N-Tosylhydrazine-mediated deoxygenative hydrogenation of aldehydes and ketones catalyzed by Pd/C

Article abstract of DOI:10.1016/j.tet.2013.05.070

A mild and efficient method for the deoxygenative hydrogenation of aldehydes and ketones has been developed. The reaction is mediated by N-tosylhydrazine with H₂ (1 atm) as the reductant and 10% Pd/C as the catalyst.

Full text of DOI:10.1016/j.tet.2013.05.070

Tetrahedron 69 (2013) 6083e6087
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Tosylhydrazine-mediated deoxygenative hydrogenation
of aldehydes and ketones catalyzed by Pd/C
,
,
a,
*
Lei Zhou a b, Zhenxing Liu a, Yizhou Liu a, Yan Zhang a , Jianbo Wang
*
a Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, Peking University, Beijing 100871, China
b School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method for the deoxygenative hydrogenation of aldehydes and ketones has been
developed. The reaction is mediated by N-tosylhydrazine with H2 (1 atm) as the reductant and 10% Pd/C
as the catalyst.
Received 31 January 2013
Received in revised form 11 May 2013
Accepted 20 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 23 May 2013
Keywords:
Reduction
Hydrogenation
Deoxygenation
N-Tosylhydrazone
Aldehydes
Ketones
1. Introduction
hydrogen as a clean hydrogen source for reduction of carbonyl
compounds to hydrocarbons have also been reported, such as
The deoxygenative reduction of aldehydes and ketones to
methyl or methylene derivatives is one of the fundamental pro-
cesses in organic chemistry, which was first developed by Wolff and
Kishner via hydrazone or semicarbazone cleavage in basic media1
and Clemmensen by using ZneHg and HCl.2 The original Wolf-
feKishner reduction procedure was to mix the carbonyl compound
with 100% H2NNH2 and potassium hydroxide in a sealed tube and
heat the mixture at high temperature (160e200 ꢀC) for days. Huang
Minlon late modified this procedure by using 85% H2NNH2$H2O in
a high boiling point solvent (ethylene glycol) (Scheme 1).3 Over the
many decades, the WolffeKishnereHuang Minlon reduction has
been widely used in organic synthesis.4,5 In the meantime, the
original procedures have been modified in order to make the re-
action conditions milder and more efficient.6,7 Other methods in-
volving the use of aluminum hydride,8 boron hydride,9 or
hydrosilane10 with a combination of protic acids or Lewis acids
have been well studied. In addition, supercritical 2-propanol11 and
metallic selenium with CO and water12 were also used for the
deoxygenative reduction. Moreover, for the consideration of green
chemistry and atom economy aspects, catalytic systems utilizing
the reduction using H2/Raney nickel,13 catalytic hydrogenation with
polyoxometalates,14 Cu/SiO2,15 montmorillonite,16 and hydro-
genolysis over Pd in the presence of HCl.17
O
NNH2
R'
H H
R'
H2NNH2
base
R
R'
R
R
Wolff-Kishner-Huang Minlon Reduction
NNHTs
R'
TsNHNH2
cat. Pd/C
H2 (1 atm), base
R
Scheme 1. Deoxygenative reduction of carbonyl compounds.
In the WolffeKishnereHuang Minlon reduction mechanism, the
carbonyl compound is first converted to hydrazone. The hydrazone
is then deprotonated under strong basic conditions to generate
diimide intermediate. The diimide intermediate undergoes
further deprotonation and loss of N2 to form
a carbanion,
which is protonated to afford the final reduction product.18 Re-
cently, Furrow and Myers reported a modified reaction by using
* Corresponding authors. E-mail address: wangjb@pku.edu.cn (J. Wang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.070

6084
L. Zhou et al. / Tetrahedron 69 (2013) 6083e6087
N-tert-butyldimethylsilylhydrazones (TBSHs) as alternatives to
hydrazones in WolffeKishnereHuang Minlon reduction.7 Sub-
sequently, the same authors described the preparation of diazo-
alkanes by the oxidation of TBSHs with (difluoroiodo)benzene.19
However, the use of freshly prepared dry solvents, the risk of det-
onation during the distillation of anhydrous TBSHs, and the tenu-
ous operations might limit its applications in large scale synthesis.
