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A method for the transformation of cyclic ketones to homologous α,β-unsaturated ketones
Tetralmlron. Suppl. 8, Pan I, pp. 105412.
A METHOD
Permmon Press Ltd. Printed in Great Britain
FOR THE TRANSFORMATION
KETONES TO HOMOLOGOUS
OF CYCLIC
a&UNSATURATED
KETONES G.STORK, M.Nussm Department
and B. AUGUST
of Chemistry, Columbia University, New York, New York 10027 (Received 15 July 1966)
Abstract-The addition of dichlorocarbene to enol acetates of cyclic ketones can be carried out efficiently in many cases using the neutral trihalomethyl phenyl mercury reagents. Since en01 acetates of de&rite structures are readily prepared, the method provides a convenient first step to a ring enlargement sequence which can be carried out under basic conditions.
ONEofthe most interesting schemes for the expansion of acyclic ketone to a homologous enone involves the addition of dihalocarbenes to an enol ether derivable from the ketone.‘“,’ This scheme suffers, however, from a lack of generality caused by the difficulty of transforming an unsymmetrical ketone into a single enol ether of predictable structure. For instance, acid-catalyzed splitting of one equivalent of methanol from the dimethyl ketal of 2-methylcyclohexanone gives an equilibrium mixture consisting of 51 ‘A of I and 49% of II.2 The method is nevertheless of considerable value when enol ethers of known structures can be prepared, as for instance by Birch reduction of anisole derivatives. Conspicuous success has been achieved by Birch’” in the synthesis of tropone derivatives by this procedure (cf. III + IV). ?
OEt
OEt
5 - tY+6”’ Me
I
\ o-
Me
\
III
&e
-
II
0
(J I
-
\
IV
1 s A. J. Birch, J. M. H. Graves and F. StanfIeld, Proc. Chrm. Sec. 282 (1962); A. J. Birch, J. M. H. Graves and J. B. Siddall. J. Chem. Sot. 4234 (1963); ’ W.E. Parham. R. W. Soeder and R. M. Dodson, J. Amer. Chem. Sot. 84.1755 (1962); W. E. Parham, R. W. Soeder, J. R. Throckmorton. K. Kuncl and R. M. Dodson, Ibid. 87,321(1965). 2 A. House and V. Kramar, J. Org. Chem. 38,3362 (1963). 105
IQ6
G. !hDRK, M. Nusmt ANDB. Auousr
In order to circumvent some of the difficulties associated with enol ethers we considered the use of enamines, since we have shown that pyrrolidine enamines, e.g. of 2-substituted ketones, have a predictable structure. 3 Unfortunately, although we were able to obtain readily the adduct of morpholinocyclohexene with dichlorocarbene,a these rearranged thermally without expansion of the ring.
We then turned our attention to the possibility offered by enol acetates. These can be prepared readily5 and norma.lIy have at equilibrium the structure which corresponds to the more stable enol in the system. For instance, and in contrast with enol ether formation, the enol acetate derivable from 2-methylcyclohexanone has structure V.2 Furthermore, it is possible to prepare enol acetates corresponding to the less stable of the possible enols by making use of our specific enolate synthesis.6 This is illustrated for the two enol acetates corresponding to cholestanone. Enol acetylation
G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovin and R. Terrell, J. Amer. Chem. Sec. 85, 207 (1963). 4 Susan Ramseyer, Ph.D. Thesis, Columbia University (1962); cf. G. Stork, America Chemical Society, Absfracts of Meetkzgs p. 450 (1961) and J. Wolinsky, D. Chan and R. Novak, Chem. di Id 720 (1%5). 5 D. H. R. Barton, R. M. Evans, J. C. Hamlet, P. G. Jones and T. Walker, J. Chem. Sot. 748 (1954). 6 G. Stork, P. Rosen and N. Goldman, R. V. Coombs and J. Tsuji, J. Amer. Chem. Sot. 87, 275 (1965). 3
A method for the transformation
of cyclic ketones to homologous
c+msaturated
ketones
107
of 3-cholestanone produces the well-known D-enol acetate (VI).7 On the other hand, the ds-lithium enolate can readily be produced by the specific enolate synthesis,6 and its trapping by acetic anhydrides then produces the heretofore unreported dsenol acetate (VII). This substance has almost the same m.p. (88-90”) as its d2 isomer but, in addition to depressing its m.p. it is smoothly converted to &cholestenone by bromination, followed by lithium carbonate-lithium chloridedimethylformamide dehalogenation. The problem of synthesizing enol acetates of specific structures thus being essentially solved, we now consider the addition of halocarbenes to these substances. The main problem with this reaction is connected with the instability of enol acetates toward bases, thus precluding the use of haloform-t-alkoxide mixtures. Even the method involving the decomposition of the weakly basic sodium trichloroacetate has given only fair to poor yields with enol acetates.9 The recent introduction of the halomethyl mercury compounds as neutral halocarbene precursors10 appeared especially promising and we were gratified to find that many enol acetates give very good yields of adducts on heating with these reagents. For instance, heating the dz-enol acetate of cholestanone (VI) with phenyl bromodichloromethyl mercury in benzene gave 83 % yield of the anticipated dichlorocarbene adduct VIII, m.p. 135136”, while the isomeric d3-enol acetate (VII) gave the corresponding adduct IX, m.p. 183-184” in 72% yield.
Cl IX
Under the same conditions, the enol acetates of cyclohexanone, cycloheptanone and 2-methylcyclohexanone (V) were all converted to the corresponding dichlorocarbene adducts X, XI and XII in good yields. The case of the enol acetate of cyclopentanone is of some interest. Under the prolonged heating conditions we used, the initial adduct was unstable and rearranged largely to 2chlorocyclohexenone. The dihalocyclopropane derived from enol ethers can be rearranged either thermally or, when the halogens are bromine, with silver ion.l” It was expected that the acetoxy dichlorocyclopropanes described here would arrange readily under any conditions that would produce cyclopropanol anions from the acetates. The simplest procedure was tested with the dichlorocyclopropane adduct IX of 3-acetoxy-dscholestene: treatment of IX with ethanolic potassium hydroxide at room temperature for about a day gave the anticipated product of ring expansion, Schloro-A-homo-dSx-cholesten7 W. G. Dauben, R. A. Micheli and J. F. Eastham, J. Amer. Chem. Sec. 74,3852 (1952). 8 H. J. Ringold and S. K. Malhotra, J. Amer. Chem. Sot. 84,3402 (1962); cf. H. House et al. Ref. 2. 9 C. E. Cook and M. W. Wall, Chem. dr Ind. 1927 (1963); W. M. Wagner, H. Kloosterziel and S. van der Ven, Rec. Truv. Chim. 80.740 (1961). lo D. Seyferth, J. M. Burlitch, R. J. Minasz, J. Yick-Pui, H. D. Simmons, A. J. H. Treiber and S. R. Dowd, J. Amer. Chem. Sot. 87,4259 (1965).
