69 (1950) R E C U E I S 539 - - .. -. . ._

547.596.2-2 I I N-METHYLATED MENTHYLAMINES AND

PIPERITY LAMINES

BY

JOHN READ and WILLIAM WILSON CUTHBERTSON (Chemistry Research Laboratory, United College of St. Salvator and St Leonard,

T h e University, St . Andrcws. Scotland).

T h e N-methyl- and N-dimcthyl-derivatives of I - and d-ncomenLhyln nines, as well a s the Corresponding trirnethylammoni~~ni iodides and hydrcxides. have been descrihed by Kcad and Hen&!/ I ) . Corresponding deriviiti,v,es of d-iso- and d-neoisornenthylamine have now bzcn prepared and char;lct.!riscd. together with those of the closely related I-piperitylaniine. d-ncorsoMenthyl- amine has been obtained in a new way. starti:ig from I-pipcritonc.

As a result of investigations originating in the Univcrsity of Sydney, Australia. upon the eucalyptus ketone, I-piperitone, and continued in the University of St. AndreLvs. Scotland. it has proved possible to establish the relative molecular configurations of the piperitones. piperitols. menthones. menthols and menthylamines, an achievement found possible hitherto in few other comprehensive groups of organic compounds. I n the C O U J ’ . ~ ~ of th i s work a remarkable parallelism has been observed betlveen the optical rotatory po\vers of the four fanlilies of menthylamines and the stereochemically analogous menthols 2 ) ) . I t is therefore of interest to obtain information respecting Ihe optical rotatory powers of derivatives of these two groups of stereoisorners. As regards the rnenthyliirnines ( I ) . da ta of this kind for N-methylated derivatives in the I - and d-nco-series h.ivc been given by Read and Hcridry 1 ) . In the present paper infornation is brought forward concerning some similar derivatives in the d-iso- and d-ncoiso-series of menthylamines. and also in the I-piperitylamine series (11):

. ..

1 ) J. &ad rind 1. A. Hendry , Rer. 71, 2541 (1938). 2 ) For ii surnmary of much of this work see 1. Rcad, “A Chaptcr in thr Chemistry

of Essential Oils.’’ Nineteenth Streatfcild Memorial Lecture, London, 1936.

CHMe

H2C CH2 /\

I 1 H2C CH'NH2 \/

01 CH ' CH(CH&

N-methyl-d-isomenthylamine was prepared through the substituted glycine by the method of Read and Mendry 1 ) : but I-piperitylamine gave an unsatisfactory result by this method.

The molecular rotatory powers of the free bases are summarised in table I. the solvent being chloroform (c 2 to 4 ) : the values for the quaternary iodides were taken in aqueous solution ( c 2 ) . T h e data for the primary bases were observed by Rcad and Storey 3 ) , and for the methylated 1- and d-neomenthylamincs by Read and Hendry 1) ; the remainder are the result of the present research. I t is noteworthy that d-neoisomenthylamine has been isolated for the first time from the mixture of menthylamines produced in the reduction .of the crudz oxime of d-isomenthone. obtained from hydrogenated l-piperitone.

T a b l e I Values of IMl,, for Menthylamines and Piperitylamines

Ment h ylamines . . . - . .

d-neo- d-iso- ti-neoiso. . . -

R . NH2 1 -- 59'' + 13'5 f 4 6 +17 -107

R . NMe2 i - - 109 ' f 7 4 . 5 , +67 - - - I 3 -107 H . NHMe ' - - I 17 , +45 ' f36 unobserved I - 85

R.NMejl ' - - 1 2 8 , 63 I + 6 '5 , + 5 4 . 5 - 1 5 ' 5 I i

These figures shon: ( I ) that thc attachment of the first methyl group to the nitrogen atom may either increase or decrease the optical rotation: ( 2 ) that the introduction of two methyl groups is more decisive, since i t enhances o r at least maintains the rotation of the original base except for the instance in which optical reversal occurs: (3) that the formation of the quaternary ammonium salt i s usually accompanied by a profound disturbance of the optical effect, leading indeed to a strong reversal of the direction of rotation Lvhen the bulky quaternary ammonium group is brought into the cis-position to the isopropyl group 2 ) : and ( 4 ) that the optical rotations of the . - . -

3 ) I . Read and R. A. Storey. J. Chem. S O ~ . 1930, 2764. 2777.

