Copper-Catalyzed C–N, C–O Coupling Reaction of Arylglyoxylic Acids with Isatins

Article abstract of DOI:10.1002/adsc.201600516

The copper(II)-catalyzed decarboxylative coupling reactions of arylglyoxylic acids with isatins afford 4H-benzo[d][1,3]oxazin-4-ones via decarbonylation and concurrent C–N, C–O bond formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201600516

COMMUNICATIONS
DOI: 10.1002/adsc.201600516
Copper-Catalyzed C–N, C–O Coupling Reaction of Arylglyoxylic
Acids with Isatins
Rashmi Prakasha and Sanjib Gogoia,*
a
Chemical Sciences & Technology Division, CSIR–North East Institute of Science and Technology, Jorhat – 785006,
AcSIR, India
Fax : (+91)-37–6237-0011; phone: (+91)-37–6237-2948; e-mail: skgogoi1@gmail.com
Received: May 15, 2016; Revised: July 12, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600516.
Abstract: The copper(II)-catalyzed decarboxylative
coupling reactions of arylglyoxylic acids with isatins
afford 4H-benzo[d][1,3]oxazin-4-ones via decarbon-
ylation and concurrent C–N, C–O bond formation.
Keywords: arylglyoxylic acids; benzooxazinones;
copper; decarbonylation; decarboxylative C–N cou-
pling
In the past decade, transition metal-catalyzed decar-
boxylative coupling reactions have attracted consider-
able interest in C–C bond formation reactions.[1] As
the carboxyl group can direct the regioselectivity of
the reaction and the only waste material is carbon di-
oxide, this metal-catalyzed reaction turns out to be
a very useful synthetic method for C–C bond forma-
Scheme 1. Decarboxylative C–N coupling reactions.
Initially, isatin 1a and phenylglyoxylic acid 2a were
tion. Recently, arylcarboxylic acids have been used chosen as the model compounds to optimize the reac-
for the transition metal-catalyzed decarboxylative C– tion conditions for the synthesis of 3aa[5j] (Table 1).
N cross-coupling reactions with N-nucleophiles which Fortunately, in the presence of 20 mol% of Cu(OAc)2,
afford C–N coupling products [Scheme 1, Eq. (1)].[2] the reaction afforded a 67% yield of 3aa in t-AmOH
Similarly, a-oxocarboxylic acids have also been suc- (entry 1). Increasing the catalyst loading to 30 mol%
cessfully utilized as acyl nucleophiles in transition provided a better yield of 3aa (entry 2). Among a set
metal-catalyzed decarboxylative coupling reactions of copper sources screened for this reaction, none of
for C–C bond formation reactions.[3] Nevertheless, a- them provided better yields than Cu(OAc)2 (en-
oxocarboxylic acids have never been used in metal- tries 3–7). Further screening of solvents showed that
catalyzed decarboxylative coupling reactions for C–N t-AmOH was superior to other solvents such as NMP,
bond formation reactions. In continuation of our H2O and toluene (entries 8–10). Performing the reac-
work on the development of novel metal-catalyzed tion under 1 atm of O2 did not further improve the
routes for the syntheses of important heterocycles,[4] yield of 3aa (entry 11). The use of commonly used li-
herein, we report an unprecedented Cu(II)-catalyzed gands in copper-catalyzed reactions such as 1,10-phen-
decarboxylative coupling reaction for the formation
ACHTUNGTRENaNUNG nthroline, DABCO and 2,2’-bipyridine provided
of C–N bonds [Scheme 1, Eq. (2)]. This decarboxyla- lower yields of 3aa (entries 12–14).
tive cross-coupling reaction of arylglyoxylic acids with
With the optimized reaction conditions in hand, we
isatins as nucleophiles leads to the formation of C–N first tested its scope in the coupling reaction of phe-
and C–O bonds simultaneously, via decarbonylation nylglyoxylic acid (2a) with representative isatins 1a–1j
of isatin, to afford a wide range of pharmaceutically (Table 2). The isatins substituted with electron-donat-
important substituted 4H-benzo[d][1,3]oxazin-4-ones.[5]
ing groups and electron-withdrawing groups such as
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 1. Optimization of the reaction conditions.[a]
Table 2. Scope of substituted isatins (1a–j).[a]
Entry [Cu] (30 mol%) Ligand
Solvent 3aa [%][b]
1[c]
2
3
4
5
Cu(OAc)2
Cu(OAc)2
CuCl2
CuBr2
Cu(OTf)2
CuI
–
–
–
–
–
–
–
t-AmOH 67
t-AmOH 82
t-AmOH 21
t-AmOH 61
t-AmOH 60
t-AmOH 58
t-AmOH 31
6
7
Cu2O
8
9
10
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
–
–
–
NMP
H2O
toluene 48
t-AmOH 77
t-AmOH 64
t-AmOH 50
72
57
11[d] Cu(OAc)2
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
1,10-Phen
DABCO
2,2-bipyridine t-AmOH 61
[a]
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol),
copper salt (30 mol%), ligand (40 mol%) and solvent
(4 mL) at 958C under air for 24 h; unless otherwise men-
tioned.
