Microwave-assisted palladium-catalysed isonitrile insertion in 2-bromophenylureas for efficient synthesis of 4-substituted imino 4H-benzo[d][1,3]oxazin-2-amines

Article abstract of DOI:10.1039/c5ra03062e

A general route to the synthesis of 4-substituted imino 4H-benzo[d][1,3]oxazin-2-amines via palladium-catalysed isonitrile insertion in 2-bromophenylureas succeeded by a C-O cross-coupling of the intermediate imidoylpalladium species under microwave irradiation is reported. This journal is

Full text of DOI:10.1039/c5ra03062e

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Microwave-assisted palladium-catalysed isonitrile
insertion in 2-bromophenylureas for efficient
synthesis of 4-substituted imino 4H-benzo[d][1,3]-
oxazin-2-amines†
Cite this: RSC Adv., 2015, 5, 28875
Received 17th February 2015
Accepted 18th March 2015
a
ab
*
Garima Pandey and Sanjay Batra
DOI: 10.1039/c5ra03062e
www.rsc.org/advances
A general route to the synthesis of 4-substituted imino 4H-benzo[d]- aminobenzoxazin-4-ones via palladium-catalyzed oxidative
[1,3]oxazin-2-amines via palladium-catalysed isonitrile insertion in coupling of isonitrile with anthranilic acid.5
2-bromophenylureas succeeded by a C–O cross-coupling of the
The 2-substituted amino-benzoxazin-4-ones are considered
intermediate imidoylpalladium species under microwave irradiation is important as they are endowed with diverse pharmacological
reported.
activities including antiviral, antiobesity, cardiovascular, and
anti-inammatory.6 However, as indicated by Beller3 and later by
Orru and Ruijter,5 the synthetic methodologies for their prepa-
ration are rare.7,8 A careful search of the literature revealed that
only two reports describe the synthesis of 4H-3,1-benzoxazine-4-
imines. The rst one relied upon aza-Wittig reaction between
iminophosphorane derived from N-substituted ortho-azido-
benzamides and isocyanates whereas the more recent synthesis
was accomplished from ortho-cyanoanilides and diaryliodonium
triates via copper-mediated oxidative arylation–cyclization.9,10
In view of the current interest in palladium-catalysed isonitrile
insertion in the C-halogen bond for obtaining diverse heterocy-
cles11 we considered exploring our strategy and we present the
details of the results herein.
Recently, we have disclosed palladium-catalysed isonitrile
insertion into 2-bromophenylthioureas followed by cross
coupling reaction by the thiol group as a novel approach to 4-
substituted imino-4H-benzo[d][1,3]thiazin-2-amines.1 Based on
the results of this protocol, we considered investigating similar
palladium-catalysed isonitrile insertion into 2-bromophenylur-
eas which would allow direct synthesis of 4-substituted imino
4H-benzo[d][1,3]oxazin-2-amines in one-pot. Our reasoning to
anticipate the formation of 4H-benzo[d][1,3]-oxazin-2-amine
was inuenced by very recent work of Li and Wu who have
reported palladium-catalyzed carbonyl insertion in N(o-bro-
moaryl)amides for the synthesis of benzoxazinones.2 Earlier Wu
and Beller et al.3 have demonstrated similar palladium-
catalyzed carbonylative synthesis of substituted 2-(phenyl-
amino)-4H-benzo[d][1,3]oxazin-4-ones from 2-bromoanilines
and isocyanates whereas Lloyd-Jones and Booker-Milburn and
co-workers have reported palladium-catalyzed ortho-selective
carbonylation of N-phenylurea derivatives for preparing 2-
substituted amino-benzoxazin-4-ones (Fig. 1).4 They also
reported that in the presence of TsOH in methanol/THF as
medium, methanolysis of the imidate takes place leading to the
isolation of anthranilate in excellent yields. More recently, Orru
and Ruijter and co-workers reported efficient synthesis of 2-
aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute,
BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, PO Box 173,
Lucknow-226031, UP, India. E-mail: batra_san@yahoo.co.uk; Fax: +91-522-
2771941; Tel: +91-522-2772450/2772550 extn 4705, 4727
bAcademy of Scientic and Innovative Research, New Delhi, India
† Electronic supplementary information (ESI) available: Experimental protocols,
spectroscopic details and copies of 1H and 13C-NMR spectra of all the
compounds are included. See DOI: 10.1039/c5ra03062e
Fig. 1 Different strategies for the synthesis of 4H-benzo[d][1,3]oxazin-
2-amines.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 28875–28878 | 28875

View Article Online
RSC Advances
Communication
Our study commenced with the reaction of 1.0 equiv. of 1-(2- afforded 3aA in comparable yields. We also screened the reac-
bromophenyl)-3-phenylurea (1a) with 1.5 equiv. of tert-butyl tion under DMF and DMSO as medium and found that the yield
isonitrile 2A in the presence of 10 mol% of Pd(OAc)2, 10 mol% of 3aA was comparable in DMF but inferior when DMSO was
of dppf and 2.0 equiv. of Cs2CO3 in dry toluene under nitrogen employed. However as compared to DMF, the work up of the
atmosphere by heating at reux as reported earlier.1 The reac- reaction mixture in toluene was straightforward. Thus the
tion was complete in 12 h to afford a major product in 62% yield reaction condition that worked best in our hands was 1.0 equiv.
