SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai.
Carbonylative Synthesis of Phthalimides and Benzoxazinones using Phenyl Formate as a
Efficient Carbon Monoxide Source
Sujit P. Chavan and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai- 400 019, India.
*Corresponding author. Tel.: + 91- 22 3361 1111/2601; Fax: (+91)-22-33611020.
E-mail address: deepaknale1386@gmail.com, bm.bhanage@ictmumbai.edu.in
1. Introduction:
Annulated heterocycles like phthalimides and benzoxazinones are important motifs present in the numerous biological active
molecules. Hence, the development of environmentally benign protocol for the synthesis of annulated heterocycles has always
being a key area of interest among the organic chemist. Classical approach for the phthalimide synthesis involves the
condensation of a phthalic anhydride with primary amine. Benzoxazinones are commonly synthesized by the cyclization of
anthranilic acids, N-acylanthranilic acids or isatonic anhydrides. In recent years, transition metal catalyzed direct carbonylation
reaction serves as a prime method for the synthesis of various heterocycles using carbon monoxide as C1 source. In this regard,
few methods were reported on transition metal catalyzed carbonylative synthesis of phthalimides and benzoxazinones using CO
gas as a C1 source. Indeed the CO gas is most widely used as a C1 source, but it is highly lethal gas, with a main concern of its
handling, storage, transport and need of specially designed high pressure reactor may restricts its common use by academic
researchers. Hence, the development of new methodology which involves the use of simple, easy to handle and less toxic CO
surrogates is highly desirable. In recent years, much development has been made in this direction, and various inorganic and
organic carbon monoxide alternatives were intensively investigated for the organic synthesis. Ilhyong Ryu and co-workers
developed two chamber technique and continuous microflow a “tube-in-tube” reactor system for aminocarbonylation using
Morgan reaction for CO generation. Recently, two groups were independently reported the aryl formate as a CO source for
esterification of aryl halides. Yasushi Tsuji and co-workers reported hydroesterification of alkynes and alkenes using aryl
formate as CO source. Later Yian Shi and co-workers synthesized variety of lactones via hydro-esterification of alkenylphenols
using phenyl formate as CO source. Very recently, Beller and co-workers also reported aryl formates as bifunctional reagent i.e.
pseudohalide as well as CO source for various carbonylation reactions.
In continuation with our ongoing research on exploring simple, less toxic, atom efficient and carbon monoxide free protocols for
carbonylation reactions. Herein, we report CO free synthesis of N-substituted phthalimides and benzoxazinones using phenyl
formate as a simple and efficient carbon monoxide source. Moreover, the methodology has also successfully applied for the
synthesis of amino acid derived phthalimides (Fig. 1).
2. Material and Methods:
Reagents and anhydrous solvents were used as it is obtained from commercial vendors. All reactions were performed in oven
dried glassware under nitrogen atmosphere. Reactions were monitored by TLC on Merck silica gel 60 F254 plates visualized by
UV lump at 254 nm. Products were purified by column chromatography on silica gel (120–200) mesh.
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SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai.
3. Significant Results and Discussion
We started our initial investigations by choosing 2-iodo-N-phenylbenzamide (1a) as a model substrate, phenyl format as CO
source in the presence of palladium catalyst and NEt3 as a base at 80 °C (Table 1). Initially, different bidentate nitrogen ligands
such as 1,10-phenanthroline, 2,2'-bipyridine, bathophenanthroline were screened (Table 1, entries 2–4). It was found that 2,2’bipyridine provided N-phenyl phthalimide (3a) in 60% yield (Table 1, entry 2). Furthermore, switching from aromatic bidentate
ligand towards aliphatic bidentate ligand significant improvement in the yield of 3a was observed (Table 1, entry 5).
Subsequently, we have screened various palladium precursors (Table 1, entries 6–9), among them PdCl2(PhCN)2 gave 3a in
93% yield (Table 1, entry 7). However, the reaction did not proceed in the absence of catalyst (Table 1, entry 10). Next, we
have also studied the effect of various solvents and it was observed that polar solvents are more effective for this transformation
(Table 1, entries 11–13). Surprisingly, reaction also works very well in solvent free condition furnishing 3a in 92% yield (Table
1, entry 14).
To evaluate the scope and limitations of developed protocol, we have applied optimized reaction parameters to various Nsubstituted 2-iodobenzamides and series of N-substituted 2-iodobenzamides were converted to the corresponding phthalimides
in good to excellent yields (Table 2). Notably, various substituents on N-phenyl ring were also well tolerated, including halo
groups such as -F, -Cl, electron-donating groups such as -CH3, -OMe and electron-withdrawing group such as nitro group
providing corresponding products in excellent yields (3b–3f). Furthermore, N-benzyl, N-benzyl bearing cyano and t-butyl
substituents were also sustainable at present condition (3g–3i). Next, various simple N-aliphatic as well as N-cyclic substituents
also works well and furnished corresponding N-substituted phthalimides (3j–3o) in good yields. Moreover, heterocyclic
substituents such as pyridine, substituted pyridine, thiazole and quinoline are also compatible under the present catalytic system
(3p–3s). Chiral N-substituted 2-iodobenzamides are also works under the present reaction conditions which furnish the
corresponding phthalimides (3t and 3u) in good yields. To our delight, chiral amino acid derived 2-iodobenzamides were tested
under the optimized reaction condition, giving good yield of the corresponding phthalimides (5a and 5b) (Scheme 1).
