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T E T R A H E D R O N

L E T T E R S

T e t r a h e d r o n L e t t e rs 3 9 (1 9 9 8 ) 6 2 5 7 - 6 2 6 0

P e r g a m o n . ,

M i c r o w a v e - A s s is t e d S o l v e n t -F r e e O r g a n i c R e a c t io n s :

Syn thes i s o f 13 -Lactams from 1 , 3 -Aza di enes

G iorgio M artel lia , G iuseppe Spun taa and Ma uro Panun ziob

a : I .Co.E .A-C .N .R . V ia Gobe t t i 1 01 , 1-40129 Bologna , I t aly

b: C .S .F .M. -C .N .R , D ip a r t im e nto d i Chim ic a "G . C ia m ic ia n" V ia Se lm i 2 , 1 -40126 Bologn a I ta ly

R e c e i v e d 1 4 M a y 1 9 9 8 ; a c c e p t e d 2 3 J u n e 1 9 9 8

A b s t r a c t

Ring-closure of 1,3-azadienes to 13-1actam rings is efficiently and qu ick ly carr ied out u nd er solvent-free

conditions in an open-vessel microwave system . The synthesis o f

N-tert-butyldimethylsilyl

azetidinones is

r e po r te d . 1998 E lse vie r Sc ie nc e L td . A l l r igh t s r e se rve d .

K e y w o r d s : M i c r o w a v e h e a t i n g , A z e t i d i n o n e s , S ta u d i n g e r , C y c l iz a t i o n .

D u r i n g r e c e n t y e a r s n u m e r o u s s t ud i e s h a v e b e e n r e p o r t e d o n t h e v e n e r a b l e S t a u d i n g e r

r e a c t i o n [ 1 ] f o r t h e p r e p a r a t i o n o f a z e ti d i n o n e s w h i c h a r e v a l u a b l e b u i l d i n g b l o c k s i n t h e

c o n s t r u c t i o n o f s y n t h e t i c I~ -l ac ta m a n ti b i o t i c s [ 2 ] . R e c e n t l y B o s e r e p o r t e d t h e u t i li s a t io n o f a

m i c r o w a v e - t e c h n i q u e ( th e M O R E t e c h n i q u e ) f o r t h e p r o d u c t io n o f s u c h d e r i v a t iv e s [ 3, 4] .

T h e f i r s t e x a m p l e s o f t h e r a p i d s y n t h es i s o f o r g a n ic c o m p o u n d s u s i n g m i c r o w a v e o v e n s

w e r e r e p o r t e d b y G e d y e [5 ]. S i n c e t h e n a n u m b e r o f p a p e r s h a v e a p p e a r e d c o n c e r n i n g

m i c r o w a v e - a s s i s t e d o r g a n i c r e a c t io n s a n d t h e n u m b e r o f a r t ic l e s c o n t i n u e s to g r o w q u i c k l y

[ 6 -8 ] . T h e m a i n a d v a n t a g e s o f m i c r o w a v e - a s s i s t e d o r g a n i c s y n t h e s i s a r e s h o r t e r r e a c t i o n

t i m e s , m i n i m u m w a s t e a n d g e n e r a l l y h i g h e r y i e ld s . A p a r t i c u l a r l y a t t r a c t i v e f e a t u r e o f t h e

m i c r o w a v e t e c h n i q u e i s t h e p o s s i b i li t y o f c a r r y i n g o u t r e a c ti o n s i n t h e a b s e n c e o f s o l v en t

s i n c e The day may be coming when dras t ic res t r ic t ions on so lven t po l lu t ion wi l l requ ire the

adop t ion o f no-so lven t reac t ions

[ 6] . F o l l o w i n g o u r r e c e n t w o r k o n t h e s y n t h e s i s o f

a z e t i d i n - 2 - o n e s t h r o u g h a t w o - s t e p S t a u d i n g e r r e a c t i o n , w e b e g a n a s y s t e m a t i c s t u d y t o

a d d r e s s t h e u s e o f m i c r o w a v e t e c h n i q u e s i n t h e s y n t h e s i s o f [3 -1 ac ta m r i n g s f r o m 1 , 3 -a z a d i en e s

