Selenium-promoted intramolecular oxidative amidation of 2-(arylamino)acetophenones for the synthesis of N-arylisatins

Article abstract of DOI:10.1002/ejoc.201300477

A convenient method for the synthesis of N-arylisatins from 2-(arylamino)acetophenones by using SeO₂ as an oxidant is described. Various substituted N-arylisatins were selectively obtained in good to excellent yields. The reaction tolerates a wide range of functionalities. Copyright

Full text of DOI:10.1002/ejoc.201300477

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SHORT COMMUNICATION
Oxidative Amidation
An efficient method for the synthesis of N-
arylisatins from 2-(arylamino)aceto-
Y. Liu, H. Chen, X. Hu, W. Zhou,*
G.-J. Deng* ....................................... 1–5
phenones by using SeO2 as an oxidant un-
der transition-metal-free conditions is de-
scribed. The reaction proceeds smoothly in
dioxane at 80 °C and gives the correspond-
ing products in high yields. The reaction
tolerates a wide range of functionalities.
Selenium-Promoted Intramolecular Oxi-
dative Amidation of 2-(Arylamino)aceto-
phenones for the Synthesis of N-Arylisatins
Keywords: Nitrogen heterocycles / Fused-
ring systems / Amidation / Selenium / Oxi-
dation
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Y. Liu, H. Chen, X. Hu, W. Zhou, G.-J. Deng
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300477
Selenium-Promoted Intramolecular Oxidative Amidation of 2-(Arylamino)-
acetophenones for the Synthesis of N-Arylisatins
Yong Liu,[a] Hui Chen,[a] Xiong Hu,[a] Wang Zhou,*[b] and Guo-Jun Deng*[a]
Keywords: Nitrogen heterocycles / Fused-ring systems / Amidation / Selenium / Oxidation
A convenient method for the synthesis of N-arylisatins from
2-(arylamino)acetophenones by using SeO2 as an oxidant is
described. Various substituted N-arylisatins were selectively
obtained in good to excellent yields. The reaction tolerates a
wide range of functionalities.
formamides by using oxygen as an oxidant [see Eq. (2) in
Scheme 1].[8] Various N-alkylisatins were synthesized under
relatively mild reaction conditions.
Introduction
Isatins (indoline-2,3-diones) are an important class of
heterocycles and are commonly found in many natural com-
pounds, pharmaceuticals, and dyes.[1] The higher reactivity
of the C3 ketone carbonyl in isatins can be exploited to
further introduce functionalization for the preparation of 3-
substituted oxindoles, and this makes isatins versatile syn-
thetic building blocks in organic synthesis.[2] Consequently,
the development of efficient methods for the rapid con-
struction of isatins has stimulated considerable interest.
Conventional methods for the synthesis of these important
compounds mainly involve the strong acid (often H2SO4)
or base-mediated condensation of aniline with diethyl keto-
malonate (Martinet procedure),[3] oxalyl chloride (Stollé
procedure),[4] or chloral hydrate [Sandmeyer procedure, see
Eq. (1) in Scheme 1].[5] Isatin is commercially available in
large quantities and readily undergoes aromatic substitu-
tion reactions at C-5 and N-alkylation via an anion; thus,
direct functionalization of unsubstituted isatin can provide
an alternative approach for the preparation of substituted
isatins.[6] Although these methods provided useful access to
substituted isatins,[7] there are noticeable drawbacks associ-
ated with them, such as harsh reaction conditions, limited
substrate scope, and the need for an excess amount of acid
or base. Transition-metal-catalyzed cross-coupling reactions
have proved to be very useful tools for constructing substi-
tuted heterocycles. In 2010, Li et al. reported a protocol for
the synthesis of N-substituted isatins through the copper-
catalyzed intramolecular C–H acylation of formyl-N-aryl-
Scheme 1. Different strategies for the formation of substituted isa-
tins.
