Engaging isatins in solvent-free, sterically congested Passerini reaction

Article abstract of DOI:10.1039/c3gc40454d

A facile, atom-economic and environmentally-benign protocol for the synthesis of biologically important oxindole derivatives in high yields has been demonstrated by employing isatins as carbonyl compound surrogates in a Passerini reaction carried out under solvent-free conditions. Moreover, electron-deficient phenols can also be used as the acid component in this reaction. In addition, the synthetic utility of the present methodology was examined by the one-pot synthesis of oxindoles with a free -OH group at the benzylic position.

Full text of DOI:10.1039/c3gc40454d

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Engaging isatins in solvent-free, sterically congested
Passerini reaction†
Cite this: DOI: 10.1039/c3gc40454d
Trinadh Kaicharla, Santhivardhana Reddy Yetra, Tony Roy and Akkattu T. Biju*
A facile, atom-economic and environmentally-benign protocol for the synthesis of biologically important
oxindole derivatives in high yields has been demonstrated by employing isatins as carbonyl compound
surrogates in a Passerini reaction carried out under solvent-free conditions. Moreover, electron-deficient
phenols can also be used as the acid component in this reaction. In addition, the synthetic utility of the
present methodology was examined by the one-pot synthesis of oxindoles with a free –OH group at the
benzylic position.
Received 8th March 2013,
Accepted 29th March 2013
DOI: 10.1039/c3gc40454d
www.rsc.org/greenchem
Introduction
The Passerini reaction, the three-component reaction between
a carboxylic acid, a carbonyl compound such as an aldehyde or
a ketone, and an isocyanide, offers direct access to α-acyloxy
carboxamide derivatives (Scheme 1, eqn (1)).1 This is the first
isocyanide based multicomponent reaction playing a central
role in combinatorial chemistry,2 and is widely utilized for the
synthesis of various drug-like molecules, and in the total
syntheses of biologically active natural products.3,4 Intrigu-
ingly, the Passerini reaction employing ketones is generally
slower and in some cases, the reactions carried out with bulky
carbonyl substrate and the bulky isocyanide fail to afford the
desired product.5 However, the use of high pressure is one way
to increase the efficiency of Passerini reactions involving bulky
reactants.6
Scheme 1 The Passerini reaction.
In the context of the Passerini reactions of sterically con-
gested carbonyl compounds, it was envisaged that the multi-
component reaction involving isatin derivatives,7 isocyanides
and carboxylic acids could provide simple and straightforward
access to oxindole derivatives (eqn (2)). This will be interesting
because oxindoles having a quaternary benzylic centre rep-
resent a common structural motif in many natural products
and biologically active compounds. Among them, the oxi-
ndoles with a heteroatom at the benzylic position are a useful
class of compounds including the bioactive natural products
(R)-convolutamydine A,8 maremycin B9 and the potent growth
hormone secretion promoter SM-130686 (Fig. 1).10 Herein, we
report a practical and efficient solvent-free Passerini reaction11
of isocyanides, isatins and carboxylic acids, leading to the
Fig. 1 Selected biologically active oxindoles having
a quaternary benzylic
centre having an OH group.
formation of 3,3-disubstituted oxindole derivatives, and inter-
estingly the reaction is carried out under air.12
Results and discussion
Optimization of the reaction conditions
The present studies were initiated with the treatment of
N-methyl isatin 1a with benzoic acid 2a and tert-butyl isocya-
nide 3a. To our delight, when the reaction was carried out in
CH2Cl2 at 25 °C, the expected product 3-benzoyloxy 3-carba-
moyl indol-2-one derivative 4a was formed in 49% yield (based
on 1H NMR spectroscopy, Table 1, entry 1). Increasing the
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL),
Dr Homi Bhabha Road, Pune 411008, India. E-mail: at.biju@ncl.res.in
†Electronic supplementary information (ESI) available: 1H-NMR and 13C-NMR
spectra of all compounds. See DOI: 10.1039/c3gc40454d
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Table 1 Optimization of the reaction conditionsa
Table 2 Employing istains in a solvent-free Passerini reaction: scope of car-
boxylic acidsa
2a
3a
Temp.
(°C)
Time
(h)
Yield of
Entry (equiv.) (equiv.) Solvent
4ab (%)
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.5
1.5
1.5
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.2
1.2
1.2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
(CH2Cl)2
THF
CH3CN
Solvent-free
Solvent-free
Solvent-free 100
under air
25
50
70
80
80
70
70
80
90
24
24
24
24
24
24
24
24
20
12
49
57
61
76
60
33
63
82
92
10
96(91)c
a All reactions were carried out at the 0.25 mmol scale of 1a in 1.0 mL
of solvent under an Ar atmosphere unless otherwise specified. b The
yields were determined by 1H NMR analysis of crude products using
CH2Br2 as the internal standard. c Isolated yield at the 0.50 mmol scale
in parentheses.
reaction temperature resulted in an improved yield of the
product (entry 2). Moreover, the reactions carried out in CHCl3
at a higher temperature furnished better yields of the product
(entries 3, 4). However, other chlorinated solvent including
(CH2Cl)2 and solvents like THF and CH3CN afforded the
product in diminished yields (entries 5–7). At this stage, we
thought of carrying out reactions under solvent-free con-
ditions. Interestingly, when the reaction was carried out under
solvent-free conditions at 80 °C, the product 4a was formed in
82% yield (entry 8). Increasing the reaction temperature under
solvent-free conditions improved the yield of 4a, and finally when
the reaction was carried out at 100 °C under solvent-free con-
ditions in air for 12 h, 4a was isolated in 91% yield (entry 10).
a General conditions: 1a (0.50 mmol), 2 (0.75 mmol), 3a (0.60 mmol)
solvent-free conditions under air, 100 °C and 12 h.