i n t h e a b s e n c e o f s o l v e n t s . W e w i s h t o r e p o r t h e r e o u r p r e l i m i n a r y r e s u l t s o n a p r a c ti c a l a n d

s i m p l e te c h n i q u e u s i n g a n o r m a l d o m e s t i c m i c r o w a v e o v e n , w i t h o u t a l t e r a ti o n , a s a s a f e a n d

c o n v e n i e n t l a b o r a t o r y d e v i c e . A s w i l l b e s e e n f r o m t h e s u b s e q u e n t d is c u s s i o n , t h e c y c l iz a t i o n

c a n b e c o n d u c t e d o n a s c a l e f r o m m i l l i g r a m s t o f i f ty g r a m s i n 1 - 2 0 m i n u s i n g i n e x p e n s i v e

e q u i p m e n t . F u r t h e r m o r e , t h e r e is n o n e e d f o r s e a l e d v e s s e l s , r e f l u x c o n d e n s e r s , s t i r re r s o r

a n i n e r t -g a s a t m o s p h e r e . T h e k e y t o o u r s o l v e n t f r e e o r g a n i c r e a c t i o n s i s t h e p r o p e r c h o i c e

o f i rr a d ia t io n t i m e a n d c o n t r o l o f th e e n e r g y i n p u t f r o m t h e m i c r o w a v e o v e n i n t o t h e r e a ct i o n

m i x t u r e . I n t h is w a y , th e r e a c t i o n t e m p e r a t u r e i s k e p t b e l o w a c r i t ic a l v a l u e w h i c h m a y b e

r e s p o n s i b l e f o r t h e d e c o m p o s i t i o n o f t h e s t a rt i n g a z a d i e n e a n d / o r t h e t a rg e t c o m p o u n d . S i n c e

i t i s n o t e a s y t o p r e d i c t t h i s v a l u e , w h i c h d e p e n d s o n t h e n a t u r e o f t h e s u b s t r a t e a n d t h e

q u a n t i t y o f s t a r ti n g m a t e r i a l , a s e t o f e x p e r i m e n t s w e r e p e r f o r m e d t o f i n d o u t t h e b e s t

e ra : p a n u n z i o @ c i a r a , u n i b o , i t

0 0 4 0 - 4 0 3 9 / 9 8 / $ - s e e f ro n t m a t t e r 1 9 9 8 E l s e v i e r S c i e n c e L t d . A l l r i g h t s r e s e r v e d .

P I h S 0 0 4 0 - 4 0 3 9 ( 9 8 ) 0 1 3 0 2 - 1

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c o n d i t i o n s fo r o b t a i n i n g h i g h c y c l i z a t io n y i e ld . T h e s t a r t in g a z a d i e n e w a s g e n e r a t e d f r o m a

s i l y li m i n e , w h i c h w a s i n t u r n p r e p a r e d f r o m a n a l d e h y d e a n d a n a c y c h l o r i d e [ 9 -1 1 ] . I n

o r d e r t o h a v e s t a b l e a z a d i e n e s a n d a l r e a d y p r o t e c t e d N - a z e t i d i n o n e s , w e h a v e p r e p a r e d t h e N -

t r i a l k y l s i ly l - s u b s t i t u t e d a z a d i e n e s 6 w i t h t h e h y d r o l y t i c a l l y s ta b l e T B D M S - g r o u p . T h e

r e q u i r e d

N- te r t - b u t y ld im e th y l s i l y l

i m i n e 4 w a s p r e p a r e d f r o m l i t h iu m

N, N- ( t e r t -

b u t y l d i m e t h y l ) t r im e t h y l s i l y l a m i d e 3 a n d a n a l d e h y d e 2 a c c o rd i n g t o t h e r e p o r t e d p r o c e d u r e s

( S c h e m e 1 ) [ 1 2 , 1 3 ] .

