Indian Journal of Chemi stry Vol. 40B, November 200 I, pp. 1134- 11 39

Note

A new synthetic method for the reduction of imines by samarium-induced reaction t

Bimal K Bani k"', Anj an Ghatak, Susanta Samajdar, Manas K. Basu, Linda Hackfeld, Indran i Bani k, Oliwia

Zegrocka & Frederick F Becker

The Uni versity of Texas, M. D. Anderson Cancer Ce nter, Department of Mo1ccular Pathology, Box-89, 15 15 Ho lcombe

Bl vd. Houston, TX 77030, USA . E- mail : banik @mdanderson.org

Received 30 January 200 I .. accepted 4 July 200 I

Samarium metal induced reduction o f the imines towards the synthesis of secondary amines has been inves tigated.

Synthesis of secondary amines is an attractive area of research. Several groups have described the synthesis of secondary amines using various reagents. t For example; recently, Lopez and Fu2 described the synthesis of secondary amines by tin-catalyzed reduction of imines . However, the reduction of the tmlnes either by catalytic hydrogenation or borohydride type reagents3 is still the best-established method to produce secondary amines in reasonably good yield. Unfortunately, the catalytic hydrogenation reaction is not environmentally friendly because of its fire-sensitive catalysts, such as Pd-C and Raney Ni. The alternative of using borohydrides is not, in general, effecti ve fo r the reducti on of sterically hindered imines, and mi xtures of isomeric amines result if cyclic imines are substituted. Alternat ive methods that can overcome these drawbacks are necessary.

One possibility is to use lanthanide reagents, which have witnessed a tremendous increase in use in organic synthesis.4 Of these lanthanides, samarium diiodide has been the most attractive reagent. The efforts in this area substantiate the unique role samarium diiodide can play in promoting reactions that are very difficult to accomplish by other available reagents.5 The success of the samarium dii odide reaction, however, depends in many cases on the presence of a strong base, such as hexamethylphos­phoramide (HMPA). Furthermore, the storage of samarium diiodide is difficult because it is very sensitive to ox idation in air. On the other hand, samarium metal is stable in air, and has a strong

t Dedicatcd to Prof. UR Ghatak on his 70'h birthday.

reducing power (Sm 3/Sm= -2.41 V) similar to that of magnesium (Mg2/Mg+ -2.37 V), and is much cheaper than samarium diiodide. As a result of these unique properties, the chemistry of samarium metal has recently received increased attention from the syntheti c chemistry community.6 The operational simplicity of usi ng samarium metal over commerciall y avail able samarium diiodide has also been demonstrated in our recent publ ications.7

Our recent success in utilizing samarium metal for reduction reactions prompted us to study reduction of . . 7b R I Imlnes. ecent y, we reported samarium-medi ated reduction of various aldimines and sterically congested adamantyl imines for a projected route to the synthesis of secondary amjnes.7f This paper describes the reduction of ketimines and asymmetric synthesis of benzyl amines along with our earlier studies in this field .

Reaction of various aldimines (la-8a) with samarium metal and catalytic amounts of iodine using methanol as the solvent was accomplished. Some useful selectivity was observed. We discovered that the nature of the fin al products depended on the structures of the starting imines, and from a series of experiments, we were able to make a generali zat ion. Specifically, imines from the poly aromatic amines and anili ne derivati ves (la-Sa) give monomeric secondary ami nes (lb-5b) whereas imines from arylalky l am ines (6a-8a) give dimeric products (6b-8b) (Table I). In contrast, a similar react ion mediated by Smh produced a mixture of dimeric products (dl and meso), and the yield of the product was low.8

Moreover, an identical reaction performed within a two-week interva l, we requ ired different amounts of samarium iodide for the same yield.

