A NEW ALDEHYDESYNTHESIS via DIMETHYLAMIDES
March 20, 1964
1.4042, and 2.5 g., 8.57, yield, of capronitrile, b . p . 73" a t 53-55 m m . , n z O ~1,4070. ~ * O D
C.
Cyclohexanecarbonitrile.-Cyclohexanecarboxaldehyde,
b.p. 63-66" a t 23-24 mm., n % 1.4507, was obtained in 71y0 yield. D . Benzonitri1e.-Benzaldehyde, b . p . 81-82' a t 31 mm., R Z o D 1.5452, was obtained in 767? yield. E. p-Chlorobenzonitri1e.-Lithium triethoxyaluminohydride (0.238 mole) was prepared in 238 ml. of ether. Into this stirred solution was added 32.7 g . (0.238 mole) of p-chlorobenzonitrile all a t once a t ice-bath temperature. The reaction mixture was hydrolyzed, after an hour, with 200 ml. of 5 iV sulfuric acid. Ether was distilled and the resulting aqueous layer was steam distilled. p-Chlorobenzaldehyde, m . p . 47-47.5', was obtained (27.9 g , ) i n 8 3 . 5 ( 2 yield. Recrystallization from hot water did not change the m.p. Reduction with Lithium Tri-n-butoxyaluminohydride on a Preparative Scale .-The use of lithium tri-n-butoxyaluminohyiride is useful in cases where t h e removal of ethyl alcohol from the product offers difficulties. Cyclopropanecarbonitrile.-In a 1-1 ., three-necked, round-bottom flask equipped with a condenser, dropping funnel, and stirrer, flushed with nitrogen, was placed 0.3 mole of lithium aluminum hydride in 300 ml. of ether ( 1 M solution). T o this solution was added dropwise over a period of 7 5 min., 0.9 mole (66.6 9 . ) of 1butanol, maintaining the temperature a t - 10 to - 5 " . The reaction was stirred for another 15 min. T o this solution ( - 10") was added 20.1 g . (0.3 mole) of cyclopropanecarbonitrile over 15 min., the temperature rising t o 8 " . The reaction was stirred for 1 h r . a t 3" (ice b a t h ) and then decomposed by 300 ml. of 5 AY sulfuric acid. The ether layer was separated and the heterogen-
[COSTRIBUTION FROM
THE
1089
eous aqueous layer was extracted three times with 25-ml. portions of ether. T h e combined ether extracts were washed with sodium bicarbonate solution and water and then dried over sodium sulfate. The ether was concectrated through a small L'igreux column. The ether distillate was extracted with 130 ml. of sodium bisulfite solution (40%) to remove as adduct any aldehyde which would have passed over with the ether. Finally this solution was used to make the adduct of the aldehyde. This adduct was extracted four times with 35-1111. portions of ether to remove 1-butanol. I t was decomposed by 42 g. of sodium bicarbonate suspended in 50 rnl. of water a t 0 " . Cyclopropanecarboxaldehyde was steam distilled and the distillate was extracted with ether. The ether was dried over sodium sulfate and concentrated in a Todd fractionating column. Cyclopropanecarboxaldehyde, b.p. 97-98" a t 726 mm., n z o 1.4302 ~ (lit.30 b.p. 97-100' a t 740 mm., XZoD 1.4302), was isolated in a yield of 13.8 g., 65.7%. 2,4-Dinitrophenylhydrazones.-Three of the 2,4-dinitrophenylhydrazones have not been previously described in the literature: ( 1) The bis-2,4-dinitrophenylhydrazone of adipaldehyde, crystallized from glacial acetic acid, m.p. 190". Anal. Calcd.: C, 45.57; H , 3.82; N , 23.62. Found: C, 45.31; H, 3.99; N 21.11. ( 2 ) The 2,4-dinitrophenylhydrazoneof 7-phenoxybutyraldehyde, crystallized from ethanol, m.p. 112-113°. Anal. Calcd.: C, 58.52; H, 4.912; N, 17.06. Found: C, 58.50; H, 5.02; N, 17.22. (3) The 2,4-dinitrophenylhydrazone of y-phenoxybutyraldehpde, crystallized from ethanol, m .p. 96". Anal. Calcd.: C, 55.8; H, 4.68; X, 16.27. Found: C, 55.67; H, 4.80; N, 16.42. (30) H . C. Brown and A. Tsukamoto, J . A m . Chem. S O L .88, , 4549 (1961)
RICHARD B. WETHERILL LABORATORY OF PURDUE UNIVERSITY, LAFAYETTE, IND.]
