Dibenzoxazepinium ylides: Facile access and 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1021/ol802813a

An effective approach to azirino-fused heterocycles is disclosed. The approach, involving formation of heterocycle/C-.

Full text of DOI:10.1021/ol802813a

ORGANIC
LETTERS
2009
Vol. 11, No. 4
979-982
Dibenzoxazepinium Ylides: Facile
Access and 1,3-Dipolar Cycloaddition
Reactions
Alexander F. Khlebnikov,*,† Mikhail S. Novikov,† Petr P. Petrovskii,†
Joerg Magull,‡ and Arne Ringe‡
Department of Chemistry, St. Petersburg State UniVersity, UniVersitetskii pr. 26,
198504 St. Petersburg, Russia, and Institute of Inorganic Chemistry of
Georg-August-UniVersity, Go¨ttingen, Germany
alexander.khlebnikoV@pobox.spbu.ru
Received December 19, 2008
ABSTRACT
An effective approach to azirino-fused heterocycles is disclosed. The approach, involving formation of heterocycle/C-(arylchloromethyl)-
subsituted CdN double bond via domino isomerization of a gem-dichloroaziridine-intramolecular Friedel-Crafts acylation of the O-tethered
benzene ring and subsequent intramolecular cyclization induced by hydride, was realized for 1-aryl-1,11b-dihydroazirino[1,2-
d]dibenz[b,f][1,4]oxazepines. The latter are excellent precursors of azomethine ylides, especially in solvent-free conditions, which can undergo
a completely stereoselective 1,3-dipolar cycloaddition to CdC dipolarophiles giving derivatives of dibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepine.
Dibenz[b,f][1,4]oxazepine derivatives are attractive com-
pounds of growing pharmaceutical interest as documented
by many publications. Among compounds containing this
fragment are a non-nucleoside HIV-1 reverse transcriptase
inhibitor,1 a histamine H4 receptor agonist,2 calcium3 and
PGE2 antagonists,4 as well as antidepressants5 and analge-
sics.4 Compounds with nitrogen heterocycles ortho-fused to
dibenz[b,f][1,4]oxazepine also demonstrate various forms of
bioactivity: derivatives of dibenzo[b,f]pyrimido[3,4-d][1,4]-
oxazepine show antidepressive and anxiolytic activity,6
derivatives of dibenz[b,f]imidazo[1,5-d][1,4]oxazepine are
useful in pharmaceutical compositions for treating bronchial
asthma and allergic bronchitis,7 2,7-dimethyl-1,3,4,14b-
tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]oxazepine shows
(4) (a) Coyne, W. E.; Cusic, J. W. J. Med. Chem. 1968, 11, 1158. (b)
Sanner, J. H. Arch. Int. Pharmacodyn. Ther. 1969, 180, 46. (c) Coleman,
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Lawrence, R. A.; Jones, R. L.; Wilson, N. H. Br. J. Pharmacol. 1992, 105,
271. (e) Drower, E. J.; Stapelfeld, A.; Mueller, R. A.; Hammond, D. L.
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R. K.; Tsymbalvo, S.; Rao, S. N.; vanHoeck, J.-P.; Rafferty, M. F.;
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A.; Savage, M. A. Bioorg. Med. Chem. 2001, 9, 1.
† St. Petersburg State University.
‡ Institute of Inorganic Chemistry.
(1) (a) Klunder, J. M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal, K.;
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Adams, J. J. Med. Chem. 1992, 35, 1887. (b) Merluzzi, V. J.; Hargrave,
K. D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J. C.; Shih, C.-K.;
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R. J.; Koup, R. A.; Sullivan, J. L. Science 1990, 250, 1411. (c) Nagarajan,
K. J. Indian Chem. Soc. 1997, 74, 831.
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Indian J. Exp. Biol. 1974, 12, 217. (b) Nagarajan, K.; David, J.; Bhat, G. A.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1985, 24, 840. (c)
Nagarajan, K.; David, J.; Kulkarni, Y. S.; Hendi, S. B.; Shenoy, S. J.;
Upadhyaya, P. Eur. J. Med. Chem. Chim. Ther. 1986, 21, 21.
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10.1021/ol802813a CCC: $40.75
Published on Web 01/13/2009
2009 American Chemical Society

