Stereospecific displacement of 1-(pyridinyl)ethanols with amines and thiols via methanesulfonate esters; asymmetric synthesis of 1- (pyridinyl)ethylamines and sulfides

Article abstract of DOI:10.1055/s-1999-2564

Stereospecific reaction of optically pure (S)-1-(2-pyridinyl) ethanol methanesulfonate with aromatic and aliphatic amines, and thiols in DMSO gives (R)-1-(2-pyridinyl)ethylamine and sulfide with inversion of the configuration in good yields.

Full text of DOI:10.1055/s-1999-2564

LETTER
41
Stereospecific Displacement of 1-(Pyridinyl)ethanols with Amines and Thiols
via Methanesulfonate Esters; Asymmetric Synthesis of 1-(Pyridinyl)-
ethylamines and Sulfides
Jun’ichi Uenishi, a* Tomoko Takagi, a Tetsuya Ueno, a Takao Hiraoka, a Osamu Yonemitsu, a and Hiroshi Tsukube b
a Department of Chemistry, Okayama University of Science, Ridaicho, Okayama 700-0005, Japan
b Department of Chemistry, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
Fax +81-86-256-9419; E-mail: juenishi@high.ous.ac.jp
Received 19 October 1998
(S)-1-(2-Pyridinyl)ethanol methanesulfonate ester (1)8
Abstract: Stereospecific reaction of optically pure (S)-1-(2-pyridi-
was treated with benzylamine in DMSO at room temper-
nyl) ethanol methanesulfonate with aromatic and aliphatic amines,
ature to give (R)-N-benzyl-N-[1-(2-pyridinyl)ethyl]amine
and thiols in DMSO gives (R)-1-(2-pyridinyl)ethylamine and sul-
fide with inversion of the configuration in good yields.
(2a) in 85% yield.9 The same substitution reaction of 1
with thiophenol in the presence of triethylamine gave the
Key words: stereospecific substitution, chiral (pyridinyl)ethyl-
corresponding sulfide 3a in 87% yield. Both reactions
took place stereospecifically with perfect inversion of the
chiral center. The results with other amines and thiols are
summarized in Table 1.10 Although the substitution with
primary aliphatic amines proceeded very well (entries 1,
2), the reactions with aromatic and secondary amines
were rather slow. In such cases, the reaction can be accel-
erated by heating at 60°C without the loss of stereospeci-
ficity (entries 3-5).11 On the other hand, bulkier amines
such as diethylamine or diisopropylamine were unreac-
tive. Substitution with 2-mercaptopyridine and 2-mercap-
topyrimidine gave the corresponding sulfides 3b and 3c in
76 and 87% yields, respectively (entries 7, 8). The reac-
tions with quinoline-2-thiol, cyclohexanethiol, and dode-
cane-1-thiol were not complete under these reaction
conditions, and considerable amounts of the starting ma-
terials were recovered. When sodium salts of these thiols
amine, chiral (pyridinyl)ethylsulfide, chiral ligand, anti-AIDS drug
Stereospecific substitution reactions are important for
preparing functional groups of chiral compounds.1 The
substitution of a chiral halide, mesylate, or tosylate with a
nucleophile such as amine, sulfide, halide or azide in an
SN2 reaction proceeds with inversion of the chiral carbon
center.2 When substitution occurs at a benzylic position,
this reaction sometimes competes with an SN1 reaction
process,3 with a resulting decrease in optical purity. Since
chiral non-racemic pyridine derivatives have recently re-
ceived much attention as useful ligands for asymmetric
synthesis4 and molecular recognition chemistry,5 a ste-
reospecific substitution reaction of pyridine substrates
would be valuable. However, substitution reactions on a
(2-pyridinyl)methyl carbon center have not been well in-
vestigated.6 In this paper, we report the first stereospecific
displacement of 1-(2-pyridinyl)ethanol methanesulfonate
ester with amines and thiols occurring with perfect inver-
sion of configuration. The synthesis of C2 symmetric
bis(pyridinylethyl)amine and sulfide, and the asymmetric
synthesis of the HIV reverse transcriptase inhibitor, PNU-
142721,7 are also described.
Scheme 1
Synlett 1999, No. 1, 41–44 ISSN 0936-5214 © Thieme Stuttgart · New Yorkrk

