Pergamon

0040-4039(95)01302-4

Tetrahedron Letters, Vol. 36, No. 36, pp. 6507-6510, 1995 Elsevier Science Ltd

Printed in Great Britain 0040-4039/95 $9.50+0.00

Lithiation-Mediated C-C Silyl and Stannyl Migrations Observed in 6-Chloro-9-(13-D-ribofuranosyl)purine

Keisuke Kato, Hiroyuki Hayakawa, Hiromichi Tanaka,* Hirokl Kumamoto and Tadashi Miyasaka

School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142

Key Words: lithiation, 6-chloropurine riboside, LTMP, Silylation, Stannylation.

Abstract: l.,ithiation of 9-[2 3.$-tris-O-(tert-butyldimethylsilyl)-~-D-ribofuranasyl]-6-chloropurin¢ (1) with LTMP (lithium 22,6,6-tetramethylpiperidide) and a subsequent reaction with either Me3SiCI or Bu3SnCI was foand to effect C-2-substitution, as a result of "silyl or stannyl migration"from C-8 to C-2 position. Transformation of the resulting 2-stannyl derivative (8) to 2-substituted adenosines was also examined briefly.

Lithiation of purine nucleosides started with the finding that C-8 methylation of a purine ring is feasible by

reacting 2',3'-O-isopropylidene-N6-methyladenosine with BuLi followed by MeL t) Later, a combination of

LDA and 6-chloro-9-(2,3-O-isopropylidene-13-D-ribofuranosyl)purine appeared to be a more efficient way for

the C-8 lithiation, 2) not only due to its high lithiation level but also due to the fact that further manipulations of

the resulting products at the C-6 position provide a convenient route to various types of purine analogues such

as adenosine, inosine, 6-thioinosine and nebularine. 3)

In the course of our lithiation study of purine nucleosides, 4) lithiation of 6-chloropurine riboside was

reinvestigated by using 9-[2,3,5-lris-O-(tert-butyldlmethylsilyl)-fJ-D-ribofuranosyl]-6-chloropurine (1). When 1

was lithiated with LDA (1.2 equiv.) in THF at below -70 °C and then treated with CH3OD, deuterium was

incorporated exclusively into the C-8 position to the extent of 89% with a 98% recovery. Similarly, by using

iodine (1.2 equiv.) as an electrophile, the 8-iodo derivative 2 was formed in 93% yield. When the electrophilic

trapping was done by using Me3SiCI (1.2 equiv.), however, the following products were obtained after

Florisil @ column chromatography: the 2,8-bis(trimethylsilyl) derivative 3 (15%), recovered 1 (33%), and two

inseparable mixtures consisting of 4 plus 5 (ca. 4:1, combined yield 10%) and 6 plus 7 (ca. 2:1, combined

yield 42%). 5 ) It should be mentioned that, to reproduce the observed product distribution, one has to avoid the

use of silica gel, since the 8-trimethylsilyl group undergoes ready protonolysis to give I from 4, $ from 3, and

7 from 6. The formation of 3 and $ in this reaction suggested the possibility of hitherto unprecedented C-2

lithiation of the purine ring. 6) Based on the reasoning that a bulkier lithium dialkylamide could diminish

nucleophilic pathway at the C-6 position, several experiments were carried out by lithiating 1 with LTMP

(lithium 2,2,6,6-tetramethylpiperidide) followed by adding electrophiles. The results are summaried in Table 1.

6507

6508

CI CI

R O ~ R O ~ _ ~

R(~ OR RO ~)R

1 X= H, R.. TBDMS 3 X= Y= SiMes, R= TBDMS

2 X= I, R- TBDMS 5 X- H, Y- SiMes, R,. TBDMS 4 X= SiMes, R= TBDMS 8 X= H, Y= SnBus, R= TBDMS

Table 1. LTMP Lithiation of 1 and Subsequent Reactions with Eiectrophilas. =)

Rd ~)R

§ X= SiMea, R- TBDMS

7 X- H, R- TBDMS

Entry Equiv. of LTMP Electrophiie (equiv.) HMPA (equiv.) Product (% yield by Isolation)

1 1.2 MesSiCI (1.2) m 1 (40), 3 (49), and 4 plus 5 (10) b)

2 1.2 iodine (1.2) m 2 (90)

3 5.0 MesSiCI (1.2) - - 1 (43), 3 (23), and 5 (23)

4 5.0 CHsOD (large excess) ~ deuterated 1 (90) c)

5 5.0 MesSiCI (1.2) 10 1 (5) and 5 (83)

6 5.0 3 (1.0) 10 1 (19) and 5 (72) d)

7 5.0 BusSnCI (1.5) 10 8 (90)

a) All reactions were carded out at below -70 *C in THF. The reaction mixture was quenched by adding saturated aqueous NH4CI and purified by Florisil column chromatography.

b) The ratio of 4/5 was 1/2. c) The extents of deuterium incorporation at C-8 and C-2 positions were 95 and 11%, respectively. d) The yields were calculated based on the total amount of 1 plus 3.

