Studies on isocyanides: synthesis of tetrazolyl-isoindolinones via tandem Ugi four-component condensation/intramolecular amidation

Article abstract of DOI:10.1016/j.tetlet.2007.10.154

The Ugi four-component condensation between methyl o-formylbenzoates 1, anilines 2a-c, isocyanides 3, and trimethylsilyl azide (4) afforded the expected Ugi adducts 5a-d, which were cyclized to the title compounds 6a-d upon treatment with sodium ethoxide

Full text of DOI:10.1016/j.tetlet.2007.10.154

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 149–152
Studies on isocyanides: synthesis of tetrazolyl-isoindolinones via
tandem Ugi four-component condensation/intramolecular amidation
Carlos F. Marcos,a Stefano Marcaccini,b,* Gloria Menchi,b
b
c
´
Roberto Pepino and Tomas Torroba
aDepartamento de Quı´mica Orga´nica, Facultad de Veterinaria,Universidad de Extremadura, Avenida de la Universidad s/n,
E-10071 Ca´ceres, Spain
b
`
HeteroBioLab, Dipartimento di Chimica Organica,Universita di Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
cDepartamento de Quı´mica, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Ban˜uelos s/n, E-09001 Burgos, Spain
Received 8 October 2007; accepted 29 October 2007
Available online 4 November 2007
Dedicated to the memory of our valued co-worker and friend Cecilia Polo Polo
Abstract—The Ugi four-component condensation between methyl o-formylbenzoates 1, anilines 2a–c, isocyanides 3, and trimethyl-
silyl azide (4) afforded the expected Ugi adducts 5a–d, which were cyclized to the title compounds 6a–d upon treatment with sodium
ethoxide in ethanol. Starting from aralkyl- or alkylamines 2d–g the Ugi adducts underwent a spontaneous cyclization to tetrazolyl-
isoindolinones 6e–j.
Ó 2007 Elsevier Ltd. All rights reserved.
The tetrazole nucleus is found in many biologically ac-
tive products.1 The activity of certain derivatives of this
heterocyclic system on the CNS was recognized many
years ago.2 Among the pharmaceutically important tet-
razoles the widely used angiotensin II antagonist Losar-
tan, marketed by Merck, deserves a special mention.
Tetrazole derivatives also display interesting non-bio-
logical properties. For example, their usefulness as pri-
mary explosives3 and ligands4 has recently been
reported. A considerable attention has been focused
on 1,5-disubstituted tetrazoles in the field of peptide
chemistry because they are cis-amide bond mimics.5
For example, analogous of somatostatine,6 bradykinin,7
and deaminooxytocin8 containing the above core has
been described.
volved in their synthesis.11 Interesting natural products
structurally related to the indolinone alkaloids have
been isolated and synthesized.12 Other 3-substituted
and 2,3-disubstituted isoindolinones are pharmaceuti-
cally relevant because of their capabilities to act as
HIV-1 reverse transcriptase inhibitors,13 anxiolytics,14
15
and dopamine D4 and 5-HT16 receptor antagonists.
Interestingly, both systems are easily obtainable by
means of isocyanide-based multicomponent reactions.
The formation of isoindolin-1-ones via intramolecular
Ugi-4CC is well documented.17 The synthesis of 1,5-
disubstituted tetrazoles is one of the earlier achieve-
ments of the Ugi-4CC: in this case hydrazoic acid plays
the role of the acid component.18 The use of trimethyl-
silyl azide as hydrazoic acid source has further increased
the versatility of this route.19
A great deal of work has been devoted to the study of
2,3-dihydro-1H-isoindol-1-ones (isoindolinones) since
this moiety is found in a wide variety of natural and syn-
thetic products,9 which display very interesting activi-
ties. Among them the alkaloids lennoxamine,
aristoyagonine, nuevamine, and chilenine are specially
noteworthy10 and a number of researchers have been in-
In recent years, a variety of very interesting substituted20
and fused tetrazoles19,21 have been prepared via Ugi-
4CC by employing starting products containing suitable
additional functional groups.
Keeping in mind the above results and our interest in the
synthesis of heterocyclic systems by means of post-con-
densation modifications of the Ugi reaction22 we
*
Corresponding author. Tel.: +39 055 457 3510; fax: +39 055 457
3531; e-mail: stefano@marcaccini.unifi.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.154

150
C. F. Marcos et al. / Tetrahedron Letters 49 (2008) 149–152
decided to attempt the synthesis of a series of isoindolin-
1-ones bearing a 1-substituted tetrazol-5-yl moiety in
position 3.
temperature. The preparation of compound 6h was
achieved following the traditional Ugi procedure—in
which the amine and hydrazoic acid were generated
in situ by reacting the amine hydrochloride with sodium
azide—with equally good results (Scheme 1).
