.1 (100) [M + 1]+.
C19H17N3O (303.1372): calcd. C 75.23, H 5.65, N 13.85; found C
75.11, H 5.73, N 13.78.
1,2,3,5,12,13a-Hexahydro-13H-pyrrolo[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]-
quinolin-13-one (9a): The title compound was prepared following
the above-described general procedure and after purification by
crystallization using EtOAc [Rf = 0.75 (MeOH/CHCl3, 05:95)] was
obtained as a yellowish brown solid (0.034 g from 0.10 g); yield
43%; m.p. 121–123 °C; [α]2D7 = 312 (c = 0.064, DMSO). IR (KBr):
General Procedure for the Synthesis of Compounds 13a, 13f, 17a,
17d, 23, 27, 38a, 38e and 40 as Exemplified by Compound 13a: NaH
ν
˜
max = 1671 (CONH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = (0.10 g, 4.00 mmol) was added to a stirred solution of compound
1.72–1.86 (m, 3 H, CH2 and CHH), 2.21–2.30 (m, 1 H, CHH), 12 (0.20 g, 0.50 mmol) in dry THF (5 mL) at 0 °C and then the
2.47–2.50 (m, 1 H, CHH), 2.99–3.01 (m, 1 H, CHH), 3.49–3.58 (m, mixture was heated at reflux for 1 h. On completion of the reaction,
2 H, CH2), 4.13 (d, J = 12.1 Hz, 1 H, CH), 7.51 (t, J = 7.0 Hz, 1
H, ArH), 7.69–7.74 (m, 1 H, ArH), 7.83 (d, J = 8.3 Hz, 1 H, ArH),
7.92 (d, J = 7.9 Hz, 1 H, ArH), 8.32 (s, 1 H, ArH), 10.58 (s, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.2, 24.6,
53.2, 53.3, 61.9, 125.0, 125.4, 125.8, 127.2, 127.6, 129.9, 137.6,
146.2, 152.0, 171.5 ppm. MS (ES): m/z (%) = 254.1 (100) [M +
1]+. EI-HRMS: calcd. for C15H15N3O 253.1215; found 253.1204.
excess THF was evaporated in vacuo and EtOAc was added to the
residue. Then the contents were poured into water (20 mL) and
extracted with EtOAc (5ϫ15 mL). The combined organic layers
were washed with brine (30 mL), dried with Na2SO4 and concen-
trated to yield a brown solid. The product was further purified on
a short silica gel column using MeOH/CHCl3 [3:97; Rf = 0.40
(MeOH/CHCl3, 05:95)] as eluent to furnish 0.12 g (68%) of 13a as
a yellow solid.
8,9-Dimethoxy-1,2,3,5,12,13a-hexahydro-13H-pyrrolo[1Ј,2Ј:1,2][1,4]-
diazepino[5,6-b]quinolin-13-one (9d): The title compound was pre-
pared following the above-described general procedure and after
purification by column chromatography [MeOH/CHCl3, 02:98; Rf
= 0.52 (MeOH/CHCl3, 05:95)] was obtained as a yellowish brown
6,7a,8,13,14,16-Hexahydro-7H-indolo[3ЈЈ,2ЈЈ:4Ј,5Ј]pyrido[1Ј,2Ј:1,2]-
[1,4]diazepino[5,6-b]quinolin-7-one (13a): M.p. 210–212 °C; [α]3D3
=
6.0 (c = 0.600, DMSO). IR (KBr): ν
= 1673 (CONH), 3385
˜
max
(NH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 2.65 (d, J =
14.2 Hz, 1 H, CHH), 3.09–3.19 (m, 2 H, CH2), 3.79 (d, J = 14.7 Hz,
1 H, CHH), 3.92 (d, J = 14.6 Hz, 1 H, CHH), 4.06 (d, J = 14.7 Hz,
1 H, CHH), 4.23 (d, J = 14.6 Hz, 1 H, CH), 6.90–7.02 (m, 2 H,
solid (0.046 g from 0.12 g); yield 46%; m.p. 158–160 °C; [α]2D7 = 308
1
(c = 0.112, DMSO). IR (KBr): ν
= 1677 (CONH) cm–1. H
˜
max
NMR (300 MHz, [D6]DMSO): δ = 1.72–1.94 (m, 3 H, CH2 and
CHH), 2.28 (t, J = 9.8 Hz, 1 H, CHH), 2.44–2.50 (m, 1 H, CHH), ArH), 7.25 (d, J = 7.8 Hz, 1 H, ArH), 7.37 (d, J = 7.5 Hz, 1 H,
3.00 (s, 1 H, CHH), 3.79–3.82 (m, 2 H, CH2), 3.88 (s, 3 H, OCH3), ArH), 7.55 (t, J = 7.5 Hz, 1 H, ArH), 7.71–7.76 (m, 1 H, ArH),
3.90 (s, 3 H, OCH3), 4.05 (d, J = 12.0 Hz, 1 H, CH), 7.17 (s, 1 H, 7.86 (d, J = 8.4 Hz, 1 H, ArH), 7.98 (d, J = 8.0 Hz, 1 H, ArH),
ArH), 7.29 (s, 1 H, ArH), 8.12 (s, 1 H, ArH), 10.37 (s, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.3, 24.4,
53.3, 55.7, 61.6, 105.6, 106.4, 121.0, 122.6, 136.0, 143.0, 150.0,
8.40 (s, 1 H, ArH), 10.72 (s, 1 H, NH), 10.75 (s, 1 H, CONH) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 23.9, 48.8, 55.3, 60.8, 105.8,
111.0, 117.5, 118.4, 120.5, 122.1, 125.6, 125.7, 126.7, 127.4, 127.8,
152.5, 171.4 ppm. MS (ES): m/z (%) = 314.11 (100) [M + 1]+. EI- 130.2, 131.8, 136.1, 138.8, 146.5, 152.0, 171.4 ppm. MS (ES): m/z
HRMS: calcd. for C17H19N3O3, 313.1426; found 313.1434.
