Facile approach to diverse range of 1,3-diaza-heterocycles: angular/linear selectivity paradigm and a remarkable intramolecular methyl migration

Article abstract of DOI:10.1016/j.tet.2009.04.088

Starting from cyclic anhydrides and tert-butyl 2-aminobenzylcarbamate, simple and efficient synthesis of diverse range of kinetically controlled angular and thermodynamically controlled linear tricyclic and tetracyclic 1,3-diaza-heterocycles have been des

Full text of DOI:10.1016/j.tet.2009.04.088

Tetrahedron 65 (2009) 5244–5250
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile approach to diverse range of 1,3-diaza-heterocycles: angular/linear
selectivity paradigm and a remarkable intramolecular methyl migration
*
Umesh A. Kshirsagar, Narshinha P. Argade
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from cyclic anhydrides and tert-butyl 2-aminobenzylcarbamate, simple and efficient synthesis of
diverse range of kinetically controlled angular and thermodynamically controlled linear tricyclic and
tetracyclic 1,3-diaza-heterocycles have been described via the intramolecular cyclizations of the corre-
sponding imides/anilic acid esters. The effect of imide stability on the angular/linear product selectivity
has also been described. The kinetically controlled angular products were successfully transformed to the
corresponding thermodynamically controlled linear products by refluxing in methanol or methanol and
acetic acid mixture. An interesting in situ 1,2-intramolecular methyl group migration has also been
described.
Received 12 February 2009
Received in revised form 24 April 2009
Accepted 24 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
butyl 2-aminobenzylcarbamate to provide an avenue to both
angular and linear 1,3-diaza-heterocycles in line with their se-
A large number of biological activities have been conferred to
heterocycles and they play a pivotal role as both pharmaceutical
and agrochemical products.1 Batracylin displays antitumor activity
in vivo against murine leukemia P-388 and colon adenocarcinoma
38 cell lines that are resistant to adriamycin, cisplatin, and meth-
otrexate.2,3
lective formation with respect to the thermodynamic stability.
Now, starting from imides/anilic acid esters, we report herein
a simple and efficient access to several angular/linear 1,3-dia-
zatricyclic/tetracyclic batracylin analogs along with a very in-
teresting case of intramolecular methyl group migration
(Schemes 1 and 2).
O
H2N
2. Results and discussion
N
B
N
A
C
D
The reactions of tert-butyl 2-aminobenzylcarbamate (1) with
succinic anhydride (2a), glutaric anhydride (2b), maleic anhydride
(2c), phthalic anhydride (2f), and homophthalic anhydride (2g) in
diethyl ether at room temperature furnished the required anilic
acids 3a, 3b, 3c, 3f, and 3g, respectively, in very good yields. The
reaction of tert-butyl 2-aminobenzylcarbamate (1) with methyl-
maleic anhydride (2d) was not completely regioselective and as
expected, the mixture of two regioisomers [major (attack at un-
hindered carbonyl): minor (attack at hindered carbonyl)¼85:15]
in quantitative yield was obtained. One recrystalization of the
above mixture from ethyl acetate provided the desired major
isomer 3d in good yield (71%). The reaction of tert-butyl 2-amino-
benzylcarbamate (1) with dimethylmaleic anhydride (2e) directly
furnished the expected imide 5e in quantitative yield via the
unisolable intermediate anilic acid 3e. The anilic acids 3a, 3b, 3c,
3d, and 3g on treatment with requisite amount of diazomethane
in diethyl ether at 0 ꢀC in 30–40 min furnished the corresponding
methyl esters 4a, 4b, 4c, 4d, and 4g in high yields. The reaction of
phthalanilic acid 3f with diazomethane directly provided the
Batracylin
However, because of the high toxicity of batracylin, it has
never been approved for further clinical trials in human beings.4a
In this context, new approaches to provide a wide variety of
analogs of the antitumor agent batracylin have been reported in
the literature by using intramolecular aza-Wittig reactions,
Mitsunobu coupling reactions and condensation of o-amino-
benzylamine with o-cyanomethylbenzoic acid but with some
limitations.4 In continuation of our studies on the cyclic anhy-
drides chemistry to design the bioactive natural and unnatural
heterocyclic compounds,5 we reasoned and planned to study the
nucleophilic reactions of several cyclic anhydrides with tert-
* Corresponding author. Tel.: þ91 20 25902333; fax: þ91 20 25902629.
E-mail address: np.argade@ncl.res.in (N.P. Argade).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.088

U.A. Kshirsagar, N.P. Argade / Tetrahedron 65 (2009) 5244–5250
5245
NHBoc
NHBoc
O
N
O
iii
v
O
N
N
+
(for 5e)
z
z
z
O
NH2
O
O
1
2a-e
5c-g
6d,d',e
ii
v
i
vii
iv
(for 7c,f,g)
(for 5f)
NHBoc
NHBoc
O
O
ii
v (for 7a,c,g)
vi (for 7b)
OMe
O
O
N
O
z
N
H
N
H
z
N
7a-g,d'
z
OH
3a-d,f,g
4a-d,g
Z = a, -CH2-CH2-; b, -CH2-CH2-CH2-; c, -CH=CH-; d, -CH=CCH3-; e, -CH3C=CCH3-; f, o-C6H4-; g, o-CH2-C6H4-
Scheme 1. General theme for synthesis of linear and angular 1,3-diaza-heterocycles. Reagents and conditions: (i) Et2O, 0 ꢀC to rt, 3 h; (ii) CH2N2, Et2O, 0 ꢀC, 30 min; (iii) EtOH, reflux,
1 h; (iv) Et3N, DCM, rt, 5 h; (v) TFA, DCM, rt, 5 h; (vi) TFA, DCM, rt, 5 h then MeOH, reflux, 5 h; (vii) AcOH, MeOH, reflux, 24/48 h.
more stable ring closed product, the imide 5f in 97% yield and the
conditions to obtain the phthalanilic esters are still elusive. In our
hands, the dehydrative cyclizations of 3a/b and the intra-
molecular cyclizations of 4a/b to obtain the corresponding suc-
cinimide/glutarimide 5a/b under the several known standard
reaction conditions met with failure and we always ended up
with corresponding starting materials. Our studies revealed that
the formed imides 5a/b (by TLC) are unstable and they undergo
an in situ facile ring opening with the anchimeric assistance of
the nitrogen lone pair from the suitably ortho-substituted
–CH2NHBoc moiety. The base catalyzed intramolecular cycliza-
tions of esters 4c, 4d, and 4g, respectively, furnished the corre-
sponding imides 5c, 5d, and 5g in very good yields. Having
prepared several imides and esters, we planned to systematically
study the Boc-deprotection and intramolecular double cyclizations
of these advanced starting materials to obtain the corresponding
desired angular/linear 1,3-diaza-heterocycles, respectively (Scheme
1 and Table 1).
