Novel Pd/C-catalyzed redox reactions between aliphatic secondary alcohols and ketones under hydrogenation conditions: Application to H-D exchange reaction and the mechanistic study

Article abstract of DOI:10.1021/jo062582u

A liquid-phase redox system between secondary alcohols and ketones is described. Deuteration of either secondary alcohols or ketones using the Pd/C-H₂-D₂O system gave a mixture of deuterium-labeled secondary alcohols and ketones. The results indicated that the secondary alcohol was oxidized to the corresponding ketone without oxidants under the hydrogenation conditions and the hydrogenation of the aliphatic ketone to the corresponding secondary alcohol simultaneously proceeded. Detailed mechanistic studies on the redox system as well as the H-D exchange reaction are discussed.

Full text of DOI:10.1021/jo062582u

Novel Pd/C-Catalyzed Redox Reactions between Aliphatic
Secondary Alcohols and Ketones under Hydrogenation Conditions:
Application to H-D Exchange Reaction and the Mechanistic Study
Hiroyoshi Esaki, Rumi Ohtaki, Tomohiro Maegawa, Yasunari Monguchi, and
Hironao Sajiki*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical UniVersity, 5-6-1 Mitahora-higashi,
Gifu 502-8585, Japan
sajiki@gifu-pu.ac.jp
ReceiVed December 16, 2006
A liquid-phase redox system between secondary alcohols and ketones is described. Deuteration of either
2 2
secondary alcohols or ketones using the Pd/C-H -D O system gave a mixture of deuterium-labeled
secondary alcohols and ketones. The results indicated that the secondary alcohol was oxidized to the
corresponding ketone without oxidants under the hydrogenation conditions and the hydrogenation of the
aliphatic ketone to the corresponding secondary alcohol simultaneously proceeded. Detailed mechanistic
studies on the redox system as well as the H-D exchange reaction are discussed.
pyridine system.5 Stoltz5n,r,s and Sigman5o-q,t-v independently
reported the oxidative kinetic resolution of secondary alcohols
using a modification of Uemura’s method. They showed that
i-k
Introduction
Oxidation of alcohols and reduction of ketones are both
fundamental organic transformations. Palladium is one of the
1
most active and versatile transition metals employed for
the oxidation of alcohols2 including the Wacker process.
,3
4
(5) (a) Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun.
977, 157-158. (b) van Benthem, R. A. T. M.; Hiemstra, H.; Speckamp,
1
Traditionally, palladium-catalyzed oxidation of alcohols required
a stoichiometric amount of an oxidant, such as benzoquinone
W. N. J. Org. Chem. 1992, 57, 6083-6085. (c) Larock, R. C.; Hightower,
T. R. J. Org. Chem. 1993, 58, 5298-5300. (d) G o´ mez-Bengoa, E.; Noheda,
P.; Echavarren, A. M. Tetrahedron Lett. 1994, 35, 7097-7098. (e) A ¨ı t-
Mohand, S.; H e´ nin, F.; Muzart, J. Tetrahedron Lett. 1995, 36, 2473-2476.
2
,3
or CuCl2, but these oxidants usually complicate the reaction
progress and product isolation, reduce the atom economy, and/
or are accompanied with formation of a large quantity of metal
sludge. From both the economic and environmental points of
view, numerous effective palladium-catalyzed systems have been
developed for the oxidation of alcohols using molecular oxygen
(
3
f) R o¨ nn, M.; B a¨ ckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995,
6, 7749-7752. (g) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.;
Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585. (h) Peterson, K. P.;
Larock, R. C. J. Org. Chem. 1998, 63, 3185-3189. (i) Nishimura, T.;
Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron Lett. 1998, 39, 6011-6014.
