Synthesis of stable 1H-azirines reinvestigated: A structural corrigendum

Article abstract of DOI:10.1055/s-0032-1317494

The isoquinoline-catalyzed synthesis of pretended 1H-azirines from phenacyl bromides and N,N-dialkylcarbodiimides was repeated. The products do not possess the structure of antiaromatic 1H-azirines, but simple N-acyl-N,N-dialkylureas were formed instead. This structural corrigendum was confirmed by the independent synthesis of the known ureas and comparison of their ¹H NMR and ¹³C NMR spectroscopic data in the case of six compounds. Thus, 1H-azirines keep their classification as very short-lived intermediates. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317494

LETTER
▌2943
lSetyternthesis of Stable 1H-Azirines Reinvestigated: A Structural Corrigendum
Synthesis of Stable 1H-Azirines Reinvestigated
Klaus Banert,* Manfred Hagedorn, Heiko Peisker
Organic Chemistry, Chemnitz University of Technology, Strasse der Nationen 62, 09111 Chemnitz, Germany
Fax +49(371)53121229; E-mail: klaus.banert@chemie.tu-chemnitz.de
Received: 21.09.2012; Accepted: 30.09.2012
1 as short-lived intermediates, which cannot be isolated at
Abstract: The isoquinoline-catalyzed synthesis of pretended 1H-
room temperature.
azirines from phenacyl bromides and N,N′-dialkylcarbodiimides
was repeated. The products do not possess the structure of antiaro-
R1
N
CN
N
matic 1H-azirines, but simple N-acyl-N,N′-dialkylureas were
formed instead. This structural corrigendum was confirmed by the
independent synthesis of the known ureas and comparison of their
1H NMR and 13C NMR spectroscopic data in the case of six com-
pounds. Thus, 1H-azirines keep their classification as very short-
lived intermediates.
N
R2
R3
R1
R3
R2
R2
R1
1
2
3a, b
a R1 = NPh2, R2 = P(O)Ph2
b R1 = OMe, Oi-Pr, Os-Bu, OCHEt2
Key words: acylation, antiaromatic heterocycles, structure, assign-
ment by spectroscopy, ureas
R
2 = H
Figure 1 Structures of 1H-azirines and 2H-azirines
Strained compounds are of special interest because of
their increased energy content and the enhanced reactivi-
ty, which frequently results from this. For 1H-azirines 1
and 2H-azirines 2, it is obvious that both types of hetero-
cycles include considerable ring strain (Figure 1). Howev-
er, the properties of 1 and 2 are quite different.1 A great
number of 2H-azirines 2, especially those with R1 ≠ H,
were isolated and characterized by spectroscopic methods
in solution or even by X-ray crystallographic structure de-
termination. Although compounds of type 2 are highly re-
active, the 2H-azirine unit has been found in a few natural
products.2 On the other hand, only five examples of short-
lived 1H-azirines 3a,b were photochemically generated
and detected at very low temperatures by IR spectroscopy,
which indicated absorptions in the region of 1867–1890
cm–1 attributed to C=C valence vibration.3 Most probably,
the push-pull substitution pattern of 3a,b diminishes the
antiaromatic character of the 1H-azirine structure and in-
creases the relative stability. Thus, attempts to isolate or
observe the parent compound (1 with R1 = R2 = R3 = H)
by cycloaddition4 or cyclorevision5 approaches and by us-
ing argon-matrix isolation technique were unsuccessful
and yielded unsubstituted 2 and other isomeric species.
