Synthesis of w-Bromo Ketones
J . Org. Chem., Vol. 42, No. 10, 1977 1709
S u p p l e m e n t a r y M a t e r i a l A v a i l a b l e . (1)T h e f i n a l atomic positions a n d temperature factors for isotetrahydroanemonin (15), a n d t h e f i n a l atomic positions a n d temperature factors f o r d i - a - m e t h y leneanemonin (4b) (Tables 1-4); (2) supplements t o Tables I, 11,VII, a n d VIII, w h i c h l i s t t h e b o n d lengths a n d angles involving hydrogen atoms in 15 a n d 4b; (3) Tables IV, V, VI, VII, VIII, X, XI, XII, a n d XIII, w h i c h are mentioned in t h e text; a n d (4) Figures 2 , 4 , 5 , a n d 6 mentioned in t h e t e x t (15 pages). Ordering i n f o r m a t i o n is given o n any c u r r e n t masthead page.
References a n d Notes (1)
(2)
(3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16)
S.M. Kupchan, M. A. Eakin, and A. M. Thomas, J. Med. Chem., 14, 1147 (1971), and references cited therein. (a) I. L. Karle and J. Karle, Acta Crystallogr., 20, 555 (1966); (b) H. H. Wassermann, R. M. Waters, and J. E. McKeon, Chem. lnd. (London). 1795 (1961); (c) J. E. Harris, Ph.D. Thesis, Brown University, Providence, R.I.. 1958. H. Kataoka. K. Yamada, and N. Sugiyama, Bull. Chem. SOC.Jpn., 38, 2027 (1965). P. Camps, J. Font, and J. M. Marques, Tetrahedron, 31, 2581 (1975). E. H. Rodd, Ed., "Rcdd's Chemistry of Carbon Compounds", Vol. 11, Part A, American Elsevier, New York, N.Y., 1953, p 68. Y. Asahina and A. Fujita, Acta Phytochim., 1, 1 (1922). Beilstein's Handbuch Organische Chemie, Vol. 19, 2nd ed, p 181. S. M. Kupchan, R. J. Hemingway, D. Werner, and A. Karim, J. Org. Chem., 34, 3903 (1969). H. B. Wood, Cancer Chemother. Rep., 2,9(1971); S. G. Yates, H. L. Tookey, J. J. Ellis, and H. J. Burkhardt. 7, 139 (1968). V. Zikan, M. Semonsky, and V. Jelinek, Collect. Czech. Chem. Commun., 34, 2157 (1969); V. Zil.tan, L. Vrba, B. Kakac, and M. Semonsky, ibid., 38, 1091 (1973). C. Grundmann and E. Kober, J. Am. Chem. SOC.,77,2332 (1955). Y. Asahina, Arch. Phtirm. (Weinheim, Ger.), 253, 590 (1915); 10, 1520 (1916). J. M. Conia and J. M. IDenis, TetrahedronLett., 2845 (1971); J. M. Denis, J. Champion, and J. VI, Conia, Org. Synth., 53, 158 (1973). G. A. Howie, I. K . Steimos. and J. M. Cassady, J. Med. Chem., 19, 309 (1976). J. S.McKechnie and I. C. Paul, J. Am. Chem. SOC.,90,2144 (1968). S. H. Kim, G. A. Jeffery. R . D.Rosenstein, and R. W. R. Cornfield, Acta
Crystallogr., 22, 733 (1967). (17) G. A. Jeffery. R. D. Rosenstein, and M. Flasse, Acta Crystallogr., 22, 725 (1967). (18) J. D. M. Asher and G. A. Sim, J. Chem. Soc., 1584 (1964). (19) T. A. Dullforce, G. A. Sim, and D. N. J. White, J. Chem. SOC.6, 1399 (1971). (20) J. D. M. Asher and G. A. Sim, J. Chem. SOC., 6041 (1965). (21) D. F. Koenig, C. C. Chiu, 8. Krebs, and R. Walter, Acta Crystallogr., Sect. 8, 25, 1211 (1969). (22) H. M. Berman. R . D. Rosenstein, and J. Southwick, Acta Crystallogr., 27, 7 (1971). (23) J. Hvoslef, Acta Crystallogr., Sect. 6, 28, 916 (1972). (24) J. Fridrichsons and A. McL. Mathieson, Acta Crystallogr., 15, 119 (1962). (25) J. A. Hamilton, A. T. McPhail. and G. A. Sim, J. Chem. Soc., 708 (1961). (26) M. UI-Haque. D. Rogers. and C. N. Caughlan, J. Chem. SOC.,Perkin Trans. 2,223 (1974). (27) M. Currie and G. A. Sim, J. Chem. SOC.,Perkin Trans, 2,400 (1973). (28) H. D. Burgi, J. D. Dunitz, and E. Shefter, Acta Crystallogr., Sect. 6, 30, 1517 (1974). (29) A. T. McPhail and G. A. Sirn, J. Chem. SOC.8, 198 (1971). (30) Mazhar-ul-Haque and C. N. Caughlan, J. Chem. SOC.8, 355 (1967). (31) Mazhar-ul-Haque and C. N. Caughlan, J. Chem. SOC.8,956 (1969). (32) D. G. Leppard, M. Rey, A. S.Drieding, and R. Grieb, Helv. Chim. Acta, 57, 602 (1974). (33) A. T. McPhail and K. D. Onan. J. Chem. SOC., Perkin Trans. 