(
6
j) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64,
5
as a stoichiometric oxidant. For example, Peterson and Larock
750-6755. (k) Nishimura, T.; Maeda, Y.; Kakiuchi, N.; Uemura, S. J.
reported a Pd(OAc)2-DMSO system for oxidation for a wide
range of benzylic and allylic alcohols.
workers also developed an efficient and versatile oxidation
method for primary and secondary alcohols using a Pd(OAc)2-
Chem. Soc., Perkin Trans. 1 2000, 4301-4305. (l) ten Brink, G.-J.; Arends,
I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636-1639. (m) Kakiuchi,
N.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Org. Chem. 2001, 66, 6620-
5g,h
Uemura and co-
6
7
2
625. (n) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725-
726. (o) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc.
001, 123, 7475-7476. (p) Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J.
*
To whom correspondence should be addressed. Phone: +81-58-237-3931.
Fax: +81-58-237-5979.
1) Handbook of Reagents for Organic Synthesis: Oxidizing and
Am. Chem. Soc. 2002, 124, 8202-8203. (q) Jensen, D. R.; Sigman, M. S.
Org. Lett. 2003, 5, 63-65. (r) Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B.
M. Org. Lett. 2003, 5, 835-837. (s) Trend, R. M.; Ramtoful, Y. K.; Ferreira,
E. M.; Stoltz, B. M. Angew. Chem. 2003, 115, 2998-3001; Angew. Chem.,
Int. Ed. 2003, 42, 2892-2895. (t) Mandal, S. K.; Jensen, D. R.; Pugsley,
J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600-4603. (u) Mueller, J.
A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005-7013. (v) Mandal,
S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535-7537. (w) ten Brink,
G.-J.; Arends, I. W. C. E.; Hoogenraad, M.; Verspui, G.; Sheldon, R. A.
AdV. Synth. Catal. 2003, 345, 1341-1352. (x) Mori, K.; Hara, T.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2004, 126, 10657-10666.
(y) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126,
11268-11278.
(
Reducing Agents; Burke, S. D., Danheiser, R. L. Eds.; John Wiley & Sons:
New York, 1999.
(
2) (a) Henry, P. M. Palladium Catalyzed Oxidation of Hydrocarbons;
Kluwer: Boston, 1980. (b) Tsuji, J. Palladium Reagents and Catalysts;
Wiley: New York, 1995.
(
3) (a) B a¨ ckvall, J.-E. Acc. Chem. Res. 1983, 16, 335-342. (b)
Hosokawa, T.; Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49-54.
4) Jira R. In Applied Homogeneous Catalysis with Organometallic
Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: New York,
002; Vol. 1, pp 386-405.
(
2
1
0.1021/jo062582u CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/22/2007
J. Org. Chem. 2007, 72, 2143-2150
2143

Esaki et al.
the addition of (-)-sparteine achieved highly enantioselective
oxidation of secondary alcohols. Additionally, Sheldon and co-
workers developed an efficient aerobic oxidation of alcohols
in aqueous solvent catalyzed by a water-soluble palladium
complex,5 which meets the needs of green chemistry. While
many excellent palladium-catalyzed oxidation methods of
alcohols have been reported, comparatively few examples
for palladium-catalyzed hydrogenation of ketones have been
developed. One notable exception is the heterogeneous Pd/C-
catalyzed hydrogenation of aromatic ketones (ArCOR, R ) alkyl
or aryl) although aromatic ketones are easily susceptible to
SCHEME 1
l,w
SCHEME 2
hydrogenolysis to the corresponding methylene compounds
6
(
ArCH2R). It is commonly considered that heterogeneous
palladium catalysts have almost no activity for the hydrogenation
7
-9
of aliphatic ketones except for some steroidal ketones.
hydrogenation conditions have been reported before.17 Herein
We have recently reported that an efficient Pd/C-catalyzed
H-D exchange reaction at the aliphatic positions of aromatic
derivatives readily proceeded in D2O under a hydrogen atmo-
we report a liquid-phase and interactive redox system between
secondary alcohols and ketones using the Pd/C-H2-D2O
system and provide a detailed discussion regarding the mecha-
nistic studies of the H-D exchange reaction of secondary
alcohols and ketones based upon the redox reaction.