N-Alkylisatins can be easily prepared, but in contrast, N-
arylisatins remain underexplored partly because there is a
limited number of methods available for their preparation,
and most of those methods suffer from poor yields and lim-
ited scope.[9] The direct arylation of free N-H isatins with
aryl boronic acids is a useful approach for the preparation
of N-arylisatins.[10] However, this method suffers from low
yields and only para- and meta-substituted aryl boronic ac-
ids work well in most cases. More recently, Larock et al.
developed a F–-promoted reaction of arynes with methyl 2-
oxo-2-(arylamino)acetates to afford various N-arylisatins in
good yields [see Eq. (3) in Scheme 1].[11] Because N-arylisat-
ins have exhibited impressive biological properties and be-
cause they can be readily used as key intermediates for the
[a] Key Laboratory of Environmentally Friendly Chemistry and
Application of Ministry of Education, College of Chemistry,
Xiangtan University
Xiangtan 411105, China
Fax: +86-731-5829-2251
E-mail: gjdeng@xtu.edu.cn
[b] College of Chemical Engineering, Xiangtan University,
Xiangtan 411105, China
E-mail: wzhou@xtu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300477.
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Selenium-Promoted Intramolecular Oxidative Amidation
synthesis of potent drugs (Scheme 2),[10c,10d] the design of entry 18). Temperature also played an important role, and
general and direct approaches for the preparation of N-aryl- the reaction yield decreased to 53% if the reaction tempera-
isatins is highly desirable. In recent years, the transition- ture was decreased to 50 °C (Table 1, entry 19). A high yield
metal-catalyzed oxidative amidation of aldehydes (or from could be achieved if the reaction was carried out under an
alcohols by dehydrogenation) with amines has proved to atmosphere of argon (Table 1, entry 20).
be a powerful and environmentally benign strategy for the
Table 1. Optimization of the reaction conditions.[a]
preparation of amides.[12] Other carbonyl-containing com-
pounds such as α-carbonyl aldehydes[13] and acetophen-
ones[14] (the methyl group adjacent to the carbonyl group
was oxidized in situ) were also successfully employed for
this kind of transformation and afforded α-ketoamides in
high yields. Peroxides and even molecular oxygen can act
as an efficient oxidant for this kind of amidation reaction
between amines and carbonyl compounds. Inspired by these
discoveries, herein we report the SeO2-promoted intramo-
lecular oxidative amidation of 2-(arylamino)acetophenones
to afford various N-arylisatins in high yields under mild
reaction conditions.
Scheme 2. N-Arylisatins as key intermediates for drug synthesis.
Results and Discussion
Our investigation began with the reaction of 1-[2-(phen-
ylamino)phenyl]ethanone (1a) under oxidative reaction
conditions in 1,4-dioxane. As the screening of transition
[c] Under an atmosphere of argon.
metal catalysts did not improve the reaction yield, we fo-
[a] Reaction conditions: 1a (0.5 mmol), solvent (1 mL), 24 h in air
unless otherwise noted. NMP = N-methylpyrrolidone. [b] GC yield.
cused our investigation on transition-metal-free conditions,
With the optimized reaction conditions in hand, we then
and the results are summarized in Table 1. Organic and in- explored the scope and generality of this transformation.
organic oxidants such as benzoyl peroxide (BPO), dicumyl The effect of different substituents on the N-aryl ring is
peroxide (DCP), di-tert-butyl peroxide (DTBP), 1,4-benzo- listed in Table 2. Substrates bearing electron-donating
quinone (BQ), PhI(OAc)2, 2,2,6,6-tetramethylpiperidyl-1- groups such as methyl and methoxy groups on the aromatic
oxyl (TEMPO), and K2S2O8 were tested for this transfor- ring could be selectively converted into the corresponding
mation, but the desired 1-phenylindoline-2,3-dione (2a) products in excellent yields (Table 2, entries 2 and 3). Hal-
product was not formed, as determined by GC–MS and 1H ogens such as fluoro, chloro, bromo, and iodo were well
NMR spectroscopy (Table 1, entries 1–8). To our delight, tolerated under the optimized reaction conditions, and the
the desired product was obtained in 98% yield if SeO2 desired products were obtained in high yields (Table 2, en-
(2 equiv.) was used as the oxidant in air at 80 °C (Table 1, tries 5–8). Functional groups such as trifluoromethyl and
entry 9). Solvents played an important role, and the use of ester were tolerated, and desired products 2i and 2j were
solvents other than dioxane led to much lower yields obtained in 95 and 93% yield, respectively (Table 2, en-
(Table 1, entries 10–16). The use of 2 equiv. of SeO2 is nec- tries 9 and 10). The position of the substituents on the
essary to achieve a satisfactory yield, and the reaction yield phenyl ring affected the reaction yield slightly. Good to ex-
decreased to 59% when 1 equiv. of SeO2 was used (Table 1, cellent yields were obtained if 1-[2-(o-tolylamino)phenyl]-
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Y. Liu, H. Chen, X. Hu, W. Zhou, G.-J. Deng
SHORT COMMUNICATION
ethanone (1k) and 1-[2-(m-tolylamino)phenyl]ethanone (1l) Table 3. Substituent effect on acetophenone ring.[a]
were used as starting materials (Table 2, entries 11 and 12).