108
G. STORK, M. NUWM AND B. AUGUST
3-one (XIII). This compound, m.p. 94-96” showed the expected high intensity” absorption maximum in the UV (254 rnp, E 13,700). The IR carbonyl stretching frequency at 1689 cm-l and the vinyl hydrogen as a doublet (3*82,3*93 T) in the nmr.
The ring homologation method now described would be more flexible if it could also be used to produce homoenones not having a halogen on the a-carbon. We considered two methods for accomplishing this. The first was to remove one of the halogens of the dichlorocyclopropane adduct+ in the anticipation that the acetoxy monochloro cyclopropanes would then rearrange with base directly to the halogen-free homoenones.
Unfortunately, although we were able to accomplish this selective reduction without involvement of the acetoxy group, the yield e.g. from VII to XIV was, in our hands, quite unsatisfactory. It can be anticipated that the well-known reduction of vinylic halides by metal and *I Compare 4-chlorocholestenoneAmu -256
mp,c 14,100: 0. N. Kirk, D. K. Pate1 and V. Petrow, J. Chem. Sot. 1184 (1956). 12 D. Seyferth, H. Yamazaki and D. L. Alleston, J. Org. Chem. 28,703 (1963).
A method for the transformation of cyclic ketones to homologous
a,/?-unsaturated ketones
109
ammoniats should be applicable to the chlorovinyl carbinols which are the expected products of the treatment of the acetoxydichlorocyclopropanes with LAH.14 We illustrate this process with the transformation of 2-acetoxy-2-methylcyclohexene (V) into 3-methylcycloheptenone (XVI).
OAc \
Me
_
@ze
_
&Me
_
b
xv
XII
OH
0
n
’ “,e XVI
The dichlorocarbene adduct (XII) produced, as mentioned previously, by the reaction of V with phenyl bromodichloromethyl mercury, was obtained in 85 % yield as an unstable substance, b.p. 60-62” (O-15 mm), exhibiting acetate absorption at 5-68 and 8.19 ~1quite similar to that of the starting enol acetate, but the methyl group hydrogens gave rise to absorption as a singlet at 8.78 T, definitely higher than the position of the allylic methyl group in the enol acetate (V) whose hydrogens give rise to a singlet at 850 7. Reduction with LAH in ether gave the chlorocycloheptenol (XV) in 73 % yield. Reduction with sodium in liquid ammonia to remove the halogen (negative Beilstein test), followed by oxidation with the chromic acid-acetone reagent, led to 3-methyl-2-cycloheptenone (XVI) in very good yield. The cycloheptenone appeared to contain a small amount of ,!3,y-isomer15 (- 12 %) as shown by VPC, and by the presence of a shoulder at 5.82 ~1in addition to the main carbonyl stretching peak at 6.02 CL.The UV of the pure compound showed typical absorption at 238 rnp (13NQ). In a similar manner the adducts X and XI from the enol acetates of cyclohexanone and of cycloheptanone were converted to cycloheptenone and to cyclooctenone. The ring expansion methods which have been described in this communication depend on the success of the initial dichlorocarbene addition. Although these additions take place readily in the unhindered cases reported here, there are indications that they can be adversely affected by certain steric environments: The enol acetate (XVII) derived from cedrene, did not react with phenyl tribromethyl mercury, presumably because of the strong steric hindrance between the methyl group on the cyclopropane and one of the gem-dimethyl groups in the eventual adduct (XVIIa) (and the transition state leading to it). I3 M. C. Hoff, K. W. Greenlee and C. E. Roord, J. Amer. Chem. Sm. 73,3329 (1951). I4 The formation of a-chlorohomocyclenols via the LAH reduction of dichlorocarbene adducts of cyclanone enol acetates has independently been observed by R. C. De. Selms, TerruhedronLetters 1965 (1966). IS For a recent discussion of CC&&y-equilibrium in cyclic unsaturated ketones, see. N. Heap and G. H. Whitham, J. C/rem. Sot. 164 (1966).
G. %l-ORK, M. NUSSIMANDB. Auciusr
110
OAc
XVila
XVII
EXPERIMENTAL 3-Acefoxy As-cholestene (VII). To a soln of 20 ml dried (over Na) and distilled liquid ammonia and 14 mg (2 mmole) Li was added a soln of 390 mg (1.01 mmole) A*-3cholestenone in 10 ml dry THF. At the end of the addition the blue color disappeared. The ammonia was evaporated and a soln of 1 ml AczO in 5 ml THF was added. After stirring for 45 min at room temp. water was added and the mixture extracted with ether. The ether extracts were washed with 5% NaHCOs aq. then with water, dried over NazS04 and evaporated. The residue (405 mg) showed IR absorption (CCL) at 5.70 p (enol acetate), and small peaks of saturated and unsaturated ketones at 5.83 and 5.98 p. Chromatography over 12 g of neutral alumina and crystallization from MeOH afforded 205 mg (47%) of VII, m.p. 88-90”. The IR spectrum of the pure compound had a single carbonyl absorption at 5.70 p (CCL) and was different from that of the A* isomer, m.p. 87-89”. The m.p. of a mixture of the two substances was depressed to 80-83”. (Found: C, 81.27; H, 11.52. Cak. for Ca9H4&: C, 81.25; H, 11.29%). The structure of the enol acetate was further con8rmed by bromination and dehydrobromination to A’-3cholestenone: To a soln of VII (50 mg) in 3 ml of a buffer soln (prepared by dissolving 1 g of anhyd AcONa in 80 ml glacial AcOH and 20 ml Ccl., 16 3 ml Br soln (0.3 ml Br in 50 ml buffer soIn) was added during 20 min. After 15 min stirring, water was added and the mixture was extracted with ether. The ether extracts were washed with 5% NaHCOs aq, then with water, dried, and evaporated. The residue (65 mg) showed absorption in the IR (CCl4) at 5.79 p indicating that the Br is equatorial. The bromo-ketone (65 mg) in 3 ml dimethylformamide was refluxed with 200 mg LisCOs and 200 mg LiCl for 4 hr.17 Extraction with ether gave crude ketone showing an unsaturated carbonyl band at 5.98 p and XEgH 241 rnp (c 13,200). Chromatography over alumina (3 g) and crystallization from MeOH afforded 21 mg A’-3cholestenone., m.p. 7678”, undepressed on admixture with an authentic sample. 