Furthermore, the reaction is not limited to aromatic and
α,β-unsaturated acids, but instead aliphatic acids including
acetic acid also worked well, leading to the desired products in
moderate yields (4n–p).14
Next, we investigated the scope of this reaction with various
substituted isatin derivatives and isocyanides (Table 3). Substi-
tuents on nitrogen of isatin including the benzyl group and
allyl moiety are well tolerated (4q, 4r). It is interesting to note
that even unprotected isatin also afforded moderate yield of
the Passerini adduct (4s), demonstrating the versatility of the
present method. Moreover, various substituents at the carbo-
cyclic ring of isatin also underwent a smooth three-component
reaction leading to the desired product in excellent yield
(4t–w). Furthermore, various isocyanides also furnished good
to excellent yields of the desired products, further expanding
the scope of this isocyanide initiated three-component reac-
tion (4x–z). It is noteworthy, however, that in preliminary
experiments commercially available isocyanide such as p-tolyl-
sulfonyl methyl isocyanide and 4-methoxyphenyl isocyanide
failed to undergo this reaction under optimized reaction
conditions.
Investigation of the substrate scope of the reaction
With the optimized reaction conditions in hand, we then
examined the substrate scope of this sterically congested,
solvent-free Passerini reaction. First we evaluated the variation
of the carboxylic acid moiety (Table 2). The unsubstituted
benzoic acid worked well and a variety of electron releasing
and -withdrawing groups at various positions of the aromatic
ring of benzoic acid are well tolerated, leading to the formation
of the oxindole derivatives in ≥80% in all cases (4a–g). Gratify-
ingly, a range of heterocyclic carboxylic acids also resulted in a
smooth conversion to the desired product, further expanding
the scope of this three-component reaction (4h–l). It is impor-
tant to note in this context that N-unprotected indole 2-car-
boxylic acid also afforded the expected product 4k in moderate
yield.13 Moreover, the reaction of α,β-unsaturated acid
furnished an excellent yield of the oxindole derivative 4m.
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Table 3 Variation of the isatin moiety and isocyanide moietya
Scheme 2 One-pot synthesis of oxindoles with a free –OH group at the
benzylic position.
One-pot synthesis of oxindoles with a free –OH group
The synthetic utility of the present methodology was further
examined by the one-pot synthesis16 of oxindoles with a free
–OH group at the benzylic position by combining the Passerini
reaction employing isatins with a base-mediated hydrolysis
under mild conditions. The one-pot reaction worked well fur-
nishing the oxindole derivative 7 in 91% yield (Scheme 2). It is
important to note that oxindole derivatives are ubiquitously
present in many natural products and biologically active
compounds.7
a General conditions: 1 (0.50 mmol), 2a (0.75 mmol), 3 (0.60 mmol)
solvent-free conditions under air, 100 °C and 12 h.
Table 4 Utility of 2-nitrophenol in the reaction as an acid surrogatea
Conclusions
In conclusion, we have demonstrated an efficient, atom-eco-
nomic and environmentally-benign sterically congested Passer-
ini reaction by employing isatins as the carbonyl compound
component under solvent-free conditions. The reaction
resulted in the synthesis of biologically important 3-acyloxy
3-carbamoyl indol-2-ones in high yields. Moreover, electrophi-
lic phenols are used as the acid component in these reactions
and the utility of the reaction was established by a one-pot syn-
thesis of oxindoles with a free –OH group at the benzylic posi-
tion. Further studies on the application of isatins in various
multicomponent reactions are ongoing in our laboratory.
a General conditions: 1 (0.50 mmol), 5 (0.75 mmol), 3 (0.60 mmol)
solvent-free conditions under air, 100 °C and 12 h.
Experimental section
The reaction temperature is reported as the temperature of the
Utility of 2-nitrophenol as an acid surrogate
1
bath surrounding the reaction vessel. H and 13C NMR spectra
The synthetic potential of this solvent-free Passerini reaction
has been demonstrated by utilizing electron-deficient phenols
were recorded on a Bruker AV 400, in solvents as indicated.
Chemical shifts (δ) are given in ppm. The residual solvent
as the acid component in the reaction. Thus treatment of signals were used as references and the chemical shifts were
N-substituted isatins 1 with 2-nitrophenol 5 and isocyanides 3
converted to the TMS scale (CDCl3: δH = 7.26 ppm, δC =
under optimized reaction conditions resulted in the synthesis
77.16 ppm). Infrared spectra were recorded on a Perkin-Elmer
of O-arylated oxindole derivative 6 in moderate yields (Table 4). 1615 FT Infrared Spectrophotometer Model 60B. The wave
numbers (n) of the recorded IR-signals are expressed in cm−1
.
This reaction is an example of the use of the Smiles rearrange-
ment in a Passerini reaction and the key step is the irreversible
HRMS data were recorded on a Thermo Scientific Q-Exactive,
Smiles rearrangement of the intermediate phenoxyimidate Accela 1250 pump. Analytical thin layer chromatography was
adducts leading to the formation of the O-arylated product 6.15
performed on TLC Silica gel 60 F254
.
The substituted isatin derivative as well as cyclohexyl isocya-
nide worked in the O-arylative Passerini reaction under
solvent-free conditions leading to moderate yield of the
product (6a–c). It is anticipated that the presence of the nitro
group in the final adduct allows interesting applications to
heterocyclic synthesis.
General procedure for the solvent-free Passerini reaction
To a flame-dried screw-capped test tube equipped with a mag-
netic stir bar was added the isatin derivative 1 (0.5 mmol,
1.0 equiv.), the isocyanide 3 (0.6 mmol, 1.2 equiv.) and car-
boxylic acid 2 or 2-nitrophenol 5 (0.75 mmol, 1.5 equiv.) under
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air. Then the reaction mixture was placed in a preheated oil 128.34, 124.95, 124.80, 124.38, 123.58, 109.10, 81.61, 52.47,
bath at 100 °C for 12 h under solvent-free conditions. Then the 28.67, 27.12. HRMS calculated [M + Na]+ for C21H21O6N3Na:
crude reaction mixture was purified by silica gel column 434.1323, found: 434.1323. FTIR (cm−1): 3446, 3020, 2928,
chromatography (eluting with a CH2Cl2–EtOAc solvent system, 2856, 1735, 1692, 1617, 1537, 1352, 1216, 1123, 757, 669.
typically 1% EtOAc in CH2Cl2).
