Sequential five-component construction of the cyclopenta [e]-[1,3]oxazine skeleton using stable 2-azetine derivatives

Article abstract of DOI:10.1002/anie.200906357

(Chemical Equation Presented) Hawaii Five-Oxazine: The sequential onepot reaction of a methoxy-stabilized carbene with an acetylide and an imine provides stable, metal-carbene-containing 2-azetines. Subsequent mild treatment with an alkyne affords a regioselective, three-component cyclization route to fully substituted fused 1,3-oxazines.

Full text of DOI:10.1002/anie.200906357

Communications
DOI: 10.1002/anie.200906357
Synthetic Methods
Sequential Five-Component Construction of the Cyclopenta[e]-
[1,3]oxazine Skeleton using Stable 2-Azetine Derivatives**
Josꢀ Barluenga,* Arꢁnzazu Gꢂmez, Javier Santamarꢃa, and Miguel Tomꢁs
Dedicated to Professor Julius Rebek, Jr. on the occasion of his 65th birthday
Small-ring heterocycles are of prominent importance because
of their potential as bioactive compounds and synthetic
building blocks. Whilst the chemistry of three-membered
nitrogen heterocycles has been widely reported, studies on
their four-membered counterparts have focused primarily on
2-azetidinones and, to a much lesser extent, azetidine rings.[1]
The 2-azetine system 1,2-dihydroazete, which has a strained
cyclic enamine ring, is particularly elusive.[2] Most 2-azetine
compounds undergo spontaneous electrocyclic ring opening
to afford their 1-azadiene analogues; as such, there are few
examples of stable 2-azetines in the literature and those
reported require electron-withdrawing substituents, for exam-
ple, carbonyl, carboxyl, sulfonyl, or nitro groups, attached to
the nitrogen atom.[3,4] As a consequence, the chemistry of 2-
azetines remains largely unexplored, and has been predom-
inantly focused on their potential as a precursor to azadienes.
Moreover, there are no general synthetic routes to 2-
azetines.[5] Although, the [2+2] cycloaddition of alkynes and
imines appears to be a convenient route to this type of
heterocyclic framework, only a few specific examples have
been reported; in these cases, electron-rich alkynes, as
ynamines,[6] alkynyl selenides,[7] or alkynyl sulphides,[8] are
able to form the expected 2-azetine skeleton, which is not
isolated but rapidly opens to the azadiene system. The [2+2]
cycloaddition of electron-poor alkynes and imines has only
previously been suggested as an intermediate in the cycliza-
tion reaction between an alkynyl(ethoxy)carbene of tungsten
and imine fluorenones to afford pyrroline derivatives.[9]
As part of our interest in Fischer-type metal carbenes, we
have recently considered more-electrophilic metal carbenes,
the so-called non-heteroatom-stabilized carbenes.[10] These
compounds are particularly useful in organic synthesis, and
our preliminary results have revealed significant differences
in the reactivity of both heteroatom-[11] and non-heteroatom-
stabilized systems.
