2-Aryl-N-tosylazetidines as formal 1,4-dipoles for [4 + 2] cycloaddition reactions with nitriles: An easy access to the tetrahydropyrimidine derivatives

Article abstract of DOI:10.1021/ol048161l

(Chemical Equation Presented) A new synthetic route to 2-aryl-N-tosyl azetidines has been developed starting from N-tosylarylaldimines in two steps in an overall yield of 63-70%. A formal [4 + 2] cycloaddition of these 2-aryl-N-tosylazetidines with nitril

Full text of DOI:10.1021/ol048161l

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4829-4831
2-Aryl-N-tosylazetidines as Formal
1,4-Dipoles for [4 2] Cycloaddition
+
Reactions with Nitriles: An Easy
Access to the Tetrahydropyrimidine
Derivatives
B. A. Bhanu Prasad, Alakesh Bisai, and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur, 208 016, India
Vinodks@iitk.ac.in
Received September 12, 2004
ABSTRACT
A new synthetic route to 2-aryl-N-tosyl azetidines has been developed starting from N-tosylarylaldimines in two steps in an overall yield of
63 70%. A formal [4 2] cycloaddition of these 2-aryl-N-tosylazetidines with nitriles in the presence of BF3 OEt2 has been described for the
synthesis of substituted tetrahydropyrimidines. It is proposed that the reaction proceeds in Ritter fashion.
−
+
‚
Since the discovery of the â-lactam ring as the essential fea-
ture of antibiotics, much has been learned about the chemical
reactivity of this four-membered heterocycle. The chemistry
of 2-azetidinone rings is well-known1 and used synthetically.
However, the chemistry of azetidine has not been much
investigated. Many of the efforts involving the azetidine
nucleus have been directed toward its synthesis,2 as it is a
component of many biologically active drugs and natural
products.3 Very few examples of rearrangements or frag-
mentations of the azetidine ring are known. Recently, Mann
and co-workers have reported that 2-phenyl-N-tosylaze-
tidines, in the presence of a Lewis acid, generate a double
exo-stabilized 1,4-dipole or a zwitterion.4 They have pre-
sented evidence for the existence of the 1,4-dipole and uti-
lized it in [4 + 2] cycloaddition reactions with alkenes.5
Later, the same group extended this formal [4 + 2] cyclo-
addition to exo-methylene cycloalkanes. The formation of
spiro-piperidines was precisely anticipated via a formal [4
+ 2] cycloaddition reaction.
Although most of the nitriles are known to be poor di-
polarophiles for intermolecular [3 + 2] cycloaddition reac-
tions,6 we recently reported that nitriles are good dipolaro-
philes for formal [3 + 2] cycloaddition reactions of 2-aryl-
(3) (a) Kobayashi, J.; Ishibashi, M. Heterocycles 1996, 42, 943. (b)
Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith, G. F.; Gifford-
Moore, D. S. J. Med. Chem. 1995, 38, 4446. (c) Frigola, J.; R. J. Med.
Chem. 1994, 37, 4195. (d) Dureault, A.; Portal, M,; Carreaux, F.; Depezay,
J. C. Tetrahedron 1993, 49, 4201.
(4) Ungureanu, I.; Koltz, P.; Schoenfelder, A.; Mann, A. Tetrahedron
Lett. 2000, 42, 6087.
(5) Ungureanu, I.; Koltz, P.; Schoenfelder, A.; Mann, A. Chem. Commun.
2001, 958.
(6) For reaction of activated nitriles with azides, see: (a) Demko, Z. P.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2113. (b) Demko, Z. P.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2110.
(1) For reviews, see: (a) The Organic Chemistry of â-Lactams, Georg,
G. I., Ed.; VCH: New York, 1993. (b) Manhas, M. S.; Wagle, D. R.;
Chiang, J.; Bose, A. K. Heterocycles 1998, 27, 1755. (c) Ojima, I. AdV.
Asymm. Synth. 1995, 1, 95.
(2) For reviews on the synthesis and chemistry of azetidines, see: (a)
De Kimpe, N. In ComprehensiVe Heterocyclic Chemistry II; Padwa, A.,
Ed.; Elsevier: Oxford, 1996; Vol. 1B, Chapter 1.18, pp 507-589. (b) Moore,
J. A.; Ayers, R. S. In Chemistry of Heterocyclic Compounds-Small Ring
Heterocycles; Hassner, A., Ed.; Wiley: New York, 1983; Part 3, pp 1-217.
(c) Cromwell, N. H.; Philips, B. Chem. ReV. 1979, 79, 331.
10.1021/ol048161l CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/20/2004

