Diaziridine ring expansion in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes on treatment with nitriles assisted by ionic liquids

Article abstract of DOI:10.1016/j.mencom.2008.07.013

The ionic-liquids-assisted insertion of activated nitriles into the diaziridine ring of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes catalysed with BF₃·Et₂O provides a simple method for the preparation of 1-aryl-6,7-dihydro-1H,5H-pyrazolo[1,2-a][1,2,4]triazoles.

Full text of DOI:10.1016/j.mencom.2008.07.013

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 207–208
Diaziridine ring expansion in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes
on treatment with nitriles assisted by ionic liquids
Yuliya S. Syroeshkina, Vladimir V. Kuznetsov, Marina I. Struchkova,
Margarita A. Epishina and Nina N. Makhova*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
DOI: 10.1016/j.mencom.2008.07.013
The ionic-liquids-assisted insertion of activated nitriles into the diaziridine ring of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes catalysed
with BF3·Et2O provides a simple method for the preparation of 1-aryl-6,7-dihydro-1H,5H-pyrazolo[1,2-a][1,2,4]triazoles.
Reactions of diaziridines with ring expansion on treatment with
electrophilic reagents are known; however, the majority of com-
Ar
Et2O·BF3, 20 °C
N
pounds studied so far belong to N-unsubstituted diaziridines.1–3
We found that these reactions are also possible for N,N'-disub-
stituted diaziridines (both mono- and bicyclic) with sufficiently
reactive electrophilic reagents (ketenes, aroylisocyanates and
aroylisothiocyanates, but not CS2).4–8 Recently,9 we found con-
ditions for the efficient insertion of CS2 into the CN bond of
the three-membered ring in bicyclic diaziridines 1. The insertion
of CS2 into the C–N bond of the diaziridine ring requires ionic
liquids to be used as a reaction medium and Et2O·BF3 as a
catalyst. These reactions starting from 6-aryl-1,5-diazabicyclo-
[3.1.0]hexanes 1 gave 3-aryldihydro-5H-pyrazolo[1,2-c][1,3,4]-
thiadiazole-1-thiones 2; the yields were nearly quantitative for
compounds 2 containing electron-donating substituents at the
4-position of the aryl substituent (Scheme 1). NMR spectroscopy
revealed the formation of dipolar intermediates 3, i.e. precursors
of products 2; intermediate 3 with Ar = 4-MeC6H4 was isolated
and characterised (Scheme 1).
+
RC
N
N
[bmim]BF4
1a–d
4a,b
R
N
Ar
R
N
N
N
N
N
Ar
6
5a–h
1a Ar = 4-EtOC6H4
5a Ar = 4-EtOC6H4, R = COOEt
5b Ar = 4-PriOC6H4, R = COOEt
5c Ar = 4-MeOC6H4, R = COOEt
5d Ar = 4-MeC6H4, R = COOEt
5e Ar = 4-EtOC6H4, R = CCl3
5f Ar = 4-PriOC6H4, R = CCl3
5g Ar = 4-MeOC6H4, R = CCl3
5h Ar = 4-MeC6H4, R = CCl3
1b Ar = 4-PriOC6H4
1c Ar = 4-MeOC6H4
1d Ar = 4-MeC6H4
4a R = COOEt
4b R = CCl3
Scheme 1
S
S
order 4b > 4a. The syntheses of compounds 5e,f containing
strong electron-donating substituents at the aromatic ring of
starting compounds 1a,b and a strong electron-withdrawing
substituent in starting nitrile 4b took 30 min, whereas the
reaction of diaziridine 1a with nitrile 4a containing a weaker
electron-withdrawing substituent was completed in 18 h. The
reactions of bicyclic diaziridines 1c,d with nitrile 4a at 20 °C
occurred so slowly that only due to the temperature increase up
to 70 °C the reaction could be completed in 20 h in both cases.
Attempts to use 6-aryl-1,5-diazabicyclo[3.1.0]hexane containing
an electron-withdrawing substituent at the aromatic fragment
(4-ClC6H4) did not result in reactions with any of nitriles 4a,b.
