Hexamethyldisilazane-iodine induced intramolecular dehydrative cyclization of diamides: a general access to natural and unnatural quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2007.03.032

A simple and efficient general approach to various quinazolinone scaffolds, including peptidomimetic examples, has been demonstrated by employing HMDS/I₂ for the intramolecular dehydrative cyclization of diamides. The protecting groups -Boc, -F

Full text of DOI:10.1016/j.tetlet.2007.03.032

Tetrahedron Letters 48 (2007) 3243–3246
Hexamethyldisilazane-iodine induced intramolecular
dehydrative cyclization of diamides: a general access to natural
and unnatural quinazolinones
Umesh A. Kshirsagar, Santosh B. Mhaske and Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 10 January 2007; revised 27 February 2007; accepted 6 March 2007
Available online 12 March 2007
Abstract—A simple and efficient general approach to various quinazolinone scaffolds, including peptidomimetic examples, has been
demonstrated by employing HMDS/I2 for the intramolecular dehydrative cyclization of diamides. The protecting groups –Boc,
–Fmoc and –Cbz tolerated the present reaction conditions and we did not observe any racemization. The present protocol has also
been used as a key step for the efficient four-step syntheses of the naturally occurring quinazolinones, sclerotigenin, (ꢀ)-circumdatin-
F and (ꢀ)-fumiquinazoline-F.
Ó 2007 Elsevier Ltd. All rights reserved.
Quinazolinones are an important class of compounds
and a large number of natural and unnatural quinazol-
inone skeletons with a variety of substituents have been
prepared via several synthetic strategies, owing to the
wide range of biological activities that they possess.1
Retrosynthetically, intramolecular dehydrative cycliza-
tion of suitably substituted N-benzoylanthranilamides
constitutes a concise and biomimetic route to all types
of quinazolinone alkaloids.1 However, previous condi-
tions reported for such a dehydration are harsh and
are suitable only for dehydrative cyclizations of unhin-
dered 2,3-disubstituted-quinazolin-4-ones.2 Quinazol-
inone based natural products demanding more
structurally complex precursors have been constructed
indirectly via thioamide formation,3 oxidation of dehy-
droquinazolinone,4 aza-Wittig condensations5 or start-
ing from the benzoxazinones.6 Recently, a two-step
approach for such a dehydration of diamides has been
developed using PPh3/I2/EtN(i-Pr)2 (Wipf’s protocol)7
to form the benzoxazine intermediate, followed by
piperidine induced rearrangement to the target mole-
cules.8 The above approach has been successfully
applied by different research groups for the synthesis
of several complex bioactive natural quinazolinones.7–9
These studies indicate that the development of a
straightforward and efficient approach to natural and
unnatural quinazolinones, more specifically for pepti-
domimetic examples bearing a variety of protecting
groups, is a useful and challenging task of current inter-
est. In continuation of our studies,10 we herein report a
new, facile and general approach to natural and unnat-
ural quinazolinones (Schemes 1 and 2).
Anthranilamides 1 were prepared in very good yields
from the reactions of isatoic anhydride/sulfinamide
anhydride with a variety of primary amines using known
O
O
O
O
R
NHR
N
NHR
(i)
(ii)
+
R'
X
NHCOR'
N
R'
NH2
4a-k (65-97%)
2
3a-k (82-98%)
1
Scheme 1. Synthesis of unnatural quinazolinones and precursors of natural quinazolinones.
Keywords: Diamides; HMDS/I2; Intramolecular dehydrative cyclizations; Natural and unnatural quinazolinones; Synthesis.
*
Corresponding author. Tel.: +91 20 25902333; fax: +91 20 25902624; e-mail: np.argade@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.032

