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New Methods for the Synthesis of Vinyl Azides.

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New Methods for the Synthesis of Vinyl Azides
By Gerrit L'abbe and Alfred Hassner[*l
A critical survey of synthetic approaches to vinyl azides is presented, focusing especially
on stereo- and regiochemicalproblems. 7-hecombined procedure of azidohdogenationof
olefins followed by dehydrohalogenation, leads to regiospecificand, in the case of ionic
additions, also to stereospecificformation of vinyl azides. Nucleophilicsubstitutions by
azide ions on activated olefinichalides result in p-azidovinyl ketones, esters,nitriles, etc.,
and proceed predominantly with retention of configurationabout the C=C bond. m e
known synthetic methods leading to a-azidovinyl ketones and esters give rise to the
thermodynamically more stable trans-vinylazides.
1. Introduction
During the last few years unsaturated azides have acquired considerable importance as intermediates in organic syntheses and new methods for their preparation
have been devised. It is remarkable that vinyl azide
(CH,=CHN,), the simplest of this class of unsaturated
azides, was first described in 1910[11,yet most of the
knowledge concerning the synthesis and reactions of
these compounds has been gained during the past five
years. The reason for interest in this class of compounds is
the high reactivity of the azide function which is susceptible to photolysis, pyrolysis, cycloadditions and attack
by nucleophiles as well as by electrophilesl2I. The presence of a neighboring double bond accentuates the
reactivity of the azide group and provides additional intramolecular pathways for reaction. A few examples are
shown below.
Among the recently studied transformations of vinyl azides are their
and phot~lysis[~]
which serve
as a general method of synthesis of azirines, a heretofore
rare class of heterocycles.
Pyrolysis of some vinyl azides has furnished indole derivative@ 51.
H
Examples of intramolecular[6] and of interm~lecular[~]
cycloadditions have been reported.
CN
\
N P
/
c-c
&
CN-CH=CH-N3
H
,h
p;J
H
M eOOC\
Ph-CZCH, + Me00C-CzC-COOMe
N3
,COOM e
F=C
+
,Ph
N, ,N-C,,
N
CHZ
Formation of the heterocycles isoxazoles and oxazoles
can likewise be accomplished via unsaturated azides[*].
4
['I
Dr. G. L'abM, Department of Chemistry,
University of Louvain (Belgium)
Prof. A. Hassner, Department of Chemistry,
University of Colorado,
Boulder, Colorado 80302 (USA).
[l] a) M. 0.Forster and S. H. Newman. J . Chem. SOC.97,2570 (1910);
b) see also R. H. Wjleyand J. Moffat, J . Org. Chem. 22,995 (1957).
[2] a) G. L'abk', Chem. Rev. 69,345 (1969); b) G. L'abbp, Ind. Chim.
Belge 34, 519 (1969).
[3] a) G. Smolinsky, J. Amer. Chem. SOC. 83, 4483 (1961); J. Org.
Chem. 27,3557 (1962); b) G.Smolinskyand C. A. Pxyde,ibjd. 33,2411
(1968); c) G.Srnolinsky, Trans N . Y .Acad. Sci., Ser. II,30,511(1968).
[4] a) L. Homer, A. Christmann, and A. Gross, Chem. Ber. 96, 399
(1963); b) A. Hassnerand F. W. Fowler, Tetrahedron Lett. 1967,1545;
J. Amer. Chem. SOC.90, 2869 (1968); c) J. S. Meek and J. S. Fowler,
J. Org. Chem. 33, 3418 (1968); d) F. P. Woerner, H. Rejmlinger, and
D. R. Arnold, Angew. Chem. 80,119 (1968); Angew. Chem. internat.
Edit. 7, 130 (1968); e) K. Isomura, M. Okada, and H. Taniguchi, Tetrahedron Lett. 1969, 4073.
[5] a) K. Isomura, S. Kobayashi, and H. Taniguchi, Tetrahedron Lett.
1968, 3499; b) H. Hernetsberger, D. Knittel, and H. Weidmann,
Monatsh. Chem. 101, 161 (1970).