3-Acetoxy AWtolestene (VI). This and other known enol acetates were prepared by Barton’s method.5 From 3cholestenone (1 g) in 30 ml AcOH containing 2 ml of AczO and 2 drops of 60% perchloric acid soln kept 6 hr at room temp we obtained 910 mg (82%) of VI, m.p. 92-94” (lit.7 m.p. 90-90.5) after chromatography on alumina and crystallization from ether-MeOH. Similarly, cyclehexanone gave 68% of acetoxycyclohexene b.p. 64-68” (12 mm) (lit.‘* b.p. 92” (34 mm)); 2-methylcyclohexanone gave 71% of V, b.p. 80-96” (12 mm) (lit. 19 b.p. 70” (6mm). All these enol acetates showed IR carbonyl absorption at _ 1754 cm-*. 2,3-Dichloromethylene-3-acetoxycholestune (VIII). To a soln of 1.75 g (4.0 mmoles) 3-acetoxyZcholestene in 10 ml benzene, 1.91 g (4.4 mmoles) phenyl(bromodichloromethyl)mercuty was added and the mixture. was refluxed with stirring for 48 hr. After standing at room temp for 4 days, it was filtered and the filtrate yielded 1.76 g (83%) product, m.p. 135-136” recrystallized from MeOHabs ether, A”::. 5.70 p. (Found: C, 70.52; H, 9.52. Calc. for CjeH+sOaClz: C, 70.42; H, 9.45%). 3,4-Dichloromethylene-3-ucetoxycholestune (IX). A soln of 700 mg of VII and 700 mg phenyl(bromodichloromethyl)-mercury in 20 ml purified cyclohexane was refluxed for 20 hr. The PhHgBr 16Cf. B. Berkoz, E. P. Chavez and C. Djerassi, J. Chem. Sot. 1323 (1962). R. Joly and J. Wamant, Bull. Sot. Chim. Fr. 357 (1958). I* R. J. P. Allen. J. McGee and P. D. Ritchie, J. Chem. Sot. 4700 (1957). 19 A. C. Cope, T. A. Liss and G. W. Wood, J. Amer. Chem. Sot. 79.6287 (1957). 17
A method for the tr~sfo~tion
of cyclic ketones to homologous
a&unsaturated
ketone-s
111
which precipitated during the reaction was filtered off and washed well with cyclohexane. It was recovered in 90% yield (570 mg; m.p. 284-286”). The filtrate was evaporated and the residue (750 mg was chromatographed on 25 g of alumina (Merck-acid washed). Ehation with 9: 1 pentane-benzene afforded IX in 72% yield (6%) mg, m.p. 181-183”). NMR showed cyciopropane hydrosn absorption at 9.65 T. (Found : C, 7@05; H, 9.63. Cak. for C&H4s02C12: C, 7@42; H, 9.45%). l-Aceroxy-7,7-diclrlorobicyclo(4.1 .O)hepfune (X). Cyclohexenol acetate (3M) g, 21.4 mmoles) and 11.80 g (27.2 moles) of phenyl(dichlorobromomethyl)mercury in 15 ml benzene under N after 18 hr of refluxing at 85”, filtzation and distillation gave 4.01 g (85%) of product, b.p. 6061’ (0.15 mm), ;\g$t 5.67, 8.21 p, VPC (SF 96/162”) one peak. The NMR spectrum (CCW showed peaks at 8.54, 840, 8.20, and 7.95 7 (5: 1: 2:4H). The product decomposes siowly on standing at room temp and in common with the following adducts, gave somewhat low carbon values. Found: C, 47.77; H, 5.42. Calc. for C9H&&Os: C, 48.47; H, 5.43%). l-~cetox~8,8-djc~~robicyc~~5.l.O)octa~e (XI). In a similar manner, l-65 g (10.7 mmoles) cycloheptenol acetate2 and 602 g (13-O mmoles) phenyl(dichlorobromomethyl)mercury in 20 ml benzene gave, after a 14 hr reaction, 1.85 g (72%) of product, b.p. 80” (@lo mm, Hickman still), AC22 5.65, 8.21 I(, VPC (SF 96,162”) one peak, NMR (CC14) 8.10-903,8,06,7.22-8.00 7 (9: 3: 1 H). The product is unstable. (Found: C, 49-85; H, 594. Calc. for C10H&l202: C, s67; H, 5*95’%). l-Acetoxy-6-merhyf-7,7-dichforobieycZ~4.l .O)hepifme (XII). In a similar manner, 3.00 g (19.5 mmoles) 2-methylcyclohexenol acetate and 10.71 g (24.8 mmoles) phenyl(bromodichlorometbyl)mercury in 15 ml benzene gave 3.32 g (85%) of product, b.p. -2” (0.15 mm), h$$ 5.68, 8.19 I*, VPC (SF 96, 132”) one peak, NMR (Ccl,) 8.78,8.53 (b), 8.18 (b), S+lO, 7.55-ET (3:4:2:3:2 H). The product is unstable. (Found: C, 49.89; H, 590. CU. for C~~H&120~: C, 5@65; H, 595%). 4-Chloro-A-homo-A~-5-claolesten-3-one (XUl). A soln of 200 mg IX in 5 ml pyridine and 10 ml EtOH containing 25 mg (N l-2 es) KOH, was stirred at room temp for 16 hr. Extraction with ether and chromatography on 10 g of silica gel afforded 28 mg (-IS’%) starting material (eluted with 4: 1 hexane-benzene) and 70 mg of XIII (50% based on material reacted), eluted with 1: 1 hexane-benzene. After crystallization from MeOH XIII had m-p. 94-96”. X,,, CC“ 1698 cm-i, I\z%H 254 rnp (C 13,700). The NMR showed the vinyl proton as a doublet (J=6 c/s) centered at 3.87 7. (Found: C, 77.78, H, 10.65. Calc. for C2sH4&Cl: C, 77.64; H, 10.47%). The chloroenone was reduced with Pd-C in AcOEt to A-homo_3cholestanone, m.p. 82-85” (reported20 m.p. 85-85.5”). Reduction of ~3dich~oro~t~yiene-3~cetoxyc~~st~e (VIII) with tributyl tin hydride to XIV. To a soln of 760 mg (1.48 mmoles) 2,3_dichloromethylene-3-acetoxycholestane in O-5 ml xylene kept refluxing under N at 140”, 495 mg (1.70 mmoles) tributyltin hydride was added over 30 min. After refluxing for 6 hr, NaF aq was added to the cooled reaction mixture which was stirred for 30 rnin to complete the pr~ipitation of the insoluble