Ar
Ar
S
N
N
CS2
N
S
N
N
N
Ar
1
3
2
Scheme 1
Here we report the reactions of 6-aryl-1,5-diazabicyclo-
[3.1.0]hexanes 1a–d with insufficiently electrophilic reagents,
viz., nitriles 4a,b. Numerous attempts to perform these reac-
tions in ordinary organic solvents, including those catalysed by
Et2O·BF3, failed: in all cases, complex inseparable mixtures of
at least seven compounds were formed. However, when an ionic
liquid ([bmim][BF4]) was used as the solvent, Et2O·BF3 was
used as the catalyst and the reaction was carried out at 20 °C,
the expected result was achieved, namely, target 6,7-dihydro-
1H,5H-pyrazolo[1,2-a][1,2,4]triazoles 5a–h were obtained in
all cases (Scheme 2). The molar ratio between starting com-
pounds 1 and 4 was 1:1.3–1.5. The completion of the reaction
was judged from the full conversion of starting bicyclic diazi-
ridines 1 (TLC monitoring).
Table 1 Reactions of diaziridines with nitriles.
Starting compounds
Reaction
Product
Yield (%)
time/h
Diaziridine
Nitrile
1a
1b
1c
1d
4a
4a
4a
4a
18
5a
5b
5c
5d
43
40
45
37
11
20a
20a
1a
1b
1c
1d
4b
4b
4b
4b
0.5
0.5
1
5e
5f
5g
5h
~99
~99
82
The reaction time depended on the substituents in starting
bicyclic diaziridines 1 and nitriles 4 used in the reaction (see
Table 1). The reactivity of the starting bicycles decreased in
the order 1b ³ 1a > 1c > 1d, and that of nitriles decreased in the
5
83
aAt 70°C.
– 207 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 207–208
The yields of 1-aryl-6,7-dihydro-1H,5H-pyrazolo[1,2-a][1,2,4]-
tures containing the 1,2,4-triazole ring fused with other hetero-
cyclic systems are of interest as inhibitors of NO synthase and
as antidiabetic agents.12,13
triazoles 5a–h also depended on the substituents in the starting
compounds, mainly in nitriles 4 (see Table 1). The smallest
yields of compounds 5 (£ 45%) were observed in reactions with
nitrile 4a. Formation of polymeric products was observed in
these cases. Compounds 5e,f, i.e. reaction products of nitrile 4b
and diaziridines 1a,b, were obtained in the highest yields (~99%).
TLC monitoring of the reactions showed that one more com-
pound with a smaller Rf was formed in addition to end products
5; this compound disappeared when the process approached
completion. It was assumed that this compound was dipolar
intermediate 6 similar to intermediate 3, which was found
previously9 in the reaction of 6-aryl-1,5-diazabicyclo[3.1.0]-
hexanes with CS2 (Scheme 1). The NMR spectra of the isolated
reaction products of diaziridines 1a–d with nitrile 4a contained
This work was supported in part by the Presidium of the
Russian Academy of Sciences (the programme ‘Development
of Methods for Synthesising Chemical Compounds and Creating
New Materials’).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2008.07.013.
References
1
2
E. Schmitz, Adv. Heterocycl. Chem., 1979, 24, 63.
E. Schmitz, in Comprehensive Heterocyclic Chemistry, ed. W. Lwowski,
1
no signals of the intermediate product; however, the H and
Pergamon Press, Oxford, 1984, vol. 1, p. 195.
13C NMR spectra† of the reaction products of diaziridines 1a–d
with nitrile 4b showed the presence of ~10% of intermediates 6.
The most characteristic feature of the 1H NMR spectra of
compounds 5 and 6 is the position of the signal of the proton at
the carbon atom bound to the aromatic fragment: for com-
pounds 5e–h, it manifests itself as a singlet at d 5.20–6.00 ppm,
whereas for corresponding intermediates 6e–h, it appears in the
region d 9.80–10.0 ppm. A similar picture is observed in the
13C NMR spectra: in compounds 5e–h, this carbon atom resonates
in the region d 86.00–87.50 ppm, whereas in compounds 6e–h,
in the region d 190.00–192.00 ppm. These differences in the
NMR spectroscopic characteristics of intermediates and products
agree with the differences found9 for dipolar intermediate 3.
Attempts to isolate individual intermediates 6e–h failed: the
column chromatography of mixtures of compounds 5e–h and 6e–h
resulted in the quantitative conversion of the latter to bicyclic
compounds 5e–h.