Elusive 1H-azirine intermediates were merely postulated
in several other reactions, which finally led to 2H-
azirines,6 pyrroles,7 indoles,8 oxazoles,9 isoquinolines,10
ketenimines,11 nitriles,12 or anilines.13 Furthermore, many
quantum chemical calculations, that analyzed the energy
content,14 the molecular geometry,15 the nitrogen inver-
sion barrier,16 the basicity,17 and the vibrational frequen-
cies and IR intensities18 of the parent 1H-azirine 1, have
been published. All experimental and theoretical results
emphasize the properties of the antiaromatic heterocycles
Recently, Alizadeh and Rezvanian reported on the synthe-
sis of 1H-azirines 6a–f by reaction of phenacyl bromides
4a–d with carbodiimides 5a,b in the presence of potassi-
um carbonate and a catalytic amount of isoquinoline (10
mol%) in anhydrous acetonitrile (Scheme 1).19 The prod-
ucts 6a–f were isolated by chromatography in 65–82%
yield as yellow powders and characterized by their sharp
melting points (150–176 °C), IR, 1H NMR, 13C NMR and
MS data as well as elemental analyses. It was claimed that
the antiaromatic heterocycles 6 were formed from 4 and 5
in 35–64% yield even when protic ethanol was used as
solvent and strong bases such as potassium hydroxide
were utilized. Surprisingly, phenacyl bromide 4e did not
isoquinoline
K2CO3, MeCN
O
R
Br
+
N
C
N
Ar
r.t., 6 h
R
4
5
a Ar = Ph
a R = i-Pr
b Ar = 4-MeOC6H4
c Ar = 4-O2NC6H4
d Ar = 3-O2NC6H4
e Ar = 3-BrC6H4
b R = c-Hex
f
Ar = 4-BrC6H4
65–82%
R
N
O
O
O
R
R
i-Pr
Ar
N
N
R
Ar
Ar
N
N
H
H
H
O
7
6
8
a Ar = 4-O2NC6H4
b Ar = 4-BrC6H4
a Ar = Ph, R = i-Pr
b Ar = Ph, R = c-Hex
c Ar = 4-MeOC6H4, R = i-Pr
d Ar = 4-MeOC6H4, R = c-Hex
e Ar = 4-O2NC6H4, R = c-Hex
f
Ar = 3-O2NC6H4, R = c-Hex
SYNLETT 2012, 23, 2943–2946
Advanced online publication: 09.11.2012
DOI: 10.1055/s-0032-1317494; Art ID: ST-2012-D0803-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 Synthesis of 1H-azirines 6a–f reported in the literature19
and the corrected structures 8a–f of the products from 4 and 5

2944
K. Banert et al.
LETTER
give any product of type 6 after treatment with 5a or 5b, cases, however, our 13C NMR data sets included one qua-
and the reaction of 4c or 4f with 5a exclusively led to the ternary carbon signal less if compared to the 13C NMR
simple amides 7a or 7b, respectively (yields: 78–80%).19
spectra published19 by Alizadeh and Rezvanian. This is
shown in Table 1 for the example20 of the product from 4b
and 5a that obviously cannot have the structure 6c. Our
corrected 13C NMR spectroscopic data excluded the 1H-
azirines 6a–f and led to the alternative structures 8a–f.
These N-acylureas were described in the literature,21 and
We had strong doubts about the antiaromatic structures 6
because the corresponding substances obviously are sta-
ble at room temperature, which is absolutely incompatible
with 1H-azirine moieties.1,3–18 The heterocycles 6a–f
should be even less stable than 3a,b since the electron-
withdrawing cyano group of 3 is replaced in 6 by an elec-
tron-releasing alkyl group that emphasizes the antiaro-
matic character of the three-membered ring. Moreover,
1H-azirines of type 6 should cause IR signals similar to
those of 3a,b. But IR absorptions within or near the region
of 1867–1890 cm–1 were not found for 6a–f.
1
in the cases 8a,c,d not only H NMR but also 13C NMR
spectra were reported.21a,b We prepared 8a–f for compari-
son by known procedures and found that 1H NMR and 13C
NMR data were identical with those of the products 8a–f
synthesized from 4a–d and 5a,b.20
The intermediates 9, 14, and 15 were used to interpret the
generation of the alleged 1H-azirines 6, and the ylides 16
were discussed as precursors, which lead to the amides
7a,b by hydrolysis (Scheme 2).19 However, these interme-
diates should alternatively play a role in the formation of
When we repeated the reaction of 4a–d with 5a,b, we ob-
tained substances with 1H NMR data which were identical
with those reported19 for 6a–f. Nearly the same was true
for the corresponding 13C NMR spectra. In each of the six
O
O
O
Br
R
+N
Ar
N
H
N
R
Ar
+
Me
X–
4
8
11
O
R
R
isoquinoline
N
N
H
H
10
O
H2O
O
O–
11
+
+N
Ar
base
Ar
Br–
12
9
base
– HBr
RN
O
C
NR
5
O
O
Ar
NR
+N
8
R
Ar
N
–
H
13
14
R
5
N–
R
N
+N
+N
NR
–
5
O
O
O
+N
Ar
NR
Ar
N
R
Ar
N
R
RN–
NR
15
16
17
H2O
H2O
10
+N
+
+
8
11
8
18
8
+
–
R
NR
18
N
H
Scheme 2 Some of the possible reaction mechanisms to explain the formation of 8
Synlett 2012, 23, 2943–2946
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Stable 1H-Azirines Reinvestigated
2945
Table 1 Comparison of 13C NMR Dataa of the Product from 4b and
5a with those of 8c20
In an alternative reaction mechanism, base-induced trans-
formation of the salts 9 into the stabilized ylides 14 fol-
lowed by nucleophilic addition at 5 should produce the
intermediates 15. Nucleophilic attack of 10 at the carbon-
yl group of 15 can yield 8 and the stabilized ylides 18. On
the other hand, intramolecular attack of the NR unit at the
carbonyl group of 15 would initiate N-acylation and for-
mation of the stabilized ylides 16. The latter can be hydro-
lyzed to give 8 and 11. If 16 adds to a second molecule of
5, the resulting intermediates 17 should lead to 8 and 18
on hydrolysis.