The trifluoroacetic acid induced Boc-deprotection of succina-
nilic ester 4a in CH2Cl2 at room temperature directly furnished the
pyrrolidinoquinazoline 7a in 91% yield via dehydrative cyclization
to form unisolable intermediate 8a followed by an intramolecular
lactamization route. The Boc-deprotection of glutaranilic ester 4b
in CH2Cl2 at room temperature furnished the intermediate qui-
nazoline 8b in quantitative yield via intramolecular monocycliza-
tion
route,
which
in
refluxing
methanol
furnished
intramolecularly ring closed final product piperidinoquinazoline
7b in 87% yield. These observations revealed that 4a passes
through an unisolable intermediate 8a to directly furnish the
product 7a. Itermediate 8a is less stable relative to 7a than 8b is to
7b. We failed to obtain the corresponding imide intermediates 5a/
b and in our hands the intermediate compounds 8a/b furnished
only the linear products 7a/b, hence we could not prepare the
angular products 6a/b.
The Boc-deprotection of maleanilic ester 4c in CH2Cl2 at room
temperature directly furnished the linear product 7c via the double
intramolecular cyclization pathway. The Boc-deprotection of mal-
eimide 5c under the similar reaction conditions also furnished only
linear product 7c. We feel that, the formation of angular product 6c
via proposed imide 9, exclusively provides thermodynamically
more stable product 7c in quantitative yield via opening and closing
of the ring ‘C’. The corresponding maleanilic acid 3c on treatment
with trifluoroacetic acid underwent decomposition. The Boc-
deprotection of maleanilic ester 4d exclusively furnished the col-
umn separable mixture of the ring closed angular products 6d/d0 in
85% yield with 13:7 ratio and it could be an effect of the methyl
group conferring more stability to the possible imide intermediate
5d/9. The imide 5d on Boc-deprotection also provided the mixture
of ring closed angular products 6d/d0 in same yield but at this time
H
O
O
N
i
N
A
B
N
C
(Path B)
N
[12]
7d'
i
(Path A)
O
O
N
O
H
N
with a 1:1 ratio. As expected, in 1H NMR spectra, the
proton signal in 6d ( 6.69) was more deshielded than the
proton in the corresponding 6d0
b
a
-vinylic
-vinylic
N
H
NH2
d
[13]
[11]
(
d
6.33). The column purified
product 6d on refluxing in methanol for 75 h gave corresponding
thermodynamically more stable linear product 7d in high yield via
the ‘C’ ring opening and closing pathway. However, the corre-
sponding unhindered regioisomer 6d0 under the same set of re-
action conditions was transformed into 7d0 but only to the extent of
+
OH
O
-OAc
H
N
N
N
N
11% in 75 h. As expected, in 1H NMR spectra, the
signal in 7d ( 6.83) was more deshielded than the
in the corresponding 7d0 (
6.27). The relatively slow conversion of
unhindered 6d0 to 7d0 can be attributed to the hyperconjugative
b
-vinylic proton
H
7d
[14]
d
a-vinylic proton
d
Scheme 2. Proposed mechanisms for the observed 1,2-methyl shift. Reaction condi-
tion: (i) AcOH/MeOH, reflux, 15 days (96%).

5246
U.A. Kshirsagar, N.P. Argade / Tetrahedron 65 (2009) 5244–5250
Table 1
Nucleophilic reactions of cyclic anhydrides with tert-butyl 2-aminobenzylcarbamate (1): synthesis of angular/linear 1,3-diaza-heterocycles from the corresponding esters/
imides: 4a to 7a, 4b to 8b to 7b, 4c/5c to 7c, 4d/5d to 6d/6d0 to 7d/7d0, 5e to 6e to 7e, 5f to 7f, and 4g/5g to 7g synthetic transformations
Sr. No.
Anhydride
Anilic acid/ester
Imide
NHBoc
Angular product
Linear product
NHBoc
O
O
N
O
O
O
N
N
OR
i
N
H
N
N
O
O
O
O
3a: R = H (92%)
4a: R = Me (98%)
(91%)
7a
6a (Not prepared)
2a
5a (Unstable)
NHBoc
NHBoc
O
O
N
O
O
O
N
O
N
ii
N
N
H
OR
N
O
O
O
3b: R = H (93%)
6b (Not prepared)
2b
7b (87%)
4b: R = Me (95%)
5b (Unstable)
NHBoc
NHBoc
O
O
N
O
OR
O
O
O
N
N
iii
N
N
H
N
(90%)
O
O
O
3c: R = H (98%)
4c: R = Me (80%)
7c
6c (Unisolable)
2c
(75%)
5c
NHBoc
O
N
NHBoc
O
O
A
B
N
O
OR
O
N
Y
O
A
B
N
X
C
C
N
iv
N
H
O
X
Y
O
O
3d: R = H (71%)
4d: R = Me (90%)
7d: X = Me, Y = H (99%)
7d': X = H, Y = Me (87%)
6d: X = Me, Y = H (55%)
6d': X = H, Y = Me (30%)
(90%)
5d
2d
NHBoc
O
O
NHBoc
N
O
O
OH
O
O
N
N
v
N
N
H
N
O
O
O
(~100%)
7e
3e (Unisolable)
NHBoc
(94%)
6e
2e
5e
(95%)
NHBoc
O
O
O
COOR
N
O
O
N
N
H
N
N
vi
N
O
O
O
3f: R = H (95%)
(85%)
7f
(97%)
5f
4f: R = Me (Unisolable)
6f (Unisolable)
2f
NHBoc
NHBoc
NH
O
O
O
O
N
N
N
O
A
B
N
C
D
vii
N
H
O
O
O
COOR
H
3g: R = H (90%)
4g: R = Me (93%)
2g
(87%)
7g
(87%)
5g
6g (Unisolable)
O
O
NH
2
NH
OMe
NH
N
O
O
N
N
N
N
OMe
z
[8a]
8b (94%)
O
[10]
[9] (Z = Imide backbone)

U.A. Kshirsagar, N.P. Argade / Tetrahedron 65 (2009) 5244–5250
5247
influence of the
b
-methyl group in 6d0 on the reactivity of the
synthesized were in complete agreement with the assigned struc-
tures/reported data.4 The angular and linear products were also
clearly distinguished from each other on the basis of 1H NMR data.
