reductive amination with sodium triacetoxyborohydridereductive amination with sodium...

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Reductive Amination of Aldehydes and Ketones with SodiumTriacetoxyborohydride. Studies on Direct and I ndirect Reductive

Amination Procedures1

Ahmed F. Abdel-Magid,* Kenneth G . Ca rson, Bruce D. Ha rris, Cynth ia A. Mary anoff , andR e k h a D . S h a h

Th e R. W. J ohnson P harm aceut i cal Research I n st i t ut e, Depart m ent of Chemi cal D evel opment ,S pri n g H ouse, P ennsyl vani a 19477

Received J anuar y 8, 1996X

Sodium tria cetoxyborohydride is presented as a genera l reducing agent for the reductive am ina tion

of aldehydes an d ketones. P rocedures for using th is mild and selective reagent ha ve been developedf or a wide va riety of sub strat es. The scope of the reaction includes a l ipha tic acyclic and cyclicketones, al ipha tic and a romatic aldehydes, and primary an d secondary a mines including a va riety

of weakly b asic and nonb asic amines. Limita tions include reactions with aromat ic and unsatura tedketones and some sterica lly hindered ketones and a mines. 1,2-Dichloroetha ne (DC E) is the preferred

reaction solvent, b ut reactions can also b e carried out in t etrah ydrofuran (THF) a nd occasionallyin acetonitr i le. Acetic acid may b e used as cata lyst w ith ketone reactions, but i t is generally notneeded wit h a ldehydes. The procedure is carried out effectively in th e presence of acid sensitive

functional groups such as acetals and ketals; it can also be carried out in the presence of reduciblefunctiona l groups such as C-C multiple bonds and cyano and nit ro groups. Reactions are generally

f aster in D CE tha n in THF, a nd in b oth solvents, reactions a re faster in t he presence of AcOH. Incomparison wit h other reductive amina tion procedures such as Na B H 3CN /MeOH , bora ne-pyridine,

an d cata lytic hydrogenation, NaB H(OAc)3 gave consistently higher yields and fewer side products.In the reductive amination of some aldehydes with primary amines where dialkylation is a problemwe adopted a stepwise procedure involving imine formation in MeOH followed by reduction with

N a B H 4.

Introduction

The rea ctions of aldehydes or ketones w ith a mmonia,

primary amines, or secondary amines in the presence of

reducing agents to give primary, secondary, or tertiary

amines, respectively, known as reductive aminations (of

the ca rbonyl compounds) or reductive a lkylat ions (of th e

amines) are a mong the most useful and importa nt toolsi n t h e s y n t he si s of d if fe re nt k in d s of a m i n es . Th e

reaction involves the initial forma tion of the intermediat e

carb inol a mine 3 (Scheme 1) which dehydrat es t o forma n i mi n e. U n d e r t h e r ea c t ion con d it i on s , w h ich a r e

usually w eakly a cidic to neutra l , the imine is protonat ed

to form an iminium ion 4.2 Subsequent reduction of thisiminium ion produces the alkylated amine product 5.However, there a re some reports tha t provide evidence

suggesting a direct reduction of the carbinol amine 3 a sa p os s ib le p a t h w a y l ea d i n g t o 5.3 The choice of t her e du ci n g a g e n t i s v e r y cr i t ica l t o t h e s u cc es s of t h e

reaction, since the reducing agent must reduce imines(or iminium ions) selectively over aldehydes or ketones

under the reaction conditions.The reductive amination reaction is describ ed as a

direct r e a c t i o n w h e n t h e c a r b o n y l c o m p o u n d a n d t h e

amine are mixed with the proper reducing agent without

prior formation of the intermediate imine or iminiums a l t . A stepwiseor indirect rea ction involves th e prefor-ma tion of the intermediat e imine followed b y reduction

i n a s e pa r a t e s t e p .

The two most commonly used direct reductive amina-

tion methods dif fer in th e na ture of the reducing a gent.The f irst method is catalytic hydrogenation with plati-n u m , p a ll a d iu m , or n ick el ca t a l ys t s .2a,4 Th i s i s a neconomical and ef fective reductive amination method,particularly in la rge scale reactions. However, the reac-

t i on m a y g iv e a m ix t u re of p rod u ct s a n d l ow y ie ld sd e pe n d in g o n t h e m o l a r r a t i o a n d t h e s t r u c t u r e of t h e

r e a c t a n t s .5 H y d r o g e n a t i o n h a s l i m i t e d u s e w i t h c o m -pounds conta ining carbon-carbon multiple bonds a nd int h e p r es e n ce of r e d uci bl e f u n ct i on a l g r ou p s s u ch a s

nitro6,7 a n d c y a n o7 groups. The cat a lyst ma y be inhibitedb y compounds conta ining diva lent sulfur .8 The second

m e t h od u t i li ze s h y d r i de r e d uc in g a g e n t s p a r t i cu l a r l ysodium cyanoborohydride (NaBH 3CN) for reduction.9 The

successful use of sodium cyanoborohydride is due to itssta b ili ty in relatively st rong acid solutions (pH 3), itssolub ili ty in hydroxylic solvents such a s metha nol, a nd

its different selectivities at different pH values. 10 At pH

X Abstract published in Advance ACS Abstracts, May 1, 1996.(1) Pr esented in part at the 33rd ACS Na tional Organ ic Symposium,

Bozeman, Mo, J une 1993, Paper A-4. Preliminary communications: (a)Abdel-Magid, A. F.; Ma rya noff, C. A.; Ca rson, K. G . Tetrahedron Lett.1990, 31, 5595. (b) Abdel-Magid, A. F.; Maryanoff, C. A. Synlett 1990,537.

(2) The forma tion of imines or iminium ions wa s reported a s possibleintermediates in reductive aminat ion rea ctions in cat alytic hydrogena-t i on m e t hods, se e ( a) E m e rson, W. S . Org. React. 1948, 4, 1 7 4 andreferences therein. It was also proposed in hydride methods, see (b)Schellenberg, K. A. J . O r g . C h em . 1963, 28, 3259.

(3 ) Tada ni e r, J . ; H a l l as, R. ; Ma rt i n, J . R. ; S t an asz e k, R. S. Tetra-hedron 1981, 37, 1309

(4) (a) Emerson, W. S.; U ra neck, C. A. J. Am. Ch em. Soc. 1941, 63,749. (b) J ohnson, H. E.; Crosby, D. G. J . O r g . C h em . 1962, 27, 2205.(c) Klyuev, M. V.; Kh idekel, M. L. Russ. Chem. Rev. 1980, 49, 14.

(5) Skita , A.; K eil , F. Chem. Ber. 1928, 61B, 1452.(6) Roe, A.; Montgomery, J . A. J. Am. Chem. Soc. 1953, 75, 910.(7 ) R y la n d e r , P . N . I n C a t a l y t i c H y d r o gen a t i o n o ver Pl a t i n u m

M e t a l s ; Academic Pr ess, New York, 1967; p 128.(8 ) R y la n d e r , P . N . I n C a t a l y t i c H y d r o gen a t i o n o ver Pl a t i n u m

M e t a l s ; Academic Pr ess, New York, 1967; p 21.(9) For a r ecent review on reduction of CdN compounds with hydride

re ag e nt s se e : H ut c hi ns, R. O ., H ut c hi ns, M. K. Re duct i on of CdN t oCHNH by Meta l Hydrides. In Comprehensive Organi c Synthesis; Trost,B. N., Fleming, I ., Eds.; P ergam on Press: New York, 1991; Vol. 8.

3849J . O r g . C h em . 1996, 61 , 3849-3862

S0022-3263(96)00057-6 CCC : $12.00 1996 America n Chem ical Society


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3-4 it reduces aldehydes and ketones effectively, but thisreduction becomes very slow at higher pH values. 11 AtpH 6-8, the more basic imines are protonated preferen-

t i a l l y a n d r e d u c e d f a s t e r t h a n a l d e h y d e s o r k e t o n e s . 10

This selectivity allows for a convenient direct reductive

a m i n a t i o n p r oce d u re . Th e l it e r a t u r e i s r e p le t e w i t hpublicat ions t ha t document the use of sodium cya noboro-

hydride in reductive amina tion reactions.12 Limitationsare t ha t t he reaction ma y require up to a f ivef old excessof the a mine,10 is usually slow and sluggish with a romatic

ketones10 and w ith weakly b asic amines,13 and ma y resultin the contamina tion of the product w ith cyanide.14 The

reagent is highly toxic15 and produces toxic byproductss u ch a s H C N a n d N a C N u p on w or k u p.

Other reported reductive amina tion reagents includeborane-pyridine,13a Ti(OiPr)4/Na B H 3C N,13b borohydride

exchange resin,16a Zn /AcOH ,16b N a B H 4/Mg (C lO 4)2,16c a n d

Zn(BH 4)2/Zn C l2.16d In addition, there are some reports

of electrochemical reductive amination reactions. 17

In our work on hydride-induced reductive aminationsof a l d eh y d e s a n d k et o n es , w e s o ug h t a n a l t e r n a t i v e t othe toxic sodium cyanoborohydride to eliminate the risk

o f r e s i d u a l c y a n i d e i n t h e p r o d u c t a n d i n t h e w o r k u pwa ste stream, part icularly for large scale reactions. Af-

t e r s u r v ey i n g m a n y of t h e com m e r ci a l ly a v a i la b l e h y -dride reagents, we selected sodium triacetoxyborohydride

[NaBH(OAc)3].18 This b orohydride reagent is mild a ndexhib its remarkab le selectivi ty as a reducing agent. I treduces aldehydes selectively over ketones,18 except for

-hydroxy ketones w hich can b e reduced selectively t ogive 1,3-t r a n s diols.19 Th e s t e r ic a n d t h e e le ct r o n -

withdrawing effects of the three acetoxy groups stabilizeth e boron-hydrogen bond and are responsible for its mild

reducing properties.20 Our selection w as also b ased onthe results of reductive alkylation of amines using sodiumb or oh y d r id e i n n e a t l iq u i d c a r b ox y li c a c i ds r e por t e d

earl ier b y G rib ble et al.21

In this paper we report the results of our comprehen-

sive investigat ion of the scope a nd limita tions of sodiumtria cetoxyborohydr ide in a procedure for direct reductivea m i n a t i o n o f a l d e h y d e s a n d k e t o n e s w i t h a v a r i e t y o f

a lipha tic and a romat ic a mines. This report also includesan a lterna tive stepwise route for the reductive am inat ion

of a l d eh y d e s w i t h p r im a r y a m i n e s w h i ch i n vol ve s t h epreformation of imines a nd their sub sequent reductionw i t h N a B H 4 in one-pot rea ctions.

