Some Observations on the Hydrolysis of the Amides of Primary a-Acetylenic Amines

JOHN NICHOLSON GARDNER T~,cl~nicnl Developrner~t Depcir~tnenl, HofJn~rrr~n-Lri Roclle Ir~c. , Nlrfley, New Jersey 07110

Received October I I . 1972

Some amides of primary a-acetylenic amines were made from the corresponding a-acetylenic alcohols by the Ritter reaction. Depending upon the other substituents on the carbon atom bearing nitrogen and the ethynyl group, hydrolysis resulted in formation of the a-acetylenic amine or in hydration of the triple bond to yield a ketone.

Quelques amides d'amines primaires a-acetilCniques ont e t t p r tpar tes par la reaction Ritter sur les alcools a-acetylCniques correspondants. Dependant de la nature des autres substituants portes par I'atome de carbone portant I'azote et le groupe ithynyle, I'hydrolyse des amides conduit soit a I'amine a-ace- tylknique ou a I'hydratation de la triple liaison fournissant la cetone. [Traduit par le journal] C m . J . Che 11.. 51. l1lh (1973)

The amide 1 (R, = R, = CH,) undergoes hydration to 2, via the oxazolini~~m salt 3, upon reaction with aqueous hydrochloric acid (I), but the corresponding formamide derivative 1 (R, =

CH,, R, = H) yields, under similar conditions,

Rl--N-COR2 CH3-N-COCH3 I

CH3-C-CeCH I

CH3-C-COCH3 I I

CH3 CH3 1 2

tlie acetylenic ainine (1). In contrast the amide 1 (R, = H, R, = CH,) was reported (2) to be insoluble in dilute liydrochloric acid and to yield with the concentrated acid a product in which 3-amino-3-methyl-2-butanone was detected spec- troscopically. In the case of 1 (R, = R2 = H), almost quantitative hydrolysis to the aniine 4 occurs (3) with aqueous mineral acid. Our interest in the efficiency of this last reaction has resulted in observations which extend those already reported.

We prepared the amide 1 (R, = H, R, = CH,) by the Ritter reaction of acetonitrile with 3-hydroxy-3-methyl-1-butyne, using a modified version of the p~rblished proced~ire (4). We found that upon hydrolysis with sulfuric or hydro- chloric acid in aqireous methanol, followed by basification of the reaction mixture and steam distillatioil, the dihydropyrazine 5 (R = CH,) was formed in good yield. This prod~ict was obtained even when the reaction mixture was

carefully adjusted to pH 7 prior to the steain dis- tillation, arid thus it may be concluded that alka- line conditions are not iiecessary for its formation. It clearly results from hydration of 1 (R, = H, R, = CH,) to 3-amino-3-methyl-2-b~itanone and condensation of two molecules of the latter to yield 5 (R = CH,). The formation of dihydropy- razines from a-amino ketones is well doc~imented (5) and conditions for interconversion of these two classes of compound have been recorded (5), so that this reaction sequence provides a conveni- ent route to coliipounds of these types. A proced- ure (which has not been optimized) for obtaining 5 (R = CH,) fro111 3-hydroxy-3-methyl-1-butyne in 54% yield, without isolation of the inter- mediate alnide 1 (R, = H, R, = CH,), is given in tlie Experimental. The reaction sequence is thus a viable alternative to tlie recently reported synthesis (5) of 5 (R = CH,), in 37% yield, by

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GARDNER: HYDRATION O F

reaction of methyl isopropyl ketone with aqueous alkaline potassium ferricyanide. The two pro- cedures are not fully equivalent, however, for although 3-liydroxy-3-methyl-1-pentyne was suc- cessfi~lly converted to the dihydropyrazine 5 (R = C,H,) (isolated as the dihydrochloride), with I-ethynylcyclohexanol as substrate, the product was the aniido ketone 6 . It may be that under more rigorous conditions it woi~ld be possible to hydrolyze the amide function in 6 and to obtain the corresponding diliydropyrazine which has been prepared (5) by the reaction of cyclohexyl methyl ketone with ferricyanide.

The conditions for hydrolysis of 1 (R, = H, R, = CH,) which led to 5 (R = CH,) also gave a very minor amount of the amine 4, which was detected by gas chromatography. It was thus of interest to investigate the hydrolysis of the amide 7 to see whether it yielded the corresponding amine or (through hydration of the triple bond, liydrolysis of the amide, condensation, and autoxidation) 2,3,5,6-tetrainethylpyrazine. The product obtained from this reaction was 3- amino-1-butyne hydrochloride. Thus, we may conclude that the behavior of the ainides of primary a-acetylenic amines on hydrolysis is critically influenced by alterations in the sub- stituents on nitrogen and on the carbon atom a to the triple bond.