Selective Reductions. V. The Partial Reduction of Tertiary Amides by Lithium Di- and Triethoxyaluminohydrides-A New Aldehyde Synthesis uia the Dimethylamides'b2 B Y HERBERT c. BROWNA N D
AKIRA TSUKAMOT03
RECEIVED OCTOBER 18, 1963 T h e reduction of tertiary amides by lithium di- and triethoxyaluminohydrides, conveniently synthesized in situ by the reaction of ethyl alcohol with lithium aluminum hydride, was explored as a useful synthetic route from the carboxylic acid t o the corresponding aldehyde. With the exception of the highly hindered amide derivative ~,N-diisoproppl-n-butyramide,a wide variety of n-butyryl tertiary amides were readily converted into n-butyraldehyde in satisfactory yields. The results realized for the simplest derivative, K,N-dimethyl-nbutyramide, were especially favorable. Moreover, the same procedure served to convert the dimethylamides of n-butyric acid, isobutyric acid, pivalic acid, and benzoic acid into the corresponding aldehydes in yields of 80 t o 90%. Accordingly, the scope of this new aldehyde synthesis was explored by applying i t t o 24 representative acid derivatives. With the exception of conjugated unsaturated derivatives, such as crotonic and cinnamic, wide variation in structural type could be tolerated, with the corresponding aldehyde being produced in yields from 60 to 9 0 ~ o o .
The ready availability of carboxylic acids makes it highly desirable to have available convenient synthetic routes from such acids to the corresponding aldehydes. The catalytic hydrogenation of acid chlorides4 and the Stephen reduction of nitriles5 have served for many years, but suffer from a number of disadvantages. The preparation of aldehydes from various acid derivatives by reduction with lithium aluminum hydride has been widely studied.6 The most successful developments in this direction have involved the selective reduction of a number of tertiary amides. Thus, Wittig and Hornberger synthesized a series of unsaturated aldehydes, CsHj(CH=CH)nCHO ( n = 1, 2, 4, (1) Based upon a thesis submitted b y Akira Tsukamoto in June, 1959, in partial fulfillment of t h e requirements f o r t h e degree of Doctor of Philosophy. ( 2 ) A preliminary communication reporting some of t h e results in this paper was published earlier: H. C. Brown and A. T s u k a m o t o , J . A m . Chem. Soc., 81. 502 (1959). (3) Research assistant on a g r a n t provided by t h e Eli Lilly and C o . , 19571959 ( 4 ) K . W. Rosenmund, Ber., 61, 585 (1918). ( 5 ) H . Stephen, J Chrm. Soc , 1874 (1926). (6) For a general review of these synthetic routes from carboxylic acid derivatives t o t h e corresponding aldehydes, see E. Mosettig, "Organic Reactions." Vol. V l I I , John Wiley and Sons,I n c , New York, 1954, p p . 2182.57
and 5 ) , by the partial reduction of the corresponding Nacylcarbazoles with lithium aluminum hydride.' Similarly, Weygand and his co-workers demonstrated that the N-methylanilides could be utilized to produce a wide variety of aldehydes in good yields (60 to go%).* Moreover, it has been established t h a t the partial reduction of the 1-acyl-3,5-dimethylpyrazolesga or the N-acylimidazolesgb gives a general synthetic route t o aldehydes from carboxylic acids. Finally, we recently reported that lithium aluminum hydride reacts with 1acylaziridines to provide a synthetic route to the aldehyde. l o In these syntheses it is evident that the electronic and steric characteristics of the tertiary amide group are being utilized a s a means of controlling the exceedingly powerful reducing action of the reagent, lithium aluminum hydride. The introduction of alkoxy substituents into lithium aluminum hydride provides a simple method of modifying the reducing power of the ( 7 ) G. Wittig and P . Hornberger, A n n , 677, 11 (1952) (8) (a) F. Weygand and G Eberhardt, Angew. C h e m . , 64, 458 (1952); (b) F . Weygand, G . E b e r h a r d t . H Linden, F Schafer, a n d I . Eigen, ibid , 66,525 ( 1 9 5 3 ) , ( c ) F Weygand and H l,inden, ibid , 66, 174 (1954) (9) (a) W. Ried a n d F J , Konigstein, ibid., 70, 165 (1958); (b) H A. S t a a b and H . Braeunling, A n n , 664, 119 (1962) ( I O ) H . C Brown and A Tsukamoto, J . A m Chem. So6 , 83,4549 (1961)