3244
U. A. Kshirsagar et al. / Tetrahedron Letters 48 (2007) 3243–3246
Table 1, entries 1–11). Compounds 3a,b in DCM did not
O
N
O
N
undergo reaction on treatment with cyanuric chloride/
triethylamine, chlorotrimethylsilane/iodine and dieth-
ylazodicarboxylate/triphenylphosphine. We felt that
the cheap and readily available hexamethyldisilazane
(HMDS) would be a better reagent to induce the intra-
molecular dehydrative cyclizations of 3a–k to obtain
quinazolinones 4a–k via the highly regioselective silyla-
tion of the more reactive anilide carbonyl oxygen, fol-
lowed by deoxysilylation. To our delight, treatment of
3a,b with HMDS/ZnCl2 in benzene solution under
reflux (Vorbruggen’s protocol)11 furnished the desired
products 4a,b in ꢁ100% yields. However, in our hands,
treatment of peptidomimetic precursor 3d with HMDS/
ZnCl2 resulted in the formation of a complex reaction
mixture, while 3j did not react under the same condi-
tions. We envisaged12 that the use of the soft Lewis acid
iodine in place of the borderline Lewis acid zinc chloride
would result in efficient conversion of 3a–k to 4a–k.
Rewardingly, the reactions of 3a–i with HMDS/I2 in
DCM at room temperature furnished the desired quin-
azolinones 4a–i in 65–97% yields (entries 1–9). How-
ever, compounds 3j,k in DCM at room temperature,
or under reflux conditions, were reluctant to react with
HMDS/I2, while the same reactions in refluxing chloro-
form furnished the desired compounds 4j,k in 55/41%
yields and in refluxing benzene furnished compounds
4j,k in 75/65% yields, respectively (entries 10 and 11),
revealing that a higher temperature was necessary for
those two intramolecular dehydrative cyclizations. For
the conversion of 3a–k to 4a–k, we noticed that an
increase in the molar equivalents of HMDS and iodine
reduced the reaction time with an improvement in the
(i)
N
N
CO2Me
NHFmoc
CO2Me
NH2
X
X
4h, X = H
4j, X = Me
[5], X = H
[6], X = Me
(90%)
O
N
O
N
(ii)
O
CO2Me
NHCbz
(65%)
N
N
X
N
H
4i
X = H, Sclerotigenin (7)
X = Me, (-)-Circumdatin-F (8)
H
N
H
N
O
O
N
O
N
(i)
CO2Me
NHFmoc
NH
N
(90%)
N
4k
(-)-Fumiquinazoline-F (9)
Scheme 2. Reagents and conditions: (i) Piperidine in DCM (20%), rt,
15 min (90%); (ii) (a) HBr in AcOH (33%), 60 °C, 1 h; (b) SiO2, TEA,
AcOEt, rt, 12 h (65%).
procedures.9b,c Intermediates 3a–k were prepared by
condensing anthranilamides 1 with the appropriate acid
chlorides/carboxylic acids 2 in 82–98% yield (Scheme 1,
Table 1. Conversion of anthranilamides 1 to diamides 3 and quinazolinones 4
Entry
–R
–R0
–X
Conditions (i)
Product (yield)
Conditions (ii)a
Product (yield, %)
1
–CH2CH3
Cl
TEA, DCM, rt, 8 h
3a (98)
HMDS (1.5), I2 (0.5),
DCM, rt, 30 min
4a (93)
CH3
CH3
2
Cl
TEA, DCM, rt, 10 h
TEA, DCM, rt, 12 h
3b (97)
HMDS (1.5), I2 (0.5),
DCM, rt, 30 min
4b (95)
3
4
Cl
3c (86)
3d (82)
HMDS (2.0), I2 (1.0),
DCM, rt, 4 h
4c (86)
4d (70)
NO2
CH3
CH3
NHBoc
OH
EDCI,b HOBT,c
DCM, rt, 16 h
HMDS (3.0), I2 (0.7),
DCM, rt, 4 h
5
–CH2CH3
Cl
TEA, DCM, rt, 12 h
3e (96)
HMDS (1.5), I2 (0.5),
DCM, rt, 3 h
4e (97)
OMe
6
7
Cl
Cl
TEA, DCM, rt, 12 h
TEA, DCM, rt, 14 h
3f (90)
3g (85)
HMDS (1.5), I2 (0.5),
DCM, rt, 7 h
4f (96)
4g (90)
OMe
OMe
HMDS (2.0), I2 (1.0),
DCM, rt, 5 h
Cl
8
–CH2NHFmoc
Cl
Aq. Na2CO3,
DCM, rt, 1 h
3h (96)
HMDS (3.0), I2 (3.0),
DCM, rt, 4 h
4h (75)
CO2Me

U. A. Kshirsagar et al. / Tetrahedron Letters 48 (2007) 3243–3246
3245
Table 1 (continued)
Entry
–R
–R0
–X
Conditions (i)
Product (yield)
Conditions (ii)a
Product (yield, %)
9
–CH2NHCbz OH
EDCI, DCM, rt, 16 h 3i (82)
HMDS (4.0), I2 (3.0), 4i (65)
DCM, rt, 4 h
CO2Me
CO2Me
NHFmoc
10
11
Cl
Aq. Na2CO3,
DCM, rt, 1 h
3j (95)
HMDS (5.0), I2 (4.0), 4j (75)
benzene, reflux, 4 h
H
N
NHFmoc
Cl
Aq. Na2CO3,
DCM, rt, 1 h
3k (90)
HMDS (5.0), I2 (4.0), 4k (65)
benzene, reflux, 3 h
CO2Me
a HMDS and I2 equivalents used are indicated in brackets.
b N-Ethyl-N0-(3-dimethylaminopropyl)carbodiimide.
c Use of HOBT was necessary to avoid racemization.
yields (Table 1). The protecting groups –Boc, –Fmoc
and –Cbz tolerated the present reaction conditions and
in addition, we did not observe any racemization.
Supplementary data
Experimental procedures for the synthesis of com-
pounds 3, 4, 7, 8 and 9 along with analytical and spectral
data are included. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.03.032.
In the present reaction, the formation of 4a was not
observed even in trace amounts in the absence of either
HMDS or iodine and the presence of a catalytic amount
of iodine was necessary to induce the first silylation of
the more reactive amide carbonyl group, which was fol-
lowed by in situ ring closure with deoxysilylation.
References and notes
Finally, the piperidine induced deprotection of the pro-
tecting group Fmoc in 4h,j led to unisolable amino-
ester intermediates 5,6 which on in situ intramolecular
cyclization furnished the natural products scleroti-
genin (7)6a and (ꢀ)-circumdatin-F (8)9c in 90% yields
(Scheme 2). Similarly 4k, also on Fmoc deprotection,
directly furnished (ꢀ)-fumiquinazoline-F (9)9e in 90%
yield. Quinazolinone 4i on treatment with 33% HBr
in acetic acid at 60 °C for one hour furnished the cor-
responding hydrobromide salt of the amino-ester inter-
mediate, which on treatment with triethylamine in ethyl
acetate at room temperature furnished sclerotigenin (7)
in 65% yield via an instantaneous intramolecular cycli-
zation pathway. The natural quinazolinones 7–9 were
obtained in four steps with very good overall yields
and the analytical and spectral data obtained for 7–9
were in complete agreement with the reported
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the intramolecular dehydrative cyclization of diamides.
We feel that our approach will be useful for the design
of libraries of quinazolinone congeners for structure-
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Acknowledgement
U.A.K. thanks the CSIR, New Delhi, for the award of a
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