N-tosylaziridines for the synthesis of substituted imidazolines
in the presence of BF3‚Et2O.7 It is surprising to note that
nitriles have not been used as dipolarophiles for synthesis
of tetrahydropyrimidines. In this paper, we report the first
formal [4 + 2] cycloaddition of 2-aryl-N-tosylazetidines with
nitriles for synthesis of tetrahydropyrimidines, which are
known to exhibit a wide range of pharmacological activities.8
Further, these tetrahydropyrimidine derivatives are useful
synthetic intermediates for synthesis of bacterial sidero-
phores.9
Table 1. Synthesis of (2a-d) and 2-Aryl-N-tosylazetidines
(3a-d) from N-tosylarylaldimines 1
Only a few reports are known for synthesis of 2-aryl-N-
tosylazetidines.10 However, these methods are not reliable
and suffer from poor yields. Hence, there was a need to
develop a simple and flexible method for the synthesis of
2-aryl-N-tosylazetidines. N-tosylarylaldimines 1 were chosen
as starting precursors (Scheme 1).11 The synthesis com-
Scheme 1. Synthesis of a Variety of 2-Aryl-N-tosylazetidines
from N-tosylarylaldimines
a Isolated yield for vinyl Grignard addition. bIsolated yield after the
Mitsunobu reaction.
mences with vinylation of 1 with vinylmagnesium chloride.
The resulting addition products (2a-d) were subjected to
hydroboration with BH3‚DMS followed by alkaline peroxide
treatment. This gave the 1,3-N-tosylamino alcohols, which
led to the formation of 2-aryl-N-tosylazetidines 3 via
Mitsunobu reaction in 63-70% overall yield starting from
1 (Table 1).12
Table 2. Formal [4 + 2] Cycloaddition of
2-Phenyl-N-tosylazetidines with a Variety of Nitrilesa
After successfully demonstrating the synthesis of a variety
of azetidines, we studied the reaction of azetidines with
nitriles in the presence of various Lewis acids. Among the
several Lewis acids examined, BF3‚Et2O was found to be
the best for catalyzing the [4 + 2] cycloaddition of 2-phenyl-
N-tosylazetidine with nitriles. When 20 mol % BF3‚Et2O was
used at room temperature, the reaction was completed in 3
h and gave good yields of products. The reaction could be
completed in 5 min using 1 equiv of BF3‚Et2O, but the yields
were very poor. Hence, it was decided to carry out all the
reactions with 20 mol % BF3‚Et2O, conditions that afforded
the products in good yield (Table 2, entries a-e). The other
substituted phenyl azetidines gave pyrimidines in moderate
entry
R
product
time
yield (%)b
a
b
c
d
e
Me
i-Pr
Ph
Bn
CH2Cl
4a
4b
4c
4d
4e
2 h
3 h
2 h
2 h
3 h
60
61
72
65
42
a All reactions were performed at room temperature under an argon
atmosphere. Isolated yield after column chromatography.
b
yields (Table 3, entries a-f). In the case of 2-(p-OMe)-
phenyl-N-tosylazetidine, the reaction was complete within
15 min at -30 °C even with 20 mol % BF3‚Et2O (Table 3;
entries c and d). This could be due to increased stabilization
of the benzylic cation by the p-OMe group. In most of the
cases, the cyclized tetrahydropyrimidines were obtained in
moderate to good yield.
(7) Prasad, B. A. B.; Pandey, G.; Singh, V. K. Tetrahedron Lett. 2004,
45, 1137.
(8) Messer, W. S., Jr.; Abuh, Y. F.; Ryan, K.; Shepherd, M. A.;
Schroeder, M.; Abunada, S.; Sehgal, R.; El-Assadi, A. A. Drug DeV. Res.
1997, 40, 171.
(9) (a) Linger, C.; Azadi, P.; MacLeod, J. K.; Dell, A.; Abdallah, M. A.
Tetrahedron Lett. 1992, 33, 1737 and refs cited therein. (b) Jones, R. C.
F.; Crockett, A. K. Tetrahedron Lett. 1993, 34, 7459.
(10) (a) Gensler, W. J.; Koehler, W. R. J. Org. Chem. 1962, 27, 2754.
(b) Nadir, U.K.; Sharma, R. L.; Koul, V. K. Tetrahedron 1989, 45, 185.
(11) For preparation of aldimines, see: Love, B. E.; Raje, P. S.; Williams,
T. C., III. Synlett 1994, 493.
(12) During the hydroboration/alkaline oxidation followed by Mitsunobu
reaction, we observed the formation of N-tosylaziridines in 15-18% yield,
which can be separated by column chromatography in the final step.
The mechanism of this [4 + 2] cycloaddition reaction is
similar to the [3 + 2] cycloaddition of aziridines with
nitriles.7 BF3‚Et2O can attach to the sulfonyl oxygen, and
the nitrile group attacks the benzylic center in a typical Ritter
fashion, which can lead to the formation of nitrilium salt.
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Org. Lett., Vol. 6, No. 26, 2004