Results and Discussions

The direct reductive amination reactions were carried

out in 1,2-dichloroethane (DCE), tetrahydrofuran (THF),or acetonitr i le. The sta nda rd reaction conditions are a s

f ol low s : a m i xt u r e o f t h e c a r b on y l c om p ou n d a n d t h ea m i n e ( 0-5% molar excess) in the desired solvent isstirred with 1.3-1.6 equiv of sodium triacetoxyborohy-

dride under a nitrogen at mosphere at r oom temperat ure.In some reactions, acetic acid (1-2 mol equiv) is addedto the mixt ure. The progress of the rea ction is followed

b y GC an d G C/M S a na lysis. The results f rom variousreductive am inat ion rea ctions of ketones a nd a ldehydes

a re listed in Ta bles 1 a nd 2, respectively. Solvents suchas w at er or metha nol ar e not recommended. Reactionsin metha nol resulted in a fast reduction of the carb onyl

compound, a nd t he reagent decomposed in wa ter .

(a) Reductive Amination of Ketones. The resultsin Tab le 1 show that the reductive amination of a wide

variety of cyclic and acyclic ketones with primary and

(10) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. A m. Chem. Soc.1971, 93, 2897.

(1 1) Borc h, R. F. , Durst , H . D. J . Am . C h em . So c . 1969, 91, 3996.(12) (a) Hut chins, R. O.; Na ta le, N. R. Org. Pr ep. Proced. I nt. 1979,

11(5), 201. (b) Lane, C. F. Synthesis 1975, 135.(13) Occasional use of weakly basic or nonbasic amines was reported,

see for exam ple: (a) P elter, A., Rosser, R. M., Mills, S. J . Chem. Soc.,Perkin Trans. 11984, 717. (b) Mattson, R. J ., P ha m, K. M.; L euck, D.J .; Cowen, K. A. J. Or g. Chem. 1990, 55, 2552. (c) Borch, R. F.; Hassid,A. I. J. Or g. Chem. 1972, 37, 1673. (d) Marchini, P.; Liso, G.; Reho, A.;Liberatore, F.; Moracci, F. M. J. Org. Chem. 1975, 40, 3453.

(14) (a) The product from large scale reduction of the imine (i) withsodium cyanoborohydride wa s contaminat ed with cyanide. (b)A similarresult wa s reported recently: Moorma nn, A. E. Synth. Commun. 1993,23, 789.

(1 5) For i nform at i on on t he safe t y da t a and he al t h ha z ards associ -ated with sodium cyanoborohydride see: The Si g m a - Al d r i c h L i b r a r y of Chemi cal Safety D ata, 1 st e d. ; L e ng a, R. E . , E d. , Si g m a- Al dri c hCorp.: Milwau kee, 1985, p 1609.

(16) (a) Yoon, N. M.; K im, E. G .; Son, H . S.; C hoi, J . Synth. Commu n.1993, 23, 1595. (b) Micovic, I. V.; Ivanovic, M. D.; Piatak, D. M.; Bojic,V. Dj. Synthesis1991, 1043. (c) Brussee, J .; van Benthem, R. A. T. M.;Kruse , C . G. ; van de r Ge n, A. Tetrahedron: Asymmetry 1990, 1, 163.(d) Bha tta charyya , S.; Cha tterjee, A.; Dutt achowdhhury, S. K. J. Chem.Soc., Perkin Trans. 1 1994, 1.

(17) (a) P ienemann , T.; Scha fer, H.-J . Synthesis 1987, 1005. (b)Smirnov, Yu. D.; Tomilov, A. P. J. Org. Chem. U.S.S.R. 1992, 28(1),42. (c) Smirn ov, Yu. D.; P a vlichenko, V. F.; Tomilov, A. P. J. Org. Chem.U.S.S.R. 1992, 28(3), 374.

(1 8) (a) Gri bbl e , G . W.; Fe rg uson, D. C . J . C h em . Soc. , C h e m .C o m m u n . 1975, 535. (b) Nutaitis, C. F.; Gribble, G. W. TetrahedronLett. 1983, 24, 4287. (c) Gribble, G. W. In Encyclopedia of Reagentsfor Organic Synthesis; Pa quette, L. A., Ed., J ohn Wiley and S ons: NewYork, 1995; Vol. 7, p 4649.

(1 9) See for e x am pl e: (a) Sa kse na, A. K. ; Ma ng i ara c ina, P. Tetra-h ed r o n L e t t . 1983, 24, 273. (b ) E v a n s , D . A. ; C h a p ma n , K . T.Tetrahedron Lett. 1986, 27, 5939. (c) Evans, D. A., Chapman, K. T.;C a r r e ir a , E . M . J. Am. Chem. Soc. 1988, 110, 3560.

(20) Gribble, G . W.; Nuta itis, C. F . Org. Prep. Proced. Int. 1985, 17,317.

(21) Earlier work by Gribble et al. de m onst rat e d t he pot e nt i al oftriacyloxyborohydrides generated from NaB H4 in neat liquid carboxylicac i ds i n re duc t ive al ky l at i on of am i ne s: (a) Gr i bble , G. W.; L ord, P.D.; S kotnicki, J . ; Dietz, S. E.; E at on, J . T.; J ohnson, J . L. J. Am. Chem.Soc. 1974, 96, 7812. (b) Gr ibble, G. W.; J asinski, J . M.; P ellicone, J .T.; P ane t t a , J . A. Synthesis 1978, 766.

Scheme 1

3850 J. Org. Chem., Vol. 61, No. 11, 1996 Abdel-Magid et al.


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s e c o n d a r y a m i n e s w a s s u c c e s s f u l u n d e r t h e s t a n d a r dcon d i t ion s a n d g a v e t h e d e si r ed p r od u ct s i n g oo d t oexcellent yields. The scope of t he reaction includes

dif ferent al icyclic ketones, f rom cyclob uta none t o cy-clododeca none (Ta ble 1: entries 1-23), bicyclic ketones

such as norca mphor an d tr opinone (Ta ble 1: entries 24-30), sa tur a ted a cyclic ketones (Ta ble 1: entries 31-39),a n d k et o e s t e r s (Ta b l e 1 : e n t r ie s 4 7-4 9). N e a r l y a l l

primary and nonhindered secondary amines were usedsuccessfully in these reactions. For the sam e ketone, the

r a t e o f t h e r e a c t i o n w a s d e p e n d e n t o n t h e s t e r i c a n delectronic factors associat ed with the a mines. In general,

p r i m a r y a l i p h a t i c a m i n e s r e a c t e d f a s t e r t h a n p r i m a r yaroma tic and secondary a l ipha tic amines (Tab le 1: en-tries 10 vs 11; 14 and 15 vs 16 and 17; 24 vs 26 an d 27).

C y c li c s e con d a r y a m i n e s s u ch a s m or p h ol in e r e a ct e df a s t e r t h a n a c y c l i c s e c o n d a r y a m i n e s s u c h a s d i e t h y l -

a m i n e (Ta b l e 1 : e n t r y 3 3 v s 3 6 ) w h i le t h e s t e r ica l l yhindered diisopropylamine did not react even after days(Ta ble 1: entry 45). In some slow rea ctions (e.g., Ta ble

1: entries 11, 27, 32, 34, and 36), sma ll am ounts of sideproducts were formed (1-5 % b y G C a r e a % a n a l y s is )

from N-e t h y la t i o n a n d N-a c et y l a t i on of t h e s t a r t i n gamines.22 These impurities were easily removed in the

workup or during t he recrysta l l izat ion of the sa l ts.The reaction conditions a re very mild an d can t olera te

the presence of acid sensitive functional groups such asaceta ls and ketals. For example, the reductive a minat ion

of cyclohexanedione monoethylene ketal with primaryan d seconda ry a mines a fforded good to excellent isola ted

yields of th e corresponding a mines (Ta ble 1: ent ries 14-1 8). An ot h e r e xa m p l e i s t h e r e d uct i v e a l ky l a t i on ofaminoacetaldehyde diethyl acetal with cyclododecanone

(Ta ble 1: entry 9). A part icula rly useful exam ple is thereaction involving cyclohexan edione monoethylene keta l

an d am inoaceta ldehyde diethyl aceta l (Table 1: entry 18)which provides a secondary am ine product conta iningprotected aldehyde a nd ketone functionalities in a nea rly

quanti tative yield.Of al l the ketones used in this study, small al iphatic

cyclic ketones, ra nging from cyclobuta none t o cyclohex-anone, were most reactive. Lar ger cyclic ketones such

a s cycloocta none a nd cyclododeca none an d a cyclic ketonessuch a s 2-hepta none reacted somewh a t slower. Reactiv-

ity of cyclob utanone was so high that i ts reaction withb enzylam ine ga ve a mixture of mono- and dicyclobutyl-

benzylamines even with the use of excess amine (Table1: entry 2). Clean forma tion of N ,N-dicyclobutylbenzyl-am ine resulted with t he use of a 1:2 molar ra tio of amine

to ketone (Ta ble 1: entry 1). The reactions w ith second-a r y a m i n es w e r e v e ry e ff ect i ve s in ce t h e re w a s n o

dialkyla tion product (Ta ble 1: entry 3).

The least reactive ketones w ere aroma tic, R,-unsatur-at ed, a nd sterica lly hindered ketones. Aromat ic an d R,-unsaturated ketones reacted very slowly (Table 1: entries

40, 41, an d 43). Experimenta l ly, a sa tura ted al iphat icketone wa s reductively amina ted, selectively, and q uan -ti ta tively in the presence of an aroma tic or R,-unsatur-a ted ketone (Ta ble 1: entries 42 an d 44). The unrea ctedketones were recovered unchan ged except for the forma -

tion of trace a mounts of their imines (as determined b yG C /M S a n a l y s is of t h e r e a ct i on m i xt u r e ). S t e r i ca l l yhindered ketones were even less reactive tha n a romatic

a n d R,-unsaturated ketones, e.g. , camphor showed noreaction with benzylamine a fter four da ys (Ta ble 1: entry

46). The steric fa ctors associated w ith both ketones anda m i n e s s e em t o b e v e r y i m p or t a n t i n d e t e r m in i n g t h e

outcome of the reaction.In reactions where the formation of diastereomers was

possib le, w e observed varying degrees of selectivi ty.