(%) = 355.1.0 (100) [M + 1]+. C22H18N4O (354.1481): calcd. C
74.56, H 5.12, N 15.81; found C 74.62, H 5.17, N 15.61.
6,7a,8,9,10,12-Hexahydro-7H-[1,3]dioxolo[4,5-g]pyrrolo[1Ј,2Ј:1,2]-
[1,4]diazepino[5,6-b]quinolin-7-one (9e): The title compound was 6,7a,8,13,14,16-Hexahydro-7H-[1,3]dioxolo[4,5-g]indolo[3ЈЈ,2ЈЈ:
prepared following the above-described general procedure and after
purification by crystallization using EtOAc [Rf = 0.65 (MeOH/
CHCl3, 05:95)] was obtained as a yellowish brown solid (0.045 g
from 0.11 g); yield 49%; m.p. 151–153 °C; [α]2D8 = 363 (c = 0.114,
4Ј,5Ј]pyrido[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]quinolin-7-one (13e): The
title compound was prepared following the above-described general
procedure and after purification by column chromatography
[MeOH/CHCl3, 03:97; Rf = 0.38 (MeOH/CHCl3, 05:95)] was ob-
DMSO). IR (KBr): ν
= 1678 (CONH) cm–1 1H NMR tained as a yellow solid (0.17 g from 0.25 g); yield 73%; m.p. 195–
.
˜
max
(300 MHz, [D6]DMSO): δ = 1.72–1.98 (m, 4 H, 2 CH2), 2.27 (br.
s, 1 H, CHH), 2.44–2.50 (m, 2 H, CHH and CHH), 2.98 (br. s, 1
H, CHH), 4.03 (d, J = 11.3 Hz, 1 H, CH), 6.18 (s, 2 H, OCH2O),
197 °C; [α]3D3 = 15 (c = 0.600, DMSO). IR (KBr): ν
= 1669
˜
max
(CONH), 3413 (NH) cm–1. H NMR (300 MHz, [D6]DMSO): δ =
1
3.08 (d, J = 7.3 Hz, 2 H, CH2), 3.73 (d, J = 14.5 Hz, 2 H, CH2),
7.17 (s, 1 H, ArH), 7.28 (s, 1 H, ArH), 8.09 (s, 1 H, ArH), 10.34 3.89 (d, J = 14.6 Hz, 1 H, CHH), 3.95 (d, J = 14.7 Hz, 1 H, CHH),
(s, 1 H, CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.4, 4.16 (d, J = 14.6 Hz, 1 H, CH), 6.18 (s, 2 H, OCH2O), 6.88–7.02
24.3, 53.4, 61.6, 102.1, 102.8, 103.9, 122.4, 122.7, 136.8, 144.3,
146.9, 150.4, 150.9, 171.4 ppm. MS (ES): m/z (%) = 298.1 (100) [M
+ 1]+. EI-HRMS: calcd. for C16H15N3O3 297.1113; found
297.1119.
(m, 2 H, ArH), 7.24 (t, J = 8.7 Hz, 2 H, ArH), 7.35 (s, 1 H, ArH),
7.37 (s, 1 H, ArH), 8.18 (s, 1 H, ArH), 10.56 (s, 1 H, NH), 10.72
(s, 1 H, CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.9,
48.8, 55.3, 60.8, 102.2, 103.0, 104.0, 105.9, 111.1, 117.6, 118.5,
119.7, 120.7, 122.4, 126.7, 131.9, 136.2, 137.8, 144.7, 147.1, 150.2,
151.1, 171.4 ppm. MS (ES): m/z (%) = 399.0 (100) [M + 1]+.
C23H18N4O3 (398.1379): calcd. C 69.34, H 4.55, N 14.06; found C
69.55, H 4.29, N 13.88.
8,10,11,12,12a,14-Hexahydro-13H-benzo[h]pyrrolo[1Ј,2Ј:1,2][1,4]di-
azepino[5,6-b]quinolin-13-one (9f): The title compound was pre-
pared following the above-described general procedure and after
purification by crystallization using EtOAc [Rf = 0.73 (MeOH/
CHCl3, 05:95)] was obtained as a yellowish brown solid (0.051 g
from 0.12 g); yield 51%; m.p. 171–173 °C; [α]2D9 = 123 (c = 0.100,
14-Phenyl-6,7a,8,13,14,16-hexahydro-7H-indolo[3ЈЈ,2ЈЈ:4Ј,5Ј]pyrido-
[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]quinolin-7-one (17a): The title com-
DMSO). IR (KBr): ν
= 1672 (CONH) cm–1 1H NMR pound was prepared following the above-described general pro-
.
˜
max
Eur. J. Org. Chem. 2009, 3454–3466
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3463

V. Singh, S. Hutait, S. Batra
FULL PAPER
cedure (13a) and after purification by using short silica gel column
[EtOAc/hexane, 25:75; Rf = 0.50 (hexane/EtOAc, 20:80)] was ob-
tained as a yellow solid (0.09 g from 0.25 g); yield 37%; m.p. 194–
62.5, 122.3, 122.6, 125.6, 126.0, 127.5, 127.6, 127.8, 130.6, 138.2,
146.5, 170.3, 170.5 ppm. MS (ES): m/z (%) = 286.1 (100) [M +
1]+. C15H15N3O3 (285.1113): calcd. C 63.15, H 5.30, N 14.73; found
C 63.27, H 5.42, N 14.54.