1
0,11
sphere.
The procedure was general and efficient for a wide
12
13
variety of substrates such as nucleic acids, amino acids, and
heterocyclic compounds.14 We have also reported that the use
of Pt/C accomplished an effective deuterium incorporation into
the aromatic nuclei.15 During the course of our further study to
explore the scope of H-D exchange reaction using the
Pd/C-H2-D2O system, we have found that the use of either
secondary alcohols or ketones as substrates led to formation of
a mixture of secondary alcohols and ketones together with
effective deuterium incorporation into both of the products. The
results indicated that dehydrogenation of secondary alcohols
proceeds even under the hydrogenation conditions without
oxidants and that palladium-catalyzed hydrogenation of aliphatic
ketones to the corresponding secondary alcohols took place
without difficulty. Although alcohol-ketone pair interchange
is well-known as the Meerwein-Ponndorf-Verley reduction
Results and Discussion
To investigate the scope of our H-D exchange method, we
initiated the studies using secondary alcohols and ketones as
substrates. When 4-phenyl-2-butanol (1; 300 mg, 2 mmol) was
heated with 10% Pd/C (30 mg, 10 wt % 1, ca. 0.03 mmol of
Pd metal) in D2O (4 mL) under a H2 atmosphere for 24 h, a
6
4
2
0:40 mixture of the expected deuterium-labeled substrate,
-phenyl-2-butanol-dn (1-dn), and an unexpected ketone, 4-phenyl-
-butanone-dn (2-dn) was obtained (Scheme 1). The alkyl chain
of the ketone 2-dn was nearly quantitatively deuterated.
On the other hand, when 4-phenyl-2-butanone (2) was used
as a substrate for the deuteration, a 39:61 mixture of 1-dn and
2-dn was obtained with progress of an efficient H-D exchange
on both alkyl chains of 1-dn and 2-dn (Scheme 2).
These results suggested the simultaneous progress of dehy-
drogenation of a secondary alcohol and hydrogenation of a
ketone under the heterogeneous Pd/C-catalyzed hydrogenation
conditions. To confirm the generality of these palladium-
catalyzed redox reactions in a hydrogen atmosphere, we
investigated the H-D exchange reactions of a variety of
secondary alcohols and the corresponding ketones, and the
results are summarized in Table 1.
16
or Oppenauer oxidation, only a few examples of transformation
of secondary alcohols and ketones into the corresponding
oxidized or reduced forms under transition-metal-catalyzed
(
6) (a) Hartung, W. H.; Simonoff, R. Org. React. 1953, 7, 263-326. (b)
Marques, C. A.; Selva, M.; Tundo, P. J. Org. Chem. 1995, 60, 2430-
435. (c) Nishimura, S. Handbook of Heterogeneous Catalytic Hydrogena-
tion for Organic Synthesis; Wiley-Interscience: New York, 2001; pp 185-
18.
2
2
(
7) Nishimura, S.; Murai, M.; Shiota, M. Chem. Lett. 1980, 1239-1242.
(
8) Selected review, see: Larock, R. C. In ComprehensiVe Organic
Chemistry, 2nd ed.; Wiley-VCH: New York, 1999.
9) Ru(II) complex-catalyzed hydrogenation of ketones to alcohols was
All of the reactions (160 °C, 24 h) except for entry 8 led to
formation of a mixture of a deuterium-labeled secondary alcohol
and a ketone (Table 1). It is noteworthy that nonactivated
secondary alcohol and ketone derivatives which lack a benzene
(
pioneeringly reported by Noyori et al. See: Hashiguchi, S.; Fujii, A.;
Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562-
7
2
2
2
563.