tributyltin fluoride. Filtration and removal of the solvent gave XlV, m.p. 152.5-153-S’ after recrystallization from MeOH-ether, /\zix 5.72. (Found: C, 75.45; H, 10.35. Calc. for C,oH4902Cl: C, 75.51; H, 10.35%). Reduction-rearrangement of acetoxydichlorocyclopropanes with lithium aluminum hydride. These reductions were all conducted as described below for the reduction of XII. 2-~h~oro-3-~thy~-2-~ycIohepte~ol (XV). A soln of 2.50 g of XII in 25 ml dry ether was added to 1.50 g LAH in 80 ml dry ether during 15 min. The mixture was refluxed for 2 brand excess hydride was then decomposed by the addition of sat Na2SO4 aq. Tbe ether layer was washed with water, dried and concentrated, and residue was distilled evaporatively to give 1.52 g (81%) of XV, b.p. 85” (l-3 mm), XE? 2*96,6*08,9-10 p several bands, WC (SF 96,162”) 91% pure, NMR (Ccl,) 8*25-8*43, 8.16, 7-80 (b), 6.75, 5.62 (3:4*5:3: 1: 1 H). The mass spectrum showed the parent peak at m/e= 160. An analytical sample was collected by gas chromatography. (Found: C, 60.26; H, 8.37. WC. for CsH&IO: C, 59.81; H, 8*16%). 2-Chloro-2-cyc/oheptenoenol.In a similar manner, 2.91 g of X gave 1.54 g (57%) f-chloro-2-cycleheptenol, b.p. 75” (@IS mm), A$,$:’ 291,6*09,9-10 p several bands, VPC (SF 96, 162”) single peak, NMR &Cl’) 8.20 (b). 7.92 fb), 7.37,5.72,4*10 (t) (6: 2: 1: 1: 1 H). An analytical sample was collected by gas chromatography. (Found: C, 57.61; H, 7.84. Calc. for CTHI~CIO: C, 57.34; H, 7.56%). 2-Chloro-2-cycloocteenol. Similarly, 1.70 g of XI gave 900 mg (78%) 2chloro-2cycloccteno1, b.p. 5 63” (0.10 mm. Hickman stil), hg:p 2.95,609,960 I*, VPC (SF 96,162”) one peak, NMR (CC13 20 N. A. Nelson and R. N. Schut, J. Amer. Chem. Sot. 81.6486 (1959).
112
G.
STORK,
M. Nussi~ AND B. Aucusr
7.10-9a20, 5.97, 573,4.15 (10: 1: 1: 1 H). An analytical sample was collected by gas chromatography. (Found: C, 59.08; H, 8.19. C&c. for CsH&lO: C, 59.81; H, 8.16%). Sodium -ummonia dehalogemztion, and oxidation to unsuturuted ketones. These processes were conducted as described below for the preparation of XVI. 3-~etky~-2~y~io~pte~ne (XVI). A soln of 1.03 g of XV in 2 ml dry ether was added to a soln of 900 mg Na in 25 ml liquid ammonia. The mixture was stirred for 1 hr, NH&l was then added, the ammonia was allowed to evaporate and the mixture was extracted with water and ether. The ether layer was washed with dil HCl aq, dil NaHCOs aq and tinally with water. After dryin and concentrating 762 mg (86%) of product, b.p. 85” (18 mm, Hickman stil), showing 5% close boiling impurity in p. A Beilstein test was negative for Cl. The crude ally& the VPC (SF 96,162”), 1\~$3.00,610,9-72 alcohol (419 mg) in 10 mf acetone was oxidized directIy with l-8 ml Jones m-age&t at 0”. After stirring for 20 min, the solvent was removed and the residue was extracted with water and ether. Work up aa usual gave 410 mg (88%) 3-methyl-2-cycloheptenone (containing some As-isomer, vide infiu), b.p. 106” (18 mm) (reported22 b.p. 81-82” (2-S mm)), h,,, cc” 6.02,582 p shoulder, VPC (SF 96,162”) 12% 3-methyl-3cycloheptenone, hggrr 236 rnp (6 11,550). A sample was collected by VPC and the semicarbazone, m.p. 198-201” (reported22 208-210’) was prepared. The first crystals obtained on crystallization of the red 2,4dinitrophenylhydrazone had m.p. 159-164”. Most of the derivative obtained had m.p. 137-139”, ,%zgrr 259, 383 rnp (c: 18,000, 31,700). (Found: C, 5498; H, 5.31. Calc. for C14HlaN10,: C, 5525; H, 5*30’/0). 2- and 3-Cyctbheptenone, Reduction of 2-chloro-2cycloheptenol and subsequent oxidation as described above gave an excellent yield of what proved to be a mncture of AZ- and AJ-cycloheptenone by VPC analysis (SF 96, 162’). The substance showed b.p. 60-70” (19 mm) (reported23 b.p. 73-74’ (11 mm)). The sample showed some absorption at 5.83 p in addition to the major absorption at 6.01 p (CQ). Nmr absorptions (CCb) werepresent at 8*22,7-51.4.30,4*10 and 360 in the ratio of 4:4: 1: 1 H. Some isomer~tion toward the ~ui~bri~ mixture of a& and /3,y-unsaturated ketones may have taken place before the UV spectrum was taken since it showed XzgK 230 mp, c 3575 which, although close to that reported by Braude et al. N (227 mp, e 4800), is lower than expected and a value of 228 rnp, E 10,060 has in fact been reported recently. 24b The semicarbazone, recrystaliized from EtOH showed an initial m.p. of 149-150” which rose on repeated crystallization to 156-158” (reporteda4~ for 3cycloheptenone: m.p. 155-156”). 2-Cyclooctenone. This was obtained in a similar manner to that described for 3-methyl-2-&oheptenone. The resulting cyclooctenone was purified by VPC (SF 96, 140”) and although it, like cycloheptenone, was a mixture of the a&3 and &y isomers as shown by the IR spectrum (5-86 and 6.02 p) is was mostly the former as evidenced by the high extinction in the UV at 230 rnp (reported hEzxH 230 rnp, c 7700).2s Acknowie&em.ent-This
work was supported in part by a grant from the National Science Foundation.
21 K. Bowden, I. M. Heilbron, E. R. N. Jones and B. C. L. Weedon, J. Gem. Sot. 39 (1946). 22 H. Jager and R. Keymer, Arch. Pharm. IB3,896 (1960). 23J. E. Hodgkins and R. I. Fiores, J. Org. Chem. a,3356 (1963). 24 n E. A. Braude and E. H. Evans, /. Chem. Sot. 607 (1954); b I. Maclean and R. P. A. Sweden, Tetrahedron 21,31 (1965). 2s A. C. Cope, M. R. Kinter and R. T. Keller, J. Amer. C/rem. Sue. 76,2757 (1954).