Scheme 1

L i ( ~ , - 0

R \ /H 1 . TBD MS TMS (3) H / OCl

D

N TBDMS

O 2. TMSCI TBDMS TEA TBDMSO N R

2 4 6 1

A z a d i e n e s 6 th u s p r e p a r e d a r e r e a s o n a b l y s t a b l e a n d w e r e u s e d a s s u c h o r p u r i f i e d b y f l a s h

c h r o m a t o g r a p h y o n a sh o r t s i li c a g e l - c o l u m n d e p e n d i n g o n t h e p u r i t y o f t h e c r u d e r e a c ti o n

m i x t u r e a s e v a l u a t e d b y I H N M R ( Y i e l d s o f i s o l a t e d a z a d ie n e s a r e r e p o r t e d i n s q u a r e b r a c k e t s

i n T a b l e 1 ). A z a d i e n e s d e r i v e d f r o m t e r t -bu ty ld ime thy ls i ly l imines m a y b e s t o r e d a t - 1 8 C

w i t h o u t a p p r e c i a b l e d e c o m p o s i t i o n ~ [1 4 ]. I r r a d i a t io n o f a z a d i e n e 6 i n a n o p e n - v e s s e l

m i c r o w a v e s y s t e m , fo r th e a m o u n t o f t i m e a n d w i t h t h e e n e r g y r e p o r t e d i n T a b l e 1, g a v e th e

a z e t i d in o n e s 1 i n s a t i s f a c t o r y to g o o d y i e ld s . T h e r e a c t i o n h a s b e e n s c a l e d - u p t o 1 0 0 m m o l

s c a l e w i t h o u t a p p r e c i a b l e v a r i a t i o n s i n t h e y i e l d s a n d d i a s t e r e o m e r i c r a t i o . I t m u s t b e p o i n t e d

o u t th a t, e v e n w i t h t h i s n e w m e t h o d o f c y c l i z a t io n , the s imple d iastereoselect iv i ty is invariably

trans

w h i l e t h e f a c i a l d i a s t e r e o s e l e c t i v i t y r e s e m b l e s t h a t o b t a i n e d u p o n r e f l u x i n g t h e a z a d i e n e

i n t o l u e n e . T h i s s h o w s t h e i n d e p e n d e n c e o f t h e d i a s t e r e o m e r i c r a t i o f r o m t h e s o l v e n t .

P r o c e d u r e f o r t h e s y n th e si s o f a zet i d in o n e

6 a

on 100 mm ol sca le .

T o a s o l u t i o n o f N, N- ( t e r t - b u t y ld im e th y l s i l y l ) t r im e th y l s i l y l a m in e ( 2 0 . 2 g , 1 0 0 m m o l ) i n

h e p t a n e ( 8 0 m l ) w a s a d d e d b u t y l l i t h i u m ( 1 0 0 m m o l , 4 0 m l o f a 2. 5 M s o l u t i o n i n h e x a n e ) a t

0 C ; O - t r i i s o p r o p y l s i l y l l a c t a l d e h y d e 2 a ( 2 3 . 0 g , 1 0 0 m m o l ) i n h e p t a n e ( 2 0 m l ) w a s a d d e d

a f t e r 3 0 min . , t o th e l i th iu m

N, N- ( t e r t - b u t y ld im e th y l s i l y l ) t r im e th y l s i l y l a m id e

3 a t -10C.

T h e r e a c t i o n m i x t u r e w a s s t i rr e d f o r 3 0 m i n . a n d T M S C 1 ( 1 3 m l , 1 0 0 m m o l ) w a s a d d e d i n

o n e p o r t i o n a t 0 C . S t i r ri n g w a s c o n t i n u e d a t r .t . f o r l h . a f t e r w h i c h t i m e t h e r e a c t i o n

m i x t u r e w a s c o o l e d t o 0 C a n d T E A ( 2 7 .8 m l , 2 0 0 m m o i ) w a s a d d e d . T h e p h t h a l o y lg l y c y l

c h l o r i d e 5 a ( 2 2 . 3 g , 1 0 0 m m o l ) i n t o l u e n e ( 8 0 m l ) w a s a d d e d d r o p w i s e . S t i rr i n g w a s

m a i n t a i n e d f o r 1 .5 h. d u r i n g w h i c h t i m e a l a r g e a m o u n t o f p r e c i p i t a t e a p p e a r e d . T h e

p r e c i p i t a t e w a s f i l t e r e d t h r o u g h d i a t o m a c e o u s e a r t h a n d t h e s o l v e n t r e m o v e d in vacuo. T h e

c r u d e a z a d i e n e 6 a [ 1 5 ] t h u s o b t a i n e d w a s p u r i f i e d b y f l a s h - c h r o m a t o g r a p h y o n a s h o r t s i l i c a

g e l c o l u m n e l u t i n g w i t h h e x a n e - e t h y l a c e t a t e 8 0 / 2 0 ( 4 5 g , 8 5 % y i e l d ) .