(
11
10) Sajiki, H.; Hattori, K.; Aoki, F.; Yasunaga, K.; Hirota, K. Synlett
ring are deuterated effectively (entries 1-9). Whereas a cyclic
alcohol, cyclooctanol, was also deuterated to give a mixture of
secondary alcohols and ketones (entry 7), the deuterium-labeled
substrate cyclooctanone-dn was exclusively obtained when
cyclooctanone was used for the H-D exchange reaction (entry
002, 1149-1151.
(
11) Sajiki, H.; Aoki, F.; Esaki, H.; Maegawa, T.; Hirota, K. Org. Lett.
004, 6, 1485-1487.
12) (a) Sajiki, H.; Esaki, H.; Aoki, F.; Maegawa, T.; Hirota, K. Synlett
005, 1385-1388. (b) Esaki, H.; Aoki, F.; Maegawa, T.; Hirota, K.; Sajiki,
H. Heterocycles 2005, 66, 361-369.
13) Maegawa, T.; Akashi, A.; Esaki, E.; Aoki, F.; Sajiki, H.; Hirota,
K. Synlett 2005, 845-847.
14) Esaki, H.; Ito, N.; Sakai, S.; Maegawa, T.; Monguchi, Y.; Sajiki,
H. Tetrahedron 2006, 62, 10954-10961.
15) (a) Sajiki, H.; Ito, N.; Esaki, H.; Maesawa, T.; Maegawa, T.; Hirota,
(
8
). When secondary alcohols were employed as substrates, the
(
deuterium efficiency of the deuterated alcohols was lower than
that of the ketone which formed from the substrate (entries 1,
(
3
, 5, 7, 9, and 10). On the other hand, the H-D exchange of
(
K. Tetrahedron Lett. 2005, 46, 6995-6998. (b) Ito, N.; Watahiki, T.;
Maesawa, T. Maegawa, T.; Sajiki, H. AdV. Synth. Catal. 2006, 348, 1025-
(17) Burwell and co-workers have studied the vapor-phase interchange
1
028.
reactions accompanied by hydrogenation and dehydrogenation occurring
upon passage of the vapor of a secondary alcohol-ketone mixture using
H2 as a carrier gas over various metal catalysts; see: (a) Newham, J.;
Burwell, R. L., Jr. J. Am. Chem. Soc. 1964, 86, 1179-1186. (b) Patterson,
W. R.; Burwell, R. L., Jr. J. Am. Chem. Soc. 1971, 93, 833-838.
(
16) Selected reviews, see: (a) Kellogg, R. M. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
, pp 79-106. (b) de Graauw, C. F.; Peters, L. A.; van Bekkum, H.;
Huskens, J. Synthesis 1994, 1007-1017.
8
2144 J. Org. Chem., Vol. 72, No. 6, 2007

Aliphatic Secondary Alcohol/Ketone Redox Reactions
TABLE 1. Pd/C (10%)-Catalyzed Redox Reactions between Secondary Alcohols and Ketones and the H-D Exchange Results in D2Oa
a
Unless otherwise noted, 2 mmol of the substrate was stirred with 10% Pd/C (10 wt % substrate) in D2O (4 mL) under a H2 atmosphere at 160 ˚C for
b
1
c
2
4 h. All reactions were carried out in a sealed tube. Determined by H NMR. A 4 mmol amount of the substrate was used. d A trace amount of cyclohexanol-
dn was detected by TLC.
ketones led to high deuterium efficiency of both the starting
ketone and the corresponding alcohol (Table 1, entries 2, 4, 6,
and 8). In addition, a comparison of the product ratio showed
that a ketone was the major product from either the alcohol or
ketone in all cases. Furthermore, the H-D exchange reaction
of 4-methyl-3-heptanol, which possesses a blanched methyl
substituent, also proceeded smoothly (entry 9). When 1-phenyl-
conditions, and the highest proportion of 4-dn was observed
when 10% Pd/C was used (entry 1).