A METHOD
Permmon Press Ltd. Printed in Great Britain
FOR THE TRANSFORMATION
KETONES TO HOMOLOGOUS
OF CYCLIC
a&UNSATURATED
KETONES G.STORK, M.Nussm Department
and B. AUGUST
of Chemistry, Columbia University, New York, New York 10027 (Received 15 July 1966)
Abstract-The addition of dichlorocarbene to enol acetates of cyclic ketones can be carried out efficiently in many cases using the neutral trihalomethyl phenyl mercury reagents. Since en01 acetates of de&rite structures are readily prepared, the method provides a convenient first step to a ring enlargement sequence which can be carried out under basic conditions.
ONEofthe most interesting schemes for the expansion of acyclic ketone to a homologous enone involves the addition of dihalocarbenes to an enol ether derivable from the ketone.‘“,’ This scheme suffers, however, from a lack of generality caused by the difficulty of transforming an unsymmetrical ketone into a single enol ether of predictable structure. For instance, acid-catalyzed splitting of one equivalent of methanol from the dimethyl ketal of 2-methylcyclohexanone gives an equilibrium mixture consisting of 51 ‘A of I and 49% of II.2 The method is nevertheless of considerable value when enol ethers of known structures can be prepared, as for instance by Birch reduction of anisole derivatives. Conspicuous success has been achieved by Birch’” in the synthesis of tropone derivatives by this procedure (cf. III + IV). ?
OEt
OEt
5 - tY+6”’ Me
I
\ o-
Me
\
III
&e
-
II
0
(J I
-
\
IV
1 s A. J. Birch, J. M. H. Graves and F. StanfIeld, Proc. Chrm. Sec. 282 (1962); A. J. Birch, J. M. H. Graves and J. B. Siddall. J. Chem. Sot. 4234 (1963); ’ W.E. Parham. R. W. Soeder and R. M. Dodson, J. Amer. Chem. Sot. 84.1755 (1962); W. E. Parham, R. W. Soeder, J. R. Throckmorton. K. Kuncl and R. M. Dodson, Ibid. 87,321(1965). 2 A. House and V. Kramar, J. Org. Chem. 38,3362 (1963). 105
IQ6
G. !hDRK, M. Nusmt ANDB. Auousr
In order to circumvent some of the difficulties associated with enol ethers we considered the use of enamines, since we have shown that pyrrolidine enamines, e.g. of 2-substituted ketones, have a predictable structure. 3 Unfortunately, although we were able to obtain readily the adduct of morpholinocyclohexene with dichlorocarbene,a these rearranged thermally without expansion of the ring.
We then turned our attention to the possibility offered by enol acetates. These can be prepared readily5 and norma.lIy have at equilibrium the structure which corresponds to the more stable enol in the system. For instance, and in contrast with enol ether formation, the enol acetate derivable from 2-methylcyclohexanone has structure V.2 Furthermore, it is possible to prepare enol acetates corresponding to the less stable of the possible enols by making use of our specific enolate synthesis.6 This is illustrated for the two enol acetates corresponding to cholestanone. Enol acetylation
G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovin and R. Terrell, J. Amer. Chem. Sec. 85, 207 (1963). 4 Susan Ramseyer, Ph.D. Thesis, Columbia University (1962); cf. G. Stork, America Chemical Society, Absfracts of Meetkzgs p. 450 (1961) and J. Wolinsky, D. Chan and R. Novak, Chem. di Id 720 (1%5). 5 D. H. R. Barton, R. M. Evans, J. C. Hamlet, P. G. Jones and T. Walker, J. Chem. Sot. 748 (1954). 6 G. Stork, P. Rosen and N. Goldman, R. V. Coombs and J. Tsuji, J. Amer. Chem. Sot. 87, 275 (1965). 3
A method for the transformation
of cyclic ketones to homologous
c+msaturated
ketones
107
of 3-cholestanone produces the well-known D-enol acetate (VI).7 On the other hand, the ds-lithium enolate can readily be produced by the specific enolate synthesis,6 and its trapping by acetic anhydrides then produces the heretofore unreported dsenol acetate (VII). This substance has almost the same m.p. (88-90”) as its d2 isomer but, in addition to depressing its m.p. it is smoothly converted to &cholestenone by bromination, followed by lithium carbonate-lithium chloridedimethylformamide dehalogenation. The problem of synthesizing enol acetates of specific structures thus being essentially solved, we now consider the addition of halocarbenes to these substances. The main problem with this reaction is connected with the instability of enol acetates toward bases, thus precluding the use of haloform-t-alkoxide mixtures. Even the method involving the decomposition of the weakly basic sodium trichloroacetate has given only fair to poor yields with enol acetates.9 The recent introduction of the halomethyl mercury compounds as neutral halocarbene precursors10 appeared especially promising and we were gratified to find that many enol acetates give very good yields of adducts on heating with these reagents. For instance, heating the dz-enol acetate of cholestanone (VI) with phenyl bromodichloromethyl mercury in benzene gave 83 % yield of the anticipated dichlorocarbene adduct VIII, m.p. 135136”, while the isomeric d3-enol acetate (VII) gave the corresponding adduct IX, m.p. 183-184” in 72% yield.
Cl IX
Under the same conditions, the enol acetates of cyclohexanone, cycloheptanone and 2-methylcyclohexanone (V) were all converted to the corresponding dichlorocarbene adducts X, XI and XII in good yields. The case of the enol acetate of cyclopentanone is of some interest. Under the prolonged heating conditions we used, the initial adduct was unstable and rearranged largely to 2chlorocyclohexenone. The dihalocyclopropane derived from enol ethers can be rearranged either thermally or, when the halogens are bromine, with silver ion.l” It was expected that the acetoxy dichlorocyclopropanes described here would arrange readily under any conditions that would produce cyclopropanol anions from the acetates. The simplest procedure was tested with the dichlorocyclopropane adduct IX of 3-acetoxy-dscholestene: treatment of IX with ethanolic potassium hydroxide at room temperature for about a day gave the anticipated product of ring expansion, Schloro-A-homo-dSx-cholesten7 W. G. Dauben, R. A. Micheli and J. F. Eastham, J. Amer. Chem. Sec. 74,3852 (1952). 8 H. J. Ringold and S. K. Malhotra, J. Amer. Chem. Sot. 84,3402 (1962); cf. H. House et al. Ref. 2. 9 C. E. Cook and M. W. Wall, Chem. dr Ind. 1927 (1963); W. M. Wagner, H. Kloosterziel and S. van der Ven, Rec. Truv. Chim. 80.740 (1961). lo D. Seyferth, J. M. Burlitch, R. J. Minasz, J. Yick-Pui, H. D. Simmons, A. J. H. Treiber and S. R. Dowd, J. Amer. Chem. Sot. 87,4259 (1965).