The synthesis was accomplished by reacting methyl o-
formylbenzoates 1 as bireactive carbonyl components,23
amines 2, isocyanides 3, and trimethylsilyl azide (4).
When anilines 2a–c were employed as the starting amines
the Ugi adducts 5a–d were isolated in good yields.26 The
Ugi adducts 5e–j arising from aralkyl- or alkylamines
2d–g were never detected because of the enhanced nucleo-
philic character of the amino group, which is strong
enough to allow the attack onto the ester group with sub-
sequent cyclization to isoindolinones 6e–j.27 However,
the Ugi adducts 5a–d were easily cyclized to the
corresponding isoindolinones 6a–d in very good yields
upon treatment with sodium ethoxide in ethanol.28
All of the starting products are commercially available
or easily obtainable. Methyl o-formylbenzoates 1 were
easily prepared starting from the commercially available
2-formylbenzoic and opianic acids.24 4-Ethoxyphenyl
isocyanide (3c) was prepared from p-phenetidine.25
The Ugi reactions took place smoothly, by simple
stirring the reactants in methanol for 2 days at room
R2
R1
R1 NH2
CHO
R1
H
N
N
N
2
X
CO2Me
X
CO2Me
HN3
C
MeOH rt
2 d
_
α-addition
R2 NC
X
N3
X
X
CO2Me
1
3
R2 NC
X
HN3
(from TMSN3 (4) and MeOH
or from MeNH2.HCl + NaN3)
N
N
N
N
N
N
N
R2
R1HN
R2
R2
N
N
NHR1
O
N3
R1
NaOEt, EtOH,
Δ (5a-d)(84-92%)
N
1,5-dipolar cyclization
X
CO2Me
X
or spontaneous (5e-j) (11-79%)
X
X
X
OMe
O
X
5
6
5a-d
5e-j
isolated (73-83%)
not isolated
1
a
b
X
H
OCH3
2
a
b
c
d
e
f
R1
3
R2
C6H5CH2
c-C6H11
4-C2H5OC6H4
4-CH3C6H4
4-ClC6H4
4-FC6H4
C6H5CH2
4-ClC6H4CH2
C5H9Oa
a
b
c
d
4-CH3C6H4SO2CH2
b
g
CH3
a) Tetrahydrofurfurylmethyl.
b) Starting amine as
hydrochloride.
5,6
X
R1
R2
Yield (%) 5
Products 5 Mp ˚Ca
Yield (%) 6
Products
6 Mp ˚Ca
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-FC6H4
4-ClC6H4CH2
C6H5CH2
C5H9O
CH3
C6H5CH2
4-ClC6H4CH2
C6H5CH2
-C6H11
C6H5CH2
78
83
73
75
132-135
178-179
151-152
150-151
90
92
88
84
74
11c
77
68
79
71
186-187
171-173
193-195
120-121b
170-171
204-205
144-145
138-141
139-140
145-146
c
c
c
-C6H11
-C6H11
4-CH3C6H4SO2CH2
4-C2H5OC6H4
4-C2H5OC6H4
OCH3
OCH3
c
c
-C6H11
-C6H11
j
a) Solvent EtOH unless otherwise stated. b) Solvent MeOH/i-Pr2O. c) Product isolated by filtration; after column chromatography 6f was
obtained in 52% yield.
Scheme 1. Synthesis of tetrazolyl-isoindolinones via Ugi-CC/intramolecular amidation.

C. F. Marcos et al. / Tetrahedron Letters 49 (2008) 149–152
151
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The structure of the Ugi four-component adducts 5a–d
was in agreement with their IR and H NMR spectra.
1
In the IR spectra two strong absorptions at about 3350
and 1700 cmÀ1 were detected, due to the secondary amino
group and to the ester carbonyl group, respectively. In
the 1H NMR spectra a singlet signal at about 3.80 d, due
to the ester methyl protons was detected. Furthermore, a
doublet signal at about 4.60 d due to the NH proton cou-
pled with the benzyl proton at about 7.00 d as seen. The
benzyl proton doublet was not always clearly detected
because of the overlapping with the aromatic protons.
1
The comparison of the IR and H NMR spectra of 5a–
d with those of 6a–d clearly confirmed the cyclization.
In the IR spectra of 6a–d no NH peak was detected
and the CO peak was shifted to about 1690 cmÀ1 in
agreement with the presence of a c-lactam ring. As
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1
expected in the H NMR spectra of 6a–d the signals
attributable to the ester methyl protons and to the NH
proton disappeared and a singlet signal at about 6.90 d
due to the benzyl proton was detected. In the H NMR
spectra of 6e–j the benzyl proton singlet was always
clearly detected at about 6.00 d; consequently, it was well
separated from the aromatic protons signals.