Reductive amination of 4-tert-butylcyclohexanone withpyrrolidine a nd cyclohexylamine occurred w ith a moder-

ate diastereoselectivi ty to give the thermodynamically

less favored ci s products. This results f rom equa torialat ta ck by the hy dride reagent on the intermediat e imine,

to form t he a xial a mine (Tab le 1: entr ies 19 an d 20).23

The reductive amination of androstanolone with isopro-

pylamine ga ve a mixture of 3R- a n d 3-(isopropylamino)-androstan-17-ol in a bout 25:75 ra tio (Ta ble 1: entr y 21).The reactions involving bicyclic ketones showed higher

degrees of diast ereoselectivity . For example, the reduc-t i v e a m i n a t i on s of n or ca m p h or l ed t o t h e e xc lu s iv e

formation of the endo products, from exo a t t a ck b y t h ehydride reagent. The reductive amina tion of norcam phorwit h benzyla mine (Ta ble 1: entry 24) produced a single

product. This product wa s identical t o that obta ined fromt h e r e d uct i v e a m i n a t i on of b en z a l d e h yd e w i t h endo-2-

a minonorborna ne (Ta ble 2: entry 13), thus confirmingt he endo stereochemistry of the product.

Reductive am inat ion of tropinone with primar y a mines

such as benzylam ine and a niline (Table 1: entries 28 an d29) wa s accomplished in good yield an d high dia stereo-

selectivity giving the endo isomer a s t he ma jor product(determined by 1H NMR).24 The r eaction with b enzyl-

a m i n e g a v e t h e endoa n d exo products in approximately2 0 : 1 r a t i o w h i l e t h e r e a c t i o n w i t h a n i l i n e s h o w e d n odetectab le exo product. The rea ction of tropinone w ith

piperidine w a s extremely slugg ish giving low conversionto about a 1:1 mixture of the exo- a n d endo-products after

four day s of reaction (Ta ble 1: entry 30).The poor solubility of a mmonium a cetat e in DCE , THF ,

o r C H 3C N l im i t s i t s u s e i n t h e r e d uc t iv e a m i n a t i on ofketones to prepare primary a mines. The init ial primaryamine product is much more solub le than ammonium

a c et a t e a n d r ea c t s f a s t e r w i t h t h e k et on e t o g en er a t ed ia l k yl a m in es , s o t h i s r ea c t ion ca n b e u s e d f or t h e

prepara tion of symmetrical dialkylamines. The amina -tion reaction is relatively slow and some ketone reductionm a y oc cu r i f AcO H i s a d d ed . E v e n t h e u s e o f a l a r g e

excess (10 equiv) of am monium a cetat e in THF , DC E, orC H 3C N , i n t h e p re se nce of E t 3N , d i d n ot f a vor t h e

f or m a t i o n o f t h e m on oa l k y l a m i n e, t h e o nl y p r od u ctf or m e d w a s d i cy c loh e pt y l a m i n e (Ta b l e 1 : e n t r i es 2 2

and 23).

N-Substituted R-a m i n o e s t e r s w e r e p r ep a r e d b y t h ereductive a minat ion of R-keto esters with primary and

(22) The N-ethylation of amines is a major process in reaction ofamines with sodium borohydride in neat acetic acid and is believed toproceed through an acetaldehyde formation.21a

(23) This result is consistent with literature reports on the reductionof 4-substituted cyclohexanone imines or iminium salts which con-cl u de d t h a t b u lk y h y d r id e r e a g en t s s u ch a s L -S e le ct r i d e a t t a c kpre fe re nt i al ly from t he l e ss hi nde re d e q uat ori al si de t o g i ve t he ci s-products, while less bulky hydride reagents such a s NaB H4 a n d N a B H 3-C N sl i g ht l y favor t h e a x i al approac h, se e: (a) Wrobe l , J . E . ; Ga ne m ,B . Tetrahedron Lett. 1981, 22, 3447. (b) Hutchins, R. O.; Markowitz,M. J . O r g . C h em . 1981, 46, 3571. (c) Hutchins, R. O.; Su, W.-Y.;Sivakuma r, R.; Cistone, F.; Stercho, Y. P. J. Org. Chem. 1983, 48, 3412.(d) Hutchins, R. O.; Adams, J .; Rutledge, M. C. J . O r g . C h em . 1995,60, 7396.

(24) Chemical sh ift ass ignments of individual protons were a rrivedat by C O SY, H E TC O R, and I nve rse H MBC N MR e x pe ri m e nt s. Thestereochemistry of N-phenyl-3-am inotropane an d N-benzyl-3-aminotro-pane was assigned based on 1D NOE and coupling experiments. Theassi g nm e nt s w e re i n l i ne wi t h ot he r l i t e rat ure re port s; cf. Ba g l ey , J .R. ; Ri l e y , T. N . J. Hetrocycl. Chem. 1977, 14, 5 9 9 and re fe re nc e stherein.

Reductive Amination of Aldehydes and Ketones J. Org. Chem., Vol. 61, No. 11, 1996 3851


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Table 1. Reductive Amination of Ketones



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secondary a mines. The reductive amina tion of methylp yr u va t e w i t h b en z y la m i n e w a s a f a s t a n d e ff ici en t

r e a ct i on u n d er t h e s t a n d a r d c on d i t ion s t h a t g a v e N-benzylalanine methyl ester in an excellent yield (Table1: entry 47). The reaction wa s slower w ith hindered keto

esters such as methyl 3-methyl-2-oxobutanoate (Table

1: entry 48), an d th e competing ketone reduction wa s ama jor reaction. The aroma tic keto ester, methy l benzoylformate reacted even slower with b enzylamine and was

a lso accompa nied by considera ble ketone reduction (Ta ble1 : e n t r y 4 9 ). R e a ct i on s i n vo lv in g ot h e r l es s r e a c t i v e

amines such as aniline or morpholine were much slower

Table 1. (Continued)



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a n d g a v e i n cr ea s i n g a m o un t s of k et on e r ed u ct i on s .Whenever ketone reduction wa s a problem, the conditionsw e r e m o d if ie d t o u s e t h e a m i n e s a s l im i t in g r e a g e nt s .

Th e e xce s s k et o n es w e r e c om p le t el y r e d uce d t o t h ecorresponding alcohols which required the occasiona l

ad dition of excess reducing a gent. N-Substituted R-ami-no esters were a lso prepar ed b y t he reductive a minat ionof R-am ino esters w ith ketones, e.g. , N-(2-butyl)glycine

ethyl ester was prepared in very good yield f rom ethylglycinat e an d 2-buta none (Ta ble 1: entry 50).

The reductive amination of cyclohexanedione mono-e t h y le n e k et a l w i t h p h en y l h y d ra z i n e g a v e c le a n l y t h e

N-sub sti tuted phenylhydra zine (Tab le 1: entry 51) innearly qua nti ta tive yield. Other ketones such a s cyclo-

hexanone and 2-heptanone reacted to give similar prod-ucts (Tab le 1: entr ies 52 and 53); however, there w ere

s om e c om p et i n g s i d e r e a ct i on s . Th e c ru d e p r od u ct sshowed t he f ormat ion of b yproducts, a b out 15% withcyclohexanone a nd 31% with 2-heptanone. Attempted

reductive amination of cyclooctanone with hydroxylaminewa s not successful a nd resulted in the oxime forma tion

(Ta ble 1: entry 54).

Reductive aminations in which diamines containingb oth primary a nd seconda ry a mino groups were studied

a n d i n g e n e ra l , p r im a r y a m i n e s r ea c t e d fa s t e r . I n t h eca s e w h e r e t h e p r im a r y a m i n o g r ou p w a s a l ip h a t i c a n dthe secondary group was aromatic, e.g. , N-phenylethyl-

enediamine, t here wa s a clear dif ference in rea ctivi tybetween the tw o a mines. The reaction with 4-hepta nonegave a quanti tative yield of the product resulting from

e xcl u si ve r e a ct i on w i t h t h e p r im a r y a m i n e (Ta b l e 1 :e n t r y 5 5). I n t h e c a s e w h e r e b ot h a m i n o g r ou p s w e r e

a liphat ic, such a s 1-(2-a minoethyl)piperazine, t here w a sa high selectivity (94:6) for the primary group in reaction

wit h a cety lcyclohexan e (Ta ble 1: entry 56).

(b) Reductive Amination of Aldehydes. Unlikeketones, aldehydes can b e reduced with sodium tr iac-etoxyborohydride.18 Thus, the possibility exists that the

reduction of the a ldehyde would compete wit h t he reduc-tive amination process under the standard conditions.H o w e ve r , t h e s e c on d i t ion s w e r e s o s e l ec t iv e t h a t t h e

reductive aminations with aldehydes occurred very ef-fectively a nd resulted in f ast reactions w ith no a ldehydereductions in most cases st udied (Ta ble 2). One case in

which a ldehyde reduction wa s detected involved a reac-tion w ith the very sterical ly hindered diisopropylamine

(Ta ble 2: entr y 6). All other examples in Ta ble 2 resultedin fast a nd ef f icient reductive amina tions with a varietyo f a l i p h a t i c p r i m a r y a n d s e c o n d a r y a m i n e s a s w e l l a s

a n i l in e w i t h n o d e t e ct a b l e a l d eh y d e r e d u ct i on s . B o t haliphatic and a romatic aldehydes were very reactive and

gave reductive amina tion products w ith a b road varietyof primary a nd secondary a mines. The reaction t imesran ged f rom 20 min to 24 h. The mildness of the rea c-

tion conditions is well i l lustra ted in the reductive ami-nation of 1,1,2-tr is-nor-squa lene a ldehyde with dieth-

ylamine a nd diisopropylamine (Tab le 2: entr ies 19 and20). The a ldehyde wa s clea nly converted to t he corre-sponding a mines in high y ields w ith n o detecta b le side

reactions.

In t he reductive amina tion of aldehydes with primaryamines, formation of dialkylated amines is a common side

reaction. 5 This side reaction wa s ra rely a prob lem inm os t r e a ct i on s r e p or t e d i n Ta b l e 2 . I n t h e f e w ca s e s

when i t w as detected, it w as suppressed b y the a dditionof up to 5%molar excess of the primar y a mine. However,

t h e d i a l ky l a t i on of a m i n es r e m a i n ed a p r ob le m w i t h

certain sub strates.25 An alternative stepwise procedurefor such syst ems is discussed lat er in t his paper.

Some aldehydes, such as formaldehyde and glutaral-d eh y d e a r e on l y a v a i la b l e com m er ci a ll y a s a q u e ou s

solutions which may restr ict their use under the ab overeaction conditions because of the decomposition of thehydride reagent with wa ter . However, the reaction ma y

b e carr ied out in DCE with excess hydride reagent, e.g. ,the reductive am inat ion of either a queous gluta ra ldehyde

or formaldehyde with 1-phenylpiperazine and ab out 4

hydride equivalents was carried out on 10 mmol scale(Table 2: entries 21 and 22) an d gave near ly qua ntita tive

yields of the corresponding am ines. This, however, maynot b e suita b le for la rge scale reactions.

