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α-Cyanation of Tertiary AminesW. C. Groutas a , M. Essawi a & P. S. Portoghese aa Department of Medicinal Chemistry, College of Pharmacy University of Minnesota,Minneapolis, MN, 55455Version of record first published: 05 Dec 2006.

To cite this article: W. C. Groutas , M. Essawi & P. S. Portoghese (1980): α-Cyanation of Tertiary Amines, SyntheticCommunications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 10:7, 495-502

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SYNTHETIC COMMUNICATIONS, 10(7), 495-502 (1980)

a-CYANATION OF TERTIARY AMTNES -

W. C. Groutas', M. Essawi and P. S . Portoghese* Department o f Medicinal Chemistrf

Col lege o f Pharmacy

U n i v e r s i t y of Minnesota

Minneapol i s r4N 55455

The a-cyanation o f t e r t i a r y an ines i s customari ly accomplish-

ed by mercuric acetate ox ida t i on of the amine t o form the enamine,

which on treatment w i t h base y i e l d s the corresponding S c h i f f ' s

base.

the des i red produc t . A l t e r n a t i v e l y , and less commonly, the a-

394 cyanation o f t e r t i a r y amines can bt c a r r i e d o u t e l e c t r o l y t i c a l l y .

As p a r t o f a p r o j e c t r e l a t e d t o the synthesis o f novel ana lge t ics ,

we des i red t o prepare a se r ies o f o-cyanated amine5 der ived from

precursor compounds o f b i o l o g i c a l s ign i f i cance. The mercur ic ace-

t a t e ox ida t i on o f morphine, codeine, levorphanol and some o ther b i o -

a c t i v e amines i s known t o r e s u l t i n the format ion o f i n t r a c t a b l e

products . We have found t h a t the r-cyanation of a se r ies o f sensi-

t i v e amines (Table 1) can be c a r r i e j o u t under m i l d cond i t ions and

Subsequent t reatment w i t h aqJeous potassium cyanide y i e l d s

2

5

* To whom correspondence should be addressed.

495

Copyright 0 1980 by Marcel Dekker, Inc.

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496 GROUTAS, ESSAWI, AND PORTOGHESE

i n good o v e r a l l y i e l d s by sequent i 11 t rea tmen t o f t h e amine w i t h 30%

aqueous hydrogen pe rox ide i n metha 101 6 , es t e r i f i c a t i o n of t he r e -

s u l t i n g N-oxide w i t h t r i f l u o r o a c e t i c anhydr ide i n methylene c h l o r i d e

a t room temperature7 and, f i n a l l y , t rea tmen t w i t h excess aqueous

potass ium cyanide a t room temperat Are. The t h r e e - s t e p process

can be c a r r i e d o u t w i t h o u t i s o l a t i i n of t he i n t e r t i e d i a t e s . I n a l l

t he examples s t u d i e d t h e major p r o l u c t appears t o a r i s e f rom the 8 r e a c t i o n of cyanide w i t h an endocy : l i c imin ium ior i . I n each case

t h e p roduc ts ( l b -5b ) c o n s i s t e d o f t m i x t u r e o f d iastereomers which

e q u i l i b r a t e d on s tand ing .

4-phenyl-4-propionoxypiperidine @ , e l i m i n a t i o n o f t h e propionoxy

f u n c t i o n l e d t o t h e o l e f i n n i t r i l e & due t o a c i d - c a t a l y z e d e l i m i n a -

t i o n .

With r e l a r d t o the r e a c t i o n of l - m e t h y l - 2

Tab le 1. P r e p a r a t i o i o f u-Cyanoamines

% y i e l d .- R - __ A m i ne

Ph C O O E t aR I

CH3

73

HO

71

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a -CYANATION 497

1 2 -b ( 3 2 ) -CN 3) 70

Ho &-CH3 R

crude yield a

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49 8 (,& I I SS?WI, AND I'ORTOGHESE

E Y P E R r.1'.;41P3L

'H NMR s p e c t r a were o b t a i r e d o n a V i r I d r fi-hOC spectrorileter us-

r i f v ' a w j s p e c t r a were recorded ing e i t h e r CDC13/TMS o r CU30E/TMS.

on a Perkin-Elmer 281 i n f r a r e d spem tz,oF i;otoiueter.

4-Phenyl-4-carbethoxy-Z-cyan~-e- k i j l i j i e t . i d i n e (&) .