[6] N. S. Zefirov and N. K. Chapovskaya, Zh. Org. Khim. 4, 1300
(1968); J. Org. Chem. USSR 4, 1252 (1968).
98
Me
\
N3
R-4
0
Me
I
c=c
\
d_
R - CF-8C'0'
The most recent synthetic application of vinyl azides is
the synthesis of a reactive ketene in pure form[9].
0
[7J a) G. L'abbk, J. E. Galle, and A. Hassner, Tetrahedron Lett. 1970,
303; b) G. L'abbd and A. Hassner, J. Heterocycl. Chem. 7,361 (1970);
c) J. H. Boyer, W. E. Krueger, and R. Modler, Tetrahedron Lett. 1968,
5979.
[8] M. I. Rybinskaya, A. N. Nesmeyanov, and N. K. Kochetkov, Usp.
Khim. 38, 961 (1969); Russian Chem. Rev. 38,433 (1969).
[9] H. W.Mooreahd W. Weyler,J. h e r . Chem. SOC. 92,4132(1970).
Angew. Chem. internat. Edit. / Vol. 10 (1971) / N o . 2
A few remarks about nomenclature are in place here.
Though the term vinyl azide strictly applies to
CH,=CHN,, it has been generally adopted, and hence
is used in this review to denote any a,@-unsaturatedazide. In addition to these two terms, that of enazide has
been employed on occasion.
In this review we will discuss methods leading to the synthesis of vinyl azides. For convenience the topics have
been divided according to the type of substituentspresent
on the double bond.
Another aspect that will be emphasized is the stereochemistry and regiochemistry of these compounds. The
stereochemistry refers to the configuration of substituents about the C = C bond, i.e. cis and trans compounds
are to be differentiated.
R\
H
R\
/
c=c,
R
Nl
H
/c=C\1
N3
trans
2.1. Ionic Addition
The ionic additions of IN, to olefins occur stereospecifically anti"] via a cyclic halonium ion (6),as was
clearly shown by the exclusive formation of the threo(8) and erythro-2-azido-3-iodobutane(1I), respecla].
tively, from cis-(7) and trans-2-butene (lo)[*
r.,o,.?
X
H
MH
Me
Me
(7) cis
IN
A
I H H
Y-d
M e M e N,
(8)threo
cis
(10) trans
2. Simple Vinyl Azides'*l
A general synthetic method for vinyl azides, discovered
by Hassner et al.I1l], involves the addition of halogen
azides to olefins, followed by treatment of the resulting
@-haloalkyl azides with a base such as potassium tertbutoxide, sodium methoxide, or 1,4-diazabicycl0[2.2.2]octane. The addition of halogen azides can occur by
either an ionic or a free radical process and leads to
regioisomeric vinyl azides as illustrated below in the case
of styrene [i.e. (1) -+ (2) --f (3) or (1) + (4) --f (5)].
(11) erythro
XN i
rad ,(.:,I
Ph-CH-CHZN,
I
>I
(41
Me
N,
(9) trans
KOtB"
(12) cis
cis- and trans-Stilbene gave similar results, cyclohexene
was transformed into the trans adduct, and 2-cholestene
afforded the trans-diaxial adduct. The threo- and eryrhro- adducts (8) and (1 1 ) are dehydrohalogenated in
an anti fashion by potassium tert-butoxide to give the
trans- and &-vinyl azides (9) and (12), respectively. In
most cases the transition state for anti-dehydrohalogenation to the vinyl azide is of lower energy than
that leading to the allyl azide; hence regiospecific elimination of HX to the vinyl azide is usually observed. An
exception is provided by trans-halocycloalkyl azides (in
rings with less than eight members) which lead to allyl
azides, i.e. (14). The cis-isomer (15) furnishes (16). In
eight-membered rings syn elimination to a vinyl azide
occurs.
(13) trans
__I_)
-HI
R
Regiochemistry refers to directional preference in bond
and in the case under study inmaking or
dicates the point of attachment of the azide function on
the C=C bond, i.e. R-CN,=CH, and R-CH=CHN,
are regioisomers.