Figure 1. ORTEP representation of compounds 8a, 19, and 20.
antiserotoninergic and antihistaminic effects,8 and 2,3,4,14b-
tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepines are
progesterone receptor agonists.9 Approaches to potentially
bioactive heterocycles with a pyrrole ring ortho-fused to
dibenz[b,f][1,4]oxazepine have been until now unknown.
Due to our research interest concerning the synthesis of
nitrogenated heterocycles via nitrogen ylide reactions,10 we
envisioned the possibility of assembling a new heterocyclic
systemsdibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepinesaccord-
ing to the retrosynthetic sequence described in Scheme 1.
(compound 3). This could potentially be realized via an
intramolecular Friedel-Crafts acylation of the O-tethered
benzene ring by 2-aryl-2-chloroacetimidoyl chlorides, which in
turn can be generated from gem-dihaloaziridines.11 1,3-Diaryl-
2,2-dichloroaziridines are readily available via reaction of imines
with dichlorocarbene. The synthesis of compounds 5 was
performed by reaction of imines 6 with dichlorocarbene
generated from CHCl3 and solid KOH in the presence of TEBA
as phase-transfer catalyst at 19-21 °C.
gem-Dichloroaziridines isomerize to imidoyl chlorides
under the action of Lewis acids,10i which are well-known
catalysts of Friedel-Crafts acylation. Hence, we tried to
realize aziridine ring opening and intramolecular Friedel-
Crafts acylation in a domino reaction. We tested BF3·Et2O,
TiCl4, and anhydrous AlCl3 as catalysts. It was found that
with BF3·Et2O or TiCl4 as catalyst the reaction of aziridine
5a proceeded very slowly at 50 °C and long reaction times
were required at this temperature. This led to decomposition
of the reaction mixtures and yields of the target compound
were less than 10%. The Lewis acid of choice for the
realization of target domino reaction proved to be AlCl3,
giving oxazepines 3a,b in 59 and 68% yields (Scheme 2).
R-Chloroketimines when reacted with nucleophilic re-
agents give aziridines, but this approach was not used for
the synthesis of the azirino-fused compounds.12 The prepara-
tion of azirinodibenzoxazepines 8a,b was performed by
Scheme 1
The key step in the scheme is the formation of the dibenz[b,f]-
[1,4]oxazepine skeleton concurrently with an ArCHCl group
1
reduction of 3a,b with LiAlH4 in 70-90% yields. The H
NMR spectra of compounds 8a,b exhibited the characteristic
coupling constant value for trans-aziridines J ∼3 Hz (J for
cis- and trans-aziridines are 6-7 and 2.5-3.5 Hz,
respectively12a,13). The structure of compound 8a was
confirmed by X-ray analysis (Figure 1).
(8) Sulman, F. G.; Pfeifer, Y.; Superstine, E. Arzneimittelforschung 1981,
31, 109.
(9) Dols, P. P. M. A.; Folmer, B. J. B.; Hamersma, H.; Kuil, C. W.;
Lucas, H.; Ollero, L.; Rewinkel, J. B. M.; Hermkens, P. H. H. Bioorg.
Med. Chem. Lett. 2008, 18, 1461.
(10) (a) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Russ. Chem.
ReV. 2005, 74, 171. (b) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R.;
Kopf, J. Russ. J. Org. Chem. 2005, 41, 1341. (c) Voznyi, I. V.; Novikov,
M. S.; Khlebnikov, A. F. Synlett 2005, 1006. (d) Konev, A. S.; Novikov,
M. S.; Khlebnikov, A. F. Tetrahedron Lett. 2005, 46, 8337. (e) Voznyi,
I. V.; Novikov, M. S.; Khlebnikov, A. F.; Kostikov, R. R. Russ. J. Org.
Chem. 2006, 42, 689. (f) Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A.;
Kostikov, R. R.; Magull, J.; Vidovic, D. Russ. J. Org. Chem. 2006, 42,
515. (g) Novikov, M. S.; Amer, A. A.; Khlebnikov, A. F. Tetrahedron Lett.
2006, 47, 639. (i) Shinkevich, E. Yu.; Novikov, M. S.; Khlebnikov, A. F.
Synthesis 2007, 2, 225. (j) Konev, A. S.; Novikov, M. S.; Khlebnikov, A. F.
Russ. J. Org. Chem. 2007, 43, 286. (k) Kadina, A. P.; Novikov, M. S.;
Khlebnikov, A. F.; Magull, J. Chem. Heterocycl. Compd. 2008, 44, 576.
(l) Shinkevich, E. Yu.; Abbaspour Tehrani, K.; Khlebnikov, A. F.; Novikov,
M. S. Tetrahedron 2008, 64, 7524. (m) Khistiaev, K. A.; Novikov, M. S.;
Khlebnikov, A. F. Magull. Tetrahedron Lett. 2008, 49, 1237. (n) Khlebni-
kov, A. F.; Novikov, M. S.; Dolgikh, S. A.; Magull, J. ARKIVOC 2008, n
9, 94. (o) Konev, A. S.; Khlebnikov, A. F. Collect. Czech. Chem. Commun.
2008, 1553.
Scheme 2
980
Org. Lett., Vol. 11, No. 4, 2009