Having a viable route of reduction of aldimines in hand, we decided to test this method for the reduction of ketimines in detail. For example, cyclohexy l im ines 9 with substitution at the 3- and 4-position · were considered. Many methods are known in the literatu re for the reduction of ketimines. However, methods ava ilable for the stereoselective red uct ion of C=N bond produce a mi xtures of products. It has been demonstrated th at small cr rcduci ng agents such as sodiu m borohydride and sodium cyanoborohydride produce equatorial amines, whereas bul kier trialky l­borohydrides produce the cOlTespondi ng ax ial amines

NOTES 1135

Table I - Reduction of imines with SmJI2

Entry starting malerial Product ')'ield(%) Time and Ccnditions

H:2C=NOOMe I-bC-~OOMe 61 RT,30min

1a 1b

2 r-N-Q-OMe rN-Q-OMe 55 RT,30min

Ph Ph H 2a 2b

trN-Ph r N-Ph 58 RT,30min 3 P 3a Ph H 3b

£0 reflux,12h

~~ O~ /-4 l,h ,h 70

,h ~

~---.... HN~ 4a Ph 4b Ph

&7 &9 5 ~ A-"N0...ph ~ ""N""'Ph 65 re flux,12h

I A- I A-

58 5b Ph Ph ,-Ph 52

"=N )=.NH meso : cI RT,30min 6 '--Ph NH 9: 1

6a Ph '--Ph 6b

rrPh Ph~ r-Ph NH HN

cO 66 7 ccJCo meso: cI RT,30min

1.,..-:: l ,h 4 : 1

7a 7b OMe

OMe ~J--6 ~CI~ I .,r;: N ~ I

42 8 I ,hi1

3N" ~ I 31 meso : cI RT,30min

QTN~ 9: 1

,h CI ~

OMe 8a 8b

in varying proportions.3 A mechanistic point of view, the stereochemical analysis of the products of the reduction of cyclic imines by samarium is interesting since an electron transfer route to the C=N bond is the first step in this process instead of hydride delivery. The reduction of methyl cyclohexyl ketimine~ by samarium and catalytic amounts of iodine afforded a mixture of trans- and cis-substituted amines 10. The ratio of the isomers depended on the location of the methyl group at the cyclohexane ring, and we noted a general tendency towards the formation of the lrans-

isomer. The ratio of the isomeric mixtures was determined by a comparison of the NMR data of known authentic compounds prepared by the sodium borohydride method (Scheme I).

In order to study the reaction in a bulkier system, for example, adamantane, the synthesis of several imines 11 with adamantyl methyl ketone was carried out with a wide variety of amines. For example, aromatic amine, aryl -alkyl amine, aliphatic cyclic amine, aliphatic amine, and heterocyclic amine were used with equal success. Mixing the ketone with the

1136 INDIAN J. CHEM., SEC.B, NOVEMBER 2001

R Sm/ 'I MeOH R ,,-H

"-=N ~ N , , Ar Ar

9 10 R Ar Product ratio (trans: cis)

cyclohexyl p-methoxyphenyl

Yield(%)

20

2 4-methylcyclohexyl p-methoxyphenyl 1 : 1 15

3 4-methylcyclohexyl phenyl

4 4-methylcyclohexyl benzyl

5 3-methylcyclohexyl phenyl

6 3-methylcyclohexyl benzyl

2: 1

3: 1

2: 1

2: 1

15

20 15

20

Scheme I

~CH, Sm /12 lltrCh, ~ CH30H

N'R HN'R

11 12

Entry R Yield (%)

1 Meo-o-~ 50 1\

2 0'---.lN~~ 28

3 ~ 51

4 ~ 47

5 H3C-(CH2)7~ 54

6 H3C-(CH2)~ 51

7 H3C-(CH2)d 48

Scheme II

amines in toluene and refluxing the solution with Dean-Stark water system for 20 hours produced the imjnes 11 in good yield. Reaction produced mono­amines 12 in good yield; no trace of diamines could be detected in the crude reaction mixtures (Scheme II). Encouraged by these results, we attempted to combine the two-step synthetic sequence into a one­pot operation. The product obtained from this reaction was found to be identical with the compound prepared by the two-step method.