108
G. STORK, M. NUWM AND B. AUGUST
3-one (XIII). This compound, m.p. 94-96” showed the expected high intensity” absorption maximum in the UV (254 rnp, E 13,700). The IR carbonyl stretching frequency at 1689 cm-l and the vinyl hydrogen as a doublet (3*82,3*93 T) in the nmr.
The ring homologation method now described would be more flexible if it could also be used to produce homoenones not having a halogen on the a-carbon. We considered two methods for accomplishing this. The first was to remove one of the halogens of the dichlorocyclopropane adduct+ in the anticipation that the acetoxy monochloro cyclopropanes would then rearrange with base directly to the halogen-free homoenones.
Unfortunately, although we were able to accomplish this selective reduction without involvement of the acetoxy group, the yield e.g. from VII to XIV was, in our hands, quite unsatisfactory. It can be anticipated that the well-known reduction of vinylic halides by metal and *I Compare 4-chlorocholestenoneAmu -256
mp,c 14,100: 0. N. Kirk, D. K. Pate1 and V. Petrow, J. Chem. Sot. 1184 (1956). 12 D. Seyferth, H. Yamazaki and D. L. Alleston, J. Org. Chem. 28,703 (1963).
A method for the transformation of cyclic ketones to homologous
a,/?-unsaturated ketones
109
ammoniats should be applicable to the chlorovinyl carbinols which are the expected products of the treatment of the acetoxydichlorocyclopropanes with LAH.14 We illustrate this process with the transformation of 2-acetoxy-2-methylcyclohexene (V) into 3-methylcycloheptenone (XVI).
OAc \
Me
_
@ze
_
&Me
_
b
xv
XII
OH
0
n
’ “,e XVI
The dichlorocarbene adduct (XII) produced, as mentioned previously, by the reaction of V with phenyl bromodichloromethyl mercury, was obtained in 85 % yield as an unstable substance, b.p. 60-62” (O-15 mm), exhibiting acetate absorption at 5-68 and 8.19 ~1quite similar to that of the starting enol acetate, but the methyl group hydrogens gave rise to absorption as a singlet at 8.78 T, definitely higher than the position of the allylic methyl group in the enol acetate (V) whose hydrogens give rise to a singlet at 850 7. Reduction with LAH in ether gave the chlorocycloheptenol (XV) in 73 % yield. Reduction with sodium in liquid ammonia to remove the halogen (negative Beilstein test), followed by oxidation with the chromic acid-acetone reagent, led to 3-methyl-2-cycloheptenone (XVI) in very good yield. The cycloheptenone appeared to contain a small amount of ,!3,y-isomer15 (- 12 %) as shown by VPC, and by the presence of a shoulder at 5.82 ~1in addition to the main carbonyl stretching peak at 6.02 CL.The UV of the pure compound showed typical absorption at 238 rnp (13NQ). In a similar manner the adducts X and XI from the enol acetates of cyclohexanone and of cycloheptanone were converted to cycloheptenone and to cyclooctenone. The ring expansion methods which have been described in this communication depend on the success of the initial dichlorocarbene addition. Although these additions take place readily in the unhindered cases reported here, there are indications that they can be adversely affected by certain steric environments: The enol acetate (XVII) derived from cedrene, did not react with phenyl tribromethyl mercury, presumably because of the strong steric hindrance between the methyl group on the cyclopropane and one of the gem-dimethyl groups in the eventual adduct (XVIIa) (and the transition state leading to it). I3 M. C. Hoff, K. W. Greenlee and C. E. Roord, J. Amer. Chem. Sm. 73,3329 (1951). I4 The formation of a-chlorohomocyclenols via the LAH reduction of dichlorocarbene adducts of cyclanone enol acetates has independently been observed by R. C. De. Selms, TerruhedronLetters 1965 (1966). IS For a recent discussion of CC&&y-equilibrium in cyclic unsaturated ketones, see. N. Heap and G. H. Whitham, J. C/rem. Sot. 164 (1966).
G. %l-ORK, M. NUSSIMANDB. Auciusr
110
OAc
XVila
XVII
EXPERIMENTAL 3-Acefoxy As-cholestene (VII). To a soln of 20 ml dried (over Na) and distilled liquid ammonia and 14 mg (2 mmole) Li was added a soln of 390 mg (1.01 mmole) A*-3cholestenone in 10 ml dry THF. At the end of the addition the blue color disappeared. The ammonia was evaporated and a soln of 1 ml AczO in 5 ml THF was added. After stirring for 45 min at room temp. water was added and the mixture extracted with ether. The ether extracts were washed with 5% NaHCOs aq. then with water, dried over NazS04 and evaporated. The residue (405 mg) showed IR absorption (CCL) at 5.70 p (enol acetate), and small peaks of saturated and unsaturated ketones at 5.83 and 5.98 p. Chromatography over 12 g of neutral alumina and crystallization from MeOH afforded 205 mg (47%) of VII, m.p. 88-90”. The IR spectrum of the pure compound had a single carbonyl absorption at 5.70 p (CCL) and was different from that of the A* isomer, m.p. 87-89”. The m.p. of a mixture of the two substances was depressed to 80-83”. (Found: C, 81.27; H, 11.52. Cak. for Ca9H4&: C, 81.25; H, 11.29%). The structure of the enol acetate was further con8rmed by bromination and dehydrobromination to A’-3cholestenone: To a soln of VII (50 mg) in 3 ml of a buffer soln (prepared by dissolving 1 g of anhyd AcONa in 80 ml glacial AcOH and 20 ml Ccl., 16 3 ml Br soln (0.3 ml Br in 50 ml buffer soIn) was added during 20 min. After 15 min stirring, water was added and the mixture was extracted with ether. The ether extracts were washed with 5% NaHCOs aq, then with water, dried, and evaporated. The residue (65 mg) showed absorption in the IR (CCl4) at 5.79 p indicating that the Br is equatorial. The bromo-ketone (65 mg) in 3 ml dimethylformamide was refluxed with 200 mg LisCOs and 200 mg LiCl for 4 hr.17 Extraction with ether gave crude ketone showing an unsaturated carbonyl band at 5.98 p and XEgH 241 rnp (c 13,200). Chromatography over alumina (3 g) and crystallization from MeOH afforded 21 mg A’-3cholestenone., m.p. 7678”, undepressed on admixture with an authentic sample. 