Table 1. Reaction of Aziridines 8a,b with CdC Dipolarophiles 9-16
a A: toluene, 90 °C. B: melt, 140 °C. b Isolated yields.
It was found that heating aziridines 8a,b in anhydrous
toluene at 90 °C in the presence of dipolarophiles
containing an activated CdC double bond gave rise to
1,3-dipolar adducts 18-27 in high yields (Table 1). When
the reactions are performed under solvent-free conditions
at 140 °C they proceed much faster with formation of the
same products.
The structures of compounds 18-27 were verified by 1H,
1
13C, H 2D NOESY NMR, IR spectroscopy, and elemental
analysis. Structures of 19 and 20 were further confirmed by
X-ray analysis (Figure 1). It was found that methanolysis of
anhydride 22, catalyzed by sulfuric acid, gives a compound
identical to compound 19, which is the product of reaction
of aziridine 8a with dimethyl maleate. As the configuration
Org. Lett., Vol. 11, No. 4, 2009
981

derivatives of butenedioic acids proceeds with complete
stereoselectivity.
According to DFT B3LYP/6-31G(d) calculations (Figure
2), the ring opening of aziridine 8a occurs conrotatory with
the formation of the nonplanar W-ylide 28. The latter can
be converted to the practically plane and much lower energy
W-ylide 29 by rotation of the Ph-ring through a ∼1.4
kcal·mol-1 activation barrier. Ylide 29 in turn can be
transformed to an even more stable S-ylide 30 by rotating
the PhCH group around the ylide C-N bond. The stereo-
chemistry of cycloadducts 18-27 testifies to the participation
of only the W-ylide in the cycloaddition. Furthermore, the
cycloaddition of cis-dipolarophiles proceeds via the exo-
transition state. One can also conclude from the results
obtained that the observed stereoselectivity is apparently due
to the lower barrier to cycloaddition of ylide 29 compared
to the barrier to transformation of ylides 29 f 30.
In summary, a novel effective approach to azirino-fused
heterocycles was described. Thus, as an example, 1-aryl-
1,11b-dihydoazirino[1,2-d]dibenz[b,f][1,4]oxazepines were
synthesized by making use of the following domino se-
quence: isomerization of gem-dichloroaziridine-intra-
molecular Friedel-Crafts acylation of the O-tethered benzene
ring and subsequent hydride induced intramolecular cycliza-
tion of the C-(arylchloromethyl)-substituted CdN unit. These
oxazepines are excellent precursors of azomethine ylides
which easily undergo completely stereospecific and stereo-
selective 1,3-dipolar cycloadditions to CdC dipolarophiles
with the formation of derivatives of the new heterocyclic
systemsdibenzo[b,f]pyrrolo[1,2-d][1,4]oxazepine. The cy-
cloaddition is very effective in solvent free conditions.
Further applications of the suggested methodology are
currently under investigation.
Figure 2. Reaction profiles for transformations of aziridines and
ylides. Relative free energies (kcal·mol-1, 298 K) computed at the
B3LYP/6-31G(d) level.
of the stereocenters is preserved during the transformation
of the anhydride to the ester in acidic conditions, the obtained
result provides further evidence for the identical stereochem-
istry of compounds 19 and 22.
It was shown that compounds 18-27 did not isomerize
1
under the reaction conditions. H NMR analysis of the
reaction mixtures obtained after heating aziridines 8 with
dipolarophiles 9-16 showed no other stereoisomers of
compounds 18-27. Thus, cycloaddition of ylides 17 to
(11) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. ReV. 2007, 107,
2080.
Acknowledgment. We gratefully acknowledge the finan-
cial support of the Russian Foundation for Basic Research
(project 08-03-00112).
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1980, 45, 5319. (b) Deyrup, J. A.; Greenwald, R. B. J. Am. Chem. Soc.
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Org. Chem. 1981, 46, 2079. (d) Kawakami, T.; Sugimoto, T.; Shibata, I.;
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Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds, CIF
files for 8a, 19, and 20, and computational details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Mayer, M. F.; Hossain, M. M. J. Org. Chem. 1998, 63, 6839–
6844. (b) Xie, W.; Fang, J.; Li, J.; Wang, P. G. Tetrahedron 1999, 55,
12929.
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