An efficient synthesis of 3-cyano-3-benzoyloxyoxindoles via cyanoacylation of isatins in the presence of 4 ? molecular sieves

Article abstract of DOI:10.1016/j.tetlet.2012.08.014

In the presence of 4 ? molecular sieves in CH₃CN, a process for the cyanobenzoylation and cyanocarbonylation of isatins with benzoycyanides and ethylcyanoformate under mild reaction conditions has been developed. This approach provides easy access to a wide range of 3-cyano-3-benzoyloxyoxindoles and 3-cyano-3-ethoxycarbonyloxyoxindoles in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.08.014

Tetrahedron Letters 53 (2012) 5605–5607
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Tetrahedron Letters
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An efficient synthesis of 3-cyano-3-benzoyloxyoxindoles via cyanoacylation
of isatins in the presence of 4 Å molecular sieves
Abbas Ali Esmaeili a,b, , Saeid Amini Ghalandarabad a, Mahdieh Zangouei a
⇑
a Department of Chemistry, University of Birjand, Birjand, PO Box 97175/615, Iran
b Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of 4 Å molecular sieves in CH3CN, a process for the cyanobenzoylation and cyanocarbony-
lation of isatins with benzoycyanides and ethylcyanoformate under mild reaction conditions has been
developed. This approach provides easy access to a wide range of 3-cyano-3-benzoyloxyoxindoles and
3-cyano-3-ethoxycarbonyloxyoxindoles in good to excellent yields.
Received 28 March 2012
Revised 22 July 2012
Accepted 2 August 2012
Available online 9 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyanobenzoylation
Cyanocarbonylation
Isatin
Catalyst-free
Molecular sieves
Cyanoacylation of aldehydes and ketones is an important car-
bon–carbon bond-forming reaction.1 Cyanohydrin derivatives can
In recent years, several effective reactions in the presence of 4 Å
molecular sieves have been developed. For example, cyanobenzoylation
be easily converted into a wide variety of compounds, such as
a-
amino acids, -hydroxy acids, -hydroxy aldehydes, -hydroxy ke-
a
a
a
Table 1
tones, b-amino alcohols, and vicinal diols.2 They are also compo-
nents of commercially significant compounds such as the
pyrethroid insecticides, cypermetrin, and fluvaliate.3 Among vari-
ous cyanide ion sources, acyl cyanides and alkyl cyanoformates
are safe and commercially available reagents.4–6 Although cyanoa-
cylation reactions are very efficient methods for the preparation of
cyanohydrins basic catalysts such as potassium carbonate,7 1,4-
diazabicyclo[2,2,2]octane (DABCO),8 DBU,9 Et3N,10 or catalyst-free
conditions11,12 are necessary to promote the reactions.
Effect of solvent on the cyanobenzoylation of N-benzylisatina
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
DMSO
DMF
CH2Cl2
THF
CH3CN
Solvent-free
20
20
60
60
10
70
85
Trace
85
Trace
95
60
a
Reactions were carried out using N-benzylisatin and benzoyl cyanide
(1.0 mmol) in solvent in the presence of 4 Å MS (200 mg) at rt for the appropriate
times.
Isatins have various biological activities. Some derivatives of
isatin are key intermediates in the synthesis of natural products.13
Oxindoles are well known among these compounds,14 which are
utilized as building blocks in the synthesis of alkaloids as well as
being potential therapeutic agents.15 In particular, 3-substituted-
3-hydroxyindolin-2-ones, a class of oxindoles, are found in several
biologically active alkaloids and pharmacological agents.16–18 Ow-
ing to the significance of this structural motif, numerous method-
ologies have been developed and continue to be explored for their
construction.19 Recently, Hanefeld and co-workers reported the
microbial catalyzed hydrolysis of the indole-2,3-dione derived cya-
nohydrin acetate.20
b
Isolated yield.
