Base-Induced Condensation of α-Chloro Oxime Derivatives Furnishes Alkynes

Article abstract of DOI:10.1002/anie.200352317

A one-carbon unit is lost in the condensation of α-chloro oxime ethers induced by lithium diisopropylamide [Eq. (1)]. This reaction, which provides alkynyl oxime ethers in good yields, is proposed to proceed via a 2-(iminomethyl)aza-cyclobutadiene intermediate.

Full text of DOI:10.1002/anie.200352317

Angewandte
Chemie
Synthetic Methods
tion of 7a is rationalized by assuming the fragmentation
of an intermediate 1-aza-2-chlorobicyclo[1.1.0]butane 5a
(Scheme 2).[4] Deprotonation of 1a affords the lithio oxime
ether 2a, which then undergoes Neber-type cyclization to
Base-Induced Condensation of a-Chloro Oxime
Derivatives Furnishes Alkynes**
Takayuki Tsuritani, Kazunari Yagi,
Hiroshi Shinokubo,* and Koichiro Oshima*
The carbon–carbon triple bond is a fundamental structural
unit in natural and unnatural organic molecules. Alkynes also
serve as important synthetic intermediates in a number of
organic transformations, and their chemistry has recently
received particular attention with respect to new materials.
The alkynyl linkage is often a key building block in highly
conjugated molecules used in light-emitting devices and
molecular wires.[1]
Azacyclobutadiene (azete) is a highly reactive and
unstable molecule, the physical properties of which have
been investigated experimentally and theoretically.[2]
Although the reaction of an isolable azacyclobutadiene
kinetically stabilized by bulky substituents has been repor-
ted,[2d–f] the utility of such compounds in organic synthesis has
remained largely unexplored. In particular, azacyclobuta-
diene is known to undergo [2+2]cycloreversion to provide
acetylene and hydrogen cyanide (Scheme 1).[2b,h] However, no
Scheme 2. Plausible reaction pathway.
provide the highly reactive azirine 3a.[5,6] The reaction of 3a
with 2a affords 4a, which yields 1-aza-2-chlorobicyclo[1.1.0]-
butane 5a. The formation of 5a is likely because 5b was
isolated in the case of the reaction of 2a with 2-methyl-3-
phenyl-2H-azirine. Removal of an a-proton of 5a with LDA
leads to the highly unstable azacyclobutadiene 6a by ring
expansion and elimination of chloride ion. The [2+2]cyclo-
reversion of 6a yields the alkynyl oxime ether 7a accom-
panied by HCN, which is then deprotonated by lithium amide.
Consequently, 2.0 equiv of lithium amide are necessary for
the reaction. With this in mind, we treated 1a with 2.2 equiv
of lithium diisopropylamide at À788C and allowed the
reaction mixture to warm to room temperature. We obtained
7a in 76% yield without the formation of 8a (entry 1 in
Table 1).[7]
Scheme 1. Fragmentation of azacyclobutadiene.
applications of azacyclobutadienes for the preparation of
alkynes have been reported. Here we wish to describe a base-
induced novel condensation reaction of a-chloro oxime
derivatives to furnish alkynyl oximes via an azacyclobuta-
diene intermediate.
The reaction of a-chloroacetophenone O-methyloxime
(1a) with 1.1 equiv of lithium diisopropylamide (LDA)
afforded 1,3-diphenylpropyn-1-one O-methyloxime (7a) and
2-chloro-1,4-diphenyl-1,4-butanedione bis(O-methyloxime)
(8a) in yields of 7% and 38%, respectively.[3] The forma-
We examined the conversion of various a-chloro oxime
ethers into alkynyl oxime ethers under the same conditions
(Table 1). Oxime ether 1b provided the corresponding
alkynyl oxime ether 7b in 81% yield, whereas 1c furnished
7c in poor yield along with other unidentified products. The
low yield was ascribed to the lower stability of the corre-
sponding lithio oxime ether 2. However, the addition of
0.5 equiv of magnesium bromide increased the yield of 7c up
to 70% yield. A noteworthy observation is the fact that the
reaction in the presence of MgBr2 proceeded even at À788C,
suggesting that magnesium bromide acts as a Lewis acid and
accelerates the conversion of 2 into 3.