S o l v e n t Fr e e M ic r o wa v e O r g a n i c Re a c ti o n .

T h e a z a d ie n e , p r e p a r e d a c c o r d i n g t h e p r o c e d u r e r e p o r t e d a b o v e , w a s p l a c e d i n a n

E r l e n m e y e r f l a s k a n d i r r a d i a t e d f o r 3 m i n$ a t 6 5 0 W t o g i v e t h e a z e t i d i n o n e l a ( 3 2 . 4 g , 7 2 % ) .

~: In contrast azadienes prepared fro m trimethylsilylimines ga ve rise , on standing, to the corresponding

azetidinone.

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Table 1: Synthesis of Az etidinones 1

Entry A za dien e ~Lactams ~me En ergy Yield Rat io 11d.1 Ref

(rain) (Watt)

OTIPS OTIPS O TIPS

FtN.,. r,~ F tN . .1~ F tN ~N 660 72 9

1 TBDMSO ~ 1 O ~ - I ~ DMS (~-N TB DMS 3 50/50

6 [Y%=85] la d - la

OTIPS OTIPS O TIPS

F t N L ~ I~ FtN ,o~ I L / F t N ~

2 , v ~ 20 660 61 85115 9

TBDMSO' TBDMS (~ 'TB DMS

7 [Y%=32] lb d- lb

..o ~ F t N ,- ~ IN,J~

tN

3

u ~''~IBUMo 20 660 44 9

TBDMS

8 [Y%=54]

r a c 1 c

( O~ QT IPS /O-, .l~O O TI P S ,~ N O.j~ TI PS

pl~ -N ~._ t / Ix P t l~ N4' l ' f IL

4TBDMSO__N O~,_N..FBDMS Pt i O A t ~ D M S 20 660 81 60/40 10

9 [Y%=54] ld d. -ld

5 pt - f )' -N~ i ( /~ P l t f ~- ' - I i ~ ph~ 1~., ~ 20 660 57 90/10 10

TBDMSO--I/L-I~I \ O/~ -'N TB M S O/2 ~ 'TB D S

1 0 [ Y% = 5 0 ] l e d - l e

p y _ J D o r I P S / o -i PO T I P S

,0 0TIPS

6 ph i - i N~ l /l ~ _ _ P h ~ o ~ _ D M ph~ N ' , / ~ . 2 0 660 6 7 5 6/4 4 10

TBDMSO S O ~TBDMS

1 1 ~ % = 6 8 ]

t ~ - i

(O., /~C) OTIP S o y O OTIPS /O ~ OTIPS

7 p h ~ ' - N L l i ~ p h ~ - -N ,IL h p h ~ , , l ~ p h

p ~ r - ~ P 2 0 6 6 0 9 0 8 o /2 0 1 0

TBDMSO~-- N O# NTB DMS O# N TBDMS

12 [Y%=25 lg d - lg

TBDMSO- -h~ ~'~0-- l/j~ 0 '~ 0 I/ ) - m h~o'o~ ' ~ D

p h N ~ ,

l~ .'~ P 2 o 6 6 o 6 o 6 ~ 7 ~ o

O rB DMS MS

13 [ Y % =5 0] l h d - l h

a: The reactionsw ere performed, except or entry 1, on a 2 mmol scale.

b: A certain amoun t (5-10% ) of the u np rotected N-a zetidinonemay be p resent n the crud e mixture.

c: Diastereomeric atio s were determined by 1H NMR of the crud e reactio n mixture.

d: Yields of p ure so lated prod ucts, All the prod ucts ga ve satisfactory R, 1H N MR, 130 NMR and MS ana lys:e,

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6 2 6 0

T a b l e 1 r e p o r t s t h e r e s u l t s o b t a i n e d i n t h e s y n t h e s i s o f a z e t i d i n o n e s f r o m a z a d i e n e s u s i n g

t h e p r o c e d u r e d e s c r i b e d a b o v e . E n t r i e s 2 - 8 w e r e p e r f o r m e d o n a t w o m m o l s c a le w i t h

i r ra d i a t i o n f o r 2 0 m i n .