(I)
-
(14)
Ph-CH=CHN,
(5)
An ionic pathway in the XN, addition is favored in
a polar medium (e.g. acetonitrile, nitromethane, DMF)
and in the presence of oxygen (a free radical inhibitor),
whereas a free radical pathway is enhanced in a solvent
of low polarity (e.g. pentane), in the presence of light,
and in the absence of oxygen. Furthermore, it has been
shown that the preference of the halogen azides for homolytic cleavage increases in the order: IN, < BrN, <
ClN,. Hence the conditions for an exclusive ionic or free
radical reaction can be readily adjusted in the case of
BrN,, whereas IN, reacts preferentially by an ionic path
and ClN, by attack of the N, radical on the double bond.
I*] By simple vinyl azides we designate those compounds lacking functional groups such as C=O, CN, F, erc.
Angew. Chem. internat. Edit. / Vol. 10 (1971) / N o .
2
The regiochemistry of most ionic additions is controlled
by electronic effects operating in the cyclic intermediate
(6). Thus 1,3-cyclooctadiene (1 7) adds IN, to give adduct (18) in 7 2 % yield. Elimination of HI from (18) oc-
I*] The terms CIS and frans are used for configurational assignments,
and syn and anti for describing transformations during chemical processes.
(lo] A. Hassner, J. Org. Chem. 33, 2684 (1968).
1111 a) A. Hassner and L. A. Levy, J. Amer. Chem. SOC.87, 4203
(1965); F. W. Fowler, A. Hassner, and L. A. Levy, ibid. 89,2077 (1967);
b) A. Hassner and F. W. Fowler, J. Org. Chem. 33, 2686 (1968); c)
A. Hassner and F. Boerwinkle, J. h e r . Chem. SOC.90, 216 (1968);
d) A. Hassner and F. Boenvinkle, Tetrahedron Lett. 1969, 3309; e)
A. Hassner, F. P. Boenvinkle, and A . B. Levy, J. Amer. Chem. SOC.
92, 4879 (1970); f) A. Hassner, Accounts Chem. Res., in press.
99
curs regiospecifically and syn, yielding the cis,cis-azidocyclooctadiene (19). Photolysis of (19) leads to the
fused azirine (2014b].
Ph-CO-CH2Br
NaN,
NaBH4
Ph-CO-CH2N3 ----+
(25)
7-
P h - H CHzN3
OH
SOCI,
*
Ph-CH-CHZN,
I
c1
KOtBu
(44
Ph-CH=CHN,
An exception to the generally observed mode of addition (electronic control) is the IN, addition to 3,3dimethyl-1-butene (21), where a pure stenc effect accounts for the exclusive formation of 1-azido-2-iodo3,3-dimethylbutane (22) which, on treatment with potassium tert-butoxide, furnishes the I-azide (23)111bl.
(5)
c1
FCH,
Ph
(26)
Finally, another method that has been used in the synthesis of some vinyl azides involves the opening of an
epoxide by NaN,, followed by dehydration, as exemplified for 2-azido- 1,l-diphenylethylene (27)[3b*14].
3. fl-Azidovinyl Ketones, Esters, Nitriles, efc.
2.2. Radical Addition
The radical additions of halogen azides occur via a free
radical intermediate such as (24) (for styrene) with the
result that no stereospecific addition to cis- and transolefins can be expected.
-+
+
It is well known that simple vinyl halides are extremely
resistant to nucleophilic substitution. However, when the
vinylic halide is activated by an electron-withdrawing
group in the @-position,halide substitution occurs readily[8~15~.
Therefore, P-haIovinyl ketones (28) are suitable
starting materials for the synthesis of /3-azidovinyl ketones (29)[16].
P h -CH= CHN,
(51
Indeed, the addition of BrN, to 2-cholestene under free
radical conditions led to a mixture of two 1:1 adducts,
one trans-diaxial and the other cis, Another example is
the ferric ion catalyzed radical addition of CIN, to cyclohexene for which a trans :cis ratio of 70130 is reported[‘*].
Previous to the discovery of the free radical method,
trans-0-azidostyrene trans-(5) was only available by a
more expensive and time-consuming sequence starting
from phenacyl bromide (25) with the formation of (26)
as a side product[l3I.