In all of the angular products 6d/6d0/6e, one of the aromatic proton
lactam carbonyl group. The angular product 6d, on treatment with
methanol plus acetic acid at reflux temperature exclusively gave
the desired linear product 7d in 24 h in quantitative yield. The pure
6d0 under the same conditions gave the desired 7d0 with 87% yield
in 24 h. We presume that both of the mentioned conversions take
place via ‘C’ ring opening and closing. Surprisingly, during these
studies on conversion of pure 6d0 to 7d0 we also noticed the for-
mation of a small amount of compound 7d (detection by TLC, 7% by
1H NMR). We were very curious about the formation of 7d in
conversion of 6d0 to 7d0 and therefore we refluxed the pure 7d0 in
methanol plus acetic acid for 5/10/15 days and obtained the rear-
ranged product 7d in 52/77/96% yields, respectively, with the
change in methyl group position. To explain the observed methyl
shift in the conversion of 7d0 to 7d, two plausible mechanisms are
depicted in Scheme 2 (path A/B). The path A with the cleavage of
ring ‘B’ by imine hydrolysis to form the unisolable imide in-
termediate 11 and an in situ intramolecular ring closing with the
other carbonyl group appears simpler and straightforward. We
strongly believe that the formation of the free imide intermediate
11 should lead to a mixture of 7d and 7d0, as the methyl group on
the imide moiety is not expected to control the complete regiose-
lectivity. The slow rate of conversion of 6d0 to 7d0 in refluxing
methanol due to the hyperconjugative effect of the methyl group
and the exclusive transformation of 6d to 7d in refluxing methanol
plus acetic acid in 24 h support the mechanistic path B, which does
not demand the cleavage of ring ‘B’. As depicted in path B, the
proton shift from the methyl group to the carbonyl group followed
by cyclopropane ring formation is possible. Its cleavage with the
signals was more deshielded (ca.
with the lactam carbonyl group.
d 8.38) due to the close proximity
3. Conclusion
In summary, we have systematically studied the nucleophilic
reactions of several cyclic anhydrides with tert-butyl 2-amino-
benzylcarbamate and provided a new practical route to the 1,3-
diazatricyclic/tetracyclic heterocycles in high yields. Our present
study clearly reveals that in all the cases, the anilic acid esters ex-
clusively provide thermodynamically more stable linear 1,3-diaza-
heterocycles, while only the methyl and dimethyl substituted
maleimides exclusively provide the corresponding kinetically
controlled angular 1,3-diaza-heterocycles. In all of the other imides
studied, the formed angular products rearranged to the corre-
sponding more stable linear products. The serendipitously wit-
nessed intramolecular shuffling of the methyl group is also
noteworthy and important from the basic chemistry points of view,
but the two different mechanistic aspects discussed on observed
methyl migration are only the proposals. We feel that our present
simple and efficient general approach to these 1,3-diaza-hetero-
cycles will be useful to design the focused libraries of analogs and
congeners of such type of new heterocyclic systems for SAR studies.
4. Experimental section
4.1. General
abstraction of the more acidic
methyl shift from the -carbon to the
a-proton can also lead to the net
b
a-carbon for thermodynamic
reasons. In a control experiment, the pure linear product 7d
remained completely unreacted in refluxing methanol plus acetic
acid mixture for 72 h and we did not observe any methyl group
shuffling. The above observation also supports the mechanistic
path B. We feel that the proposed 1,2-methyl shift via the cyclo-
propane ring formation is important from a mechanistic point of
view and appears to be very amenable to isotopic labeling.6 The
Boc-deprotection of the 2,3-dimethyl substituted imide 5e on
intramolecular condensation exclusively formed the angular
product 6e in 94% yield. Interestingly, the reaction of equimolar
amounts of o-aminobenzylamine and dimethylmaleic anhydride
(2e) in ethanol at room temperature or in refluxing THF also ex-
clusively furnished only the angular product 6e in high yield.
Herein, the observed selectivity with the presence of two free –NH2
groups (aromatic/aliphatic) is notable. The angular product 6e in
refluxing methanol remained completely unreacted for the span of
5 days. However, the same reaction in the presence of a catalytic
amount of acetic acid furnished thermodynamically more stable
linear product 7e with w100% yield in 48 h via the ring opening
and closing mechanism.
The trifluoroacetic acid induced Boc-deprotection of phthali-
mide 5f in CH2Cl2 at room temperature also formed the linear
product 7f in 85% yield via deprotection, ring closing to 6f and then
the ring opening and ring closing sequence. The Boc-deprotection
of homophthalanilic ester 4g in CH2Cl2 at room temperature di-
rectly provided the isoquinolinodihydroquinazoline 7g in 87%
yield. Herein, both the intramolecular cyclizations to form the
unisolable isoquinolinone intermediate 10 and the prototopic shift
to confer the quasi-aromatic character on ring ‘C’ took place in one
pot for thermodynamic reasons. The corresponding imide 5g on
Boc-deprotection also formed only the linear product 7g in high
yield via the unisolable intermediate 6g.
Melting points are uncorrected. 1H NMR spectra were recorded
in CDCl3 and DMSO-d6 using TMS as an internal standard on 200
and 400 MHz spectrometers. 13C NMR spectra were recorded on
200, 400, and 500 NMR spectrometers (50, 100, and 125 MHz, re-
spectively). IR spectra were recorded on an FT-IR spectrometer.
Elemental analyses were obtained by using Flash EA 1112 series and
Elementar Vario EL analyser. Column chromatographic separations
were done on silica gel (60–120 mesh). Commercially available
anhydrides and trifluoroacetic acid, were used. tert-Butyl 2-ami-
nobenzylcarbamate (1) was prepared from commercially available
o-aminobenzylamine using known procedure.7
4.2. General procedure for the preparation of anilic acids
(3a–d, 3f, 3g)
To a stirred solution of anhydride (2.00 mmol) in diethyl ether
(15 mL) at 0 ꢀC was added a solution of tert-butyl 2-amino-
benzylcarbamate (1, 2.00 mmol) in diethyl ether (10 mL) in
a dropwise fashion over a period of 10 min and the reaction mix-
ture was further stirred at room temperature for 3 h. The pre-
cipitated product was filtered, washed with ether (25 mL) and
dried under vacuum to obtain the corresponding anilic acid in
quantitative yield.
4.2.1. 4-(2-((tert-Butoxycarbonylamino)methyl)phenylamino)-5-
oxobutanoic acid (3a)
Mp 134–136 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.43 (s, 9H), 2.70–
2.90 (m, 4H), 4.25 (d, J¼6 Hz, 2H), 5.16 (br s,1H), 7.07 (t, J¼8 Hz,1H),
7.14 (t, J¼8 Hz, 1H), 7.32 (dd, J¼8 and 2 Hz, 1H), 8.12 (d, J¼8 Hz, 1H),
9.74 (br s, 1H); 13C NMR (CD3OD, 50 MHz)
d 28.7, 30.1, 32.0, 41.5,
80.6, 126.1, 126.9, 128.9, 130.4, 134.3, 136.5, 158.9, 173.6, 176.4; IR
(Nujol) vmax 3360, 2700–2500,1711, 1697, 1661 cmꢁ1. Rf (70% EtOAc/
petroleum ether) 0.45. Anal. Calcd for C16H22N2O5: C, 59.62; H,
6.88; N, 8.69. Found: C, 59.55; H, 6.96; N, 8.71.