Our success in carbonylative cyclization of N-substituted 2-iodobenzamides inspired us to investigate the cyclization of 2iodoanilides. Initially, optimized parameters for phthalimide synthesis were applied for synthesis of benzoxazinone. However,
formation of 7a was observed in poor yield. Consequently, we switched towards phosphine ligands and various phosphine
ligands were tested. Among them xantphos serves as a best ligand giving 7a in 90% yield (See SI). We pleased to mention that
various 2-iodoanilides were converted into corresponding benzoxazinones in good to excellent yields (Table 3). Using
optimized conditions various substituents on aryl groups having both electron-donating and electron-withdrawing groups (7b–
7e), halide groups (7f–7i), benzyl and substituted benzyl groups (7j–7k), simple and functionalized alkyl groups (7l–7n) and
heterocycle (7o) were introduced at second position of benzoxazinones. Next, we have engaged 2-iodoanilide with m-chlorine
substituent, giving corresponding benzoxazinone 7p in 75% yield.
Phenyl formate decomposes into CO and phenol in presence of triethylamine (Table 4).11 Our blank experiment clearly
indicates that metal and solvent are not mandatory for the decomposition of phenyl formate into CO and phenol (Table 4, entry
4).
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SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai.
3.2 Figures, Schemes and Tables
Fig 1. Carbon monoxide free synthesis of phthalimide and benzoxazinone .
Table 1. Screening of Reaction Parameater a
a
entry
catalyst
ligand
solvent
yield (%)b
1
Pd(OAc)2
-
DMF
10
2
Pd(OAc)2
2,2'-bipyridine
DMF
60
3
Pd(OAc)2
1,10-phenanthroline
DMF
38
4
Pd(OAc)2
bathophenanthroline
DMF
45
5
Pd(OAc)2
TMEDA
DMF
88
6
PdCl2(PPh3)2
TMEDA
DMF
70
7
PdCl2(PhCN)2
TMEDA
DMF
93
8
Pd (PPh3)4
TMEDA
DMF
69
9
Pd (dba)2
TMEDA
DMF
70
10
-
TMEDA
DMF
00
11
PdCl2(PhCN)2
TMEDA
THF
64
12
PdCl2(PhCN)2
TMEDA
Toluene
45
13
PdCl2(PhCN)2
TMEDA
ACN
81
14
PdCl2(PhCN)2
TMEDA
-
92c
Reaction conditions: 1a (0.5 mmol), 2 (1 mmol), catalyst (4 mol %), ligand (8 mol %)
and NEt3 (1 mmol) in solvent (1 mL) then the reaction mixture was stirred for 18 h at
80 °C. bGC yields. cusing 2 mmol of NEt3.
3
SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai.
Table 2. Scope for CO Free Phthalimide Synthesis a
a
Reaction conditions: 1a-1u (0.5 mmol), 2 (1 mmol), PdCl2(PhCN)2 (4 mol %), TMEDA (8 mol %)
and NEt3 (2 mmol), then the reaction mixture was stirred for 18 h at 80 °C. b1 mL DMF was used as
solvent.
Scheme 1. Amino acid derived chiral phthalimide synthesis
4
SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai.
Table 3. Scope for CO Free Synthesis of Benzoxazinones a
a
Reaction conditions: 6a-6p (0.5 mmol), 2 (1 mmol), PdCl2(PhCN)2 (4 mol %), xantphos (8 mol %)
and NEt3 (1 mmol) were dissolved in toluene (1 mL), then the reaction mixture was stirred for 18 h
at 80 °C.
Table 4. Decomposition of phenyl formate into CO and phenol a
entry
catalyst
base
solvent
yield of phenol
(%)b
1
PdCl2(PhCN)2
NEt3
DMF
99
2
-
NEt3
DMF
99
3
-
-
DMF
>10
4
-
NEt3
-
99
a
Reaction conditions: Phenyl formate (2 mmol), PdCl2(PhCN)2 (4 mol%), NEt3 (4 mmol),
DMF (1 mL), then the reaction mixture was stirred for 18 h at 80 °C. bGC yields.
5
SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai.
4. Conclusions:
In conclusion, the present protocol reports an highly efficient PdCl 2(PhCN)2 catalyzed carbonylative cyclization of 2iodobenzamides and 2-iodoanilides to give phthalimides and benzoxazinones respectively by using phenyl formate as a greener
CO source. The protocol is phosphine and solvent-free method for the synthesis of various phthalimide derivatives. Moreover,
for the first time, the process was successfully applied for CO free carbonylative cyclization of amino acid derived N-substituted
2-iodobenzamides.
References
[1] S. P. Chavan and B. M. Bhanage, Eur. J. Org. Chem., 2015: 2405–2410.
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