A tertiary amine as a hydride donor: Trichlorosilyl triflate-mediated conjugate reduction of unsaturated ketones

Article abstract of DOI:10.1021/ol2014895

Bulky tertiary amines, especially dicyclohexylisobutylamine, smoothly reduced α,β-unsaturated ketones in the presence of trichlorosilyl triflate to give the corresponding saturated ketones in excellent yields. Isotope-labeling studies revealed that an α-hydrogen of the amine was transferred to the enones during reduction.

Full text of DOI:10.1021/ol2014895

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3968–3971
A Tertiary Amine as A Hydride Donor:
Trichlorosilyl Triflate-mediated Conjugate
Reduction of Unsaturated Ketones
Shunsuke Kotani,*,† Kazuki Osakama,‡ Masaharu Sugiura,‡ and Makoto Nakajima‡
Priority Organization for Innovation and Excellence, Kumamoto University, and
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi,
Kumamoto, 862-0973, Japan
skotani@gpo.kumamoto-u.ac.jp
Received June 2, 2011
ABSTRACT
Bulky tertiary amines, especially dicyclohexylisobutylamine, smoothly reduced R,β-unsaturated ketones in the presence of trichlorosilyl triflate
to give the corresponding saturated ketones in excellent yields. Isotope-labeling studies revealed that an R-hydrogen of the amine was transferred
to the enones during reduction.
Amine is one of the most versatile and inexpensive
reagents for organic synthesis. Amine is most frequently
used as a base, of which the lone pair electrons on the nitrogen
atom act as a Brønsted base and accept a proton. Some
amines, such as the Hantzsch ester, are hydrogen donors,
which can promote reduction of organic compounds.1 Sev-
eral other hydrogen transfer reagents containing amino
functional groups also have been investigated.2,3 However,
little attention has been paid to tertiary amines as a hydrogen
transfer reagent.4À6
Recently, we described a trichlorosilyl triflate-mediated
enantioselective aldol reaction of cyclohexanone with ben-
zaldehyde using dicyclohexylmethylamine as a Brønsted
base and BINAP dioxide (BINAPO) as a Lewis base.7
While screening the reaction conditions, we were surprised to
find that using diisopropylethylamine produced benzyl alco-
hol as a byproduct (Scheme 1). This finding prompted us to
explore the possibility of developing a novel reduction meth-
od. Herein, we report that a tertiary amine in the presence of
trichlorosilyl triflate mediates the conjugate reduction of R,β-
unsaturated ketones and that an R-hydrogen of the amine is
transferred into the β-position of the enone.
† Priority Organization for Innovation and Excellence.
‡ Graduate School of Pharmaceutical Sciences.
(1) For reviews for Hantzsch ester reductions, see: (a) Ouellet, S. G.;
Walji, A. M.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327. (b)
You, S.-L. Chem. Asian J. 2007, 2, 820. (c) Connon, S. J. Org. Biomol.
Chem. 2007, 5, 3407. (d) Rueping, M.; Dufour, J.; Schoepke, F. R. Green
Chem. 2011, 13, 1084.
(2) For imidazoline or thiazoline-promoted reductions, see: (a)
Chikashita, H.; Miyazaki, M.; Itoh, K. Synthesis 1984, 308. (b) Chikashita,
H.; Itouh., K. Bull. Chem. Soc. Jpn. 1986, 59, 1747. (c) Zhang, Y.; Zhou, G.;
Guo, W. Heterocycles 2009, 78, 1541. (d) Chikashita, H.; Miyazaki, M.;
Itoh, K. J. Chem. Soc., Perkin Trans. 1 1987, 699. (e) Hasegawa, E.; Hirose,
H.; Sasaki, K.; Takizawa, S.; Seida, T.; Chiba, N. Heterocycles 2009, 77,
1147. (f) Zhu, C.; Akiyama, T. Org. Lett. 2009, 11, 4180.
Initially, reductions of chalcone (1a) were conducted
under a variety of conditions (Table 1). The conjugate
(3) For lithium amide-promoted reductions, see: (a) Woo, E. P.;
Mak, K. T. Tetrahedron Lett. 1974, 15, 4095. (b) Kowalski, C.; Creary,
X.; Rollin, A. J.; Burke, M. C. J. Org. Chem. 1978, 43, 2601. (c) Scott,
L. T.; Carlin, K. J.; Schultz, T. H. Tetrahedron Lett. 1978, 19, 4637. (d)
Majewski, M. Tetrahedron Lett. 1988, 29, 4057. (d) Takeda, K.; Ohishi,
Y.; Koizumi, T. Org. Lett. 1999, 1, 237.
(4) For reductions by amines, see: (a) Nishiguchi, T.; Tachi, K.;
Fukuzumi, K. J. Org. Chem. 1975, 40, 237. (b) Schreiber, S. L. Tetra-
hedron Lett. 1980, 21, 1027.
(5) For metal-mediated reductions with tertiary amines, see: (a)
Clerici, A.; Pastori, N.; Porta, O. Tetrahedron Lett. 2004, 45, 1825. (b)
Cho, C. S.; Kim, D. T.; Shim, S. C. Bull. Korean Chem. Soc. 2009, 30,
1931.
(6) For recent papers for intramolecular amine-mediated reductions,
ꢀ
see: (a) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polomka-Balint, A.;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Halasz-Dajka, B. Synthesis 2006, 2625. (b) Mori, K.; Ohshima, Y.;
Ehara, K.; Akiyama, T. Chem. Lett. 2009, 38, 524. (c) Murarka, S.;
Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129. (d)
Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem. 2009, 74, 419. (e)
Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009, 131,
13226. (f) Zhou, G.; Zhang, J. Chem. Commun. 2010, 46, 6593. (g)
Haibach, M. C.; Deb, I.; De, C. K.; Seidel, D. J. Am. Chem. Soc. 2011,
133, 2100. (h) Cao, W.; Liu, X.; Wang, W.; Lin, L.; Feng, X. Org. Lett.
2011, 13, 600.
(7) Kotani, S.; Aoki, S.; Sugiura, M.; Nakajima, M. Tetrahedron
Lett. 2011, 52, 2834.
r
10.1021/ol2014895
Published on Web 07/07/2011
2011 American Chemical Society