3-Acetoxy AWtolestene (VI). This and other known enol acetates were prepared by Barton’s method.5 From 3cholestenone (1 g) in 30 ml AcOH containing 2 ml of AczO and 2 drops of 60% perchloric acid soln kept 6 hr at room temp we obtained 910 mg (82%) of VI, m.p. 92-94” (lit.7 m.p. 90-90.5) after chromatography on alumina and crystallization from ether-MeOH. Similarly, cyclehexanone gave 68% of acetoxycyclohexene b.p. 64-68” (12 mm) (lit.‘* b.p. 92” (34 mm)); 2-methylcyclohexanone gave 71% of V, b.p. 80-96” (12 mm) (lit. 19 b.p. 70” (6mm). All these enol acetates showed IR carbonyl absorption at _ 1754 cm-*. 2,3-Dichloromethylene-3-acetoxycholestune (VIII). To a soln of 1.75 g (4.0 mmoles) 3-acetoxyZcholestene in 10 ml benzene, 1.91 g (4.4 mmoles) phenyl(bromodichloromethyl)mercuty was added and the mixture. was refluxed with stirring for 48 hr. After standing at room temp for 4 days, it was filtered and the filtrate yielded 1.76 g (83%) product, m.p. 135-136” recrystallized from MeOHabs ether, A”::. 5.70 p. (Found: C, 70.52; H, 9.52. Calc. for CjeH+sOaClz: C, 70.42; H, 9.45%). 3,4-Dichloromethylene-3-ucetoxycholestune (IX). A soln of 700 mg of VII and 700 mg phenyl(bromodichloromethyl)-mercury in 20 ml purified cyclohexane was refluxed for 20 hr. The PhHgBr 16Cf. B. Berkoz, E. P. Chavez and C. Djerassi, J. Chem. Sot. 1323 (1962). R. Joly and J. Wamant, Bull. Sot. Chim. Fr. 357 (1958). I* R. J. P. Allen. J. McGee and P. D. Ritchie, J. Chem. Sot. 4700 (1957). 19 A. C. Cope, T. A. Liss and G. W. Wood, J. Amer. Chem. Sot. 79.6287 (1957). 17
A method for the tr~sfo~tion
of cyclic ketones to homologous
a&unsaturated
ketone-s
111
which precipitated during the reaction was filtered off and washed well with cyclohexane. It was recovered in 90% yield (570 mg; m.p. 284-286”). The filtrate was evaporated and the residue (750 mg was chromatographed on 25 g of alumina (Merck-acid washed). Ehation with 9: 1 pentane-benzene afforded IX in 72% yield (6%) mg, m.p. 181-183”). NMR showed cyciopropane hydrosn absorption at 9.65 T. (Found : C, 7@05; H, 9.63. Cak. for C&H4s02C12: C, 7@42; H, 9.45%). l-Aceroxy-7,7-diclrlorobicyclo(4.1 .O)hepfune (X). Cyclohexenol acetate (3M) g, 21.4 mmoles) and 11.80 g (27.2 moles) of phenyl(dichlorobromomethyl)mercury in 15 ml benzene under N after 18 hr of refluxing at 85”, filtzation and distillation gave 4.01 g (85%) of product, b.p. 6061’ (0.15 mm), ;\g$t 5.67, 8.21 p, VPC (SF 96/162”) one peak. The NMR spectrum (CCW showed peaks at 8.54, 840, 8.20, and 7.95 7 (5: 1: 2:4H). The product decomposes siowly on standing at room temp and in common with the following adducts, gave somewhat low carbon values. Found: C, 47.77; H, 5.42. Calc. for C9H&&Os: C, 48.47; H, 5.43%). l-~cetox~8,8-djc~~robicyc~~5.l.O)octa~e (XI). In a similar manner, l-65 g (10.7 mmoles) cycloheptenol acetate2 and 602 g (13-O mmoles) phenyl(dichlorobromomethyl)mercury in 20 ml benzene gave, after a 14 hr reaction, 1.85 g (72%) of product, b.p. 80” (@lo mm, Hickman still), AC22 5.65, 8.21 I(, VPC (SF 96,162”) one peak, NMR (CC14) 8.10-903,8,06,7.22-8.00 7 (9: 3: 1 H). The product is unstable. (Found: C, 49-85; H, 594. Calc. for C10H&l202: C, s67; H, 5*95’%). l-Acetoxy-6-merhyf-7,7-dichforobieycZ~4.l .O)hepifme (XII). In a similar manner, 3.00 g (19.5 mmoles) 2-methylcyclohexenol acetate and 10.71 g (24.8 mmoles) phenyl(bromodichlorometbyl)mercury in 15 ml benzene gave 3.32 g (85%) of product, b.p. -2” (0.15 mm), h$$ 5.68, 8.19 I*, VPC (SF 96, 132”) one peak, NMR (Ccl,) 8.78,8.53 (b), 8.18 (b), S+lO, 7.55-ET (3:4:2:3:2 H). The product is unstable. (Found: C, 49.89; H, 590. CU. for C~~H&120~: C, 5@65; H, 595%). 4-Chloro-A-homo-A~-5-claolesten-3-one (XUl). A soln of 200 mg IX in 5 ml pyridine and 10 ml EtOH containing 25 mg (N l-2 es) KOH, was stirred at room temp for 16 hr. Extraction with ether and chromatography on 10 g of silica gel afforded 28 mg (-IS’%) starting material (eluted with 4: 1 hexane-benzene) and 70 mg of XIII (50% based on material reacted), eluted with 1: 1 hexane-benzene. After crystallization from MeOH XIII had m-p. 94-96”. X,,, CC“ 1698 cm-i, I\z%H 254 rnp (C 13,700). The NMR showed the vinyl proton as a doublet (J=6 c/s) centered at 3.87 7. (Found: C, 77.78, H, 10.65. Calc. for C2sH4&Cl: C, 77.64; H, 10.47%). The chloroenone was reduced with Pd-C in AcOEt to A-homo_3cholestanone, m.p. 82-85” (reported20 m.p. 85-85.5”). Reduction of ~3dich~oro~t~yiene-3~cetoxyc~~st~e (VIII) with tributyl tin hydride to XIV. To a soln of 760 mg (1.48 mmoles) 2,3_dichloromethylene-3-acetoxycholestane in O-5 ml xylene kept refluxing under N at 140”, 495 mg (1.70 mmoles) tributyltin hydride was added over 30 min. After refluxing for 6 hr, NaF aq was added to the cooled reaction mixture which was stirred for 30 rnin to complete the pr~ipitation of the insoluble