A novel and efficient synthesis of 3,3-disubstituted indol-2-ones via Passerini three-component reactions in the presence of 4 ? molecular sieves

Article abstract of DOI:10.1016/j.tetlet.2012.11.025

The Passerini coupling of cyclohexylisocyanide with isatins and carboxylic acids in the presence of 4 ? molecular sieves is described. This process offers a highly efficient and atom-economic access to 3-acyloxy-3-carboxamido-1, 3-dihydro-2H-indol-2-ones in high to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.11.025

Tetrahedron Letters 54 (2013) 406–408
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Tetrahedron Letters
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A novel and efficient synthesis of 3,3-disubstituted indol-2-ones via
Passerini three-component reactions in the presence of 4 Å molecular sieves
Abbas Ali Esmaeili a,b, , Saeid Amini Ghalandarabad a, Saeideh Jannati a
⇑
a Department of Chemistry, Faculty of Sciences, University of Birjand, Birjand, PO Box 97175/615, Iran
b Department of Chemistry, Faculty of Sciences, 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:
Received 3 July 2012
Revised 19 October 2012
Accepted 6 November 2012
Available online 14 November 2012
The Passerini coupling of cyclohexylisocyanide with isatins and carboxylic acids in the presence of 4 Å
molecular sieves is described. This process offers a highly efficient and atom-economic access to 3-acyl-
oxy-3-carboxamido-1,3-dihydro-2H-indol-2-ones in high to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isatin
Isocyanide
Passerini coupling reaction
Carboxylic acid
3,3-Disubstituted indol-2-ones
Isocyanides have been recognized as important building blocks
in modern organic synthesis.1 The high reactivity of isocyanides
offers possibilities for construction of substituted heterocyclic
compounds and has attracted significant attention in recent years.
3-Substituted indoles are important heterocycles found in
natural products and pharmaceuticals and are utilized in medicinal
chemistry.8–11 In particular, 3-substituted-3-hydroxyindolin-
2-ones, are found in several biologically active alkaloids and phar-
macological agents.12 Despite possessing outstanding biological
activities,13 only a few 3-acyloxy-1,3-dihydro-2H-indol-2-ones
are known. Some commonly used synthetic methods are the
acylation of isatins with carboxylic acid anhydrides or acyl chlo-
rides,13,14 as well as non isatins as starting materials under various
conditions.15 Very recently, Du et al. described an intermolecular
hydroacylation of isatins with aldehydes, leading to 3-acyloxy-
1,3-dihydro-2H-indol-2-ones.16
This reactivity involves the
a-addition of both nucleophiles and
electrophiles on the same carbon atom of the isocyanide functional
group.1a Isocyanide-based multicomponent reactions are extre-
mely useful tools in target oriented and diversity oriented organic
synthesis.2 A widely known and prominent isocyanide-based
multicomponent reaction is the Passerini reaction.2 In this three-
component reaction, an isocyanide, a carboxylic acid, and either
an aldehyde or a ketone react to yield an a
-acyloxycarboxamide.3
Passerini reactions are beginning to find utility in the drug discov-
ery process, and total syntheses of biologically relevant natural
products. This reaction has also been widely used in synthetic
and medicinal chemistry.4 For example it has often been involved
as a key step in the total synthesis of natural products due to the
In recent years, several effective reactions in the presence of 4 Å
molecular sieves have been developed. For example, cyanobenzoy-
lation of aldehydes, cyanocarbonation of aldehydes, trifluorome-
thylation of carbonyl compounds, and Henry reactions,17
Knoevenagel reactions,18 and Michael additions19a have been re-
ported. 4 Å MS principally act as water scavengers in organic
reactions as well as drying agents for organic solvents due to their
small pore sizes (0.4 nm in diameter for 4 Å MS) that preclude the
adsorption of larger molecules.19b Due to the fact that the highly
reactive b-carbonyl group of isatin is susceptible to nucleophilic
attack,20,21 we envisaged that a Passerini reaction involving isatin
derivatives might readily proceed under appropriate reaction
conditions. In the context of our experience in the chemistry of isa-
tins22 and in the light of our recent research in the area of IMCRs,23
we envisaged the possibility of the Passerini coupling of isocya-
nides with isatins and carboxylic acids in the presence of powdered
fact that the a-acyloxycarboxamide group is a frequently occurring
motif in many pharmacologically interesting natural products.5
The indole ring system is a common and important feature of
various natural products and medicinal agents.6a Compounds
carrying the indole moiety exhibit antibacterial and antifungal
activities.6b Oxindoles are well-known among these compounds
and are well-represented in nature as well as in pharmaceutically
significant substances.7
⇑
Corresponding author. Tel./fax: +98 511 8414182.