Synthesis of optically active amjnes was achieved by the reduction of imines 14 derived from chiral benzyl amine 13a and naphthyl amjne 13b. In both cases, a mixture of isomers 15 and 16 was formed.

The absolute stereochemistry of isomers 15 and 16 was assigned by a direct comparison of authentic samples9 (Scheme III).

It has been demonstrated that the reactivity of samarium metal can be increased by using certain additives.6 We have also reported a facile reduction of nitro group by samarium metal in the presence of ammonium chloride using ultrasound. 7d The reaction was very fast and the yield of the product was very high. In order to test the samarium/ammonium chloride combination for the reduction of imines, we reacted an aldimine and a ketimine 14a under these conditions. The products from these reactions were comparable to the samarium-iodine method: good yield with aldimine and poor yield with ketimjne (Scheme IV).

We believe the low yield with the ketimines, particularly with sterically uncongested ketones, is a result of the acidic nature of the medium. All attempts to increase the yield of products by decreasing the iodine concentration or by using smaller amounts of ammonium chloride failed.

The mechanism of the samarium-induced reduction reaction was investigated. The actual reactive species in the Sm-I2 reaction is not firmly established, though Molander lO suggested that the reagent is Smh. It has also been claimed ll that the reactive species is Smh It has been observed that minor changes in the concentration of iodine can produce different reactive species.

Previously, the formation of the dimeric products by SmI2-mediated reaction was explained by postulat­ing a one-electron transfer mechanism across the C=N bond and subsequent coupling of the two carbon radical. 12 Another group also proposed this type of mechanism in the reductive dimerisation of ketones.13

NOTES 1137

Phy H2Ny Me Toluene

+ H'\ Ny Me Ar ------------~~ (R) Mol. Sieves I reflux Ar

13 14

Sm/l!MeOH rt

PhyMe

HNyMe

Ar 15

+

PhyMe

HNyMe

Ar 16

(S, R) (R, R)

a, Ar= 1.7

b, Ar= 2

14 a 15 a + 16 a

1.6

Scheme III

Scheme IV

From the preliminary data, we were unable to identify the reactive species formed by the reaction between samarium metal and catalytic amounts of iodine. It could be Smh or Smh or any other iodo-samarium complex. But we can explain the final distribution of products by postulating two competing pathways resulting in the generation of the reduction product (Scheme V, path 1)

or the dimeric product (Scheme V, path 2). Second­electron transfer to the initially formed product (B) generates the dianion (C), and then protonation of the dianion results in the monoamine. This process is facilitated by the presence of the electron-releasing substituent at the nitrogen (entries 4-8), which can change the reduction potential of the radical anion (B) so that second-electron transfer becomes highly favorable. Alternatively, as a result of severe steric crowding, the

radical (B) in the polyaromatic system prevents self­coupling. Increased congestion around the carbon radical inhibits the C-C bond formation . However, the basis for the formation of monoamines with simpler aromatic amines and diamines (path 2, E, radical-radical coupling) with aryl alkyl amines is not clearly understood. The adamantyl system also supports the above mechanism. Experiments with CD30D produced the D-Iabeled compound, indicating trapping of the dianion by the solvent (Scheme VI). The radical-radical coupling product (dimeric product C) could not be formed because of the considerable steric crowding at the radical center due to the bulkier adamantane system. The fonnation of mixtures of amines with the chiral imines indicates that the dian ion can be protonated from both sides in the transition state. These results indicate that the nature of the products by samarium-induced iodine-catalyzed reduction of imines depends on the substituent present at the N- and at the C-of the imines. Electronic effects and steric effects of the imines are both responsible for detennining the product distribution and yield.

1138 INDIAN J. CHEM., SEC.B, NOVEMBER 2001

A B C

B Path 1

D

Rt = R2 = R3 = alkyl or aryl

Scheme V

Sm/12 MfCH -------~~ 3

COpO ON

~ ~OMe

Scheme VI

In conclusion, we have shown an entirely new samarium mediated reduction method of the imines to amino .derivatives.