Product from
Product from
8c,b this work
4b and 5a, ref.19
4b and 5a, this work
20.95
22.33
20.94
22.32
42.69
50.18
55.42
113.81
X
20.91
22.29
42.67
50.11
55.39
113.78
X
42.70
50.24
55.42
In summary, we have demonstrated that the reaction of
bromides 4 and carbodiimides 5 does not give products
with energetic 1H-azirine moieties. Consequently, these
antiaromatic heterocycles keep their classification as very
elusive short-lived intermediates. Instead of alleged 1H-
azirines 6, simple N-acyl-N,N′-dialkylureas 8 were gener-
ated from 4 and 5. The formation of these products is sur-
prising but can be explained by several reaction
mechanisms.
113.85
122.11
128.87
X
128.87
129.17
X
128.84
129.16
X
133.24
154.20
161.78
172.05
161.78
172.05
154.54
161.74
172.03
161.74
172.03
154 51
161.71
171.93
161.71
171.93
Acknowledgment
Dedicated to Professor Helmut Quast.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
a Measured in CDCl3, δ values. X: No signal reported19 or measured
(this work) in this region.
References and Notes
b Prepared from 4-methoxybenzoic acid and 5a as described in the lit-
erature.21
(1) For reviews on 1H-azirines and 2H-azirines, see: (a) Backes,
J. In Houben-Weyl, Vol. E16c nd; Klamann, D., Ed.;
Thieme: Stuttgart, 1992, 321. (b) Nair, V. In The Chemistry
of Heterocyclic Compounds, Small-Ring Heterocycles; Vol.
42, Part 1; Hassner, A., Ed.; Wiley: New York, 1983, 215.
(c) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In
Comprehensive Heterocyclic Chemistry II; Vol. 1A; Padwa,
A., Ed.; Pergamon: New York, 1996, 1. (d) Palacios, F.;
Ochoa de Retana, A. N.; Martinez de Marigorta, E.; de Los
Santos, J. M. Eur. J. Org. Chem. 2001, 2401. (e) Gilchrist,
T. L. Aldrichimica Acta 2001, 34, 51. (f) Rai, K. M. L.;
Hassner, A. In Advances in Strained and Interesting Organic
Molecules; Vol. 8; Halton, B., Ed.; Jai Press: Greenwich,
2000, 187. (g) Fowler, F. W. Adv. Heterocycl. Chem. 1971,
13, 45. (h) Wentrup, C. Adv. Heterocycl. Chem. 1981, 28,
231.
(2) (a) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot.
1971, 24, 48. (b) Molinski, T. F.; Ireland, C. M. J. Org.
Chem. 1988, 53, 2103. (c) Salomon, C. E.; Williams, D. H.;
Faulkner, D. J. J. Nat. Prod. 1995, 58, 1463. (d) Stapley, E.
O.; Hendlin, D.; Jackson, M.; Miller, A. K.; Hernandez, S.;
Mata, J. M. J. Antibiot. 1971, 24, 42. (e) Davis, F. A.; Reddy,
G. V.; Liu, H. J. Am. Chem. Soc. 1995, 117, 3651. (f) Davis,
F. A.; Liu, H.; Liang, C.-H.; Reddy, G. V.; Zhang, Y.; Fang,
T.; Titus, D. D. J. Org. Chem. 1999, 64, 8929.