Table 2
Effect of additives on the cyanobenzoylation of N-benzylisatina
Entry
Additive
Amount of additive (mg)
Time (min)
Yieldb (%)
1
2
3
4
5
6
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 5 Å
MgSO4
—
120
10
15
20
60
60
Trace
95
95
85
Trace
Trace
200
150
100
500
500
a
All reactions were carried out in CH3CN using N-benzylisatin (1.0 mmol) and
⇑
Corresponding author at: Department of Chemistry, Ferdowsi University of
Mashhad, Mashhad, Iran. Tel.: +98 5118797022; fax: +98 5118795457.
benzoyl cyanide (1.0 mmol) at rt.
b
Yield of isolated product.
E-mail address: abesmaeili@um.ac.ir (A.A. Esmaeili).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.014

5606
A. A. Esmaeili et al. / Tetrahedron Letters 53 (2012) 5605–5607
Table 3
atives might readily proceed under appropriate reaction conditions. As
part of our ongoing studies on the development of new reactions of isa-
tins,27 we report an efficient method for cyanobenzoylation and cyano-
carbonation of isatins in the presence of 4 Å molecular sieves in dry
CH3CN, leading to 3-cyano-3-acyloxyoxindoles in high to excellent
yields (Table 3). To the best of our knowledge, there is no precedent
for the preparation 3-cyano-3-acyloxyoxindoles from isatins.
Initially, we undertook an examination of the solvent effect for
the cyanobenzoylation of N-benzylisatin (Table 1). The reaction of
N-benzylisatin with 1.1 equiv of benzoyl cyanide in CH3CN (2 mL)
at room temperature for 10 min afforded the corresponding cyano-
hydrin product 3f in 95% yield.28 When DMF or THF were used as
solvent, the yields of the cyanohydrin benzoate 3f were disap-
pointing (Table 1, entries 2 and 4). With DMSO or CH2Cl2, the reac-
tions proceeded smoothly (Table 1, entries 1 and 3). The product
was obtained in a lower yield under neat reaction conditions (Ta-
ble 1, entry 3).
Next, we studied the reaction in the presence of various dehy-
drating reagents (Table 2). When the reaction was performed with-
out an additive, no reaction occurred (entry 1). On the other hand,
the reaction in the presence of 4 Å MS (200 mg) proceeded very
smoothly to give the desired product in 95% yield (Table 2, entry
2). Other additives such as 5 Å MS, and MgSO4 were not effective
for this transformation (Table 2, entries 5 and 6). A screening of
the amount of 4 Å MS showed that the model reaction proceeded
smoothly, when 200 mg was used. We suppose that the molecular
sieves absorb the small amount of water present in the reaction
system preventing hydrolysis of benzoyl cyanide. Accordingly,
we used dry CH3CN (solvent), 4 Å MS (200 mg), (additive) and
room temperature as optimal reaction conditions.
Reaction of isatins 1 with cyanides 2 in the presence of 4 Å MS in dry CH3CN
O
N
O
R2
O
O
R3
R2
4 Å MS
dry CH3CN, r.t.
O
+
R3
O
N
N
N
R1
R1
1
2
3
Product
R1
R2
R3
Time (min)
Yielda (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
Me
Me
Et
Et
Et
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
Me
Me
Et
C6H5CH2
C6H5CH2
C6H5CH2
H
H
H
H
Br
H
H
Br
NO2
NO2
H
Br
H
C6H5
4-MeC6H4
C6H5
4-MeC6H4
4-MeC6H4
C6H5
4-MeC6H4
4-MeC6H4
C6H5
10
10
10
15
30
10
30
30
60
70
15
15
20
10
10
15
92
90
90
92
87
95
90
87
90
75
4-MeC6H4
EtO
92b
85b
90b
95b
78b
80b
EtO
EtO
EtO
EtO
H
Br
NO2
EtO
a
Isolated yield.