42
J. Uenishi et al.
LETTER
were used, the corresponding sulfides were obtained in
good yield with an inversion of configuration (entries 9-
11).11
The absolute stereochemistry of amines 2a and 2b was de-
termined by independent synthesis from (R)-1-(2-pyridi-
nyl)ethylamine (8),12 which was prepared in 65% yield by
the substitution reaction of 1 with NaN3 in DMSO13 fol-
lowed by Pd-catalyzed hydrogenation. Treatment of 8
with benzaldehyde and cyclohexanone in the presence of
NaB(CN)H3 gave 2a and 2b with the same specificities as
shown in Table 1. On the other hand, the stereochemistry
of 3d was confirmed by X-ray analysis of the correspond-
ing sulfoxide, which was obtained upon mCPBA oxida-
tion of 3d.14
The above result suggested that the substitution reaction
proceeded via SN2 displacement. In fact, the reaction rate
decreased with a bulky nucleophile, and depended on the
concentration of the nucleophile and substrate. Due to the
stability of the benzylic cation, SN1 and SN2 reactions
competed in the case of a-phenethyl halide,15 in which an
electron-donating group on the phenyl ring increased the
proportion of SN1 product, while an electron-attracting
group increased SN2 product. Since the benzylic cation
was destabilized by the electron-withdrawing property
and unfavorable resonance effect of a 2-pyridinyl group,
the SN2 reaction favorably occurred in 1 to give the inver-
sion product. For the same reason, the methanesulfonate
of 1-(4-pyridinyl)ethanol16 was also displaced with ben-
zylamine and thiophenol stereospecifically to give opti-
cally pure benzylamines 417 and phenylsulfide 5, in 72 and
59% yields respectively, with an inversion of stereochem-
istry. On the other hand, the methanesulfonate of 1-(3-py-
ridinyl)ethanol16 was rather unstable, like that of a-
phenethylalcohol.18 The substituted amine and sulfide, 6
and 7 were obtained in poor yields with the loss of enan-
tiomeric purity.19
Structures
reacted with 1 to give bis[1-(2-pyridinyl)ethyl]sulfide 11
in 72% yield. The two pyridine rings of 10 and 11, are
connected by a four-bond tether, including carbon-sulfur
and carbon-nitrogen bonds, to give a nice C2 symmetric
structure.21
The above reaction can be used as a general and powerful
method constructing chiral non-racemic pyridines includ-
ing C2 symmetric tridentate and bidentate amine ligands,
10 and 11. The substitution reaction of 1 with optically
pure (pyridinyl)ethylamine 8 gave bis[1-(2-pyridinyl)eth-
yl]amine 10 in 77% yield. On the other hand, optically
pure 1-(2-pyridinyl)ethylmercaptan 9 was obtained in
88% yield from 1. Thus, the substitution reaction of 1 with
thioacetic S-acid in the presence of triethylamine in
DMSO followed by methanolysis of the thiol ester in the
presence of potassium carbonate gave 9.20 This chiral thiol
PNU-142721 (16) has recently been reported as a potent
synthetic anti-HIV medicine by Morris et al.7 It has a
chiral center of 1-(2-pyridinyl)ethyl 1-pyrimidinyl sul-
fide. Since only the (S)-(-)-enantiomer is desirable for me-
dicinal purposes, it would be a good target compound to
demonstrate the value of current reaction. Lipase-cata-
lyzed enantioselective acetylation of 12 gave (R)-acetate
13 in 45% yield with over 95% e. e. Reduction of the 7-
Synlett 1999, No. 1, 41–44 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of 1-(Pyridinyl)ethylamines and Sulfides
43
(8) Mesylate 1 was prepared from optically pure (S)-1-(2-pyridi-
nyl)ethanols with methanesulfonyl chloride by the standard
method and the chiral ethanol were obtained by lipase-cataly-
zed enantioselective acetylation; see Uenishi, J.; Hiraoka, T.;
Hata, S.; Nishiwaki, K.; Yonemitsu, O.; Nakamura, K.; Tsu-