The use of phenylhydrazine in reductive amination of

b enzaldehyde was not successful , resulting only in hy-drazone format ion.

Generally, with either ketones or aldehydes, reactionsin DCE were noticeab ly faster t ha n those car ried out in

THF (e.g., Ta ble 1: entries 6 vs 7; 25 vs 26 and Ta ble 2:e n t r ie s 3 v s 4 ; 9 v s 1 0). Al s o, i n t h e s a m e s o lv en t ,reactions were consistently faster in the presence of 1

(or more) mol equiv of a cetic acid. For most ketones,reactions were improved in t he presence of a cetic a cid.

H ow e ve r, t h e a d d i t ion of a c et i c a c id i s n ot a l w a y sa d v a n t a g e ou s t o t h e r e a c t i on . M os t r e a c t i on s w i t h a l -dehydes are fast and do not require addition of AcOH.

Addition of AcOH to a slow reaction, e.g., cyclohexan-ecarboxaldehyde with diisopropylamine, resulted in a fast

reaction accompanied with ab out 25% aldehyde reduc-tion, and the yield of the isolated desired product wason l y 4 1%. Wh e n t h e r e a ct i on w a s c a r r ie d o u t i n t h e

absence of AcOH, the reaction was slower; however, thea ldehyde reduction wa s only about 5%, an d the isolat ed

yield of the purified reductive a minat ion product in-creased t o 75%(Tab le 2: entr ies 6 and 7). D irect com-parisons were made b etween reactions in D C E a nd THF

and with or without added acetic acid in representative

reactions. The rat e of product forma tion wa s determinedq u a n t i t a t i v e l y26 in each case. The results of these com-

parisons were in agreement w ith th e above observa tions.

(c) Reductive Amination with Weakly Basic andNonbasic Amines. Few literature references ha ve dealtwith aromatic amines containing electron withdrawing

substituents in reductive am inat ion rea ctions.13,21a C a t a -lytic hydrogena tion conditions do not a llow t he presence

of m a n y of t h e e a s i ly r e d uce d e le ct r o n -w i t h d r a w i n gsub sti tuents such as cyano and nitro groups, since thesesub sti tuents a re often reduced under cata lytic hydroge-

na tion conditions.6,7 On the other ha nd, we a nd others13a,b

h a v e f ou n d t h e m os t u s ed h y d ri de r ea g e nt , s od iu m

cyanob orohydride [NaB H 3CN], to b e sluggish and inef -

f i c i e n t w h e n u s e d w i t h t h e s e w e a k b a s e s i n r e d u c t i v eamination reactions.

As a consequence of substitution by electron-withdraw-

ing substituents, these amines are both poor nucleophilesand weak b ases (e.g. , pKa 3.98 for 4-chloroaniline, 1.02

for 4-nitroaniline, -0.29 for 2-nit roa niline, -4.26 for 2,4-dinitroaniline).27 This slows the initial nucleophilic at-

(25) For a discussion of t he dia lkylation side r eactions involving -a nd - am i no e st e rs wi t h al de hy de s and a m e c hani st i c e x pl anat i on,see: Abdel-Magid, A. F.; Harris, B. D.; Maryanoff, C. A. Synlett 1994,81.

(2 6) The prog re ss of t he se re ac t i ons wa s foll owe d by GC . L i ne ars t a n d a r d cu r v es of t h e r e sp on s e f a c t or s b y G C a r e a s o f s t a r t i n gm a t e r i a ls a n d e xp ect e d p r od u ct s w e r e d e t e r m in e d t o a l l ow t h eq uant i t at i ve m e asure m e nt s of t he i r c onc e nt rat i ons i n t he re ac t i onmixtures.



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ta ck on t he carb onyl car b on a nd leads to slower overallr e a ct i on r a t e s (S c h em e 2 ). I n a d d i t i on , t h e c a r b on y l

g r ou p n ow c om p et e s e ff ect i v el y w i t h t h e l es s b a s i cintermediate imine for protonation and subsequently for

the hy dride in th e reduction step.2b This may lead to a

significant carbonyl reduction, consumption of both thecarbonyl compound and the reducing agent and low yields

of the reductive amina tion products. The reducing a gentand reaction conditions should b e chosen caref ully to

minimize such side reactions.

Table 2. Reductive Amination of Aldehydes



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Sodium triacetoxyborohydride is very efficient in re-ductive am inat ion rea ctions w ith such unreactive amines.

The results from several reactions are listed in Table 3.In severa l cases such a s monosubsti tuted an il ines (e.g. ,

p-nitro-p-carbet hoxy-, a nd p-cyanoan ilines), the st an da rd

reaction conditions described previously (about 1:1 rat ioof ca rbonyl compound t o amin e, 1.4 equiv of Na B H(OAc)3w i t h 1 e q u iv o f a c e t ic a c i d ) w e r e a d e q u a t e . H o w e ve r ,with less b asic amines such a s o-nit roa niline, 2,4-dichlo-

roanil ine, or 2-am inothia zole, t he reaction conditionswere modif ied to compensate for the aforementionede ff ect s a n d t o m a x im i ze t h e y ie ld s of t h e r ed u ct i ve

a mina tion products. The optimum condit ions included

the use of the a mine as t he l imiting reagent w ith 1.5-2mol equiv of the ca rbonyl compound, 2-3 equiv of Na B H-(OAc)3, a n d 2-5 equiv of AcOH in 1,2-dichloroethane.Under these conditions, a variety of weakly basic amines

were successfully employed in the reductive aminationsof ketones and aldehydes in isolated yields ranging from

60%t o 96%. The rea ction is convenient a nd t he condi-tions are mild a nd show a high degree of toleran ce for a

var iety of functiona l groups including nit ro, cya no, halo,carb oxy, a nd carb ethoxy groups.

Ketones reacted ef fectively with p-monosubstituted

anil ines to give good yields of the reductive aminationp r od u ct s (Ta b l e 3 : e n t r ie s 1-8). Th e r e a c t ion w a sslightly slower with 2,4-dichloroaniline and gave a high

y i el d o f t h e d e si r ed r e d uct i v e a m i n a t i on p r od u ct i naddition t o some ketone reduction a nd the format ion of

ab out 3%of N-eth yl-2,4-dichloroan iline (Ta ble 3: ent ry9). The reaction b ecam e very slow with o-nitroanilinewhich progressed only to ab out 30% conversion to the

r e d uc t iv e a m i n a t i on p r od u ct a n d 1 7% of N-ethyl-2-n it r oa n i li ne a f t e r 6 d a y s (Ta b le 3: e nt r y 10). Th e

reaction stopped completely when both or t ho positionswere substit uted a s in 2,6-dibromo- a nd 2,4,6-trichloro-a nilines (Ta ble 3: entries 11 an d 12).

The reactions with aldehydes were faster than thosewith ketones and gave higher yields from similar reac-

tions. Aldehyde reductions occurred only with t he leastreactive am ines. In the reductive am inat ion of a ldehydes

w i t h p-carboxyaniline and p-nitroa niline (Ta ble 3: en-tries 13, 14, and 18), no competing aldehyde reductionw a s o b se r ve d . I n t h e s e ca s e s , t h e s t a n d a r d con d i t ion s

were used. With wea ker a mines such as 2,4-dichloro-a n i l in e a n d o-nitr oaniline (Ta ble 3: entries 15 a nd 16),t h e c o n d i t i o n s w e r e m o d i f i e d t o u s e t h e a m i n e a s a

l imiting reagent since aldehyde reduction occurred tothe extent of 10-30%. This procedure w a s a pplied to

other weakly basic primary amines such as 2-aminothia-zole (Ta ble 3: entries 22 and 23) a nd secondary a minessuch a s iminosti lbene (Tab le 3: entry 24). While imi-

nosti lb ene reacted with hexanal to give a high yield oft he N-hexyl product, the dihydro analogue iminodiben-

zyl ga ve no reaction under t he sa me conditions (Ta ble 3:entry 25).

One of the most unique reactions, however, was thereductive a lkylat ion of p-toluenesulfonamide with ben-

zaldehyde t o give the N-benzyl deriva tive (Ta ble 3: entr y2 6). Th e r e a c t i on i s c a r r i ed ou t i n it i a l l y u n d e r t h estandard conditions in the presence of Et 3N (2 equiv).

The aldehyde is usually consumed in about 24 h to give

a m ix t ur e o f N-benzyl p-toluenesulfonamide an d N-b enzal p-toluenesulfonamide. The r eaction mixture is

t h en t r ea t e d w i t h AcO H (2. 5 e q u iv ) a n d a d d i t ion a lNaBH(OAc)3 (1 e q u iv ) t o f in i s h t h e r e du ct i on . Th e

reaction, however, was not successful with ketones orcarboxamides.

The least reactive amines, 2,4-dinitroaniline and 2,4,6-tr ichloroanil ine fai led to undergo reductive amination

wit h benzaldehy de (Ta ble 3: entries 20 a nd 21). Cyclo-hexanecarboxaldehyde, on t he other ha nd, rea cted slowlywith these tw o amines t o give the corresponding reduc-

t i v e a m i n a t i on p r o du ct s . I n t h e s e t w o r e a ct i on s , t h ea ldehyde reduction became a ma jor rea ction process. To

a ssure the presence of enough a ldehyde to react wit h th e

a m i n e , t h e r e a ct i on r e q u ir e d occ a s ion a l a d d i t i on s ofaldehyde a nd reducing agent, up to 5 equiv ea ch and over

a t w o t o f o ur d a y p er i od (S c h em e 3 ). Th e r e a c t i on sprogressed to reach 90-92%conversion (a s d etermined

b y GC) and gave 61%and 58%isolated yields, respec-t i v el y , a f t e r c h r om a t og r a p h y . I t i s p os s ib le t h a t t h e s e

reactions proceed via init ial formation of intermediateenamines rather than imines which may explain the lackof reactivi ty of aromatic aldehydes which cannot f orm

enamines.

(d) Comparison with Other Reducing Agents. I ngeneral , the results of reductive amination employingsodium tr iacetoxyb orohydride were a s good a s or b etter

t h a n m os t c om p a r a b l e r e po rt e d r e su l t s w h e t h er d on e

using hydrogenat ion or hydride reagents. However, inma ny cases, our results were far superior to others. For

example, we compared the reductive amination of cyclo-hexanone with morpholine using NaBH 3C N v s N a B H -(OAc)3. Th e r ea c t i on w i t h N a B H 3CN (6 hydride equiv)

in metha nol and in the a b sence of AcOH wa s only 34%complete a f ter 23 h w ith t he formation of ab out 10%ofthe corresponding ena mine. The conversion improved to

5 0% i n 2 3 h w i t h AcO H (1 e q u i v ) w i t h n o e n a m i n eforma tion. The reaction using the stand ar d NaB H(OAc)3conditions was 99.8%complete in 3 h without a trace ofe na m i n e f or m a t i on (Ta b l e 1 : e nt r y 5). I n a n o t he r

comparison, the reductive amination of 1-carbethoxy-4-piperidinone with p-chloroa niline w a s only 45%completew i t h N a B H

3C N a f t er 2 2 h b ut w a s >9 6 % w i t h N a B H -

(OAc)3 in 2.5 h (Ta ble 3: entry 4).