A representative procedure is as follows: To the imine 0.5 mmole) in methanol (1.5 mL) was added samarium metal (4 mmole) and iodine (20 mol%). The suspension was stirred at room temperature or reflux under argon atmosphere (Table I). Water (2 mL) and dichloromethane (10 mL) was added to the reaction mixture and the mixture filtered. The organic layer was collected, washed with sodium thiosulfate solution (5%, 5 mL), water (5 mL), dried with sodium sulfate, evaporated, and the product was purified by column chromatography on silica gel using ethyl acetate-hexanes as the eluent. All the new compounds were characterized by spectroscopic data? or by a direct comparison with authentic samples.9

Acknowledgement We gratefully acknowledge the funding support

received for this research project from the Golden Family Fund for cancer research and NIH Cancer

Center Support Grant, 5-P30-CAI6672-25, in particular the shared resources of the Pharmacology and Analytic Center Facility.

References and Notes For example, see: (a) Fujimori K, Yoshimoto H & Oae S, Tetrahedron Lett, 21,1980, 3385. (b) Matsumura Y, Maruoka K & Yamamoto H, Tetrahedron Lett, 23,1982,1932.

2 Lopez R M & Fu G C, Tetrahedron, 53, 1997, 16349. 3 Ranu B C, Sarkar A & Majee A, J Org Chern, 62, 1997,1841. 4 Kagan H B & Namy J L, Tetrahedroll, 42, 1986, 6573. 5 Molander G A & Harris C R, Chern Rev. 1996, 307. 6 (a) Murakami M, Hayashi M & Ito Y, Synlett, 1994, 179. (b)

Ogawa A, Nanke T, Takami N, Sumino Y & Ryu I, Chemistry Lett, 1994, 379. (c) Huang Y, Zhang Y & Wang Y Tetrahedron Lett, 38, 1997, 1065.

7 (a) Banik B K, Mukhopadhyay C, Venkatraman M S & Becker F F, Tetrahedron Lett, 39, 1998, 7343. (b) Banik B K, Zegrocka 0, Banik I, Hackfeld L & Becker F F, Tetrahedron Lett, 40,1999, 6731. (c) Ghatak A, Becker F F & Banik B K Tetrahedron Lett, 41, 2000, 3793. (d) Basu M K, Becker F F & Banik B, Tetrahedron Lett, 41, 2000, 6551. (e) Basu M K, Becker F F & Banik B K, J Chern Res, 8, 2000, 406. (f) Banik B K, Zegrocka 0 & Becker F F, J Chern Res 8, 2000, 321 . (g) Basu M K & Banik B K, Tetrahedron Lett, 42, 2001, 187.

8 Enholm and his group first reported reductive dimerisation of the imines by samarium iodide. For example, see Enholm E J,

NOTES 1139

Forbes 0 C & Holub 0 P, Synth Cornrnun, 21,1990,981. 9 Yamada H, Kawate T, Nishida A & Nakagawa M, J Org

Chern , 64,1999, 8821. 10 Molander G & Wolfe C N, J Org Chern 63, 1998, 9031. In

this report, samarium diiodide was prepared by reacting samarium metal (1.1 eq) with iodine (1.0 eq).

II Lu L, Chang H Y & Fang J M, J Org Chern, 64, 1999, 843. In this report samarium triiodide was prepared by reacting

samarium metal (I eq) with iodine (1.5 eq). 12 (a) Nickel iodide has been used for the effective dimerisation

of the imines. For example, see: Machrouhi F & Namy J L, Tetrahedron Lett, 40,1999, 1315. (b) Collin J, Giuseppone N, Machroul1i F, Namy J-L & Nief F Tetrahedron Lett 40, 1999, 3161.

13 For a recent example see: Zhang W C & Li C J, J Org Chern, 64, 1999, 3230.