In all of the studied examples, as expected the linear products
had higher melting points than the corresponding angular prod-
ucts. The analytical and spectral data for all the compounds

5248
U.A. Kshirsagar, N.P. Argade / Tetrahedron 65 (2009) 5244–5250
4.2.2. 5-(2-((tert-Butoxycarbonylamino)methyl)phenylamino)-5-
using ethyl acetate–petroleum ether as an eluent afforded the
corresponding pure ester product. The reaction of 3f with
diazomethane directly furnished the corresponding imide 5f in
97% yield.
oxopentanoic acid (3b)
Mp 113–115 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.43 (s, 9H), 2.08
(quint, J¼8 Hz, 2H), 2.50 (t, J¼8 Hz, 2H), 2.56 (t, J¼8 Hz, 2H), 4.25 (d,
J¼6 Hz, 2H), 5.16 (br s, 1H), 7.05 (t, J¼8 Hz, 1H), 7.15 (d, J¼6 Hz, 1H),
7.30 (dt, J¼8 and 2 Hz, 1H), 8.16 (d, J¼8 Hz, 1H), 9.56 (br s, 1H); 13C
4.3.1. Methyl 4-(2-((tert-butoxycarbonylamino)methyl)phenyl-
NMR (CDCl3, 50 MHz)
d
20.6, 28.3, 33.2, 36.0, 41.6, 80.7, 122.8, 124.3,
amino)-4-oxobutanoate (4a)
128.8 (two carbons), 130.2, 136.5, 157.3, 171.8, 178.0; IR (Neat) vmax
3329, 2974, 2700–2500, 1713, 1682, 1659 cmꢁ1. Rf (75% EtOAc/Pe-
troleum Ether) 0.52. Anal. Calcd for C17H24N2O5: C, 60.70; H, 7.19; N,
8.33. Found: C, 60.51; H, 7.04; N, 8.29.
Thick oil; 1H NMR (CDCl3, 200 MHz)
d 1.44 (s, 9H), 2.65–3.85 (m,
4H), 3.69 (s, 3H), 4.25 (d, J¼8 Hz, 2H), 5.17 (br t, J¼6 Hz,1H), 7.02 (dt,
J¼8 and 2 Hz,1H), 7.13 (dd, J¼8 and 2 Hz,1H), 7.28 (dt, J¼8 and 2 Hz,
1H), 8.16 (d, J¼8 Hz, 1H), 9.51 (br s, 1H); 13C NMR [CDCl3: CCl4 (4:1),
50 MHz]
d 28.3, 29.1, 31.5, 41.5, 51.6, 80.3, 122.7, 124.1, 128.6, 128.8,
4.2.3. (Z)-4-(2-((tert-Butoxycarbonylamino)methyl)phenylamino)-
130.2, 136.6, 157.2, 170.4, 173.1; IR (CHCl3) vmax 3447, 3327, 1738,
1688, 1682 cmꢁ1. Rf (30% EtOAc/petroleum ether) 0.56. Anal. Calcd
for C17H24N2O5: C, 60.70; H, 7.19; N, 8.33. Found: C, 60.57; H, 7.03;
N, 8.24.
4-oxobut-2-enoic acid (3c)
Mp 140–142 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.45 (s, 9H), 4.28
(d, J¼8 Hz, 2H), 5.45 (br t, J¼8 Hz, 1H), 6.48 (d, J¼14 Hz, 1H), 6.72
(d, J¼12 Hz, 1H), 7.15–7.29 (m, 2H), 7.34–7.44 (m, 1H), 8.18 (d,
J¼8 Hz, 1H), 11.19 (br s, 1H); 13C NMR (DMSO-d6, 50 MHz)
d
28.5,
4.3.2. Methyl 5-(2-((tert-butoxycarbonylamino)methyl)phenyl-
40.1, 78.6, 125.0, 125.9, 127.5, 128.4, 130.3, 132.9, 133.8, 134.8,
156.5, 164.2, 167.0; IR (Nujol) vmax 3487, 3057, 2700–2500, 1707,
1636 cmꢁ1. Rf (70% EtOAc/petroleum ether) 0.38. Anal. Calcd for
C16H20N2O5: C, 59.99; H, 6.29; N, 8.74. Found: C, 60.08; H, 6.13; N,
8.65.
amino)-5-oxopentanoate (4b)
Mp 73–75 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 1.44 (s, 9H), 2.08
(quint, J¼8 Hz, 2H), 2.46 (t, J¼8 Hz, 2H), 2.52 (t, J¼8 Hz, 2H), 3.67 (s,
3H), 4.24 (d, J¼8 Hz, 2H), 5.25 (br s, 1H), 7.04 (t, J¼8 Hz, 1H), 7.14 (d,
J¼8 Hz, 1H), 7.29 (t, J¼8 Hz, 1H), 8.17 (d, J¼8 Hz, 1H), 9.50 (br s, 1H);
13C NMR (CDCl3, 100 MHz)
d 20.8, 28.3, 33.3, 36.2, 41.6, 51.5, 80.6,
4.2.4. (Z)-4-(2-((tert-Butoxycarbonylamino)methyl)phenylamino)-
122.5, 124.0, 128.5, 128.8, 130.3, 136.7, 157.2, 171.4, 173.6; IR (CHCl3)
vmax 3323, 3277, 1734, 1686, 1676 cmꢁ1. Rf (30% EtOAc/petroleum
ether) 0.53. Anal. Calcd for C18H26N2O5: C, 61.70; H, 7.48; N, 7.99.
Found: C, 61.77; H, 7.39; N, 8.04.
