A sterically bulky cyclic thiourea as an efficient ligand for palladium-catalyzed aerobic oxidation of alcohols

Article abstract of DOI:10.1055/s-2006-951501

Sterically bulky N,N′-disubstituted cyclic thiourea ligand L1 has been demonstrated as an efficient ligand in palladium-catalyzed oxidation of alcohols using molecular oxygen as an oxidant. This new catalyst system has been applied to a wide variety of substrates such as benzylic alcohols, aliphatic secondary alcohols and allylic alcohols, producing the corresponding carbonyl compounds in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951501

LETTER
3057
A Sterically Bulky Cyclic Thiourea as an Efficient Ligand for Palladium-
Catalyzed Aerobic Oxidation of Alcohols
P
alladium-Catalyze
d
A
i
erobic
n
O
xidation of
A
lc
o
Y
a
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228592159; E-mail: yangdan@hku.hk
b
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
Received 17 April 2006
palladium–thiourea complex, for the oxidation of primary
and secondary alcohols, leading to various ketones or al-
dehydes in high yields.
Abstract: Sterically bulky N,N′-disubstituted cyclic thiourea
ligand L1 has been demonstrated as an efficient ligand in palladi-
um-catalyzed oxidation of alcohols using molecular oxygen as an
oxidant. This new catalyst system has been applied to a wide variety
of substrates such as benzylic alcohols, aliphatic secondary alcohols
and allylic alcohols, producing the corresponding carbonyl com-
pounds in good to excellent yields.
Over the last decade, considerable attention has been fo-
cused on the development of thiourea ligands, which are
air- and moisture-stable and readily to be modified, for
transition-metal-catalyzed reactions.9,10 Recently, we re-
ported that sterically bulky thiourea–Pd(0) complexes are
highly active catalysts for Heck and Suzuki reactions.11 In
an effort to extend the application of thiourea ligands in
other kinds of transition-metal-catalyzed reactions, we
have investigated the aerobic oxidation of alcohols by
thiourea (L1–4)–Pd complexes. The thiourea ligand L1,
with the bulky tert-butyl substituents on aryl moiety, has
been found superior in suppressing the Pd-black forma-
tion and exhibits good stability against molecular oxy-
gen.12
Key words: ligands, palladium, homogenous catalysis, alcohols,
oxidation
Palladium-catalyzed aerobic oxidation of alcohols is an
attractive transformation for both laboratory and industri-
al chemistry.1 However, there is a persistent problem of
the aggregation of Pd(0) intermediate, resulting in catalyst
decomposition and, consequently, gradual loss of catalyt-
ic activity.2 To overcome this intrinsic problem, a variety
of ligands including DMSO,3 nitrogen-based ligands4–6
and N-heterocyclic carbenes7 have been developed to sta-
bilize the palladium intermediates to avoid decomposition
and, therefore, enhance the overall turnover.1,2 In particu-
lar, with the phenanthroline-type ligands, a turnover rate
up to 1800 h–1 was achieved as reported by Sheldon and
coworkers.8 Herein we report a new catalyst system, the
The preparation of cyclic thiourea ligands L1–4 is shown
in Scheme 1.13 Disubstituted diimines 4 were synthesized
by the condensation of the corresponding amines 3 with
glyoxal and subsequent reduction of 4 by sodium borohy-
dride, affording diamines 5 in good yields. Diamines 7
were obtained by treating diamines 6 with benzaldehyde
R2
R2
ii
i
iv
Ar NH2
Ar
N
N
Ar
N
N
Ar NH HN Ar
3
4
5
R1
R1
S
L1: R1 = R2 = t -Bu
L2: R1 = t -Bu;
R2
=
tBu
R
R
N
N
iii
iv
S
L3: R = Bn
L4: R = CH2, -mesityl
HN
NH
NH2
NH2
R
R
7
6
Scheme 1 Reagents and conditions: (i) glyoxal, EtOH, H2O, 41–84%; (ii) NaBH4, EtOH, reflux, 80–86%; (iii) PhCHO, NaBH(OAc)3,
CH2Cl2–MeOH, 0 °C to r.t., 89–92%; (iv) thiophosgene, Na2CO3, THF, r.t., 59–89%.
SYNLETT 2006, No. 18, pp 3057–3060
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951501; Art ID: S08506ST
© Georg Thieme Verlag Stuttgart · New York