N-Methylatcd menthylamincs and prperrryiamrnes. OY \ 1950) RECUEIL 541

N-methylated l-piperitylamines. now prepared for the first time, are broadly analogous to those of the corresponding methylated menthyl- amines. This last observation is of interest because in a rrsearch on the production of piperitol from piperityltrimethylammonium iodide, Read and Walker ') obtained a highly laevo-rotatory base with [ 7 1 ,,13.5-355O. which was then supposed to be N-methyl-l-piperityl- amine. I t is now shown that this abnormal value does not correspond to any N-methyl derivative of I-piperitylamine, the values for the mono- and di-methyl derivatives being [ x J ,)17--5 1 .Oo and [ X ] ,.,lH-

59.2'. respectively. The possibility remains that Read and Walker's base may have been derived from a stereoisomeric piperitylamine.

Table I1 shows more fully the effect upon the rotatory po-wer of salt formation, leading to the production of optically active c,itions; the observations were made for aqueous solutions (c 2). The values for the substituted neo- and neoiso-menthylamines have been cbtained in the present research; the rest are taken from the work of Rcad and Hendry I ) , Read and Store!y : j ) , and Read and Robertson 5 ) .

- .. . ..- _. .~ . - . .- . .

T a b l e I1 Values of [MI,, for Salts in Aqueous Solution

[R . NH3J CI [ R . NMeHz] CI [ R . NMeZH] CI IR . NMe3] I

Menthy lamines

1- d-neo- d-rso- d-neoisJ- _ ._ .. . . . - . .

_ _ ~. .. -~

- 70° ! f 4 1 4-45 + 40 -108 + 34 f 3 5 . 5 unobseried -110 f 3 4 + 5 9 + 2 9 . 5 -128 -63 I + 6 . 5 + 5 4 . 5

I

The most noticeable features of this table are ( 1 ) the steady increase of the numerical values for derivatives of I-menthylamine: ( 2 ) the strong optical inversion shown in the final stage of the methylation of d-neomenthylamine: and ( 3 ) the formation 0' a dextro- rotatory ion when laevo-rotatory N-dimethyl-d-neoisomeiithylamine is converted into its hydrochloride. I t may be added that '-piperityl- amine. like d-neomenthylamine, shows a striking difference between the initial and final types, the molecular rotatory powers of I-piperityl- amine hydrochloride and I-piperitvltrimethylammonium iodide being --I 58' and -1 5.5', respectively.

In considering the data as a whole, the outstanding conclusion is

4 ) J. Kcad and J. W a l k e r , J. Chein. SOC. 1934, 308. 5 ) J. Read and G. J. Robertson, J. Chem. SOC. 1927, 2169.

-. . . . . .- . . -

542 Iohn Read and William Wilson Cufhbcrrson. - - - _. - - _

that in this series of closely related stereoisomers. of known relative molecular configurations, no prediction of approximate optical rotatory power can be made at any stage in the methylation processes. Primary I-piperitylamine shows a very marked exaltation of molecular rotatory power when compared with any one of the optically active primary menthylamines (table I ) . This exaltation. due to the A'-double bond of primary I-piperitylamine. is partly lost in the secondary base. N-methyl-l-piperitylamine; and although restored in the tertiary base. N-dimethyl-I-piperitylamine, the effect fades out in the quaternary compound.

Apart from the general interest attaching to the optical rotatory powers and other physical properties of these substances, the quater- nary ammonium compounds have an important specific application in affording access to menthenes of known constitution, through pyrogenic decomposition of the iodides or the derived hydroxides. This method has been successfully applied in the I- and d-nco-series of mcnthylamines by Read and Hendry 1 ) ; further results of value, as yet unpublished, in this interesting field of terpene chemistry have accrued from current studies of a similar kind in the St. Andrews 1 a bo r R t o r i es .

E x p e r i m e n t a l p a r t . I . Derivatives of d-isomenthylamine. tl-isoMenthyl,imiiie w;is prepared from I-piperitonc Ihaving [ z ] ,,"'--42" in a I-din

t u l v ) liy the method of Rcad and Robcrfsun I ; ) . W i t h the usu,il pallxiiiim catalyst this ketone yic:dcd almost its own weight of crude tl-iso-menthone with[ 2 ) 'Ii I 47" ( I-dni t u l ) ~ ) ; this (170 y ) gave J viscid oxiine (202 g) having [ I ] l 1 1 7 - L 26.8" (c. 2.6. ethanol). Rcductiori of the oxitne (100 g) with sodium and anhydrous ethanol yielded crudc d - i~o ine i i t l i~ l i i i i i i i i~~ hydrochloride (100 $1) with [ 1 1 Ill'i 16.3" (c 2, water ) . Fractional crystallisation from a mixture of hot acctone (700 cm:') and mcth;inol (70 cm") g , i w the pure hydrochloride ( 24 g ) , [ 7 1 l l c 5 7 23.0 ( c 2.0, water ) , from xvhich pure tl-is~inentliylamine. [ Y] I ) 29.4" ( c . 4.0. CHCI,). Iiberiitcd. W h e n treated according to the method of Read a i d Hendry ') with cthyl chloroacetate, this base ( 4 0 g) gave d-isonienth!iIRl!I'.inc ( 13 g) , crystallising from hot water a s a colour le~s hygroscopic. fibrous mass. m.p. 183". (Found: C 66.5: H 10.6. C,,H,,,O,N requires C 67.6; H 10.8.)

