Diastereoselectivity in the reduction of α-oxy- and α-amino-substituted acyclic ketones by polymethylhydrosiloxane

Article abstract of DOI:10.1021/jo0260544

Diastereoselectivity in the reduction of α-alkoxy-, α-acyloxy-, and α-alkylamino-substituted ketones with polymethylhydrosiloxane (PMHS) in the presence of fluoride ion catalysis was investigated. High syn-selectivity was observed in the reduction of α-alkoxy, α-acyloxy, and α-dialkylamino ketones. Reduction of α-monoalkylamino ketone proceeded in anti-selective manner with moderate selectivity. The observed selectivity is explained based on Felkin-Anh and Cram-chelate models.

Full text of DOI:10.1021/jo0260544

TABLE 1. Dia ster eoselective Red u ction of r-Am in o a n d
r-Oxy Keton es by th e P MHS/F - Red u cin g System
Dia ster eoselectivity in th e Red u ction of
r-Oxy- a n d r-Am in o-Su bstitu ted Acyclic
Keton es by P olym eth ylh yd r osiloxa n e
syn:antib
entry
ketone 1
% yielda
2:3
Durgesh Nadkarni,* J ames Hallissey, and Carlos Mojica
1
2
3
4
5
6
7
8
9
R1 ) Ph, R2 ) piperidine (1a )
R1 ) Ph, R2 ) N(C2H5)2 (1b)
R1 ) Ph, R2 ) N(CH3)CH2Ph (1c)
R1 ) Ph, R2 ) N CH2Ph)2 (1d )
R1 ) Ph, R2 ) NHCH2Ph (1e)
R1 ) Ph, R2 ) OCOCH3 (1f)
R1 ) Ph, R2 ) OCOPh (1g)
R1 ) Ph, R2 ) OCH3 (1h )
80
76
87
95
88
76c
71c
77
79
90
100:0
100:0
100:0
100:0
26:74
97:3
Process Development Laboratories,
Pfizer Global Manufacturing, Eastern Point Road,
Groton, Connecticut 06340
durgesh.nadkarni@pfizer.com
Received J une 13, 2002
97:3
87:13
73:27
95:5
R1 ) CH3, R2 ) OCH2Ph (1i)d
R1 ) CH3, R2 ) N(CH2Ph)2 (1j)
Abstr a ct: Diastereoselectivity in the reduction of R-alkoxy-,
R-acyloxy-, and R-alkylamino-substituted ketones with poly-
methylhydrosiloxane (PMHS) in the presence of fluoride ion
catalysis was investigated. High syn-selectivity was observed
in the reduction of R-alkoxy, R-acyloxy, and R-dialkylamino
ketones. Reduction of R-monoalkylamino ketone proceeded
in anti-selective manner with moderate selectivity. The
observed selectivity is explained based on Felkin-Anh and
Cram-chelate models.
10
a
b
Total isolated yield. Ratio determined by 1H NMR of crude
product. c Yield as diol after ester hydrolysis. S enantiomer.
d
Use of these reagents for synthesis on a large scale can
be hampered by their limited availability in bulk, pyro-
phoric nature, and high cost.5 Also often sub-zero tem-
peratures are required for good selectivity.3a,5 Silyl hy-
drides on the other hand are generally air-stable liquids,
inexpensive, and amenable to scale-up. Hydrosilanes can
be used as reducing agents in the presence of transition
metal catalysts, acids, bases, or fluoride ions.6 Hiyama
and Fujita have reported high diastereoselectivities for
the reduction of R-oxy and R-amino ketones using tri-
alkyl- or triarylalkylsilanes in the presence of fluoride
ion catalysis.7 The applicability of this methodology is
limited by the need to use a coordinating solvent such
as HMPA. Use of such a high boiling and toxic solvent is
impractical for large-scale synthesis. PMHS is an inex-
pensive nontoxic liquid that is readily available in bulk.8
Polymeric hydrosiloxanes reduce carbonyl compounds
rapidly under mild conditions with catalysis by fluoride
ions.9 The rate enhancement during reactions with
PMHS/F- has been explained by what is called as “zipper
catalysis” mechanism.10 Herein we report the extension
of our results observed for I with PMHS to diastereose-
lective reduction of several ketones substituted at the R
position with alkoxy, acyloxy, and alkylamino substitu-
ents.
