Synthesis of fused isoindoles via 1,3-dipolar cycloaddition of 1,3-oxazolium-5-olates (muenchnones) with nitro benzazoles

Article abstract of DOI:10.1016/j.mencom.2012.01.013

1,3-Dipolar cycloaddition of 1,3-oxazolium-5-olates at benzazoles nitrated at the benzene ring affords the corresponding azoloisoindole derivatives.

Full text of DOI:10.1016/j.mencom.2012.01.013

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 35–36
Synthesis of fused isoindoles via 1,3-dipolar cycloaddition
of 1,3-oxazolium-5-olates (münchnones) with nitro benzazoles
Sergey Yu. Pechenkin, Aleksei M. Starosotnikov,* Maxim A. Bastrakov,
Vadim V. Kachala and Svyatoslav A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: alexey41@list.ru
DOI: 10.1016/j.mencom.2012.01.013
1,3-Dipolar cycloaddition of 1,3-oxazolium-5-olates at benzazoles nitrated at the benzene ring affords the corresponding azolo-
isoindole derivatives.
O
Although the 1,3-dipolar cycloaddition of dipoles to nitro alkenes
is well-known,1 there is only a few examples of similar reactions
involving aromatic nitro compounds, mostly nitro hetarenes.2 The
first examples of the [3+2]-cycloaddition to nitroarenes, namely,
reactions between nonstabilized N-methyl azomethine ylide and
mono- and dinitrobenzene fused with azoles and azines, were
published recently by our group.3 In all cases cycloaddition by
one or two C=C bond(s) activated by the nitro group occurred
giving rise to the loss of aromaticity of the nitrobenzene ring and
formation of tetrahydroisoindole or isoindoline systems.3 Later,
Lee et al. described4 ‘facile dearomatization of nitrobenzene
derivatives and other nitroarenes’ under the action of N-benzyl
azomethine ylide.
1,3-Oxazolium-5-olates (münchnones) are known to undergo
1,3-dipolar cycloaddition at conjugated nitro alkenes5 as well as
at nitro heteroaromatics, e.g., 2- and 3-nitroindoles.6 Since münch-
none molecule contains the cyclic azomethine ylide fragment
(Scheme 1), its reaction with nitro alkene affords bicyclic inter-
mediate which is prone to eliminate HNO2 and carbon dioxide
leading to pyrrole derivatives.1,5
Me
Me
Bn
i
OH
O
N
N
Bn
O
O
R
R
1a,b
2a,b
a R = Ph
b R = Me
NO2
O2N
N
N
N
N
X
X
3a–c
3d–f
Bn
Bn
Me
Ph
ii
ii
N
N
Ph
Me
N
+
N
N
X
X
N
5a–c
4a–c
a X = O
b X = S
c X = Se
R5
R3
R3
Scheme 2 Reagents and conditions: i, DCC (1 equiv.), THF, reflux; ii, 2a
(3 equiv.), THF, reflux.
R2
R1
R2
R1
R4
NO2
N
N
O
O
In most cases the cycloadditions appeared to be regioselec-
tive, the selectivity being dependent on the nature of heteroatom
in starting nitro compound 3. The best selectivity was observed in
case of thiadiazole derivatives. The resulting isomers 4 and 5 are
quite difficult to separate since they had almost identical Rf values
in a wide range of common eluents. However, it was possible to
isolate and fully characterize the major isomers excluding 4c.
The ratio of the isomers in each case was determined from 1H NMR
data of the crude mixture using the ratio of integral intensities
of characteristic signals of benzyl CH2 groups or methyl groups.
O
O
O
R2
R3
R3
R4
R2
R1
R5
N
N
O
R5
R1
– HNO2, – CO2
R4
NO2
Scheme 1
In this connection it was of interest to verify nitroarene be-
haviour in [3+2]-cycloadditions with münchnones. Available
nitrated benzofurazans, benzothiadiazoles and benzoselenadiazoles
were used as dipolarophiles. 1,3-Oxazolium-5-olates 2a,b were
synthesized in situ from N-benzyl-N-benzoyl- 1a or N-benzyl-
N-acetylalanine 1b6 under the action of dicyclohexyl carbodi-
imide (DCC) (Scheme 2).
Heating of münchnone 2a in the presence of nitro benzazoles
3a–f resulted in formation of the mixtures of isomeric isoindoles
4a–c and 5a–c (Scheme 2, Table 1). Here the reactions proceed
similarly to those of nitro alkenes.
Table 1 Reaction of münchnone 2a with compounds 3a–f.
Com-
pound
X
Reaction Products Yield of the Isomer
Isolated yield
isomer (%)
time/h
mixture (%) ratio 4:5 of major
3a
3b
3c
3d
3e
3f
O
S
Se
O
S
0.5
0.75
2
0.5
0.75
2
4a + 5a 88
4b + 5b 79
4c + 5c 50
4a + 5a 85
4b + 5b 64
4c + 5c 67
58:42
87:13
79:21
41:59
13:87
35:65
29 (4a)
45 (4b)
Not isolated
13 (5a)
20 (5b)
41 (5c)
Se
© 2012 Mendeleev Communications. All rights reserved.
– 35 –