[*] Dr. H. Shinokubo,Prof. Dr. K. Oshima,T. Tsuritani,K. Yagi
Department of Material Chemistry
Graduate School of Engineering
Kyoto University
Kyoto-Daigaku Katsura,Nishikyo-ku,Kyoto 615-8510 (Japan)
Fax: (+81)75-753-2438
E-mail: shino@fm1.kuic.kyoto-u.ac.jp
oshima@fm1.kuic.kyoto-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Priority Area No. 412: Exploitation of Multi-Element Cyclic Mole-
cules) and by a COE research grant from the Ministry of Education,
Culture,Sports,Science,and Technology,Japan. H.S. thanks
Tokuyama Science Foundation for financial support.
In order to verify the reaction mechanism, an additional
experiment was performed. When the reaction mixture
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 5613 –5615
DOI: 10.1002/anie.200352317
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Communications
Table 1: Self-condensation of a-chloro oxime ethers.
Entry
Starting
cmpd.
Ar
Cond.[a]
Prod. Yield
[%]
Sel.
[Z/E]
1
2
3
4
5
6
1a
1b
1c
1c
1d
1e
Ph
A
A
A
B
B
C
7a
7b
7c
7c
7d
7e
76
81
19
70
65
67
>95/5
>95/5
>95/5
95/5
94/6
>95/5
4-MeO-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
2-naphthyl
Scheme 4. Cross-condensation of oxime derivatives.
affords 2 and 12, respectively. If the cyclization of 12 proceeds
much faster than that of 2, haloazirine 3 is selectively
generated and then reacts with 2 to furnish alkynyl oxime
ether 13. With this working hypothesis, we examined the
reaction of various imines derived from a-chloroacetophe-
none.
[a] Conditions: A: LDA (2.2 equiv), À788C to room temperature; B: LDA
(2.5 equiv),MgBr 2 (0.5 equiv), À788C,3 h; C: same conditions as B,but
À788C to room temperature.
After screening a series of leaving groups, we found that
oxime p-toluenesulfonate (X = Ts, 14) and ethoxycarbonate
(X = EtOCO, 15) are both good partners with oxime methyl
ether 1 in this cross-condensation.[9] It is noteworthy that the
cross-condensation reaction proceeded even at À788C,
whereas homocondensation did not occur without magnesium
bromide at À788C. Furthermore, no homocondensation
product was obtained in any reaction.
derived from 1a in the absence of MgBr2 was treated with
benzaldehyde and TMSCl, mandelonitrile (9) and its silylated
product 10 were obtained along with 7a (Scheme 3). This
supports the generation of HCN from the fragmentation of
6a.
With the cross-condensation protocol in hand, we synthe-
sized a variety of alkynyl oxime ethers (Table 2). Several
observations are worth noting: 1) Alkyl-substituted a-chloro
oxime ethers 1h–j, which have a-protons on both sides,
afforded the corresponding products in moderate to good
yields (entries 9–12). 2) The use of 14j with R2 = Me afforded
none of the desired product. 3) The initial stereochemistry of
Scheme 3. Trapping of HCN with an aldehyde. TMS=trimethylsilyl.
Next, we attempted to perform
Table 2: Cross-condensation of a-chloro oxime derivatives.
a cross-condensation reaction. The
reaction of 2 with 2-halo-2H-azir-
ine 3 would furnish alkynyl oxime
ethers. Although the synthesis of
azirines has been extensively
explored, there are very few
reports on the synthesis of halo-
azirine 3.[8] The reaction of chlorine
azide with chloroalkenes followed
by elimination of hydrogen chlor-
ides yields the corresponding chloro-
vinylazides, which can be converted
into chloroazirines. However, not
only is this complicated synthetic
route inconvenient but also halo-
azirines are unstable (e.g., 2-chloro-
3-ethyl-2-methyl-2H-azirine rear-
ranges into 2-chloro-2-ethyl-3-
methyl-2H-azirine).[8c] We there-
fore turned our attention towards
a preparation of haloazirines in situ
(Scheme 4).
Entry
1, R1
14 or 15, R2[a]
Prod.
Yield [%]
Sel. [Z/E]
1
2
3
1a,Ph
1a,Ph
1a,Ph
14c,4-Cl-C 6H4
15l, iPr
14j,Me
(Z/E=88/12)
14a,Ph
14a,Ph
13ac
13al
–
73
63
–
94/6
>95/5
–
4
5
6
1b,4-MeO-C 6H4
1c,4-Cl-C 6H4
1c,4-Cl-C 6H4
13ba
13ca
13ca
68
65
63
>95/5
>95/5
>95/5
15a,Ph
7
8[b]
9
10
11
15a,Ph
13 fa
54
84/16
1g, tBu
14a,Ph
14a,Ph
14a,Ph
15l, iPr
(Z/E=57/43)
14a,Ph
13ga
13ha
13ia
13il
63
73
69
74
62/38
>95/5
>95/5
>95/5
1h, c-C5H9
1i, n-C8H17
1i, n-C8H17
12
13
1j,Me
13ja
57
40
>95/5
15a, Ph
13ka
ca. 1/4
Deprotonation of 1 and 11,
which possesses a good leaving
group on the nitrogen atom,
[a] Configuration of 14 and 15 is Z/E=>95/5 except for entries 3 and 11. [b] Reaction temperature
À788C to room temperature.