Exceptionally high syn-selectivities were observed in
the reduction of ketones substituted with dialkylamino
substituents at the R position under mild conditions with
PMHS/cat. F- (Table 1, entries 1a -d ). We chose com-
mercially available tetrabutylammonium fluoride (TBAF)
as the source of fluoride. With monoalkylamino-substi-
tuted ketone 1e the reduction proceeded in anti-selective
manner with moderate selectivity. It is noteworthy that
reduction of the above ketones with commonly used
reducing agents such as sodium borohydride proceeds in
only moderate to poor selectivity.11
Significant progress has been made in recent years in
controlling the diastereoselectivity during reduction of
R-substituted acyclic carbonyl compounds. It is commonly
recognized that reduction of R-hydroxy and R-amino
ketones with common metal hydrides is generally anti-
selective.1 This has been explained based on Cram’s cyclic
chelate model. Syn-selectivity in ketone reductions is
observed if chelation cannot occur, either due to the
absence of chelating metal cations in the reducing agent
or due to the preferred conformation of ketones (Felkin-
Anh model).2 In addition, the degree of diastereoselec-
tivity has been found to be dependent on several factors
such as reaction temperature, solvent, steric bulk of the
reducing agent, and the steric and stereoelectronic
environment around carbonyl group.1,3,5
In connection with our studies aimed at improving syn-
selectivity in the reduction of pharmaceutical intermedi-
ates of the general structure Ar-CO-CH(NR2)-CH3 (I)
we examined the diastereoselectivity of reduction of I
with several silyl hydride reducing agents. High syn-
selectivity was observed in the reduction of I with
polymethylhydrosiloxane (PMHS) in the presence of
fluoride ion catalysis. Syn-selective reductions for sub-
strates similar to I have been reported in the literature
using bulky alkyl hydrides of boron, tin, or aluminum.3,4
(1) Review: (a) Reiser, O.; Mengel, A. Chem. Rev. 1999, 99, 1191.
(b) Tramontini, M. Synthesis 1982, 605.
(2) (a) Cram, D.; Wilson, D. R. J . Am. Chem. Soc. 1963, 85, 1245.
(b) Cherest, M.; Felkin, H.; Prudent, N Tetrahedron Lett. 1968, 18,
2199. (c) Anh, N. T. Top. Curr. Chem. 1980, 88, 145.
(3) (a) Faucher, A.; Brochu, C.; Landry, S. R.; Duchesne, I.; Hantos,
S.; Roy, A.; Myles; Legault, C. Tetrahedron Lett. 1998, 39, 8425. (b)
Muller, H. K.; Schuart, J .; Baborowski, H.; Muller, E. J . Prakt. Chem.
1973, 315, 449.
(4) (a) Shibata, I.; Yoshida, T.; Kawakami, T.; Baba, A.; Matsuda,
H. J . Org. Chem. 1992, 57, 4049. (b) Takai, H.; Obase. H.; Teranishi,
M.; Karasawa, A.; Kubo, K.; Shuto, K.; Kasuya, Y.; Hashikami, M.;
Karashima, N.; Shigenobu, K. Chem. Pharm. Bull. 1985, 33, 1129.
(5) (a) Brown, H. C.; Ramchandran, P. V. In Reductions in Organic
Synthesis: Recent Advances and Practical Applications; ACS Symp.
Ser.; Abdel-Magid, A. F., Ed.; American Chemical Society: Washington,
DC, 1996. (b) Hudlicky, M. Reductions in Organic Chemistry; ACS
Monograph; American Chemical Society: Washington, DC, 1996;
Chapter 2.