Isolated yields.
20 mol% catalyst.
[b]
[c]
[d]
Under O2 (1.0 atm).
CH3, OCH3, OCF3, F, Cl and Br at different positions
of the phenyl ring were well tolerated, providing ben-
zooxazinones 3aa–3ja in good yields.
Isatins bearing electron-withdrawing groups on the
aromatic ring provided slightly higher yields of ben-
zooxazinones (3fa–3ja). The halo-substituted ben-
[a]
Reaction conditions: isatin (1.0 mmol), a-keto acid
(1.0 mmol) and Cu catalyst (30 mol%) in t-AmOH
(4.0 mL) were heated at 958C for 24 h under air; isolated
yields.
zooxazinone derivatives thus obtained could be used that a-naphthyl- and a-heteroaryl- substituted oxocar-
for further transformations. The position of the sub- boxylic acids (2i and 3j) were also well tolerated to
stituents on the aromatic ring of isatin had little effect provide benzooxazinones 3ai and aj under the stan-
on the yields of products (3ga–3ja). However, the re- dard conditions. To probe the wide scope of the de-
action between nitro group-substituted isatin and 2a carbonylative and decarboxylative coupling reaction,
did not work under the standard conditions.
electron-rich isatin (1b) was treated with electron-
Next, the coupling reaction of isatin 1a was tested poor a-oxocarboxylic acid (2e) to afford a good yield
with various functionalized a-oxocarboxylic acids 2b– of 3be. Similarly, the reaction of electron-poor isatin
j, which is shown in Table 3. Phenylglyoxylic acids (1g) with electron-rich a-oxocarboxylic acid (2b) and
substituted with electron-donating groups (2b–d), electron-poor a-oxocarboxylic acid (2c) also provided
electron-withdrawing groups (2e–g) and both elec- good yields of benzooxazinones 3gb and 3ge, respec-
tron-donating and electron-withdrawing groups (2h) tively. However, under the standard conditions, 3-ni-
were found to be good substrates for this cyclization trophenylglyoxylic acid, alkylglyoxylic acids such as
reaction to provide the corresponding benzooxazi- pyruvic acid and trimethylpyruvic acid did not react
nones (3ab–ah) in good yields. However, o-substituted with isatin. Finally, the new methodology was tested
phenylglyoxylic acid 2c afforded slightly inferior yield for the synthesis of the HDL elevator 3il
of benzooxazinone 3ac. We were delighted to observe (Scheme 2).[5c] To understand the mechanism of this
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 3. Synthesis of various substituted benzooxazinones.[a]
Scheme 2. Synthesis of the HDL elevator 3il.
[a]
Reaction conditions: isatin (1.0 mmol), a-keto acid
(1.0 mmol) and Cu catalyst (30 mol%) in t-AmOH
(4.0 mL) was heated at 958C for 24 h under air; isolated
yields.
Scheme 3. Control and isotope labelling experiments.
lecular kinetic isotope effect experiment performed
reaction, a series of experiments was conducted between 1a+1a-d4 (1:1) and 2a, displayed a secondary
(Scheme 3). Under the optimized reaction conditions, kinetic isotope effect [kH/kD =1.25, Eq. (6)].
the reaction of N–H protected isatin (4a) and phenyl-
Although the exact mechanism of the coupling re-
glyoxylic acid 2a did not proceed; it provided benzoic action is still not clear, based on our results and litera-
acid as the sole product [Eq. (3)]. This result indicat- ture reports, a plausible mechanism is proposed which
ed the presence of the free N–H group of the isatin is shown in Scheme 4.[6] The copper acetate-catalyzed
ring to be a crucial factor for this reaction. The ex- decarboxylation of a-oxocarboxylic acid (2a) gener-
pected intermediate 4b of the reaction, which was in- ates Cu(II) species 4a, which further reacts with isatin
dependently prepared, could not afford either the ex- to generate 4b. This Cu(II) species 4b might remain
pected amide bond cleavage products 2-(2-benzami- in equilibrium with Cu(II) species 4c due to migration
dophenyl)-2-oxoacetic acid/2-benzamidobenzoic acid of Cu into the neighbouring amide bond which, on
or the final compound 3aa under the standard reac- decarbonylation and subsequent rearrangement,
tion conditions [Eq. (4)]. Similarly, the reaction of forms seven-membered Cu intermediate 4e. Finally,
isatin alone [Eq. (5)] or the reaction of isatin with reductive elimination of 4e in presence of air and
benzoic acid could not provide the desired product acetic acid affords the desired product 3aa and regen-
under the optimized reaction conditions. The intermo- erates the Cu(II) catalyst. In the case of Cu(I)-cata-
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Acknowledgements
The authors thank SERB (DST), New Delhi, for financially
supporting us with GPP-0303 (File no. YSS/2014/001018)
project. We are grateful to the Director, CSIR–NEIST for his
keen interest.
References
[1] a) L. J. Goossen, N. Rodriguez, K. Goossen, Angew.