196 °C; [α]3D2 = 118 (c = 0.126, DMSO). IR (KBr): ν
= 1665
˜
max
(CONH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.30, 3.32 (dd, J1
= 4.1, J2 = 15.3 Hz, 1 H, CHH), 3.79 (d, J = 15.0 Hz, 1 H, CHH),
4.10 (d, J = 16.2 Hz, 1 H, CHH), 4.32 (d, J = 16.2 Hz, 1 H, CHH),
4.48 (d, J = 3.6 Hz, 1 H, CH), 4.93 (s, 1 H, ArCH), 7.07–7.18 (m,
6 H, ArH), 7.33 (d, J = 7.6 Hz, 3 H, ArH), 7.45 (t, J = 7.6 Hz, 1
H, ArH), 7.60 (t, J = 4.1 Hz, 1 H, ArH), 7.68 (d, J = 9.3 Hz, 3 H,
ArH and NH), 7.86 (d, J = 8.7 Hz, 1 H, ArH), 8.51 (br. s, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.9, 55.8,
59.8, 62.8, 107.6, 110.9, 118.8, 119.6, 122.0, 122.4, 125.6, 127.0,
127.1, 127.6, 128.7, 128.9, 129.0, 130.4, 133.3, 136.8, 138.6, 139.9,
146.8, 149.6, 173.8 ppm. MS (ES): m/z (%) = 431.0 (100) [M +
1]+. EI-HRMS: calcd. for C28H22N4O 430.1794; found 430.1764.
3-[(1H-Indol-3-yl)methyl]-1,3,4,5-tetrahydro-2H-[1,4]diazepino[5,6-b]-
quinolin-2-one (38a): The title compound was prepared following
the above-described general procedure as for 13a and after purifica-
tion by crystallization with EtOAc [Rf = 0.50 (MeOH/CHCl3,
5:95)] was obtained as a yellow solid (0.09 g from 0.18 g); yield
49%; m.p. 205–207 °C; [α]3D4 = 130 (c = 0.600, DMSO). IR (KBr):
ν
max = 1670 (CONH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ =
˜
2.84–2.91 (m, 1 H, CHH), 3.18–3.25 (m, 2 H, CH2), 3.62 (br. s, 1
H, CHH), 3.95 (s, 2 H, CH2), 6.88 (t, J = 7.6 Hz, 1 H, ArH), 7.00
(t, J = 7.6 Hz, 1 H, ArH), 7.07 (s, 1 H, ArH), 7.28 (d, J = 7.5 Hz,
1 H, ArH), 7.46 (d, J = 7.2 Hz, 1 H, ArH), 7.67 (t, J = 7.2 Hz, 1
H, ArH), 7.77 (d, J = 8.0 Hz, 1 H, ArH), 7.85 (d, J = 7.5 Hz, 1 H,
ArH), 8.15 (s, 1 H, ArH), 10.41 (s, 1 H, NH), 10.77 (s, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 27.3, 47.9,
60.4, 110.9, 111.3, 118.2, 120.8, 123.8, 125.3, 125.7, 126.6, 127.1,
127.4, 129.8, 136.0, 136.9, 146.0, 152.1, 173.7 ppm. MS (ES): m/z
(%) = 343.1 (100) [M + 1]+. EI-HRMS: calcd. for C22H18N4O
342.1481; found 342.0749.
2,3-Dimethoxy-14-phenyl-6,7a,8,13,14,16-hexahydro-7H-indolo-
[3ЈЈ,2ЈЈ:4Ј,5Ј]pyrido[1Ј,2Ј:1,2][1,4]diazepino[5,6-b]quinolin-7-one
(17d): The title compound was prepared following the above-de-
scribed general procedure as for 13a and after purification by
crystallization using EtOAc [Rf = 0.50 (MeOH/CHCl3, 05:95)] was
obtained as a yellow solid (0.21 g from 0.25 g); yield 46%; m.p.
151–153 °C; [α]2D9 = 831 (c = 0.232, DMSO). IR (KBr): νmax = 1666
˜
3-[(1H-Indol-3-yl)methyl]-1,3,4,5-tetrahydro-2H-[1,4]diazepino[5,6-b]-
[1,3]dioxolo[4,5-g]quinolin-2-one (38e): The title compound was pre-
pared following the above-described general procedure as for 13a
and after purification by column chromatography [MeOH/CHCl3,
02:98; Rf = 0.48 (MeOH/CHCl3, 05:95)] was obtained as a yellow
1
(CONH), 3021 (NH) cm–1. H NMR (300 MHz, CDCl3): δ = 3.30
(d, J = 12.9 Hz, 1 H, CHH), 3.78 (d, J = 15.8 Hz, 1 H, CHH), 3.95
(d, J = 16.2 Hz, 1 H, CHH), 4.02 (s, 3 H, OCH3), 4.05 (s, 3 H,
OCH3), 4.29 (d, J = 16.2 Hz, 1 H, CHH), 4.46 (s, 1 H, CH), 4.93
(s, 1 H, ArCH), 6.92 (s, 1 H, ArH), 7.10 (s, 3 H, ArH), 7.18 (d, J
= 6.0 Hz, 3 H, ArH), 7.25 (s, 2 H, ArH), 7.33 (s, 2 H, ArH), 7.49
(s, 1 H, NH), 7.58 (d, J = 7.0 Hz, 1 H, ArH), 8.35 (s, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.4, 54.5,
55.3, 55.6, 59.9, 60.3, 105.4, 105.9, 106.1, 111.1, 117.9, 118.3, 120.3,
120.5, 120.7, 126.4, 127.9, 128.4, 128.7, 134.1, 136.3, 136.7, 140.9,
142.7, 148.5, 148.8, 152.5, 173.0 ppm. MS (ES): m/z (%) = 491.1
(100) [M + 1]+. C30H26N4O3 (490.2005): calcd. C 73.45, H 5.34, N
11.42; found C 73.53, H 5.44, N 11.34.
