195'1
DECEMBER
PSEUDOIONONE HOMOLOG^
1611
bromide on acetophenone.14 It was found to be more con- However, when 10.8 (0.04 mole) of the diol was heated with veniently prepared by the action of phenylmagnehm bro- 10.2 g, (0.06 mole) of phosphorus oxychloride in 300 ml. of dry benzene, 4 g. (44%) of the desired diene, map. 135-138', mide on acetonylacetone. The Grignard reagent was prepared in the usual way from was obtained. It did not depress the melting point of the 39 g. (0.25 mole) of bromobenzene, 6.1 g. (0.25 g.-atom) of bromomethylstyrene magnesium product and their infrared magnesium, and 150 ml. of ether. A solution of 11.4 g. (0.1 spectra were identical. Ultraviolet spectra.15 The spectra were measufed an a mole) of acetonylacetone in 50 ml. of ether was added slowly at ice-bath temperatures. The resulting mixture was ertirred Beckmann DK-1 Spectrophotometer in 1-cm. cells in acetoa t room temperature for 1 hr. and at reflux for 2 hr. Isolation nitrile solution. was carried out in the usual manner and 17.8 g. (67%) of the Acknowledgment. We are greatly indebted to br. desired diol, a mixture of the stereomers, was obtained. Preparation of 2,5-diphenyl-2,4-hexadiene.Treatment of Keith S. McCallum for helpful discussions of the in2,5-diphenyl-2,5-hexanediol with 15% sulfuric acid pro- frared and ultraviolet spectra. duces only 2,5-dipheny1-2,5-dimethyltetrahydrof~ran.~~ HUNTSVILLE, ALA. (14) M. Tout and M. Guyard, Bull.
SOC.
chim. France,
1087 (1947).
[CONTRIBUTION FROM
THE
(15) These spectra were measured by Mr. R. Donald Strahm.
TECHNICAL DEVELOPMENT DEPARTMENT OF HOFFMANN-LA ROCHE,INC.]
Synthesis of Pseudoionone Homologs and Related Compounds WALTER KIMEL, JOSEPH D. SURMATIS, JOSEPH WEBER, GEORGE 0. CHASE, NORBERT W. SAX, AND ALFRED OFNER Received May $7, 1967 A series of ketones related to 6-methyl-5-hepten-2-one have been prepared in which substitutions have been effected a t carbon atoms 3, 4, 5 and 6. These ketones were converted to the corresponding pseudoionones. I n addition to the pseudoionones, a number of compounds were prepared which may be of interest to the essential oil industry. These include (1) linalools (2) 0-cyclopentenylethyl ketones, isomeric with the corresponding pseudoionones (3) a- and 0-ionones and (4)geranyl acetones.
Also, we have converted the substituted pseudoionones, and certain of the intermediates used for their preparation, into products which may be of interest to the essential oil industry. These products include: (1) linalools (IX), obtained from the ethynylcarbinols (VIII) by selective reduction of the triple bond; (2) p-cyclopentenylethyl ketones (X), isomeric with the corresponding pseudoionones (XI) and produced as by-products of their synthesis'; (3) a- and p-ionones (XI1 and XIII), obtained by cyclization of X I ; and (4) geranylacetones (XIV), formed when the linalools (IX) were treated with diketene and the resulting acetoacetates were pyrolyzed. Many of these compounds have interesting odor characteristics, which may make them attractive as flavoring and perfumery ingredients. The complete flow sheet for preparation of the various products is shown in Table I. Series A . I n this series, R2 = R3 = R4 = H. In the simplest case, R' = CH3, and VI1 and XI are methylheptenone and pseudoionone, respectively. The starting material for those compounds was acetone (I; R' = CH,).' For other members of this series, methyl ketones other than acetone were ( I ) W. Kimel, N. W. Sax, G. Eichmann, 5.Kaiser, G. 0. used, and R' = alkyl or aryl. However, even cyclic Chase, and A. Ofner; unpublished work. ketones, such as cyclohexanone, were employed. (2) 0. Isler, W. Huber, A. Ronco, and M. Kofler, Helv. In a typical sequence, methyl ethy! ketone was Chim. Acta, 30, 1911 (1947). ethynylated to give 3-methyl-1-pentyn-3-01 (IIb) (3) 0. Mer, H. Lindlar, M. Montavon, R. Ruegg, and P. Zeller, Helv. Chim. Acta, 39, 249 (1956). which was hydrogenated selectiveiy, in the presence
Recent investigations in these laboratories' have led to a practical total synthesis for pseudoionone, starting from acetone and acetylene. The method utilized 6-methyl-5-hepten-2-one (VIIa) as a key intermediate. The process for preparation of VIIa can be extended readily to permit substitutions at different positions in the molecule. Accordingly, five series of unsaturated ketones related to VIIa have been prepared. I n the first series (A), the carbon chain was lengthened; Le., alterations were made a t carbon atom 6 . The next three series (B, C, U) involved substitution a t carbon atoms 5, 4, and 3, respectively. The fifth series (E) utilized two of the above series (A and D) to produce, simultaneously, chain lengthening and substitution. The substituted methylheptenones were converted to the corresponding pseudoionones, as previously described.l Since pseudoionone is a key intermediate in the production of Vitamin A2 and pcarotene13 these pseudoionone homologs may be employed for the preparation of corresponding Vitamin A and P-carot,ene homologs. These should be valuable for study of the relationship between chemical structure and Vitamin A activity.