F r o m t h e re s u l t s r e p o r t e d i n T a b l e 1 i t i s e v i d e n t t h a t th i s m e t h o d o f c y c l i z a t i o n , b a s e d o n

m i c r o w a v e - a s s i s t e d s o l v e n t - f r e e o rg a n i c r e a c t i o n s , is v e r y e f f i c i e n t . Y i e l d s ar e a t l e as t

e q u i v a l e n t , o r e v e n s l i g h t ly b e t t e r th a n t h o s e d e s c r i b e d i n t h e l i t e r a tu r e a n d e x p e r i m e n t a l

c o n d i t i o n s a r e e x c e p t i o n a l l y m i l d . T h e p r o c e d u r e a v o i d s s o lv e n t s a n d r e a c t i o n s a r e c o m p l e t e

i n a v e r y s h o r t t i m e u n d e r s a f e c o n d i t i o n sz F i n a l l y t h e p o s s i b i l i t y o f i s o l a t i n g t h e f i n a l p r o d u c t

a s i ts N - T B D M S d e r i v a t i v e c o n f e r s to o u r s y s t e m a n e x t r a a d v a n t a g e . E x t e n s i o n o f t hi s w o r k

t o m o r e c h a l l e n g i n g c a s e s i s c u r r e n t l y i n p r o g r e s s i n o u r l a b o r a t o r i e s .

A c k n o w l e d g e m e n t s : We w ish to than k "P rogetto Strategico sulle App licazioni Industriali della Tecn ologia a

Microonde" CNR-Rome, for f inancia l support and Dr. Gordon Kennedy of GlaxoWellcome, Verona, I ta ly for

the fruitful discussions.

R e f e r e n c e s

[1] Staudin ger , H. , Liebigs Ann. Chem. 1907, 350 , 51.

[2] Geo rg, G. I. ; Ravikumar, V. T. In The Organic Chemistry off l-Lactams; G. Georg, Ed. ; VCH : New York, 1993 ; pp 318-323.

[3] Bose , A. K. ; Man has , M. S. ; Gho sh, M.; Shah, M.; Raju, V. S. ; Bari , S. S. ; .Ne waz, S. N. ; Banik, B. K. ; Chaudhary, A. G. ;

Barakat,

K. J., J. Org. Chem.

1991,

56 ,

6968-6970.

[4] Bose , A.K. : Banik, B. K. ; M anhas , M. S. ,

Chemtech

1997,

27 ,

18-23.

[5] Ged ye, R.; Smith, F.; Westwa y, K. ; All , H.; Baldisera , L. ; Laberg el , L.; Rousse l , J . ,

Tetrahedron Lett.

1986,

27,

279.

[6] Dittmer, D. C.,

Chem. Ind.-London

1997, 780-784.

[7] Galema, S. A., Chem. Soc. Rev. 1997, 26, 233-238.

[8] Lang a , F. ; De La Cruz, P. ; De La Hoz, A. ; Diaz-Ort iz , A. ; Diez-Barra , E. , Contemp. Org. Synth 1997, 373-386.

[9] Bandini , E.; Marte l l i , G. ; Spun ta , G. ; Bon gini , A. ; Panu nzio, M. , Tetrahedron Lett. 1996, 37, 4409-4412.

[10] Band ini , E. ; Marte l l i , G. ; Spunta , G. ; Panu nzio, M. , Synlett 1996, 1017-1018.

[11] For prepara t ion and applica t ion of N-tr ia lkyls i lyl imines in organic synth esis see : Panunzio, M.; Zaranto nello, P.,

Org. Process

Research and Developm ent

1998, 2, 49-59.

[12] Bow ser , J . R. ; Neilson, R. H. ; Wells , R. L. ,

Inorganic Chemistry

1978,

17,

1882-1886.

[13] Cainell i , G. ; Giacom ini , D. ; Galle t t i , P. ; Gaiba , A. ,

Synlett

1996, 657-658.

[14} For use of azadienes in organic synthe sis see : Ghosez, L. ,

Pure & App. C hem.

1996,

68,

15-22.

[15] For applica t ions of aze t idinon e 6a to the synthesis of [$-lac tam antibiot ics see Ref. 10