might coordinate to trichlorosilyl triflate, thereby suppres-
sing the reaction. On the other hand, the bulkiness of the
amines prevented complexation with trichlorosilyl triflate,
yielding the corresponding product in excellent yield.
Conjugate reductions using various types of Lewis acids
with dicyclohexylisobutylamine (3h) were examined
(Table 2). Other silyl reagents such as silicon tetrachloride,
trimethylsilyl triflate, or boron trifluoride gave no product
(entries 2À4). Titanium tetrachloride promoted the
reduction,5a but the yield was low in comparison with that
of trichlorosilyl triflate (entry 5). These observations in-
dicated importance of combining trichlorosilyl triflatewith
dicyclohexylmethylamine for the reaction the R,β-unsatu-
rated ketone.
Scheme 1. Unexpected Reduction of Benzaldehyde to Benzyl
Alcohol
reduction of 1a was performed using trichlorosilyl triflate8
(2.0 equiv) and diisopropylethylamine (2.2 equiv) in di-
chloromethane at À40 °C, yielding not the corresponding
alcohol but the 1,4-reduction product 2a in moderate yield
(30%, entry 1). The absence of Lewis base (BINAPO)
improved the yield of 2a (50%, entry 2). Because Lewis
bases are essential for conjugate reductions with HSiCl3,9
the present reaction does not proceed via hypervalent
silicon species. A range of solvents was tested, and dichlor-
omethane was found to be optimal for the conjugate
reduction of R,β-unsaturated ketones.10 Next, we screened
amines using dichloromethane as the reaction solvent.
Reactions with small amines, such as triethylamine (3b)
or diisopropylmethylamine (3c), did not yield any product
(entries 3, 4, and 7), whereas sterically hindered amines
tended to provide high yields (entries 5, 6, 8, and 9).
Table 2. Reduction of 1a with Various Lewis Acidsa
entry
Lewis acid
time, h
yield, %b
1
2
3
4
5
SiCl3OTf
SiCl4
0.5
2
98
0
TMSOTf
8
0
BF3 Et2O
4
0
3
TiCl4
0.5
41
Table 1. Optimization of the Reaction Conditionsa
a All reactions were conducted using the ketone 1a (0.5 mmol), the
amine 3h (2.0 equiv), and a Lewis acid (2.0 equiv) in CH2Cl2 (5 mL)
at À40 °C. b Isolated yield.
With optimal conditions in hand, the conjugate reduc-
tions of various unsaturated ketones were investigated
(Table 3). Ketones substituted with aliphatic groups as
the R1 group were cleanly reduced in high yields (entries 2
and 3).11 Substrates having dibenzylidene moiety gave the
partially reduced products in good yields (entries 4 and 5).
In the reduction of ketone 1e, the unreacted olefin moiety
partially isomerized (E/Z = 12/1) presumably through
addition/elimination of chloride ion to enone. trans-
1,2-(Dibenzoyl)ethylene (1f), with carbonyl groups on
the both sides of the olefin was reduced with 4 equiv of
trichlorosilyl triflate and the amine 3h to afford the corre-
sponding adduct 2f in 96% yield (entry 6). The reductions
of enones with fixed s-trans geometry proceeded in lower
yields (entries 7 and 8). However, it is noteworthy that the
SiCl3OTf/Cy2NiBu system reduced the s-trans substrates,
which were not reduced by HSiCl3 with a Lewis base.9
These results indicate that the reaction mechanism differs
from that of the conjugate reduction with HSiCl3.
entry
amine, 3
yield, %b
1c
2d
3
iPr2NEt, 3a
iPr2NEt, 3a
Et3N, 3b
iPr2NMe, 3c
iPr2NPr, 3d
iPr2NiBu, 3e
Cy2NMe, 3f
Cy2NEt, 3g
Cy2NiBu, 3h
30
50
0
4
0
5
56
92
0
6
7
8d
9e
47
98
a Unless otherwise noted, the reactions were conducted using the
ketone 1a (0.5 mmol), the amine 3 (2.2 equiv), and SiCl3OTf (2.2 equiv)
in CH2Cl2 (5 mL) at À40 °C. b Isolated yield. c With BINAPO (10 mol %).
d 1,5-Diphenyl-5-oxopentanal (4a) was obtained (27% yield in entry 2,
38% yield in entry 8). e SiCl3OTf (2.0 equiv).
Dicyclohexylisobutylamine (3h), especially, afforded the
corresponding product in 98% yield (entry 9). Small amines
(8) For preparation of trichlorosilyl triflate, see: Bassindale, A. R.;
Stout, T. J. Organomet. Chem. 1984, 271, C1.
(9) (a) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem.
Commun. 2008, 4309. (b) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani,
S.; Nakajima, M. Chem. Asian J. 2010, 5, 478.
We next focused our attention on elucidating the reac-
tion mechanism. A hydrogen transfer reduction assumes
to proceed either via ionic species or via radical species.
(10) Solvents affected reactivities for the reduction. No products
were obtained in tetrahydrofuran (THF) or chloroform. Propionitrile
and toluene produced the reduced ketone 2a, but the yields were low
compared to dichloromethane (propionitrile: 21%, toluene: 24%).
(11) Enones bearing aliphatic substituents on R2 resulted in low
yields: 4-methyl-1-phenyl-2-penten-1-one (24%), 4,4-dimethyl-1-phenyl-2-
penten-1-one (26%).
Org. Lett., Vol. 13, No. 15, 2011
3969