Thus, this study resulted in a discovery of a new reaction of
diaziridine ring expansion. On this basis, a simple method was
developed for obtaining 1-aryl-6,7-dihydro-1H,5H-pyrazolo-
[1,2-a][1,2,4]triazoles 5a–h, which involves BF3·Et2O-catalysed
insertion of the CN group of nitriles 4a,b into the diaziridine
ring of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes 1a–d with the use
of ionic liquids as the reaction medium.
3
4
5
H. W. Heine, in Small Ring Heterocycles, part 2, ed. A. Hassner,
Wiley-Interscience, New York, 1983, ch. IV, pp. 547–629.
A. V. Shevtsov, V. Yu. Petukhova, Yu. A. Strelenko, K. A. Lyssenko,
I. V. Fedyanin and N. N. Makhova, Mendeleev Commun., 2003, 221.
A. V. Shevtsov, V. Yu. Petukhova, Yu. A. Strelenko, K. A. Lyssenko,
N. N. Makhova and V. A. Tartakovsky, Izv. Akad. Nauk, Ser. Khim.,
2005, 997 (Russ. Chem. Bull., Int. Ed., 2005, 54, 1021).
A. V. Shevtsov, V. Yu. Petukhova, Yu. A. Strelenko and N. N. Makhova,
Mendeleev Commun., 2005, 29.
A. V. Shevtsov, V. V. Kuznetsov, S. I. Molotov, K. A. Lyssenko and
N. N. Makhova, Izv. Akad. Nauk, Ser. Khim., 2006, 534 (Russ. Chem.
Bull., Int. Ed., 2006, 55, 554).
A. V. Shevtsov, V. V. Kuznetsov, A. A. Kislukhin, V. Yu. Petukhova,
Yu. A. Strelenko and N. N. Makhova, J. Heterocycl. Chem., 2006, 43,
881.
6
7
8
9
Yu. S. Syroeshkina, V. V. Kuznetsov, K. A. Lyssenko and N. N. Makhova,
Mendeleev Commun., 2008, 18, 42.
10 K. Burger, H. Schickander and M. Pinzel, Liebigs Ann. Chem., 1976,
1, 30.
11 J. Svetlik and T. Liptaj, J. Chem. Soc., Perkin Trans. 1, 2002, 1260.
12 J. Svetlik and L. Sallai, J. Heterocycl. Chem., 2002, 39, 363.
13 R. Bucala, A. Cerami and H. Vlassara, Diabetes Rev., 1995, 3, 258.
14 V. V. Kuznetsov, S. A. Kutepov, N. N. Makhova, K. A. Lyssenko and
D. E. Dmitriev, Izv. Akad. Nauk, Ser. Khim., 2003, 638 (Russ. Chem.
Bull., Int. Ed., 2003, 52, 665).
Received: 11th December 2007; Com. 07/3058
Heterocyclic systems incorporating the 6,7-dihydro-1H,5H-
pyrazolo[1,2-a][1,2,4]triazole framework have been reported in
the literature, but their syntheses require multistage processes
and more complex starting compounds.10,11 Heterocyclic struc-
1-(4-Methoxyphenyl)-3-(trichloromethyl)-6,7-dihydro-1H,5H-pyrazolo-
1
[1,2-a][1,2,4]triazole 5g: nondistilled oil, Rf 0.58. H NMR (CDCl3) d:
2.08 (m, 2H, NCH2CH2, 2J 12.24 Hz), 2.61, 2.98 (2br. m, 2H, CH2NC=N,
n 81.60 Hz), 3.65, 4.03 (2br. m, 2H, CH2N–N, n 85.70 Hz), 3.72 (s,
3H, MeOAr), 5.88 (s, 1H, ArCHN), 6.85, 7.36 (2d, 4H in Ar, 3J 8.16 Hz).
13C NMR (CDCl3) d: 24.60 (CH2CH2CH2), 46.93 (CH2N–N), 50.40 (br.,
CH2NC=N), 55.05 (MeOAr), 87.12 (br., ArCHN), 88.49 (CCl3), 113.69,
127.86, 130.67, 159.37 (Ar), 162.32 (NC=N). MS, m/z (%): 334 (M, 17),
264 (M – pyrazolidine, 12), 229 (M – MeOC6H4, 95), 144 (Cl3CCN, 100),
92 (OC6H4, 45), 76 (C6H4, 75), 71 (C3H7N2, 10).