2, 496 (1974). Perkin Trans. 2, 459 (34) P. J. Cox, G. A. Sim, and W. Herz, J. Chem. SOC., (1974). (35) M. Sundararaman and R. S. McEwen, J. Chem. SOC., Perkin Trans. 2, 440 (1974). (36) P. J. Cox and G. A. Sim, J. Chem. SOC.,Perkin Trans. 2, 1359 (1974). (37) R. B. VonDreele. G. R. Pettit, G. M. Cragg, and R. H, Ode, J. Am. Chem. SOC., 97,5256 (1975). (38) I. L. Karle and J. Karle, Acta Crystallogr., 20, 555 (1966). (39) C. N. J. White and G. A. Sim, Tetrahedron, 29, 3933 (1973). (40) A. Diels. Justus Liebigs Ann. Chem., 486, 219 (1931). (41) R. S.Urban, Chem. Absb., 49, 11695c(1955). (42) H. S.Booth. Ed., "Inorganic Syntheses", Voi. I, 1st ed, McGraw-Hill, New York, N.Y., 1938. (43) The X-Ray System, Version of June 1972, Update April 1974. Technical Report TR-192 of the Computer Science Center, University of Maryland, June 1972, was used for all crystallographic computations reported.
Synthesis of w-Bromo Ketones' Herbert 0. House,* Chia-Yeh Chu, William V. Phillips, Trevor S. B. Sayer, and Cheuk-Chung Yau School of Chemistry, Georgia I n s t i t u t e of Technology, A t l a n t a , Georgia 30332 Received October 20,1976 Various m e t h y l ketones 8,9,21,24,26,27,34, a n d 54 containing t e r m i n a l v i n y l groups have been synthesized by regiospecific alkylations o f m e t a l enolates w i t h a l l y l bromide, by t h e conjugate a d d i t i o n o f (CHz=CH)&uLi or CHz=CHMgBr w i t h M e l S C u B r as a catalyst t o enones, and by other procedures. T h e light-catalyzed radical-chain a d d i t i o n o f HBr in pentane solution t o these olefinic ketones constituted a n efficient m e t h o d f o r t h e synthesis o f w-bromo ketones 40-47 a n d 55.
We were intereste'd in preparing a group of w-bromo ketones of the type 1 a13 substrates for use in studying the behavior of the related carbon radicals 2 and the enolate anions 3 (Scheme I). The vinyl ketones 4 appeared to be particularly attractive precursors for such bromo ketones 1 since these olefinic intermediates 4 were readily accessible either by regiospecific alkylation of a preformed lithium enolate 5 with an allyl halide2 or by the conjugate addition of lithium divinylcuprate (or its equivalent) to an enone 6.334 P r e p a r a t i o n of t h e Olefinic Ketones. In the present study we utilized the ketone 7,from a previously describedza regiospecific alkylation, and prepared the a-allyl ketones 8 and 9 by allylation of the enolates 9 and 10 (Scheme 11).We also utilized a regiospecific alkylation of the enolate 10 to obtain precursors 1g-18 of the bromo ketone 19, a lower homologue of the bromo ketone system 1. The precursor 21 for a second lower homologue of the bromo ketone 1 was obtained by the previously described5 reaction of the acid 20 with MeLi. T o obtain a precursor for a higher homologue of the
Scheme I
I I I t
BrCH2CH2C-c-~0~~, 1 I
I
I
BrCH2CH2C-c
I I
l
I
p-
1 1 11
'CH2 CH,C-C-COCH, 2
M+
l
C-cH,
I
I
r CH,=CHCH,Br
/
5
6
I
I
4
Q- M+
CH,CO-C=C,
I
I
3 CHJ-c=C, I
I
I
CH,=CH-C-C-COCH, 11
/
(CH,=CH),CuLi
t
1
1710
J . Org. Chem., Vol. 42, No. 10, 1977
House, Chu, Phillips, Sayer, and Yau Scheme I11
30
I
(CH2=-CH)&uLi or CH2=CHMgBr + MeZSCuBr
+
I I CH,=CHCHZCIICOCHj 8
fr
CHz=CHCH,C(CHJ,COCH, 9
CH $;
\..