Mendeleev Commun., 2012, 22, 35–36
(münchnones) with nitro benzazoles. This can be regarded as a
new method for the annelation of pyrrole ring to benzene moiety.
H
This work was supported by the Russian Foundation for Basic
Research (project no. 10-03-00185-a), and the President of the
Russian Federation (The program of state support for young
scientists, grant MK-220.2011.3).
Me
N
N
N
N
N
N
Me
X
X
H
H H
References
Figure 1 Selected connectivities found in 2D NOESY spectra of the
products 4 and 5.
1 (a) A. Padwa and W. H. Pearson, Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products, Wiley,
New York, 2002; (b) A. Padwa, 1,3-Dipolar Cycloaddition Chemistry,
John Wiley & Sons, New York, 1984.
2 S. Roy, T. L. Kishbaugh, J. P. Jasinski and G. W. Gribble, Tetrahedron
Lett., 2007, 48, 1313, and references cited therein.
3 (a) M. A. Bastrakov, A. M. Starosotnikov, S.Yu. Pechenkin, V. V. Kachala,
I. V. Glukhov and S. A. Shevelev, J. Heterocycl. Chem., 2010, 47, 893;
(b)A. M. Starosotnikov, M.A. Bastrakov, S.Yu. Pechenkin, M.A. Leontieva,
V. V. Kachala and S. A. Shevelev, J. Heterocycl. Chem., 2011, 48, 824;
(c) L. S. Konstantinova, M.A. Bastrakov,A. M. Starosotnikov, I.V. Glukhov,
K. A. Lysov, O. A. Rakitin and S. A. Shevelev, Mendeleev Commun., 2010,
20, 353.
The structures of each isolated isomer were assigned based on
1D and 2D NOESY experiments (Figure 1).
In case of münchnone 2b containing two methyl groups the
reaction with nitrobenzofurazans 3a and 3d resulted in formation
of the individual isoindole 6 (Scheme 3). Surprisingly, thia- and
selenadiazole derivatives 3b,c,e,f did not undergo cycloaddition
reactions with 2b under standard conditions.
The structures of the polycyclic compounds obtained were
proved by NMR spectroscopy and microanalysis.†
4 S. Lee, I. Chataigner and S. R. Piettre, Angew. Chem. Int. Ed., 2011, 50,
472.
5 M. Avalos, R. Babiano, A. Cabanillas, P. Cintas, J. L. Jimenez and J. C.
Palacios, J. Org. Chem., 1996, 61, 7291.
In summary, a number of new isoindole derivatives fused with
azoles were synthesized on the basis of the previously unknown
1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-olates
6 G. W. Gribble, E. T. Pelkey, W. M. Simon and H. A. Trujillo, Tetrahedron,
2000, 56, 10133.
Me
Me
Me
Bn
7 (a) P. B. Ghosh and M. W. Whitehouse, J. Med. Chem., 1968, 11, 305;
(b) T. Murashima, D. Shiga, K. Nishi, H. Uno and N. Ono, J. Chem. Soc.,
Perkin Trans. 1, 2000, 16, 2671; (c) E. Sawicki and A. Carr, J. Org. Chem.,
1957, 22, 503; (d) T. Murashima, K. Fujita, K. Ono, T. Ogawa, H. Uno and
N. Ono, J. Chem. Soc., Perkin Trans. 1, 1996, 12, 1403.
Bn
Bn
N
N
N
O
O
O
O
O
O
Me
Me
Me
2b
Bn
Me
N
3a or 3d
THF, reflux
Me
N
N
O
6, 36% from 3a
40% from 3d
Received: 15th July 2011; Com. 11/3765
Scheme 3
7-Benzyl-8-methyl-6-phenyl-7H-[1,2,5]selenadiazolo[3,4-e]isoindole 4c:
not isolated. 1H NMR (DMSO-d6) d: 2.73 (s, 3H, Me), 5.40 (s, 2H, CH2),
6.84 (d, 2H, J 7.2 Hz), 7.04 (d, 1H, J 9.5 Hz), 7.08–7.51 (m, 9H).
7-Benzyl-6-methyl-8-phenyl-7H-[1,2,5]oxadiazolo[3,4-e]isoindole 5a:
yellow crystals, mp 125–126°C. 1H NMR (CDCl3) d: 2.39 (s, 3H, Me),
5.32 (s, 2H, CH2), 6.92 (d, 2H, J 6.1 Hz), 7.08 (d, 1H, J 9.4 Hz), 7.27–7.52
(m, 9H). 13C NMR (CDCl3) d: 10.6, 48.6, 105.4, 107.3, 119.2, 125.7, 126.9,
127.6, 127.8, 128.8, 128.9, 129.1, 130.0, 130.6, 131.6, 137.22, 145.77,
150.2. Found (%): C, 77.65; H, 4.92; N, 12.57. Calc. for C22H17N3O (%):
