981
On the Synthesis of a-Azidovinyl Ketones. Mechanism and Stereochemistry of Vinyl Bromide Substitution’ Alfred Hassner,* G . L’abbi, and M. J . Millerlb
Contribution from the Department of Chemistry, University of Colorado, Boulder, Colorado 80302. Received April 3, 1970 Abstract: A general method for the synthesis of a-azidovinyl ketones (3) involves the reaction of the dibromides of a$-unsaturated ketones with 2 equiv of sodium azide in DMF at room temperature. Although in most cases the reaction proceeds cia an a-bromovinyl ketone intermediate 2, the conversion of 2 to the vinyl azide 3 does not involve an SN2-type displacement. A detailed mechanistic study of the reaction, using nmr techniques, reveals that erythro-ethylideneacetophenone dibromide (la) reacts mainly through pathway 1 + 2 -+ 7 -+ 8 -P 3, whereas erythro-benzylideneacetophenone dibromide (lb) and erythro-benzylideneacetone dibromide (IC) react by both pathways: 1 + 2 + 3 and 1 -+ 2 + 7 ---t 8 3. Under the same reaction conditions nteso-1,2dibenzoylethylene dibromide (13) gives the isoxazole (15) exclusively. Finally, a trans configuration is assigned to the a-azidovinyl ketones on the basis of stereochemical arguments. -+
M
ore than 3 decades ago, Kusniin, Friedmann, and Semliansky ’ reported the conversion of dibromo ketone 1 to an azidovinyl ketone and concluded, on the basis of saponification, hydrolysis, and oxidation experiments, that the azido group occupies the a position (i.e., 3). Since its description in 1935 the reaction 1 -+ 3 has apparently not been investigated further, although it could constitute an excellent method for the synthesis of a-azidovinyl ketones (3). Our interest in the chemistry of azides, in particular of vinyl a ~ i d e s led , ~ us to an investigation of this synthetic sequence. We were able to show that the conversion 1 3 is general and to confirm the a-azidovinyl structure 3 (R = Ph, R ’ = Me) by nieans of ninr (see Discussion). There are several possible pathways for the transformation 1 3. A likely mechanism involves s N 2 displacement of bromide by azide ion, since the a-carbon in 1 is activated by the carbonyl group, followed by elimination of HBr. Alternately HBr elimination from 1 should lead to a-bromovinyl ketone 2, which niay undergo conversion to 3 by various pathways.4
-
l\
/ 3
RC-C=CHR’
It
0
I
Br
Recently, Nesnieyanov and Rybinskayaj developed a niethod for the synthesis of P-azidovinyl ketones (5) by treating P-chloro- (or bromo-) vinyl ketones (4) with PhCOCH=CHBr
+ NaN3 --+It011
4
5
sodium azide. Their studies led them to conclude that this nucleophilic substitution proceeds predominantly with retention of configuration about the C=C bond. This reaction undoubtedly involves conjugate addition of azide ion to the Br-carrying carbon of the a,P-unsaturated ketone. If a similar process were operating on the regioisoniericGa-broniovinyl ketone 2, then addition of N,- rather than substitution of Br- niay be expected. These considerations led us to a detailed mechanistic and stereocheniical study by nnir of the conversion 1 3 and 2 3.
+.
-
Results and Discussion By chosing ethylideneacetophenone dibromide 1 ( R = Ph, R ’ = Me) as a substrate we were able to confirni by nnir that the reaction of sodium azide with the dibromide 1 leads to the formation of an a-azidovinyl ketone 3. The product 3 (R = Ph, R ’ = Me) obtained in ca. 90% yield (for an improved general procedure, see Experimental Section) shows a coupling constant JxfcHof 7 Hz in its ninr spectrum. The magnitude of this coupling constant is consistent with a structure having both H and Me groups in a geminal position. The regioisonieric azidovinyl ketone 6 should exhibit a coupling constant J M between ~ ~ 0~and 2 Hz.
2 (1) (a) Stereochemistry. LVII. For the previous paper, see A . Hassner and V. R. Fletcher, Tetrahedron Lett., in press; (b) National Science Foundation Undergraduate Research Participant, 1968. (2) W. A. Kusmin and S. G. Friedmann, Mem. I n s t . Chem. Ukraiiz. Akad. Sci., 2, 55 (1935); Chem. Absrr., 31,46605 (1937); W. A. Kusmin and N. J. Semliansky, M e m . I n s t . Chem. Ukrain. A k a d . Sci., 2, 183, 191 (1935); Chem. Abstr., 31, 34671 (1937); M e m . Inst. Chem. Ukrain. A k a d . Sci., 3, 61 (1936); Chem. Abstr., 31, 49789 (1937); S . G. Friedmann, M e m . Inst. Chem. Ukrain. A k a d . Sci., 3, 587 (1936); Chem. Abstr., 31, 78614 (1937). (3) F. W. Fowler, A . Hassner, and L. A . Levy, J . Amer. Chem. SOC., 89, 2077 (1967); A . Hassner and F. W. Fowler, J . Org. Chem., 33, 2686 (1968). (4) For the behavior of amines with ol,P-dibromo ketones and with a-bromo-a,P-unsaturated ketones, see N. H. Cromwell, Chem. Rev., 38, 83 (1946).