[12] a) E Minisci, R. Galli, and M. Cecere, Chim. Ind. (Milan) 48,347
(1966); b) E Minisci, ibid. 49, 705 (1967).
[13] a) J. H. Boyer, W. E. Krueger, and G. J. Mikof, J. h e r . Chem.
SOC.89, 5504 (1967); b) J. H. Boyer, W. E. Krueger, and R. Modler,
J. Org. Chern. 34, 1987 (1969).
[14] K. Ponsold and G. Schubert, J. Prakt. Chem. 311, 919 (1969).
[15] A. E. Pohfand and W. R. Benson, Chem. Rev. 66, 161 (1966).
[ 161 P.Beltrame, G. Favini, M. G. Cafrania, and F: GueIfa, Gau. Chim.
Ital. 98, 380 (1968).
[17] a) A. N. Nesmeyanov and M. I. Rybinskaya, Izv. Akad. Nauk
SSSR, Otd. Khim. Nauk 1962,816; Bull. Acad. Sci. USSR, Dir. Chem.
Sci. 1962,761; b) A. N. Nesmeyanovand M. I.Rybinskaya, Dokl. Akad.
Nauk SSSR 170, 600 (1966); Proc. Acad. Sci. USSR 170,916 (1966);
c) A. N. Nesmeyanov, M. I. Rybinskaya, and 7.
G. Kelekhsaeva, Zh. Org.
Khim. 4,921 (1968); J. Org. Chem. USSR 4,897 (1968);d) A. N. Nesmeyanov, M. I. Ryhinskaya, and T G. Kelekhsaeva, In. Akad. Nauk
SSSR, Ser. Khim. 866 (1969); Chem. Abstr. 71, 2 1 4 9 5 ~(1969).
100
X
a
=
CI, Br, NH,Clo, NO2
X # S O , o , CN
Nesmeyanov and Rybinskaya[8,17]found that the substitution proceeds predominantly with retention of conThe stereofiguration about the CC double
chemical results are compatible with a conjugate addition of the azide ion to the X-carrying carbon of
(28), followed by a fast elimination of X-. The two alternative possibilities - addition of HN, followed by
elimination of HX or elimination of HX followed by addition of HN, - are excluded since the stereochemical
results of the reaction would be independent of the configuration of the starting olefin.
It is noteworthy that the cis-P-azidovinyl ketone [cis(29)] cannot be isolated in the free form from the reaction of the cis-P-halovinyl ketone [cis-(28)] and NaN,,
since it decomposes spontaneously to the isoxazole (30).
1-Acetyl-2-chloro-1-cyclopentene (33), which obviously has both substituents in the cis-position, is like[ 181 The mechanism explaining retention of configuration in nucleophilic substitution on olefinic halides is discussed by: E. L. Efiel, “Stereochemistry of Carbon Compounds”, McGraw-Hill Book Company,
Inc. New York, 1962, p 369.
[19] S. Maiorana, Ann. Chim. (Rome) 56, 1531 (1966).
Angew. Chem. internat. Edit. / Vol. 10 (1971) / N o . 2
wise converted by NaN, to the isoxazole (32)[l9I.
Whether isoxazole formation proceeds via a nitrene or
by a concerted mechanism [as shown for cis-(29)] has
not been established.
Unlike their cyclic analogs, the open-chain vinyl a, pbisazides, eg. (401, are unstable and decompose to
nitriIe~[~~].
r
1
1
Ph-C=C-Ph
A3A3
- 2 ~ , -2 P h - C N
(40)
L
cis-(29)
Unlike ,their cis-analogs, trans-P-azidovinyl ketones
[e.g, trans-(29)]are stable under ordinary conditions and
only decompose on heating into nitriles (34) and oxazoles (36)[201.The reaction -probably proceeds via a nitrene (331, which is converted either to the nitrile (34)
or via an azirine (35) to the oxazole (36):
2,S-Bisazido-3,6-di-tert-butyl-1,4-benzoquinone
(41)
undergoes a thermal fragmentation in refluxing benzene
to give two molecules of the thermally stable, yet very
reactive, tert-butyl cyanoketene (42)[91. The decomposition reaction is comparable to the formation of phenyl
cyanoketene (44) by reacting 3-halo-4-phenylcyclobutenedione (43)with NaN, in acet~nitrile[~~l.