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl benzoate benzoate (4f). Rf (EtOAc–DCM
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl
4-nitro
=
5/95): 0.63; 1H NMR
1
(4a). Rf (EtOAc–DCM = 5/95): 0.55; H NMR (400 MHz, CDCl3): (400 MHz, CDCl3): δ 8.31 (d, J = 9.0 Hz, 2H), 8.16 (d, J = 8.8 Hz,
δ 7.99 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 2H), 7.43–7.39 (m, 2H), 7.10 (t, J = 7.6 Hz, 1H), 6.95 (d, J =
7.5 Hz, 2H), 7.39–7.34 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.92 (d, 7.5 Hz, 1H), 6.73 (bs, 1H), 3.32 (s, 3H), 1.42 (s, 9H). 13C NMR
J = 7.7 Hz, 1H), 6.81 (bs, 1H), 3.32 (s, 3H), 1.44 (s, 9H). (100 MHz, CDCl3): δ 171.32, 162.34, 162.22, 151.06, 145.10,
13C NMR (100 MHz, CDCl3): δ 171.70, 163.73, 163.25, 145.25, 133.96, 131.18, 131.16, 124.96, 124.12, 123.91, 123.58, 109.08,
134.03, 130.82, 130.19, 129.97, 128.79, 128.58, 125.13, 124.16, 81.54, 52.42, 28.65, 27.11. HRMS calculated [M + Na]+ for
123.29, 108.92, 81.22, 52.23, 28.69, 27.04. HRMS calculated C21H21O6N3Na: 434.1323, found: 434.1322. FTIR (cm−1): 3020,
[M + H]+ for C21H23O4N2: 367.1652, found: 367.1650. FTIR 2400, 1732, 1693, 1616, 1532, 1472, 1350, 1272, 1216, 758, 669.
(cm−1): 3440, 3020, 2931, 17 331, 1690, 1617, 1518, 1472, 1269,
1216, 1109, 1068, 1024, 754, 710.
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 4-methoxy
benzoate (4g). Rf (EtOAc–DCM
5/95): 0.59; 1H NMR
=
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 2-fluoro (400 MHz, CDCl3): δ 7.92 (d, J = 8.6 Hz, 2H), 7.38–7.32 (m, 2H),
benzoate (4b). Rf (EtOAc–DCM
5/95): 0.50; 1H NMR 7.05 (t, J = 7.3 Hz, 1H), 6.94–6.89 (m, 3H), 6.79 (s, 1H), 3.86 (s,
=
(400 MHz, CDCl3): δ 7.91 (t, J = 7.6 Hz, 1H), 7.63–7.59 (m, 1H), 3H), 3.31 (s, 3h), 1.43 (s, 9H). 13C NMR (100 MHz, CDCl3):
7.40 (t, J = 7.8 Hz, 1H), 7.42–7.21 (m, 4H), 7.07 (t, J = 7.6 Hz, δ 171.91, 164.21, 163.44, 145.24, 132.34, 132.13, 130.70,
1H), 6.95 (d, J = 7.6 Hz, 1H), 3.34 (s, 3H), 1.46 (s, 9H). 13C NMR 124.09, 120.85, 114.07, 113.76, 108.85, 81.07, 55.64, 52.17,
(100 MHz, CDCl3): δ 171.03, 163.75, 162.20 (d, J = 257.2 Hz), 28.70, 27.01. HRMS calculated [M + H]+ for C21H25O5N2:
161.04 (d, J = 3.2 Hz), 145.71, 136.09, 136.0, 133.36, 130.92, 397.1758, found: 397.1757. FTIR (cm−1); 3439, 3060, 2968,
125.61, 124.76 (d, J = 3.3 Hz), 122.50 (d, J = 9.67), 117.29 (d, J = 1727, 1689, 1606, 1512, 1471, 1260, 1090, 732.
23.3 Hz), 116.78 (d, J = 9.7 Hz), 108.99, 81.74, 52.11, 28.64,
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl furan-2-
27.01. HRMS calculated [M + H]+ for C21H22O4N2F: 385.1558, carboxylate (4h). Rf (EtOAc–DCM = 5/95): 0.44; 1H NMR
found: 385.1556. FTIR (cm−1): 3428, 3019, 1735, 1686, 1614, (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.42–7.38 (m, 3H), 7.09 (t, J =
1524, 1369, 1300, 1216, 1119, 755, 669.
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 2-chloro (m, 1H), 3.32 (s, 3H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3):
benzoate (4c). Rf (EtOAc–DCM
5/95): 0.43; 1H NMR δ 171.23, 163.31, 155.51, 147.25, 145.47, 143.18, 130.93,
7.4 Hz, 1H), 6.93 (d, J = 7.98 Hz, 1H), 6.88 (bs, 1H), 6.57–6.56
=
(400 MHz, CDCl3): δ 7.87 (d, J = 7.8 Hz, 1H), 7.51–7.47 (m, 2H), 125.18, 123.69, 123.27, 120.13, 112.49, 108.98, 81.10, 52.20,
7.41–7.28 (m, 3H), 7.12–7.07 (m, 2H), 6.90 (d, J = 7.8 Hz, 1H), 28.65, 27.01. HRMS calculated [M + H]+ for C19H21O5N2:
3.31 (s, 3H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.12, 357.1445, found: 357.1444. FTIR (cm−1): 33 429, 3020,
163.55, 162.63, 145.66, 133.92, 133.42, 133.24, 131.41, 130.89, 2928, 1731, 1690, 1615, 1519, 1471, 1302, 1216, 112, 927, 757,
128.33, 127.28, 125.40, 123.26, 109.02, 82.17, 52.30, 28.69, 668.