PhCOCH=CHN3
at1
Me
PhCOCH=C
/
\
N3
6
We also discovered that the a-azidovinyl ketones (3) are readily prepared by treating a-broniovinyl ketones (2) with a mixture of 2 equiv of sodium azide and 1 equiv of hydrobromic acid in D M F at room teniperature. Furthermore, 2 are internlediates in the conver(5) Review: M. I. Rybinskaya, A . N. Nesnieyanov, and N. K . Kochetkov, Rum. Chem. Reo., 38, 961 (1969). (6) Regio is used to describe dirCctional preference i n bond making or breaking: A . Hassner, J . Org. Chem., 33, 2684 (1968).
Hassner, L’abbP, Miller 1 Vifiyl Bromide Substitittion
982 Table I. “r Data (7 Values)”
Scheme I RCOCHN3CHBrR’ 9
Compd
1.8-2.1(m,2H),2.3-2.6(m,3H),4.55(d, lH,
la
RCO
J = 10.5 Hz), 4.95-5.5 (octet, 1 H), 7.95 (d, 3H,J=7Hz) 1.9-2.15(m, 2 H ) , 2.2-2.7(m, 3 H ) , 3 . 5 2 ( q , l H , J = 7 . 5 Hz), 8.35 (d, 3 H , J = 7 . 5 Hz) 2.2-2.7(m, 5 H), 3 . 1 0 ( q , 1 H , J = 6 . 5 Hz), 7 . 9 7 (d, 3 H , J = 6 . 5 Hz)
cis-2a truiis-2a RCOCHN,CHN , R 8
la
1.8-2.1(m,2H),2.3-2.7(m,3H),4,88(d,l H , J = 8.0 Hz), 5.5-6.1 (octet, 1 H), 8.65 (d, 3 H , J = 6 . 5 Hz) Cu. 5 . 0 ( d , l H ) , 5 . 2 - 5 . 5 ( m , 1 H ) , 8 , 6 0 ( d , 3 H , J = 7 Hz); since this compound has not been isolated in the pure state, the exact position of the phenyl absorption is unknown 1.8-2.1 (m, 2 H ) , 2.3-2.7(m, 3 H), 5.02 (d, 1 H, J=9.0Hz),5.5-6.1(m,lH),8.43(d,3H, J = 6 . 5 Hz) 2.15-2.7(m,5H),4.15(q,lH,7Hz),8.12(d, 3H,J=7Hz) 1.8-2.0(m, 2 H ) , 2.3-2.7 (in,8 H), 4 13 (d, 1 H , J = 1 1 . 5 H z ) , 4 . 3 8 ( d , l H , J = 11.5Hz) 1.9-2.4 (m, 4 H), 2.45-2.8 (m, 6 H), 2.87 (s, 1 H)
8a
9a
3a lb RCOCHBrCHN ,R’ 7
cis-2b trails-2b
[email protected](m,2H),2.3O(s,lH),2.35-2.7(m, 3H)
1.8-2.05(m,2H),2.3-2.7(m,3 H), 2.56(s, 5 H), 4.75 (broad s, 2 H) 2.1-2.3(m,4H),2.4-2.75(m,6H),3.53(~,1 H)
7b 3b cis-2c rrulls-2c
sion of vinyl ketone dibroniides 1 into a-azidovinyl ketones 3. The results obtained with several crythrodibromides la-c point to the general mechanism presented in Scheme I (nmr data are given in Table I), which involves the following three pathways: 1 + 2 + 3, 1 2 +7 8 + 3, and 1+ 9 4 3. In order to elucidate the mechanistic and stereochemical aspects, the reaction of 1 with sodium azide was stopped at different stages and the niiir spectra were recorded and analyzed. These studies were carried out with the bromine adducts of trans-ethylideneacetophenone (la), rrans-benzylideneacetophenone (lb), and trans-benzylideneacetone (IC);each system will be considered separately. eryrhro-Ethylideneacetophenone Dibromide (la). This conipound was allowed to react with 2 equiv of sodium azide in DMF at room temperature, to furnish a-azidoethylideneacetophenone (3a) in 91 % yield after a reaction time of 30 niin. When the reaction was worked up at different stages of the overall conversion, the nmr spectra showed four intermediates, which are consistent with the structures of the cis- and trans-vinyl bromides cis-2a and trans-2a, the bromoazide 7a, and the bisazide 8a (the T values are listed in Table I). The intensities of the ninr peaks increased at first and then decreased as the reaction progressed. The last intermediate to appear, after ca. 4 min when all the other intermediates were still present, was bisazide 8a. Since the first step in the observed reaction sequence involves elimination of HBr from l a by sodium azide, it was important to test the possibility of dehydrobromination with another reagent of similar basicity. Therefore l a was treated with sodium acetate under the same reaction conditions and 2a was isolated in 90% yield. The nnir spectrum, recorded immediately after work-up, showed both isomers in a &/trans ratio of about 80/20. A trans structure is assigned t o the minor product because its vinylic proton is shifted downfield -+
-+
Journal of the American Chemical Society
2 . 6 0 ( ~ , 5 H ) , 4 . 6 5 ( d1, H , J = 11.5 Hz), 5 . 1 0 (d, 1 H , J = 11.5 Hz), 7.53 ( s , 3 H) 2.00