tributyltin fluoride. Filtration and removal of the solvent gave XlV, m.p. 152.5-153-S’ after recrystallization from MeOH-ether, /\zix 5.72. (Found: C, 75.45; H, 10.35. Calc. for C,oH4902Cl: C, 75.51; H, 10.35%). Reduction-rearrangement of acetoxydichlorocyclopropanes with lithium aluminum hydride. These reductions were all conducted as described below for the reduction of XII. 2-~h~oro-3-~thy~-2-~ycIohepte~ol (XV). A soln of 2.50 g of XII in 25 ml dry ether was added to 1.50 g LAH in 80 ml dry ether during 15 min. The mixture was refluxed for 2 brand excess hydride was then decomposed by the addition of sat Na2SO4 aq. Tbe ether layer was washed with water, dried and concentrated, and residue was distilled evaporatively to give 1.52 g (81%) of XV, b.p. 85” (l-3 mm), XE? 2*96,6*08,9-10 p several bands, WC (SF 96,162”) 91% pure, NMR (Ccl,) 8*25-8*43, 8.16, 7-80 (b), 6.75, 5.62 (3:4*5:3: 1: 1 H). The mass spectrum showed the parent peak at m/e= 160. An analytical sample was collected by gas chromatography. (Found: C, 60.26; H, 8.37. WC. for CsH&IO: C, 59.81; H, 8*16%). 2-Chloro-2-cyc/oheptenoenol.In a similar manner, 2.91 g of X gave 1.54 g (57%) f-chloro-2-cycleheptenol, b.p. 75” (@IS mm), A$,$:’ 291,6*09,9-10 p several bands, VPC (SF 96, 162”) single peak, NMR &Cl’) 8.20 (b). 7.92 fb), 7.37,5.72,4*10 (t) (6: 2: 1: 1: 1 H). An analytical sample was collected by gas chromatography. (Found: C, 57.61; H, 7.84. Calc. for CTHI~CIO: C, 57.34; H, 7.56%). 2-Chloro-2-cycloocteenol. Similarly, 1.70 g of XI gave 900 mg (78%) 2chloro-2cycloccteno1, b.p. 5 63” (0.10 mm. Hickman stil), hg:p 2.95,609,960 I*, VPC (SF 96,162”) one peak, NMR (CC13 20 N. A. Nelson and R. N. Schut, J. Amer. Chem. Sot. 81.6486 (1959).
112
G.
STORK,
M. Nussi~ AND B. Aucusr
7.10-9a20, 5.97, 573,4.15 (10: 1: 1: 1 H). An analytical sample was collected by gas chromatography. (Found: C, 59.08; H, 8.19. C&c. for CsH&lO: C, 59.81; H, 8.16%). Sodium -ummonia dehalogemztion, and oxidation to unsuturuted ketones. These processes were conducted as described below for the preparation of XVI. 3-~etky~-2~y~io~pte~ne (XVI). A soln of 1.03 g of XV in 2 ml dry ether was added to a soln of 900 mg Na in 25 ml liquid ammonia. The mixture was stirred for 1 hr, NH&l was then added, the ammonia was allowed to evaporate and the mixture was extracted with water and ether. The ether layer was washed with dil HCl aq, dil NaHCOs aq and tinally with water. After dryin and concentrating 762 mg (86%) of product, b.p. 85” (18 mm, Hickman stil), showing 5% close boiling impurity in p. A Beilstein test was negative for Cl. The crude ally& the VPC (SF 96,162”), 1\~$3.00,610,9-72 alcohol (419 mg) in 10 mf acetone was oxidized directIy with l-8 ml Jones m-age&t at 0”. After stirring for 20 min, the solvent was removed and the residue was extracted with water and ether. Work up aa usual gave 410 mg (88%) 3-methyl-2-cycloheptenone (containing some As-isomer, vide infiu), b.p. 106” (18 mm) (reported22 b.p. 81-82” (2-S mm)), h,,, cc” 6.02,582 p shoulder, VPC (SF 96,162”) 12% 3-methyl-3cycloheptenone, hggrr 236 rnp (6 11,550). A sample was collected by VPC and the semicarbazone, m.p. 198-201” (reported22 208-210’) was prepared. The first crystals obtained on crystallization of the red 2,4dinitrophenylhydrazone had m.p. 159-164”. Most of the derivative obtained had m.p. 137-139”, ,%zgrr 259, 383 rnp (c: 18,000, 31,700). (Found: C, 5498; H, 5.31. Calc. for C14HlaN10,: C, 5525; H, 5*30’/0). 2- and 3-Cyctbheptenone, Reduction of 2-chloro-2cycloheptenol and subsequent oxidation as described above gave an excellent yield of what proved to be a mncture of AZ- and AJ-cycloheptenone by VPC analysis (SF 96, 162’). The substance showed b.p. 60-70” (19 mm) (reported23 b.p. 73-74’ (11 mm)). The sample showed some absorption at 5.83 p in addition to the major absorption at 6.01 p (CQ). Nmr absorptions (CCb) werepresent at 8*22,7-51.4.30,4*10 and 360 in the ratio of 4:4: 1: 1 H. Some isomer~tion toward the ~ui~bri~ mixture of a& and /3,y-unsaturated ketones may have taken place before the UV spectrum was taken since it showed XzgK 230 mp, c 3575 which, although close to that reported by Braude et al. N (227 mp, e 4800), is lower than expected and a value of 228 rnp, E 10,060 has in fact been reported recently. 24b The semicarbazone, recrystaliized from EtOH showed an initial m.p. of 149-150” which rose on repeated crystallization to 156-158” (reporteda4~ for 3cycloheptenone: m.p. 155-156”). 2-Cyclooctenone. This was obtained in a similar manner to that described for 3-methyl-2-&oheptenone. The resulting cyclooctenone was purified by VPC (SF 96, 140”) and although it, like cycloheptenone, was a mixture of the a&3 and &y isomers as shown by the IR spectrum (5-86 and 6.02 p) is was mostly the former as evidenced by the high extinction in the UV at 230 rnp (reported hEzxH 230 rnp, c 7700).2s Acknowie&em.ent-This
work was supported in part by a grant from the National Science Foundation.
21 K. Bowden, I. M. Heilbron, E. R. N. Jones and B. C. L. Weedon, J. Gem. Sot. 39 (1946). 22 H. Jager and R. Keymer, Arch. Pharm. IB3,896 (1960). 23J. E. Hodgkins and R. I. Fiores, J. Org. Chem. a,3356 (1963). 24 n E. A. Braude and E. H. Evans, /. Chem. Sot. 607 (1954); b I. Maclean and R. P. A. Sweden, Tetrahedron 21,31 (1965). 2s A. C. Cope, M. R. Kinter and R. T. Keller, J. Amer. C/rem. Sue. 76,2757 (1954).