Arylchlorocarbenes in the synthesis of heterocycles containing two nitrogen atoms

Article abstract of DOI:10.1039/b002940h

Substituted pyrazoles and pyrrolo[1,2-c]pyrimidines were prepared from the reaction of arylchlorocarbenes with 1,2-diazabuta-1,3-dienes and 4- vinylpyrimidines, respectively.

Full text of DOI:10.1039/b002940h

Arylchlorocarbenes in the synthesis of heterocycles containing two nitrogen
atoms
Yuri N. Romashin,a Michael T. H. Liu,*a Satnam S. Nijjara and Orazio A. Attanasib
a Department of Chemistry, University of Prince Edward Island, P.E.I., Canada C1A 4P3. E-mail: Liu@upei.ca
b Instituto di Chimica Organica, Università di Urbino, 61029 Urbino, Italy
Received (in Corvallis, OR, USA) 10th April 2000, Accepted 10th May 2000
Substituted pyrazoles and pyrrolo[1,2-c]pyrimidines were
prepared from the reaction of arylchlorocarbenes with
1,2-diazabuta-1,3-dienes and 4-vinylpyrimidines, respec-
tively.
5a-c in good yield (74–83%). Attanasi and coworkers have
developed an effective approach to pyrazoles based on a
preliminary 1,4-addition of a nucleophilic reagent to the
1,2-diazabuta-1,3-diene substrates, which also gave a 70–80%
product yield.9 Vinylpyrimidines 8a,b were prepared from
4-methylpyrimidine according to previously described proce-
dures.10,11 Thermolysis of arylchlorodiazirines 1a-c in the
presence of vinylpyrimidines 8a,b leads to 6,7-disubstituted
pyrrolo[1,2-c]pyrimidines 6a–c in a 17–22% yield. The yields
and physical data of obtained pyrazoles 5a–c and pyrrolopyr-
imidines 6a–c are given in ref. 12.†
In general, solutions of chlorodiazirine 1a–c (2 mmol) and
phenylazostilbene 7 or vinylpyrimidine 8a,b (1 mmol) were
refluxed in absolute benzene (10 mL) for 24 h. After workup,
the pyrazoles 5a–c were purified by column chromatography on
silica gel with 10+1 hexane–diethyl ether eluent, followed by
crystallization from propan-2-ol–hexane (1+3); pyrrolopyr-
imidines 6a–c were purified by column chromatography on
Al2O3 (basic) with 4+1 hexane–diethyl ether eluent.
We recently reported the successful application of aryl-
chlorocarbenes generated from arylchlorodiazirines to the
synthesis of indolizines and pyrroles (Scheme 1, reactions (i)
and (ii)).1,2 The key step of the described approach produces a
nitrogen ylide, followed by 1,5-intramolecular cyclization and
HCl elimination. We now report further application of this
methodology to the synthesis of a wider array of heterocycles
containing two nitrogen atoms, such as pyrazoles and pyr-
rolo[1,2-c]pyrimidines (Scheme 1, reactions (iii) and (iv)).
Pyrazoles have attracted the attention of many chemists because
of their applications in organometallic chemistry as ligands, in
synthesis, in particular of bioactive compounds, as well as their
thermal reactions, spectroscopic applications and theoretical
calculations.3 Pyrrolo[1,2-c]pyrimidines, the aza analogues of
indolizines, have attracted substantial interest because of their
ability to facilitate easy ring cleavage, their variety of ring
transformations and recyclizations,4 and for their role as starting
materials to N-bridged heteroaromatics.5 However, the known
synthetic routes to these compounds are lengthy and result in
poor yields.5,6 In this respect, these highly reactive carbenes
have been harnessed and utilized to achieve difficult synthetic
tasks which other reactive intermediates cannot easily per-
form.
Vinylpyrimidines 8a,b are transparent at 351 nm, which is
not the case for phenylazostilbene 7. In order to learn whether
the reaction of chlorodiazirines 1a–c with vinylpyrimidines
8a,b goes through an N-ylide intermediate, we undertook laser
flash photolysis (LFP) studies14 of this system to examine the
kinetics of nitrogen ylide formation and the rate of 1,5-dipolar
cyclization.
LFP irradiation at 351 nm of a solution of chlorophenyldi-
azirine 1a in benzene (A = 1.0 at l = 376, 392 nm) at 25 °C
produces a transient absorption at 310 nm due to the formation
of the chlorophenylcarbene 2a, whose decay rate constant is
2.02 3 105 s21. In the presence of pyrimidine derivative 8b, a
new transient attributed to the pyrimidinium ylide appears at
550 nm. The plot of the observed pseudo-first-order rate
constants for the growth of the absorption at 550 nm vs.
concentration of 8b is linear, and the rate constant for the
reaction of chlorophenylcarbene 2a and pyrimidine 8b at 25 °C
is kylide = 3.24 3 108 M21s.21 The intercept of the straight line
(2.78 3 105 s21) is the chlorophenylcarbene 2a decay rate
constant in the absence of 8b, which is similar to that detected
at 310 nm (2.02 3 105 s21). The pyrimidinium ylide (at 550 nm)
decays in benzene with a lifetime equal to 102.2 ms at 22 °C,
independent of the concentration of 8b. Therefore, the rate
constant for the 1,5-dipolar cyclization of pyrimidinium ylide is
k1,5-cycl = 9.78 3 103 s21. The temperature dependence
(0–55 °C) of the pyrimidinium ylide decay to form the
The arylchlorocarbenes 2a–c were generated from aryl-
chlorodiazirines 1a–c7 by thermolysis. Phenylazostilbene 7 was
prepared from acetoxydeoxybenzoin and phenylhydrazine.8
Thermolysis of arylchlorodiazirines 1a–c in the presence of
phenylazostilbene 7 leads to 1,3,4,5-tetrasubstituted pyrazoles
Scheme 1
Scheme 2
DOI: 10.1039/b002940h
Chem. Commun., 2000, 1147–1148
This journal is © The Royal Society of Chemistry 2000
1147