kube, H. J. Org. Chem. 1998, 63, 2481.
(9) DMSO was found to be the best solvent. The solvent effects
on the reaction rate were as follows; (fast)DMSO>>HMPA~
DMF ~ CH3CN ~EtOH>benzene>>THF(slow).
chloro group with Bu3SnH in the presence of AIBN, and
subsequent methanolysis of the acetate gave (pyridi-
nyl)ethanol 14. Mesylation of the alcohol with methane-
sulfonyl chloride gave 15 in 76% yield. Sulfide formation
with 6-amino-4-chloro-2-mercaptopyrimidine in the pres-
ence of Et3N furnished the synthesis of 1622 in 59% yield
from 15.
(10) General method: Preparation of 1-(2-pyridinyl)ethylami-
ne; A mixture of 1 (0.5 mmol) and an excess of amine (Et3N
or DMAP, 4-6 eq) was stirred in dry DMSO (5 mL) at room
temperature for 1-24 h or at 60°C for 1-3 h. After the reaction
was complete, the mixture was diluted with methylene chlori-
de (150 mL) and washed with water and brine. The organic
layer was dried over MgSO4 and evaporated. The residual oil
was purified by column chromatography on silica gel eluted
with a combination of EtOAc and hexane. Preparation of 1-
(2-pyridinyl)ethyl sulfide; A mixture of 1 (0.5 mmol), thiol
or thioacetic S-acid (1 mmol), and amine (Et3N or DMAP, 3-
6 mmol) or their sodium salt was stirred in DMSO (5 mL) at
room temperature for 1-24 h or 60°C for 1-3 h. An ice cooled
solution of NaHCO3 (5%, 5 mL) was added to the mixture and
it was extracted with ether (50 mL). The organic layer was wa-
shed with brine, dried over MgSO4, and evaporated. The resi-
dual oil was purified by column chromatography on silica gel
eluted with a mixture of EtOAc and hexane.
(11) Epimerization was not observed under these conditions.
(12) Optically pure 8 was reported previously. (a) Brunner, H.;
Fisch, H. J. Organomet. Chem. 1987, 335, 1. (b) Michelsen,
K. Acta Chem. Scand. 1974, A 28, 428. (c) Cervinka, O.; Be-
lovsky, O.; Rejmanova, P. Coll. Czech. Chem. Comm., 1973,
38, 1358. (d) Mi, A.; Xiao, X.; Wu, L.; Jiang, Y. Synth. Com-
mun. 1991, 21, 2207.
(13) This substitution reaction in DMF was reported by Chelucci et
al. (see reference 6a), but the specificity was only 66% e.e. Re-
investigation of the reaction gave the product with excellent
e.e. (>95%) when the mesylate was used after purification by
silica gel chromatography.
Acknowledgement
We thank M. Ohtani, H. Yasumura, and K. Kawami for their tech-
nical assistance, including the X-ray analysis. Financial support
from the Japan Private School Promotion Foundation is gratefully
acknowledged.
References and Footnotes
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Eds.; Georg Thieme Verlag, Stuttgart, 1996.
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(16) The substrates (e.e. > 95%) were prepared as an optically pure
form by the same method described in our previous paper (see
reference 8).
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Chem. 1996, 61, 4130.
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J. Uenishi et al.
LETTER
(19) Compounds 6 and 7 were obtained in 25 and 12% yields. Their
optical purities could not be determined. However, since the
hydrolyzed product (R)-1-(3-pyridinyl)ethanol, was obtained
with 60% e.e., the substitution might be considered to take
place under both SN2 and SN1 processes.
(21) Studies of asymmetric reactions using these two chiral ligands
are underway in our laboratory.
(22) The physical and spectroscopic data of 16 were coincident
with the data reported by Morris et al. Enantiomeric purity
was independently determined by HPLC using chiral column
(SUMICHIRAL OA-2500I).
(20) The optical purity of 9 was determined to be >97% by Mosher
analysis.
Synlett 1999, No. 1, 41–44 ISSN 0936-5214 © Thieme Stuttgart · New York