(6) (a) Colvin, E. W. In The Chemistry of Organic Silicon Compound,
2nd ed.; Rappoport, Z., Apeloig, Y., Eds.; J ohn Wiley and Sons:
Chichester, UK, 1998; Chapter 28. (b) Larson, G. L. In The Chemistry
of Organic Silicon Compound, 1st ed.; Patai, S., Rappoport, Z., Eds.;
J ohn Wiley and Sons: Chichester, UK, 1989; Chapter 11.
(7) Hiyama, T.; Fujita, M. J . Org. Chem. 1988, 53, 5405.
(8) Lipowitz, J .; Bowman, S. A. Aldrichim. Acta 1973, 6, 1.
(9) (a) Review: Lawrence, N. J .; Drew, M. D.; Bushell, S. M. J .
Chem. Soc., Perkin Trans. 1 1999, 3381. (b) Kobayashi, Y.; Takahisa,
E.; Nakano, M.; Watatani, K. Tetrahedron 1997, 53, 1627.
(10) Lawrence, N. J .; Drew, M. D. Tetrahedron Lett. 1997, 38, 5857.
10.1021/jo0260544 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/06/2002
594
J . Org. Chem. 2003, 68, 594-596

SCHEME 1
SCHEME 2
accomplished with polymethylhydrosiloxane in the pres-
ence of fluoride ions under mild reaction conditions.
Next we investigated the applicability of the PMHS/
F
- reducing system for syn-selective reduction of R-alkoxy
and acyloxy ketones. It is known that the reduction of
these substrates with conventional hydride reagents
occurs with marginal stereoselection.7,12 Acyloxy- and
benzoyloxy-substituted arylalkyl ketones 1f and 1g were
reduced in remarkably high syn selectivity by PMHS in
the presence of a catalytic amount of TBAF under mild
reaction conditions. In contrast to reported anti-selective
reduction of alkoxy-substituted ketone 1h with sodium
borohydride,12 the reduction with PMHS furnished pre-
dominantly syn alcohol 2h . Good diastereoselectivity was
observed in the reduction of alkoxy- and dialkylamino-
substituted alkyl ketones 1i and 1j. No epimerization was
observed at the 3-position of the product alcohol 2i-3i
during this transformation.
The proposed catalytic cycle involved during the present
reduction methodology is depicted in Scheme 1. The
pentacoordinate hydridosilicate A transfers hydride to
the carbonyl compound. Prior to hydrolysis the product
is attached to the polymer backbone as silyl ether B. The
product is readily obtained by hydrolysis of the silyl ether
by either aqueous (acid or base) or nonaqueous (excess
TBAF) workup under mild conditions.7,9b The observed
syn-selectivity in Table 1 for ketones lacking a proton
on the heteroatom R to carbonyl can be explained by the
Felkin-Anh model shown in Scheme 2. For these sub-
strates the reducing agent attacks the carbonyl on the
preferred reactive conformation C leading to syn alcohol
2. Lack of metal cations in the PMHS/F- reducing agent
and absence of protons on the heteroatom in these
substrates precludes formation of a chelate conformer like
D. For substrates containing protons on the heteroatom
R to carbonyl (e.g. 1e) the reducing agent attacks the
preferred Cram-chelate conformation D resulting in anti-
alcohol 3. It is not clear whether the observed selectivity
is partially due to the polymeric nature of the reagent.13
It is interesting to note, however, that monomeric alkoxy-
silanes reduce ketones with poor diastereoselectivity.7
In conclusion, high syn-selectivity in reductions of
R-alkoxy, R-acyloxy, and R-dialkyl amino ketones can be
Exp er im en ta l Section
1
All H and 13C NMR spectra were recorded in CDCl3 solvent
at 400 and 100 MHz respectively with chloroform (1H, 7.26 ppm;
13C, 77.0 ppm) as an internal standard. Column chromatography
was performed using silica gel 60. Analytical TLC was performed
on silica gel (250 µm) TLC plates. Polymethylhydrosiloxane
[PMHS, -(CH3SiHO)n-, where n ∼ 35] and tetrabutylammo-
nium fluoride (1 M solution in THF) were purchased from
commercial sources. Commercially available BHT-stabilized
tetrahydrofuran (THF) was used as solvent without further
purification. Compounds 1a -f were prepared from 2-bromopro-
piophenone and appropriate amine in the presence of K2CO3 by
previously reported procedures.14 Ketones 1g7 and 1h -j14 were
prepared using literature procedures.