Herein, we report the [2+2] cycloaddition reaction of
alkynyl-substituted (pentacarbonyl)chromium or -tungsten
carbene complexes with imines as a suitable procedure for
accessing stable 2-azetine derivatives. Moreover, the conju-
gation of the resulting azetine unit with the metal carbene
allows for
a facile synthesis of novel cyclopenta[e]-
[1,3]oxazines involving treatment with alkynes. This three-
component process (azetine, alkyne, and CO ligand) features
ꢀ
cleavage of the azetine C3 C4 bond, rather than the expected
ꢀ
ꢀ
N C4 bond, and the formation of three C C bonds and one
ꢀ
C O bond (Scheme 1).
Scheme 1. The formation of cyclopenta[e][1,3]oxazines from non-
heteroatom stabilized carbene complexes by bond cleavage of azetinyl-
carbenes. Bond cleavage and formation is shown by arrows.
Stable, easy-to-handle methoxycarbenes 1 are used as
in situ precursors of alkynylcarbenes 3 using the methoxy-
acetylide 2 exchange reaction (Table 1). The resultant solu-
tion of 3 in tetrahydrofuran was treated at ꢀ808C with 1.3–
5.0 equivalents of imine 4 (see the Supporting Information)
and the mixture was allowed to warm to 08C. Removal of the
solvent followed by chromatographic purification afforded
the 2-azetine metal carbenes 5a–i in 50–75% overall yield
from the Fischer carbenes 1. The structure of azetines 5a–i
was determined by NMR spectroscopy and HRMS data. The
structure of compound 5b was unambiguously confirmed by
single-crystal X-ray diffraction analysis. It is noteworthy that
the strongly electron-accepting metal–carbene functionality
at the C3 atom confers a much improved stability on these N-
alkyl-2-azetines.[12]
[*] Prof. Dr. J. Barluenga, Dr. A. Gꢀmez, Dr. J. Santamarꢁa,
Prof. Dr. M. Tomꢂs
Instituto Universitario de Quꢁmica Organometꢂlica “E. Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
C/Juliꢂn Claverꢁa, 8, 33006 Oviedo (Spain)
Fax: (+34)985-103-450
E-mail: barluenga@uniovi.es
Homepage: http://uniovi.es/emoles/barluenga/index.htm
[**] We are grateful to the Ministerio de Educaciꢀn of Spain (Project
CTQ2007-61048) and the Principado de Asturias (Project IB08-088)
for supporting this research. A.G. thanks the Ministerio de
Educaciꢀn and European Union (Fondo Social Europeo) for a
graduate fellowship. We are also grateful to Dr. A. L. Suꢂrez-Sobrino
(Universidad de Oviedo) for his assistance in the X-ray analysis.
We also used this procedure to regioselectively synthesize
2-azetines bearing an alkyne functionality (5e,f).[13] Further-
more, the furfural imine (R3 = Fu = furfural) underwent
heterocyclization with b-ferrocenylethynylcarbenes (R2 =
Fc = ferrocene; see cycloadduct 5d).[14] Interestingly, azetine
5 f was formed with complete chemoselectivity from a
cycloaddition through the more electrophilic alkyne unit of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906357.
1306
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Angew. Chem. Int. Ed. 2010, 49, 1306 –1308