Addition 0.01 ml of DMSO.
b
of aldehydes, cyanocarbonation of aldehydes,12 trifluoromethylation of
carbonyl compounds,21 and Henry reactions,22 Knoevenagel reac-
tions,23 and Michael additions24 are documented. Due to the fact that
the highly reactive b-carbonyl group of isatin is susceptible to nucleo-
philic attack,25,26 we envisioned that the cyanoacylation of isatin deriv-
To examine the scope of this approach, different isatin deriva-
tives were subjected to the optimized reaction conditions (Table 3).
Figure 1. ORTEP diagrams of compound 3f.

A. A. Esmaeili et al. / Tetrahedron Letters 53 (2012) 5605–5607
5607
3. Lopez, O.; Fernandez-Bolanos, J. G.; Gil, M. V. Green Chem. 2005, 7, 431–442.
Various isatin derivatives bearing either electron-donating or elec-
tron-withdrawing substituents on the ring were excellent sub-
strates for this reaction leading to the corresponding products in
high to excellent yields (75–95%), (Table 3). The reaction also pro-
ceeded well with substrates bearing methyl, ethyl, and benzyl sub-
stituents at the N position in high to excellent yields. When, using
ethyl cyanoformate as the cyanoacylating component in the pres-
ence of 4 Å MS, the addition of a trace amount of DMSO was nec-
essary (Table 3, products 3k–p). The exact reason for this is not
clear, but we think that the DMSO acts as an acyl transfer agent
activating the ethyl cyanoformate, under the reaction conditions.
Accordingly, we use one drop of dry DMSO, 4 Å MS (200 mg), and
room temperature as optimal reaction conditions for the synthesis
of products 3k–p.
4. Hunig, S.; Schaller, R. Angew. Chem., Int. Ed. 1982, 21, 36–49.
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1997, 38, 1501–1504.
The structures of products 3a–p (Table 3) were deduced from
their elemental analyses, IR, mass, 1H NMR, and 13C NMR spectra.
The mass spectra of these compounds displayed molecular ion
peaks at the appropriate m/z (%) values (see Supplementary data).
For example, the IR spectrum of 3a showed two carbonyl groups
at 1730 and 1745 cmÀ1. The vibration band for the CN triple bond
stretching did not appear in the IR spectrum of 3 due to the elec-
tron-accepting oxygen and carbonyl groups.29 Nevertheless, the
appearance of a strong band at 2258 cmÀ1 in the FT-Raman spec-
trum of 3n, clearly confirmed the presence of a nitrile group in
the product (see Supplementary data). The 1H NMR spectrum of
3a exhibited a singlet readily recognized as arising from methyl
14. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970.
15. (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964; (b) Lin, H.;
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Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748–8758.
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Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem. 2002, 45, 1487–
1499.
19. (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–3415; (b) Shibata, N.;
Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001–7009; (c)
Alcaide, B.; Almendros, P.; Raquel, R. J. Org. Chem. 2005, 70, 3198–3204.
20. Paravidino, M.; Holt, J.; Romano, D.; Singh, N.; Arends, I. W. C. E.; Minnaard, A.
J.; Orru, R. V. A.; Molinari, F.; Hanefeld, U. J. Mol. Catal. B: Enzym 2010, 63, 87–
92.
21. Iwanami, K.; Oriyama, T. Synlett 2006, 112–114.
22. Oriyama, T.; Aoyagi, M.; Iwanami, K. Chem. Lett. 2007, 36, 612–613.
23. Chiba, R.; Oriyama, T. Chem. Lett. 2008, 37, 1218–1219.
24. Tomoko, K.; Takeshi, O. Tetrahedron Lett. 2010, 51, 290–292.
25. Silva, J. F. M. D.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273–324.
26. Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1–58.