8 from 4 and 5 with loss of one carbon atom. Several re-
action mechanisms can be taken into consideration to ex-
plain this result. The most simple sequence includes N-
alkylation of isoquinoline by 4 and nucleophilic attack of
ureas 10, which are the hydrolysis products of 5, at the
carbonyl group of 9. This would produce 8 and the salt 11
(X = Br) via the corresponding isoquinolinium ylide. We
found that an anhydrous solvent (acetonitrile) is not nec-
essary to prepare 8 from 4 and 5, and addition of N,N′-di-
cyclohexylurea or one equivalent of water did not prevent
the formation of 8. But no 8d was observed from 4b when
the co-reactant 5b was completely exchanged by the cor-
responding urea. Consequently, carbodiimides 5 are es-
sential to synthesize 8 from 4.
Cleavage of N-phenacylpyridinium salts in aqueous alka-
line solution has been known for 125 years and can be per-
formed under mild conditions to get benzoic acids and N-
methylpyridinium salts in good yields.22 This reaction was
intensively investigated,23 utilized in synthesis,24 and also
transferred to the corresponding quinolinium22a and
isoquinolinium25 salts. Thus, a plausible mechanism to
explain the formation of 8 from 4 and 5 includes cleavage
of 9 to generate 11 and the benzoates 12, which can add to
5. The resulting O-acylisoureas 13 are able to undergo a
Mumm-like rearrangement to yield 8. It is well known
that treatment of benzoic acids with 5a,b leads to N-acyl-
ureas beside the corresponding benzoic anhydrides.21c–e,26
(3) Regitz, M.; Arnold, B.; Danion, D.; Schubert, H.; Fusser, G.
Bull. Soc. Chim. Belg. 1981, 90, 615.
(4) (a) Jacox, M. E.; Milligan, D. E. J. Am. Chem. Soc. 1963, 85,
278. (b) Kodama, S. J. Phys. Chem. 1988, 92, 5019.
(5) Maier, G.; Schmidt, C.; Reisenauer, H. P.; Endlein, E.;
Becker, D.; Eckwert, J.; Hess, B. A.; Schaad, L. J. Chem.
Ber. 1993, 126, 2337.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2943–2946

2946
K. Banert et al.
LETTER
(6) (a) Fowler, F. W.; Hassner, A. J. Am. Chem. Soc. 1968, 90,
2875. (b) Anderson, D. J.; Gilchrist, T. L.; Rees, C. W.
Chem. Commun. 1969, 147. (c) Gilchrist, T. L.; Gymer, G.
E.; Rees, C. W. Chem. Commun. 1971, 1519. (d) Anderson,
D. J.; Gilchrist, T. L.; Gymer, G. E.; Rees, C. W. J. Chem.
Soc., Perkin Trans. 1 1973, 550. (e) Gilchrist, T. L.; Gymer,
G. E.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1973, 555.
(f) Atkinson, R. S.; Grimshire, M. J. J. Chem. Soc., Perkin
Trans. 1 1986, 1215.
(7) Gilchrist, T. L.; Gymer, G. E.; Rees, C. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1.
(8) (a) Mitchell, G.; Rees, C. W. J. Chem. Soc., Chem. Commun.
1986, 399. (b) Mitchell, G.; Rees, C. W. J. Chem. Soc.,
Perkin Trans. 1 1987, 413.
(9) (a) Huisgen, R.; Blaschke, H. Chem. Ber. 1965, 98, 2985.
(b) Meinwald, J.; Aue, D. H. J. Am. Chem. Soc. 1966, 88,
2849.
(10) Gilchrist, T. L.; Gymer, G. E.; Rees, C. W. J. Chem. Soc.,
Chem. Commun. 1973, 835.
(11) Gilchrist, T. L.; Rees, C. W.; Thomas, C. J. Chem. Soc.,
Perkin Trans. 1 1975, 8.
(12) (a) Wentrup, C.; Crow, W. D. Tetrahedron 1970, 26, 3965.
(b) Thétaz, C.; Wentrup, C. J. Am. Chem. Soc. 1976, 98,
1258.
1987, 109, 6290. (b) Alcami, M.; de Paz, J. L. G.; Yáñez, M.
J. Comp. Chem. 1989, 10, 468.
(17) (a) Würthwein, E.-U. J. Org. Chem. 1984, 49, 2971. (b) Mó,
O.; de Paz, J. L. G.; Yáñez, M. J. Phys. Chem. 1987, 91,
6484.