1612
XTMEL, SVRMATIS, WEBER, CHASR, SAX, AND OPNEP
TABLE I FLOWCHART OF REACTIONS
I
I1
IV
J."l
JRfMgX
HCSX
OH
n a
1
22
Swies B. In this series, R' = CH3; R3 = R4 = H ; R2 = alkyl. The sequence starts with a substituted methyl vinyl ketone (IV). Thus, when R2 = CHs, methyl isopropenyl ketone was treated with methylmagnesium bromide to give 2,3-dimethyl-lbuten-3-01 (IIIh). This substituted allylic alcohol gave its corresponding acetoacetate on treatment with diketene. Pyrolysis of the ester afforded the methylheptenone homolog, 5,6dimethyl-5-heptenh n e (VIIh). Ethynylation of the latter gave the acetylenic alcohol, VIIIh. Condensation of VIIIh with diketene, followed by pyrolysis, afforded 6,9,10-trimethyl-3,5,9-undecatrien-2-one(XIh), known commercially as pseudoirone. This is a precursor for the important perfume material a-irone (XIIh). The reaction sequence for Series B followed the path I V --c IIIh ---F V -+VI1 3 VI11 -+ X I in Table I.
V
VI1
VOL.
Series C. For this series, R' = CHa; R2 = R4 = H; R3 = alkyl. The series is initiated by allowing acetone to react with the Grignard reagent of an alkyne, whereby an acetylenic carbinol (11) is obtained. Thus, for example, treatment of 1-butyne (obtained by reaction of ethyl bromide with sodium acetylide3 with ethylmagnesium bromide gave 1-butynemagnesium bromide. Then, addition of acetone caused formation of 2-methyl-3-hexyn2-01 (IIf). This was reduced to the corresponding allylic alcohol, and the reaction sequence outlined for Series A was then followed; i.e., I 4 I1 I11 + V -t VI1 + VI11 + XI. In this case, the methylheptenone homolog was 4-ethyl-6-methyl-5-heptenZone (VIIf), and the pseudoionone homolog was 6,10-dimethyl-8-ethyl-3,5,9-undecatrien-2-one
(XIf). Series D. Alkylation of 2-methy1-3-buten-2-yl R? XI1
I
Diketene
~4
4
XIV
A
Iv XI11
acetoacetate (Va) in the usual manner6 gave a-substituted acetoacetates of type VI. Pyrolysis of these esters yielded methylheptenones substituted a t carbon atom 3. Thus, for this series, R' = CH3; = R3 = H * R 4 = alkyl. From Table I, the reaction sequence was I 3 I1 -+ I11 + V --t VI 4VI1
I
-+VI11 3 XI. Series E. By combining any two or more of the
R4 IX
previously described series, it was possible to subof Lindlar ~ a t a l y s t to , ~ yield 3-methyl-1-penten-3- stitute the methylheptenone nucleus (and eventu01 (IIIb). This vinylcarbinol was treated with di- ally the pseudoionone molecule) in several places. ketene to give the corresponding acetoacetate (Vb), Series E involved substitution of methylheptenone which afforded 6-methyX-5-octen-2-one (VIIb) on a t carbon atoms 3 and 7. Thus, in a typical sepyrolysis. Ethynylation of the ketone VIIb gave quence, methyl ethyl ketone was converted, as de3,7dimethy1-6nonen-l-yn-3-01 (VIIIb). Treatment scribed previously under Series A, to 3-methyl-lof the latter with diketene, and pyrolysis of the penten-3-yl acetoacetate (Vb).The latter was alresultant acetoacetate, afforded a mixture of the kylated with ethyl bromide (as in Series D) to give pseudoionone homolog, 6,10-dimethy1-3,5,9-dodeca- the corresponding ethyl-substituted acetoacetate trien-Zone (XIb), and 4-[2-methyl-5-( l-methyl- (VI). Pyrolysis of the ester afforded 3-ethyl-6methyl-5-octen-2-one (VI1 1). The corresponding propenyl)cyclopenten-l-yl]-2-butanone (Xb). The reaction scheme for Series A followed the (5) J. G . Aston, S. V. R. Mastrangelo,and G. W. Moessen, sequence I 3 I1 4I11 + V -t VI1 + VI11 + XI J . Am. C h . Soc., 72, 5287 (1950). in Table I. (6) C. S. Marvel and F. D. Hager, Org. Syntheses, Coll, Vol. I, 248, (1941). (4) H. Lindlar, Helv. Chim. Acta, 35,448 (1952).