solid (0.16 g from 0.45 g); yield 41%; m.p. 124–126 °C; [α]2D4 = 271
1
(c = 0.118, DMSO). IR (KBr): ν
= 1663 (CONH) cm–1. H
˜
max
NMR (300 MHz, [D6]DMSO): δ = 2.81–2.86 (m, 1 H, CHH), 3.15–
3.22 (m, 2 H, CH2), 3.34–3.54 (m, 1 H, CHH), 3.87 (br. s, 2 H, CH
and NH), 6.16 (s, 2 H, OCH2O), 6.88 (t, J = 7.1 Hz, 1 H, ArH),
6.97–7.05 (m, 2 H, ArH), 7.12 (s, 1 H, ArH), 7.26 (t, J = 8.1 Hz,
2 H, ArH), 7.44 (d, J = 7.8 Hz, 1 H, ArH), 8.00 (s, 1 H, ArH), 10.23
(s, 1 H, NH), 10.77 (s, 1 H, CONH) ppm. 13C NMR (75 MHz, [D6]
DMSO): δ = 27.1, 47.7, 59.9, 101.9, 102.7, 103.8, 111.0, 111.3,
118.2, 118.3, 120.8, 122.2, 123.7, 124.1, 127.4, 136.0, 136.1, 143.9,
146.6, 150.3, 150.6, 173.4 ppm. MS (ES): m/z (%) = 387.1 (100) [M
+ 1]+. C22H18N4O3 (386.1379): calcd. C 68.38, H 4.70, N 14.50;
found C 68.44, H 4.82, N 14.34.
4-(p-Tosyl)-4,5-dihydro-1H-[1,4]diazepino[5,6-b]quinolin-2(3H)-one
(23): The title compound was prepared following the above-de-
scribed general procedure as for 13a and after purification by col-
umn chromatography [MeOH/CHCl3, 02:98; Rf = 0.50 (MeOH/
CHCl3, 05:95)] was obtained as a white solid (0.05 g from 0.20 g);
3-Benzyl-1,3,4,5-tetrahydro-2H-[1,4]diazepino[5,6-b]quinolin-2-one
(39): The title compound was prepared following the above-de-
scribed general procedure as for 13a and after purification by col-
umn chromatography [hexane/EtOAc, 30:70; Rf = 0.50 (hexane/
EtOAc, 60:40)] was obtained as a yellow solid (0.20 g from 0.35 g);
yield 66%; m.p. 164–166 °C; [α]2D4 = –42 (c = 0.252, CHCl3). IR
yield 30%; m.p. 200–201 °C. IR (KBr): νmax = 1663 (CONH) cm–1.
˜
1H NMR (300 MHz, [D6]DMSO): δ = 2.26 (s, 3 H, ArCH3), 4.20
(s, 2 H, CH2), 4.63 (s, 2 H, CH2), 7.18 (d, J = 7.9 Hz, 2 H, ArH),
7.50–7.57 (m, 3 H, ArH), 7.72 (d, J = 7.5 Hz, 2 H, ArH), 7.87 (t,
J = 7.9 Hz, 1 H, ArH), 8.26 (s, 1 H, ArH), 10.56 (s, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 21.0, 49.3,
52.3, 121.2, 125.1, 125.7, 127.0, 127.2, 127.6, 129.7, 130.5, 134.7,
138.5, 143.8, 146.0, 149.7, 167.9 ppm. MS (ES): m/z (%) = 368.1
(100) [M + 1]+. C19H17N3O3S (367.0991): calcd. C 62.11, H 4.66,
N 11.44; found C 62.23, H 4.54, N 11.25.
(KBr):
ν
=
1667 (CONH), 3420 (NH) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 3.05 (dd, J1 = 8.2, J2 = 13.7 Hz, 1 H,
CHH), 3.37 (dd, J1 = 4.2, J2 = 13.7 Hz, 1 H, CHH), 3.97 (t, J =
6.5 Hz, 2 H, CH2), 4.20 (d, J = 14.9 Hz, 1 H, CH), 7.23 (t, J =
8.1 Hz, 5 H, ArH), 7.44 (t, J = 7.4 Hz, 1 H, ArH), 7.63–7.72 (m,
2 H, ArH), 7.88 (d, J = 9.5 Hz, 1 H, ArH), 8.50 (br. s, 1 H,
CONH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 38.6, 49.2,
63.0, 109.7, 125.7, 125.8, 126.9, 127.2, 127.7, 128.7, 129.5, 130.3,
137.0, 137.8, 146.5, 150.6, 174.6 ppm. MS (ES): m/z (%) = 304.1
(100) [M + 1]+. DART-HRMS (ES+): calcd. for C19H17N3O
303.1372; found 303.1365.