Table 3. Conjugate Reduction of Various Enones 1a
Scheme 2. Deuterium-labeling Experiments Using 3h-d2
how 4a was produced, the deuterized amine 3g-d2 was pre-
pared and the reduction of 1a was performed (Scheme 3).
The deuterized 4a-d was produced in 34% yield, in
addition to the reduced product 2a-dβ. After a hydrogen
transfer, an enamine intermediate derived from the amine
was generated and reacted with 1a to produce the 4a-d,
though aldehyde 5 was not detected.14 Reaction with
amine 3h did not give a Michael adduct, suggesting that
the enamine generated from 3h was unreactive toward the
ketone 1a. On the other hand, 1,4-addition of the reactive
enamines to the enone 1a competed with the reduction and
decreased the product yield.
Scheme 3. Deuterium-labeling Experiments Using 3g-d2
a Unless otherwise noted, the reactions were conducted using the
ketone 1 (0.5 mmol), the amine 3h (2.0 equiv), and SiCl3OTf (2.0 equiv)
in CH2Cl2 (5 mL) at À40 °C. b Isolated yield. c At 0 °C . d E/Z = 12/1.
e With SiCl3OTf and 3h (4 equiv each). f With SiCl3OTf and 3h (3equiveach).
To probe the possibility of a single electron transfer (SET)
mechanism, the reduction of benzophenone was examined
under optimized conditions, giving only trace amounts
(3%) of the alcohol. These results could not completely
exclude the SET mechanism; however, it suggested that the
reduction most likely proceeded through ionic processes
rather than through radical processes.12
Deuterium-labeling experiments were performed to de-
termine which hydrogen was transferred (Scheme 2). First,
the deuterated amine 3h-d2 was prepared13 and applied to
the conjugate reduction of ketone 1a. Because the β-
position of the ketone was completely deuterized to give
2a-dR in 97% yield, an R-hydrogen of amine 3h-d2 was
transferred to the β-position of the ketone.
Next, deuterium oxide was used to quench the reaction
of 1a with SiCl3OTf/Cy2NiBu (Scheme 4). The product 2a
was deuterized only at the R-position. The result suggested
that a trichlorosilyl enol ether may be generated in the
reaction medium after conjugate reduction and accept a
proton in workup to produce 2a.
Scheme 4. Deuterium-labeling Experiments with D2O
We observed a byproduct 4a in the reaction of 1a with
amine 3a and 3g (Table 1, entries 2, and 8). To investigate
(12) Addition of a radical scavenger did not prevent the reduction,
remarkably. 2,6-Di-tert-butyl-4-methylphenol (BHT) gave 2a (95%
yield), whereas the yield decreased with galvinoxyl (45%).
(13) The deuterated amines were prepared from N,N-dicyclohexyl
amides and LiAlD4. See Supporting Information.
3970
Org. Lett., Vol. 13, No. 15, 2011