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.2012.11.025

A. A. Esmaeili et al. / Tetrahedron Letters 54 (2013) 406–408
407
Table 1
To optimize the reaction conditions, the reaction of N-benzyli-
satin, acetic acid (1.3 mmol), cyclohexyl isocyanide (1.0 mmol),
and powdered 4 Å MS (100 mg) in dry CH3CN was used as a model
reaction. As shown in Table 1, the solvent had a clear influence on
reaction yield. The best result (83% yield) was obtained in 3 h in
dry CH3CN at reflux (Table 1, entry 8).
Effect of the solvent on the Passerini reaction of N-benzylisatina
Entry
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
EtOH
EtOH
EtOH
Acetone
DMSO
CH3CN
CH3CN
CH3CN
Solvent-free
35
60
60
60
60
60
80
80
80
80
80
12
12
3
Trace
0.0
10
60
70
40
Trace
83
83
83
8
Next, we examined the reaction in the presence of various addi-
tives (Table 2). When the reaction was performed without an addi-
tive, no reaction occurred (Table 2, entry 1). On the other hand, the
reaction in the presence of powdered 4 Å MS (100 mg) proceeded
very smoothly to give, the desired product in 83% yield (Table 2,
entry 2). In the presence of powdered 10 Å MS, no reaction oc-
curred. Using other additives such as MgSO4 and Na2SO4 led to
the desired product 4a in 50% and 20% yields, respectively (Table 2,
entries 6 and 7). A screening of the amount of 4 Å MS showed that
the model reaction proceeded smoothly, when 100 mg was used.25
Accordingly we used dry CH3CN (solvent) and 100 mg powdered
4 Å MS (additive) at reflux as the optimal reaction conditions. With
optimized conditions in hand, different isatin derivatives were
subjected to the reaction conditions under the influence of 4 Å
MS (Table 3). Although the role of 4 Å MS is not clear, we propose
that the molecular sieves act as a proton transfer agent and acti-
vate the b-carbonyl group of the isatin.
12
12
12
3
10
12
12
10
11
0.0
a
Reactions were carried out using N-benzylisatin (1.0 mmol), acetic acid
(1.3 mmol), and cyclohexyl isocyanide (1.0 mmol) in dry solvent in the presence of
powdered 4 Å MS (100 mg) at reflux for the appropriate times.
b
Isolated yield.
Table 2
Effect of the additive on the Passerini reaction of N-benzylisatina
Entry
Additive
Additive (mg)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
4 Å MS
4 Å MS
4 Å MS
4 Å MS
10 Å MS
MgSO4
Na2SO4
—
100
80
200
300
300
300
12
3
3
3
3
Trace
83
60
83
Trace
50
As summarized in Table 3, various isatin derivatives bearing
either electron-donating or electron-withdrawing substituents on
the ring were excellent substrates for this reaction leading to the
corresponding products in high to excellent yields (72–96%,
Table 3). The reactions also proceeded well with substrates bearing
methyl, ethyl, and benzyl substituents at the N-position.
3
3
20
a
All reactions were carried out in dry CH3CN using N-benzyl isatin (1.0 mmol),
The reaction also occured with an N-unsubstituted isatin within
24 h leading to product 4o in a good yield (60%). The Passerini cou-
pling of isatin derivatives and cyclohexyl isocyanide proceeded
well with carboxylic acids such as acetic acid, benzoic acid, and
p-methylbenzoic acid. However, no product was produced when
other isocyanides, including tert-butylisocyanide, 1,1,3,3-tetra-
methylbutylisocyanide, ethyl isocyanoacetate, and benzylisocya-
nide under the same conditions.
acetic acid (1.3 mmol), and cyclohexyl isocyanide (1.0 mmol) at reflux.
b
Yield of isolated product.
4 Å molecular sieves (MS) in dry CH3CN, leading to a wide range of
3-acyloxy-3-carboxamido-1,3-dihydro-2H-indol-2-ones (Table 3).24
A literature survey revealed that the Passerini coupling of isocya-
nides with isatins and carboxylic acids had not been investigated.