Scheme 2. Proposed Mechanism for Formal [4 + 2]
Cycloaddition of 2-Aryl-N-tosylazetidines with Nitriles in the
Presence of BF3‚OEt2
Table 3. Formal [4 + 2] Cycloaddition of
2-Aryl-N-tosylazetidines with Variety of Nitriles
in the synthesis of various N-substituted compounds after
the cleavage of sulfonamide and alkylation.14,15
Acknowledgment. We thank Department of Science and
Technology, New Delhi, for financial support. A.B. thanks
Council of Scientific and Industrial Research, New Delhi,
for JRF.
a Isolated yield after column chromatography, b Performed at -30 °C,
c Performed at room temperature.
Supporting Information Available: Experimental pro-
cedures, compound characterization data for selected com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Subsequent attack of the sulfonamide nitrogen led to the
formation of tetrahydropyrimidines (Scheme 2).13
In summary, we have developed a simple and flexible
method for the synthesis of 2-aryl-N-tosylazetidines. We have
demonstrated for the first time a formal [4 + 2] cycloaddition
of 2-aryl-N-tosylazetidines with a variety of nitriles and
applied this to the synthesis of many substituted tetrahydro-
pyrimidines. We have also shown that most of the nitriles
are good dipolarophiles for [4 + 2] cycloaddition reactions
with azetidines. These tetrahydropyrimidines will find use
OL048161L
(14) For cleavage of the N-tosyl group, see: (a) Baldwin, J. E.; Farthing,
C. N.; Russell, A. T.; Schofield, C. J.; Spivey, A. C. Tetrahedron Lett.
1996, 37, 3761. (b) Cantrill, A. A.; Obsorn, H. M. I.; Sweeney, J.
Tetrahedron 1998, 54, 2181. (c) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy,
R. E. Tetrahedron: Asymmetry 1995, 6, 1511. (d) Vedjes, E.; Sano, H.
Tetrahedron Lett. 1992, 33, 3261.
(15) For cleavage of the N-tosyl group by using Mg in methanol, see:
Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455. For use of
sodium naphthalenide, see: Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett.
1999, 40, 6181.
(13) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045.
(b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048.
Org. Lett., Vol. 6, No. 26, 2004
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