Ketene (44),
however, was only prepared in situ and was subsequently
trapped by hydroxylic compounds. It is also noteworthy
that azidoketenes (46) can be prepared in situ by dehydrohalogenation of (45) and can be trapped with Schiff
bases to give azetidinones (47)[251.
N
tBu
0
f 33)
trans-(29)
1
r
(35)
(36)
The formation of different products in the decomposition
of cis- and trans-P-azidovinyl phenyl ketones (29)
(isoxazoles versusnitriles and oxazoles) was used by Nesmeyanov and Rybinskaya[8.l7l as a criterion for elucidating the geometrical structure of the vinyl azides (29).
Azidoquinones[2'l [e.g. (37) and (38)l and azidomaleimides[221[e.g. (39)] are structurally related to trans-azidovinyl ketones and are therefore readily prepared from
the corresponding chloro derivatives.
0
t
N,
[20] For photolysis of 6-azidovinyl ketones see: S. Sam, Bull. Chem.
Soc. Jap. 41, 2524 (1968).
[21] a) K. Friesand P. Ochwat, Ber. dtsch. chem. Ges. 56,1291 (1923);
b) L. F. Fieserand J. L. Hartwell, J. Amer. Chem. SOC. 57, 1482 (1935);
c ) L A. Van Allan, W. 1. Priest, A. S. Marshall, and G. A. Reynolds,
J. Org. Chem. 33, 1100 (1968); d) H. W. Moore, H. R. Shelden, D. W.
Deters, and R. J. Wikholm, J. Amer. Chem. SOC. 92, 1675 (1970).
[22] a) A. Mustafa, S. M. A. D. Zayed, and S. Khattab,J. Amer. Chem.
Soc. 78, 145 (1956); b) The structure assignment for (39)by the above
authors has been incorrectly interpreted and criticized by: W. I. Awad,
S. M. A. R. Omran, and F. Nagieb, Tetrahedron 19, 1591 (1963).
[23] A. Hassner, R. J. Isbisrer, and A. Friederang, Tetrahedron Lett.
1969, 2939.
Angew. Chem. internat. Edit. / Vol. 10 (1971) / N o .
2
ROH
R-CH-C=O
I
1
N, C1
EtJN
NC\
,CH-COOR
Ph
R-C=C=O
Ph-CH=N-Ph
H
Modena and Todesco1261reported that the reaction of
both cis- and trans-@-chlorovinylarylsulfones (48)with
NaN, proceeds with retention of configuration and follows a second order rate law. Their kinetic results clearly
indicate that the reaction rate is only slightly influenced
by the geometrical structure of the starting olefin. Substituents in the phenyl ring, on the contrary, affect the
rate profoundly and to the same extent for cis- as for
trans-olefins. A plot of log k, versus u gives two parallel
lines with a @-value of + 1.84, thereby demonstrating
the accelerating effect of electron-withdrawing substituents.
1241 a) R. C.DeSelms, TetrahedronLett. 1969,1179;b) A. H. Schmidl
and W. Ried, ibid. 1969, 2431.
[25] a) A. K. Bose, B.Anjaneyulu, S. K . Bhattacharya, and M. S. Manhas, Tetrahedron 23,4769 (1967); b) M. s. Manhas, J. s. Chib, Y. H.
Chiang, and A. K. Bose, ibid. 25, 4421 (1969); c) A. Hassner, R. 1.
Isbister, R. B. Greenwald, J. T. Klug, and E. C. Taylor, ibid. 25, 1637
(1969).