Table 3
Reactions of isatins 1 with carboxylic acids 2 and cyclohexyl isocyanide 3 in the presence of 4 Å MS in dry CH3CN
NH
O
R2
O
O
R2
O
O
4 Å MS (100 mg)
CH3CN, 80 °C
NC
R3
R3
2
OH
N
O
N
O
1
R1
3
R1
4
Product
R1
R2
R3
Time (h)
Yielda (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
PhCH2
PhCH2
PhCH2
PhCH2
Me
Me
Et
Et
Et
PhCH2
Me
Et
p-BrC6H4CH2
Me
H
H
Me
Ph
Ph
Me
Ph
Ph
Ph
Ph
3
5
5
4
3
5
6
6
5
3
3
3
2
6
24
83
82
88
96
83
85
86
85
91
84
80
72
89
72
60
Cl
Br
Cl
Br
Cl
H
Br
Cl
H
H
H
H
Br
Br
Ph
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
Ph
p-MeOC6H4
Me
a
Isolated yield.

408
A. A. Esmaeili et al. / Tetrahedron Letters 54 (2013) 406–408
4. Okimoto, M.; Chiba, T. Synthesis. 1996, 1188–1190.
The structures of the products 4a–o (Table 3) were deduced
5. Hoffmann, H. M. R.; Ismail, Z. M.; Hollweg, R.; Zein, A. R. Bull. Chem. Soc. Jpn.
1990, 63, 1807–1810.
6. (a) Hoalihan, W. J.; Remers, W. A.; Brown, R. K. Indoles: Part 1; Wiley: New York,
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7. Baeza, A.; Nájera, C.; Retamosa, M. G.; Sansano, J. M. Synthesis 2005, 2787–
2797.
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). As an example,25 the IR spectrum of 4a showed three car-
bonyl groups at 1752, 1714, and 1660 cmÀ1, respectively. The 1H
NMR spectrum of 4a, exhibited the multiplet signals for the cyclo-
8. Watahiki, T.; Ohba, S.; Oriyama, T. Org. Lett. 2003, 5, 2679–2681.
9. Iwanami, K.; Hinakubo, Y.; Oriyama, T. Tetrahedron Lett. 2005, 46, 5881–5883.
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1997, 38, 1501–1504.
hexyl ring (d = 1.22–2.04 ppm),
a singlet for methyl group
(d = 2.20 ppm), a multiplet for the NCH of the cyclohexyl ring
(d = 3.81 ppm), an AB-quartet system for the diastereotopic meth-
ylene protons of the CH2Ph moiety (d = 4.90 and 5.10 ppm), and
multiplets for the aromatic protons (d = 6.61–7.40 ppm, 9 ArH
and 1 NH). The 1H-decoupled 13C NMR spectrum of 4a showed
21 distinct resonances in agreement with the suggested structure,
partial assignment of these resonances is given in the experimental
section. Characteristic 13C NMR signals were present due to the
three ester carbonyls at d = 163.4, 167.5, and 171.4. The 1H and
13C NMR spectra of 4b–o were similar to those of 4a except for
the ester, amide, and aromatic moieties (see Supplementary data).
11. Sundberg, R. J. The Chemistry of Indoles; Academic press: New York, 1970.
12. (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964; (b) Lin, H.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51; (c) Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
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T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990–995.
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Biossard, C. G. Bioorg. Med. Chem. Lett. 1997, 7, 1255–1260; (c) Hewawasam, P.;
Erway, M.; Moon, S. L.; Knippe, J.; Weiner, H.; Biossard, C. G.; Post-Munson, D.
J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem. 2002, 45,
1487–1499.
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Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507–
509; (c) Wang, X.-N.; Zhang, Y.-Y.; Ye, S. Adv. Synth. Catal. 2010, 352, 1892–
1895.
In conclusion, we have developed
a convenient Passerini
coupling reaction of isatins in CH3CN in the presence of 4 Å MS
to give 3-[(cyclohexylamino) carbonyl]-3-acyloxyindolin-2-ones
in good to excellent yields. Further investigations to broaden the
scope and synthetic applications of this efficient and convenient
Passerini-MCR are underway in our laboratory.
17. Oriyama, T.; Aoyagi, M.; Iwanami, K. Chem. Lett. 2007, 36, 612–613.
18. Chiba, R.; Oriyama, T. Chem. Lett. 2008, 37, 1218–1219.
19. (a) Tomoko, K.; Takeshi, O. Tetrahedron Lett. 2010, 51, 290–292; For a recent
review, see: (b) Sen, S. E.; Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55,
12657–12698.
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273–324.
21. Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1.
Acknowledgment
22. (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.;
Amini, S.; Bodaghi, A. Synlett 2007, 1452–1454.