An impressive result was ob tained in the reductiveamination of 1,1,2-tris-nor-squalene aldehyde with di-ethylamine a nd isopropylamine. These reactions w ere

reported to give ab out 5% yield under regular Borchconditions.28 The y ields w ere improved t o 46 a nd 42%,

respectively, when the reactions were carried out withN a B H 3CN in a nhydr ous THF in the presence of HC l (pH3).29 Un der our sta nda rd conditions, these reactions ga ve

(27) (a) Albert, A.; Ser jeant , E. P . In The Determ inati on of IonizationConstants; Cha pman an d Ha ll: London, 1971; p 91. (b) Yat es, K; Wai,H . J. Am. Chem. Soc. 1964, 86, 5408.

(2 8) Duri at t i , A. ; Bouvi er-N ave , P. ; Be nve ni st e , P . ; Sc huber, F. ;De l pri no, L . ; Bal l i ano, G. ; C at t e l , L . Biochem. Pharmacol. 1985, 34,2765.

(29) Ceruti, M.; B alliano, G .; Viola, F.; Ca ttel; L.; G erst, N.; Schuber,F . Eu r . J . M ed . C h em . 1987, 22, 199.

Scheme 2



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9 8 a n d 9 0% y i el d of p r od u ct s i n h i g h p u ri t y w i t h o ut

chromat ography (Ta ble 2: entries 19 and 20).

The reductive amination of ei ther 2-indanone, -te-tralone, or phenylacetone with anil ine was reported to

w o r k w h e n a n i li n e w a s u s ed a s s o lv en t u n d er c a t a l y t i c

hydr ogenat ion conditions a nd ga ve 72%, 54%, a nd 21%

yield of products, respectively.30 We obt a in ed 85%, 87%,

and 80% yield of t hese products using stoichiometric

a m o un t s of r ea g e nt s u n d er t h e s t a n d a r d con d it i on s(Ta ble 1: entries 12, 13, and 38).

B o r a n e-pyridine is another reducing agent used f or

reductive am inat ion reactions.13a It s use in the reductiveam inat ion of ei ther pyridine-4-carb oxaldehyde or m-

nitrobenzaldehyde with ethyl piperidine-2-carb oxylate

(3 0) C a m p b el l, J . B . ; L a v a g n i n o, E . P . I n C a t al y si s i n O r g an i c Syntheses; J ones, W. H., E d.; Academic P ress: New York, 1980; p 43.

Table 3. Reductive Amination with Weakly Basic Amines



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gave 12%and 13%yield of isolated reductive amination

p r od u ct s , r e sp ect i v el y , a n d co n si d er a b l e a l d e h y d ereduction.14b Un der our sta nda rd conditions, we did notobserve any aldehyde reduction, a nd the isolated yields

were nearly q uant i tat ive (Tab le 2: entr ies 17 and 18).

(e) Stepwise (I n d i r ect) Reductive Amination ofAldehydes. Occasionally, some reactions of aldehydesa n d p r im a r y a m i n e s g a v e c on s i de r a b le a m ou n t s of d i -

a l k y la t i on or o t h er s i de p r o du ct s . As w e m e n t io ne dpreviously, th e ad dition of a slight excess of the prima ry

a m i n e m a y s u pp r es s t h i s s i d e r e a ct i on . H o w e ve r , t h ed i a l k y l a t i o n o f c e r t a i n p r i m a r y a m i n e s s u c h a s - or-amino esters and cyclobutylamine, remained a problem.This also occurred when certain aldehydes were used,s u ch a s ci n n a m a l d e h y d e, h y d r oc in n a m a l d eh y d e , a n d

some stra ight chain a ldehydes. Those part icular casesgave mixtures of monoalkylated a nd dialkylat ed aminesi n r a t i os r a n g in g f rom 5: 1 a n d u p t o 1: 1 u n d er t h e

s t a n d a r d r e a ct i on c on d i t io ns . S u r p r is i n gl y , i n s om ereactions, t he dia lkylat ion side reaction happened even

w h e n e x ce s s a m i n e w a s u s e d o r w h e n t h e r e a c t i on w a sca r r i e d o u t w i t h a pr e for m e d i m i n e a n d n o e x ce s s

aldehyde present. A discussion a nd a possib le explana -tion of some of these results in case of - a n d -aminoe s t er s w a s r e por t e d .25 We d e ve lop ed a n a l t e r n a t i v eprocedure f or such reactions which involves the fastreduction of preformed imines. I m i n e for m a t i o n , h ow -

ever, is a reversible reaction and requires long reactiont im es a n d t h e u s e o f a d eh y dr a t in g a g en t s uch a s

molecular sieves or azeotropic removal of water to drivethe reaction to completion. We studied the relative rat esof imine forma tion from a ldehydes a nd primary am ines

in dif ferent solvents, namely THF, DCE, and methanolw i t h o ut a d d ed c a t a l y s t s or d e h y d r a t i n g a g e n t s . A com -

p a r i s on o f t h e r e l a t i v e r a t e s o f i m i n e f or m a t i o n i n t h ethr ee solvents is listed in Ta ble 4. The relat ive rat io ofproduct imine to reactant aldehyde was determined b y

G C a n a l y s i s o f t h e r e a c t i o n m i x t u r e a n d c o n f i r m e d i nsome cases by 1H NM R in CD 3OD, THF -d8, or CDC l3. I n

all t he cases listed in Table 4, reactions in met ha nol wereconsistently faster a nd ga ve nearly qua nti ta tive conver-

sions relat ive to those carried out in THF or DCE . Thei m in e f or m a t i o n w a s s l ow e r f or k et o n es i n a l l t h r e esolvents; however, the reaction was still faster in metha-

nol (Ta ble 4: entry 7).

The reduction of the a ldimines wa s carried out directlyin metha nol with sodium b orohydride to give th e corre-sponding secondary amines in very high yields and very

short reaction t imes. Thus, th is stepwise (or indirect)one-pot procedure involving imine forma tion in met ha nol

followed by i n s i t u reduction with sodium borohydride is

a very convenient an d ef f icient a l ternat ive for carry ing

out reductive amina tions on substra tes wh ich tend t o gives i gn i fi ca n t a m o u n t s of d i a l ky l a t e d p r od u ct s u s in g t h e

direct procedure.

A s im il a r t r a n s for m a t i on a l on g t h e l in es of p ri orf or m a t i on of t h e i mi ne i s p ri or f or m a t i on a n d t h en

reduction of the enamine. We have found tha t sodiumtriacetoxyb orohydride reduces ena mines q uickly a ndefficiently in DCE to give products in high yields (Table

5: entr ies 6 an d 7), making i t a useful reagent f or this

stepw ise procedure.Another very ef f icient stepwise reductive amination

procedure was developed b y M attson et al .13b I n t h i s

procedure, the amine and the carb onyl compound aremixed in neat titanium(IV) isopropoxide and the result-

ing intermediate is reduced with NaBH 3CN in ethanol .The a uthors reported t he formation of a carb inol a mineintermedia te (see Ta ble 5: entries 8-10) rat her tha n the

usua l iminium ion. The method is a pplicable to prima ryan d seconda ry a mines. We modif ied t his procedure to

r e d u c e t h e i n t e r m e d i a t e w i t h N a B H 4 in methanol (in-s t ea d of N a B H 3CN /et ha nol).31 This modified reduction

is very fast a nd gives the desired amine in very good yielda n d h i g h p u r i t y , e . g . , t h e r e d u c t i v e a m i n a t i o n o f t h e

unsa tura ted ketone 1-acetylcyclohexene with b enzyl-lamine, which wa s very slow under our sta nda rd condi-tions, proceeded very fa st under t hese modified conditions

t o g i v e a q u a n t i t a t i v e y i el d o f t h e r e d uct i v e a m i n a t i o nproduct (Tab le 5: entry 8). Of particular interest , thereductive amina tion of tropinone with benzyla mine using

this procedure which gave a near q uant i tat ive yield of a3:2 mixture of th e endo- a n d exoproducts (Ta ble 5: ent ry

10). As reported ea rlier, this reaction gave approximat ely20:1 rat io of th e endoa nd exoproducts using NaBH(OAc)3(Ta b l e 1 : e n t r y 2 8). At t e m p t s t o a c h i ev e a r e a ct i onbetween tropinone and aniline using this modified systemresulted in incomplete reactions. In rega rds to secondary

amines, M attson et al .13b reported a successful reductive

am inat ion of tropinone with piperidine in 58% yield;h ow e v er , t h e s t e r eoch e m is t r y of t h e p r od u ct w a s n otdisclosed. Our modified conditions ga ve the product in

a 9 0% cr u d e y i el d a s a m i xt u r e o f t h e endo- a n d exo-products in ab out 1:7 rat io. The pure oxalat e sal t of the

exo product w a s isola ted in 66%yield (Ta ble 5: entry 9).

Th e exo-stereoselectivity of this reaction is opposite totha t ob tained from the primary a mines. We are examin-

ing these systems to better understand their mechanisticp a t h w a y .

Summary and Conclusions

The results presented here indicate that sodium tr i-

acetoxyborohydride is a synthetically useful reagent for

reductive aminat ions of aldehydes and ketones. I t is amild, commercial ly a vailab le reagent, a nd i t is a reagent

of choice for reductive amination of carbonyl compounds.Th e s co pe of t h e r e a ct i on co ve r s a l l a l d e h y d es a n d

unhindered al iphatic ketones. Aliphat ic ketones (an da ldehydes) can be selectively reductively a mina ted in t he

(3 1) (a) We re port e d t he use of t hi s m odifi cat i on of Ma t t sonsprocedure (Ti(OiP r)4-N a B H 4/MeOH, rt ) at t he 198th ACS Na tionalMeeting, Miami B each, FL, S eptember 1989; paper ORG N 154 and a tTh e I n t e r n a t io n a l C h e m ica l C on g r e ss of P a ci fi c B a s i n S o ci et i es ,Honolulu, HI, December 1989; paper ORGN 409, Abdel-Magid, A. F.;Mary a noff, C . A.; Sorg i , K. L . ; C arson, K. G. A si m il ar m odifi cat i on[Ti(OiP r)4-N a B H 4 i n di g l y m e at 6 0 C or i n e t hanol at 2 5 C ) ] wasre port e d re ce nt l y : (b) Bha t t a c hary y a, S . Tetrahedron Lett. 1994, 35,2401. (c) Bhattacharyya, S. Synlett 1994, 1 02 9; ( d) Bha t t a c hary y a, S .Sy n t h . C om m u n . 1995, 25, 9.

