8/3/2019 Mayer 1998 Tetrahedron-Letters

1/4

P e r g a m o n Te t rahedron Le t t e r s 39 (1998) 6655-66 58T E T R A H E D R O N

L E T T E R S

S o l id - P h a s e S y n t h e s is o f B e n z i m i d a z o l e sJohn P. Mayer*, Geo rge S . Lewis, Celesta McG ee andDanute Bankaitis-DavisA mg e n Inc . , 3200 W al nu t S t ., B ou l de r . CO , 80301

Rece ived 22 May 1998; r ev i sed 2 Ju ly 1998 ; accep ted 6 Ju ly 1998

A b s t r a c t . A r e a d i l y a u t o m a t e d s o l i d - p h a s e a p p r o a c h t o th e s y n t h e s i s o f d i v e r s e b e n z i m i d a z o l e s i s d e s c r i b e d .T h e p r o c e d u r e u t i l i z e s p o l y m e r s u p p o r t ed 4 - f l u o r o - 3 - n i t ro b e n z o i c a c i d a n d a w i d e r a n g e o f c o m m e r c i a l l ya v a i l a b le a m i n e s a n d a l d e h y d e s . T h e k e y h e t e r o c y c l i za t i o n s t ep i s a c h i e v e d u n d e r m i l d c o n d i t io n s a n d w a sfou nd to be ge ne r a l fo r a l a r ge n um be r o f d i ve r se inpu t s . 1998 E lsev ie r Sc ience L td . A l l r igh ts r e se rved .K e y wor ds s o l i d -phas e , be nz i mi daz o l e , c ombi na t or ia l c he m i s t ~

O n e o f t h e m a j o r c h a l l e n g e s f o r c o m b i n a t o r i a l c h e m i s t r y i s t h e a c c e l e r a t i o n o f t h e l e a dg e n e r a t i o n a n d o p t i m i z a t io n p h a s e s o f d r u g d i s c o v e ry . l D e s p i t e im p r e s s i v e a d v a n c e s t o d a tet h e c o m b i n a t o r i a l p r a c t i ti o n e r c o n t i n u e s t o f a c e a n u m b e r o f h u r d l e s i n r e d u c i n g t h i s c o n c e p t t or o u t i n e u s e . T h e s e i n c l u d e t h e d i f f ic u l t i e s o f a d a p t i n g e s t a b l is h e d s o l u t i o n - p h a s e p r e c e d e n t s top o l y m e r s u p p o r t e d r e a c t io n s a n d c o n s i st e n t ly r e p r o d u c i n g c o n d i t i o n s s u c h a s a n h y d r o u s a n d / o ri n e rt a t m o s p h e r e o r e x t r e m e t e m p e r a t u r e r a n g e s w h i l e r e m a i n i n g w i t h in t h e c o n s t r a in t s o f am i n i a t u r i z e d , r o b o t i c fo r m a t . W h i l e a u t o m a t i o n c a p a b i l i t y c o n t i n u e s to i m p r o v e , it i sf r e q u e n t l y d e s i r a b l e t o a v o i d o r m i n i m i z e d e m a n d i n g s y n t h e t i c c o n d i t i o n s w h e n p l a n n i n g ac o m b i n a t o r i a l l i b r a ry .