30% aqueous hydrogen peroxide vdas I d lea t o , \ -phen j l -4 -ca rb t : t hoxy- l -

methvlDiper id ine l0 ( 4 . 0 g ; 16 llitnol

r a t u r e . The s o l u t i o n was s t i r r e d t ro111 tcmpera tJ re f o r 48 h and

then heated on the steam bath u i t i - L C d n a l y s i s slowed no s t a r t i n g

m a t e r i a l ( a b o u t 2 h ) . Excess pero, ii!e d a s i les t rodsd by adding 1OY0

Pd on carbon (0.1 g ) and s t i r r i n g Iqe c'J3led r e a c t i o n mixture f o r 1

h . After f i l t e r i n g o f f the ca ta lyc t . t ) i e sc ' lvent Mas evapcra ted i n

vacuo l e a v i n g an o i l . T h i s was dirjolv6jd i n inethylene c h l o r i d e

(100 ml) and d r i e d over anhydrous r3dius8i s u : f a t e . The d r i e d o i l

(4 .27 g ; 98%) was d i s s o l v e d i n rnetlylene c h ' o r i d e I n d t r e a t e d with

12 ml o f t r i f l u o r o a c e t i c anhydride I t 0'' C.

h a t room tempera ture t h e r e a c t i o n nixtAre was heated i n a water

bath (50' C ) f o r 20 min. E v a e o r a t i i r 0 " the s o l v e n t l e f t a n o i l

which was used w i t h o u t f u r t h e r o u r i f i c a L : i o n . 18 .9 g ( 0 . 2 9 iiiol) of

potassium cyanide i n 38 ml water w a ; added t o the o i l a t 0' C with

s t i r r i n g . The mixture was s t i r r e d f o r h d t room temperature and

was then e x t r a c t e d with e t h y l e t h e r ( 4 x 50 m l ) ant] d r i e d over an-

hydrous sodium s u l f a t e .

o i l (3.19 g ; 73%).

IR ( n e a t )

NMR(CDC13/TMS): 67.3 (s ,5H), 4 . 1 3 (],2H , 3.88 ( t , ' H ) , 2 . 7 (m,3H),

10 ml of

7n L O a i : methanol a t room tempe-

A f t e r s t i r r i n c f o r 1

Evapora t io i of t h e solven: l e f t a yel lowish

2220 cm-l (V C Z N ) , 1730 L L O ) , 22113 ( ' C r N ) .

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a -CYANATION 4 9 9

2.4 ( s , 3 H ) , 2.15 (m,4H), 1 .15 ( t , 3 H ) .

Mass Spectrum m/e ( r e 1 i n t e n s i t y ) 2 7 2 ( , ) , 1 7 2 (!GO), 46 (20), ~2

( 2 0 ) , 28 ( 3 3 ) .

Anal. Calcd. f o r C H 0 11 C1 ( h y d r o c t l u r i d e s c i l t j : C , 62.24; H,

6.81; C 1 , 11.51; N , 9 .08. F o u n d : C , 6, . r 1 6 ; t i , 6 . 9 4 ; ( 1 , 11.69 . :4,

8.94.

15-Cyanolevorphanol (z). S t a r t i n g witt ev,rphanol ' ' a n d fo l lowing

the same procedure a s f o r (k), a crude N h i t - I s o l i d was obtainecl

which was r e c r y s t a l l i z e d from aqueous e'h<inol (714), m . 2 . 97-99 C .

IR (KBr)

NMR(CDC13/TMS): 6 7.2-6.5 ( n , 3 H ) , 5 . 1 ( . , - H ) , 2 . l ) ( s , 3 t i ) .

Mass Spectrum m/e ( r e 1 i n t e n s i t y ) 28% (!5:, l i 6 ( 1 9 ) , 255 ( 7 7 ) . 199

( 3 1 ) , 198 (46), 160 ( l o o ) , 28 ( 6 6 ) .

Anal. Calcd. f o r C H N 0. C , 76.60; b , 7 . 3:); !(, 9 . 9 3 . Found: C ,

76.69; H , 7.93; N , 9 .76.

1 2 3-Cyanometazocine (3). Metazocine w i ~ cy inated i n t , ie usual manner.

An o i l y mixture of the C( and isomers h 3 : o!)tair;ed (70 : ) . T r i t u r a -

t i o n of the o i l w i t h e t h y l ether y i e l d e c 2 bv'own s o l i d which was p u -

r i f i e d f u r t h e r by column chromatography : s i l i a uel 7 " ( 1 " column,

CHC? ) and r e c r y s t a l l i z a t i o n froin e t h y l ?thep', 'ethyl d c f - a t e , m . p .