The H-D exchange reaction of 2-decanone (4) using a variety
of heterogeneous catalysts was also investigated (Table 3). In
each case, efficient incorporation of deuterium atoms into 4 was
observed and simultaneous hydrogenation of 4 occurred to give
the corresponding alcohol 3-dn. On the other hand, significant
hydrogenation of 4 did not proceed when 10% Pt/C was used
3
-heptanol was used as a substrate for the H-D exchange
1
8
reaction, effective deuterium incorporation into the benzylic
position took place (entry 10).
as a catalyst (entry 3).
To investigate the mechanism of our unique H-D exchange
reaction accompanied by dehydrogenation of secondary alcohols
and hydrogenation of aliphatic ketones, we initially examined
Not only palladium but also other transition metals were
active for the redox reactions between secondary alcohols and
ketones (Tables 2 and 3). When 2-decanol (3) was used as a
substrate, the use of Pd/C led to relatively high deuterium
efficiency (Table 2, entry 1). All heterogeneous transition-metal
catalysts worked well for the oxidation of 3 under the reaction
(
18) Although suspicions are raised about the effect of the contaminated
21
acid in the catalyst toward the reduction of 2-decanone (4), the acidity of
the catalyst (Pd/C, Rh/C, or Pt/C) did not correlate with the present redox
reaction (see the Supporting Information).
J. Org. Chem, Vol. 72, No. 6, 2007 2145

Esaki et al.
TABLE 2. H-D Exchange of 3 with a Variety of Heterogeneous Catalystsa
a
A 2 mmol amount of the substrate was used in D2O (4 mL) under a H2 atmosphere at 160 ˚C for 24 h. Reactions were carried out in a sealed tube.
b
1
Determined by H NMR.
TABLE 3. H-D Exchange of 4 with a Variety of Heterogeneous Catalystsa
a
A 2 mmol amount of the substrate was used in D2O (4 mL) under a H2 atmosphere at 160 °C for 24 h. Reactions were carried out in a sealed tube.
b
1
c
Determined by H NMR. 3-dn was hardly detected. 3-dn:4-dn ) 36:44 was obtained when 5% Pt/C (Aldrich) was used as a catalyst.
TABLE 4. Dehydrogenation of 3 Catalyzed by Pd/C in H2O under a Hydrogen Atmosphere
entry
1
time (h)
3:4a
24
24 × 3
67:33
24:69
b
2
a
1
b
Determined by H NMR or GC. A trace amount of decane was detected.
whether the redox reaction would reach an equilibrium between
secondary alcohols and ketones. When 3 was heated with Pd/C
in H2O at 160 °C for 24 h, a 67:33 mixture of 3 and 4 was
obtained (Table 4), and the reaction of 4 for 24 h led to
formation of a mixture of 3 and 4 in a ratio of 16:84, respectively
reaction mixture (Tables 4 and 5, entries 2), indicating the redox
reaction between the dehydrogenation of a secondary alcohol
and hydrogenation of a ketone is in equilibrium under the
reaction conditions.
Furthermore, the reaction using optically active (R)-(-)-2-
decanol [(R)-(-)-3] as a substrate gave the partially racemized
alcohol after 24 h (Scheme 3). A longer reaction time of up to
7 days resulted in complete racemization of (R)-(-)-3 together
(
Table 5). Although the distribution of the products was
completely opposite, the 3:4 ratios were reached closely after
4 h of stirring was repeated three times using the resulting
2
2146 J. Org. Chem., Vol. 72, No. 6, 2007

Aliphatic Secondary Alcohol/Ketone Redox Reactions
TABLE 5. Hydrogenation of 4 Catalyzed by Pd/C in H2O under a Hydrogen Atmosphere
entry
1
time (h)
3:4a
24
24 × 3
16:84
27:65
b
2
a
1
b
Determined by H NMR or GC. A trace amount of decane was detected.