27.01. HRMS calculated [M + H]+ for C21H22O4N2Cl: 401.1263,
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl thiophene-
found: 401.1259. FTIR (cm−1) 3671, 3440, 3352, 2970, 2936, 2-carboxylate (4i). Rf (EtOAc–DCM = 5/95): 0.52; 1H NMR
2253, 1719, 1691, 1607, 1581, 1494, 1471, 1352, 1260, 1169, (400 MHz, CDCl3): δ 7.79 (d, J = 3.8 Hz, 1H), 7.63 (d, J = 4.9 Hz,
1106, 1030, 911, 846, 732, 648.
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 2-bromo 3.8 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H),
benzoate (4d). Rf (EtOAc–DCM
5/95): 0.52; 1H NMR 6.78 (bs, 1H), 3.3 (s, 3H), 1.44 (s, 9H). 13C NMR (100 MHz,
1H), 7.37 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.12 (t, J =
=
(400 MHz, CDCl3): δ 7.80–7.78 (m, 1H), 7.69–7.67 (m, 1H), CDCl3): δ 171.34, 163.21, 158.88, 145.38, 135.05, 133.77,
7.40–7.33 (m, 4H), 7.09–7.06 (m, 2H), 6.90 (d, J = 7.9 Hz, 1H,), 131.49, 130.92, 128.36, 125.15, 123.87, 123.28, 108.95, 81.34,
3.32 (s, 3H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.11, 52.23, 28.68, 27.02. HRMS calculated [M
+
H]+ for
163.47, 145.66, 145.66, 134.59, 133.79, 133.11, 130.88, 130.73, C19H21O4N2S: 373.1217, found: 373.1216. FTIR (cm−1): 3438,
127.79, 125.35, 123.55, 123.22, 121.30, 109.03, 82.21, 52.37, 3020, 2400, 1729, 1690, 1617, 1494, 1472, 1361, 1215, 1072,
28.75, 27.02. HRMS calculated [M + H]+ for C21H22O4N2Br: 929, 759, 669.
445.0757, found: 445.0756. FTIR (cm−1): 3407, 2969, 1734,
1686, 1614, 1590, 1433, 1115, 1025, 874, 748.
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl
benzo-
furan-2-carboxylate (4j). Rf (EtOAc–DCM = 5/95): 0.44; 1H NMR
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl
3-nitro (400 MHz, CDCl3): δ 7.71 (d, J = 7.8 Hz, 1H), 7.60–7.58 (m, 2H),
benzoate (4e). Rf (EtOAc–DCM
=
5/95): 0.58; 1H NMR 7.53–7.49 (m, 1H), 7.43–7.33 (m, 3H), 7.07 (t, J = 7.6 Hz, 1H),
(400 MHz, CDCl3): δ 8.82 (s, 1H), 8.46–8.44 (m, 1H), 8.30 (d, J = 6.94 (bs, 1H), 6.91 (d, J = 8.1 Hz, 1H), 3.32 (s, 3H), 1.47 (s, 9H).
7.8 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.10 13C NMR (100 MHz, CDCl3): δ 171.12, 163.18, 156.24, 156.02,
(t, J = 7.5 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.78 (bs, 1H), 3.33 145.53, 143.88, 131.07, 128.54, 126.79, 124.94, 124.26, 123.96,
(s, 3H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.30, 123.40, 123.22, 115.99, 112.44, 109.06, 81.40, 52.34, 28.69,
162.49, 161.90, 148.40, 145.19, 135.59, 131.19, 130.38, 130.17, 27.08. HRMS calculated [M + H]+ for C23H23O5N2: 407.1601,
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found: 407.1599. FTIR (cm−1) 3428, 2930, 1732, 1688, 1614,
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 2-(4-methoxy-
1569, 1519, 1494, 1471, 1369, 1350, 1298, 1215, 1173, 1092, phenyl)acetate (4p). Rf (EtOAc–DCM = 5/95): 0.52; 1H NMR
1006, 748.
(400 MHz, CDCl3): δ 7.33 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.7 Hz,
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 1H-indole- 2H), 7.10 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 6.89 (d, J =
2-carboxylate (4k). Rf (EtOAc–DCM = 10/90): 0.55; 1H NMR 8.4 Hz, 2H), 6.84 (d, J = 7.8 Hz, 1H), 6.32 (bs, 1H), 3.79 (s, 3H),
(400 MHz, CDCl3): δ 9.10 (bs, 1H), 7.67 (d, J = 7.4 Hz, 1H), 3.66 (s, 2H), 3.23 (s, 3H), 1.29 (s, 9H). 13C NMR (100 MHz,
7.34–7.19 (m, 5H), 7.13 (t, J = 6.4 Hz, 1H), 7.02 (t, J = 7.8 Hz, CDCl3): δ 171.33, 168.39, 163.42, 159.03, 145.40, 130.74,
1H), 6.85 (d, J = 7.9 Hz, 1H), 6.79 (bs, 1H), 3.24 (s, 3H), 1.42 (s, 130.43, 125.34, 125.12, 123.12, 123.09, 114.36, 108.92, 81.08,
9H). 13C NMR (100 MHz, CDCl3): δ 17.55, 163.21, 159.14, 55.38, 52.0, 40.19, 28.55, 26.91. HRMS calculated [M + H]+ for
145.24, 137.63, 130.88, 127.18, 126.23, 125.27, 125.12, 124.18, C23H27O5N2: 411.1914, found: 411.1913. FTIR (cm−1): 3413,
123.35, 122.76, 121.30, 112.34, 109.98, 108.95, 81.28, 52.31, 3019, 1736, 1687, 1614, 1514, 1370, 1217, 1133, 1037, 770, 669.
