Ligand-free palladium assisted insertion of isocyanides to urea derivatives for cascade synthesis of phenylamino-substituted quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2014.09.027

Palladium catalyzed cascade coupling of substituted urea derivatives and tert-butyl isocyanide for the efficient synthesis of phenylamino-substituted quinazolinones has been developed in moderate to good yields. This method provides a short and alternative approach for the synthesis of quinazolinones derivatives which are valuable compounds with biological and pharmacological potentials. A plausible mechanistic scheme is proposed.

Full text of DOI:10.1016/j.tetlet.2014.09.027

Tetrahedron Letters 55 (2014) 6051–6054
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand-free palladium assisted insertion of isocyanides to urea
derivatives for cascade synthesis of phenylamino-substituted
quinazolinones
b
Siddharth Sharma a, , Abhilasha Jain
⇑
a Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar 143005, India
b Department of Chemistry, St. Xavier’s College, Mumbai 400001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2014
Revised 4 September 2014
Accepted 6 September 2014
Available online 16 September 2014
Palladium catalyzed cascade coupling of substituted urea derivatives and tert-butyl isocyanide for the
efficient synthesis of phenylamino-substituted quinazolinones has been developed in moderate to good
yields. This method provides a short and alternative approach for the synthesis of quinazolinones
derivatives which are valuable compounds with biological and pharmacological potentials. A plausible
mechanistic scheme is proposed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide insertion
Metal catalyzed
Quinazolinone
Quinazolinones are among the most privileged scaffolds found in
synthetic and natural products of biological and pharmacological
importance.1,2 Therefore, the development of efficient synthetic
methods to prepare new types of quinazolinone molecules for
screening in medicinal and pharmaceutical programmes is continu-
ously gaining enormous interest in both academia and industry. In
particular, fused quinazolinones are widely found in several biologi-
cally active natural products such as, 2-methyl-4(3H)-quinazolinone,3
bouchardatine,4 luotonin (A, B, E),5 auranthine,6 circumdatin (C, F),7
and sclerotigenin.8
O
N
O
N
NH
NH
R1
R1
N
I
II
H
General approach
using metal catalysts (Ref. 9)
Our approach
Figure 1. Structural comparison of substituted 2-phenyl quinazolinone and phe-
nylamino-substituted quinazolinones.
In recent years plethora of methods have been developed for the
synthesis of substituted 2-phenyl quinazolinone derivatives (I) cat-
alyzed by metal catalysts.9 Whereas only handful of approaches are
available for the synthesis of 2-(phenylamino)quinazolin-4(3H)-
ones derivatives (II), that also suffer from low yields and/or poorly
accessible precursors and most importantly require several steps
to achieve the final product (Fig. 1).10 In view of their broad range
of biological activities and high pharmacological potential a concise
method involving commercially available and cheap starting
materials is still required for their practical synthesis. Recently,
palladium assisted isocyanide insertion has become an attractive
and efficient approach because of its intriguing selectivity and
atom-economy toward the C–C and C–N bond formations.11 In our
ongoing efforts to develop new strategies for the diversity oriented
Conventional approach
O
COOMe
4-Steps
NH
NH2
N
Cl
R1-NH2
Our approach
O
H
N
H
N
NC
R1
NH
R1
O
I
N
N
H
2
1
3
⇑
Corresponding author.
E-mail addresses: sidcdri@gmail.com, organicchemgndu@gmail.com (S. Sharma).