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Chemie
the oxime carbonates does not have a significant effect on the
reaction (entries 2 and 11).[10]
In conclusion, we have achieved a facile synthesis of
alkynyl oxime ethers from a-chloro oxime derivatives with
lithium diisopropylamide. This reaction probably involves
azacyclobutadienes as a key intermediate. Further efforts to
verify the reaction mechanism and develop applications of
this highly reactive heterocycle are currently under way in our
laboratory.
Received: July 7, 2003 [Z52317]
Keywords: alkynes · nitrogen heterocycles · oximes ·
.
small ring systems
[1] Modern Acetylene Chemistry (Eds.: P. J. Stang, F. Diederich),
VCH, Weinheim, 1995.
[2]a) N. de Kimpe in Comprehensive Heterocyclic Chemistry II,
Vol. 1A (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon, Oxford, 1996, p. 507; b) M. N. Glukhovtsev, S. Laiter,
J. Phys. Chem. 1996, 100, 1569; c) F. Neumann, K. Jug, J. Org.
Chem. 1994, 59, 6442; d) U.-J. Vogelbacher, M. Regitz, R.
Mynott, Angew. Chem. 1986, 98, 835; Angew. Chem. Int. Ed.
Engl. 1986, 25, 842; e) M. Ledermann, M. Regitz, K. Angermund
P. Binger, C. Krüger, R. Mynott, R. Gleiter, I. Hyla-Kryspin,
Angew. Chem. 1988, 100, 1615; Angew. Chem. Int. Ed. Engl.
1988, 27, 1559; f) U. Hess, U.-J. Vogelbacher, G. Michels, M.
Regitz, Tetrahedron 1989, 45, 3115; g) R. K. Mishra, B. K.
Mishra, Chem. Phys. Lett. 1988, 151, 44; h) G. Maier, U. Schäfer,
Liebigs Ann. Chem. 1980, 798; i) W. W. Schoeller, T. Busch,
Angew. Chem. 1993, 105, 635; Angew. Chem. Int. Ed. Engl. 1993,
32, 617.
[3]We assume 8a resulted from SN2-type displacement of 1a by 2a.
[4]For review on 1-azabicyclo[1.1.0b]utane, see: R. Bartnik, A. P.
Marchand, Synlett 1997, 1029. No studies of this type of 1-
azabicyclo[1.1.0]butane with a halo substituent at C2 have been
reported to our knowledge.
[5]P. W. Neber, A. Friedolsheim, Justus Liebigs Ann. Chem. 1926,
449, 109.
[6]For mechanistic study of the Neber reaction, see: a) H. O.
House, W. F. Berkowitz, J. Org. Chem. 1963, 28, 2271; b) T. Ooi,
M. Takahashi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2002,
124, 7640.
[7]Similar results were obtained when lithium tetramethylpiper-
idide was used instead of lithium diisopropylamide. The reaction
with lithium hexamethyldisilazide yielded 1,4-diphenyl-2-
butene-1,4-dione bis(O-methyloxime) as a single product.
[8]a) F. Palacios, A. M. Ochoa de Retana, E. Martines de Mari-
gorra, J. M. de los Santos, Eur. J. Org. Chem. 2001, 2401;
b) T. M. V. D. Pinho e Melo, C. S. J. Lopes, A. L. Cardoso,
A. M. d'A. Rocha Gonsalves, Tetrahedron 2001, 57, 6203; c) J.
Ciabattoni, M. Cabell, Jr., J. Am. Chem. Soc. 1971, 93, 1482.
[9]The corresponding oxime methanesulfonate and benzoate
provided 13ca in yields of 38% and 51%, respectively.
[6a]
[10]According to the report by House and Berkowitz,
the initial
stereochemistry of oxime sulfonates is irrelevant in the Neber
reaction. However, Maruoka's group has recently reported that
the stereochemistry has some effects. They suggested that the
generation of azirines from oxime sulfonates with a base favors
anti displacement.[6b]
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