Experimental 2,2,3,5,5,6-H~xnt11et/t~l-2,5-~liltj~dropj~rnzitie (5, R = CH,)

Acetonitrile (500 g) was added witli stirring to s u l f ~ ~ r i c acid (98% w/w, 500 g), while cooling to maintain a temperature of 0-5". When the addition was complete, the ~ i i ix t~ l re was stirred for 15 min at the same temperature and then 3-liydroxy-3-methyl-I-butyne (250 g) was added slowly while continuing to maintain a ternperat~~re of 0-5". Upon conipletion of the addition, the solution was brought to 10' and stirred for 2.5 h. Ice (2 kg) was added and the res~~l t ing mixture was distilled at atmospheric pressure, using a 20-plate Oldersliawl column ( r c f l ~ ~ x ratio 4:2) ~ ~ n t i l the vapor temperature reached 97'. The distillation residue was cooled and, while maintaining < 5 0 by the addition of ice, sodium hydroxide (50% w/w, 750 nil) was introduced. The r e s ~ ~ l t a n t alkaline s o l ~ ~ t i o n was subjected to steam distillation. The dihydropyrazine 5 (R = CH,) (219 g, yield2 54:4) was isolated from tlie distillate by filtration, n1.p. 88-91" (lit. (5) m.p. 88-89"). Tlie assignment of s t r ~ ~ c t u r e was confirmed by the prod~lct 's i.r., L I . ~ . , n.ni.r., and mass spectra.

'The column was ~ ~ s e d a s it was desired to recover the excess acetonitrile.

ZMicroanalysis indicated that the material was approx- imately a hexahydrate, and the yield was calculated on this basis.

hr-(3-Metlrjflpetrt-I-j~rr-3-yl)ncetnttride 3-Hydroxy-3-methyl-I-pentyne (75 g) was reacted with

s ~ ~ l f i ~ r i c acid (98% w/w. 150 g) and acetonitrile (1 50 g) a s described for the preparation of 5 (R = CH,). After q ~ ~ e n c l i i n g with ice, the reaction n i i x t ~ ~ r e was made alkalinc with sodium hydroxide solution (20% w/w), saturated with s o d i ~ ~ n i chloride, and extracted with ether (3 x 600 ml). The extracts were washed with water and brine, then dried ( s o d i ~ ~ n i s~llfate) and evaporated to dryncss. Tlic rcsid~rc was distilled (b.p. 60-75"/2.0 nini) to yield a distillate (27.5 g) which crystallized. T w o recrystallizations from liexane-dichloromethane gave pure hl-(3-mcthylpcnt-I-yn-3-yl)acetamide: m.p. 62-65"; i.r. (CHCI,) 3445, 3300, 1680, and 1500 cni-I ; n.ni.r. (CDC13) 0.98 (t, 3, J = 7 HZ, CH3CH2). 1.60 (s, 3, CH.,C), 1.9 (s, 3, CH3CO), 2.33 (s, I , --CH), and 5.92 p.p.m. (br, I, N H ) .

Anal. Calcc!. for C,H,,NO: C, 69.03; H , 9.41; N , 10.06.Fo~1nd:C,69.16;H,9.50;N,9.87.

3,6-Dietl~yl-2,3,5,6-tetrnttiet/~j~l-3,6-clil~y~lropj~rozitre Dilryrlroclrloride (5, R = C2 H,)

The aforegoing amide (5.2 g) in methanol (25 ml) and sulfuric acid (12% w/w, 25 nil) was heated under reflux for 3 h. Tlie niixture was then steam-distilled, 200 nil of distillate bcing collected. Tlie residue was niade alkaline witli sodium hydroxide s o l ~ ~ t i o n (20% w/w, 15 ml) and again steam-distilled, 100 nil of distillate being collected. The distillate was bro~lglit to p H 2 by addition of hydro- chloric acid (37% w/w) and then evaporated to dryness a t reduced pressure. Tlie residue was crystallized from ethanol-ether to yield 5 (R = C 2 H j ) as a dihydrate (1.9 g): m.p. 196-199"; i.r. (KBr) 1705 and 1570 cni- ' ; n.m.r. (CDCI,) 1.02 (t, 6, J = 7 Hz, CH3CH2) , 1.68 (s, 6, CH,C), 2.26 (s, 6, CH3C=), and 8.86 p.p.m. (br, 6, N H and H 2 0 ) .

Anal. Calcd. for ClZH2,C12N2.2HZO: C, 47.53; H, 9.31; N , 9.24; CI, 23.38. Found: C, 47.50; H, 9.33; N, 9.20; C1,23.68.