As can be seen from the Table 1, product derived from the nucleophilic attack of LTMP was not formed

even in a trace amount throughout entries 1-7. Although entry 1 shows formation of the 2-substituted products 3

and 5, it would be reasonable to assume that the initial lithiation took place dominantly, if not exclusively, at the

C-8 position, since a high-yield formation of 2 was ascertained under the identical reaction conditions in entry 2.

Even when the silylation was conducted with an increased amount of LTMP (entry 3), recovery of 1 remained

much the same. However, it was interesting to see that a higher yield of 5 resulted at the expense of 3 and 4.

Also, the combined yield (46%) of 3 plus 5 exceeds the extent of C-2 deuteration (11%) in entry 4 (see

footnote). These and the afore-mentioned results of LDA lithiation are consistent with "silyl migration"7, 8) from

C-8 to C-2 position, one possible explanation of which is depicted in Scheme 1.

We found the presence of HMPA in the silylation reaction mixture permits exclusive and high-yield

conversion to $ (entry 5). An additional evidence of the silyl migration is given in entry 6, wherein 5 was

isolated in more than 50% yield. This clearly indicates that 5 originated not only from C8-Si cleavage of 3 but

also through the formation of 4 from la (and, to a lesser extent, directly by the cleavage of 3 with 2,8-

dilithiated species of 1). 9) In these reactions, HMPA may be working for increasing silaphilicity of a series of

lithiated species. As shown in entry 7, the C-2 stannylation of 1, which presumably follows similar reacdon

pathway, can be accomplished under these reaction conditions to give 8 in high yield.t0,11)

6509

CI CI ,,,N I N

I I Rf RI

1 l a

CI 4 I a CI I a 4 N N Li-'~ I~/IJ.= :~ J Me3Si--~/N I'~/_NL =~,.._ J N " ~ " N " "SiM e 3 N ~ N "" "SiM e 3 I I

Rf Rf

5 e 3

S c h e m e 1 Rf= 2,3,5-tris-O-TBDMS:~-D-dbofuranosyl

CI

Me3Si'~/~ ~ N ; I Fff

4

1 CI

M%Si"~/~ I ~ N L U I

Rf

4 a

We considered that the anticipated reactivity of 8 at both C-6 and C-2 positions could provide a new entry

to 2-substituted adenosines which are known to show a variety of biological activities. 12) The fact that the

available method for C-2 functionalization of purine nueleosides 13) is based on radical reaction and necessitates

the corresponding 2-amino derivative as a starting material also encouraged the following synthetic study. A

series of reactions briefly examined in these contexts are shown below in Scheme 2 [isolated yields of products

(not optimized) are given in parentheses]. Treatment of 8 with iodine (in THF, for 4 h, at room temp.) 14) readily

furnished 9 which has been used as a key precursor for the preparation of antihypertensive 2-alkynyladeno-

sines. 12) Compound 10 was prepared by a modification (PhCOC1/pyridine, in refluxing toluene, for 19 h) of

the published procedure. 15) It was possible to transform 8 to 11 (NH3/EtOH, 90 °C for 24 h, in a sealed tube),

although partial protodestannylation was also observed. As exemplified by the preparation of 12-15, Stille

reaction 16) worked with 11 [Pd(PPh3)4/CuI, in refluxing THF, for 9-22 h] to furnish a variety of 2-substituted

adenosines. CI

g l N

R O . ~ X= el

R(~ ()R 9 R'- I (98%)

10 R'= COPh (60%)

Scheme 2 R= TBDMS

X NH 2

RO SnBu3 RO R' " ~ Stille reaction " ~

. ;. X= NH2 .6 s= =4 8 X= CI 12 R'= CH2Ph (83%)

11 X= NH 2 (69%) 13 R'= Ph (89%) 14 R'= CHfCHPh (20%) 15 R' - CH2CH=CH2 (50=/0)

In conclusion, we have observed C-C silyl and stannyl migrations during lithiation of 1. Also, the 2-

stannyl derivative (8), obtained in almost quantitative yield in this reaction, has been transformed to a series of

2-substituted adenosines. Application of this method to the synthesis of 2-substituted analogues of some purine

nuclooside antibiotics is currently under investigation in our laboratory.