Ethyl 2-[2-Oxo-1,4-dihydro-2H-pyrimido[4,5-b]quinolin-3-yl]acetate
(27): The title compound was prepared following the above-de-
scribed general procedure as for 13a and after purification by
crystallization with EtOAc [Rf = 0.50 (MeOH/CHCl3, 05:95)] was
obtained as a white solid (0.27 g from 0.33 g); yield 90%; m.p. 195–
196 °C. IR (KBr): ν
= 1718 (CO2Et), 1676 (CONH) cm–1. 1H
˜
max
NMR (300 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3), Typical Procedure for the Synthesis of Compound 18: Et3N
4.10 (q, J = 7.1 Hz, 2 H, OCH2CH3), 4.63 (s, 2 H, CH2), 4.66 (s, (0.42 mL, 3.04 mmol) was added to a stirred solution of the glycine
2 H, CH2), 7.47 (s, 1 H, ArH), 7.68 (s, 1 H, ArH), 7.76 (t, J =
ethyl ester hydrochloride salt (0.42 g, 3.04 mmol) in dry MeOH
(10 mL) and the mixture was stirred for 15 min at room tempera-
7.4 Hz, 1 H, ArH), 7.83 (s, 1 H, ArH), 8.08 (s, 1 H, ArH), 8.44 (s,
1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.6, 49.4, 52.8, ture. Then a solution of 2a (0.50 g, 2.03 mmol) in MeOH (80 mL)
3464
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3454–3466

Synthesis of Fused Polycyclic Quinolines
was added dropwise to the reaction. After completion of the reac-
tion, as monitored by TLC, MeOH was evaporated in vacuo and
the residue was extracted with EtOAc (3ϫ30 mL) and water
(70 mL). The organic layers were combined and washed with brine
(50 mL), dried with Na2SO4 and concentrated to yield the crude
product. Purification by column chromatography through a short
column using hexane/EtOAc (25:75, v/v) afforded 0.50 g (85%) of
pure 18 as a yellow oil.
J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6,
44.2, 50.7, 106.1, 110.5, 110.7, 127.6, 128.9, 129.1, 129.9, 130.8,
133.0, 136.6, 143.1, 143.9, 146.0, 148.8 ppm. MS (ES): m/z (%) =
444.0 (100) [M + 1]+. C21H21N3O6S (443.1151): calcd. C 56.87, H
4.77, N 9.48; found C 56.92, H 4.83, N 9.33.
Typical Procedure for the Synthesis of Compound 24: Et3N
(0.48 mL, 3.46 mmol) was added to a stirred solution of 18 (0.50 g,
1.73 mmol) in dry CH2Cl2 (10 mL) and the reaction was stirred at
room temperature for a further 15 min. Subsequently ethyl chloro-
acetate (0.28 mL, 2.60 mmol) in CH2Cl2 was added dropwise at
0 °C and the mixture was stirred for a further 1 h at the same tem-
perature. On completion, as monitored by TLC, the contents were
poured into water (50 mL) and extracted with CH2Cl2 (3ϫ40 mL).
The usual work-up followed by purification by column chromatog-
raphy using hexane/EtOAc [80:20; Rf = 0.60 (hexane/EtOAc,
30:70)] furnished 0.53 g (93%) of 24 as a colourless oil.
Ethyl 2-{[(Z)-2-Cyano-3-(2-nitrophenyl)prop-2-enyl]amino}acetate
(18): Rf = 0.50 (hexane/EtOAc, 30:70). IR (KBr): ν
= 1734
˜
max
(CO2Et), 2221 (CN) cm–1. H NMR (200 MHz, CDCl3): δ = 1.30
(t, J = 7.1 Hz, 3 H, OCH2CH3), 3.51 (s, 2 H, CH2), 3.68 (s, 2 H,
CH2), 4.22 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.26 (s, 1 H, NH),
7.56–7.70 (m, 2 H, ArCH and ArH), 7.77 (t, J = 7.5 Hz, 2 H, ArH),
8.19 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3):
δ = 14.3, 49.5, 52.2, 61.2, 115.2, 117.1, 125.2, 129.9, 130.6, 131.0,
134.2, 141.4, 172.2 ppm. MS (ES): m/z (%) = 290.1 (100) [M +
1]+. C14H15N3O4 (289.1063): calcd. C 58.13, H 5.23, N 14.53; found
C 58.33, H 5.39, N 14.37.
1
Ethyl 2-{[(Z)-2-Cyano-3-(2-nitrophenyl)prop-2-enyl](ethoxycarbonyl)-
amino}acetate (24): IR (neat): νmax = 1708 (CO2Et), 1745 (CO2Et),
˜
1
2222 (CN) cm–1. H NMR (200 MHz, CDCl3): δ = 1.22–1.35 (m,
6 H, 2 OCH2CH3), 4.11 (s, 2 H, CH2), 4.16 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.32 (q, J = 7.1 Hz, 2 H, OCH2CH3), 4.39 (s, 2 H,
CH2), 7.61 (t, J = 6.7 Hz, 2 H, ArH), 7.77 (d, J = 6.7 Hz, 2 H,
ArH), 8.22 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.3, 14.6, 48.7, 51.1, 61.6, 62.8, 112.5, 116.5, 125.3,
131.0, 131.1, 134.4, 142.4, 142.7, 147.2, 156.1, 169.5 ppm. MS (ES):
m/z (%) = 362.0 (80) [M + 1]+. C17H19N3O6 (361.1274): calcd. C
56.51, H 5.30, N 11.63; found C 56.67, H 5.43, N 11.55.