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HERBERT C . BROWXA N D XKIRATSUKAMOTO
reagent,l1-l4 opening u p a new means of achieving selective reductions. For example, lithium tri-t .butoxyaluminohydride is a highly selective reagent which has made possible the partial reduction of acid chlorides15 and phenyl estersI6 to aldehydes, and the stereospecific reduction of steroids. Similarly, lithium trimethoxyaluminohydride'" has proved very valuable for the stereospecific reduction of bicyclic ketones. l y Finally, lithium triethoxyaluminohydride has proved applicable to the reduction of both aliphatic and aromatic nitriles to aldehydes in good yield. 14, l9 Accordingly, we decided to explore the possible utility of these new alkoxy derivatives of lithium alutninum hydrides for the selective conversion of tertiary amides into the corresponding aldehydes.2o Results and Discussion The Reaction of Various Alkoxy Substituted Lithium Aluminum Hydrides with N ,N-Dimethyl-n-butyramide. -Various alkoxy derivatives of lithium aluminum hydride can be prepared conveniently by adding the calculated amount of an alcohol to a standardized solution of lithium aluminum hydride in diethyl ether. tetrahydrofuran, or diglyme.'3,14 The hydride reagents thus preparedz1 were used in sifir for the reduction of N,N-dimethyl-n-butyramide, adopted as a test amide. All of the reactions were carried out under essentially identical conditions so as to make it possible to compare the results realized with the different reagents. -1s a consequence of this procedure, the yields observed may not necessarily be the maximum possible for the reaction in question. In all cases 1 equivalent of the hydride reagent was used per mole of the amide. In some cases the amide was added to the hydride reagent (normal addition); in others, the hydride was added to the amide (reverse addition). The results revealed that 80 to 90% yields could be realized by the use of lithium di- and triethoxyaluminohydride in ether solution a t 0'. In the case of lithium triethoxyaluminohydride there was no difference in the yield whether normal or reverse addition was utilized. In the case of lithium diethoxyaluminohydride it was necessary to add the hydride t o the amide to achieve a high yield, although normal addition was possible providing the reagents were mixed a t -SOo and then brought to the reaction temperature. The experimental results are summarized in Table I . The Reaction of Lithium Di- and Triethoxyaluminohydride with Representative Tertiary Amides of nButyric Acid.-The partial reduction of tertiary amides by lithium aluminum hydride has proved to be very (11) 0. Schmitz-IIuLIont and \-, Hahernickel, B e y , 90, 105.1 ( 1 9 5 7 ) . ( 1 2 ) G Hesse and K Schrodel, A n n . , 607, 2-1 (1957). (13) H C Brown and K . F McFarlin, J A m Chem Soc., 78, 232 (1936) 8 0 , ,5372 (1958). (11) H C Brown a n d C J S h o a f , % b i d ,86, 1079 (1961) (1,:) H C Brown and B. C Suhha Iiao, i b d , 8 0 , ,5377 (1938). (16) H C Brown and P hl IVeissman. manuscript in preparation. (17) 0 H Wheeler and J . L . hlateos, C a n J Chem , 36, 12 (1958) (18) H C Brown and H . R Deck, manuscript in preparation ( I 9 1 H C Brown and C P Garg, J . A m C h e w S o c , 86, 1088 (196.1) (20) Attention should he called to the simple reduction of ethyl esters t o aldehydes with diisobutylaluminum hydride: L I Zakharkin a n d I hl Khorlina. Teivahedron I . e l i e r s , No. 1 4 , 619 (1962) ( 2 1 ) In some cases the reagents obtained in this manner are homogeneous In other cases the evidence is t h a t they are not. For example, the product formed b y adding 2 moles of ethyl alcohol to lithium aluminum hydride appears ti, be nearly pure lithium diethoxyalurninohydride, h u t t h a t produced with 3 moles of ethyl alcohol appears t o be largely lithium triethoxyaluminohydride accompanied by significant quantities of the di- and tetraIn spite of the uncertainty, in some cases, of alkoxy derivatives ( r e f 1.1) the precise nature o f the reagents thus obtained, the products will he referred to in terms of their gross composition, such as I,i(EtO)aAlH and I.i(i-Pr0)~AIH
Yo1
Sfj
TABLEI YIELDS O F ti-BUTYRALDEHYDE I S T H E 1