W h e n heated in a n oil-bath at 200" for iin hour. 1 1 g of this suhstilnce gave 6 g of N-mcth!Il-d-isoment/i!~Iamine, a colourlcss oil with ii hasic odour. b.p. 92"!13 inm. nl,l" 1.4612. [ ~ l , ~ ~ ' ; k 2 1 . 4 " ((. 2.1. CHCI:,). (Pound: C 77.2: H 13.0. C,,H, ,N requires C 78.3; H 13.6). T h e benzo!+l deriuativc was a syrupy liquid, b.p. 170"/1.3 min. forming crystals m.p. 64", -10.8" ( c 2. CHCI,). (Found:

I)

6, I. Read and G. 1. Robcrfson, J . Chem. SOC. 1926, 2221.

N-Mcth!ilatcd merithylarnines and piperit!i/arnines. 69 ( 1950) R E C U E I L 543 . . .. __ - . - - . .

C 79.7; H 9.9. C,,H,,ON requires C 79.1: H9.9.). T h e hydrochloride had 1 7 ] I , 1 R I 17.3" ( c 2. water ) .

A mix:urc of 30 y tl-isomenthylaminc, 90 cm;% anhydrous mcth:inol, and 12 cm:l methyl iodide was heated under reflux for 30 niinutcs; 4.5 y sodium dissolved in 60 cm' mrthanol was added with further heating for 30 minutes: thc heating was rcpeated .ifter adding another 6 cm:, methyl iodide; finally, G cn18 tncthyl iodide and 4.5 g sodium dissolved in 60 c n P methanol wcrc addrd with continued heating for 30 minutes. T h e stciiin distillate wiis then acidified with dilute hydrochloric acid iitid evaporated to dryness (36.3 g ) on i i water-hiith. T h e lilwratrd mixture of haws (30 y ) was boiled i:nder reflux for a n hour with 'icetic iinhydridc (25; c d ) . T h c product w-iis poured into dilute sodum hydroxidc solution and extracted with ether. T h e ether was then extracted three times with dilute hydrochloric acid to remove tlic frer tcrtiary txisr. the acetyl-N-niethyl-tl-~so~~ienthyI~inii~ie remailling in the ether. N-dinictlr~~l-d-isorncn~li~~larriiric (22 y ) , oht,iincd by hiisifying thc acid extract, h;ld I1.p. 97" 13 m i . t i l ,14i 1.460Y. [z],,li-t 36.5' ( c 2.1. CHCI,,). (Found: C 7h.8; H 13.8. C,,H,, requires C 78.5; H 13.7). T h c hydrochloride had t27.0" ( 1 . 2, water) .

W h e n this tertiary base (10 g ) was heated gently under reflux with methyl iodide (30 cn?) in an6ydrous methanol ( 3 0 it yielded a solid residue after the inethanol and excess of methyl iodide had hcen distilled off. Recrystallisation from acetone gave colourlcss Icaflcts of d - i s o r n e n t / ~ ~ ~ / t r i r ~ t c f / ~ ~ ~ l ~ i ~ t ~ ~ o ~ i ~ i r n iodide, m.p. 184". [ X I , , ' " . 2.0" (c , 1.5. water ) . (Found: C 4R.I: 1-1 R.6. C,,,H,,NI rcquircs C 47.9; H H.6).

11. Derivatives of d-neoisomenthylamine. T h e crude mixture of hydrochlorides from the mother-liquors accumul~t ing in the

pwpiiratiori of tl-i.soinenthyl;imine hydrochloride ( u . supra) furnished ( I mixture of tnenthylamlnes (2 I 7 g ) ; this was converted into a mixture of salicylidenc-inenthyl- m i n e s (3x2 9 ) . Fractional crystallisation from light petroleum yave three successive fractions a s follows: ( 1 ) m.p. 110-1 12", [ 71 l,l; 1 67.0' (c. 2, CHCI,,), 100 g; ( 2 ) n . p . 75 80". [ Y ] ~ , I ~ - 1.2". 50 g: ( 3 ) m.p. XC&Xj0, I ~ ] ~ , ~ ~ + 1 0 . 2 ~ . 26 g. 1:raction ( 1 ) consisted chiefly of salicylidene-d-isomenthy1;iminc. Fractio 1 ( 2 ) . after two rccrystallisations from light petroleum, gave pure salic~lidene-d-nccisoinenthyl- iiminc. 111.p. 99 100". [ x J l l ~ ~ - - 1H.1". 24 g iis drscribed by Rend and Robertson ;,). Hydrolysis with dilute sulphuric acid gave the frre base. b.p. X4",'12 111ni.