1613
~SEtlDO~Oi'JObTEHOMOLOGS
TABLE I1 ACETYLENIC ALCOHOLS
B.P. IIaa# IIbb IIcb IIdb*o IIe*
IIfU IId
RS
OC.
Mm.
ny
760 760 760 760 0.5 7 10
1.4182 1.4290 1.4333
90
d
,.
I
CzHb n-CsHlr
104 121 150 180 72-5 46-7 99
75 73 80
R'
Compound
CHa C&s (CHXHCHs -4CHdr CsH6 CHJ C E
H H
H H
H
1.4392 1.4462
Yield,
.. ..
J. F. Froning and G. F. Hennion, J . Am. Chem. SOC.,62,653 (1940). Obtained from Air Reduction Co. This compound is lethynylcyclohexanol. m.p. 30". H. Rupe and L. Geisler, Helv. Chim. Acta, 11,656 (1925). 1rn.p. 51". Dupont, Compt. rad., 148, 1524 (1909). Analysis: Calcd. for CllHaO: C, 78.50; H, 11.98. Found: C, 78.37; H, 12.21.
'
TABLE I11 TERTXAEY ALLYLIC ALCOHOLS B.P. Compound
IIIaa IIIbb IIICO IIIdd IIIe"
IIIff IIIgU IIIh'
R' CH3 CzHs (CHdzCHCHz -(cHz)~ Cas CHa CHI CH8
R*
RZ H H
H H H H
"C.
97-98 116 53 72 60-62 68-69 94 82-83
H
H H H H c&S
H
n-CsH1:
CHa
H
Mm. 760 763 16 16 0.6 54 10 200
ny 1.4141 1.4263 1.4310 1.4740 1.5302 1.4330 1.4454 1.4296
a Reference (1). H. Rupe and F. Vonaesche, Ann., 442, 81 (1925). Commercial Solvents Corp., Brit. Patent 595,459, Dec. 5, 1947. P. S. Pinkney, G . A. Nesty, R. H. Wiley, and C. S. Marvel, J . Am. Chem. SOC.,58, 972 (1936). This compound is l-vinylcyclohexanol. 'A. I. Lebedeva, J . Gen. Chem. (U.S. S. E.), 20,431 (1950). I. N. Nasarov and L. B. Fisher, Bull. auzd. sci. U.S. S. R. 135 (1942). F. S. Kipping and L. L. Lloyd, J . Chem. SOC.,79,450 (1901). Reference (8).
pseudoionone homolog was 7-ethyl-6,lO-dimethyl3,5,9-dodecatrien-2-one (XI I), obtained via the sequence VI1 +.VI11 + XI. EXPERIMENTAL
The physical constants and yields obtained for all compounds are listed in Tables I1 to XI.' Ethynylearbimls (11; R3 = H). Into a stirred solution of sodium (1.2 g.-atoms) in liquid ammonia (2 1.) was bubbled acetylene until conversion to sodium acetylide was completc (as indicated by a color change from blue to white), Into this solution was added, dropwise, a ketone I, (1.0 mole) in ether (300 ml.). The mixture was stirred for 8 hr., and then the ammonia was allowed to evaporate. The residue was poured, with ice cooling, onto 20% sulfuric acid. The layers were separated and the aqueous phase was extracted three times with ether (200 ml.). The ether layers were combined and washed with e. 5y0 potassium carbonate solution (100 ml.) and with water until neutral. The organic portion was dried over calcium chloride and the product was isolated by distillation. Acetylenic alcohols (11; R3 = alkyl). Sodium (1.1 g.atoms) waa added, slowly, to liquid ammonia ( 2 1.) containing hydrated ferric nitrate (0.3 g.). Into the resultant suspension of sodamide was introduced acetylene, at a rapid rate, until a color change from grey to white to black occurred. An alkyl halide (1.0 mole) was added, dropwise, and the reaction mixture was stirred for 10 hr. The ammonia was allowed t o evaporate and the alkyne wa,a distilled from the residue. The alkyne was dissolved in ether (100 ml.) and the snlutioc was added to a Grignard reagent prepared from
(7) Melting points and boiling :>oints are uncorrected.
