Improved procedure for cyclization of vinyl azides into 3-substituted-2H-azirines

Article abstract of DOI:10.1016/S0040-4039(03)01205-X

A significantly improved procedure for the preparation of 3-substituted 2H-azirines has been developed. By cyclization of the corresponding vinyl azides in low boiling solvents in closed vessels at elevated temperature, high purity, short reaction time an

Full text of DOI:10.1016/S0040-4039(03)01205-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5339–5341
Improved procedure for cyclization of vinyl azides into
3-substituted-2H-azirines
,
Asa Sjo¨holm Time´n, Erik Risberg and Peter Somfai*
Organic Chemistry, Department of Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden
Received 1 April 2003; revised 30 April 2003; accepted 9 May 2003
Abstract—A significantly improved procedure for the preparation of 3-substituted 2H-azirines has been developed. By cyclization
of the corresponding vinyl azides in low boiling solvents in closed vessels at elevated temperature, high purity, short reaction time
and simple isolation of the product were achieved. © 2003 Elsevier Science Ltd. All rights reserved.
Azirines are highly reactive three-membered unsatu-
rated nitrogen-containing heterocycles that have found
an increased use in organic synthesis.1 They take part in
various chemical transformations since they can act as
dienophiles and dipolarophiles as well as electrophiles
and nucleophiles.2 The ring strain and the reactive
p-bond account for the high reactivity of the azirine
moiety and make it an attractive intermediate in the
synthesis of complex alkaloids.2 In order to further
develop the chemistry of the 2H-azirines a convenient
method for their preparation is of great importance.
of the vinyl azides and it has been observed that it is
sometimes difficult to separate the formed azirine from
the solvent. To circumvent this the reaction can be
performed at lower temperature, allowing the use of
solvents with low boiling point, but with substantially
longer reaction times, typically 1–7 days, as a result.11
Since azirines are thermally unstable,4 with some
decomposition even at ambient temperature,12 pro-
longed heating should be avoided. This is to suppress
undesired polymerization which is a known side reac-
tion in the formation of azirines.8,13 In an ongoing
project we needed a ready access to a variety of aziri-
nes. As a result, an optimization of the thermolysis was
undertaken and herein our results are detailed.
Several methods for the synthesis of various 2H-aziri-
nes have been described.2 A frequently used method
employs vinyl azides,3–5 which can be converted into
the corresponding 2H-azirines by thermolysis or pho-
tolysis (Scheme 1).5–8
From earlier work in our research group a convenient
improvement of existing methods for thermolysis of
vinyl azides into azirines has emerged.14 The vinyl
azides are simply heated in low boiling solvents. In
order to reach the necessary temperature to facilitate
ring closure and to avoid prolonged reaction times the
reaction must be performed in a closed vessel. While it
has been possible to use pentane or Et2O for some vinyl
azides,15 2-azidoacrylic esters do not tolerate these sol-
vents. The resulting ester-substituted azirines decom-
pose more easily than alkyl- or aryl-substituted ones
and the cyclizations are often accompanied by consider-
able amounts of byproduct formation. Consequently,
azidoacrylic ester 1a was selected as substrate for the
thermolysis optimization study.
For the thermal conversion of vinyl azides into 2H-
azirines, elevated temperatures are needed. The most
commonly used solvent has been toluene, but others
such as dioxane and heptane, all with a boiling point
between 98 and 110°C, have also been applied.6,9,10 At
these temperatures reaction times of 1.5 to 10 h are
commonly required to accomplish complete conversion
Scheme 1.
The cyclization of azide 1a in CH2Cl2 at different
temperatures clearly showed that higher reaction tem-
perature for a shorter time was more efficient than a
lower temperature which required a longer reaction
Keywords: vinyl azide; thermolysis; azirine.
* Corresponding author. Tel.: +46 8 790 6960; fax: +46 8 791 2333;
e-mail: somfai@kth.se
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01205-X