Typical Procedure for the Synthesis of Compound 25: K2CO3
(0.29 g, 2.07 mmol) was added to a solution of 18 (0.50 g,
1.73 mmol) in dry THF (10 mL) and the mixture was stirred for
15 min at room temperature. Subsequently, cyanogen bromide
(0.22 g, 2.07 mmol) was added and the reaction was allowed to
proceed for 3 h at room temperature. After completion of the reac-
tion, as monitored by TLC, THF was evaporated and the residue
was extracted with EtOAc (3ϫ30 mL) and water (70 mL). The or-
ganic layers were combined and washed with brine (50 mL), dried
with Na2SO4 and concentrated to yield the crude product. Purifica-
tion by column chromatography using hexane/EtOAc (30:70, v/v)
afforded 0.47 g (87%) of pure 25 as a white solid.
Typical Procedure for the Synthesis of Compound 29: A mixture
of 19 (0.20 g, 0.77 mmol), 2-nitrobenzaldehyde (0.14 g, 0.93 mmol),
H2O2 (0.26 mL, 3.86 mmol) and [NH4Ce(NO3)6] (0.04 g,
0.08 mmol) was heated at 50 °C for 15 h, after which the reaction
mixture was poured into ice/water and extracted with EtOAc
(3ϫ30 mL). The usual work-up of the organic layer followed by
purification by column chromatography using hexane/EtOAc
[65:35; Rf = 0.35 (hexane/EtOAc, 60:40)] as eluent gave 0.09 g
(30%) of 29 as a yellow solid.
Ethyl
2-{Cyano[(Z)-2-cyano-3-(2-nitrophenyl)prop-2-enyl]amino}-
acetate (25): M.p. 125–127 °C; Rf = 0.48 (hexane/EtOAc, 30:70). IR
(KBr): νmax = 1747 (CO2Et), 2222 (CN) cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 1.34 (t, 3 H, OCH2CH3), 3.96 (s, 2 H, CH2), 4.19 (s,
2 H, CH2), 4.31 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.64–7.70 (m, 1
H, ArH), 7.75 (s, 1 H, ArH), 7.80 (d, J = 4.1 Hz, 2 H, ArH), 8.26
(d, J = 8.1 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
14.2, 51.6, 55.2, 62.4, 109.6, 115.7, 115.8, 125.4, 128.9, 131.1, 131.4,
134.7, 146.1, 167.6 ppm. MS (ES): m/z (%) = 314.9 (50) [M + 1]+.
C15H14N4O4 (314.1015): calcd. C 57.32, H 4.49, N 17.83; found C
57.53, H 4.53, N 17.65.
Ethyl 2-[2-(2-Nitrophenyl)-1,4-dihydro-2H-pyrimido[4,5-b]quinolin-
3-yl]acetate (29): M.p. 153–155 °C. IR (KBr): ν
= 3192 (NH),
˜
max
1718 (CO2Et) cm–1. H NMR (300 MHz, CDCl3): δ = 1.25 (t, J =
7.1 Hz, 3 H, OCH2CH3), 3.36 (d, J = 16.2 Hz, 1 H, CHH), 3.53
(d, J = 16.2 Hz, 1 H, CHH), 3.66 (d, J = 17.0 Hz, 1 H, CHH), 3.86
(d, J = 17.0 Hz, 1 H, CHH), 4.16 (q, J = 7.1 Hz, 2 H, OCH2CH3),
6.21 (s, 1 H, ArCH), 7.23–7.29 (m, 1 H, ArH), 7.42–7.49 (m, 2 H,
ArH), 7.50–7.59 (m, 3 H, ArH), 7.65–7.70 (m, 2 H, ArH), 7.82–
7.85 (m, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2,
47.0, 55.1, 61.0, 70.4, 115.8, 122.8, 124.2, 125.3, 125.4, 127.4, 128.9,
129.3, 129.7, 132.2, 135.0, 135.6, 147.2, 149.0, 152.8, 169.8 ppm.
MS (ES): m/z (%) = 393.1 (100) [M + 1]+. C21H20N4O4 (392.1485):
calcd. C 64.28, H 5.14, N 14.28; found C 64.17, H 5.23, N 14.35.
1
General Procedure for the Synthesis of Compounds 21 and 32 as
Exemplified for Compound 21: Et3N (0.36 mL, 2.60 mmol) and
DMAP (catalytic amount) were added to a solution of 18 (0.50 g,
1.73 mmol) in dry CH2Cl2 (10 mL) and the mixture was stirred for
15 min at 0 °C. Thereafter p-tosyl chloride (0.41 g, 2.16 mmol) was
added to the reaction and the mixture was allowed to proceed at
room temperature for 15 h. After completion of the reaction, as
monitored by TLC, the residue was extracted with CH2Cl2
(3ϫ30 mL) and water (70 mL). The combined organic layers were
washed with a 10% NaHCO3 solution (30 mL) and brine (30 mL),
dried with Na2SO4 and concentrated to yield the crude product.
Purification by column chromatography using hexane/EtOAc
(20:80, v/v) afforded 0.64 g (84%) of pure 21 as a colourless oil.
Typical Procedure for the Synthesis of Compound 34: A 50% aq.
solution of TFA (2.00 mL) was added to a solution of 33 (0.10 g,
0.24 mmol) in CHCl3 (5 mL) and the mixture was stirred for 5 d at
room temperature. After completion of the reaction, as monitored
by TLC, the mixture was poured into a 10% aq. NaHCO3 solution
whilst stirring. The aqueous layer was further extracted with CHCl3
(4ϫ20 mL). The organic layers were combined and washed with
brine (50 mL), dried with Na2SO4 and concentrated to yield the
crude product. Purification by column chromatography using
MeOH/CHCl3 (2:98, v/v) afforded 0.03 g (35%) of pure 34 as a
yellow solid.