Scheme 3



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presence of aroma tic a nd R,-unsa tura ted ketones. Ali-phatic and aromatic primary and sterical ly unhindered

secondary a mines ca n b e used in these reactions. Theprocedure wa s superior with w eakly b asic and nonb asic

amines. In representa tive comparisons with other com-m on l y u s ed r e d uc in g r e d uc t iv e a m i n a t i on r e a g e n t s ,sodium triacetoxyborohydride reacted consistently faster,

gave b etter yields, and produced fewer side products.M ethanol a l lows a ra pid forma tion of imines from a lde-

hydes and primary a mines. Aldimines formed in metha -

nol were efficiently reduced t o their corresponding a minesu s i n g N a B H 4.

Experimental Section

Melting points are uncorrected. 1H N M R a n d 13C N M Rspectra were recorded at 400 MHz. The chemical shifts a reexpressed as uni t s w i t h M e4S i as t he i nt e r nal s t and ar d . I Rspectra were recorded on an FT-IR spectrometer and absorp-tions are reported in wave numbers (cm-1). GC -MS (EI) wererecorded on a GC /MSD instrum ent using a cross linked methyl

Table 4. Imine Formation from Aldehydes and Primary Amines

Yiel d (%)

E n t r y Aldeh yde Am in e Tim e (h ) by G C (solven t ) by 1H NMR (solvent)

1 ben za ldeh y de tert-BuNH 2 22 84 (D C E ) 80 (C D C l3)22 95 (TH F ) 98 (TH F -d8)

4 97 (MeOH ) 97 (C D 3OD )2 ben za ldeh y de a n ilin e 4.2 81 (D C E ) 90 (C D C l3)

4.3 74 (TH F ) 75 (TH F -d8)1.5 99 (MeOH ) 97 (C D 3OD )

3 m-a n isa ldeh y de a n ilin e 24 92 (D C E )26 84 (TH F )

2.4 99 (MeOH )4 m-a nisa ldeh y de 2-(3,4-dim et h oxy ph en yl)et h yla min e 2 97 (D C E) 100 (C D Cl3)

0.24 95 (TH F ) 100 (TH F -d8)0.25 98 (MeOH ) 100 (C D 3OD )

5 c-C 6H 11C H O a nilin e 5.4 89 (D C E )5.3 90 (TH F )2.7 96 (MeOH )

6 c-C 6H 11C H O tert-BuNH 2 4.6 89 (D C E )5.3 90 (TH F )2.7 94 (MeOH )

7 cy cloh ept a n on e ben zy la m in e 23 53 (D C E )23 75 (TH F )23 85 (MeOH )

Table 5. Stepwise Reductive Amination Reactions



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silicone 12 m 0.2 mm 0.33 mm capillary column. Massspectra w ere recorded as CI or FAB. Accurat e mass mea sure-ments were carried out using a double-focusing instrument ofE B c onfi g ur at i on (w he r e E i s an e l e c t r i c se c t or and B i s amagn et). The reported a ccurat e mass (mass-to-charge ra tio)measurement values (mean ( 3) ar e for t he [ M H ]+ ions ofthe an alytes of interest a nd a re the avera ge of nine individualdeterminat ions. The deviat ion of the experimenta l determina-tions from th e theoretical values a re expressed in parts-per-million (ppm). GC an a lyses were car ried out on a cross linkedmethy l silicone 12 m 0.2 mm 0.33 m capillar y column or

DB-17; 15 m

0.2 mm

0.25 m. Sodium tria cetoxyboro-hydride wa s purchased from Aldrich C hemical Company, In c.M ost r e ag ent s w e r e c omm e r ci al ly ava i lab l e r e ag e nt g r ad echemicals and used without further purification.

Procedures. 1. Dir ect Reductive Amination Methods.General Notes. (a) The a mine a nd the ca rbonyl compoundar e mixed in 1,2-dichloroetha ne a nd t reat ed with NaB H(OAc)3.THF, CH 2C l2, or C H 3C N m a y a l so be use d as sol vent s .

(b) Acetic a cid (1-2 mol equiv) may be used in reactions ofketones but is not necessary with most aldehydes.

(c)R eactions are norma lly car ried out using t he free amines;however, the amine salt ma y be used. In this case, 1-2 equivof Et 3N is added to the reaction mixture. The Et 3N m ust b eremoved from ba sified product prior to sa lt forma tion.

(d) The progress of the reaction is followed by GC analysisin most cases. A small al iquot is withdra wn from the reaction

mixture, quenched with aqueous NaOH or aqueous NaHCO 3and e xt r ac t e d w i t h e t he r or any ot he r sui t ab l e sol ve nt andinjected into the G C. In case of high MW or heat-sensitivecompounds HPLC or TLC could be used.

(e) The reactions are usually quenched with aqueous 1 NNaO H . I n t he pr e senc e of e st e r s , or ot he r a l kal i hy d r oxid ese nsi t i ve funct i onal g r oups, a q ue ous NaH C O3 i s use d forquench. Reactive am ines such as benzylamine ma y dissolvei n aq ue ous NaH C O3 and t hat m ay g i ve a fa l se i nd i c at i on oftheir consumption.

(f) Most amines form HC l salts clean ly in ether with eth erealHCl, and most of these salts are recrystal l ized from EtOAc/M eO H . S om e a r om a t i c H C l s a lt s m a y t u r n d a r k a n d a f ew aliphat ic amine salts ma y be difficult t o crysta l l ize or ma y behy g r osc opi c ; i n t he se c ase s t he oxal at e sal t s ar e pr e par e d ,usual ly i n M e OH . P i c r at e sal t s a r e pr epar e d i n et han ol.

Method I. This procedure is used for most ketone rea ctions.A representative example is the reductive amination of cyclo-pent anone w i t h he xam e t hy l ene im i ne (Tab l e 1 : e nt r y 4):Hexamethyleneimine (1.0 g, 10 mmol) and cyclopentanone(0.84 g, 10 mmol) were mixed in 1,2-dichloroethane (35 mL)and then treated with sodium triacetoxyborohydride (3.0 g,14 mmol) a nd AcOH (0.6 g, 10 mmol). The mixtur e wa s stirr edat r t und e r a N2 at mosphere for 24 h unt i l the reactant s werecon s u me d a s d et e rm i ne d b y G C a n a l y s is . Th e r ea c t io nmixture wa s quenched by adding 1 N NaOH, a nd the productwa s extra cted with ether. The ether extra ct was wa shed withbrine and dried (MgSO4). The solvent wa s evaporated to givet he c rud e fr e e b ase (1 .6 0 g , 9 6%). The oxal at e sal t w a spr epar e d i n E t O Ac /M eO H as shi ny w hi t e cr y st al s (2 .2 g ,85.5%): mp 171-172 C ; F T-IR (KB r) 3435 (w ), 2934 (s), 2872(m), 2683 (m), 2648 (m), 2585 (m), 2524 (m), 1720 (m), 1623(m), 1455 (m), 1404 (m), 1204 (m), 1116 (m), 717 (m), 499 (m),466 (m) cm-1; 1H NMR (free base, CDCl3) 2.94-2.83 (m, 1H),2.68-2.65 (m, 4H), 1.87-1.25 (m, 16H); 13C NMR (free base,C D C l3) 65.9 (CH), 53.6 (CH 2), 30.2 (CH 2), 27.9 (CH 2), 26.9(CH 2), 24.1 (CH 2); EI MS m / z(relative intensity) 167 (M+, 15),138 (100), 124 (17), 110 (24), 96 (9), 82 (7), 55 (16). Ana l. C a lcdfor C 13H 23NO 4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.69;H, 9.03; N, 5.44.

Method II. The a bove procedure is followed without theaddition of glacial a cetic acid. The reaction mixture rema insc loudy t hr oughout t he r e ac t ion. Thi s pr oc ed ur e i s m oreappr opr i at e w i t h m ost a l d e hy d e s and unhi nd e r e d al i phat i cketones. A representa tive exam ple is the reductive a mina tionof 4-pyridinecarboxaldehyde with ethyl 2-piperidinecarboxylate(Ta ble 2: ent ry 17): Et hy l-2-piperidineca rboxyla te (1.57 g, 10mmol) an d 4-pyridinecarboxa ldehyde (1.07 g, 10 mm ol) weremixed in 1,2-dichloroethane (35 mL) and then treated with

sodium tr iacetoxyborohydride (3.0 g, 14 mmol). The mixtur ew a s s t ir r ed a t r t u n d er a N2 at mosphere for 1.5 h. The GCanalysis showed >90%conversion in 30 min, but the remain-der of the time wa s needed for th e complete conversion. Thereaction mixture was quenched by adding aqueous saturatedN a H C O3, and t he pr od uct w as e xt r ac t e d w i t h E t O Ac . TheE t O Ac e xt r a c t w a s d r ie d (M gS O4), a n d t h e s ol ve nt w a sevapora ted to give th e crude fr ee ba se (2.40 g, 96.7%), >98%pur e by a r e a % G C ana l y sis . A sm al l por t ion w as c onve r t edt o t he d i oxal at e sal t : an off-w hi t e soli d , m p 1 09-1 1 1 C(Et OAc/MeOH ); FT-IR (KB r) 3076 (w), 2968 (w ), 2870 (w), 2521

(m), 1738 (s), 1603 (s), 1504 (m), 1460 (w), 1372 (w), 1204 (s),999 (w), 714 (m) cm-1; 1H NMR (free base, CD Cl 3) 8.52 (d, J) 5.2 Hz, 2H), 7.29 (d, J ) 5.2 Hz, 2H), 4.19 (q, J ) 7.1 Hz,2H), 3.80 (d, J ) 14.4 Hz, 1H ), 3.43 (d, J ) 14.4 Hz, 1H ), 3.20(m, 1H), 2.90 (m, 1H), 2.20 (m, 1H), 1.85 (m, 2H), 1.55 (m,3H), 1.45 (m, 1H), 1.28 (t, J ) 7.1 Hz, 3H); 13C NMR (free base,C D C l3) 174.1 (C), 153.3 (C), 149.7 (CH), 125.8 (CH), 64.8(CH ), 61.8 (CH 2), 59.9 (CH 2), 51.0 (CH 2), 30.5 (CH 2), 26.4 (CH 2),23.1 (CH 2), 15.8 (CH 3); EI MS m / z(relative intensity) 175 (M+

- C O2E t, 100), 147 (4), 93 (5), 92 (25), 82 (5), 65 (15). Ana l.Ca lcd for C 18H 24N2O10: C, 50.47; H, 5.65; N, 6.54. Found: C,50.26; H, 5.74; N, 6.44.