as white solid. Based on the spectroscopic analysis, the struc- of 2-bromphenylurea, 1.5 equiv. of isonitrile, 5 mol% of
ture of the product was established as 4-(tert-butylimino)-N- Pd(OAc)2, 5 mol% of dppf and 1.0 equiv. of Cs2CO3 in toluene at
ꢀ
phenyl-4H-benzo[d][1,3]oxazin-2-amine 3aA (Table 1, entry 1). 110 C under microwave irradiation.
The presence of tert-butyl group inferred that hydrolysis of the
In the next stage we tested the scope of the developed
imino group to carbonyl group did not occurred during the protocol with respect to the 2-bromophenylurea and isonitrile
course or work up of the reaction. In our effort to explore the and the results are presented in Fig. 2. Initially several 2-bro-
possibility of improving the isolated yield of the product, reac- mophenylureas were readily prepared by treating 2-bromoani-
tion was conducted under different conditions and the results line with aryl or alkylisocyanates in methylene chloride in the
are summarized in Table 1. This short screening revealed that presence of triethylamine. In the rst set of reactions 2-bro-
increasing the amount of Pd(OAc)2 to 20 mol% did not increase mophenylureas (1b–i) were treated with tert-butyl isonitrile (2A)
the yield of 3aA whereas changing the ligand from dppf to PCy3 to furnish the respective 4-(tert-butylimino)-N-substituted
resulted in inferior yield of 3aA (entries 2 and 3). Testing the phenyl or N-substituted alkyl-4H-benzo[d][1,3]oxazin-2-amines
reaction with different palladium source also did not improve 3bA–iA in excellent yields. Next set of reactions was performed
the yield (entries 4–6). Next the reaction in the presence of 10% with 2-bromophenylureas (1a–i) and cyclohexylisonitrile (2B)
Pd(OAc)2, 10% dppf and 2.0 equiv. of Cs2CO3 was probed under leading to the synthesis of the products (3aB, 3cB–iB). We
ꢀ
heating at 110 C via microwave irradiation instead of conven- discovered that the reaction between 1b and 2B did not result in
tional heating. It was gratifying to discover that the reaction was the expected product under the optimized conditions. Fortu-
completed in 15 min and the yield of the product improved to nately however, altering the palladium source to Pd(dppf)Cl2
95% (entry 8). Subsequently we found that the reaction was gave the corresponding product 3bB in 79% yield. But we were
successful even in the presence of 5 mol% of Pd(OAc)2, 5 mol% unable to assign a reason for this anomaly. The protocol was
of dppf and 1.0 equiv. of Cs2CO3 without compromising the also probed with other isonitriles including 2,6-dimethylphe-
yield of 3aA (entry 9). Use of 5 mol% of Pd(dppf)Cl2 under nylisonitrile (2C) and tosylmethylisonitrile (2D) to furnish the
identical condition gave 3aA in 85% yield (entry 10). Further the corresponding products 3aC, 3cC and 3aD, 3fC and 3hC in good
reaction failed to furnish the product in the absence of a ligand yields. To enhance the scope of the method, next the reaction
or palladium source. Moreover, we found that replacing was investigated with 2-bromophenylureas (4–6) bearing
bromine with iodine in 1-(2-bromophenyl)-3-phenylurea substitutions on the phenyl ring and it was observed that these
Table 1 Optimization of the palladium-catalysed isocyanide insertion in 2-bromophenylurea
Entrya
[Pd] source (mol%)
Ligand (mol%)
Cs2CO3 (equiv.)
Heating (time)
Yieldb (%) 3aA
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (10)
Pd(dppf)Cl2 (10)
PdCl2 (10)
dppf (10)
dppf (20)
PCy3 (10)
—
Dppf (10)
PCy3 (10)
dppf (10)
dppf (5)
dppf (5)
—
2
2
2
2
2
2
2
2
1
1
1
1
T (12 h)
T (11 h)
T (14 h)
T (14 h)
T (14 h)
T (16 h)
mW (15 min)
mW (15 min)
mW (15 min)
mW (20 min)
mW (15 min)
mW (15 min)
62
60
36
66
48
30
95
94
95
85
90
65
PdCl2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(dppf)Cl2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
9
10
11c
12d
dppf (5)
dppf (5)
a
All reactions were performed using 100 mg (0.34 mmol) of 1a and 61 mL (0.52 mmol) of tert-butyl isocyanide (2A), PhMe (2.0 mL). b Isolated yields
of chromatographically pure product. c DMF as medium. d DMSO as medium. T ¼ thermal heating.