1261 G. Modena and P. E. Todesco, Gazz. Chim. Ital. 89,866 (1959).
101
A r -SOz-CH=CHC1
NaN,
---+
MeOH
Ar-SO,-CH= CHN,
(48)
(49)
Meek and
investigated the reaction of cis- and
trans-l,2-ditosylethylene(50)with NaN, in several solvents, and their stereochemical findings [retention of
configuration €or (50)-+(51)]agree with those of Modena and Todesco. In addition they found that cis-(51)
is formed from cis4501 in the early stage (3 min) of the
reaction in DMSO, but it isomerizes into trans-(51)
within 30 minutes. On standing for a longer time (24 h)
in DMSO under the basic conditions (N3-), trans-(51)
cyclizes to the triazole (52). Evidently, the acidic hydrogen atom a to the sulfone in trans-(51)is removed under
the basic-reaction conditions, resulting in cyclization to
the aromatic triazole (52).
H
>-t'
Tos Tos
NaNj
DMSo
cis - (50)
>=<"
Tos
N,
cia-(51)
-
TOS
H
Tos
h
N3
H
--*
N,JVH
(521
trans-(51)
The generality of the synthetic method described in this
section is further substantiated by the facile conversion
of B-halovinyl nitriles[281and fluorides[29]into the corresponding azides, e.g. (53)and (55),at 0 C. Both (53)
and (55) decompose at room temperature, the former
yielding a ketenimine (54) and the latter an azirine (56).
The ketenimine was not isolated in the free form but
its presence was inferred from trapping experiments.
O
When the @-positionis activated by a nitro group as in
the case of a-nitro-0-iodoolefins or a$-dinitroolefins,
the corresponding a-nitro+azidoolefins, e.g. (58),are
not isolated but instead give rise to furoxanes in high
The conversion of trans-2,3-dinitro-2-butene
(57) by NaN, into 3,4-dimethylfuroxane (59)is a typical
example.
Recently, /3-azidovinyl esters [e.g. (61)] and amides were
prepared by treating allenic esters [e.g. (6U)] and amides
with an excess of NaN3t3*].Although the stereochemistry
of the reaction was not elucidated by the authors, structure (61) is suggested since the same product was obtained by Hassner's method from ethyl crotonate
(62)[11b]
(DABCO = 1,4-diazabicyclo[2.2.2]octane).
EtOOC-CH=C=CKz
H)
5
q
EtOOC
(60)
3
CH,
(61)
T
D A I3CO
I VMe
EtOOC
7%
H
EtOOC H N ,
vic-Tria~oles[~~]
and i~oxazoles[~~1
normally result from
the addition of HN, and NaN, to acetylenes, and only
e.g. methyl azidofumarate (64), have
in a few cases[33,341,
vinyl azides been obtained.
HN
MeOOC - CZC- COOMe 2
f 55)
(56)
[27] J. S. Meek and J. S. Fowler, J. Amer. Chem. SOC.89,1967 (1967);
J. Org. Chem. 33, 985 (1968).
1281 K.Friedrich, Angew. Chem. 79, 980 (1967); Angew. Chem. internat. Edit. 6, 959 (1967).
(291 a) C. S. Cleaverand C. G. fiespan, J. h e r . Chem. SOC.87,3716
(1965); b) R. E. Banks and G. J. Moore, J. Chem. Sac. C. 1966,2304;
c) C. G. Krespan, J. Org. Chem. 34, 1278 (1969).
1301 a) W. D. Emmonsand J. P. Freeman, J. Org. Chem. 22,456 (1957);
b) T. E. Stevens and W. D. Emmons, J. Amer. Chem. SOC.80, 338
(1958).
(311 a) G. R. Harveyand K. W. Ratts, J. Org. Chem. 31, 3907 (1966);
b) G. R. Harvey, US-Pat. 3471523 (1969), Chem. Abstr. 72, 3252f
(1970).
[32] a) 0. Dimroth and G. Fester, Ber. dtsch. chem. Ges. 43, 2219
(1910); b) E. OlivenGMandala and A. Coppola, Gazz. Chim. Ital. 40
11, 435 (1910); c) R. Hiiftel, Ber. dtsch. chem. Ges. 74, 1680 (1941);
d) J. C. Sbeehan and C. A. Robinson, J. Amer. Chem. SOC.71, 1436
(1949);e) L. W.HartzelandF. R.Benson,ibid. 76,667(1954);f)A. N.
Nesmeyanov and M. I. Rybinskaya, Dokl. &ad. Nauk SSSR 158,408
(1964); Proc. Acad. Sci. USSR 158, 902 (1964).