More sterically congested substrates such as 1-[2-(naphth-
alen-1-ylamino)phenyl]ethanone (1m) also efficiently cou-
pled to give desired product 2m in 79% yield (Table 2, en-
try 13). Notably, this method is also suitable for the prepa-
ration of N-alkylisatins without further optimization of the
reaction conditions. When 1-[2-(ethylamino)phenyl]eth-
anone (1n) was used as the starting material, corresponding
product 2n was obtained in 78% yield (Table 2, entry 14).
Table 2. SeO2-promoted formation of N-arylisatins.[a]
[a] Conditions: 1 (0.5 mmol), dioxane (1 mL), SeO2 (1.0 mmol),
80 °C, 24 h in air. [b] Isolated yield.
On the basis of observations by others[13,14] and our-
selves, a tentative mechanism to rationalize this transforma-
tion is illustrated in Scheme 3. The methyl group in 1a is
oxidized into the corresponding carbonyl group in the pres-
ence of SeO2 and generates intermediate A.[15] The addition
of the glyoxal group with amine generates hemiaminal in-
termediate B. Subsequently, intermediate B is oxidized by
SeO2 to produce 2a.
[a] Conditions: 1 (0.5 mmol), dioxane (1 mL), SeO2 (1.0 mmol),
80 °C, 24 h in air. [b] Isolated yield.
Scheme 3. Proposed reaction pathway.
To explore the scope of the reaction further, a number of
substituted acetophenone derivatives were employed under
the optimized conditions (Table 3). A series of functional
Conclusions
groups including methyl, methoxy, fluoro, chloro, and
In summary, we have developed an efficient method for
bromo were well tolerated under the optimal reaction con- the synthesis of N-arylisatins from 2-(arylamino)aceto-
ditions (Table 3, entries 1–5). However, a trifluoromethoxy phenones by using SeO2 as an oxidant under transition-
substituent dramatically decreased the reaction yield, and metal-free conditions. The reaction proceeds smoothly in
desired product 2t was obtained in only 56% yield (Table 3, dioxane at 80 °C and gives the corresponding products in
entry 6). The position of the substituents on the aromatic high yields. Functional groups such as methyl, methoxy,
ring of acetophenone significantly affected the reaction fluoro, chloro, bromo, iodo, and ester were all tolerated un-
yield (Table 3, entries 7 and 8).
der the optimized reaction conditions. This method affords
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Selenium-Promoted Intramolecular Oxidative Amidation
Senwar, R. Sharma, V. Grover, V. A. Nair, Green Chem. 2011,
an efficient alternative for the synthesis of N-arylisatins
with a wide substrate scope and good functional group
tolerance. The scope, mechanism, and synthetic applica-
tions of this reaction are under investigation.
13, 2553–2560.
[6] a) F. D. Popp, Adv. Heterocycl. Chem. 1975, 18, 1–58; b) O. L.
Erdmann, J. Prakt. Chem. 1840, 19, 321–362; c) A. Laurent,
Ann. Chin. Phys. 1840, 3, 393–434; d) A. Laurent, J. Prakt.
Chem. 1842, 25, 430–474; e) J. S. Yadav, Synthesis 2007, 693–
696.
[7] For other examples of the synthesis of isatins, see: a) K. Smith,
G. A. El-Hiti, A. G. Hawes, Synthesis 2003, 2559–2563; b) K.
Smith, G. El-Hiti, A. C. Hawes, Synthesis 2003, 2047–2052; c)
J. S. Yadav, B. V. Reddy, C. Reddy, A. D. Krishna, Tetrahedron
Lett. 2007, 48, 2029–2032; d) C. Kumar, C. Devi, V. J. Rao, S.