Br,
0-M f
COCH, O E r 26 L k H z
;iF'H
7 4 -
Br,
t-Bu H CH=CHz 27a, axial CH,CO group b, equatorial CH,CO group HO-$!(CH,)CH=CH,
O-Ll+
I
NaH
I
Ph-CH=C-CH, 9a, M = L
13
I
(CH2-;CH)iCuLi or C H F C H M g B r Me,SCuBr
PI1
PhCHzCOCHj
31
(CHJzC=C--CHj 10
b, M = N a
t
MeLi
OCOCH,
Ph
I CH,CWCH,CH=CH,),
I
Ph-CH=C-CH,
14
PhCH20CHzCI
OCOCH
+ 10
t-Bu
I (CHJ,C=C-CH,
11
36
12
-* PhCH20CH2C(CH,),COCH,
-
15 --+
\MeLi
16
ROCH,C(CH ),C'OCH, BrCH,C(CH,),COCH, 17, R = H 19 18, R = C-H-SO, CH*=CHC(CH&ZCO--R
CH=CH2
&-
20, R = O H Zl, R = C H 3
FH3
1 C1-Iq=CHCH2MgBr
CH,CH=CHCOCH
HO
Et20
CH3CH=CH2-C-OH
I
CHz=CH-CH2
22 heat
CH,CH-CH-COCHi
I
CH-CHZ H
1
CHZ-CH-
CHj
25
bromo ketone 1, the known dienol 236 was subjected to an oxy-Cope rearrangement7 to obtain the unsaturated ketone 24.
In a previous studyIh the unsaturated ketones 26 and 27 (Scheme 111),also characterized as their ketals 28 and 29, had been obtained by the conjugate addition of (CH2=CH)zCuLi to the enones 30 and 31. The same procedure had been used3a to obtain the ketone 34 from the enone 35. During the course of this work, the commercial solutions of CHz=CHLi in T H F were removed from the market leading us to explore the use of the more easily prepared CH,=CHMgBr with a copper(1) catalyst4 in place of (CHZ=CH)zCuLi. We found the use of a T H F solution of CHz=CHMgBr with the complex, M e ~ S - c u B r as , ~ a~ catalyst to be an effective substitute for (CH2=CH)ZCuLi in the preparation of ketones 2 6 , 2 7 , 3 4 , and 54 provided that the temperature of the reaction solution was maintained at -30 to -40 "C so that the vinylcopper derivative did not undergo thermal de~omposition~g,~,8 before reaction with the enone could occur. Preparation of the w-Bromo Ketones. In an earlier stuthe unsaturated ketone 37 (Scheme IV) had been con-
CH=CH~
32
(CH,),C=CHCOCH,
29
&QH,
CH=CHz
t-Bu
H
H
H 33
Ck2-CHMgBr+CHz=CHC(CH3),CH2COCH~
(CH =CHLCuL or
+ Me,SCuBr
CHiT:r:Br* -- - -
CH,CH=CHCOCH, 22
24
+ 22 +
t.Bu
35
23
CH =:CHCH,CH(CH,)CH,COCH,
+
H
28
34
CH,-CHCH(CH,)CH,COCH,
54
-
verted to the bromo ketone 38 by the reaction sequence unsaturated ketone 37 unsaturated ketal alkylborane primary alcohol mesylate primary alkyl bromide 38. In exploring an analogous sequence with the ketals 28 and 29, we were plagued by the tendency of the hydroboration-oxidation product 39a to undergo trans ketalization forming ketal 39b and related materials. For this reason, we concluded that a more efficient route for the conversion, RCH=CH2 RCH2CH2Br,was clearly required. Accordingly, we were led to consider the addition of anhydrous HBr in a free-radical chain process. Although this reaction seems only rarely to have been applied to molecules containing both a terminal CH=CH2 group and a second functional group? it was not apparent that a ketone function would interfere with this reaction if conditions were chosen that would minimize the tendency for the ketone to be present in equilibrium with its enol form. This expectation has proved to be correct. When anhydrous HBr gas was passed through pentane solutions of the various unsaturated ketones 7 , 8 , 9 , 2 1 , 2 4 , and 34 and the mixtures were irradiated with light from a medium pressure Hg lamp, the addition reactions were complete within 5-10 min and practically quantitative yields of the crude bromo ketones 40-45 were obtained. After purification by distillation or column chromatography, the pure bromo ketones 40-45 were obtained. Neither 1H NMR nor I3C NMR measurements gave any indication that these products were contaminated -+
J . Org. Chem., Vol. 42, No. 10, 1977 1711