2-methyl-4-oxobut-2-enoic acid (3d)
Mp 111–113 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.46 (s, 9H), 2.24 (s,
3H), 4.29 (d, J¼8 Hz, 2H), 5.37 (br t, J¼6 Hz, 1H), 6.76 (s, 1H), 7.02–
7.26 (m, 2H), 7.32–7.44 (m, 1H), 8.17 (d, J¼8 Hz, 1H), 10.86 (br s, 1H);
13C NMR (CDCl3, 50 MHz)
d
24.1, 28.3, 41.5, 81.3, 123.3, 126.2, 127.9,
4.3.3. (Z)-Methyl 4-(2-((tert-butoxycarbonylamino)methyl)-
129.0, 129.9, 130.8, 135.0, 146.4, 158.0, 165.2, 165.9; IR (CHCl3) vmax
3389, 1720, 1715, 1697, 1645 cmꢁ1. Rf (75% EtOAc/petroleum ether)
0.42. Anal. Calcd for C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C,
60.92; H, 6.54; N, 8.27.
phenylamino)-4-oxobut-2-enoate (4c)
Mp 93–95 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.42 (s, 9H), 3.82
(s, 3H), 4.28 (d, J¼6 Hz, 2H), 5.18 (br t, J¼6 Hz, 1H), 6.25 (d,
J¼12 Hz, 1H), 6.54 (d, J¼12 Hz, 1H), 7.09 (dt, J¼8 and 2 Hz, 1H),
7.21 (dd, J¼8 and 2 Hz, 1H), 7.32 (dt, J¼8 and 2 Hz, 1H), 8.17 (d,
4.2.5. 2-(2-((tert-Butoxycarbonylamino)methyl)phenyl-
J¼8 Hz, 1H), 10.05 (br s, 1H); 13C NMR (CDCl3, 50 MHz)
d 28.3,
carbamoyl)benzoic acid (3f)
41.5, 52.2, 80.5, 123.1, 124.8, 127.8, 128.8, 129.4, 130.2, 133.9,
136.0, 157.1, 162.9, 166.9; IR (Nujol) vmax 3342, 3234, 1732, 1690,
1641 cmꢁ1. Rf (35% EtOAc/petroleum ether) 0.51. Anal. Calcd for
C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C, 61.23; H, 6.54;
N, 8.41.
Mp 155–157 ꢀC; 1H NMR (DMSO-d6, 200 MHz)
d 1.35 (s, 9H),
4.21 (d, J¼6 Hz, 2H), 7.12–7.40 (m, 4H), 7.45–7.75 (m, 4H), 7.88 (d,
J¼8 Hz, 1H), 9.94 (br s, 1H); 13C NMR (DMSO-d6, 50 MHz)
d 28.5,
40.1, 78.4, 125.8 (two carbons), 127.3, 128.2 (two carbons), 129.7,
129.8, 130.3, 132.0, 134.4, 135.7, 139.2, 156.5, 168.0, 168.2; IR (Nujol)
vmax 3350, 3288, 2700–2500, 1707, 1690, 1657 cmꢁ1. Rf (80% EtOAc/
petroleum ether) 0.51. Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99;
N, 7.56. Found: C, 64.98; H, 5.87; N, 7.60.
4.3.4. (Z)-Methyl 4-(2-((tert-butoxycarbonylamino)methyl)-
phenylamino)-2-methyl-4-oxobut-2-enoate (4d)
Mp 105–107 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.45 (s, 9H), 2.10 (s,
3H), 3.86 (s, 3H), 4.27 (d, J¼8 Hz, 2H), 5.13 (br t, J¼6 Hz, 1H), 6.18 (q,
J¼2 Hz, 1H), 7.04 (t, J¼8 Hz,1H), 7.14 (dd, J¼8 and 2 Hz,1H), 7.30 (dt,
J¼8 and 2 Hz, 1H), 8.28 (d, J¼8 Hz, 1H), 9.61 (br s, 1H); 13C NMR
4.2.6. 2-(2-(2-((tert-Butoxycarbonylamino)methyl)phenylamino)-
2-oxoethyl)benzoic acid (3g)
Mp 148–150 ꢀC; 1H NMR (DMSO-d6, 200 MHz)
d
1.39 (s, 9H),
(CDCl3, 50 MHz) d 20.5, 28.3, 41.6, 52.3, 80.7, 122.5, 124.2 (two
4.10 (s, 2H), 4.12 (d, J¼8 Hz, 2H), 7.05–7.28 (m, 2H), 7.30–7.60 (m,
carbons), 128.5, 128.9, 130.2, 136.5, 142.6, 157.3, 162.9, 170.5; IR
(Nujol) vmax 3369, 3346, 1736, 1678, 1663 cmꢁ1. Rf (40% EtOAc/pe-
troleum ether) 0.58. Anal. Calcd for C18H24N2O5: C, 62.05; H, 6.94;
N, 8.04. Found: C, 62.10; H, 7.00; N, 8.21.
5H), 7.89 (dd, J¼8 and 2 Hz, 1H), 9.61 (br s, 1H); 13C NMR (DMSO-d6,
50 MHz)
d 28.5, 40.1, 41.9, 78.5, 124.7, 125.0, 127.2, 127.3, 128.3,
130.7, 131.2, 132.1, 132.7, 133.1, 136.0, 137.3, 156.6, 168.9, 169.7; IR
(Nujol) vmax 3346, 3300, 1700, 1693, 1670 cmꢁ1. Rf (75% EtOAc/pe-
troleum ether) 0.49. Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29;
N, 7.29. Found: C, 65.55; H, 6.40; N, 7.16.
4.3.5. Methyl 2-(2-(2-((tert-butoxycarbonylamino)methyl)-
phenylamino)-2-oxoethyl)benzoate (4g)
Mp 117–119 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.43 (s, 9H), 3.92
4.3. General procedure for the preparation of anilic esters
(4a–d, 4g)
(s, 3H), 4.12 (s, 2H), 4.21 (d, J¼6 Hz, 2H), 5.15 (br t, J¼6 Hz, 1H),
7.06 (dt, J¼8 and 2 Hz, 1H), 7.23 (d, J¼8 Hz, 2H), 7.27–7.41 (m,
1H), 7.43–7.57 (m, 2H), 7.89–8.03 (m, 2H), 9.26 (br s, 1H); 13C
An ether solution of diazomethane was added dropwise to
a suspension of acid (2.00 mmol) in diethyl ether (15 mL) at 0 ꢀC
until the acid dissolved with persistence of light yellow color.
The reaction mixture was stirred further 30 min at 0 ꢀC. The
solvent was removed under reduced pressure and silica gel
column chromatographic purification of the resulting residue
NMR (CDCl3, 50 MHz) d 28.3, 41.4, 42.9, 52.3, 79.9, 123.2, 124.5,
127.2, 128.4, 129.5, 129.6, 130.1, 130.9, 132.2, 132.6, 136.3, 136.8,
156.6, 168.3, 169.8; IR (Nujol) vmax 3341, 3246, 1719, 1674,
1605 cmꢁ1. Rf (50% EtOAc/petroleum ether) 0.59. Anal. Calcd for
C22H26N2O5: C, 66.32; H, 6.58; N, 7.03. Found: C, 66.29; H, 6.56;
N, 6.88.