Gen er a l P r oced u r e for Red u ction of Keton es w ith
P MHS Ca ta lyzed by TBAF . To a clean dry flask equipped with
a thermometer, a magnetic stirrer, and an addition funnel were
added ketone (5 mmol, 1 equiv), THF (25 mL), and PMHS (0.2-
0.3 mmol, 2-2.5 hydride equiv). The solution was cooled to 0 to
-5 °C in an ice-acetone bath. The solution of tetrabutylammo-
nium fluoride (5 mol % with respect to ketone) in THF was added
to the reaction mixture slowly with a syringe over a 15-min
period maintaining the temperature between 0 and 5 °C. The
reaction mixture was stirred at 0-5 °C for 2 h. After TLC
indicated the disappearance of starting ketone additional solu-
tion of TBAF (5 mmol, 1 equiv) was slowly added to the reaction
mixture. The reaction mixture was allowed to warm to room
temperature over 1 h. Solvent was evaporated to dryness on a
rotary evaporator. The residue was dissolved in 25 mL of
methylene chloride. The methylene chloride solution was stirred
with 25 mL of water for 1 h. Layers were separated and the
organic layer was washed with water (15 mL). Methylene
chloride solution was dried over sodium sulfate, filtered, and
evaporated to dryness to furnish crude product. All crude
products were purified by column chromatography on silica gel
using ethyl acetate/hexane solvent mixture. The diastereomeric
ratios were determined by integration of diagnostic peaks in 1H
NMR spectra of the isolated crude product mixture.
Ack n ow led gm en t. We thank Mr. Kyle Leeman for
chiral assay and Dr. Raymond Bemish and Mr. Michael
Burns for high-resolution mass spectra of products. We
(14) . 1a : Takamatsu, H.; Minaki, Y. J . Pharm. Soc. J pn. 1956, 76,
1227. 1b: Sekiya, M.; Kawarbata, J . Chem. Pharm. Bull. 1970, 18,
2081. 1c, 1d , 1e: Reference 3b. 1f: Hiyama, T.; Fujita, M. J . Org.
Chem. 1988, 53, 5415. 1h : Moriarty, R. M.; Prakash, O.; Duncan, M.
P.; Vaid, R. K.; Musallam, H. K. J . Org. Chem. 1987, 52, 150. 1i:
Denmark, S. E.; Stavenger, R. A. J . Org. Chem. 1998, 63, 9524. 1j:
Lagu, B. R.; Crane, H. M.; Liotta, D. C. J . Org. Chem. 1993, 58, 4191.
(11) (a) References 1b, 3b, and 7, (b) Koga, K.; Yamada, S. Chem.
Pharm. Bull. 1972, 20, 539.
(12) Yamada, S.; Koga, K. Tetrahedron Lett. 1967, 18, 1711.
(13) High syn-selectivity was also observed for reduction of I with
dimeric siloxane, tetramethyldisiloxane (TMDS): unpublished results
by authors.
J . Org. Chem, Vol. 68, No. 2, 2003 595

NMR and HRMS data of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
also thank Dr. Stanley Wallinsky and Mr. Terry Sinay,
J r., for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the reduction of ketones 1a -j and selected H, 13
C
J O0260544
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