14. (a) Suzuki, M.; Uchiumi, M.; Marasaki, M. Psychophar-
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1
In conclusion, we have developed a method for assem-
bling two interesting heterocyclic systems by means of
a very simple experimental procedure. The desired prod-
ucts 6e–j were obtained by mixing the reactants at room
temperature and precipitated from the mother liquors in
a pure form, avoiding the need of tedious work-up pro-
cedures. When anilines were employed as the starting
amines the Ugi adducts were easily isolated and cyclized
to 6a–d in a very simple and rapid fashion.
16. Zhuang, Z. P.; Kung, M. P.; Mu, M.; Kung, H. F. J. Med.
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´
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References and notes
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Z. J. Comb. Chem., Web release date: 18 August 2007,
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dehydic acid and methyl iodide in acetonitrile Ye, B.-H.;
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finely powdered opianic acid in Et2O/CHCl3 (1:1) with
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Tetrahedron Lett. 2005, 46, 7977–7979.
Compounds 6f,g,i,j were prepared analogously.
3-[1-(4-Ethoxy)phenyl-1H-tetrazol]-5-yl-2,3-dihydro-2-
methyl-1H-isoindol-1-one (6h): A stirred solution of methyl
2-formylbenzoate (1a) and methylamine hydrochloride
(dried overnight over P2O5) (2g) (135 mg, 2.0 mmol) in
MeOH (4 ml) was treated with 4-ethoxyphenyl isocyanide
(3d) (294 mg, 2.0 mmol) and a saturated aqueous solution
of sodium azide (130 mg, 0.2 mmol). The resulting mixture
was stirred at rt for 2 days and then cooled with ice-salt
and filtered. The collected solid was washed with cold
i-Pr2O (2 ml) and then with pentane. After air-drying the
solid was stirred with water and filtered again to give 6h
(438 mg, 65%). Mp 138–141 °C from EtOH. IR (KBr):
26. Methyl 2-[(1-Benzyl-1H-tetrazol)-5-yl-(4-methylphenyl)-
amino]methylbenzoate (5a): A solution of methyl 2-form-
ylbenzoate (1a) (328 mg, 2.0 mmol) in methanol (4.5 ml)
was treated as quickly as possible with 4-toluidine (2a)
(214 mg, 2.0 mmol), benzyl isocyanide (3a) (234 mg,
2.0 mmol), and trimethylsilyl azide (4) (230 mg, 2.0 mmol)
in the order given. The resulting mixture was stirred at rt
for 2 days and then cooled with ice-salt and filtered to give
5a (612 mg, 74%) as white crystals. Mp 132–135 °C from
EtOH. IR (KBr): 3356, 1706, 1620, 1527, 1273, 1261, 1071,
739, 717, 697 cmÀ1; 1H NMR (200 MHz, CDCl3) d (ppm):
8.08 (d, J = 7.7 Hz, 1H, Ar-H), 7.60–7.33 (m, 2H, Ar-H),
7.28–7.16 (m, 5H, Ar-H), 6.93–6.87 (m, 3H, Ar-H+CH-
NH), 6.35 (d, J = 8.4 Hz, 2H, Ar-H), 5.69 (AB system,
2H, CH2Ar), 4.33 (d, J = 8.8 Hz, 2H, NH), 3.79 (s, 3H,
OCH3), 2.20 (s, 3H, CH3Ar); 13C NMR (50 MHz, CDCl3)
d (ppm): 167.4 (s), 155.6 (s), 142.9 (s), 139.2 (s), 138.6 (s),
133.3 (s), 133.1 (d), 131.8 (s), 131.3 (d), 129.7 (d), 128.8 (d,
2C), 128.6 (d), 128.4 (d, 2C), 128.3 (d), 128.1 (d, 2C), 114.0
(d, 2C), 52.5 (d), 51.4 (t), 49.6 (q),20.6 (q). Anal. Calcd for
C24H23N5O2: C, 69.72; H, 5.61; N, 16.94. Found: C, 69.89;
H, 5.51; N, 17.03.
1698, 1516, 1479, 1388, 1256, 1179, 1046, 735, 547 cmÀ1
;
1H NMR (200 MHz, CDCl3) d (ppm): 7.66–7.42 (m, 3H,
Ar-H), 7.28–7.24 (m, 1H, Ar-H), 6.66–6.53 (m, 4H, Ar-H),
6.10 (s, 1H, CHN), 3.95 (q, J = 7.0 Hz, 2H, CH2O), 2.92
(s, 3H, NCH3), 1,37 (t, J = 7.0 Hz, 3H, CH2–CH3); 13C
NMR (50 MHz, CDCl3) d (ppm): 167.1 (s), 160.3 (s),
151.5 (s), 140.1 (s), 132.2 (d), 131.8 (s), 129.6 (d), 126.3 (d,
2C), 124.6 (s), 123.8 (d), 122.7 (d), 114.8 (d, 2C), 64.0 (t),
56.5 (d), 28.0 (q), 14.7 (q).