28.69, 27.02. HRMS calculated [M + H]+ for C23H24O4N3:
406.1761, found: 406.1762. FTIR (cm−1): 3347, 3019, 2974, (4q). Rf (EtOAc–DCM = 5/95): 0.61; 1H NMR (400 MHz, CDCl3):
2400, 1725, 1690, 1617, 1369, 1311, 1215, 758, 669. δ 8.05 (d, J = 7.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.52 (t, J =
1-Benzyl-3-(tert-butylcarbamoyl)-2-oxoindolin-3-yl benzoate
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl picolinate 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.41–7.36 (m, 3H), 7.28 (t,
(4l). Rf (EtOAc–DCM = 20/80): 0.50; 1H NMR (400 MHz, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H),
CDCl3): δ 8.76 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.82 6.83 (bs, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.08 (d, J = 16.5 Hz, 2H),
(t, J = 7.7 Hz, 1H), 7.53–7.50 (m, 1H), 7.35 (t, J = 7.67 Hz, 1H), 5.07 (d, J = 19.5 Hz, 1H), 1.49 (s, 9H). 13C NMR (100 MHz,
7.31 (d, J = 7.3 Hz, 1H), 7.25 (bs, 1H), 7.03 (t, J = 7.5 Hz, 1H), CDCl3): δ 171.80, 163.62, 163.34, 144.28, 135.29, 134.05,
6.91 (d, J = 7.9 Hz, 1H), 3.29 (s, 3H), 1.43 (s, 9H). 13C NMR 130.63, 130.04, 128.95, 128.81, 128.66, 127.68, 127.20, 125.32,
(100 MHz, CDCl3): δ 171.05, 163.74, 162.04, 150.00, 146.67, 123.87, 123.27, 110.09, 81.44, 52.25, 44.99, 28.75. HRMS calcu-
145.66, 137.11, 130.86, 127.70, 125.60, 125.30, 123.34, 123.17, lated [M + H]+ for C27H27O4N2: 443.1965, found: 443.1961.
108.87, 81.36, 52.06, 28.60, 26.94. HRMS calculated [M + H]+ FTIR (cm−1) 3020, 2926, 2855, 1731, 1688, 1615, 1516, 1468,
for C20H22O4N3: 368.1605, found: 368.1602. FTIR (cm−1): 3407, 1367, 1268, 1216, 1178, 1088, 770, 669.
2969, 1734, 1686, 1614, 1590, 1433, 1115, 1025, 874, 748.
1-Allyl-3-(tert-butylcarbamoyl)-2-oxoindolin-3-yl
cinna- (4r). Rf (EtOAc–DCM = 5/95): 0.56; H NMR (400 MHz, CDCl3):
benzoate
1
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl
1
mate (4m). Rf (EtOAc–DCM = 5/95): 0.50; H NMR (400 MHz, δ 7.99 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.47 (t, J =
CDCl3): δ 7.67 (d, J = 16.1 Hz, 1H), 7.50 (d, J = 7.7 Hz, 2H), 7.4 Hz, 2H), 7.35–7.31 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (d,
7.41–7.35 (m, 4H), 7.33 (d, J = 7.4 Hz, 1H), 7.09–7.06 (m, 1H), J = 7.1 Hz, 1H), 6.78 (bs, 1H), 5.93–5.88 (m, 1H), 5.45 (d, J =
6.90 (d, J = 7.9 Hz, 1H), 6.74 (bs, 1H), 6.52 (d, J = 16.26 Hz, 19.2 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.45–4.42 (m, 2H), 1.44
1H), 3.30 (s, 3H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.42, 163.56, 163.31,
δ 171.78, 164.08, 163.40, 147.82, 145.35, 133.91, 131.10, 144.40, 134.60, 130.78, 130.61, 129.97, 128.77, 128.61, 125.29,
130.72, 129.12, 129.05, 128.47, 128.40, 125.50, 123.83, 123.25, 123.88, 123.17, 117.97, 109.86, 81.29, 52.19, 42.95, 28.70.
115.83, 108.87, 81.13, 52.22, 28.69, 27.0. HRMS calculated HRMS calculated [M + H]+ for C23H25O4N2: 393.1809, found:
[M + H]+ for C23H25O4N2: 393.1809, found: 393.1807. FTIR 393.1805. FTIR (cm−1) 3439, 3020, 2400, 1734, 1689, 1615,
(cm−1): 3020, 2400, 1731, 1688, 1635, 1616, 1418, 1216, 1154, 1517, 1424, 1267, 1215, 1115, 929, 850, 780, 669.
1042, 929, 767, 669.
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl
3-(tert-Butylcarbamoyl)-2-oxoindolin-3-yl benzoate (4s). Rf
acetate (EtOAc–DCM = 10/90): 0.30; 1H NMR (400 MHz, CDCl3):
(4n). Rf (EtOAc–DCM = 5/95): 0.45; 1H NMR (400 MHz, CDCl3): δ 8.02–7.90 (m, 3H), 7.66–7.59 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H),
δ 7.36 (t, J = 8.2 Hz, 1H), 7.28–7.26 (m, 1H), 7.07 (t, J = 7.6 Hz, 7.30 (t, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 6.90 (d, J =
1H), 6.87 (d, J = 7.01 Hz, 1H), 6.63 (bs, 1H), 3.26 (s, 3H), 2.17 (s, 7.7 Hz, 1H), 6.74 (s, 1H), 1.44 (s, 9H). 13C NMR (100 MHz,
3H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.67, 167.75, CDCl3): δ 173.03, 163.83, 163.26, 142.48, 134.08, 130.78,
163.30, 145.33, 130.70, 125.47, 123.50, 123.18, 108.90, 81.06, 130.03, 128.82, 128.57, 125.54, 124.33, 123.14, 110.92, 81.50,
52.15, 28.64, 26.93, 20.91. HRMS calculated [M + H]+ for 52.29, 30.93, 28.69. HRMS calculated [M + H]+ for C20H21O4N2:
C16H21O4N2: 305.1496, found: 305.1494. FTIR (cm−1): 3341, 353.1496, found: 353.1495. FTIR (cm−1): 3683, 3436, 3019,
3019, 1720, 1612, 1374, 1216, 1111, 771, 669, 507, 474, 487, 479. 2977, 2400, 1736, 1689, 1623, 1519, 1268, 1215, 1110, 929, 758,
3-(tert-Butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl
nate (4o). Rf (EtOAc–DCM = 5/95): 0.39; 1H NMR (400 MHz,
CDCl3): δ 7.35 (t, J = 7.2 Hz, 1H), 7.26–7.23 (m, 1H), 7.05 (t, J = benzoate (4t). Rf (EtOAc–DCM
propio- 669.