27. (a) Esmaeili, A. A.; Bodaghi, A. Tetrahedron 2003, 59, 1169–1171; (b) Esmaeili,
A. A.; Darbanian, M. Tetrahedron 2003, 59, 5545–5548; (c) Esmaeili, A. A.;
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protons (3.35 ppm) and
a
characteristic multiplet (6.94–
7.19 ppm) due to one of the aromatic protons, along with three
multiplets for the other aromatic protons (7.43–7.51, 7.60–7.65
and 7.97–8.05 ppm).
The 13C NMR spectrum of 3a showed 15 distinct resonances in
agreement with the suggested structure (see Supplementary data).
Additionally, the structure of 3f was determined by single-crystal
X-ray analysis; two ORTEP diagrams of 3f, from different view-
points are shown in Figure 1, confirming unambiguously the struc-
tures and the presence of CN in the products.30
28. Typical procedure for the synthesis of products 3f: A mixture of an N-substituted
isatin (0.237 g, 1.0 mmol), benzoyl cyanide (0.145 g, 1.1 mmol), and 4 Å MS
(200 mg) in dry CH3CN (2 mL) was stirred at room temperature for the
indicated time (Table 3). The progress of the reaction was monitored by TLC.
After completion of the reaction, the MS were recovered by filtration, and
In conclusion, we have developed a convenient cyanoacylation
of isatins in CH3CN in the presence of 4 Å MS to give 3-cyano-3-
acyloxyindolin-2-ones in good to excellent yields. Further investi-
gations to broaden the scope and synthetic applications of this
efficient and convenient cyanation are underway in our laboratory.
washed with CH3CN. The filtrate was evaporated to dryness on
a rotary
evaporator under reduced pressure and the residue was crystallized from a
mixture of CH2Cl2 and petroleum ether, which yielded the pure product 1-
benzyl-3-cyano-2-oxoindon-3-yl-benzoate (3f): White solid, Mp: 137–139 °C.
Yield: 0.35 g (95%); IR (KBr) (m
max/cmÀ1): 1736 and 1720 (C@O), 1608 (Ar);
Acknowledgement
Anal. Calcd for C23H16N2O3 (368.38): C, 74.99; H, 4.38; N, 7.60. Found: C, 75.1;
H, 4.3; N, 7.7.; 1H NMR (299.8 MHz, CDCl3): dH (ppm) 4.88–5.07 (2H, AB
2
3
We gratefully acknowledge financial support from the Research
Council of the University of Birjand.
quartet, JHH = 7.9 Hz), 6.73 (2Harom, d, JHH = 3.9 Hz), 7.55–7.02 (8Harom, m),
7.59 (2Harom, d, 3JHH = 3.5 Hz), 8.03 (2Harom, d, 3JHH = 4 Hz); 13C NMR (75.4 MHz,
CDCl3): dC (ppm) 44.98 (NCH2), 70.91 (C3), 110.70 (CHarom), 113.63 (CN),
121.96 (Cipso), 124.16 (CHarom), 125.39 (CHarom), 127.30 (CHarom), 127.42 (Cipso),
128.12 (CHarom), 128.73 (CHarom), 129.06 (CHarom), 130.35 (CHarom), 132.40
(CHarom), 134.29 (Cipso), 134.47 (CHarom), 143.20 (Cipso), 163.48 (O–C@O),
166.51 (N–C@O); MS: m/z (%) 368 (M+, 28.1), 263 (1.3), 246 (7.2), 105 (100), 91
(55.6).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
014.
29. Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric Identification of
Organic Compounds, 7 ed.; John Wiley & Sons Inc: New York, 2005. p 103.
30. Crystal data for 3f: C23H16N2O3 (CCDC 760175): MW = 368.38, monoclinic,
space group P21/c, a = 10.944(2) Å, b = 12.153(2) Å, c = 28.799(6) Å,
b = 91.53(3), = 90°, V = 3828.8(13) Å3, Z = 8, Dc = 1.278 mg/m3,
(000) = 1536, crystal dimension 0.41 Â 0.33 Â 0.25 mm, radiation, MoK
a = 90
References and notes
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F
a
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