Ethyl 2-{[(Z)-2-Cyano-3-(2-nitrophenyl)prop-2-enyl](methylphenyl-
sulfonamido)amino}acetate (21): Rf = 0.52 (hexane/EtOAc, 30:70).
IR (neat): νmax = 1738 (CO Et), 2223 (CN) cm–1. 1H NMR
˜
2
(300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.43
(s, 3 H, ArCH3), 4.10 (q, J = 7.1 Hz, 2 H, OCH2CH3), 4.22 (s, 2
H, CH2), 4.37 (s, 2 H, CH2), 7.32 (d, J = 7.6 Hz, 2 H, ArH), 7.63
(d, J = 7.6 Hz, 2 H, ArH), 7.77 (t, J = 7.6 Hz, 4 H, ArH), 8.21 (d,
(Z)-4-(p-Tosyl)-4,5-dihydro-3H-[1,4]diazepino[5,6-b]quinoline (34):
M.p. 200–202 °C; Rf = 0.63 (MeOH/CHCl3, 05:95). 1H NMR
Eur. J. Org. Chem. 2009, 3454–3466
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3465

V. Singh, S. Hutait, S. Batra
FULL PAPER
(300 MHz, [D6]DMSO): δ = 2.05 (s, 3 H, ArCH3), 4.62 (s, 2 H,
CH2), 5.70 (d, J = 3.8 Hz, 1 H, CH2), 7.01 (d, J = 8.1 Hz, 1 H,
ArH), 7.30 (t, J = 7.8 Hz, 1 H, ArH), 7.46–7.54 (m, 4 H, ArH),
Supporting Information (see also the footnote on the first page of
this article): The spectroscopic data for all the remaining com-
pounds and copies of the 1H and 13C NMR spectra for all com-
7.71 (d, J = 7.7 Hz, 1 H, ArH), 7.87 (s, 1 H, ArH), 8.76 (s, 1 H, pounds.
=CH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 20.7, 40.1, 51.2,
106.1, 119.1, 120.1, 123.3, 123.4, 125.6, 127.1, 127.5, 129.3, 129.9,
Acknowledgments
135.1, 137.7, 143.3, 146.4, 155.7 ppm. MS (ES): m/z (%) = 352.1
(100) [M + 1]+. C19H17N3O2S (351.4222): calcd. C 64.94, H 4.88,
N 11.96; found C 65.03, H 4.79, N 11.89.
V. S. and S. H. gratefully acknowledge financial support from the
Council of Scientific and Industrial Research, New Delhi in the
form of fellowships. This work was supported by a grant (SR/SI/
OC-16/2006) from the Department of Science and Technology,
New Delhi.
Typical Procedure for the Synthesis of Compound 40: K2CO3
(0.66 g, 4.88 mmol) was added to a stirred solution of phthalimide
(0.60 g, 4.07 mmol) in dry DMF (10 mL) and the reaction was al-
lowed to proceed for 15 min at room temperature. After that 2a
(1.00 g, 4.07 mmol) was added and the reaction as allowed to pro-
ceed for a further 2 h. After completion of the reaction, as moni-
tored by TLC, the mixture was poured into water (150 mL) whilst
stirring. A solid separated out, which was filtered and redissolved
in EtOAc (100 mL), washed with brine (40 mL), dried with Na2SO4
and concentrated to yield a crude solid product. The product was
further purified by crystallization with EtOAc to afford 1.15 g
(85%) of pure 40 as a white solid in a 10:1 ratio of the Z/E isomers.
[1] T. Laird, Org. Process Res. Dev. 2008, 12, 357.
[2] a) S. Madapa, Z. Tusi, S. Batra, Curr. Org. Chem. 2008, 12,
116–1183, and references cited therein; b) V. V. Kouznetsov,
L. Y. Mendez, C. M. M. Gomez, Curr. Org. Chem. 2005, 9,
141–161; c) C. H. McAteer, M. Balasubramanian, R. Muru-
gun, Comprehensive Heterocyclic Chemistry (Eds.: A. R. Ka-
trizky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor), Perga-
mon Press, London, 2008, Vol. 6, Chapter 7.06, pp. 309–336;
d) P. K. Agarwal, S. K. Sharma, D. Sawant, B. Kundu, Tetrahe-
dron 2009, 65, 1153–1161; e) S. Some, J. K. Ray, Tetrahedron
Lett. 2007, 48, 5013–5016; f) G. S. M. Sundaram, C. Venka-
tesh, U. K. Syam Kumar, H. Ila, H. Junjappa, J. Org. Chem.
2004, 69, 5760–5762; g) E. Rossi, G. Abbiati, A. Arcadib, F.
Marinellib, Tetrahedron Lett. 2001, 42, 3705–3708.
[3] a) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev. 2009, 109,
1–49, and references cited therein; b) V. Singh, S. Batra, Tetra-
hedron 2008, 64, 4511–4574, and references cited therein; c) D.
Basavaiah, J. R. Rao, T. Satyanarayana, Chem. Rev. 2003, 80,
811–890, and references cited therein.