R1I

T h e b e n z i m i d a z o l e 1 is a n i m p o r t a n t h e t e r o c y c l ic n u c l e u s w h i c h h a s s e e n e x t e n s i v e u sei n m e d i c i n a l c h e m i s t r y , w i t h t h e a n t i h i s t a m i n e A s t e m i z o l e 2 a n d t h e a n t i u l c e r a t i v e O m e p r a z o l e 3b e i n g n o t a b le c l in i c a l e x a m p l e s . I n a d d i ti o n , b e n z i m i d a z o l e b a se d c o m p o u n d s h a v e s h o w ns u c h d i v e r s e b i o l o g i c a l a c t i v it i e s a s i n h i b i t i o n o f p h o p h o d i e s t e r a s e I V 4 a n d a n t a g o n i s m o fa n g i o t e n s i n 1s, 6 a n d n e u r o p e p t i d e Y b i n d i n g ] A s p a r t o f o u r c o n t i n u i n g e f f o r t t o a d a p th e t e r o c y c l i c m e t h o d o l o g i e s t o a h i g h s p e e d s y n t h e s i s f o r m a t w e e x a m i n e d a s o l id - p h a s es y n t h e s i s o f th i s p h a r m a c o p h o r e . 8" 9 O u r s t r a te g y e m p h a s i z e d f l e x i b il i t y , m a x i m a l u s e o fc o m m e r c i a l l y a v a i la b l e i n p u t s a n d m i l d r e a c t io n c o n d i t i o n s w h i c h c o u l d b e r e a d i l y a d a p t e d t op o l y m e r s u p p o r t a n d a u t o m a t e d o p e ra t i o n . T h e p r o c e d u r e o u t l i n e d i n S c h e m e s 1 a n d 2 w a su t i l iz e d f o r t h e s y n t h e s i s o f a r e p r e s e n t a t i v e l i b r a ry . T h e s t a r t i n g m a t e r i a l , 4 - fl u o r o - 3 -n i t r o b e n z o i c a c i d 2 w a s t e t h e r e d t o W a n g 1 o r R i n k xt d e r i v a t i z e d p o l y s t y r e n e r e s i n i n m u l t i -

0040-4039/98/$ - see front matter 1998 Elsevier Science Ltd. All r ights reserved.P l l : S0040-4039(98)01427-0

8/3/2019 Mayer 1998 Tetrahedron-Letters

2/4

6656

gram quantit ies. Init ial attempts to carry out the loading step using the 1-hyd roxy ben zotriazole(HO BO ester of 2 were unsuccessful due to the unanticipated ipso- f luoride displacem ent by thenucleophi l ic hydroxyl group of HOBt.t2 T he coupl ing in both cases wa s sub sequent ly carriedout using the corresponding di isopropylcarbod i imide (DIC) generated sym metrical anhydride,w i t h 0 . 1 e q u i v a l e n t s o f N , N - d i m e t h y l a m i n o p y r i d i n e ( D M A P ) a d d e d t o c a t a l y z e t h eesterif ication of W ang resin. F ollo win g the loading step the resins 3 and 4 were treated with

,W aog osin, 02i ~ , . , . O O

~ " " ~ n ~ Fii(RinkResin) ( ~ NH~ ~ " N O NO2

4

~ FHO NO2O

2

S c h e m e 1 . L e g e n d : i) 4.0 eq. 4 - f lu o r o - 3 - n i t r o b e n z o i c a c i d , 2, 2.0 eq DIC, 0.1 eq. DM AP n DM F, 12h o u r s , i i) 3.0 eq. 4-fluoro-3-nitrobenzoic c i d , 2, 1.5 eq. DIC in DM F, 3 h o u r s .

~ X O ~ ~ i ~ , X ~ N O2 D 2O3 , 4 5

RtH x R 2o 7-15

X-O , NH

i i i , i vii

l ii

~ , / X N H 2O 6

S c h e m e 2 . L e g e n d : i) 5.0 eq. amine, 5% DIEA n N M P o r DMF, O/N, ii) 3.0 M SnCI2 n DMF, 5 h o u r s , i i i ) 4.0 eq. a l d e h y d e ,2.0 eq. DDQ in DM F. 5 h o u r s , i v ) 5 0 % t r i fl u o r o a c e t i c a c i d i n DCM, 2 h o u r s .5 . 0 equ iva len t s o f se l ec t ed pr imary amines in a 5% so lut ion o f N , N-d i i sopropy le thy lamine(DIE A ) in DMF or N -methylpyrrol idone (NMP ) overnight at room temperature. Th e react ionproceeded ef f ic ient ly with a wide range (> 100 ) o f primary al iphat ic , b enzyl and 2-alkylb enzylamines, ani l ines were not included. Displacem ents by be nzylam ine inputs with e i ther e lectrondonating or withdrawing substituents p roceeded to com p letion within the overnight t ime frame.R eduction of the polym er supp orted nitroanilines 5 was achieved b y treatment with 3.0 M SnC12