Synthesis of o-BromNo Ketones Scheme IV
Scheme V H I
CH ,
CH,
37
38 CH3
CH\c/O,l
J J
'ON
R
,
H
R
CH,CII,OH
CH=CH2
I
H
28,R=H 29, R = t-Bu OCH.CH20H
26, R 27, R
05)
= =
46, R = H 4 7 , R = t-Bu
H
t-Bu H. atetraction 1.1
CH-CH,
I
Br 48a, R = H b, R = t-Bu
Br. pentane
39b
3%
CH,=CHC(CH,),COCH,
HBr, hu
pent an^
BrCH,CH,C(CH,),COCH,
21
40
HBr, hu
CH,=CHCH*C( CH ),COCH, pentane BrCH,CH,CH,C(CH&COCHj 9
50
51
41
CH2=CHC(CH,),CH2COCH, 34
HBr,
hy
pentane
Ph
I
CH2=CHCHFHCOCH
HBr, hu
~
8
"
BrCH,CH,C(CH,),CH,CC)CH,
pentane or hexane
42
Ph
I
HBr. hv
pentane
7
~H,-cH~B~ 52, R = H 53, R = t-Bu HBr, H,O IHF
46 o r 47
54
BrCH,CH,CH&H(CH,)CH,COCH, 0
CH2CH=CH2
H
43
44
0
H CH=CH2 28, R = H 2 9 , R = t-Bu
BrCH,CH,CH,CHCOCH,
CH,=CHCH,CH(CH,)CH,COCH, 24
H*R
CH,CH,CH,Br
45
with the isomeric secondary alkyl bromides (the products expected from addition in the Markownikoff sense). In our initial studies of this free-radical addition where hexane was employed as the reaction solvent, we were constantly troubled by the instability of the crude bromo ketone products. The crude products rapidly turned black when warmed or allowed to stand at 25 OC. We were able to demonstrate that this rapid decomposition was not attributable to an inherent instability of the bromo ketones but rather to minor impurity formed in the reaction from an impurity in the hexane. Although our identification of this reactive impurity is tentative, we believe that it may be PhCH2Br formed from the small amounts of PhCH3 impurity in the hexane solvent. When the reaction conditions used successfully for HBr addition to form bromo ketones 40-45 were applied to the unsaturated ketones 26 and 27 (Scheme V) we were puzzled to find that the crude bromo ketone products 46 and 47 were again unstable and rapidly darkened on storage or distillation. The l H NMR spectra of each of these crude products contained two sets of extraneous signals, a doublet at 6 1.66-1.68 (J = 7 Hz, CH3) and a multiplet at 6 4.23-4.26, an appropriate location for a X H B r grouping. A product with the same NMR spectrum as this contaminant was obtained when the unsaturated ketone 26 was allowed to react with aqueous 48% HBr. Thus, we conclude that the contaminants formed along with the bromo ketones 46 and 47 are the secondary bromides 48 (ca. 5%of the product from ketone 26 and ca. 20-30% of the product from ketone 27). These same minor contaminants 48
BrCH2CH2CH(CH,)CH,COCH,+ CH,CHBrCH(CH,)CH,COCH, 55
56
were also present in bromo ketones 46 and 47 formed by the light-catalyzed addition of HBr in pentane to the ketals 28 and 29 followed by hydrolysis of the ketals 52 and 53. Consequently, the presence of a ketone function is not responsible for the formation of the by-products 48. A variety of additional experiments in which special care was taken to ensure anhydrous reactants and in which small amounts of HzO were deliberately added had little influence on the amount of the by-product 48 that was formed. Therefore, we concluded that the by-products 48 were also being formed by a free-radical process. Since the unsaturated ketones 26 and 27 differed from the other ketones studied ( 8 , 9 , 2 1 , 2 4 , 3 4 ) in containing a tertiary allylic CH grouping, we were prompted to consider the possibility that reaction of the ketones 26 and 27 with a Br atom resulted not only in addition of this radical to form precursors of the primary bromides 46 and 47 but also in H atom abstraction to form the allylic radicals 50. Further reaction of these allylic radicals 50 to abstract an H atom from the excess