(18) Čársky, P.; Hess, B. A.; Schaad, L. J. J. Am. Chem. Soc.
1983, 105, 396.
(19) Alizadeh, A.; Rezvanian, A. Synlett 2012, 23, 859.
(20) For the complete characterization of 8a–f, see the
Supporting Information.
(21) (a) Lessene, G.; Smith, B. J.; Gable, R. W.; Baell, J. B.
J. Org. Chem. 2009, 74, 6511. (b) Corriu, R. J. P.; Lanneau,
G. F.; Perrot-Petta, M. Synthesis 1991, 954. (c) Neves Filho,
R. A. W.; de Oliveira, R. N.; Srivastava, R. M. J. Braz.
Chem. Soc. 2007, 18, 1410. (d) Quintanilla, M. G.; Montero,
G.; Hierro, A. G.; Diaz, J. M.; Bassani, S. Acta Chem. Scand.
1999, 53, 928. (e) Kishikawa, K.; Eida, H.; Kohmoto, S.;
Yamamoto, M.; Yamada, K. Synthesis 1994, 173.
(22) (a) Bamberger, E. Ber. Dtsch. Chem. Ges. 1887, 20, 3338.
(b) Schmidt, E.; van Ark, H. H. Arch. Pharm. 1900, 238,
321. (c) Babcock, S. H.; Nakamura, F. I.; Fuson, R. C. J. Am.
Chem. Soc. 1932, 54, 4407. (d) Krollpfeiffer, F.; Müller, A.
Ber. Dtsch. Chem. Ges. B 1933, 66, 739. (e) Babcock, S. H.;
Fuson, R. C. J. Am. Chem. Soc. 1933, 55, 2946.
(13) Wentrup, C. Helv. Chim. Acta 1972, 55, 1613.
(14) (a) Clark, D. T. Theoret. Chim. Acta (Berl.) 1969, 15, 225.
(b) Hopkinson, A. C.; Lien, M. H.; Yates, K.; Csizmadia, I.
G. Int. J. Quantum Chem. 1977, 12, 355. (c) Bock, H.;
Dammel, R. Chem. Ber. 1987, 120, 1971. (d) Alcami, M.;
Mó, O.; Yáñez, M. J. Am. Chem. Soc. 1993, 115, 11074.
(e) Lathan, W. A.; Radom, L.; Hariharan, P. C.; Hehre, W.
J.; Pople, J. A. Top. Curr. Chem. 1973, 40, 1.
(15) (a) Mó, O.; Yáñez, M.; Elguero, J. J. Mol. Struct.
(Theochem) 1989, 201, 17. (b) Byun, Y.-G.; Saebo, S.;
Pittman, C. U. J. Am. Chem. Soc. 1991, 113, 3689. (c) Malar,
E. J. P. Tetrahedron 1996, 52, 4709.
(23) (a) Kröhnke, F.; Heffe, W. Ber. Dtsch. Chem. Ges. B 1937,
70, 864. (b) Pearson, R. G.; Dillon, R. L. J. Am. Chem. Soc.
1948, 70, 1933. (c) Pearson, R. G.; Sandy, A. C. J. Am.
Chem. Soc. 1951, 73, 931.
(24) (a) King, L. C. J. Am. Chem. Soc. 1944, 66, 894. (b) King, L.
C. J. Am. Chem. Soc. 1944, 66, 1612. (c) King, L. C.;
McWhirter, M.; Rowland, R. L. J. Am. Chem. Soc. 1948, 70,
239. (d) Huffman, J. W.; Zengin, G.; Wu, M.-J.; Lu, J.;
Hynd, G.; Bushell, K.; Thompson, A. L. S.; Bushell, S.;
Tartal, C.; Hurst, D. P.; Reggio, P. H.; Selley, D. E.; Cassidy,
M. P.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem. 2005,
13, 89. (e) Brusotti, G.; Habermann, J.; Azzolina, O.;
Collina, S. Lett. Org. Chem. 2006, 3, 943.
(16) (a) Budzelaar, P. H. M.; Cremer, D.; Wallasch, M.;
Würthwein, E.-U.; Schleyer, P. v. R. J. Am. Chem. Soc.
(25) Kröhnke, F. Ber. Dtsch. Chem. Ges. B 1933, 66, 604.
(26) Ślebioda, M. Tetrahedron 1995, 51, 7829.
Synlett 2012, 23, 2943–2946
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.