Anal. Calcd for C18H17N5O2: C, 64.47; H, 5.11; N, 20.88.
Found: C, 64.29; H, 5.21; N, 21.05.
Ugi adducts 5b–d were prepared in the same manner.
27. 2-(4-Chloro)benzyl-3-(1-cyclohexyl-1H-tetrazol)-5-yl-2,3-
dihydro-1H-isoindol-1-one (6e): A solution of methyl 2-
formylbenzoate (1a) (328 mg, 2.0 mmol) in methanol
(4.5 ml) was treated with 4-chlorobenzylamine (2e)
(283 mg, 2.0 mmol), cyclohexyl isocyanide (3b) (218 mg,
2.0 mmol), and trimethylsilyl azide (4) (230 mg, 2.0 mmol)
in the order given. The resulting mixture was stirred at rt
for 2 days and then cooled with ice-salt and filtered to give
6e (607 mg, 74%) as white crystals. Mp 170–171 °C from
EtOH. IR (KBr): 2944, 2856, 1691, 1441, 1396, 1092, 1016,
28. 3-(1-Benzyl-1H-tetrazol)-5-yl-2,3-dihydro-2-(4-methyl)-
phenyl-1H-isoindol-1-one (6a): A saturated solution of 5a
(207 mg, 0.5 mmol) in boiling ethanol was prepared in a
large-mouthed small flask. The vessel was removed from
the heating bath and the solution treated, as quickly as
possible, with ethanolic EtONa (1 M, 0.5 ml, 0.5 mmol).
The reaction mixture was allowed to stand for 5 min and
then cooled at 0 °C. Cold EtOH (2 ml) was added and the
resulting sludge was filtered with the aid of a spoon-
shaped spatula to afford 6a (172 mg, 90%) as a white solid.
Mp 186–187 °C from EtOH. IR (KBr): 1695, 1519, 1456,
1
1
848, 803, 722, 575 cmÀ1; H NMR (200 MHz, CDCl3) d
1367, 802, 722, 690, 509; H NMR (200 MHz, CDCl3) d
(ppm): 8.01 (m, 1H, Ar-H), 7.62–7.55 (m, 2H, Ar-H),
7.26–7.15 (m, 5H, Ar-H), 6.10 (s, 1H, CHN), 4.96 (d,
J = 14.6 Hz, 1H, CH2Ar), 4.09 (d, J = 14.6 Hz, 1H,
CH2Ar), 3.18–2.98 (m, 1H, H-1cyclohexyl), 1.90–0.45
(m, 10H cyclohexyl); 13C NMR (50 MHz, CDCl3) d
(ppm): 167.5 (s), 149.3 (s), 140.2 (s), 134.1 (s), 133.2 (s),
132.9 (d), 131.3 (s), 130.1 (d, 2C), 129.3 (d), 129.0 (d, 2C),
124.5 (d), 123.0 (d), 58.9 (d), 54.4 (d), 44.7 (t), 32.7 (t), 32.3
(t), 25.3 (t), 25.2 (t), 24.5 (t). Anal. Calcd for
C22H22ClN5O: C, 64.78; H, 5.44; N, 17.17. Found: C,
64.55; H, 5.52; N, 16.98.
(ppm): 7.86–7.81 (m, 1H, Ar-H), 7.50–7.45 (m, 2H, Ar-H),
7.37 (d, J = 8.4 Hz, 2H, Ar-H), 7.20–7.00 (m, 6H, Ar-H),
6.85 (s, 1H, CHN), 6.58 (d, J = 7.3 Hz, 2H, Ar-H), 5.05
(AB system, 2H, CH2Ar), 2.29, (s, 3H, CH3); 13C NMR
(50 MHz, CDCl3) d (ppm): 166.4 (s), 150.9 (s), 138.6 (s),
135.5 (s), 133.6 (s), 133.1 (s), 131,9 (d), 131.7 (s), 130.0 (d,
2C), 129.9 (d, 2C), 128.7 (d, 2C), 128.4 (d), 126.7 (d), 124.6
(d), 122.9 (d), 120.0 (d, 2C), 55.6 (d), 51.5 (t), 21.0 (q).
Anal. Calcd for C23H19N5O: C, 72.42; H, 5.02; N, 18.36.
Found: C, 72.46; H, 4.90; N, 18.59.
Compounds 6b–d were prepared in a similar manner.