3-(tert-Butylcarbamoyl)-1-methyl-5-nitro-2-oxoindolin-3-yl
5/95): 0.55; 1H NMR
=
7.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.62 (bs, 1H), 3.25 (s, 3H), (400 MHz, CDCl3): δ 8.35 (d, J = 8.5 Hz, 1H), 8.19 (m, 1H), 7.96
2.52–2.38 (m, 2H), 1.38 (s, 9H), 1.09 (t, J = 7.5 Hz, 3H). 13C (d, J = 6.8 Hz, 2H), 7.65 (t, J = 8.5 Hz, 1H), 7.50 (t, J = 6.8 Hz,
NMR (100 MHz, CDCl3): δ 171.71, 171.29, 163.40, 145.32, 2H), 7.01 (d, J = 8.5 Hz, 1H), 6.77 (bs, 1H), 3.38 (s, 3H), 1.45 (s,
130.68, 125.54, 123.35, 123.16, 108.88, 80.89, 52.10, 28.63, 9H). 13C NMR (100 MHz, CDCl3): δ 171.82, 163.79, 162.22,
27.33, 26.92, 8.72. HRMS calculated [M + H]+ for C17H23O4N2: 150.93, 143.84, 134.62, 130.06, 129.04, 127.76, 126.36, 119.79,
319.1652, found: 319.1651. FTIR (cm−1): 3347, 2938, 1759, 108.59, 80.19, 52.71, 28.69, 27.50. HRMS calculated [M + H]+
1724, 1671, 1611, 1532, 1216, 1156, 1110, 890, 755.
for C21H22O6N3: 412.1503, found: 412.1502. FTIR (cm−1) 3684,
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3437, 3020, 2400, 1736, 1691, 1617, 1524, 1496, 1337, 1215, [M + H]+ for C20H21O4N2: 353.1496, found: 353.1495. FTIR
1267, 1108, 1067, 929, 768, 669, 625.
(cm−1): 3020, 2406, 1732, 1679, 1616, 1416, 1270, 1215, 1021,
3-(tert-Butylcarbamoyl)-5-fluoro-1-methyl-2-oxoindolin-3-yl 758, 669.
benzoate (4u). Rf (EtOAc–DCM 3-((2-Ethoxy-2-oxoethyl)carbamoyl)-1-methyl-2-oxoindolin-3-
5/95): 0.44; 1H NMR
=
(400 MHz, CDCl3): δ 7.98–7.96 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), yl benzoate (4z). Rf (EtOAc–DCM = 5/95): 0.37; 1H NMR
7.48 (t, J = 7.9 Hz, 2H), 7.13–7.06 (m, 2H), 6.85–6.83 (dd, J1 = (400 MHz, CDCl3): δ 8.08–8.04 (m, 2H), 7.60–7.33 (m, 6H), 7.07
4.0 Hz, J2 = 8.8 Hz, 1H), 6.80 (bs, 1H), 3.31 (s, 3H), 1.44 (s, 9H). (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 4.30–4.20 (m, 3H),
13C NMR (100 MHz, CDCl3): δ 171.51, 163.78, 162.67, 159.44 4.08–4.02 (dd, J1 = 4.5 Hz, J2 = 18.6 Hz, 1H), 3.32 (s, 3H), 1.31
(d, J = 244.2 Hz), 141.20, 134.22, 130.0, 128.66, 128.31, 126.52, (t, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.02,
126.43, 117.02 (d, J = 24.4 Hz), 112.72 (d, J = 25.6 Hz), 109.49 169.34, 164.84, 163.59, 145.37, 134.11, 133.67, 131.08, 130.22,
(d, J = 7.8 Hz), 80.97, 52.37, 28.66, 27.19. HRMS calculated 130.11, 128.81, 128.53, 128.35, 124.39, 123.87, 123.33, 109.07,
[M + H]+ for C21H22O4N2F: 385.1558, found: 385.1556. FTIR 81.22, 61.96, 41.81, 27.07, 14.25. HRMS calculated [M + H]+ for
(cm−1) 3384, 2973, 2934, 1731, 1671, 1623, 1523, 1497, 1473, C21H21O6N2: 397.1394, found: 397.1393. FTIR (cm−1) 3430,
1454, 1369, 1351, 1268, 1233, 1162, 1112, 1008, 820, 711, 559.
3-(tert-Butylcarbamoyl)-5-chloro-1-methyl-2-oxoindolin-3-yl 1108, 759, 669, 497.
benzoate (4v). Rf (EtOAc–DCM N-(tert-Butyl)-1-methyl-3-(2-nitrophenoxy)-2-oxoindoline-3-
5/95): 0.69; 1H NMR
3020, 2400, 1732, 1693, 1616, 1524, 1473, 1422, 1273, 1215,
=
(400 MHz, CDCl3): δ 7.98 (d, J = 7.9 Hz, 2H), 7.64–7.61 (m, 1H), carboxamide (6a). Rf (EtOAc–DCM = 5/95): 0.45; 1H NMR
7.48 (t, J = 2.9 Hz, 2H), 7.36–7.33 (m, 2H), 6.85 (d, J = 8.4 Hz, (400 MHz, CDCl3): δ 7.98 (d, J = 7.5 Hz, 1H), 7.78 (s, 1H), 7.37
1H), 6.80 (bs, 1H), 3.30 (s, 3H), 1.44 (s, 9H). 13C NMR (t, J = 7.6, 1H), 7.28–7.19 (m, 2H), 7.07–7.01 (m, 2H), 6.92 (d,
(100 MHz, CDCl3): δ 171.36, 163.74, 162.66, 143.85, 134.26, J = 8.8 Hz, 1H), 6.46 (d, J = 6.8 Hz, 1H), 3.32 (s, 3H), 1.45 (s,
130.69, 130.21, 130.01, 128.89, 128.69, 128.52, 128.26, 126.68, 9H). 13C NMR (100 MHz, CDCl3): δ 171.19, 164.54, 148.59,
124.75, 109.86, 80.80, 52.41, 28.68, 27.18. HRMS calculated 145.00, 140.76, 135.00, 131.57, 126.81, 123.92, 123.90, 123.25,
[M + H]+ for C21H22O4N2Cl: 401.1263, found: 401.1263. FTIR 118.43, 109.47, 85.19, 52.21, 28.65, 27.02. HRMS calculated
(cm−1): 3439, 3020, 1732, 1692, 1615, 1492, 1366, 1268, 1216, [M + H]+ for C20H22O5N3: 384.1554, found: 384.1554. FTIR
1108, 759, 709, 669.