U.A. Kshirsagar, N.P. Argade / Tetrahedron 65 (2009) 5244–5250
5249
4.3.6. tert-Butyl 2-(1,3-dioxoisoindolin-2-yl)benzylcarbamate (5f)
Mp 98–100 ꢀC; 1H NMR (CDCl3, 200 MHz)
1.34 (s, 9H), 4.23 (d,
mixture was stirred at room temperature for 5 h. The reaction
mixture was basified slowly with saturated solution of NaHCO3
(10 mL) and extracted with DCM (25 mLꢂ3). The combined organic
layer was washed with brine (20 mL) and dried over Na2SO4. The
concentration of organic layer in vacuo followed by silica gel col-
umn chromatographic purification of the resulting residue using
ethyl acetate–petroleum ether as an eluent afforded the corre-
sponding pure quinazolinone product. The compound 8b on
refluxing methanol for 5 h time furnished desired ring closed
product 7b in 87% yield.
d
J¼4 Hz, 2H), 4.95 (br s,1H), 7.18–7.26 (m,1H), 7.37–7.48 (m, 2H), 7.49–
7.58 (m, 1H), 7.74–7.85 (m, 2H), 7.90–8.01 (m, 2H); 13C NMR (CDCl3,
50 MHz)
d28.2, 40.9, 79.3,123.8,128.6,129.1,129.8,130.0,130.3,131.9,
134.3,137.3,155.6,167.6; IR (Nujol) vmax 3327, 1744,1713, 1684 cmꢁ1
.
Rf (30% EtOAc/petroleum ether) 0.63. Anal. Calcd for C20H20N2O4: C,
68.17; H, 5.72; N, 7.95. Found: C, 67.99; H, 5.64; N, 8.05.
4.4. General procedure for the preparation of imides
(5c/d, 5g)
4.5.1. 2-Methylpyrrolo[1,2-a]quinazolin-1(5H)-one (6d)
To a stirred solution of ester (1.00 mmol) in dry DCM (10 mL)
was added triethylamine (1.00 mmol) at room temperature and the
reaction mixture was stirred for 5 h. Then the solvent was removed
under reduced pressure and silica gel column chromatographic
purification of the resulting residue using ethyl acetate–petroleum
ether as an eluent afforded the corresponding pure imide product.
The reaction of tert-butyl 2-aminobenzylcarbamate (1) with
dimethylmaleic anhydride (2e) in ethanol under reflux for 1 h time
provided the corresponding imide 5e in 95% yield.
Mp 93–96 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
2.12 (d, J¼2 Hz, 3H),
5.00 (s, 2H), 6.69 (br s, 1H), 7.04–7.18 (m, 2H), 7.27 (dt, J¼6 and 2 Hz,
1H), 8.39 (d, J¼8 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
d 11.1, 50.5,
115.3, 120.1, 124.8, 125.6, 127.9, 128.7, 132.3, 142.4, 151.5, 168.5; IR
(CHCl3) vmax 1720, 1678,1640 cmꢁ1. Rf (30% EtOAc/petroleum ether)
0.57. Anal. Calcd for C12H10N2O: C, 72.71; H, 5.09; N, 14.13. Found: C,
72.48; H, 5.01; N, 14.22.
4.5.2. 3-Methylpyrrolo[1,2-a]quinazolin-1(5H)-one (6d0)
Mp 155–158 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
2.21 (d, J¼2 Hz,
4.4.1. tert-Butyl 2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)benzyl-
3H), 5.04 (s, 2H), 6.33 (q, J¼2 Hz, 1H), 7.06–7.19 (m, 2H), 7.20–7.33
carbamate (5c)
(m, 1H), 8.37 (d, J¼8 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
d 11.2, 50.6,
Mp 104–106 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
1.41 (s, 9H), 4.18 (d,
J¼6 Hz, 2H), 4.85 (br s, 1H), 6.86 (s, 2H), 7.08–7.18 (m, 1H), 7.34–7.52
(m, 3H);13CNMR(CDCl3, 50 MHz)
28.3, 41.0, 79.5,128.7,129.1,129.6,
115.3, 119.4, 124.8, 125.6, 126.9, 128.0, 132.6, 145.9, 153.2, 167.7; IR
(CHCl3) vmax 1722, 1676, 1630 cmꢁ1. Rf (30% EtOAc/petroleum ether)
0.59. Anal. Calcd for C12H10N2O: C, 72.71; H, 5.09; N, 14.13. Found: C,
72.79; H, 5.03; N, 14.02.
d
129.7, 130.2, 134.4, 137.4, 155.5, 169.8; IR (CHCl3) vmax 3445, 1776,
1715 cmꢁ1. Rf (30% EtOAc/petroleum ether) 0.53. Anal. Calcd for
C16H18N2O4:C, 63.57;H, 6.00;N, 9.27. Found:C, 63.42;H, 6.11;N, 9.39.
4.5.3. 2,3-Dimethylpyrrolo[1,2-a]quinazolin-1(5H)-one (6e)
Mp 117–119 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.01 (s, 3H), 2.09 (s,
4.4.2. tert-Butyl 2-(3-methyl-2,5-dioxo-2H-pyrrol-1(5H)-
3H), 4.98 (s, 2H), 7.09 (d, J¼4 Hz, 2H), 7.26 (dt, J¼8 and 2 Hz, 1H),
yl)benzylcarbamate (5d)
8.37 (d, J¼8 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
d 8.7, 9.0, 50.3, 115.1,
Thick oil; 1H NMR (CDCl3, 200 MHz)
d
1.42 (s, 9H), 2.19 (d, J¼2 Hz,
119.7, 124.4, 125.6, 127.9, 132.5, 135.4, 137.9, 152.7, 168.7; IR (Nujol)
vmax 1726, 1715, 1682, 1665 cmꢁ1. Rf (35% EtOAc/petroleum ether)
0.68. Anal. Calcd for C13H12N2O: C, 73.57; H, 5.70; N,13.20. Found: C,
73.77; H, 5.82; N, 13.07.
3H), 4.19 (d, J¼6 Hz, 2H), 4.91 (br t, J¼6 Hz, 1H), 6.50 (q, J¼2 Hz, 1H),
7.08–7.17 (m, 1H), 7.33–7.53 (m, 3H); 13C NMR (CDCl3, 50 MHz)
d
11.2, 28.3, 40.9, 79.4, 127.6, 128.6, 129.0, 129.6, 129.9, 130.2, 137.3,
146.2, 155.6, 170.0, 170.9; IR (Nujol) vmax 3389, 3368, 1715 cmꢁ1. Rf
(30% EtOAc/petroleum ether) 0.56. Anal. Calcd for C17H20N2O4: C,
64.54; H, 6.37; N, 8.85. Found: C, 64.55; H, 6.49; N, 8.72.
