Selective transannular ring transformations in azirino-fused eight-membered O,N- Or S,N-heterocycles

Article abstract of DOI:10.1039/b512409c

The selective transannular ring transformations in azirino-fused eight-membered O,N- or S,N-heterocycles was investigated. The treatment of chlorofluoro-substituted azirinobenzoxazocine initially with anhydrous zinc chloride in methylene chlorine and then

Full text of DOI:10.1039/b512409c

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C O M M U N I C A T I O N
Selective transannular ring transformations in azirino-fused
eight-membered O,N- or S,N-heterocycles†
Alexander F. Khlebnikov,*a Mikhail S. Novikov,a Ekaterina Yu. Shinkevicha and Denis Vidovicb
a Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, 198504,
St. Petersburg,Petrodvorets, Russia. E-mail: Alexander.Khlebnikov@pobox.spbu.ru;
Fax: 007 812 4286939; Tel: 007 812 4284021
b Institute of Inorganic Chemistry of Georg-August University, Tammannstr. 4, 37077,
Go¨ttingen, Germany
Received 6th September 2005, Accepted 6th October 2005
First published as an Advance Article on the web 17th October 2005
The first examples of transannular ring transformations
in azirino-fused eight-membered O,N- or S,N-heterocycles
involving selective aziridine ring opening and medium-
sized ring contraction are described, which provide an
access to functionalized 1,4-benzox(thi)azines or 1,3-
benzox(thi)azoles.
derivatives 3a,b and 4a,b were isolated after heating azirinobenz-
oxazocine 2a in methanol. Reaction of azirinobenzoxazocine 2a
in trifluoroacetic acid followed by chromatographic purification
on silica yielded benzoxazine 4b in high yield. In the reaction
of azirinobenzoxazocine 2a a transannular ring contraction
reaction occurred along with the opening of the three-membered
ring.
A similar transformation also occurred when the aziri-
nobenzoxazocine 2a was heated with benzylamine in DMSO
solution. In this case a domino reaction terminates after the
formation of an additional piperidine ring, giving the pyrido[3,2-
b][1,4]benzoxazine derivative 5 (Scheme 2).
Transannular cyclizations are actively used not only by organic
synthetic chemists,1 but also by Nature to build polycyclic
systems from medium-sized precursors.2 The cyclizations are
mainly used in the preparation of carbocyclic systems1 and,
more rarely, of oxygen-containing3 or nitrogen-containing4
heterocyclic systems. Transannular reactions involving sulfur are
poorly studied.5 A wide range of transannular cyclizations were
realized in polycyclic systems containing an oxirane ring fused
with medium-sized rings.1b,3a,4c,d,6 Mechanistically they start with
an electrophilic epoxide ring opening and the generation of a
carbocation which is susceptible to cyclization. To the best of
our knowledge only one related cyclization involving azirino-
fused medium-sized rings has so far been realised.7 In this letter
we wish to report the unusual transannular reactions involv-
ing O and S atoms of 1,1-dihalogeno-1a,2,3,4-tetrahydro-1H-
azirino[2,1-e][1,6]benzoxazocines 2a,c and the corresponding
benzothiazocines 2b,d containing an aziridine fused with eight-
membered N,O- or N,S-rings.
Compounds 2 were prepared by the cycloaddition of
8
=
dichloro- or fluorochlorocarbenes to the C N bond of 1,6-
benzoxazocine 1a or 1,6-benzothiazocine 1b (Scheme 1).
Scheme 2
The structure of 5 was determined from its 1H and 13C NMR
spectra and further elucidated by X-ray diffraction (Fig. 1).‡
Unexpectedly it was found that, in contrast to protic acid
catalysis, the reaction of azirinobenzoxazocine 2a with Lewis
acid gives rise to the formation of a five-membered 1,3-oxazole
ring rather than a six-membered 1,4-oxazine ring. Thus, 1,3-
benzoxazole 6 was isolated as a product of the reaction of 2a
with ZnCl2 (Scheme 3).
A similar transformation occurred when azirinobenzoth-
iazocine 2b was reacted with ZnCl2. Benzothiazole 7 was
isolated as the sole product of this reaction. In contrast to
azirinobenzoxazocine 2a, heating azirinobenzothiazocine 2b
in methanol did not, however, result in the formation of a
new six-membered ring. Instead, compound 8, a derivative of
benzothiazole, was obtained in 55% yield. In trifluoroacetic
acid, however, a new six-membered ring (benzthiazine 9) was
formed from both azirinobenzothiazocine 2b as well as from
azirinobenzoxazocine 2a.
Scheme 1
Whilst 1,1-dichloro-1,3,4,8b-tetrahydroazireno[2,1-a]iso-
quinolines can give the cleavage products of any of the
three aziridine bonds,9a,b the most typical transformation of
1,3-diaryl-2,2-dihalogenoaziridines by heating or treating with
nucleophiles is ring opening with cleavage of the N–C(3)
aziridine bond.9 One might therefore expect that, on heating
compounds 2a–d, nine-membered heterocycles are formed by
a cleavage of the C(1a)-N(10) bond. Instead, 1,4-benzoxazine
† Electronic supplementary information (ESI) available: Spectro-
scopic data, analytical data and experimental procedures. See DOI:
10.1039/b512409c
4 0 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 4 0 – 4 0 4 2
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Unlike dihloro-substituted azirinobenzoxazocine 2a,
chlorofluoro-substituted azirinobenzoxazocine 2c reacts with
zinc chloride to give not the corresponding 1,3-benzoxazole
derivative, but the 1,4-benzoxazine derivative 4b. After
heating azirinobenzoxazocine 2c in methanol under the same
conditions as azirinobenzoxazocine 2a only the corresponding
1,4-benzoxazine derivatives 4a,b were isolated.
Treatment of the chlorofluoro-substituted azirinobenzoxa-
zocine 2c initially with anhydrous zinc chloride in methy-
lene chloride and then with a primary amine in DMSO
gave the pyrido[3,2-b][1,4]benzoxazine 5. Similarly, pyrido[3,2-
b][1,4]benzothiazine 10 was obtained from azirinobenzothia-
zocine 2d.
These results indicate that the transannular reactions leading
to formation of a five-membered ring are not characteristic
of chlorofluoro-substituted azirinobenzox(thi)azocines 2, even
upon treatment with Lewis acid.
A possible mechanism, accounting for the observed depen-
dence of transunnular reactions on the nature of the halogen and
chalcogene atoms, as well as the reaction conditions, is presented
in the Scheme 5.
Fig. 1 X-Ray crystal structure of compound 5.
Scheme 3
When studying the influence of the nature of the halo-
gen atom on transannular transformations of the azirino[2,1-
e][1,6]benzoxazocines 2 essential distinctions in reactivity of
dichloroderivatives 2a,b and chlorofluoroderivatives 2c,d were
found (Scheme 4).
Scheme 5
In strong protic acid (CF3CO2H) ring opening of the pro-
tonated aziridine in A occurs by transannular nucleophilic
attack of the endocyclic O or S atom, leading to B. Further
transformations of this intermediate B, including elimination
of HCl and attack by an external nucleophile, will lead to
intermediate E, which is a precursor of all benzox(thi)azine
derivatives obtained in CF3CO2H.
In the absence of a highly acidic medium the usual ther-
mal transformation of dihalogenoaziridine to nine-membered
imidoyl halogenide C occurs.9,10 Further transformation of the
imidoyl halogenide C depends on the nature of the chalcogene
(O/S) and on the presence of Lewis acid in the reaction mixture.
The Lewis acid catalyses the transformation of intermediate C to
the onium salt H, firstly, making the imidoylic carbon atom more
electrophilic and secondly, facilitating elimination of a chloride
ion.11 The onium salt H is a precursor of the benzox(thi)azole
derivative J. When Z = S the transformation of C to J can
also be realized in the absence of ZnCl2, possibly because
Scheme 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 4 0 – 4 0 4 2
4 0 4 1