Figure 2. Cascade approach for the synthesis of phenylamino-substituted
quinazolinones.
http://dx.doi.org/10.1016/j.tetlet.2014.09.027
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6052
S. Sharma, A. Jain / Tetrahedron Letters 55 (2014) 6051–6054
Table 1
the synthesis of phenylamino-substituted quinazolinones deriva-
tives.12 Interestingly, the synthesis of these molecules traditionally
require 4–5 steps in contrast to our highly concise and cascade pro-
cess (Fig. 2).10b
Optimization of reaction condition for the formation of phenylamino-substituted
quinazolinonesa
O
H
N
H
N
NC
Catalyst/Base
Solvent
To prove our working hypothesis, urea derivative (1a) and
tert-butyl isocyanide (2) were chosen as the model substrates to
optimize the reaction conditions (Table 1). Subsequently, the effect
of bases and solvents was further investigated using Pd(OAc)2 as a
catalyst. No product was formed when only Cs2CO3 was used to
catalyze the isocyanide insertion reaction (Table 1, entry 1). A vari-
ety of palladium catalysts such as, Pd(PPh3)4 (Table 1, entry 2),
PdCl2(PPh3)2 (Table 1, entry 3), Pd2(dba)3 (Table 1, entry 4), and
PdCl2 (Table 1, entry 5) can effect this transformation to some
extent, but Pd(OAc)2 was selected as optimal catalyst for further
studies. Many bases such as Cs2CO3, K2CO3, K3PO4, and KOtBu were
used for the optimization, however the best results were obtained
with Cs2CO3 (Table 1, entry 6). DMF emerged as the most suitable
solvent among all the tested solvents such as DMSO, dioxane, and
toluene (Table 1, entries 10–12). Lowering of the yield from 71% to
46% was observed when catalyst loading was decreased from
10 mol % to 5 mol % (Table 1, entry 13). Pleasingly, this reaction
was very simple, high yielding, and most importantly, preliminary
result is all the more interesting as no further addition of any
ligand was required.
NH
O
I
N
3a
N
H
1a
2a
Entry
Catalyst
Solvent
Base
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13c
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
0
36
25
21
13
71
31
36
29
56
43
28
46
Pd(PPh3)4
PdCl2(PPh3)2
Pd2(dba)3
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K3PO4
DMF
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
Dioxane
Toluene
DMF
a
Reaction conditions: urea 1a (1.0 mmol), tert-butyl isocyanide (1.2 mmol) (2),
[Pd] catalyst (10 mol %), and base (2.0 mmol) in solvent (5 mL) under N2 for 12 h at
120° C.
b
Isolated yield.
Catalyst loading was 5 mol %.
c
As depicted in Scheme 1, there are two possible products A and
B from reaction under Pd-catalyzed conditions. 1H NMR, 13C NMR,
and mass spectral data of compounds confirmed that the products
have the general structure B. For the better insight of the reaction
product B, a tentative mechanism has also been proposed, where
the first step involves the oxidative insertion of Pd to the urea
synthesis of bioactive heterocycles, and enlightened by the recent
advancement, we have developed an isocyanide insertion reaction
between substituted urea derivatives and tert-butyl isocyanide for
O
H
N
H
H
R2
R2
N
R2
N
N
N
R1
R1
NH
R1
O
O
N
N
X
H
X = I, Br
B
A
Scheme 1. Possible structure and selectivity in isocyanide insertion reaction.
H
N
H
N
R1
O
Pd I
N
C
H
N
H
N
R1
4
O
I
R1
Pd = Pd (II)
2
NH
O
H
N
Pd
I
DMF
Pd(OAc)2
Pd(0)
N
R1
5
NH
Base
N
O
Pd
H
N
N
N
R1
6
N
HI
O
7
R1
N
H
N
N
R1
C
N
O
NH
H
N
Mazurciewitcz-Ganesan
type rearrangment
O
3
H
Base
8
Scheme 2. Plausible reaction pathway for the synthesis of phenylamino-substituted quinazolinones.

S. Sharma, A. Jain / Tetrahedron Letters 55 (2014) 6051–6054
6053
Table 2
With the optimized condition in hand, we next surveyed the
generality of this palladium mediated coupling process (Table 2).