6510

Acknowledgement. Financial support from the Ministry of Education, Science and Culture (Grant-in-Aid

No. 06672240 to T. M. and No. 07672289 to H. T.) is gratefully acknowledged. This work has also been

supported by a British Council Collaborative Research Project (to H. T.).

REFERENCES AND NOTES

1) Barton, D. H. R.; Hedgecock, C. J. R.; Lederer, E.; Motherwell, W. B. Tetrahedron Left. 1979, 279-

282.

2) Tanaka, H.; Uchida, Y.; Shinozaki, M.; Hayakawa, H.; Matsuda, A.; Miyasaka, T. Chem. Pharm. Bull.

1983, 31, 787-790.

3) Lithiation of 6-chloropurine riboside with BuLi has also been reported: Honjo, M.; Maruyama, T.;

Horikawa, M.; Balzarini, J.; De Clercq, E. Chem. Pharm. Bull. 1987, 35, 3227-3234.

4) For precedents of the (2-8 lithiation of naturally occurring purine nucleosides with LDA: a) Hayakawa,

H.; Haraguchi, K.; Tanaka, H.; Miyasaka, T. Chem. Pharm. Bull. 1987, 35, 72-79. b) Hayakawa, H.;

Tanaka, H.; Sasaki, K.; Haraguchi, K.; Saitoh, T.; Takai, F.; Miyasaka, T. J. Heterocyclic Chem. 1989,

26, 189-192.

5) These ratios were calculated based on 1H NMR spectroscopy by integrating H-2 and H-8.

6) Leonard, N. J.; Bryant, J. D. J. Org. Chem. 1979, 44, 4612-4616.

7) There have been many reports on the organolithium-mediated "silyl migration" from nitrogen or oxygen to

carbon. For example: a) Hellwinkel, D.; L~immerzahl, F.; Hofmann, G. Chem. Ber. 1983, 116, 3375-

3405. b) Billedeau, R. J.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett. 1983, 24, 4515-4518.

8) In lithiation chemistry, C-trimethylsilyl group has been used to mask the ortho position of N,N-diethyl-

benzamides" Mills, R. J.; Snieckus, V. J. Org. Chem. 1983, 48, 1565-1568.

9) Compatibility of the 2-trimethylsilyl group to these lithiation conditions was confLrmed by the fact that

treatment of 5 with LTMP (5 equiv.) for 0.5 h followed by usual workup (see footnote in Table 1)

resulted in almost quantitative recovery (98%) of the starting material.

10) When the stannylation of I was carried out by using 4.0 equiv, of LTMP and 4.0 equiv, of Bu3SnC1,

8 and the 2,8-bis(tributylstannyl) derivative (ca. 2:1) were formed. Silica gel column chromatography of

this mixture gave 8 in quantitative yield.

1 I) The regiochemical assignments of 5 and 8 are based on 13C-IH COLOC (Correlation via Long-Range

Couplings) spectroscopy. Partial 13C NMR data of these compounds and I are given below in Table 2. Table 2. Partial 13C NMR data (400 MHz, (5 ppm in CDCI3) of 1, 5, and 8.

Compd. C-2 C-4 C-5 C-6 C-8

1 151.9 151.5 132.1 151.0 144.0 5 174.8 150.7 131.0 150.0 143.7 8 181.9 150.7 130.6 149.2 142.4

12) For a recent example: Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma, H.; Nomoto, R.; Miyasaka,

T.; Watanab¢, Y.; Abiru, T. J. Med. Chem. 1992, 35, 241-252.

13) Nair, V.; Richardson, S. G. Synthesis 1982, 670-672.

14) Sakamoto, T.; Funami, N., Kondo, Y.; Yamanaka, H. Heterocycles 1991, 32, 1387-1390. 15) Yamamoto, Y.; Yanagi, A. Chem. Pharm. Bull. 1982, 30, 2003-2010.

16) For areview: Mitchell, T. N. Synthesis 1992, 803-815.

(Received in Japan 16 June 1995; revised 5 July 1995; accepted 6 July 1995)