SCHEME 3. Racemization and H-D Exchange Reaction of Optically Active (R)-(-)-2-Decanol
TABLE 6. Time-Course Study of the H-D Exchange Reaction of 3 under the Pd/C-H2-D2O Systema
a
A 2 mmol amount of the substrate was used with 10% Pd/C (10 wt % substrate) in D2O (4 mL) under a H2 atmosphere at 160 °C. Reactions were carried
out in a sealed tube. Determined by H NMR. Indicated on the basis of the isolated yields. d 4-dn was hardly detected.
b
1
c
with quite high deuterium efficiency.19 The racemization of (R)-
-)-3 is more evidence of the presence of equilibrium between
dehydrogenation of a secondary alcohol and hydrogenation of
a ketone during the deuteration reaction under the Pd/C-H2-
D2O system.
efficiency and component ratio of products at each reaction time
(
(Tables 6 and 7). When 3 was used as a substrate, the deuterium
efficiency of the alkyl chain of 3-dn was slowly increased,
whereas the deuterium efficiency of 4-dn rapidly improved even
after 6 h (Table 6). It is noteworthy that 4-dn was hardly detected
after 3 h and the deuterium efficiency of the corresponding
alcohol (3-dn) was practically nil. However, the ratio of 4 to 3
varied significantly within 24 h and led to an excess percentage
of 4-dn against 3-dn (26:74) after 24 h (entry 4).
Next, we examined the time-course study of the H-D
exchange reactions of both 3 and 4 to compare the deuterium
(19) Derdau and Atzrodt reported the deuteration at the benzylic position
of the optically active 1-phenylbutan-1-ols using the Pd/C-NaBD4-D2O
system was accompanied by racemization; see: Derdau, V.; Atzrodt, J.
Synlett 2006, 1918-1922. We also observed racemization during the
deuteration of L-phenylalanine; please see ref 13.
On the other hand, when 4 was used as a substrate, not only
the deuterium efficiency of 4-dn but also that of 3-dn was high
even at a short reaction time (Table 7). The proportion of 4-dn
J. Org. Chem, Vol. 72, No. 6, 2007 2147

Esaki et al.
TABLE 7. Time-Course Study of the H-D Exchange Reaction of 4 under the Pd/C-H2-D2O Systema
a
A 2 mmol amount of the substrate was used with 10% Pd/C (10 wt % substrate) under a H2 atmosphere in D2O (4 mL) at 160 °C. Reactions were carried
out in a sealed tube. Determined by H NMR. Indicated on the basis of the isolated yields. d 3-dn was hardly detected.
b
1
c
SCHEME 4. H-D Exchange Reaction of 5
SCHEME 5. H-D Exchange Reaction of 6
was always higher than that of 3-dn at each reaction time. While
-dn was hardly detected within 3 h, the corresponding ketone
4-dn) indicated a comparatively high level of deuterium
efficiency (entry 1). It is quite interesting to compare the results
of Table 6, entry 1.
either 2-methoxydecane (5) or 2-[(tert-butyldimethylsilyl)oxy]-
3
(
decane (6) was observed (Schemes 4 and 5). The low isolated
yield of 6 was due to the exclusive cleavage of the TBDMS
2
0
group in the course of the reaction.
Furthermore, the deuteration of tertiary alcohol 7, which
cannot also be transformed into the ketone, resulted in a nearly
no deuteration level (Scheme 6). These results strongly support
our presumption that the H-D exchange of the alkyl chain of
the secondary alcohol 3 proceeds through the corresponding
ketone derivative 4.