from the R-position of amine 3 to afford the trichlorosilyl
enol ether 7 and the iminium intermediate 8.15 The desired
product 2 was obtained by hydrolysis of 7, whereas the
iminium ion 8 was enolized to give the enamine 9. The 1,4-
addition of 9 to ketone 1 afforded a byproduct 4, whereas
hydrolysis of 9 gave the corresponding aldehyde 5.
In conclusion, we demonstrated that the combination of
trichlorosilyl triflate and a tertiary amine reduced R,β-
unsaturated ketones to afford saturated ketones in good
yield. Furthermore, analysis using deuterized amines
proved that the R-hydrogen of the amine was transferred
to the β-position of the ketone. Further investigations to
utilize this reduction system in asymmetric reactions are
currently in progress.
Scheme 5. Plausible Reaction Mechanism of the Conjugate
Reduction
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
Note Added after ASAP Publication. Errors were corrected
in Tables 1À3 and this paper reposted July 12, 2011.
Supporting Information Available. Experimental de-
tails and characterization of new products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
These labeling experiments supported the reaction path-
way outlinedinScheme 5for thereduction. First, SiCl3OTf
coordinates to the oxygen atom of ketone 1 to increase
the electrophilicity. This complex 6 accepts a hydrogen
(15) For generation of iminium intermediates from tertiary amines,
see: (a) Bharathi, P.; Periasamy, M. Org. Lett. 1999, 1, 857. (b) Kagawa,
N.; Sasaki, Y.; Kojima, H.; Toyota, M. Tetrahedron Lett. 2010, 51, 482.
(14) Formation of deuterized hydrocinnamaldehyde was confirmed
in the reaction with N,N-dicyclohexyl-2-phenylethylamine.
Org. Lett., Vol. 13, No. 15, 2011
3971