172-175' C .

IR(KBr) 2220 cm-l ( V F N ) .

,MR(CDC13/TMS): 6 5 . 0 (m,lH), 2.54 : s , 3 l - j .

Mass Spectrum m/e ( r e 1 i n t e n s i t y ) 256 ( l ! ) , ,29 ( 7 5 ) , 2 4 ( 3 5 ) , 172

( l o o ) , 159 ( 3 9 ) .

16 21 2 2

(

2220 cm-l ( v CZN).

1 8 22 2 .

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500 ( ,RI)UTAS, ESSAWI, AND PORTOGHESE

Anal. Calcd. for ClFH2,,N20 C , 7 ) . V l . H , 7.81; !I, 10.94. Found:

C, 75.02; H, 7.95; N, 10.69

Evaporation of the ether left an j i l . H M R analys-s indicated the

presence of the u and r' iscimers.

N-(Z-Cyano-l-methyl-4-piperidino) N LhenyJpropanc amide (4k).

Following the same general procedir- torwound ( 4 t ) was obtained i n

41% yield. Recrystallization frov izoiropanol/herane qave white

crystals, m.p. 125' C.

IR(KBr) 2205 cm-' ( v CZN), 1660 ( , C = O ) .

NMR(CC14/TMS): 6 7.45-6.66 (n i ,5H) 1.EI, (ni,lH), 2.7 (m,lH), 2.48

(m,2H), 2.26 (s,3H), 2.23-1.08 (m 6H), 1 . 1 I (t,3k).

Mass Spectrum m/e (re1 intensity) 271 (6), 245 (l), 214 (13), 122

(100).

Anal. Calcd. for C16H2,N30: C, 0 84; H , 7.74; Y , 15.49. Found:

C, 70.79; H, 7.88; N, 15.45.

N- [Z-Cyano- l - (Z-phenethy l ) -4-p ipc ridlpo] -N-phenylpropane amide (s). Compound (s) was obtained (45';) 'rom fentanyl14 in a similar manner

and was subsequently recrystallizcd f r m isopropanol/hexane, m.p.

167-8' C.

IR (KBr) 2218 cm-l ( v CSN), 1660 ( C.0).

NMR (CDC13/TMS): 6 7.66-6.33 (m,l(H:, 1 . 7 6 (m,3H), 3.75 (nl,lH),

3.5-1 .O (m,15H).

Mass Spectrum m/e (re1 intensity) 361 ,2), 270 ( 1 ) 0 ) , 214 ( 3 1 ) , 186

(74), 105 (42).

Anal. Calcd. for CZ3Hz7N30: C, 6 45; H , 7.47; N, 11.63. Found:

C, 76.19; H, 7.40; N, 11.47.

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a-CYANATION

7 ,2,5,6-Te t r a hydro- 1 -met hy 1 - 4- p h e ny 1 - 2 -J yt id I n e

The same genera l procedure y i e l d e d ( @ ) i r i 4 I y l e l d .

was r e c r y s t a l l i z e d f rom pe t ro leum e t h e r / i e x a l i p , . , I . 6

IR ( m e l t ) : 2210 cm-l ( c ~ N ) .

5 rbo!

NYR(CDC13/TMS): 6 7 .3 (s,5H), 5.92 : d , l H ) , 4.

(m,4H), 2.5 (s,3H).

Mass Spectrum m/e ( r e 1 i n t e n s i t y ) 198 ( 1 1 ) , 1;O 1 l f ) O : , 2 ( 2 2 ) .

Anal. Calcd. f o r C13H14N2: C , 7 8 . 7 9 ; H . 7.(7; Pi, 14.11. Found

C, 78.91; H, 7.27; N, 14.15.

( d , l H ) , ? 8-2.6

501

t r i l e (6t , ) ..

i e produc t

.5-65O c .

Acknowledgement

T h i s research was suppor ted by N I D A se,earch q r a n t LA 02220.

We w i s h t o thank Hoffmann-La Roche I n c . 0)- l evo rphano l , S t e r l i n c i -

Winthrop Research I n s t i t u t e f o r nornietazc c i n e and McNeil Labora to -

r i e s f o r f e n t a n y l .

References

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*

-~

-~__. -__ -

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