Reaction Pathway. When the reaction was carried out in
D2O under a hydrogen atmosphere in the absence of a Pd
catalyst, the conversion of secondary alcohols into ketones or
ketones into secondary alcohols was not observed and no H-D
exchange reaction proceeded (Table 8, entries 1 and 4). While
oxidation of 3 took place even under an argon atmosphere, H-D
exchange proceeded only on 4 formed via oxidation of 3
(entry 2). On the other hand, no detectable amount of reduced
product 3 was observed in the same investigation using 4 as a
Compared with the results of Tables 6 and 7, the H-D
exchange reaction of a ketone is much faster and more efficient
than that of a secondary alcohol. In addition, considering the
significant change of the ratio of 3-dn to 4-dn in Table 6 and
the constant high proportion of 4-dn in Table 7, the transforma-
tion of secondary alcohols into ketones seems to be faster than
the reverse reaction. Taking into account the equilibrium
between secondary alcohols and ketones, we presumed that the
high deuterium efficiency of the secondary alcohol starting from
the ketone as a substrate was attributed to the hydrogenation of
the deuterated ketone rather than direct deuterium incorporation
into the secondary alcohol; that is to say, the H-D exchange
reaction of secondary alcohols would exclusively proceed via
deuteration of the corresponding ketones and reduction to the
deuterated secondary alcohols.
If our presumption is correct, the use of the methyl and
TBDMS ethers 5 and 6 derived from 3 would lead to a decrease
of deuterium efficiency, since they cannot be transformed into
a ketone. As a result, almost no deuterium incorporation into
(20) (a) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron Lett. 2000, 41,
5
2
711-5714. (b) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57,
109-2114. (c) Sajiki, H.; Ikawa, T.; Hattori, K.; Hirota, K. Chem.
Commun. 2003, 654-655.
(21) Ikawa, T.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60, 6189-6195.
2148 J. Org. Chem., Vol. 72, No. 6, 2007

Aliphatic Secondary Alcohol/Ketone Redox Reactions
SCHEME 6. H-D Exchange Reaction of 2,5-Dimethyl-2,5-hexanediol (7)
TABLE 8. Investigation of the Role of Pd/C and H2 Gasa
a
A 2 mmol amount of the substrate was used with 10% Pd/C (10 wt % substrate) in D2O (4 mL) at 160 °C. Reactions were carried out in a sealed tube.
b
1
c
Determined by H NMR. A trace amount of 4-dn was detected by TLC.
SCHEME 7. Plausible Mechanism for the H-D Exchange Reaction
substrate under an argon atmosphere, and the high deuterium
oxidation of alcohols to ketones (entry 3); (4) the direct
deuterium incorporation into secondary alcohols may not
proceed (entry 2). Consequently, the H-D exchange of ketones
which formed from the starting secondary alcohols and subse-
quent reduction are necessary to produce deuterated secondary
alcohols.
efficiency of only both R-positions of the ketone was observed
(entry 5). These experimental results indicate the following
facts: (1) both Pd/C and hydrogen gas are necessary to effect
the redox reactions and deuteration at the nonactivated carbons;
(2) whereas dehydrogenation of secondary alcohols to ketones
is feasible under an inert atmosphere, no hydrogenation of
ketones is available without hydrogen gas conditions (entries 2
and 5); (3) application of heat is also necessary to effect the
A plausible mechanism for the redox reaction and H-D
exchange reaction of secondary alcohols and ketones using the
Pd/C-H2-D2O system is outlined in Scheme 7. Dehydroge-
J. Org. Chem, Vol. 72, No. 6, 2007 2149

Esaki et al.
nation of secondary alcohols would proceed via oxidative
addition of Pd to the O-H bond of A (A to B) followed by
â-hydride elimination (B to C), and hydrogenation of ketones
could occur through the reverse mechanism (C to A). These
mechanisms are reasonable to explain why oxidation of second-
ary alcohols did not proceed in the absence of palladium catalyst
p-anisic acid as an internal standard. EI and FAB mass spectra,
GC spectra, and optical rotations were obtained. 10% Pd/C
(
(
Aldrich), other catalyst (N.E.ChemCat Cop.) and deuterium oxide
99.9% isotopic purity) were obtained from commercial supplier.