(Z)-2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-(2-nitro-
phenyl)prop-2-enenitrile (40): M.p. 179–181 °C; Rf = 0.48 (hexane/
EtOAc, 20:80). IR (KBr): ν
= 1720 (CO) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 4.43 (d, J = 1.3 Hz, 2 H, CH2), 4.69 (d, J
= 1.2 Hz, 2 H, CH2), 7.58–7.64 (m, 1 H, ArH), 7.70–7.81 (m, 6 H,
ArCH and ArH), 7.84–7.96 (m, 2 H, ArH), 8.19–8.32 (m, 1 H,
ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 40.4, 111.0, 124.0,
125.3, 129.2, 131.0, 131.9, 134.4, 134.6, 143.9, 167.3 ppm. MS (ES):
m/z (%) = 334.1 (100) [M + 1]+. C18H11N3O4 (333.0750): calcd. C
64.86, H 3.33, N 12.61; found C 64.97, H 3.42, N 12.52.
[4] Y. D. Wang, D. H. Boschelli, S. Johnson, E. Honores, Tetrahe-
dron 2004, 60, 2937–2942.
[5] S. Madapa, V. Singh, S. Batra, Tetrahedron 2006, 62, 8740–
8747.
Typical Procedure for the Synthesis of Compound 41: NaBH4
(0.16 g, 4.20 mmol) was added in portions to a stirred solution of
40 (0.70 g, 2.10 mmol) in dry MeOH (15 mL) and the mixture was
stirred for a further 10 min at room temperature. Then MeOH was
evaporated in vacuo and the residue was extracted with EtOAc
(3ϫ30 mL) and water (70 mL). The organic layers were combined
and washed with brine (30 mL), dried with Na2SO4 and concen-
trated to yield a white solid. The product was further purified by
crystallization with EtOAc to afford 0.45 g (60%) of pure 41 as a
white solid in a 10:1 ratio of the Z/E isomers.
[6] R. Saxena, V. Singh, S. Batra, Tetrahedron 2004, 60, 10311–
10320.
[7] K. P. Lippke, W. G. Schunack, W. Wenning, W. E. Muller, J.
Med. Chem. 1983, 26, 499–503.
[8] a) E. D. Cox, J. Cook, Chem. Rev. 1995, 95, 1797–1842; b) F.
Ungemach, D. Soerens, R. Weber, M. Dipierro, O. Campos, P.
Mokey, J. M. Cook, J. V. Silverton, J. Am. Chem. Soc. 1980,
102, 6976–6980; c) P. D. Bailey, S. P. Hollinshead, N. R.
McLay, K. Morgan, S. J. Palmer, S. N. Prince, C. D. Reynolds,
S. D. Wood, J. Chem. Soc. Perkin Trans. 1 1993, 1431–1436; d)
B. Saha, S. Sharma, D. Sawant, B. Kundu, Tetrahedron Lett.
2007, 48, 1379–1383.
(Z)-2-[(1-Hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-(2-
nitrophenyl)prop-2-enenitrile (41): M.p. 145–147 °C; Rf = 0.35 (hex-
ane/EtOAc, 50:50). IR (KBr): ν
= 3244 (OH), 2226 (CN), 1683
˜
max
(CO), 1665 (CO) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 4.27
(d, J = 15.8 Hz, 2 H, 2 CHH), 4.65–4.72 (m, 2 H, 2 CHH), 5.95
(d, J = 8.9 Hz, 1 H, CHOH), 6.03 (d, J = 9.1 Hz, 1 H, CHOH),
6.71 (d, J = 9.1 Hz, 1 H, CHOH), 6.82 (d, J = 8.9 Hz, 1 H,
CHOH), 7.55–7.61 (m, 3 H, ArCH and ArH), 7.66–7.70 (m, 5 H,
ArH), 7.74 (d, J = 7.4 Hz, 2 H, ArH), 7.82–7.91 (m, 6 H, ArH),
8.08 (dd, J1 = 1.7, J2 = 8.1 Hz, 1 H, ArH), 8.21 (dd, J1 = 0.8, J2
= 8.2 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
32.1, 41.3, 80.5, 81.4, 111.9, 116.8, 122.7, 123.7, 123.9, 124.9, 125.1,
128.9, 129.4, 129.5, 130.8, 130.9, 131.0, 132.1, 132.5, 133.1, 133.8,
134.4, 143.2, 145.0, 147.0, 166.2, 166.6 ppm. MS (ES): m/z (%) =
336.0 (100) [M + 1]+, 358.1 (100) [M + Na]+. C18H13N3O4
(335.0906): calcd. C 64.47, H 3.91, N 12.53; found C 64.63, H 3.98,
N 12.37.
[9] K. Baharami, M. M. Khodaei, F. J. Naali, J. Org. Chem. 2008,
73, 6835–6837.
[10] S. Nag, A. Mishra, S. Batra, Eur. J. Org. Chem. 2008, 4334–
4343.
[11] For a few examples, see: a) F. Pin, S. Comesse, B. Garrigues,
T. Marchaln, A. Dach, J. Org. Chem. 2007, 72, 1181–1191; b)
N. Hucher, A. Pesquet, P. Netchitaïlo, A. Daïch, Eur. J. Org.
Chem. 2005, 2758–2770; c) S. Gowrisankar, K. Y. Lee, J. N.
Kim, Bull. Korean Chem. Soc. 2005, 26, 1112–1115; d) J. Royer,
M. Bonin, L. Micouin, Chem. Rev. 2004, 104, 2311–2352; e)
B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi, C. A.
Maryanoff, Chem. Rev. 2004, 104, 1431–1628; f) P. Pigeon, B.
Decroix, Tetrahedron Lett. 1997, 38, 2985–2988.
Received: March 28, 2009
Published Online: May 28, 2009
3466
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3454–3466