[33] a) U. Tiirck and H. Behringer, Chem. Ber. 98, 3020 (1965); b)
A. N. Nesmeyanov and M. I. Rybinskaya, Zh. Org. Khim. 2, 2081
(1966); J. Org. Chem. USSR 2, 2041 (1966).
1341 V. G. Ostroverkbov and E. A. Sbilov, Ukrain. Khim. Zh. 23, 615
(1957), Chem. Abstr. 52, 7828d (1958).
102
N3===(!cooMe
H
MeOOC
(64)
The isoxazoles (67) are obtained when acetylenic ketones (65) are treated with HN,, and their formation
is probably a result of decomposition of cis-(3-azidovinyl
(67)
1
Ar-COI--\
N,
dNH
(69)
Angew. Chern. internat. Edit. / Vol. 10 (I 971) / No. 2
tone (76). It was further observed that when R' = Ph, the
direct conversion of (71) to (76) via intermediate (77)
competes with the sequence (71)-(73)-1(74)+(76).
Both the activation of the a-carbon in (71) by the carbony1 group and the stabilization of the negative charge
in (77) by the phenyl group provide the driving force
of the competing reaction (71)+(76).
ketones (66), produced initially. Interestingly, when the
acetylenic ketones (65) are allowed to react with NaN,
in an aprotonic solvent, such as DMF, no isoxazoles, but
triazoles (69), are obtained in high yields. This is logical
if one considers the reaction as proceeding via the carbanionic intermediate (@)which, in the absence of a proton source, cyclizes to the stable aromatic triazole ring
(69). This result is similar to that discussed above for
vinyl sulfones. Further support for this interpretation is
provided by the fact that trans-(29) is also converted
by NaN, in DMF via (68) into benzoyl-1,2,3-triazole
(69)[191
From the mechanism outlined above, it is obvious that
a-bromovinyl ketones (71) and the BrN, or IN, adducts
of a$-unsaturated ketones, e.g. (73), are also starting
materials for the synthesis of the a-azidovinyl ketones
(76)[361.
All three synthetic methods afford (76) in high
yields.
4. a-Azidovinyl Ketones and Esters
Under the same reaction conditions, meso-l,2-dibenzoyl-1,2-dibromoethane
(78) gives 3-benzoyl-5~ ~ ~ . product
phenylisoxazole (SO) e x c l ~ s i v e l y [ ~This
apparently results from decomposition of vinyl azide
(79), which has both the a-azido- and f3-carbonyl groups
in a &-configuration.
A general synthetic method for a-azidovinyl ketones
(76) involves the reaction of a,@-dibromoketones(70)
with two equivalents of NaN, in DMF at room tempera t ~ r e [ ~ ~ .A' ~detailed
I.
mechanistic study on three a, f3dibromoketones, using NMR techniques, revealed that
the
reaction
proceeds
through
pathway
(70)-1(71)-+(73)-+(74)-1(76). Sodium azide in DMF
eliminates HBr from (70) to give cis-bromovinyl ketone
(71) which isornerizes more or less readily to the transisomer under the reaction conditions. Both geometrical
isomers are converted to the bromo azide (73), via intermediate (72), by NaN, in the presence of the proton
source HN,. Compound (73) then undergoes further nucleophilic substitution by azide ion to give the unstable
bis-azide (74), which, on elimination of HN,, yields the
thermodynamically most stable trans-a-azidovinyl ke-
-
R'
cis-(71)
%-I
Ph-CO
'H
(80)
Unlike in the case of (70), treatment of the dibromides
of a$-unsaturated esters (e.g. cinnamate dibromide)
"rw"
R-CO
0
N"C-Ph
I . N1@
2. HNI
R - CO- C H B r - CHN,- R'
"la
R-y'
,C-C€1,
N,
i 73)
0
"kR'
0
R-CO
H
(72)
$rans-(71)
*
0
0
f 75)
[35] a) W. A. Kusmin and S. G. Friedmann, Mem. Inst. Chem. Ukrain.