Typical Procedure for the H-D Exchange Reaction of
2
-Decanone (4) using the Pd/C-H
Entry 2). A mixture of 2-decanone (313 mg, 2 mmol) and 10%
Pd/C (31.3 mg, 10 wt % substrate) in D O (4 mL) in a sealed tube
was stirred at 160 °C under a H atmosphere. After 24 h the mixture
2
-D
2
O System (Table 1,
(Table 8, entry 1) and the necessity of both Pd/C and hydrogen
2
gas for the reduction of ketones (Table 8, entries 4 and 5).
As described in Scheme 7, an oxidative insertion of palladium,
which is coordinated and activated by the H2 gas and D2O, to
the C-H bond would take place via the formation of the
corresponding Pd-π-allyl complex (C to E). Then, intramo-
lecular H-D exchange reaction and subsequent reductive
elimination could give the deuterium-labeled compound G
through F. G submits to further deuteration as well as C to G
until the formation of an R fully deuterated carbonyl product.
Deuterium incorporation into another nonactivated C-H bond
would proceed via â-hydride elimination of F to give olefin H.
The subsequent formation of a palladium complex (H to I) and
continuous isomerization of the olefin via the corresponding
Pd-π-allyl complex would cause further deuteration.
2
was cooled to rt, diluted with diethyl ether (10 mL), and passed
through a membrane filter (0.45 µm) to remove the catalyst. The
filtered catalyst was washed with diethyl ether (2 × 10 mL). The
combined filtrates were washed with H
2
O (2 × 30 mL) and brine
(30 mL), dried over MgSO
The residue was purified by flash column chromatography (hexane:
ether ) 40:1 to 10:1) on silica gel to afford 2-decanol-d (3-d
7.7 mg) and 2-decanone-d (4-d ; 199 mg).
Data for 3-d OD, p-anisic acid as an internal
1H NMR (CD
4
, and evaporated under reduced pressure.
n
n
;
3
n
n
n
:
3
standard) δ 3.59 (s, 0.15H), 1.32-1.17 (m, 4.23H), 1.05-1.01 (m,
2
0
1
3
.46H), 0.83-0.76 (m, 1.36H); H NMR (CH OH) δ 3.65 (br s),
.31-1.22 (m), 1.07 (br s), 0.82 (br s).
1
Data for 4-d
n
:
H NMR (CD
3
OD, p-anisic acid as an internal
standard) δ 2.41 (s, 0.13H), 2.09-2.08 (m, 0.21H), 1.48 (s, 0.27H),
2
1
3
.27-1.17 (m, 2.28H), 0.90-0.83 (m, 0.96H); H NMR (CH OH)
Conclusion
δ 2.36 (br s), 2.03 (br s), 1.43 (br s), 1.17 (br s), 0.78 (br s).
In conclusion, we have demonstrated that the efficient H-D
exchange reaction of secondary alcohols and ketones using the
Pd/C-H2-D2O system was accompanied with a simultaneous
redox reaction: the oxidation of alcohols and reduction of the
corresponding ketones under the hydrogenation conditions. The
H-D exchange reaction of both secondary alcohols and ketones
might take place only in ketone form via a Pd-π-allyl complex.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (No. 18590009) from the
Japan Society for the Promotion of Science and by the Research
Foundation of Gifu Pharmaceutical University. H.E. acknowl-
edges the Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists (Grant 176469). We
thank N.E. Chemcat Corp. for supplying 10% Rh/C and 10%
Pt/C used in this study.
Experimental Section
Supporting Information Available: Experimental procedures
and H and/or H NMR data of each compound in Table 1. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
General Procedures. 1H, 2H, and 13C NMR spectra were
recorded ( H, 400 MHz; H, 61 MHz; C, 100 MHz). Chemical
shifts (δ) are given in parts per million relative to the peak for the
residual solvent. The deuterium content was determined using
1
2
1
2
13
JO062582U
2150 J. Org. Chem., Vol. 72, No. 6, 2007