magnesium (1.2 g.-atoms), ethyl bromide (1.25 moles), and ether (500 ml.). The resultant complex was stirred for 1 hr., acetone (1.25 moles) was introduced slowly, and the reaction mixture w a ~stirred overnight. Saturated aqueous ammonium chloride waa used to decompose the complex. The aqueous layer was separated, and was extracted with ether (300 ml.). The organic layers were combined, washed with water and dried. The product waa purified by fractional distillation. Allylic akohols (111). An acetylenic alcohol (11, 1.0 mole) was dissolved in hexane (two volumes of solvent per weight of carbinol) to which was added 5% by weight of Lindlar catalyst.' The hydrogenation was performed a t atmospheric pressure and was continued until one molar equivalent of hydrogen was consumed, at which time the rate of absorption had decreased markedly. The catalyst was removed by filtration and the product was isolated by distillation. Yields of 90-95% were obtained, in every instance. d , . ~ - ~ ~ t h y Z - ~ - b u f e n - d -(IIIh). oZ This carbinol was prepared from methyl isopropenyl ketone (IV, RZ = CH3)according to the procedure of Ogloblii,8 in yield of 70%. AZZylZc acetoacetates (VI. The appropriate allylic alcohol (111, 1.0 mole) was dissolved in an equal volume of hexane and to the solution was added 0.01 mole % of sodium methoxide. Diketene (1.1 moles) was then added, dropwise, maintaining the reaction temperature at 25-30'. After the addition was complete, the reaction was stirred a t 25-30' for 10 hr. The solution was washed with saturated aqueous sodium bicarbonate and then with water. Remova! of the solvent unaer diminished pressure afforded crude esters, V, in quantitative yield, of sufficient purity for use in succeeding steps. ~
I
_
(8) E. A. Ogloblin, J . Cen. Chem. ( G . S. AS'. R.), 18, 2153 (1945); CSWL Ab&. 43,3777 (1949).
1614
KIMEL, SURMATIS, WEBER, CHASE, SAX, AND OPNER
000000
00000
00000
00000
. . . . . . . . . . . . -4-43444-44-4433
i
x"
0
x i
I
DECEMBER 1YSI
1615
PSEUDOIONONE HOMOLOGS
a CI 3
a
E!
8
Id,
E!
E
a
F9
P
2 0
P
C
I
1616
BIME'L, StJF&A!l'IS, WEBER, CHABE, SAX, AND OFNEB
VOL.
6-
e: 3
I
" F;
N
Fz
2
-
3 3 3 3 3 3 rl
7
22
DECEMBER
1957
PSEUDOIONONE HOMOLOGS
1617
1618
JURD AND HOROWITZ
Allylic a-alkyl acetoacetates (VI). To a solution of sodium (1.05 g.-atoms) in ethanol (350 mi.) was added an allylic acetoacetate (V, 1.0 mole), and the mixture was stirred for 8 hr. An alkyl halide (1.05 moles) was added, dropwise, and stirring was continued for 48 hr. The sodium halide was removed by filtration and ethanol was removed under diminished pressure. To the residue was added water (2 1.) nn.d petroleum ether (500 ml.), the layers were separated, arid the aqueous phase was extracted twice with fresh petroleum ether (300 ml.). The organic portions were combined and were washed successively with ice-cold I N sodium hydroxide (4 times 100 ml,), with ice water (2 times 100 ml.), with ice-cold 1N acetic acid (4 times 100 ml.) and finally with ice water (6 times 100 ml.). The solution was dried over calcium sulfate, the solvent was removed in vacuo, and the residue (VI) was used directly in the next step. Unsaturated ketones (VII). The allylic acetoacetate (either V or VI, 1.0 mole) was heated with an aluminum alkoxide (3.0 g.) at a temperat,ure sufficient to maintain a vigorous evolution of carbon dioxide (120-160"). Heating was continued until the gas evolution ceased, normally several hours. The product, VII, was then purified by fractional distillation. Ethynylcarbinols (VIIX). The unsaturated ketones (VII) were ethynylated by the same procedure as described for the ethgnylearbinols (11). In some cases, distillation afforded some unchanged ketone (VII) in addition to the $wired ethynylcarbinol (VIII). However, based on reacted ketone, yields were in excess of 90yoin every instance. Vinylcarbinob (IX). These compounds were obtained by seleat,ive reduction of the et,hynylcarbinols (VIII j in the same manner described earlier for the conversion of I1 to 111. 'Yields were 90-95% in every instance.