28876 | RSC Adv., 2015, 5, 28875–28878
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
Scheme 1 Transformations of 4-(substituted imino)-N-substituted-
4H-benzo[d][1,3]oxazin-2-amines to 2-aminobenzoxazin-4-one and
2-(substituted amino)quinazolin-4(3H)-one.
Pd(II) intermediate species which is expected to undergo the
isonitrile insertion resulting in an imidoyl derivative II. Subse-
quent deprotonation of the oxamidine II would result in a seven-
member transition state III. The 4-imino-4H-benzo[d][1,3]oxazin-
2-amine 3 would be formed by reductive elimination with
regeneration of Pd(0) catalyst concurrently (Fig. 3).
It is worth mentioning that during the course of this work
Sharma and Jain reported a ligand-free palladium-assisted
insertion of isocyanide to urea derivative for cascade synthesis
of phenylamino-substituted quinazolinones.12 The mechanistic
details proposed by these authors indicated that the initially
formed benzoxazine species during the reaction undergoes a
base mediated Mazurciewitcz–Ganesan type rearrangement to
yield the quinazoline. Unfortunately, lack of key physical attri-
butes (color and melting points) and chemical analyses or
HRMS data of the isolated quinazolines in their report resulted
in ambiguity, and therefore we considered reinvestigating the
reaction. Performing the reaction in the absence of ligand in
DMF or toluene however did not produce quinazoline in our
hands as reported.
Fig. 2 Scope of the synthesis of 4H-benzo[d][1,3]oxazin-2-amines.
Finally in pilot experiments we tested the utility of 4-
(substituted
imino)-N-substituted-4H-benzo[d][1,3]oxazin-2-
amines for preparing 2-aminobenzoxazin-4-one and 2-
(substituted amino)quinazolin-4(3H)-one following the litera-
ture procedures.13,14 Initially compound 3aA was treated with
HCl (3 M) in THF as medium under heating at reux for 3 h to
afford 2-(phenylamino)-4H-benzo[d][1,3]oxazin-4-one (10) in
91% yield (Scheme 1). In other reaction compound 3aB was
treated with neat piperidine at room temperature for 3 h fol-
lowed by addition of silica gel and leaving the reaction over-
night. This resulted in transformation of 3aB to the quinazolin-
4(3H)-one 11 in 67% yield.
Conclusions
In summary, we have demonstrated the microwave-assisted
palladium-catalysed isonitrile insertion into 2-bromophenylur-
eas for an efficient synthesis of 4-substituted imino 4H-benzo[d]-
[1,3]oxazin-2-amines. The scope of the methodology accommo-
dates all types of 2-halophenylureas (aromatic and aliphatic) and
the commercially available isonitriles. The use of microwave
allows the reaction to be completed in very short span of time. The
Fig. 3 Plausible mechanism for the formation of 4-imino-4H-benzo-
[d][1,3]oxazin-2-amines.
substrates readily afforded the oxazine-2-amines 7–9, respec- products generated during the study are demonstrated to be
tively in 83–93% yields. viable precursor for accessing 2-aminobenzoxazin-4-ones and 2-
It is proposed that the reaction proceeds via a mechanism (substituted amino)quinazolin-4(3H)-ones.
which is identical to the one reported by us earlier (Fig. 3).1 In
One of the authors (GP) acknowledges the nancial assis-
the rst step halogen exchange with palladium would offer a tance in the form of fellowship from University Grants
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 28875–28878 | 28877

View Article Online
RSC Advances
Communication
Commission, New Delhi. The authors acknowledge the SAIF
division of CSIR-CDRI‡ for providing the spectroscopic data.
The nancial assistance from the network project BSP0014
(HOPE) is acknowledged.
W. Michael, R. Nadimpalli, R. Nath, K. J. Raser,
D. Stafford, D. Watson, K. Wang and J. C. Jaen, J. Med.
Chem., 1998, 41, 1060–1067; (i) H. F. Hodson,
R. Downham, T. J. Mitchell, B. J. Carr, C. R. Dunk and
M. J. R. Palmer, WO 2000040247, 2000, Chem. Abstr., 133,
105042.