C, 77.86; H, 5.05; N, 12.38.
†
Melting points were measured on a Boetius apparatus and are uncor-
rected. NMR spectra were recorded on a Bruker DRX-500 spectrometer
using TMS as a standard. All reactions were monitored by TLC using
Silufol UV-254 plates which were visualized with UV light. Flash column
chromatography was performed with MN Kieselgel 60 (0.04–0.063
mm/230–400 mesh) as the stationary phase and toluene as an eluent. For
allnewcompoundssatisfactorymicroanalyseswereobtained. Compounds
3a–f were prepared according to the described procedures.7
Compounds 4–6 (general procedure). A mixture of compound 1a or
1b (3 mmol), nitro compound 3 (1 mmol) and DCC (0.61 g, 3 mmol) in
20 ml of dry THF was heated under reflux for the time indicated in Table 1.
After the starting material disappeared (TLC) the mixture was cooled to
room temperature and filtered. The solvent was evaporated under reduced
pressure and the residue was recrystallized from EtOH to give a mixture
of isomers 4 and 5. The major isomer was isolated from the mixture by
column chromatography (SiO2/toluene).
7-Benzyl-8-methyl-6-phenyl-7H-[1,2,5]oxadiazolo[3,4-e]isoindole 4a:
yellow crystals, mp 131–132°C. 1H NMR (CDCl3) d: 2.70 (s, 3H, Me),
5.32 (s, 2H, CH2), 6.92 (d, 2H, J 6.7 Hz), 7.07 (d, 1H, J 9.6 Hz), 7.29–7.45
(m, 9H). 13C NMR (CDCl3) d: 12.3, 48.4, 105.6, 108.3, 119.1, 125.6,
127.6, 128.4, 128.5, 128.8, 130.0, 130.4, 130.5, 130.7, 137.1, 146.0, 150.0.
Found (%): C, 78.10; H, 5.13; N, 12.06. Calc. for C22H17N3O (%): C, 77.86;
H, 5.05; N, 12.38.
7-Benzyl-6-methyl-8-phenyl-7H-[1,2,5]thiadiazolo[3,4-e]isoindole 5b:
brown crystals, mp 61–62°C. 1H NMR (CDCl3) d: 2.44 (s, 3H, Me), 5.32
(s, 2H, CH2), 6.89 (d, 2H, J 6.7 Hz), 7.27–7.60 (m, 11H). 13C NMR
(CDCl3) d: 10.6, 48.4, 112.7, 114.5, 119.8, 124.2, 125.0, 125.7, 127.5,
128.4, 128.6, 129.0, 129.6, 130.8, 131.4, 137.6, 151.6, 156.0. Found (%):
C, 74.50; H, 4.68; N, 11.97. Calc. for C22H17N3S (%): C, 74.34; H, 4.82;
N, 11.82.
7-Benzyl-6-methyl-8-phenyl-7H-[1,2,5]selenadiazolo[3,4-e]isoindole 5c:
brown crystals, mp 137–138°C. 1H NMR (DMSO-d6) d: 2.37 (s, 3H, Me),
5.26 (s, 2H, CH2), 6.83 (d, 2H, J 7.0 Hz), 7.04 (d, 1H, J 9.5 Hz), 7.15–7.65
(m, 9H). 13C NMR (DMSO-d6) d: 11.8, 47.48, 114.1, 118.2, 118.9, 119.7,
124.1, 125.6, 126.0, 127.3, 127.9, 128.1, 128.9, 130.0, 130.4, 137.5, 156.7,
160.7. Found (%): C, 65.49; H, 4.13; N, 10.65. Calc. for C22H17N3Se (%):
C, 65.67; H, 4.26; N, 10.44.
7-Benzyl-6,8-dimethyl-7H-[1,2,5]oxadiazolo[3,4-e]isoindole 6: orange
crystals, mp 136–137°C. 1H NMR (CDCl3) d: 2.38 (s, 3H, Me), 2.66 (s,
3H, Me), 5.25 (s, 2H, CH2), 6.90 (d, 2H, J 7.0 Hz), 7.98 (d, 1H, J 9.5 Hz),
7.27–7.38 (m, 4H). 13C NMR (CDCl3) d: 10.3, 12.1, 47.6, 104.6, 106.6,
117.9, 125.2, 125.7, 127.2, 127.8, 127.9, 129.1, 136.4, 146.1, 150.1.
Found (%): C, 73.48; H, 5.58; N, 14.90. Calc. for C17H15N3O (%): C, 73.63;
H, 5.45; N, 15.15.
7-Benzyl-8-methyl-6-phenyl-7H-[1,2,5]thiadiazolo[3,4-e]isoindole 4b:
brown crystals, mp 90–91°C. 1H NMR (CDCl3) d: 2.83 (s, 3H, Me), 5.38 (s,
2H, CH2), 6.90 (d, 2H, J 6.8 Hz), 7.18–7.53 (m, 11H). 13C NMR (CDCl3)
d: 11.9, 48.4, 112.9, 115.6, 118.4, 120.0, 125.7, 126.0, 127.0, 127.6, 128.1,
128.8, 128.9, 130.4, 131.1, 137.5, 152.3, 155.6. Found (%): C, 74.60;
H, 4.61; N, 11.59. Calc. for C22H17N3S (%): C, 74.34; H, 4.82; N, 11.82.
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