5-Bromo-3-(tert-butylcarbamoyl)-1-methyl-2-oxoindolin-3-yl 733.
benzoate (4w). Rf (EtOAc–DCM 5-Bromo-N-(tert-butyl)-1-methyl-3-(2-nitrophenoxy)-2-oxoin-
5/95): 0.45; 1H NMR
(cm−1) 3389, 3063, 2971, 2252, 1735, 1685, 1609, 1348, 911,
=
(400 MHz, CDCl3): δ 7.97 (d, J = 6.8 Hz, 2H), 7.63 (t, J = 6.6 Hz, doline-3-carboxamide (6b). Rf (EtOAc–DCM = 5/95): 0.45; 1H
1H), 7.51–7.46 (m, 4H), 6.79 (d, J = 8.3 Hz, 2H), 3.29 (s, 3H), NMR (200 MHz, CDCl3): δ 8.05–8.01 (m, 1H), 7.77 (s, 1H),
1.44 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.27, 163.73, 7.55–7.50 (m, 1H), 7.35–7.26 (m, 2H), 7.10 (t, J = 7.2 Hz, 1H),
162.66, 144.36, 130.02, 128.89, 128.54, 128.26, 127.42, 127.02, 6.82 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 8.3 Hz, 1H), 3.29 (s, 3H),
115.92, 110.34, 80.73, 52.42, 28.69, 27.16. HRMS calculated 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.41, 163.88,
[M + H]+ for C21H22O4N2Br: 447.0737, found: 447.0727. FTIR 148.35, 143.98, 140.61, 135.14, 134.45, 127.10, 126.63, 123.50,
(cm−1) 3439, 3020, 2972, 2400, 1732, 1691, 1611, 1453, 1107, 117.87, 116.60, 110.92, 84.69, 52.43, 50.35, 28.64, 27.16. HRMS
757.
calculated [M +
H]+ for C20H21O5N3: 462.0659, found:
3-(Cyclohexylcarbamoyl)-1-methyl-2-oxoindolin-3-yl benzoate 462.0662. FTIR (cm−1) 3390, 3020, 2400, 1740, 1688, 1607,
1
(4x). Rf (EtOAc–DCM = 5/95): 0.50; H NMR (400 MHz, CDCl3): 1526, 1347, 1215, 1104, 1037, 858, 757, 669.
δ 7.99 (d, J = 7.4 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.46 (t, J =
N-Cyclohexyl-1-methyl-3-(2-nitrophenoxy)-2-oxoindoline-3-
7.8 Hz, 2H), 7.39–7.34 (m, 2H), 7.06 (t, J = 7.7 Hz, 1H), 6.90 (d, carboxamide (6c). Rf (EtOAc–DCM 5/99): 0.30; 1H NMR
J = 8.04 Hz, 1H), 6.80 (bs, 1H), 3.88–3.80 (m, 1H), 3.32 (s, 3H), (400 MHz, CDCl3): δ 7.98 (d, J = 7.12 Hz, 1H), 7.78 (s, 1H),
2.04–1.95 (m, 2H), 1.74–1.71 (m, 2H), 1.64–1.60 (m, 1H), 7.37–7.19 (m, 3H), 7.05–6.91 (m, 3H), 6.87 (d, J = 7.42 Hz, 1H),
1.43–1.21 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 171.55, 3.78 (s, 1H), 3.31 (s, 3H), 1.99 (s, 2H), 1.78 (s, 2H), 1.60 (s, 1H),
163.79, 163.32, 145.19, 134.02, 130.85, 129.99, 128.77, 128.57, 1.39–1.38 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 171.03,
125.04, 124.26, 123.27, 108.92, 81.01, 49.0, 32.88, 32.64, 27.03, 164.52, 148.62, 144.97, 140.84, 134.99, 131.59, 126.81, 124.41,
25.55, 24.77, 24.72. HRMS calculated [M + H]+ for C23H25O4N2: 124.08, 123.86, 123.29, 118.57, 109.46, 85.11, 48.94, 32.79,
393.1809, found: 393.1799. FTIR (cm−1): 3020, 2936, 2858, 32.64, 27.04, 25.59, 24.75. HRMS calculated [M + H]+ for
1732, 1683, 1617, 1518, 1375, 1270, 1215, 929, 759, 669.
C22H24O5N3: 410.1710, found: 410.1711. FTIR (cm−1) 3944,
3-(Isopropylcarbamoyl)-1-methyl-2-oxoindolin-3-yl benzoate 3054, 2987, 2685, 2410, 2305, 1731, 1604, 1421, 1265, 1021,
1
(4y). Rf (EtOAc–DCM = 5/95): 0.36; H NMR (400 MHz, CDCl3): 896, 739, 706.
δ 7.99 (d, J = 7.19 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.46 (t, J =
5-Bromo-N-(tert-butyl)-3-hydroxy-1-methyl-2-oxoindoline-3-
7.8 Hz, 2H), 7.39–7.35 (m, 2H), 7.07 (t, J = 7.4 Hz, 1H), 6.92 (d, carboxamide (7). Rf (EtOAc–DCM = 20/80): 0.41; 1H NMR
J = 7.7 Hz, 1H), 6.74 (d, J = 7.06 Hz, 1H), 4.17–4.10 (m, 1H), (400 MHz, CDCl3): δ 7.46 (d, J = 6.4 Hz, 1H), 7.36 (d, J = 1.8 Hz,
3.32 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 6.7 Hz, 3H). 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.64 (bs, 1H), 4.99 (s, 1H,), 3.14 (s,
13C NMR (100 MHz, CDCl3): δ 171.55, 163.81, 163.38, 145.21, 3H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 174.70, 166.99,
134.03, 130.85, 130, 128.77, 128.59, 125.02, 124.29, 123.29, 143.76, 133.34, 130.69, 126.84, 116.21, 110.53, 78.37, 52.05,
108.92, 80.99, 42.41, 27.03, 22.69, 22.48. HRMS calculated 28.67, 26.85. HRMS calculated [M + H]+ for C14H18O3N2Br:
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341.0495, found: 341.0497. FTIR (cm−1): 3373, 2969, 2923,
1734, 1607, 1488, 1366, 1218, 1099, 878, 824, 760.