7 G. M. Coppola, J. Heterocycl. Chem., 2000, 37, 1369–1388.
8 (a) M. M. Hemdan, A. F. Fahmy, N. F. Ali, E. Hegazi and
A. Abd-Elhaleem, Chin. J. Chem., 2008, 25, 388–391; (b)
M. Shariat, M. W. Samsudin and Z. Zakaria, Chem. Cent. J.,
2013, 7, 58, DOI: 10.1186/1752-153x-7-58; (c) W. Takahashi,
N. Watanabe and Y. Saito, WO 2003002558, 2003, Chem.
Notes and references
‡ CDRI communication no. MS no. 74/2015/SB.
1 G. Pandey, S. Bhowmik and S. Batra, RSC Adv., 2014, 4,
41433–41436.
2 W. Li and X.-F. Wu, J. Org. Chem., 2014, 79, 10410–10416.
3 X.-F. Wu, M. Sharif, K. Shoaib, H. Neumann, A. Pews-
Davtyan, P. Langer and M. Beller, Chem.–Eur. J., 2013, 19,
6230–6233.
¨
Abstr., 138, 89816; (d) M. Gutschow, L. Kuerschner,
´
¨
M. Pietsch, A. Ambrozak, U. Neumann, R. Gunther and
H.-J. Hofmann, Arch. Biochem. Biophys., 2002, 402, 180–191;
(e) M. Kawanishi and W. Takahashi, WO 2001003697, 2001,
Chem. Abstr., 134, 100878; (f) B. O. Buckman,
M. M. Morrissey and R. Mohan, Tetrahedron Lett., 1998, 39,
1487–1488; (g) M. F. Gordeev, Biotechnol. Bioeng., 1998, 61,
13–16.
4 C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford,
´
S. N. G. Tyler, M. R. Gagne, G. C. Lloyd-Jones and
K. I. Booker-Milburn, Angew. Chem., Int. Ed., 2009, 48,
1830–1833.
5 T. Vlaar, R. V. A. Orru, B. U. W. Maes and E. Ruijter, J. Org.
Chem., 2013, 78, 10469–10475.
9 P. Molina, M. Alajarin and A. Vidal, Tetrahedron, 1989, 45,
4263–4286.
¨
6 For selected examples, see the following: (a) M. Gutschow,
¨
M. Schlenk, J. Gab, M. Paskaleva, M. W. Alnouri, S. Scolari,
`
10 K. Aradia and Z. Novaka, Adv. Synth. Catal., 2015, 357, 371–
¨
J. Iqbal and C. E. Muller, J. Med. Chem., 2012, 55, 3331–
376.
¨
3341; (b) M. Pietsch and M. Gutschow, J. Med. Chem., 2005,
11 For selected reviews on isonitrile insertions, see: (a) S. Lang,
Chem. Soc. Rev., 2013, 42, 4867–4880; (b) G. Qiu, Q. Ding and
J. Wu, Chem. Soc. Rev., 2013, 42, 5257–5269; (c) T. Vlaar,
E. Ruijter, B. U. W. Maes and R. V. A. Orru, Angew. Chem.,
Int. Ed., 2013, 52, 7084–7097; (d) S. Chakrabarty,
S. Choudhary, A. Doshi, F.-Q. Liu, R. Mohan,
M. P. Ravindra, D. Shah, X. Yang and F. F. Fleming, Adv.
Synth. Catal., 2014, 356, 2135–2196.
48, 8270–8288; (c) W. Takahashi, N. Watanabe and Y. Saito,
Patent EP1403269 A1, 2003, Chem. Abstr., 2004, 138,
89816; (d) A. Krantz, R. W. Spencer, T. F. Tam, T. J. Liak,
L. J. Copp, E. M. Thomas and S. P. Rafferty, J. Med. Chem.,
1990, 33, 464–479; (e) H. F. Hodson, R. Downham,
T. J. Mitchell, B. J. Carr, C. R. Dunk and R. M. J. Palmer,
Patent US 2003/0013707 A1, 2003, Chem. Abstr., 2004, 133,
105043; (f) U. Neumann, N. M. Schechter and
12 S. Sharma and A. Jain, Tetrahedron Lett., 2014, 55, 6051–
6054.
¨
M. Gutschow, Bioorg. Med. Chem., 2001, 9, 947–954; (g)
R. L. Jarvest, M. J. Parratt, C. M. Debouck, J. G. Gorniak,
J. L. Jennings, H. T. Seranowska and J. E. Strickler, Bioorg.
Med. Chem. Lett., 1996, 6, 2463–2466; (h) S. J. Hays,
B. W. Caprathe, J. L. Gilmore, N. Amin, M. R. Emmerling,
13 X. D. Fe, Z.-Y. Ge, T. Tang, Y.-M. Zhu and S. J. Ji, J. Org. Chem.,
2012, 77, 10321–10328.
14 F. He and B. B. Snider, J. Org. Chem., 1999, 64, 1397–1399.
28878 | RSC Adv., 2015, 5, 28875–28878
This journal is © The Royal Society of Chemistry 2015