On the other hand, it is known that diazoalkanes can be hy-
drogenated by H2 with palladium catalyst.20 It is also well estab-
lished that diazoalkanes can be generated from N-tosylhydrazones
by treatment with base (BamfordeStevens reaction).21,22 Based on
this background, we have conceived that a mild method of deox-
ygenative reduction of carbonyl compounds may be developed by
the combination of N-tosylhydrazone formation and diazo hydro-
genation. Although the reduction of tosylhydrazones to hydrocar-
bons with other hydride donors have been developed,23 the
reactions suffered some drawbacks, such as the generation of
a large amount of wastes and undesired by-products. Herein we
wish to report a one-pot, two-step deoxygenation reaction con-
verting carbonyl group to methyl or methylene group. This method
employs hydrogen as the clean reductant with 10% Pd/C as the
catalyst under weak base conditions (Scheme 1).
our delight, 1-(naphthalen-2-yl)ethanone could be deoxygenated
successfully in good yield without isolation of N-tosylhydrazone,
affording the corresponding product 2a in 81% isolated yield
(Scheme 2, 2a). Reduction of other three arylealkyl ketones gave the
corresponding hydrocarbons 2bed in moderate to good yields. In
the case of cyclooctanone, the product cyclooctane 2e was only
obtained in 40% yield. The diminished yield in this case may be at-
tributed to the relatively high stability of N-tosylhydrazone gener-
ated from cyclooctanone. Forarylearyl ketones, the reduction of 9H-
fluoren-9-one and benzophenone proceeded smoothly in 76% and
88% (GC) yields, respectively. The methyl, chloro, methoxy, or phenyl
substituted benzophenones were also converted to the corre-
sponding methylene compounds 2hek in good yields.
2. Results and discussion
At the outset, we investigated the reduction of N-tosylhy-
drazone 1 under Pd/C-catalyzed reaction conditions (Table 1). In
the initial experiment, we used triethylsilane (TES-H) as the hy-
dride donor. In the presence of 10% Pd/C (5 mol %) and t-BuOLi
(3 equiv) in dichloroethane (DCE) at 80 ꢀC, we were pleased to
observe that the expected reduction product 2a was formed in 72%
GC yield (Table 1, entry 1). With MeOH as solvent, the reaction
afforded sightly higher yield (Table 1, entry 2). In the absence of
TES-H, 2a could only be detected in trace amount (Table 1, entry 3).
The Pd/C catalyst was also proved indispensable (Table 1, entry 4).
To our delight, when H2 (1 atm) was used to replace TES-H as hy-
drogen source, 2a could be formed in 90% yield (Table 1, entry 5).
t
Furthermore, we observed that BuOLi could be replaced by in-
expensive K2CO3, although the yields were slightly diminished
(Table 1, entries 6e8). Based on these experiments, we concluded
following optimized reaction conditions: 10% Pd/C (5 mol %), H2
(1 atm), K2CO3 (4.0 equiv), MeOH, 65 ꢀC, 24 h.
Table 1
Optimization experiments
a Reaction conditions: ketone (0.5 mmol), TsNHNH2 (1.05 equiv), MeOH (10
o
mL), stirring at 60 C until the disappearance of the ketone; then 10% Pd/C
o
(5% mol), K2CO3 (4 equiv), H2 (1 atm) at 65 C for 24 h; b Isolated yield by
column chromatography if not otherwise noted. c Due to the product volatility,
the yield was determined by GC with dodecane as the internal standard.
Scheme 2. Deoxygenative hydrogenation of ketones.a
Entry
Base (equiv)
Solvent
T (ꢀC)
[H]
2a
Yielda (%)
1
2
3
4b
5
6
7
8
9
tBuOLi
DCE
80
80
80
80
80
80
65
65
65
TES-H (2 equiv)
TES-H (2 equiv)
d
72
84
Trace
6
90
77
63
75
85
The present catalytic system was further applied to the de-
oxygenation of aldehydes. As shown in Scheme 3, various
substituted benzaldehydes were smoothly reduced to their
substituted toluene derivatives in good yields (Scheme 3, 3aeg).
Functional groups, such as methoxy, chloro, carboxyl, amino, and
hydroxy were well tolerated in the reaction. The electronic prop-
erty and position of the substituent on the aromatic ring does not
significantly affect the reaction. The aldehyde group on the naph-
thalene and N-methyl indole was readily converted to the corre-
sponding methyl group in good yields (3h,i). The reduction of
aliphatic aldehydes also proceeded well (3jeo). A low yield was
observed in the deoxygenation of 1-adamantanealdehyde, which
may be attributed to the poor solubility of corresponding N-tosyl-
hydrazone in MeOH (3p).
tBuOLi
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
tBuOLi
tBuOLi
TES-H (2 equiv)
H2 (1 atm)
H2 (1 atm)
H2 (1 atm)
H2 (1 atm)
H2 (1 atm)
tBuOLi
K2CO3
K2CO3
K2CO3 (3)
K2CO3 (4)
a
The yield was determined by GC with dodecane as internal standard.