Palaniappan, Synlett 2008, 2023–2027; e) B. Soederberg, S. P.
Gorugantula, C. R. Howerton, J. Petersen, S. Dantale, Tetrahe-
dron 2009, 65, 7357–7363; f) M. Oezil, E. Mentese, F. Yilmaz,
F. Islamoglu, B. Kahveci, J. Chem. Res. Synop. 2011, 35, 268–
271; g) R. Shah, B. Chauhan, M. Patel, N. Modi, M. J. Parel,
L. Patel, Med. Chem. Res. 2011, 20, 587–594.
[8] B. X. Tang, R. J. Song, C. Y. Wu, M. B. Zhou, W. T. Wei, G. B.
Deng, D. L. Yin, J. H. Li, J. Am. Chem. Soc. 2010, 132, 8900–
8902.
[9] a) D. Chan, Tetrahedron Lett. 1996, 37, 9013–9016; b) L. He,
P. Chan, W. Tsui, W. Yu, C. M. Che, Org. Lett. 2004, 6, 2405–
2408; c) A. V. Shindikar, F. Khan, C. L. Viswanathan, Eur. J.
Med. Chem. 2006, 41, 786–792; d) S. N. Murhty, B. Madhav,
V. P. Reddy, Y. Nageswar, Adv. Synth. Catal. 2010, 352, 3241–
3245.
[10] a) P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon, P. K. Jad-
hav, Tetrahedron Lett. 2001, 42, 3415–3418; b) G. Chiang, T.
Olsson, Org. Lett. 2004, 6, 3079–3082; c) M. J. Konkel, M.
Packiarajan, H. Chen, U. P. Topiwala, H. Jimenez, I. J. Talis-
man, H. Coate, M. W. Walker, Bioorg. Med. Chem. Lett. 2006,
16, 3950–3954; d) M. G. Bursavich, A. M. Gilbert, S. Lom-
bardi, K. E. Georgiadis, E. Reifenberg, C. R. Flannery, E. A.
Morris, Bioorg. Med. Chem. Lett. 2007, 17, 5630–5633; e) R.
Romagnoli, P. G. Barldi, O. Cruz-Lopez, D. Preti, J. Bermejo,
F. Estavez, ChemMedChem 2009, 4, 1668–1676.
Experimental Section
General Procedure: A 25 mL, oven-dried reaction vessel was
charged with 1-[2-(phenylamino)phenyl]ethanone (1a, 0.5 mmol,
106 mg), SeO2 (1 mmol, 110 mg), and 1,4-dioxane (1 mL). The re-
sulting solution was stirred at 80 °C for 24 h in air. After cooling
to room temperature, the volatiles were removed under vacuum,
and the residue was purified by column chromatography (silica gel,
petroleum ether/ethyl acetate = 5:1) to give 2a as a red solid
(109 mg, yield 98%).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H NMR and
NMR spectra.
C
13
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (grant number 21172185), the Hunan Prov-
incial Natural Science Foundation of China (grant numbers
11JJ1003, 12JJ7002), the New Century Excellent Talents in Univer-
sity from Ministry of Education of China (grant number NCET-11-
0974), and the Research Fund for the Doctoral Program of Higher
Education of China, Ministry of Education of China (grant
number 20124301110005).
[1] a) W. C. Sumpter, Chem. Rev. 1944, 34, 393–434; b) S. N. Pand-
eya, S. Smitha, M. Jyoti, S. Sridhar, Acta Pharm. 2005, 55,
27–46; c) K. L. Vine, L. Matesic, J. M. Locke, M. Ranson, D.
Skropeta, Anti-Cancer Agents Med. Chem. 2009, 9, 397–414;
d) S. J. Shuttleworth, D. Nasturica, C. Gervais, M. A. Siddiqui,
R. F. Rando, N. Lee, Bioorg. Med. Chem. Lett. 2000, 10, 2501–
2504; e) A. K. Franz, P. D. Dreyfuss, S. L. Schreiber, J. Am.
Chem. Soc. 2007, 129, 1020–1021; f) K. J. Kilpin, W. Hender-
son, B. K. Nicholson, Polyhedron 2007, 26, 204–213; g) J. Itoh,
S. B. Han, M. J. Krische, Angew. Chem. 2009, 121, 6431–6434;
Angew. Chem. Int. Ed. 2009, 48, 6313–6316.