†
All new compounds exhibited satisfactory elemental analyses. IR spectra
were measured on a UR-20 spectrometer; 1H and 13C NMR spectra were
recorded on Bruker AC-200-31 (200 MHz for 1H and 50.3 MHz for 13C)
and Bruker AM-300 (300 MHz for H and 75.5 MHz for 13C) spectro-
1
meters (CDCl3 was used as an internal standard). 13C NMR spectra
were recorded under proton decoupling conditions. The signals in the
13C NMR spectra of compounds 5 were assigned using {1H-1H}NOESY,
{1H-13C}HMBC and {1H-13C}HSQC on Bruker DRX500 (500 MHz for
1H and 126 MHz for 13C) for compound 5a as an example. Mass spectra
were measured on a Finnigan MAT INCOS-50 instrument. TLC was
carried out on Silufol UV-254 plates. Rf [n-hexane–ethyl acetate, 2:1 (v/v)].
Melting points were measured on a Gallenkamp instrument (Sanyo).
6-Aryl-1,5-diazabicyclo[3.1.0]hexanes 1a–d were synthesised by a published
method.14
1-(4-Methylphenyl)-3-(trichloromethyl)-6,7-dihydro-1H,5H-pyrazolo-
[1,2-a][1,2,4]triazole 5h: nondistilled oil, Rf 0.77. 1H NMR (CDCl3) d:
2.11 (m, 2H, NCH2CH2, J 14.04 Hz), 2.39 (s, 3H, MeAr), 2.68, 3.05
(2br. m, 2H, CH2NC=N, n 102.08 Hz), 3.69, 4.08 (br. m, 1H, CH2N–N,
n 127.60 Hz), 5.98 (s, 1H, ArCHN), 7.19, 7.39 (2d, 4H in Ar, 3J 6.38 Hz).
13C NMR (CDCl3) d: 21.10 (MeAr), 24.68 (CH2CH2CH2), 47.01 (CH2N–N),
50.72 (br., CH2NC=N), 87.46 (br., ArCHN), 88.40 (CCl3), 126.63, 129.08,
137.83 (Ar), 162.43 (NC=N).
2
1
Ethyl 1-(4-methoxyphenyl)-6,7-dihydro-1H,5H-pyrazolo[1,2-a][1,2,4]-
Intermediate 6g: Rf 0.46. H NMR (CDCl3) d: 3.84 (s, 3H, MeOAr),
triazole-3-carboxylate 5c: nondistilled oil, Rf 0.30. 1H NMR (CDCl3) d:
6.95, 7.79 (2d, 4H in Ar, 3J 8.16 Hz), 9.85 (s, 1H, ArCH=N). 13C NMR
(CDCl3) d: 55.36 (MeOAr), 114.14, 131.74 (Ar), 162.80 (NC=N), 190.49
(ArCHN).
Intermediate 6h: Rf 0.62. 1H NMR (CDCl3) d: 2.43 (s, 3H, MeAr),
7.32, 7.78 (2d, 4H in Ar, 3J 6.38 Hz), 9.95 (s, 1H, ArCH=N). 13C NMR
(CDCl3) d: 20.96 (MeAr), 29.59 (CH2CH2CH2), 36.40 (CH2N–N), 60.26
(br., CH2NC=N), 171.10 (NC=N), 191.85 (ArCHN).
For spectral characteristics of compounds 5a,b,d–f and 6e,f see Online
Supplementary Materials.
3
1.23 (t, 3H, COOCH2Me, J 7.39 Hz), 1.98, 2.34 (2m, 2H, NCH2CH2,
2J 11.10 Hz, n 68.96 Hz), 3.03 (m, 2H, CH2NC=N, 2J 13.78 Hz), 3.72 (m,
2H, CH2N–N, 2J 8.96 Hz), 3.77 (s, 3H, MeOAr), 4.14 (q, 2H, COOCH2Me,
3J 7.39 Hz), 5.28 (s, 1H, ArCHN), 6.88, 7.47 (2d, 4H in Ar, 3J 8.95 Hz).
13C NMR (CDCl3) d: 14.43 (MeCH2OCO), 24.92 (CH2CH2CH2), 46.46
(CH2N–N), 55.27 (CH2NC=N), 60.35 (MeOAr), 61.99 (MeCH2OCO),
62.37 (ArCHN), 114.15, 124.29, 129.55, 146.59 (Ar), 157.15 (NC=N),
160.25 (OC=O).
– 208 –