In the absence of Pd/C.
b
With the optimal reaction conditions in hand, we then examined
the possibility of the formation of N-tosylhydrazone and the sub-
sequent deoxygenative hydrogenation in a single reaction vessel. To

L. Zhou et al. / Tetrahedron 69 (2013) 6083e6087
6085
Scheme 4. The reduction of N-tosylhydrazone 1 in MeOD.
a Reaction conditions: aldehyde (0.5 mmol), TsNHNH2 (1.05 equiv), MeOH
(5 mL), stirring at 60 oC until the disappearance of the ketone; then 10% Pd/C
o
b
(5% mol), K2CO3 (4 equiv), H2 (1 atm) at 65 C for 24 h. Isolated yield by
Scheme 5. Proposed reaction mechanism.
c
column chromatography if not otherwise noted.
Due to the product
volatility, the yield was determined by GC with dodecane as the internal
standard. d Yield was determined by GC with bromobenzene as the internal
standard. The N-tosylhydrazone was prepared and separated, then it was
directly used for the reduction.
e
3. Summary
Scheme 3. Deoxygenative hydrogenation of aldehydes.a
In summary, we have developed a one-pot, two-step de-
oxygenation reaction of carbonyl to methyl or methylene, which
employs hydrogen as the clean reductant with 10% Pd/C as the
catalyst. Various functional groups are tolerated to this reduction
system. This mild deoxygenative hydrogenation provides an alter-
native method for converting a carbonyl group into CH2, which is
one of the most important functional group transformations in
organic synthesis.
To gain insight into the reaction mechanism, we have carried
out the reduction of N-tosylhydrazone 1 under Pd/C-catalyzed re-
action conditions in MeOD (Scheme 4). The reaction was complete
in 24 h and we observed the formation of 2a, 2a-d1 and 2a-d2 in
a ratio of 1:1:0.4, based on the analysis of the product with GCeMS
and 1H NMR.
The observed scrambling of the deuterium in the product can be
rationalized by the proposed reaction mechanism shown in
Scheme 5. First, the Pd(II) species A, B and C can be formed in
equilibrium by exchange of deuterium and hydrogen though the
process shown in the Scheme. In the presence of base, the N-
tosylhydrazone 1 is converted to diazo intermediate D, which re-
acts with A, B or C to form Pd carbene intermediate E. Migratory
insertion of hydrogen or deuterium from Pd to generate in-
termediate F,24 which is followed by reductive elimination to afford
the final product.
4. Experimental section
4.1. General
All reactions were performed under a nitrogen atmosphere in
a flame-dried reaction flask. All solvents were distilled prior to
use. THF and toluene was dried over Na before use. For chroma-
tography, 200e300 mesh silica gel was employed. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded in parts
per million using tetramethylsilane (TMS) as the internal

6086
L. Zhou et al. / Tetrahedron 69 (2013) 6083e6087
standard. IR spectra are reported in wave numbers, cmꢁ1. For
HRMS measurements, the mass analyzer is FT-ICR. Substrates
3feg,25 3ken,26 and 3p27 were prepared according to the refer-
ences. Unless otherwise noted, materials obtained from com-
mercial suppliers were used without further purification. The
identity and purity of all products were confirmed via spectro-
scopic (1H and/or 13C NMR) or analytical GC against commercial
standards.
4.2.11. 1,2-Dichloro-4-methylbenzene (3b).36 Colorless oil. 1H NMR
(400 MHz, CDCl3)
(s, 3H).
d 7.26e7.20 (m, 2H), 6.95e6.92 (m 1H), 2.25
4.2.12. N,N,4-Trimethylaniline (3c).37 Yellow solid. 1H NMR
(400 MHz, CDCl3)
d
7.04 (d, J¼8.2 Hz, 2H), 6.67 (d, J¼8.2 Hz, 2H),
2.87 (s, 6H), 2.24 (s, 3H).
4.2.13. 2-Methylbenzoic acid (3d).38 White solid. 1H NMR
4.2. General procedure for the N-tosylhydrazine mediated
reductive deoxygenation of aldehydes and ketones with Pd/
CeH2
(400 MHz, CDCl3) d 12.44 (br, s, 1H), 8.09e8.07 (m, 1H), 7.47e7.43
(m 1H), 7.27 (q, J¼7.5 Hz, 2H), 2.69 (s, 3H).