Angewandte
Chemie
Table 1: Synthesis of azetinylcarbenes 5.[a]
compounds 7a and 7d were unambiguously confirmed by X-
ray crystallography.
From a synthetic standpoint, some features are notice-
able: 1) hexasubstituted cyclopentaoxazines were obtained as
a single isomer; 2) the three components, the azetine-3-yl
carbene, the alkyne, and carbon monoxide, assembled regio-
[M]=Cr(CO)5
[M]=W(CO)5
R1 R2 R3
ꢀ
ꢀ
selectively; and 3) one C O and three C C bonds were
R1
R2 R3
yield[b] [%]
yield[b] [%]
ꢀ
formed. Moreover, the C3 C4 bond of the azetine unit was
5a Ph
5b Ph
5c Ph
5d Ph
Ph Ph
Fc Ph
Ph p-Tol 56
62
75
5g Ph Ph Ph
5h Ph Fc Ph
74
73
ꢀ
cleaved, in sharp contrast with the C4 N cleavage-initiated
reactivity pattern of simple azetines (electrocyclic ring open-
ing).
5h Ph Ph c-C6H11 63
Fc Fu
64
50
72
We proposed a mechanism on the basis of the reactivities
of Group 6 metal–carbenes, and azetines (Scheme 2). In this
mechanism, the reaction is initiated by the regioselective
ꢀ ꢁ
5e Ph C C Ph Ph
ꢀ ꢁ
5 f Fc C C Ph Ph
[a] The diynylcarbene precursor for 5e was synthesized from
3
1
2
ꢀ ꢁ
(R =Ph C C, R =Fc). Fc=ferrocenyl; Fu=2-furyl. [b] Overall yield
from Fischer carbenes 1.
ꢁ
ꢁ
the carbene 3 (Ph-C C versus Fc-C C). Therefore, the
nonstabilized (alkynyl)carbene system, unlike the traditional
heteroatom-stabilized analogues, readily undergoes a [2+2]
heterocyclization reaction with imines to afford stable 2-
azetines. This procedure also suggests that the C3 metal–
carbene functionality is an efficient stabilizing motif for the 2-
azetine ring.
We then examined the reactivity of the chromium azetinyl
carbene towards neutral and activated alkyne substrates
(Table 2). Therefore, the treatment of an acetonitrile solution
Scheme 2. Proposed mechanism for the formation of cyclopentadiene-
fused oxazines 7.
Table 2: Three-component synthesis of bicyclic [1,3]oxazines 7.
=
insertion of an alkyne into the Cr C bond to form inter-
mediate I. A carbon monoxide ligand inserts into the newly
formed metal–carbene to generate metal–ketene complex II.
Subsequent intramolecular nucleophilic attack affords azeti-
nium species III, which would advance through electrocyclic
ring opening (intermediate IV) and cyclization to give
product 7. Whilst the insertion reaction of alkynes and
carbon monoxide into the related metal alkoxycarbenes is
well documented,[16] to the best of our knowledge the
postulated electrocyclic ring opening of 1-azetinium species
(III!IV) has not been reported.[17]
R1
R2
R3
R4
R5
Yield [%]
7a
7b
7c
7d
7e
7 f
7g
7h
7i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Fc
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Tol
Ph
Ph
p-Tol
Ph
Fc
p-Tol
c-C6H11
p-Tol
Fc
H
H
H
H
H
H
H
H
CO2Me
64
65
32
69
57
36
82
78
62
ꢀ ꢁ
Ph C C
p-Tol
Ph
Ph
Ph
CO2Me
CO2Me
CO2Me
In conclusion, we have developed a two-step, regioselec-
tive route to the 2,3-dihydrocyclopenta[e][1,3]oxazine skel-
eton 7 from readily available acyclic adducts. This route
enables the synthesis of a heterocyclic motif with very high
structural complexity from five units: an aryl-
(methoxy)carbene, acetylide, imine, alkyne, and carbon
monoxide, in an ordered and selective sequence. The first
step of the process is an efficient and simple procedure to
access the N-alkyl-2-azetine skeleton 5. A preliminary study
of the reactivity of this system towards alkynes shows that the
reactivity of the azetine unit is controlled by the conjugated
metal–carbene moiety, which is responsible for the unex-
of chromium carbene 5a–c,e with terminal alkynes 6 at 808C
resulted in the formation of substituted 2,3-dihydrocyclopen-
ta[e]oxazines 7a–f in moderate to good yields after chromato-
graphic purification. Higher yields were obtained for the
electron-poor alkyne methyl propiolate (7g,h). Although the
non-activated internal alkyne 4-octyne reacted poorly
(<15% yield, not shown), dimethyl acetylenedicarboxylate
afforded the expected cycloadduct 7i in 62% yield.[15] NMR
spectroscopy (1H/13C, and 1D/2D experiments) was used to
determine the structures 7a–i. Moreover, the structures of
ꢀ
pected C3 C4 bond-cleavage via an azetinium ion. Further-
more, this synthesis is tolerant of valuable functional groups,
such as alkyne and ester groups. We believe that the intrinsic
Angew. Chem. Int. Ed. 2010, 49, 1306 –1308
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1307

Communications
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reactivity of both carbene and azetine moieties makes 5 a
valuable intermediate in the preparation of nitrogen-contain-
ing polycyclic arrays.
Received: November 11, 2009
Published online: January 18, 2010
Keywords: alkynes · azetines · carbenes · heterocycles ·
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[13] When an alkyl acetilyde (R2 = Bu; R1 = R3 = Ph) is employed,
the expected azetine was not formed, but a [4+3] cyclization was
observed wherein the phenylimine behaves as the 1-azadiene
unit.
.
regioselectivity
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