HBr could form the isomeric olefins 51 that would yield the secondary bromides 48 upon addition of HBr in a radical chain process. There are reported examples'O of just this type of isomerization in other studies of the free-radical addition of HBr to terminal olefins. To provide additional evidence that the presence of tertiary allylic CH bonds in ketones (which would enhance the stability of the allylic radicals 50) favor this side reaction leading to secondary bromide by-products, we also examined the addition of HBr to the ketone 54 (Scheme V), an acyclic system that also contains this structural feature. Upon lightcatalyzed addition of HBr, the expected bromo ketone product 55 again contained ca. 5% of a contaminant believed to be the secondary bromide 56. In these cases, the small amounts of secondary bromide impurities 48 and 56 could be readily separated from the desired primary bromides by chromatography on silica gel.
1712 J . Org. Chem., Vol. 42, No. IO, 1977
House, Chu, Phillips, Sayer, and Yau
27a (7.8 min) and 27b (11.0 min) accompanied by minor amounts of the stereoisomeric ketone 32 (8.8 min) and the starting enone 31 (9.6 rnin)]. Distillation afforded 4.61 g of pure ketone 27, bp 98.5-99 O C Preparation of the Ketone 34. A. With (Vinyl)2CuLi.12 T o a cold (1.3 mm), nz5D 1.4720 (lit.3hnZ5D1.4728),accompanied by 3.53 g (total (-35 "C) solution of (vinyl)&uLi, prepared by the addition (dropwise yield 8.14 g or 81%) of less pure fractions [bp 94-98.5 "C (1.3 mm)] all with stirring a t -50 to -65 "C during 15 min) of 270 mL of a T H F of which could be used for the subsequently described fractional solution containing 0.433 mol of vinyllithium (Alfa Inorganics) to a crystallization. solution of 45.2 g (0.220 mol) of MeZSCuBr in 100 mL of MezS and In a similar experiment where the order of addition was changed 100 mL of EtzO, was added, dropwise with stirring during 20 min, a so that the vinyl-MgBr from 10.4 mg-atoms of Mg was treated with solution of 20.0 g (0.200 mol) of ketone 35 in 20 mL of Et20 while the 0.4 mmol of MezSCuBr followed by 5.0 mmol of the enone 31, the temperature of the reaction mixture was maintained a t -20 to -35 crude product contained (NMR analysis) ca. 25% of the alcohol 36 and "C. The resulting mixture was stirred for 1 h while it was allowed to ca. 75% of the ketones 27 and 32. Employing this same order of addiwarm to room temperature and then the mixture was filtered and tion with 30 mol % (based on the enone 31) of the MezSCuBr catalyst, partitioned between Et20 and an aqueous solution (pH 8) of NH:, and the crude product contained ca. 10% alcohol 36 and ca. 90% of the NH4C1. The organic solution was washed successively with aqueous ketones 27 and 32. Further increases in the mol % MeZSCuBr used NH3 and with aqueous NaCl and then dried and concentrated. diminished the content of alcohol 36 in the crude product but inFractional distillation of the residual yellow liquid (63.4 g) separated creased the amount of enone 31 recovered. Standardi~ation'~ of 18.06 g (72%) of the ketone 34, bp 55-62 "c (13 mm), nZ5D1.4307 [lit. ~ n Z o ~ various T H F solutions of vinyl-MgBr indicated that the typical yield bp 45-50 "C (30 mm),13a69-71 "C (45 mm),13bn Z o1.4375,13a in this Grignard reagent preparation was 80-85% based on the Mg 1.430513b]that contained (GLC, silicone SE-30on Chromosorb P) the used. Using standardized vinyl-MgBr reagent and the optimim inketone 34 (retention time 4.0 min) accompanied by a small amount verse addition procedure, the molar proportions 1.0 mol of enone 31, (