4.2.14. o-Toluidine (3e).39 Yellow solid. 1H NMR (400 MHz, CDCl3)
The aldehyde or ketone (0.5 mmol), N-tosylhydrazine (98 mg,
1.05 equiv), and MeOH (10 mL) were placed in a 50 mL two-necked
round bottle equipped with magnetic stirring bar and condenser.
The reaction was heated at 60 ꢀC until aldehyde or ketone was
completely consumed. (For diarylmethanones, the preparation of
corresponding N-tosylhydrazines often need 1 mol % TsOH$H2O as
catalyst.) After cooling to the room temperature, 10% w/w of Pd/C
(26.5 mg, 5 mol %) and K2CO3 (276 mg, 4 equiv) were added. The
mixture was degassed by ‘pump-freeze-thaw’ cycles (ꢂ3) and
flushed with hydrogen. The resulting solution was heated at 65 ꢀC
for 24 h under 1 atm of hydrogen atmosphere. Resulting product
mixture was filtered through a short path of silica gel, eluting with
ethyl acetate. The volatile compounds were removed in vacuo and
the crude residue was purified by column chromatography (SiO2,
hexane) or analyzed by GC.
d
7.05e7.00 (m, 2H), 6.72e6.55 (m, 2H), 3.59 (br, 2H), 2.16 (s, 3H).
4.2.15. 2-Methylbiphenyl (3f).40 Colorless oil. 1H NMR (400 MHz,
CDCl3) 7.41e7.38 (m, 2H), 7.33e7.30 (m, 3H), 7.26e7.22 (m, 4H),
2.26 (s, 3H).
d
4.2.16. (20-Methylbiphenyl-4-yl)methanol (3g). Colorless oil. IR
(film) 3333, 2924, 1483, 1456, 1406, 1207, 1006, 908, 821, 759, 728,
691 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.40 (d, J¼8.0 Hz, 2H), 7.31
(d, J¼8.0 Hz, 2H), 7.26e7.20 (m, 4H), 4.72 (s, 2H), 2.26 (s, 3H), 1.97
(br, s, 1H). 13C NMR (100 MHz, CDCl3)
141.6, 141.4, 139.4, 135.4,
d
130.4, 129.8, 129.4, 127.3, 126.8, 125.8, 65.2, 20.5. HRMS (ESI)
calcd for C14H14ONa [(MþNa)þ] 221.0939, found: 221.0938.
4.2.17. 1,3-Dimethyl-1H-indole (3i).41 White solid. 1H NMR
(400 MHz, CDCl3)
7.11e7.07 (m, 1H), 6.79 (s, 1H), 3.70 (s, 3H), 2.31 (s, 3H).
d
7.56 (d, J¼8.0 Hz, 1H), 7.26e7.18 (m, 3H),
4.2.1. 2-Ethylnaphthalene (2a).28 White solid. 1H NMR (400 MHz,
CDCl3)
d
7.74 (dd, J¼7.6, 14.7 Hz, 3H), 7.56 (s, 1H), 7.41e7.28 (m, 3H),
2.75 (q, J¼7.6 Hz, 2H), 1.28 (t, J¼7.6 Hz, 3H).
4.2.18. 1-Propylnaphthalene (3k).42 White solid. 1H NMR (400 MHz,
CDCl3)
d
8.04 (d, J¼8.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 1H), 7.70 (d,
4.2.2. 1,2-Dichloro-4-ethylbenzene (2b).9f Colorless oil. 1H NMR
(400 MHz, CDCl3)
(d, J¼1.9, 8.2 Hz, 1H), 2.60 (q, J¼6.0 Hz, 2H), 1.22 (t, J¼7.6 Hz, 3H).
J¼8.0 Hz, 1H), 7.51e7.43 (m, 2H), 7.38 (t, J¼7.6 Hz, 1H), 7.31 (d,
J¼6.8 Hz, 1H), 3.04 (t, J¼7.6 Hz, 2H), 1.83e1.74 (m, 2H), 1.03 (t,
J¼7.3 Hz, 3H).
d
7.33 (d, J¼8.2 Hz, 1H), 7.27 (t, J¼1.8 Hz, 1H), 7.02
4.2.3. 5-Butylbenzo[d][1,3]dioxole (2c).29 Colorless oil. 1H NMR
4.2.19. Methyl 4-propylbenzoate (3l).43 White solid. 1H NMR
(400 MHz, CDCl3)
2H), 1.50e1.43 (m, 2H), 1.30e1.20 (m, 2H), 0.83 (t, J¼7.2 Hz, 3H).