Method II I. Sa me as Method I except for using THF as asolvent. An example is the reductive amina tion of 2-heptan onewith morpholine (Table 1: entry 33): 2-Hepta none (2.28 g,20 mmol) and morpholine (1.92 g, 22 mmol) were m ixed in

THF (80 mL) at rt under N 2. Sodium triacetoxyborohydride(6.36 g, 30 mmol) and glacial AcOH (1.20 g, 20 mmol) wereadd ed, and the mixture wa s stirred at rt for 27 h. The reactionm ix t u re w a s q u en ch e d w i t h a q u e ou s s a t u r a t e d N a H C O3solution, and the product w as extra cted with Et 2O. The Et 2Oextract wa s dried (MgSO4) and cooled in an ice bath an d thentrea ted with ethereal HCl. The product precipitat ed as a wh itesolid. The solid w as collected by fi l trat ion a nd dried; yield:3.24 g, 73% (>9 8%b y G C a r e a % ana l y sis) m p 15 0-151 C.The ana lytical sample wa s obtained as a whit e crysta lline solidby recrysta llizat ion from EtOAc/MeOH: mp 151-153 C; F T-IR (KB r) 3410 (m), 2924 (s), 2863 (s), 2656 (s), 2604 (s), 2462(m), 1434 (m), 1266 (m), 1114 (s), 1073 (m), 928 (m), 881 (m);1H NM R (C DC l3) 12.60 (bs, 1H), 4.43 (dt, J ) 12.8, 2.1 Hz,2H), 3.98 (dd, J ) 12.8, 3.0 H z, 2H ), 3.30-3.16 (m, 3H), 3.09-2.95 (m, 2H), 2.15-2.06 (m, 1H), 1.64-1.10 (m, 10H), 1.44 (d,J ) 6.7 Hz, 3H), 0.90 (t, J ) 6.5 Hz, 3H); 13C NMR (CDCl3) 63.43 (CH 2), 63.37 (CH 2), 62.5 (CH), 47.9 (CH 2), 47.4 (CH 2),31.2 (CH 2), 30.0 (CH 2), 25.8 (CH 2), 22.2 (CH 2), 13.7 (CH 3), 13.4(C H 3); E I M S m / z (relative intensity) 185 (M+, 5), 170 (28),115 (31), 114 (100), 86 (7), 84 (7), 70 (28). Ana l. Ca lcd forC 11H 24ClNO: C, 59.58; H, 10.91; N, 6.32; Cl, 15.99. Found:C, 59.66; H, 11.00; N, 6.42; Cl, 16.09.

Method IV. Sa me as meth od II except for using THF a s asolvent. An example is th e reductive amina tion of -tetralonewith cyclohexylamine (Table 1: entry 10): Cyclohexylamine(1.09 g, 11 mmol) a nd -tet ra lone (1.46 g, 10 mmol) wer e mixedin THF (50 mL) at rt under N 2. The mixture cha nged in about1 min from yellow to da rk blue in color. Sodium tria cetoxy-b or ohy dr i d e (3 .1 8 g , 1 5 m m ol) w a s ad d e d and t he m i xt ur estirred at rt under a N 2 a tmosphere for 24 h. The color of thereaction mixture became l ight pink at the end of t he reactiontime. The reaction mixture wa s quenched by adding a queous3 N NaOH (the color changed to dark green), and the productwas extracted with Et 2O. The Et 2O extract was dried (MgSO4)an d cooled in an ice bat h an d then trea ted with ethereal HC l.The product precipitated as a white solid with a l ight pinksha de. The solid w as collected by fi ltra tion an d dried; yield:2.27 g, 85% (>9 8% b y G C a r e a % ana l y sis). The anal y t i calsample wa s obtained as a white solid by recrystal l izat ion fromEt OAc/MeOH : mp 230-233 C ; F T-IR (KB r) 3415 (s), 2941(s), 2819 (s), 2679 (m), 2506 (w), 2430 (w), 1452 (m), 742 (m)cm-1; 1H NM R (C DC l3) 9.60 (bs, 2H), 7.16-7.02 (m, 4H),3.62-3.45 (m, 1H), 3.43-3.12 (m, 3H), 2.91-2.80 (m, 2H),2.61-2.50 (m, 1H), 2.40-2.17 (m, 3H), 1.91-1.60 (m, 6H),1.39-1.18 (m, 3H); 13C NM R (C DC l3) 134.6 (C), 132.4 (C),129.2 (CH ), 128.6 (CH ), 126.5 (CH ), 126.1 (CH ), 54.2 (CH ), 51.0(CH ), 32.3 (CH 2), 29.5 (CH 2), 28.9 (CH 2), 27.9 (CH 2), 26.0 (CH 2),24.7 (CH 2); EI MS m / z (relative intensity) 229 (M+, 46), 187



13/14

(13), 186 (85), 158 (12), 132 (11), 131 (77), 130 (100), 129 (34),128 (20), 116 (14), 115 (26), 104 (23), 100 (17), 91 (35), 78 (11),77 (12), 56 (28), 55 (31). Anal. Ca lcd for C 16H 24ClN: C, 72.29;H, 9.10; N, 5.27; Cl, 13.34. Foun d: C, 72.41; H, 9.27; N, 5.17;Cl, 13.53.

Method V. T hi s m e t hod i s s i m i l ar t o m e t hod s I and I Iexcept for the use of acetonitri le a s a solvent.

Method VI. This method was used with those reactionsinvolving hindered R-keto esters or weakly basic amines inwhich a competitive reduction of t he car bonyl compoundsoccur. The amine is used as a limiting reagent. A representa -

tive example of the R-keto esters is the reductive aminationof methyl 3-methyl-2-oxobutanoate with benzylamine (Table1: entr y 48): meth yl-3-meth yl-2-oxobuta na te (1.8 g, 12.48mmol) and benzyla mine (0.446 g, 4.16 mmol) in DC E (14 mL)wa s treat ed w ith sodium tria cetoxyborohydride (1.76 g, 8.32m m ol ) at 0 C . Aft e r s t i r r ing 2 1 h, G C ana l y sis show e d t ot alconsum pt ion of t he b enz y l am i ne w i t h t he pr ese nce of t heproduct amine and the intermediate imine in an 8:1 relativerat io. The reaction was t hen treated with a dditiona l sodiumtria cetoxyborohydride (0.88 g, 4.16 mmol). After stirring anadditional 21 h, GC an alysis showed completion of the rea ction.The reaction mixture was diluted with EtOAc (20 mL) andquenched with dist illed wa ter (10 mL). After furt her dilutionwith EtOAc (20 mL), the pH of the water layer was adjustedt o 7 w i t h sat ur at e d aq ue ous NaH C O 3. The E t O Ac lay e r w a sseparated and dried (MgSO 4). The solvent w a s removed under

reduced pressu re to give the crude product (2.45 g). The crudeproduct wa s dissolved in ether and t reated with ethereal HClto give the HCl sa lt , 0.92 g, 81%yield, as a white solid: mp190-191 C ; F T-IR (KB r) 2966 (m), 2806 (m), 2696 (m), 1742(s), 1565 (m), 1469 (m), 1424 (m), 1249 (s), 1030 (m), 753 (m),704 (m) cm-1; 1H NMR (CDCl3) 10.65 (bs, 1H), 10.00 (bs 1H),7.66-7.63 (m, 2H), 7.41-7.38 (m, 3H), 4.40 (d, J ) 13.3 H z,1H), 4.25 (d, J ) 13.3 Hz, 1H ), 4.20 (q, J ) 7.1 Hz, 2H), 3.45-3.35 (m, 1H), 2.75-2.60 (m, 1H), 1.30 (t, J ) 7.1 Hz, 3H), 1.15(d, J ) 6.9 Hz, 3H), 1.09 (d, J ) 6.9 Hz, 3H); 13C NMR (CDC l3) 166.7 (C), 130.9 (CH), 129.5 (CH), 129.0 (CH), 63.1 (CH),62.2 (CH 2), 50.3 (CH 2), 29.4 (CH), 19.5 (CH 3), 17.6 (CH 3), 14.0(C H 3); CI MS m / z (rel intensity) 236 (MH+, 100), 162 (38), 91(20). Anal. Ca lcd for C14H 22ClNO2: C, 61.87; H, 8.16: N, 5.15.Found: C, 61.94; H, 8.21: N, 5.05.

An e xa m p le o f t h e u s e of w e a k ly b a s ic a m in e s i s t h ereductive amina tion of 1-Ca rbethoxy-4-piperidone with p-nitr oan iline (Ta ble 3: entr y 5): 1-Ca rbeth oxy-4-piperidone (3.2g, 19 mmol), p-nitroaniline (1.4 g, 10 mmol), and glacial AcOH(3.6 g, 60 mmol) were mixed in 1,2-dichloroethane (45 mL).Sodium tria cetoxyborohydride (6.0 g, 28 mmol) was added tothe above solution and the reaction mixture stirred at roomt e m pe r at ur e und e r N2 f or 18 h (G C a n a l y s is i nd ica t e d acomplete reaction in addition to ca 20%ketone reduction). Ther e act i on w as q ue nche d w i t h sat ur at e d a q ue ous NaH C O 3, a n dt he pr od uc t w as e xt r ac t e d w i t h E t O Ac (3 75 mL). TheE t O Ac e xt r a c t w a s d r ie d (M gS O4), a n d t h e s ol ven t w a sevapora ted t o give a yellow semisolid (4.7 g). The semisolidwa s tri tura ted with ether/hexane (7:3) to disolve t he excesspiperidone and t he piperidol byproduct. The yellow solid wa scollected by f iltr a tion a nd d ried (1.75 g, 60%), >99%pure byG C a r e a %a nal y si s . The anal y t i cal sam pl e w a s obt ai ne d b yrecrysta llization from Et OAc/hexa ne: mp 172-174 C ; F T-IR(KB r) 3327 (s), 3182 (w), 3097 (w), 2929 (w), 2870 (m), 2398(m), 1679 (s), 1600 (s), 1546 (m), 1460 (s), 1387 (m), 1296 (s),1234 (m), 1184 (m), 1144 (m), 1105 (s), 1033 (m), 937 (m); 1HNMR (CDC l3/d6-DM S O ) 8.03 (d, J ) 9.0 Hz, 2H), 6.59 (d, J) 9.0 Hz, 2H), 6.14 (d, J ) 7.5 Hz, 1H), 4.16-4.10 (m, 4H),3.58-3.50 (m, 1H), 3.02 (m, 2H), 2.04-2.00 (m, 2H), 1.51-1.42 (m, 2H), 1.27 (t, J ) 7.0 Hz, 3H); 13C NM R (C DC l3/d6-DM S O ) 154.9 (C), 152.5 (C), 136.4 (C), 125.9 (CH), 110.6(CH), 60.8 (CH 2), 49.0 (CH), 41.9 (CH 2), 31.0 (CH 2), 14.2 (CH 3);MS (EI ), 293 (95), 277 (15), 276 (76), 264 (9), 248 (12), 220(23), 177 (19), 156 (29), 155 (100), 154 (9), 131 (10), 130 (23),129 (16), 128 (13), 127 (37), 126 (41), 117 (14), 100 (21), 96(19), 82 (28), 57 (18), 56 (57). Ana l. C a lcd for C 14H 19N3O4: C ,57.33; H, 6.53; N, 14.33. Foun d: C, 57.27; H, 6.54; N, 14.21.