Chem. 2008, 120, 3111; Angew. Chem. Int. Ed. 2008, 47,
3100; b) O. Baudoin, Angew. Chem. 2007, 119, 1395;
Angew. Chem. Int. Ed. 2007, 46, 1373; c) N. Rodrꢁguez,
L. J. Goossen, Chem. Soc. Rev. 2011, 40, 5030.
[2] For decarboxylative C–N coupling reactions, see a) Y.
Zhang, S. Patel, N. Mainolfi, Chem. Sci. 2012, 3, 3196;
b) W. Jia, N. Jiao, Org. Lett. 2010, 12, 2000; c) C.-C.
Cho, J.-N. Liu, C.-H. Chien, J.-J. Shie, Y.-C. Chen, J.-M.
Fang, J. Org. Chem. 2009, 74, 1549.
Scheme 4. Plausible reaction mechanism.
[3] For selected references of use of a-oxocarboxylic acids,
see, a) G.-Z. Wang, R. Shang, W.-M. Cheng, Y. Fu, Org.
Lett. 2015, 17, 4830; b) H. Wang, L.-N. Guo, S. Wang,
X.-H. Duan, Org. Lett. 2015, 17, 3054; c) Ref.[1a]; d) Z.
Yang, X. Chen, J. Liu, Q. Gui, K. Xie, M. Li, Z. Tan,
Chem. Commun. 2013, 49, 1560.
lyzed reactions (entries 6–7, Table 1), initially, air oxi-
dation of Cu(I) to Cu(II) occurs, which catalyzes the
decarboxylation of the a-oxocarboxylic acid (2a) to
generate benzoyl Cu(II) species (4a).[6d]
[4] a) R. Prakash, K. Shekarrao, S. Gogoi, Org. Lett. 2015,
17, 5264; b) K. Shekarrao, P. P. Kaishap, S. Gogoi, R. C.
Boruah, Adv. Synth. Catal. 2015, 357, 1187; c) R. Pra-
kash, K. Shekarrao, S. Gogoi, R. C. Boruah, Chem.
Commun. 2015, 51, 9972.
In summary, we have described the first metal-cata-
lyzed decarboxylative cross-coupling reaction of aryl-
glyoxylic acids with N-nucleophiles isatins for the for-
mation of C–N bonds. This unprecedented Cu(II)-cat-
alyzed reaction which proceeds through decarboxyla-
tion, decarbonylation, C–N and C–O bond formation
affords a wide range of pharmaceutically important
4H-benzo[d][1,3]oxazin-4-ones efficiently in good
yields.
[5] For the importance and synthesis of 4H-benzo[d]
[1,3]oxazin-4-ones, see, a) R. Padwal, Curr. Opin. Invest.
Drugs 2008, 9, 414; b) G. Grover, S. G. Kini, Eur. J.
Med. Chem. 2006, 41, 256; c) G. Fenton, C. G. Newton,
B. M. Wyman, P. Bagge, D. I. Dron, D. Riddell, G. D.
Jones, J. Med. Chem. 1989, 32, 265; d) R. Giri, J. K.
Lam, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 686;
e) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford,
S. N. G. Tyler, M. R. Gagne, G. C. Lloyd-Jones, K. I.
Booker-Milburn, Angew. Chem. 2009, 121, 1862; Angew.
Chem. Int. Ed. 2009, 48, 1830; f) C. Larksarp, H. Alper,
Org. Lett. 1999, 1, 1619; g) Z. Zheng, H. Alper, Org.
Lett. 2008, 10, 829; h) X.-F. Wu, J. Schranck, H. Neu-
mann, M. Beller, Chem. Eur. J. 2011, 17, 12246; i) X.-F.
Wu, H. Neumann, M. Beller, Chem. Eur. J. 2012, 18,
12599; j) S. V. F. Hansen, T. Ulven, Org. Lett. 2015, 17,
2832.
Experimental Section
Typical Experimental Procedure
A solution of isatin 1 (1.0 mmol), a-oxocarboxylic acid 2
(1.0 mmol) and copper acetate (30 mol%) in tert-amyl alco-
hol (4.0 mL) was heated at 958C under air for 24 hours.
After completion of the reaction, the solvent was removed
under vacuum. The crude product obtained was purified by
column chromatography over silica gel (100–200 mesh)
using EtOAc/hexane (1:9) as the eluant to afford the 4H-
benzo[d][1,3]oxazin-4-one.
[6] a) L. Yu, P. Li, L. Wang, Chem. Commun. 2013, 49,
2368; b) X. Li, F. Yang, Y. Wu, Y. Wu, Org. Lett. 2014,
16, 992; c) T. Inami, T. Kurahashi, S. Matsubara, Org.
Lett. 2014, 16, 5660; d) S.-Y. Moon, J. Nam, K. Rathwell,
W.-S. Kim, Org. Lett. 2014, 16, 338.
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Copper-Catalyzed C–N, C–O Coupling Reaction of
Arylglyoxylic Acids with Isatins
5
Adv. Synth. Catal. 2016, 358, 1 – 5
Rashmi Prakash, Sanjib Gogoi*
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!