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of an additional stabilization due to hypervalent bonding in
Research Program of the Ministry of Education of the Russian
Federation (project ur. 05.01.316) for support of this research.
intermediate I, which is formed by the addition of the S atom
12
=
to the C N bond. When X = F the transformation of G
to H cannot, however, be realized since fluoride is a very bad
leaving group and the equilibrium is shifted in the direction of
intermediate D. The six-membered ring compounds are the only
products in this case.
Notes and references
‡ Crystal data for 5: C24H22N2O, M = 354.44, triclinic, a = 9.4130(19),
˚
b = 10.281(2), c = 11.618(2) A, a = 101.32(3), b = 109.63(3), c =
◦
3
˚
112.28(3) , U = 909.85(30) A , T = 133(2) K, space group P −1 (no. 2),
It should be noted that the dichlorides 6,7 can serve as suitable
building blocks for the preparation of 2-pyrrol-2-yl derivatives
of 1,3-benzoxazole and 1,3-benzothiazole. Thus, compounds
11,12 can be easily prepared from the dichlorides 6,7 and
primary amines. These compounds can also be prepared directly
from compounds 2 in a one-pot mode without isolation of
intermediate dichlorides (Scheme 6).
˚
Z = 2, k(Mo Ka) = 0.71073 A, 9324 reflections measured, 3128 unique
(Rint = 0.062) which were used in all calculations. The final wR(F2) was
0.1196 (all data). CCDC reference number 283218. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b512409c
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Scheme 6
In conclusion, we report the first examples of transannular
ring transformations in azirino-fused eight-membered O,N-
or S,N-heterocycles involving selective aziridine ring opening
and medium-sized ring contraction, which provide an access to
functionalized 1,4-benzox(thi)azines or 1,3-benzox(thi)azoles.
Halogenated 1a,2,3,4-tetrahydro-1H-azirino[2,1-e][1,6]benz-
oxazocines and benzothiazocines can be considered as attractive
precursors for the preparation of unknown 2,3,4,4a-tetrahydro-
1H-pyrido[3,2-b][1,4]benzox(thi)azine derivatives by a domino
or one-pot reaction with primary amines.
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Acknowledgements
We gratefully acknowledge the Russian Foundation for Basic
Research (project 05-03-33257) and University of Russia – Basic
4 0 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 4 0 – 4 0 4 2