2. StepwiseProcedures. Aldimine Formation/Reduc-tion in Methanol. An example is the preparation of N-cy-

clobut yl-4-chlorobenzyla mine (Ta ble 5: ent ry 4): p-Chloroben-zaldehyde (1.40 g, 10 mmol) and cyclobutylamine (0.75 g, 10.6m m ol ) w er e m i xed i n M eO H (40 m L ) a t r t u n der a N2at m ospher e . The m i xt ur e w a s st i r r e d at r t for 3 h, unt i l t healdimine forma tion wa s completed (determined by G C). Thealdimine in MeOH was carefully treated with solid NaBH 4 (0.6g, 16 mmol). The reaction mixtur e wa s stirred for 10 min a ndq ue nche d w i t h 1 M NaO H . The pr od uct w a s e xt r ac t ed w i t hether. The ether extra ct wa s wash ed with sat urat ed aq ueousNaC l and dried (MgSO4). The solvent wa s evaporated to giveth e crude product a s a nea rly colorless oil (1.92 g, 98%) w hich

w a s>

97%pure by a rea %G C a na lysis. The oil wa s dissolvedi n e t he r and t r e at e d w i t h e t he r e al H C l t o g i ve t he H C l sal twh ich w a s recrysta llized from EtOAc/MeOH a s wh ite crysta ls,2.07 g, 89%, m p 237-238 C; FT-IR (KB r) 2917 (s), 2804 (s),2762 (s), 2435 (m), 1497 (m), 1432 (m), 1092 (m), 808 (m), 520(m) cm-1; 1H NM R (fr e e b ase , C DC l3) 7.25-7.22 (m, 4H),3.64 (s, 2H), 3.28-3.21 (m, 1H), 2.23-2.16 (m, 2H), 1.71-1.63(m, 4H), 1.38 (bs, 1H ); 1H NM R (H C l sal t , C DC l3 + C D 3OD ) 9.70 (bs, 1H), 7.50 (d, J ) 8.4 Hz, 2H), 7.37 (d, J ) 8.4 Hz,2H), 3.94 (s, 2H), 3.52 (q, J ) 8.15 Hz, 1H), 2.95 (bs, 2H), 2.41-2.35 (m, 2H), 2.22-2.13 (m, 2H), 1.99-1.89 (m, 1H), 1.83-1.73 (m, 1H); 13C NMR (free base, CDCl3) 138.9 (C), 132.4(C), 130.1 (CH ), 129.4 (CH ), 50.2 (CH ), 53.4 (CH 2), 30.9 (2 CH 2),14.6 (CH 2); EI MS m / z (rela tive int ensity) 196 (M+), 167 (48),125 (100), 89 (26), 39, (18). Ana l. Ca lcd for C 11H 15C l2N : C ,56.91; H , 6.51; N, 6.03; Cl, 30.54. Found: C, 56.89; H, 6.45;N, 5.87; Cl, 30.82.

Reduction of Enamines. An example is the reduction of1-morpholino-1-cyclohexene (Ta ble 5, en try 6 a nd Ta ble 1,entry 5): 1-Morpholino-1-cyclohexene (1.67 g , 10 mmol) inDCE (30 mL) and AcOH (0.61 g, 10 mmol) wa s t reat ed withsodium triacetoxyborohydride (3.0 g, 14 mmol) and stirredunder argon. The GC a nalysis determined tha t the reductionw a s c om pl et e a f t e r 1 0 m in. The r e ac t ion w a s q ue nche d b yadding 1 M NaOH, and t he product wa s extra cted with ether.The e t he r e xt r ac t w a s d r i ed (M g S O 4), a nd t he sol vent w a sevaporated under reduced pressure to give the crude producta s a colorless oil (1.70 g). The oil wa s dissolved in eth er (50mL), cooled in an ice bath, and treated with ethereal HCl togive the HCl sa lt a s a white solid. The solid wa s collected byfiltrat ion a ir-dried, a nd then recrysta llized from Et OAc/MeOHto g ive th e purified product (1.88 g, 91.4%): mp 260-262 C.P i c r at e sal t : a y e ll ow sol id , m p 1 74-175 C (ethanol) (lit.11

176-177 C); F T-IR (HCl sa lt, KB r) 3425 (s), 2937 (s), 2861(m), 2672 (s), 2606 (s), 2478 (m), 1448 (m), 1399 (w), 1267 (w ),1110 (s), 1070 (w), 950 (w ) cm-1; 1H NMR (free base, CD Cl3) 3.74 (t, J ) 5.0 Hz, 4H), 2.43 (t, J ) 5.0 Hz, 4H), 2.29 (m, 1H ),1.88 (d, J ) 10.0 Hz, 4H), 1.61 (d, J ) 13.0 Hz, 1H), 1.28 (m,5H); 13CNMR (free base, CDC l3) 66.9 (CH 2), 63.4 (CH), 49.3(C H 2), 28.4 (CH 2), 25.9 (CH 2), 25.4 (CH 2); EI MS m / z(relativeintensit y) 169 (M+, 16), 127 (11), 126 (100), 98 (7), 83 (10), 82(12), 68 (10), 56 (19), 55 (36). Ana l. Ca lcd for C 10H 20ClNO:C, 58.38; H, 9.80; N, 6.81; Cl, 17.23. Foun d: C, 58.22; H, 9.69;N, 6.72; Cl, 17.25.

The Use of Titanium(IV) Isopropoxide. An example isthe synt hesis of N-[1-(1-cyclohexeny l)ethy l]benzyla min e (Ta ble5, entr y 8): 1-Acetylcyclohexene (1.24 g, 10 mmol) a ndbenzylamine (1.2 g, 11.2 mmol) were mixed in neat titanium-(IV) isopropoxide (4.78 g, 16.8 mm ol) a nd stirred underni t r og e n for 3 h. M et han ol (45 m L ) w a s a d d ed foll ow e d b ycareful addition of NaBH 4 (0.6 g, 16 mmol). Analysis of ther e act i on m i xt ur e a f t e r 5 m i n b y G C i nd ic at e d a com pl et ereduction to the amine. The reaction w as q uenched by adding0 .1 N NaO H . The r e sult i ng m i xt ur e w a s f il t e re d t hr oug hC e li t e, a nd t he r e sid ue w a s w ashe d w i t h e t he r (2 50 mL)a n d w i t h C H 2C l2 (50 mL). The organic lay er wa s separat edan d dried (MgSO4). The solvent w a s removed under reducedpressure t o give the crude product (2.2 g). The crude productw a s d i ssol ved i n e t her a nd t r e at e d w i t h e t her e al H C l t o g i vet h e H C l s a l t a s a w h i t e s ol id . Th e s ol id w a s p ur if ie d b yrecryst a llizat ion from E tOAc/MeOH to give 2.1 g, 83%, of w hitec ry st al s : m p 2 15-217 C ; F T-IR (KB r) 3417 (m), 2932 (vs),2835 (m), 2782 (s), 2732 (s), 2481 (w), 2422 (w ), 1581 (m), 1454(m), 1381 (w), 748 (m), 680 (m) cm -1; 1H NMR (CDCl3) 9.65(bs, 1H), 7.61 (d, J ) 7.4 Hz, 2H), 7.35 (t, J ) 7.4 Hz, 2H),



14/14

7.29 (d, J ) 7.0 Hz, 1H), 5.73 (s, 1H), 3.95-3.92 (m, 1H), 3.78-3.72 (m, 1H), 3.44 (bs, 1H ), 2.25-2.21 (m, 1H), 2.05-1.95 (m,3H), 1.72-1.51 (m, 4H), 1.52 (d, J ) 6.8 Hz, 3H); 13C NM R(CDCl3) 132.6 (C), 130.6 (CH ), 130.5 (C), 129.9 (CH ), 128.9(CH ), 128.7 (CH ), 59.0 (CH ), 48.3 (CH 2), 25.1 (CH 2), 23.8 (CH 2),22.2 (CH 2), 21.9 (CH 2), 17.4 (CH 3) ; E I M S m / z (relativeintensity) 215 (M+, 4), 201 (16), 200 (83), 134 (17), 109 (4),108 (4), 105 (10), 93 (5), 92 (13), 91 (100), 79 (13), 77 (11). Ana l.C al c d for C 15H 22ClN: C, 71.55; H, 8.81; N, 5.56; Cl , 14.08.Found: C, 71.73; H , 8.92; N, 5.40; Cl, 13.96.

Acknowledgment. W e a r e g r a t e f u l t o t h e P R Ispectroscopy group for t heir help and assista nce: D.Gauthier, G. Leo, and P. McDonnell for NMR spectra,J . M a s u cci a n d W. J on es f or t h e F T-I R a n d m a s sspectra, a nd X. Xiang, D. B urinsky, and R. Dun phy for

t h e h i g h re s ol u t ion m a s s s p ect ra . We a l s o t h a n k D r.Norman Santora, the chemical information special ist ,for his va luable help wit h the librar y search. We tha nkprofessor Robert O. Hutchins (Drexel Un iversi ty) forhelpful discussions and for supplying some authenticsamples.

Supporting Information Available: Supporting da ta forne ar l y al l pr od uc t s ar e avai l ab l e i nc l ud i ng m p, FT - I R , 1HNMR, 13C NMR, MS, a nd elementa l an alysis (39 pages). Thismat erial is conta ined in l ibraries on microfiche, immediatelyfollows th is ar ticle in th e microfilm version of the journal, a ndcan be ordered from the ACS; see any current ma sthead pagefor ordering information.

J O960057X


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