N-(l-Ac~etylcyclol~e~~j~l)ae~tntttide 6 N-(I -Etliynylcyclohexyl)acetamide (2, 4) (5.2 g) was

heated with s u l f ~ ~ r i c acid exactly as for the preparation of 5 ( R = C2Hj), a reaction time of 15 h being ~ ~ s e d . The reaction mixture was cooled, diluted with its own volume of water, and niade alkaline witli sodium hydroxide solution (20% w/w, 25 nil). Extraction with ethyl acetate and crystallization from ethyl acetate- hexane gave 6 (1.9 g): 1n.p. 140-142" (lit. (2) 133-135'); i.r. (CHCI,) 3445, 1715, 1680, and 1500 cni-I ; n.m.1.. (CDCI,) 2.02 (s, 3, CH,CO), and 2.12 p.p.m. (s, 3, CH3CO).

Anal. Calcd. for C1,H,,NO2: C, 65.54; H, 9.52; N, 7.64.Found:C,65.8l;H,9.52;N,7.65.

N-(B~tt-l-yt~-3-~~1)o~e/oti1i~Ic~ (7) Acetic anhydride (30 nil) was added slowly to sulfuric

acid (98% w/w, 50 nil) while tlie temperature was held at < 4 0 . The n i i x t ~ ~ r c was cooled and, at 15-25", but-I-yn- 3-01 (14.5 g) in acetonitrile (21 g) was added. The reaction vessel was cooled3 to hold tlie temperature at 15-25" and after 7 I1 at this t c m p e r a t ~ ~ r e it was poured onto crushed

3The reaction is very slowly cxotliermic and on one occasion the te~iiperature rose to 175" after tlie reactants had been niixed and the mixture was t l i o ~ ~ g h t to be quiescent.

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1418 CAN. J . CHEM. VOL. 51. 1973

ice (200 g) and, using external cooling, made alkaline residue sublimccl at 135-140/0.5 mm. Tlie sublimate was with s o d i ~ ~ m liydroxicle solution (50';/, w/w, 125 ml). Tlie recrystallized from methanol - ethyl acetate to give tlie product was isolated by extraction witli ether and s ~ ~ b - anline hydrocliloride (370 mg); n1.p. 162-165'. Three limed a t 50-80G/2.0 mm. Tlie s ~ ~ b l i r n a t e (1.53 g) comprised recrystallizations from tlie same solvents gave analytically 7, suficiently piwe for further reactions. Two recrystalli- pure material: m.p. 166-169' ; i.r. (KBr) 3250 c m - ' ; zations froni diclilorometliane-liexane gave pure 7: n.m.r. ( D Z O ) 2.02 (d, 3, J = 7 Hz, CH,CH), and 2.45 1n.p. 94-95"; i.r. (CHCI,) 3450, 3310, 1680, and 1510 p.p.ni. (el, I, J = 2 Hz,-CH). cn i - ' ; n.ni.r. (CDCI,) 1.23 (d, 3, J = 7 Hz, CH,CH), Anal. Calccl. for C,HSCIN: C , 45.52; H, 7.64; N, 2.00 (s, 3, CH,CO), and 2.26 p.p.ni. (d, 1, J = 2.5 Hz, 13.27. Found: C, 45.25; El, 7.39; N, 13.44. =CH).

Anal. Calcd. for C ~ H B N O : C , 64.84; H, 8.16; N, 12.60. The a~ l t l io r is indebted to the staff of the Physical Found: C, 64.87; H, 8.05; N, 12.47. Chemistry Department of H o h a n n - L a Roclie Inc. for

~ - A I ~ ~ I I ~ - / - ~ ~ I ~ J J I I ~ Hyrlrocl~lo~.irle the measurement of spectral da ta and for niicroanalyses.

C o r n p o ~ ~ n d 7 (1.17 g) was heated i~ncler reflux for 4 h in sulfuric acid (12% w/w, 25 nil). Tlie niixtt~re was 1. N . R . EASTON and R. D. DILLARD. J . Org. Chern. 28, coolecl to 60°, diluted with water (25 nil), and made 2465 (1963). alkaline witli sodium hydroxide solution (20% w/v, 35 2. N. R . EASTON, D. R. CASSADY, and R . D. DILLARD. ml). This solution was steam-distilled anel the distillate J . Org. Chern. 30, 3884 (1965). (700 ml) adjusted to p H 3 witli liydrocliloric acid (37% 3. Belgian Patent 751 189. w/w). Tlie water was evaporated ancl tlie resicl~~e, dis- 4. N. M. LIBMAN and S . G . KUZNETSOV. Zh. Org. Khirn. solved in nietlianol, was treated with charcoal. The 4, 2122 (1968). methanol solution was evaporated to dryness and tlie 5. D. G. FARNUM and G. R. CARLSON. Synth. 191 (1972).

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