4.5.4. 2,3-Dihydropyrrolo[2,1-b]quinazolin-1(9H)-one (7a)
Mp 185–187 ꢀC (lit.4c 189–191 ꢀC); 1H NMR (CDCl3, 200 MHz)
d
2.55–2.80(m, 2H), 2.85–3.00(m, 2H), 4.80(s, 2H), 6.95–7.30(m, 4H);
4.4.3. tert-Butyl 2-(3,4-dimethyl-2,5-dioxo-2H-pyrrol-1(5H)-
13C NMR (CDCl3, 50 MHz)
d
26.1, 27.4, 41.5, 119.2, 126.0, 126.4 (two
yl)benzylcarbamate (5e)
carbons), 128.8, 140.1, 157.0, 175.8; IR (CHCl3) vmax 1736, 1665, 1655,
1649 cmꢁ1. Rf (35% EtOAc/petroleum ether) 0.61. Anal. Calcd for
C11H10N2O:C,70.95;H, 5.41;N,15.04. Found:C, 71.11;H, 5.44;N,15.15.
Thick oil; 1H NMR (CDCl3, 200 MHz)
d
1.42 (s, 9H), 2.06 (s, 6H), 4.16
(d, J¼6 Hz, 2H), 4.93 (br t, J¼4 Hz,1H), 7.05–7.15 (m,1H), 7.31–7.54 (m,
3H); 13C NMR (CDCl3, 50 MHz)
8.9, 28.3, 40.9, 79.3,128.5,128.9 (two
d
carbons), 129.4, 130.2, 137.3, 137.8, 155.7, 171.3; IR (CHCl3) vmax 3443,
1765, 1713 cmꢁ1. Rf (25% EtOAc/petroleum ether) 0.56. Anal. Calcd for
C18H22N2O4:C,65.44;H, 6.71;N,8.48.Found:C,65.55;H,6.82;N,8.53.
4.5.5. 7,8-Dihydro-6H-pyrido[2,1-b]quinazolin-9(11H)-one (7b)
Mp 101–103 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
1.99 (quint, J¼6 Hz,
2H), 2.72 (t, J¼6 Hz, 2H), 2.83 (t, J¼6 Hz, 2H), 4.90 (s, 2H), 7.00–7.30
(m, 4H); 13C NMR (CDCl3, 50 MHz)
17.7, 31.7, 33.1, 42.2, 122.1,
d
4.4.4. tert-Butyl 2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-
125.0, 125.7, 126.7, 128.5, 138.7, 152.4, 170.2; IR (CHCl3) vmax 1692,
1682, 1620, 1601 cmꢁ1. Rf (35% EtOAc/petroleum ether) 0.67. Anal.
Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 72.06; H,
6.00; N, 14.05.
yl)benzylcarbamate (5g)
Mp 290–292 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.26 (s, 9H), 3.99–
4.45 (m, 4H), 4.78 (br t, J¼4 Hz,1H), 7.08–7.18 (m,1H), 7.35 (d, J¼8 Hz,
1H), 7.39–7.52 (m, 4H), 7.64 (dt, J¼8 and 2 Hz, 1H), 8.23 (dd, J¼8 and
2 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
d
28.1, 36.9, 41.4, 79.2, 125.2,
4.5.6. Pyrrolo[2,1-b]quinazolin-1(9H)-one (7c)
127.3, 127.6, 128.9, 129.3, 129.4 (two carbons), 130.4, 134.0, 134.2,
134.7, 136.2, 155.5, 165.2, 170.2; IR (Nujol) vmax 3368, 1701, 1663,
1609 cmꢁ1. Rf (40% EtOAc/petroleum ether) 0.70. Anal. Calcd for
C21H22N2O4:C,68.84;H, 6.05;N,7.65. Found:C, 68.68;H, 6.17;N,7.53.
Mp 128–130 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 4.85 (s, 2H), 6.61 (d,
J¼6 Hz,1H), 7.05–7.47 (m, 4H), 7.48 (dd, J¼8 and 2 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) d 40.4, 121.9, 127.0, 128.5, 128.8, 128.9, 129.8, 136.3,
140.3, 152.4, 169.5; IR (CHCl3) vmax 1720, 1647, 1641 cmꢁ1. Rf (40%
EtOAc/petroleum ether) 0.49. Anal. Calcd for C11H8N2O: C, 71.73; H,
4.38; N, 15.21. Found: C, 71.82; H, 4.44; N, 15.13.
4.5. General procedure for the preparation of quinazolin-1-
one (6d/d0, 6e, 7a–c, 7f, 7g, 8b)
4.5.7. Isoindolo[1,2-b]quinazolin-12(10H)-one (7f)
To a stirred solution of imide/ester (2.00 mmol) in dry DCM
(15 mL) was added trifluoroacetic acid (10 mmol) and the reaction
Mp 175–177 ꢀC (lit.4b 175–177 ꢀC); 1H NMR (CDCl3, 200 MHz)
5.00 (s, 2H), 7.13–7.40 (m, 3H), 7.50 (dd, J¼8 and 2 Hz, 1H), 7.61–
d

5250
U.A. Kshirsagar, N.P. Argade / Tetrahedron 65 (2009) 5244–5250
7.77 (m, 2H), 7.85–7.96 (m, 1H), 8.01–8.12 (m, 1H); 13C NMR (CDCl3,
50 MHz) 40.6, 121.3, 122.2, 123.2, 126.9, 127.7, 128.1, 128.8, 130.4,
C12H10N2O: C, 72.71; H, 5.09; N, 14.13. Found: C, 72.66; H, 4.83; N,
14.02.
d
132.1, 132.9, 134.4, 140.3, 148.9, 166.9; IR (Nujol) vmax 1726, 1651,
1597 cmꢁ1. Rf (35% EtOAc/petroleum ether) 0.59. Anal. Calcd for
C15H10N2O: C, 76.91; H, 4.30; N, 11.96. Found: C, 77.08; H, 4.41; N,
12.13.
4.6.2. 3-Methylpyrrolo[2,1-b]quinazolin-1(9H)-one (7d0)
Mp 165–168 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
2.29 (d, J¼2 Hz,
3H), 4.82 (s, 2H), 6.27 (q, J¼2 Hz, 1H), 7.13–7.38 (m, 3H), 7.48 (dd,
J¼8 and 2 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d 11.4, 40.5, 122.1,
4.5.8. 5H-Isoquinolino[3,2-b]quinazolin-11(13H)-one (7g)
124.7, 126.9, 128.2, 128.7, 128.8, 140.5, 147.8, 153.2, 169.7; IR (Nujol)
vmax 1718, 1648, 1634, 1461 cmꢁ1. Rf (30% EtOAc/petroleum ether)
0.59. Anal. Calcd for C12H10N2O: C, 72.71; H, 5.09; N, 14.13. Found: C,
72.85; H, 5.11; N, 14.04.