23. (a) Esmaeili, A. A.; Nasseri, M. A.; Vesalipoor, M. A.; Bijanzadeh, H. Arkivoc
2008, xv, 343; (b) Esmaeili, A. A.; Vesalipoor, H. Synthesis 2009, 1635; (c)
Esmaeili, A. A.; Hosseinabadi, R.; Habibi, A. Synlett 2010, 1477; (d) Esmaeili, A.
A.; Zangoei, M.; Fakhari, A.; Habibi, A. Tetrahedron Lett. 2012, 53, 1351–1353;
(e) Esmaeili, A. A.; Zangoei, M.; Hosseinabadi, R.; Habibi, A.; Fakhari, A.; Habibi,
A. Mol. Diversity 2012, 16, 145–150.
We gratefully acknowledge financial support from the Research
Council of the University of Birjand.
Supplementary data
Supplementary data (experimental details and spectroscopic
characterization of all compounds along with 1H, 13C NMR, IR
and mass spectra associated with this article can be found, in the
online version.
24. General procedure for the synthesis of products 4: To a solution of carboxylic acid
(1.3 mmol) in dry CH3CN (3 mL), were added the isatin derivative (1.00 mmol),
cyclohexyl isocyanide (1.0 mmol), and sufficiently activated 4 Å MS (100 mg).
The resultant mixture was stirred at 80 °C for the appropriate time as specified
in Table 3 and was monitored by TLC. After completion of the reaction, for
compounds 4a–o, the solvent was removed under reduced pressure and the
residue dissolved in dry CH2Cl2. The 4 Å MS was recovered by simple filtration
and addition of n-hexane to the filtrate yielded the pure solid products. For
compound 4o, the solvent was removed under reduced pressure and the
residue was washed with dry CH2Cl2. The solid residue was then dissolved in
EtOH, the 4 Å MS was recovered by simple filtration, and the filtrate
crystallized from ethanol to yield the pure product 4o in 60% yield.
25. 1-Benzyl-3-[(cyclohexylamino)carbonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl acetate
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.
11.025.
References and notes
(4a): White Powder; mp 249-–251 °C, 0.34 g, Yield 83%.IR (KBr) (t
max/cmÀ1):
3345 (NH), 1660, 1714, 1752 (3 C@O). 1H NMR (300.13 MHz, CDCl3): dH
1. For reviews on isocyanides in organic synthesis, see: (a) Dömling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (b) Josien, H.; Ko, S.-B.; Bom, D.;
Curran, D. P. Chem. Eur. J. 1998, 4, 67–83; (c) Saegusa, T.; Ito, Y. Synthesis 1975,
291–300.
2. (a) Marvel, C. S.; Brace, N. O.; Miller, F. A.; Johnson, A. R. J. Am. Chem. Soc. 1949,
71, 34–36; (b) Li, F.; Widyan, K.; Wingstrand, E.; Moberg, C. Eur. J. Org. Chem.
2009, 3917–3922.
3. (a) Aoki, Sh.; Kotani, Sh.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2010, 51,
3547–3549; (b) Deardorff, D. R.; Taniguchi, C. M.; Tafti, S. A.; Kim, H. Y.; Choi, S.
Y.; Downey, K. J.; Nguyen, T. V. J. Org. Chem. 2001, 66, 7191–7194; (c) Sandberg,
M.; Sydnes, L. K. Org. Lett. 2000, 2, 687–689.
(ppm): 1.22–2.04 (10H, m, 5 CH2 of cyclohexyl), 2.20 (3 H, s, Me), 3.81 (1 H,
2
m, CH of cyclohexyl), 4.91 (1 H, ABquartet, JHH = 16.0 Hz, Ph-CHAHB), 5.04 (1 H,
ABquartet,
2JHH = 16.0 Hz, Ph-CHAHB), 6.61–7.41 (10 H, m, NH, and arom.). 13C
NMR (75.4 MHz, CDCl3): dC (ppm): 20.8 (CH3), 24.73, 24.74, 25.4, 32.7, 32.9 (5
CH2 of cyclohexyl), 44.2 (CH2-Ph), 48.8 (CH-N), 81.0 (O–C–C@O), 110.0, 122.9,
123.0, 125.4, 127.0, 127.5, 128.8, 130.5, 135.1, 144.2, 163.4 (C@O), 167.5
(C@O), 171.4 (C@O). MS: (m/z,%) 406 (M, 4), 282 (56), 239 (100), 91 (31).;
Anal. Calcd for C24H26N2O4: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.67; H,
6.51; N, 6.79.