tl-ri~~oi?;omcnth~lainiiic ( 6 g ) , when mcthylatcd with methyl Iodide 11s the mcthqd dcscribrd iihovc for tl-i.~omenthyl;iiiiiIie, yielded ii mixture of bas,ss (5.8 9 ) . -1'he ciwde product wiis acetyl;ited iind worked up according to the procrd.irc ;iI,.e;idy given. The resulting N-dirnc~thyl .d-iicoisomenfh!~/amirlc ( 2 9 ) . ii colourl(.ss o i l with :I biisic odoiir. hcid h.p. 93 -94":l 1 mm. [ I ] 7.15" ((. 2. CHCI,,). (Fuund: C 7X.5: H 13,s: N 7.8. C,21.1,-,N requires C 78.5: H 13.7; N 7.6)) T h e hldrochloride crystalliscd from ;Icctonc in fine colourlcss needles. m.p . 209". [ l,2z-i. 13.4" ( c 2. u a t c r ) .

d~~cl~~/ -N-mcth~~/ -d-neoisoni r r t th~~/ani i r ic (2.5 g) was i i syrup. 1i.p. 153- 155" '1 1 mm. I x ] , , ' ~ ! 44.9' (c 2.5. CHCL,). (Found: C 74.0: H 11.8: N 6 6. C,.,H,.,ClN requircs C 74.0: H 11.8; N 6.6).

W h e n the tertiary h a w (0.65 g) was warmed wth methyl iodide [ I cm") in anhydrous methanol (10 cm:') it yiclded d-neoisontcr ihi! i l f r i~tet / i !~/ '~~n~~i~)r i i~i~i i irdidc, crystiillising from ;iretone in colourless leaflets (0.54 9 ) . m.p. 195".

5fQ John Read and William Wilson Cuthbertson. N-Methylated menth ylamines, etc. - - __ . ..

[ 2 ] I ) y 5 + 16.8" (c 1.5. water). (Found: C 47.6; H 8.4; N 4.4. C,,H,,NI requires C 47.9; H 8.6; N 4.3.)

111. Derivatives of I-piperitylamine. An attempted monomethylation of I-piperitylamine (Read and Storey : I ) ) by the

mcthod of Read and Hendry I ) being unsuccessful. the methylation of this base (25 9 ) was accomplished as described above for d-isomenthylamine. The resulting niixture of secondary and tertiary bases (15 g ) when acetylated and treatcd as described in the same place gave neutral (11.7 g ) and basic (3.2 g ) products, The ncutral product contained terpene material; from it was isolated, by fractional crystallisation from aqueous methanol. slightly impure accfyI-N-mcthyl-I-piperityl- itmine, m.p. 111--112". [:,JI,"-87.9" (c 2, CHCI,). (Found: C 73.8; H 10.7. C,,H,,,ON requires C 74.8; H 11.0.) Hydrolysis of this derivative, by heating with concentrated hydrochloric acid in a sealed tube at 100" for S hours, yielded some- what impure N - n i e t h ~ l - l - ~ ) i ~ ~ ~ ~ r i t y l n m i n c . b.p. 98"/9 mni. n,,18 1.4729. [ I ] ,,I7 - 51.0" (c 2. CHCI,). (Found: C 73.2; H 11.3. C,,H1,N requires C 79.0; H 12.6.)

The basic product (3.2 g) , N-dimethyl-I-piperifyInmine. was a pale yellow oil, which anlike the primary base did not appear to combine readily with atrnosphzric carl)on dioxide. It had I1.p. 91" 7 mm. n1,15 1.4763. [ ~ ] , , ' " ~ 5 9 . 2 ' (c 2, CHCI,,). (Found: C 79.8: H 12.6. C12HZIN requires C 79.5; H 12.7.) This tertiary base (1.5 g ) when boiled with methyl iodide ( 5 cm:') in methanol ( 5 crncr) for 15 minutes yielded I-piperitylfrimcthyl;Immonitim iodide (compare Rcad and Storey 3 ) ) crystal- lising from acctone in colourless prisms, n1.p. 186" (decomp.). [ x ] ~ , ~ ~ - - 4.8" ( c 2. water). (Found: C 48.3; H 8.2. C,,,H,,NI requires C 48.2; H 8.1.)

T h e authors express their thanks to the Department of Scientific and Industrial Research, London, for a Grant which enabled one of them (W. W. C . ) to take part in this investigation.

(Receiivtl Scptenrbcr 29th 1949).