8 For selected reports, see: (a) G. Luppi, M. Monari,
R. J. Corrêa, F. A. Violante, A. C. Pinto, B. Kaptein,
Q. B. Broxterman, S. J. Garden and C. Tomasini, Tetra-
hedron, 2006, 62, 12017; (b) T. Nakamura, S.-I. Shirokawa,
S. Hosokawa, A. Nakazaki and S. Kobayashi, Org. Lett.,
2006, 8, 677.
Acknowledgements
9 For selected examples, see: (a) Z. Zhang, W. Zheng and
J. C. Antilla, Angew. Chem., Int. Ed., 2011, 50, 1135;
(b) A. Singh and G. P. Roth, Org. Lett., 2011, 13, 2118.
10 T. Tokunaga, W. E. Hume, T. Umezome, K. Okazaki,
Y. Ueki, K. Kumagai, S. Hourai, J. Nagamine, H. Seki,
M. Taiji, H. Noguchi and R. Nagata, J. Med. Chem., 2001,
44, 4641.
Generous financial support from CSIR-NCL (start-up grant to
A.T.B., MLP022426) and CSIR-New Delhi (Network project
ORIGIN; CSC0108 and CSIR-OSDD; HCP0001; and for the
award of an SPM Fellowship to T.K. and a Junior Research Fel-
lowship to S.R.Y.) is gratefully acknowledged. We thank Dr
P. R. Rajamohanan (CSIR-NCL) for the NMR spectra and
Ms. B. Santhakumari (CSIR-NCL) for HRMS data.
11 For recent reports on solvent-free Passerini reactions using
aldehydes as the carbonyl component, see: (a) K. Sato,
T. Ozu and N. Takenaga, Tetrahedron Lett., 2013, 54, 661;
(b) T. Bousquet, M. Jida, M. Soueidan, R. Deprez-Poulain,
F. Agbossou-Niedercorn and L. Pelinski, Tetrahedron Lett.,
2012, 53, 306; (c) D. Koszelewski, W. Szymanski, J. Krysiak
and R. Ostaszewski, Synth. Commun., 2008, 28, 1120; for a
report on the ultrasound-promoted sterically congested
Passerini reactions utilizing ketones under solvent-free
conditions, see ref. 6a.
12 While this manuscript was under preparation, a three-com-
ponent reaction involving isatins and carboxylic acids with
cyclohexyl isocyanide in CH3CN proceeding in the presence
of 4 Å molecular sieves was reported by Esmaeili et al. For
details, see: A. A. Esmaeili, S. A. Ghalandarabad and
S. Jannati, Tetrahedron Lett., 2013, 54, 406. Notably, this
protocol is not applicable under solvent-free conditions
and with bulky isocyanides including tert-butyl isocyanide
and proceeds only in the presence of additives.
Notes and references
1 (a) M. Passerini, Gazz. Chim. Ital., 1921, 51, 126;
(b) M. Passerini, Gazz. Chim. Ital., 1922, 52, 432; for a
review, see: (c) L. Banfi and R. Riva, in Organic Reactions,
ed. A. B. Charette, Wiley, New York, 2005, vol. 65,
pp. 1–140.
2 For a review, see: A. Dömling and I. Ugi, Angew. Chem., Int.
Ed., 2000, 39, 3168.
3 For reviews, see: (a) A. Dömling, Chem. Rev., 2006, 106, 17;
(b) A. Dömling, W. Wang and K. Wang, Chem. Rev., 2012,
112, 3083; (c) Multicomponent Reactions, ed. J. Zhu and H.
Bienaymé, Wiley-VCH, Weinheim, 2005; for a recent report
on the synthesis of 4-fluoro glutamines, see: (d) W. Qu,
Z. Zha, K. Ploessl, B. P. Lieberman, L. Zhu, D. R. Wise,
C. B. Thompson and H. F. Kung, J. Am. Chem. Soc., 2011,
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13 It may be noted that pyrrole 2-carboxylic acid afforded the
desired product in ∼15% yield.
14 In addition, α-amino acids such as (L) phenyl alanine as
well as (L) proline did not show any reactivity under the
present reaction conditions. For a successful application of
4 For a review on heterocyclic construction using isocyanides,
see: V. Nair, C. Rajesh, A. U. Vinod, S. Bindu,
A. R. Sreekanth, J. S. Mathen and L. Balagopal, Acc. Chem.
Res., 2003, 36, 899.
5 (a) M. Passerini, Gazz. Chim. Ital., 1924, 54, 529;
(b) R. Baker and A. H. Schlesinger, J. Am. Chem. Soc., 1945,
67, 1499; for a recent report on the Passerini three-com-
ponent reaction of alcohols under catalytic and aerobic oxi-
dative conditions, see: (c) J. Brioche, G. Masson and
J. Zhu, Org. Lett., 2010, 12, 1432.
6 (a) C. Cui, C. Zhu, X.-J. Du, Z.-P. Wang, Z.-M. Li and
W.-G. Zhao, Green Chem., 2012, 14, 3157; (b) G. Jenner,
Tetrahedron Lett., 2002, 43, 1235.
7 For recent reviews, see: (a) G. S. Singh and Z. Y. Desta,
Chem. Rev., 2012, 112, 6104; (b) R. Dalpozzo, G. Bartolib
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α-amino acids in
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