d
6.64e6.52 (m, 3H), 5.82 (s, 2H), 2.44 (t, J¼7.6 Hz,
(400 MHz, CDCl3)
(s, 3H), 2.64 (s, 2H), 1.70e1.61 (m, 2H), 0.94 (t, J¼7.2 Hz, 3H).
d
7.95 (d, J¼7.6 Hz, 2H), 7.24 (d, J¼7.6 Hz, 2H), 3.90
4.2.4. Chroman (2d).30 Colorless oil. 1H NMR (300 MHz, CDCl3)
4.2.20. 3-(4-Propylphenyl)furan (3m).44 White solid. 1H NMR
d
7.00e6.94 (m, 2H), 6.77e6.70 (m, 2H), 4.11 (t, J¼6.8 Hz, 2H), 2.71
(400 MHz, CDCl3)
2H), 7.26e7.13 (m, 2H), 6.68 (s, 1H), 2.61e2.57 (m, 2H), 1.69e1.60
(m, 2H), 0.95 (t, J¼7.2 Hz, 3H).
d
7.77 (s, 1H), 7.47e7.45 (m, 1H), 7.33 (d, J¼8.0 Hz,
(t, J¼8.4 Hz, 2H), 1.93 (dd, J¼2.0, 6.8 Hz, 2H).
4.2.5. 9H-Fluorene (2f).31 White solid. 1H NMR (400 MHz, CDCl3)
d
7.77 (d, J¼7.5 Hz, 2H), 7.52 (d, J¼7.3 Hz, 2H), 7.36 (t, J¼7.4 Hz, 2H),
4.2.21. 3-(4-Propylphenyl)thiophene (3n). Colorless oil. IR (film)
7.29 (t, J¼7.4 Hz, 2H), 3.88 (s, 2H).
2958, 2927, 1503, 1463, 1260, 908, 775, 733, 668 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
(m, 2H), 7.21e7.19 (m, 2H), 2.60 (t, J¼7.6 Hz, 2H), 1.71e1.62 (m, 2H),
0.98e0.94 (m, 3H). 13C NMR (100 MHz, CDCl3)
142.4, 141.7, 133.4,
d 7.52e7.50 (m, 2H), 7.41e7.40 (m, 1H), 7.37e7.36
4.2.6. Di p-tolylmethane (2h).32 White solid. 1H NMR (400 MHz,
CDCl3)
d
7.06 (m, 8H), 3.80 (s, 2H), 2.29 (s, 6H).
d
128.9, 126.4, 126.3, 126.0, 119.7, 37.7, 24.5, 13.9. HRMS (ESI) calcd for
4.2.7. Bis(4-chlorophenyl)methane (2i).33 White solid. 1H NMR
C13H15S [(MþH)þ] 203.0889, found: 203.0891.
(400 MHz, CDCl3)
3.91 (s, 2H).
d
7.25 (d, J¼8.4 Hz, 4H), 7.08 (d, J¼8.4 Hz, 4H),
4.2.22. 1-Methyl adamantane (3p).45 White solid. 1H NMR
(400 MHz, CDCl3)
6H), 0.76 (s, 3H).
d 1.92 (s, 3H), 1.70e1.59 (m, 6H), 1.45e1.44 (m,
4.2.8. 1-Benzyl-4-methoxybenzene (2j).34 White solid. 1H NMR
(400 MHz, CDCl3) 7.29e7.24 (m, 2H), 7.19e7.16 (m, 3H), 7.10 (d,
d
J¼8.8 Hz, 2H), 6.82 (d, J¼8.8 Hz, 2H), 3.92 (s, 2H), 3.77 (s, 3H).
Acknowledgements
4.2.9. 4-Benzylbiphenyl (2k).35 White solid. 1H NMR (300 MHz,
CDCl3)
d
7.58 -7.21 (m, 14H), 4.02 (s, 2H).
Financial support from Sun Yat-Sen University, Beijing National
Laboratory of Molecular Sciences (BNLMS) is gratefully acknowl-
edged, National Basic Research Program of China (973 Program,
No. 2009CB825300) and Natural Science Foundation of China
(21272010).
4.2.10. 1,2-Dimethoxy-4-methylbenzene (3a).35 Colorless oil. 1H
NMR (300 MHz, CDCl3)
2.30 (s, 3H).
d 6.75e6.70 (m, 3H), 3.86e3.82 (m, 6H),

L. Zhou et al. / Tetrahedron 69 (2013) 6083e6087
12. Hatano, B.; Tagaya, H. Tetrahedron Lett. 2003, 44, 6331.
6087
Supplementary data
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