VOL.
22
Pseudoionones and cyclopentenylbutanynes (X and XI). Acetoacetates of the acetylenic alcohols (VIII) were obtained by the reaction of VI11 with diketene in analogous fashion to the method described for the preparation of V. The requisite acetoacetate (1.0 mole), dissolved in an equal volume of decalin, was heated in the presence of acetic acid (3 g.) and aluminum isopropoxide (0.2 g.) t o a temperature sufficient to maintain a vigorous evolution of carbon dioxide (150-200"). After termination of the reaction (cessation of gas evolution) the residual liquid was subjected to careful fractionation. Two main fractions were isolated; a lowerboiling ketone, X, and a higher-boiling product, XI. a- and p-Ionones (XI1 and XIII). These ketones were obtained by cyclization of the corresponding pseudoionones (XI) according to the method of Royals.9 The cyclization agent used for the a-isomers wa,s phosphoric acid and for the p-isomers was a mixture of sulfuric and acetic acids. Geranylacetunes (XIV). These compounds were prepared fram the corresponding vinylcarbinols (IX) by pyrolysis of the acetoacetates obtained by reaction of IX with diketene. The method employed was the same as described for the sequence I11t o V to VII.
Acknowledgment. We wish to thank Dr. A1 Steyermark and his staff of the Roche Microchemical Laboratories for the carbon and hydrogen analyses. NUTLEY10, N. J.
(9) E. E. Royals, Znd. Eng. Chem., 38, 546 (1946).
[CONTRIBUTION FROM THE FRUIT AND VEGETABLE CHEMISTRY LABORATORY, WESTERN UTILIZATION RESEARCH AND DEVELOPMENT DIVISION,AGRICULTURAL RESEARCH SERVICE, u. s. DEPARTMENT O F AGRICULTURE]
Spectral Studies on Flavonols-the LEONARD JURD1
ANI)
Structure of Azalein
ROBERT M. HOROWITZ
Received M a y 87, 1957 Flavonols containing a free dihydroxyl grouping in the 3,4'- position are unstable in alcoholic sodium ethylate and can be distinguished spectrophotometrically by this instability. Sodium acetate produces a characteristic bathochromic shift of the short wave length band of flavonols containing a free 7-hydroxyl group. This shift provides a method for locating this hydroxyl group. The structure proposed for azalein, a flavonol glycoside discovered recently by Wada, has been confirmed by the application of these and other spectrophotometric procedures.
'The use of spectrophotometric measurements in determining various structural features of flavonoid compounds is attractive because of its speed, simplicity, and economy of material. Spectral procedures are reported in this paper for the detection of the 3,4'-dihydroxyl snd the 7-hydroxyl groups in flavonols. These methods, in combination with a pseviousIy reported prowdure for detecting orthod&.i droxyl groups,2make it possible t o approach a vartua 1ly complete structural analysis €or severel widel, occurring types of flavonols. The application of these methods in confirming the structure of azalein, a flavonoi glycoside recently described b y Wad&,$d l be discussed in detail,
Detection of the J,.4f-dihydroxyl group. It is generally considered that the decomposition of flavonols in alkali under ordinary conditions is not rapid, and that in the absence of other alkali-sensitive structures, e.g., the pyrogallol grouping, they may be recovered from alkaline solutions by acidification without significant Dechene,6 however, has shown that alkaline solutions of rutin, the 3-glycoside of quercetin, are more stable than those of quercetin. This indicates that the unprotected hydroxyl at Ca in quercetin contributes to its instability. In this study an attempt has been made t o define more closely tRe structural features new+ sary to produce instability in alkali. The spectre -
(4)
T. A. Geissmar!, in Modern Methods of Plant Analysis,
K. Paeeh and RI. V. Tracey, eds., Springer, Heidelberg, p. 451 (1955). (6) E, B, Dechene, J,Am, Pharm. A ~ s o c40, . , 4QG (1951)'