Akad. Sci. 2, 55 (1935); German Edlt. 5 6 6 (1935); Chem. Abstr. 31,
46605 (1937); b) W. A. Kusmin and N. 1.Semliansky, ibid. 2,183,191
(1935); German Edit. 2, 190, 194 (1935); Chem. Abstr. 31, 3467l
(1937);~)W A. Kusmm and N. 1.Sernliansky,ibid. 3,61(1936);Chem.
Abstr. 31, 497a9 (1937); d ) s. G. Friedmann, ibid. 3,587 (1936); Chem.
Abstr. 31, 78614 (1937).
[36] a) G. L'abbe, M. J. Miller, and A. Hassner, J. Amer. Chem. SOC.
in press; b) G. L'abbe and A. Hassner, J. Org. Chem. in press.
A n g e w . Chem. infernar. Edit. / Vol. 1t7 (1971) / N o . 2
with NaN, gives a mixture of a- and @-azidovinyl
esters'371.Similar results are obtained with the corresponding iodine azide a d d u c t ~ [ ~Thus
~ ] , (81) reacts with
One
Of NaN3 in DMF to give, among Other
products (such as an azirine), both regioisomers (82) and
[37] G. L'abbe, M. J. Miller, and A. Hassner, Chem. and Ind. 1970,
1321.
103
(83). Typically, when the reaction is carried out with an
excess of NaN,, (82) is formed first but isomerizes in
the presence of NaN, to the more stable trans isomer
(84). Dehydroiodination of (81) with DABCO leads to
the P-azidovinyl ester (82)
N3
MeOOC H N3
(81)
MeOOC
Ph
(82)
mx
Ph
)!'?
>=(
MeOOC
H
HN
(83)
(90)
EtOOC
On treatment of the erythro-dibromide of cinnamic acid
(85) with NaN,, CO, evolution occurs and cis-P-bromostyrene (86) is ~ b t a i n e d [ ~ ~ * ~ ~ I .
The use of azidoacetophenone instead of (87) led to the
synthesis of a-azidochal~ones[~~]
for which a trans structure [(76), R = phenyl, R = aryl] was proven in other
~ o r k [ ~In~ ~contrast
l.
to the a-azidocinnamates (89)
which decompose thermally to indoles
the aazidochalcones (76) rearrange on thermolysis to a-keto
phenylacetonitriles (92)[421.
Ph-CO-C=CH-Ph
I
N3
I 764
The examples cited above clearly indicate that the three
pathways leading to a-azidovinyl ketones in high yields
are not convenient for the synthesis of a-azidovinyl esters.
A series of a-azidocinnamates (89) were prepared
recently[39]by the condensation of azidoacetate (87) with
substituted benzaldehydes (88) in the presence of sodium
ethoxide. In order to minimize the well known base-induced decomposition of the a-azidoester (87)["1, the reactions must be carried out under well defined conditions
of temperature and time. Although the trans- configuration of (89) is to be expected on thermodynamic
grounds, the NMR method proposed for the configurational assignment in these systems has been critici~ed[~~"].
104
A
Ph-CO-CH-Ph
I
CN
(911
This work was supported by the NationalScience Foundation, the U.S. National Institutes of Health, and the
Petroleum Research Funds of the American Chemical
Society. G. L 'abbe' is indebted to the "Nationaal Fonds
voor Wetenschappelijk Onderzoek, N.F. W. 0.Belgium''
for a postdoctoral fellowship.
Received: May 19, 1970 [A 802 IE]
German version: Angew Chern. 83.103 (1971)
[38] K. A. N. Rao and P. R. Venkataraman, 3. Indian Chem. Soc. 15,
194 (1938).
[39] H. Hemetsberger, D. Knittef, and H. Weidmann, Monatsh. Chem.
100, 1599 (1969).
[40] J. H. Eoyer and F. C. Canter, Chem. Rev. 54,30 (1954).
[41]D. Knittel, H. Hernetsberger, and H. Weidmann, Monatsh. Chem.
101, 157 (1970).
[42] D. Knittei, H. Hemetsberger, R. Leipert, and H. Weidmann, Tetrahedron Lett. 1970, 1459.
Angew. Chem. internat. Edit. / Vol. 10 (1971) / N o . 2
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