8 B. F. Bonini, G. Maccagnani, G. Mazzanti, G. Rosini and E. Foresti,
J. Chem. Soc., Perkin Trans. 1, 1981, 2322.
9 O. A. Attanasi and P. Filippone, Synlett, 1977, 1128; A. Attanasi, P.
Filippone, C. Fiorucci, E. Foresti and F. Mantellini, J. Org. Chem.,
1998, 63, 9880; O. A. Attanasi, P. Filippone, C. Fiorucci and F.
Mantellini, Tetrahedron Lett., 1999, 40, 3891.
1,5-cyclization product yielded the following Arrhenius param-
eters: Ea = 10.0 kcal mol21 and A = 2.36 3 1011 s21
.
We have shown that chlorocarbenes can be successfully
applied to the synthesis of 1,3,4,5-tetrasubstituted pyrazoles and
6,7-disubstituted pyrrolo[1,2-c]pyrimidines. This methodology
is simple and effective. We have also demonstrated the
existence of nitrogen ylides as intermediates in these reactions.
The kinetics of the 1,5-dipolar cyclizations of pyrimidinium
ylides to yield pyrrolo[1,2-c]pyrimidines are reminiscent of the
cyclization of 2-vinylpyridinium ylides to indolizines1 and
azomethine ylides to pyrroles.2
10 C. G. Overberger and I. C. Kogon, J. Am. Chem. Soc., 1954, 76,
1879.
11 H.-H. Perkampus and Th. Bluhm, Tetrahedron, 1972, 28, 2099.
12 Data for 1,3,4,5-tetraphenylpyrazole 5a: 78% yield; mp 217.5–218.5 °C
[lit.13: mp 217–218 °C]; 1H NMR (300 MHz, CDCl3): d 7.0–7.4 (18H,
m), 7.5–7.6 (2H, m). For 1,3,4-triphenyl-5-(p-methylphenyl)pyrazole
1
5b: 83% yield; mp 173–174 °C; H NMR (300 MHz, CDCl3): d 2.31
M. T. H. L. and Yu. N. R. wish to thank the NSERC of
Canada for its generous financial support. We also thank Dr Wei
Ma, Rutgers University, for assistance with the LFP experi-
ments.
(3H, s), 6.9–7.4 (17H, m), 7.5–7.6 (2H, m); MS: m/z 386 (100), 385
(51%). For 1,3,4-triphenyl-5-(p-chlorophenyl)pyrazole 5c: 74% yield;
mp 178–179 °C; 1H NMR (300 MHz, CDCl3): d 6.9–7.4 (17H, m),
7.5–7.6 (2H, m); MS: m/z 408 (33), 406 (100%). For 7-(p-chloro-
1
phenyl)pyrrolo[1,2-c]pyrimidine 6a: 17% yield; H NMR (300 MHz,
CDCl3): d 6.53 (1H, d, J = 3.5, 5-Hpyr), 6.90 (1H, J = 3.5 Hz, 6-Hpyr),
7.2–7.3 (2H, m, C6H4), 7.4–7.6 (4H, m, 3-Hpyr, 4-Hpyr, C6H4), 9.04 (1H,
s, 1-Hpyr); MS: m/z 230 (34), 228 (100), 193 (16), 192 (18%). For
6-phenyl-7-(p-methylphenyl)pyrrolo[1,2-c]pyrimidine 6b: 17% yield;
1H NMR (300 MHz, CDCl3): d 2.43 (3H, s, Me), 6.65 (1H, s, 5-Hpyr),
7.1–7.5 (11H, m, 3-Hpyr, 4-Hpyr, Ph, C6H4), 8.76 (1H, s, 1-Hpyr). For
6-phenyl-7-(p-chlorophenyl)pyrrolo[1,2-c]pyrimidine 6c: 22% yield;
1H NMR (300 MHz, CDCl3): d 6.70 (1H, s, 5-Hpyr), 7.2–7.5 (11H, m,
3-Hpyr, 4-Hpyr, Ph, C6H4), 8.79 (1H, s, 1-Hpyr); MS: m/z 306 (33), 304
(100).
Notes and references
† All compounds reported herein gave satisfactory microanalysis data.
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unit comprised a 1000 W Oriel xenon arc lamp, a 1 in. Uniblitz shutter,
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Chem. Commun., 2000, 1147–1148