8/3/2019 Mayer 1998 Tetrahedron-Letters

3/4

6657

i n DM F fo r 5 ho ur s . 13 The q ua l i ty o f t he r esu l t an t i n t e rme d ia t e cou ld be assesse d by c l eav agea n d a n a l y s i s o f a p o r t i o n o f t h e r e s i n b o u n d o - p h e n y l e n e d i a m i n e 6 , p r i o r t o s p l it ti n g t h e r e s i n top e r f o r m t h e d i s c r e te c y c l i z a t i o n r e a c ti o n s . T h e p u b l i s h e d p r o c e d u r e o f P h i l li p s a n d W e i 8 w a sh a n d i c a p p e d b y t h e l i m i t e d a v a i l a b i l i t y o f t h e r e q u i s i t e a r y l i m i d a t e s a n d b y t h e p r o l o n g e dh e a t i n g r e q u i r e d fo r t h e t r a n s f o r m a t i o n . W e t h e r e f o r e s o u g h t a n a l te r n a t iv e s t r a t e g y w h i c hc o u l d n o t o n l y u t i li z e a l a r g e n u m b e r o f c o m m e r c i a l i n p u t s b u t o f f e r m i l d e r r e a c t i o n c o n d i ti o n s .T h e o n e - p o t m e t h o d o f V a n d e n E y n d e e t a l . , L 4 f e a t u r i n g a 2 , 3 - d i c h l o r o - 5 , 6 - d i c y a n o - l , 4 -b e n z o q u i n o n e ( D D Q ) m e d i a t e d c y c l o c o n d e n s a t i o n o f a n o - p h e n y l e n e d i a m i n e a n d a n a l d e h y d e ,p r e s e n t e d a n a t t r a ct i v e a l te r n a t iv e . S o l i d p h a s e a p p l i c a t i o n o f th i s p r o c e d u r e i n v o l v e d th ea d d i t i o n o f 4 . 0 e q u i v a l e n t s o f a n a l d e h y d e a n d 2 . 0 e q u i v a l e n t s o f D D Q t o 6 i n D M F f o r 5

7: 91(74) 8: 88(70) 9: 94(67)

10: 99(82) 11: 77(71) 12: 84(61)

13: 97(69) 14: 94(71) 15 : 90(73)

T a b l e 1 . Representative products and result s from a validation library. The first number refers to the crude yield, the number inparentheses to purity as assessed by integration of HPLC peak areas.h o u r s a t r o o m t e m p e r a t u r e a n d w a s s u c c e s s f u l l y d e m o n s t r a t e d f o r 1 6 0 a l d e h y d e s . F o l l o w i n gD M F a n d D C M w a s h e s , t h e r e s in s w e r e s u b j e c t e d t o c l e a v a g e w i t h 5 0 % t r if l u o ro a c e t ic a c i d inDC M for 2 hou rs . Th e st ructures, y ie ld 15" and pur i ty ~Sb data obta ined for a re prese ntat iv e set o fcom po und s (7 -15) a re sum m ar ized in Tab le 1 . Add i t iona l ly , p roduc t s f rom va l ida t ion l ib r a r iesw e r e c h a r a c t e ri z e d b y ~H N M R a n d e l e c t ro s p r a y m a s s s p e c t r o m e t r y ) 6