Mp 290–292 ꢀC (lit.4e 308–310 ꢀC); 1H NMR (DMSO-d6,
200 MHz)
d
5.07 (s, 2H), 5.86 (s, 1H), 6.88 (d, J¼8 Hz, 1H), 6.90 (t,
J¼8 Hz, 1H), 7.12 (t, J¼8 Hz, 1H), 7.20 (t, J¼8 Hz, 1H), 7.27 (d, J¼8 Hz,
1H), 7.37 (d, J¼8 Hz, 1H), 7.50 (dt, J¼8 and 2 Hz, 1H), 8.03 (d, J¼8 Hz,
1H), 9.72 (br s, 1H); 13C NMR (DMSO-d6, 50 MHz)
d
42.1, 83.3, 113.3,
4.6.3. 2,3-Dimethyllpyrrolo[2,1-b]quinazolin-1(9H)-one (7e)
117.1, 120.0, 121.0, 122.5, 124.3, 126.9, 127.5, 128.8, 132.8, 136.9,
139.0, 140.8, 161.5; IR (Nujol) vmax 1657, 1624, 1607 cmꢁ1. Rf (70%
EtOAc/petroleum ether) 0.42. Anal. Calcd for C16H12N2O: C, 77.40;
H, 4.87; N, 11.28. Found: C, 77.43; H, 4.92; N, 11.35.
Mp 170–172 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
2.02 (d, J¼2 Hz,
3H), 2.17 (d, J¼2 Hz, 3H), 4.79 (s, 2H), 7.11–7.37 (m, 3H), 7.47 (dd,
J¼8 and 2 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
d 8.7, 9.0, 40.4, 122.1,
126.8, 127.6, 128.4, 128.6, 133.7, 139.5, 140.7, 153.1, 170.7; IR (Nujol)
vmax 1712, 1638, 1599, 1459 cmꢁ1. Rf (30% EtOAc/petroleum ether)
0.66. Anal. Calcd for C13H12N2O: C, 73.57; H, 5.70; N,13.20. Found: C,
73.44; H, 5.61; N, 13.35.
4.5.9. Methyl 4-(3,4-dihydroquinazolin-2-yl)butanoate (8b)
Mp 96–98 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
2.10 (quint, J¼8 Hz,
2H), 2.44 (t, J¼8 Hz, 2H), 2.76 (t, J¼8 Hz, 2H), 3.59 (s, 3H), 4.78 (s,
2H), 6.98 (d, J¼8 Hz, 1H), 7.11–7.17 (m, 1H), 7.21 (d, J¼4 Hz, 2H), 9.88
Acknowledgements
(br s, 1H); 13C NMR (CDCl3, 100 MHz)
d 22.4, 31.2, 32.7, 42.5, 51.7,
116.8, 117.5, 126.2, 127.0, 129.0, 131.6, 162.5, 172.8; IR (Nujol) vmax
3194, 1735, 1641 cmꢁ1. Rf (80% EtOAc/petroleum ether) 0.43. Anal.
Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.09; H,
6.82; N, 12.17.
U.A.K. thanks CSIR, New Delhi, for the award of a research fel-
lowship. N.P.A. thanks the Department of Science and Technology,
New Delhi, for financial support.
References and notes
4.6. General procedure for the conversion of angular to linear
quinazolin-1-one (7d, 7d0, 7e)
1. (a) Comprehensive Natural Products Chemistry; Barton, D. S., Nakanishi, K., Meth-
Cohn, O., Eds.; Pergamon: London, 1999; Vols. 1–8; (b) Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic: New York, NY, 1962–2004; Vols. 1–86;
(c) Advances in Drug Research; Testa, B., Mayer, U. A., Eds.; Academic: New York,
NY, 1966–1996; Vols. 1–30.
2. (a) Kabbe, H. J. Justus Liebigs Ann. Chem. 1978, 398; (b) Wang, H.; Mao, Y.; Zhou,
N.; Hu, T.; Hsieh, T.-S.; Liu, L. F. J. Biol. Chem. 2001, 276, 15990.
3. (a) Plowman, P.; Paull, K. D.; Atassi, G.; Harrison, S. D., Jr.; Dykes, D. J.; Kabbe, H.
J.; Narayanan, V. L.; Yoder, O. C. Invest. New Drugs 1988, 6, 147; (b) Atassi, G.;
Dumont, P.; Kabbe, H. J.; Yoder, O. Drugs Exp. Clin. Res. 1988, 14, 571 and refer-
ences cited therein 3a,b.
4. (a) Martinez-Viturro, C. M.; Dominguez, D. Tetrahedron Lett. 2007, 48, 4707; (b)
Martinez-Viturro, C. M.; Dominguez, D. Tetrahedron Lett. 2007, 48, 1023; (c)
Potikha, L. M.; Shkol’naya, N. V.; Kovtunenko, V. A. Chem. Nat. Comp. 2006, 42,
571; (d) Eguchi, S.; Takeuchi, H. J. Chem. Soc., Chem. Commun. 1989, 602; (e)
Schefezik, V. E. Liebigs Ann. Chem. 1969, 729, 83 and references cited therein
4a–e.
To a stirred solution of angular quinazolin-1-one (1.00 mmol) in
methanol (10 mL) was added acetic acid (0.10 mL) and the resulting
reaction mixture was refluxed for 24/48 h. Then the reaction mix-
ture was allowed to cool at 25 ꢀC and the solvent was evaporated
under reduced pressure. The silica gel column chromatographic
purification of the resulting residue using ethyl acetate–petroleum
ether as an eluent afforded the corresponding pure quinazolinone
product. The transformation of 7d0 to 7d was completed using the
above procedure in 15 days time with 96% yield.
4.6.1. 2-Methylpyrrolo[2,1-b]quinazolin-1(9H)-one (7d)
Mp 150–152 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
2.15 (d, J¼2 Hz,
5. Haval, K. P.; Argade, N. P. J. Org. Chem. 2008, 73, 6936 and references cited
therein.
6. For the earlier example on 1,2-methyl migration via the cyclopropane ring in-
termediate see Hayasaka, K.; Ohtsuka, T.; Shirahama, H.; Matsumoto, T. Tetra-
hedron Lett. 1985, 26, 873.
3H), 4.82 (s, 2H), 6.83 (q, J¼2 Hz, 1H), 7.10–7.50 (m, 4H); 13C NMR
(CDCl3, 50 MHz)
d 11.1, 40.4, 121.8, 126.9, 127.9, 128.5, 128.7, 129.8,
140.5, 140.7, 151.9, 170.3; IR (Nujol) vmax 1721, 1650, 1634,
1460 cmꢁ1. Rf (30% EtOAc/petroleum ether) 0.57. Anal. Calcd for
7. Petasis, N. A.; Yao, X.; Raber, J. C. U.S. 6,927,294, 09 Aug 2005.