We observed that the reaction yields depend slightly upon the
electron-withdrawing and -donating groups present in the phenyl
ring of urea derivatives. Equally significant isolated yields for urea
containing bromides were reported with the same conditions opti-
mized for the iodides (Table 2, entry 10) but higher reaction time
was required. Whereas chloro substituted urea derivatives were
found to be completely inert toward the isocyanide insertion reac-
tion (Table 2, entry 11). Good yields were observed for the tert-
butyl isocyanide based insertion reactions (3a–3i), whereas low
yield of the product was obtained when cyclohexyl isocyanide
was used (Table 2, entry 12). These exciting preliminary results
certainly unveil the doors to the rapid synthesis of highly diverse
quinazolinones especially in the natural product synthesis.
In summary, we have developed a ligand-free palladium cata-
lyzed reactions for the synthesis of phenylamino-substituted qui-
nazolinone derivatives via isocyanide insertion approach. The
strategy allows synthesis of biologically important molecules in
a straightforward and atom-economical fashion, which otherwise
requires multistep procedures. The applications of this methodol-
ogy in the synthesis of more complex molecules are currently
underway in our group, and results will be reported in due
course.
Pd-catalyzed synthesis of phenylamino-substituted quinazolinonesa
O
H
N
H
N
R2
R2
R1
Pd(OAc)2
,Cs CO
NH
R1
O
DMF
2
3
X
N
3
N
NC
H
1
2
X = I, Br
Entry
1
1(Urea)
Quinazolinones (3a–i)
Yieldb (%)
71
O
NH
3a
1a
N
N
H
O
O
NH
3b
2
3
4
1b
1c
1d
66
62
45
N
N
H
O
NH
3c
N
O
N
H
Cl
NH
3d
Acknowledgments
N
O
N
H
S.S. is thankful to the Department of Science and Technology
(DST), Ministry of Science and Technology India for financial sup-
port (IFA13-CH-116) in the form of INSPIRE Faculty Award. The
author also acknowledges G.N.D.U. Amritsar for providing lab
facilities.
NH
3e
5
6
1e
1f
52
76
N
O
N
H
NH
3f
Supplementary data
N
O
N
H
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
027.
NH
NH
3g
7
1g
49
N
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catalyst (10 mol %), and base (2.0 mmol) in DMF (5 mL) under N2 for 12 h at 120° C.
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b
Isolated yield.
Bromourea derivative was used in place of iodo (24 h).
Chlorourea derivative was used in place of iodo.
Cyclohexyl isocyanide was used in place of 2a.
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d
e
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concentrated using
silica gel chromatography
a
rotary evaporator. The residue was purified using
(DCM–MeOH, 95:5) to afford 3a.
2-(Phenylamino)quinazolin-4(3H)-one (3a): Physical state: solid, mass (EI):
m/z = 237 (M+); 1H NMR (DMSO-d6, 500 MHz) d: 7.04 (t, J = 7.2 Hz, 1H), 7.23
(t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.41 (d, J = 11.4 Hz, 1H), 7.65 (td,
J = 1.2 Hz, 7.2 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.98 (dd, J = 1.2 Hz, 7.8 Hz, 1H),
8.49 (s, 1H), 9.30 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) d: 118.8, 119.7, 122.9,
123.4, 125.4, 126.4, 129.3, 134.9, 139.5, 148.2, 150.2, 162.1. Anal. calcd for
12.
A 50 mL Schlenk tube was charged with urea (1a) (1 mmol), Cs2CO3
(2.0 mmol), and Pd(OAc)2 catalyst (10.0 mol%) in DMF (5 mL). Vacuum was
applied and the flask was back-filled with N2. Isocyanide (1.2 mmol), was
added via syringe and the punctured septum was replaced with a new one
under a stream of nitrogen. The reaction mixture was stirred at 120 °C in N2
C
14H11N3O: C, 70.87; H, 4.67; N, 17.71, found: C, 70.98; H, 4.54; N, 77.56. IR
(KBr): 3298, 3189, 3063, 1647, 1610 cmÀ1
.
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