8/3/2019 Mayer 1998 Tetrahedron-Letters

4/4

6658

I n s u m m a r y , t h e b e n z i m i d a z o l e s r e p r e s e n t a n e x c e l l e n t c o m b i n a t o r i a l s c a f f o l d a n d o u rm e t h o d a l l o w s f o r th e i n t r o d u c t i o n o f c h e m i c a l d i v e r s i t y th r o u g h t h e u s e o f c o m m e r c i a l l ya v a i l a b l e i n p u ts w i t h a d d i t i o n a l e x p a n s i o n p o s s i b l e b y u s e o f r e s i n s p r e l o a d e d w i t h n a t u r a l a n du n n a t u r a l a m i n o a c i d s . T h e m e t h o d o l o g y is i d e a l l y s u i t e d f o r a u t o m a t e d a p p l i c a t i o n s i n c e t h ee n t i r e s y n t h e t i c s e q u e n c e c a n b e c a r r i e d o u t in D M F a t r o o m t e m p e r a t u r e .A c k n o w le d g m e n tW e t h a n k D r . L e s z e k P o p p e f o r N M R d a ta , M r . D o u g L e n z f o r m a s s s p e c t r a l a n al y s is , D r .W i l l i a m S . M a r s h a l l f o r c r i ti c a l r e a d i n g o f t h e m a n u s c r i p t a n d D r . L a w r e n c e S . M e l v i n a n d D r .T h e o d o r e J o n e s f o r t h e i r s u p p o r t .R e f e re n c e s a n d N o t es[1 ] For reports on rec ent progress in combinatorial chem istry, see: a) Sp ecial Issue on Com binatorialChem istry, Sz ostak, J. W., Ed. ; C h e m . R e v . 1997, 97 , 349. b) C h e m . E n g . N e w s 1998, 76 , 47 .[2] A1-Muhaimeed, H. J . In t . Med . Res. 1997, 2 5, 175.[3] Richter, J. E. Am . J . Ga s t ro e n te ro l . 1997, 92 , 34 .[4] Chen g, J. B.; Coo per, K.; Duplantier, A . J.; Eggler, J. F.; Kraus, K. G.; Ma rshall, S. C.; M arfat, A.;Masam une, H .; Shirley, J. T.; Tickner, J. E.; Um land, J. P. Bioorg . M e d . C he m . Le t t. 1995, 5, 1969.[5] Thom as, A. P.; Allott, C. P.; Gibson, K. H.; Major, J. S.; Masek, B . B.; Oldham , A. A .; Ratcliffe, A. H.;Roberts, D. A.; Russell, S. T.; Thomason, D. A . J . M e d . C he m . 1992, 3 5 , 877.[6] Kubo, K.; Inada, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; ltoh, K.; Furukawa, Y.; Nishikawa, K.; Naka,T. J. M e d . C h e m . 1993, 3 6 , 1772.[7] Arnold, M.; Britton, T.; Bruns, R.; Cantrell, B.; Happ, A. In t. P at . Appl . WO 9528399 .[8] For a previously published solid phase syntheses o f benzimidazoles, see: Phillips, G. B.; We i, G. P.Te t rah e dron L e t t. 1996, 2 8 , 4887 and Sun, Q.; Yan, B. Bioorg . M e d . C he m . Le t t . 1998, 8, 361.[9] Tw o additional related reports have appeared recently; 2-alkylthiobenzimidazoles: Le e, J.; Gauthier, D.;Rivero, R. A. Te t rahe d ron Le tt . 1998, 3 9 , 201; benzimidazol-2-ones: Wei, G. P.; Phillips, G. B.Te t rahe d ro n Le tt . 1998, 3 9 , 179.[10] Wang , S. S. J. Am . C he m . So c . 1973, 95 , 1328.[11] Rink, H. Te t ra h e d ro n L e t t. 1987, 2 8 , 3787.[12] The ipso-fluoride diplaceme nt by H OB t was noted in a rece nt report: Morales, G. A.; Corbett, J. W.;DeGrado, W. F. J. O rg . C h e m . 1998, 63 , 1172.[13] Meye rs, H. V.; Dilley, G. J.; Durgin, T. L.; Powers, T. S.; Winssinger, N. A.; Zhu, H.; Pavia, M. R. M ol .Div . 1995, 1, 13.[14] Vanden E ynde, J. J.; Delfosse, F.; Lor, P.; Van Haverbeke, Y. Te t rahe dron 1995, 5 1 , 5813.[15] a) Yields were calculated from the w eight of crude material and the initial loading lev el of starting resin.b) Analysis was carried out by HP LC (Vydac C18 column, 4.6 x 250mm, 0-50% acetonitrile/waterconta ining 0.1% TFA with integra tion of peak areas a t 220nm).[16] Analytical data fo r com pou nd 8, ~H NM R (400MH z, CD CI3) 15 8.97(d, 1H , J=2Hz), 8.45(m, 1H,J=5.3Hz), 8.1 l(d, 1H, J=9.0Hz), 8 .05(s, 1H ), 7.80(d, 1H, J=7.8Hz), 7.63(d, 1H, J= lH z), 7.50(t, 1H,J=8.3Hz), 7.39(t, 1H, J~7.3Hz), 6.91(d, 1 H), 3.37(m, 2H , J=7.3Hz), 1.8(m , 2H , J~7.3Hz), 1.1(t, 3H);mass spectrum (ESI) m/z 321 (M+H).