[11] D. C. Rogness, R. C. Larock, J. Org. Chem. 2011, 76, 4980–
4986.
[12] For a review, see: a) C. Gunanathan, D. Milestein, Acc. Chem.
Res. 2011, 44, 588–602; for selected examples, see: b) W. J. Yoo,
C. J. Li, J. Am. Chem. Soc. 2006, 128, 13064–13065; c) C. Gun-
anathan, Y. Ben-David, D. Milstein, Science 2007, 317, 790–
792; d) J. W. Bode, S. S. Sohn, J. Am. Chem. Soc. 2007, 129,
13798–13799; e) L. Nordstrøm, H. Vogt, R. Madsen, J. Am.
Chem. Soc. 2008, 130, 17672–17673; f) J. F. Soulé, H. Miya-
mura, S. Kobayashi, J. Am. Chem. Soc. 2011, 133, 18550–
18553; g) Y. Wang, D. Zhou, L. Tang, S. Wang, Z. Y. Wang,
Angew. Chem. 2011, 123, 9079–9083; Angew. Chem. Int. Ed.
2011, 50, 8917–8921; h) H. X. Zeng, Z. B. Guan, J. Am. Chem.
Soc. 2011, 133, 1159–1161.
[2] a) J. J. Barluenga, C. Valdés, in: Modern Heterocyclic Chemistry
(Eds.: J. Alvarez-Builla, J. J. Vaquero, J. Barluenga), Wiley-
VCH, Weinheim, Germany, 2011, p. 495–496; b) S. J. Garden,
R. D. da Silva, A. C. Pinto, Tetrahedron 2002, 58, 8399–8412; [13] a) C. Zhang, Z. J. Xu, L. R. Zhang, N. Jiao, Angew. Chem.
c) R. Shintani, M. Inoue, T. Hayashi, Angew. Chem. 2006, 118,
3431–3434; Angew. Chem. Int. Ed. 2006, 45, 3353–3356; d) P. Y.
Toullec, R. B. C. Jagt, J. G. de Vries, B. L. Feringa, A. J. Min-
naard, Org. Lett. 2006, 8, 2715–2718.
2011, 123, 11284–11288; Angew. Chem. Int. Ed. 2011, 50,
11088–11092; b) C. Zhang, X. L. Zong, L. R. Zhang, N. Jiao,
Org. Lett. 2012, 14, 3280–3283.
[14] a) F. T. Du, X. Ji, Chem. Sci. 2012, 3, 460–465; b) X. B. Zhang,
L. Wang, Green Chem. 2012, 14, 2141–2145; c) W. Wei, Y. Shao,
H. Y. Hu, F. Zhang, C. Zhang, Y. Xu, X. B. Wan, J. Org. Chem.
2012, 77, 7157–7165.
[15] a) B. Harikrishna, B. Sanjay, Eur. J. Org. Chem. 2012, 2935–
2944; b) B. Eftekhari-Sis, M. Zirak, A. Akbari, M. M. Hash-
emi, J. Heterocycl. Chem. 2010, 47, 463–467; c) S. S. Bhella, M.
Elango, M. P. S. Ishar, Tetrahedron 2009, 65, 240–246.
Received: April 3, 2013
[3] a) A. Guyot, J. Martinet, Compt. Rend. 1913, 166, 1625–1628;
b) J. Bonnefoy, J. Martinet, Compt. Rend. 1921, 172, 220–221.
[4] a) R. Stollé, J. Prakt. Chem. 1923, 105, 137–148; b) R. Stollé,
Ber. Dt. Chem. Ges. 1913, 46, 3915–3916.
[5] a) T. Sandmeyer, Helv. Chim. Acta 1919, 2, 234–242; b) S. S.
Karki, S. Thota, S. Y. Darj, J. Balzarini, E. Xlercq, Bioorg.
Med. Chem. 2007, 15, 6632–6641; c) A. C. Pinto, A. A. M.
Lapis, B. V. da Silva, R. S. Bastos, J. Dupont, B. A. D. Neto,
Tetrahedron Lett. 2008, 49, 5639–5641; d) M. Chouhan, K. R.
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