,
A. Sjo¨holm Time´n et al. / Tetrahedron Letters 44 (2003) 5339–5341
5340
time for complete consumption of 1a (compare entries
1, 2 and 3, Table 1). At prolonged reaction time,
byproduct formation increased and the yield of azirine
2a after 6 h at 100°C was 43% with 13% of 1a still
remaining. After 20 min at 150°C no starting material
was present and 2a was obtained in 85% yield.16 For
the reactions run at 100 and 125°C it was also noted
that the amount of 2a remained constant after a short
time (2 h and 30 min, respectively) despite continued
heating and consumption of 1a.
gave acceptable results (entry 3) and this solvent was
selected for further optimizations.
The concentration of the vinyl azide is an important
parameter in the thermolysis reaction and a wide range
of concentrations (0.006–0.42 M) have been reported in
the literature.5,10 In order to find the optimal condi-
tions, three concentrations were studied, 0.10, 0.25 and
0.5 M of 1a. In all cases vinyl azide 1a was completely
consumed, but with large variations in the yield of
azirine 2a (Table 3). At 0.10 M of 1a the yield of 2a was
85%, falling to 36% at 0.25 M and at 0.50 M only 2%
of the azirine could be detected (entries 1, 2 and 3).
The results in Table 2 show the solvent dependence of
the thermolysis of vinyl azide 1a. Three solvent types
were represented by CH2Cl2, toluene and Et2O.17 All
reactions were run at 150°C for 20 min at which time
all the azide was consumed. In toluene product 2a was
obtained in 52% yield, whereas in Et2O no product was
detected (entries 1 and 2). In both cases byproducts
The optimized conditions with 0.1 M vinyl azide in
dichloromethane at 150°C for 20 min proved to work
well also for azides 1b–h which were chosen in order to
demonstrate the generality of the reaction conditions
(Fig. 1 and Table 4). All compounds gave the corre-
sponding azirines 2b–h in good to excellent yields and
with high purity.
1
were clearly visible in the H NMR spectra of the crude
reaction mixtures. However, the thermolysis in CH2Cl2
Table 1. Temperature dependencea
We report in this paper the development of an
improved and general method for the preparation of
3-substituted 2H-azirines. The major advantages with
this method are the high yields, the short reaction times
and the convenient isolation of the products.
Entry
Temp. (°C)
Time (min)
Yield of 2ab (%)
1
2
3
100
125
150
360
75
20
43c
69
85
General procedure for preparation of 3-substituted-2H-
azirines: The vinyl azide 1a (140 mg, 0.69 mmol) was
a Reaction conditions: 0.1 M of 1a in CH2Cl2.
b Measured by 1H NMR.
c With 13% of azide remaining.
Table 3. Concentration dependencea
Table 2. Solvent dependencea
Entry
Concentration (M)
Yield of 2ab (%)
Entry
Solvent
Yield of 2ab (%)
1
2
3
0.10
0.25
0.50
85
36
2
1
2
3
Toluene
Et2O
CH2Cl2
52
0
85
a Reaction conditions: The azirine was heated in CH2Cl2 at 150°C for
a Reaction conditions: 0.1 M of 1a in solvent at 150°C for 20 min.
20 min.
b Measured by 1H NMR.
b Measured by 1H NMR.
Figure 1.

,
A. Sjo¨holm Time´n et al. / Tetrahedron Letters 44 (2003) 5339–5341
5341
C. A.; Risberg, E.; Somfai, P. Tetrahedron 2002, 58,
Table 4. Thermolysis of vinyl azides 1a–1ha
,
5983–5987; (d) Sjo¨holm Time´n, A.; Fischer, A.; Somfai,
P. Chem. Commun. 2003, 1150–1151.
Entry
Product
Yieldb (%)
2. Palacios, F.; Ochoa de Retana, A. M.; Mart´ınez de
Marigorta, E.; de los Santos, J. M. Org. Prep. Proced.
Int. 2002, 34, 219–269.
3. (a) Smolinsky, G. J. Org. Chem. 1962, 27, 3557–3559; (b)
Hassner, A.; Fowler, F. W. J. Org. Chem. 1968, 33,
2686–2691; (c) Hassner, A. Vinyl Azides and Nitrenes. In
Azides and Nitrenes; Scriven, E. F. V., Ed.; Academic
Press: Orlando, Florida, 1984; pp. 35–94.
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
85
>95
>95
84
95
>95
74
2g
2h
82
4. Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 4483–4484.
5. Hortmann, A. G.; Robertson, D. A.; Gillard, B. K. J.
Org. Chem. 1972, 37, 322–324.
6. Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Cardoso, A.
L.; Rocha Gonsalves, A. M.d’A. Tetrahedron 2001, 57,
6203–6208.
7. Banert, K. Chem. Ber. 1987, 120, 1891–1896.
8. Hassner, A.; Fowler, F. W. J. Am. Chem. Soc. 1968, 90,
2869–2875.
9. Gilchrist, T. L.; Mendonc¸a, R. Synlett 2000, 1843–1845.
10. Kumar, R.; Nath, M.; Tyrrell, D. L. J. J. Med. Chem.
2002, 45, 2032–2040.
11. Banert, K. Chem. Ber. 1989, 122, 1175–1178.
12. Alves, M. J.; Gilchrist, T. L. Tetrahedron Lett. 1998, 39,
7579–7582.
13. Hassner, A.; Fowler, F. W. Tetrahedron Lett. 1967, 1545–
1548.
a Reaction conditions: The azirines were heated in CH2Cl2 at 150°C
for 20 min.
b Measured by 1H NMR.
dissolved in dry CH2Cl2 (6.9 mL) and heated in a glass
tube fitted with a screw cap for 20 min (150°C, pre-
heated oil bath) and then cooled in an ice bath. CAU-
TION: Heating of azides may cause explosion.
Evaporation gave 2a as a pale yellow oil. 1H NMR (400
MHz, CDCl3) l 7.36–7.48 (5H, m), 5.42 (2H, s), 1.97
(2H, s); 13C NMR (100 MHz, CDCl3) l 165.1, 158.6,
134.0, 129.0, 128.9, 128.8, 68.6, 24.2.
Acknowledgements
14. (a) Ray, C. A.; Risberg, E.; Somfai, P. Tetrahedron Lett.
2001, 42, 9289–9291; (b) Risberg, E.; Somfai, P. Tetra-
hedron: Asymmetry 2002, 13, 1957–1959.
Financial support from the Swedish Research Council
and the Swedish Foundation for Strategic Research is
appreciated. The authors also thank Dr. Colin Ray and
Mr. Stefan Ek for their contributions.
15. Azides 1d and 1e cyclized well in pentane (125°C, 2h), 1g
and 1h in Et2O under the same conditions.
16. 1,4-Di-tert-butylbenzene (0.2 equiv.) was added before
workup and used as the standard to determine the yields
References
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17. Other solvents such as CHCl3, CH2Cl2, pentane and THF
have also been used, with results in line with those
presented in Table 2.
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