3058
M. Yang et al.
LETTER
and NaBH(OAc)3. Finally, treatment of the disubstituted
diamines 5 and 7 with thiophosgene afforded the desired
thiourea ligands L1–4.
Table 1 Screening of Thiourea Ligandsa
OH
O
Pd(dba)2, Tu ligand, NaOAc
O2 (balloon), toluene
The catalytic activities of thiourea (L1–4)–Pd(dba)2 com-
plexes in aerobic oxidation of 1-phenylethanol (1a) were
examined (Table 1). In the absence of thiourea ligands,
the transformation of 1a into acetophenone took place in-
efficiently with low conversion (30%, entry 1) due to the
serious formation of Pd-black. In contrast, the addition of
thiourea ligand L1 (L1/Pd = 2:1) significantly accelerated
the reaction (entry 2) by partially suppressing the forma-
tion of Pd-black. Increasing the ratio of thiourea to palla-
dium from 2:1 to 4:1 gave the oxidation product in almost
quantitative yield (97%) and almost no Pd-black forma-
tion was observed after 30 hours when 2 mol% Pd was ap-
plied (entry 3). The attempt to use air instead of O2
resulted in unsatisfactory product yield (entry 4). Other
thiourea ligands (L2–4) were less efficient for this reac-
tion (entries 5–7) due to the formation of Pd-black, indi-
cating that thiourea ligand L1 of appropriate steric
bulkiness effectively suppressed the Pd-black formation,
85 °C
2a
1a
Entry
Thiourea Ratio of thiourea/ Conversion Yield (%)b
Pd(dba)2
(%)b
1
2
3
4c
5
6
7
–
–
30
27
68
97
27
32
29
29
L1
L1
L1
L2
L3
L4
2:1
76
4:1
100
35
4:1
4:1
35
4:1
36
4:1
34
a Unless otherwise indicated, all reactions were carried out in the
presence of Pd(dba)2 (2 mol%), thiourea (8 mol%), 1a (2 mmol), and
thus maintained the catalytic acticity. A similar observa- NaOAc (10 mol%) in dry toluene (1 mL) at 85 °C under O2 atmo-
sphere (1 atm) for 30 h.
tion was first reported by Tsuji and coworkers that the use
b Yields and conversions were determined by 1H NMR with nitroben-
of sterically bulky pyridine-derived ligands can suppress
zene as an internal standard.
Pd-black formation.4d,12
c Use air instead of O2.
Using thiourea L1 as the ligand, the substrate scope of this
palladium-catalyzed aerobic oxidation of alcohols was in-
vestigated, and the results are summarized in Table 2.14
Table 2 Palladium-Catalyzed Aerobic Oxidation of Alcoholsa
L1:
Pd(dba)2, L1,
NaOAc
OH
O
R
R'
R
R'
N
N
O2 (balloon),
toluene
1
2
S
R' = H, alkyl
85 °C
Entry
1
Substrate
Product
Conversion (%)b
100
Yield (%)b
97
O
OH
1a
1b
2a
2b
2
97
95
Et
O
Et
OH
3
4
5
100
98
96
96
98c
OH
OH
O
1c
2c
F
F
OH
1d
2d
100
O
O
Ph
Ph
Ph
Ph
OH
O
1e
2e
Synlett 2006, No. 18, 3057–3060 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Aerobic Oxidation of Alcohols
3059
Table 2 Palladium-Catalyzed Aerobic Oxidation of Alcoholsa (continued)
L1:
Pd(dba)2, L1,
NaOAc
OH
O
R
R'
R
R'
N
N
O2 (balloon),
toluene
1
2
S
R' = H, alkyl
85 °C
Entry
6
Substrate
Product
Conversion (%)b
72
Yield (%)b
70d
OH
O
1f
2f
7
8
9
100
100
99
75
85
79
CHO
OH
2g
1g
CHO
OH
2h
i-Pr
2i
1h
i-Pr
CHO
OH
OH
1i
10
11
12
13
99
98
99
99
86d
95
OH
O
1j
1k
1l
2j
2k
2l
O
87d
75c,d
OH
O
O
OH
2m
1m
14
99
82d
CHO
Ph
OH
Ph
1n
2n
a Unless otherwise indicated, all reactions were carried out in the presence of Pd(dba)2 (2 mol%), L1 (8 mol%), substrates (2 mmol), and NaOAc
(10 mol%) in dry toluene (1 mL) at 85 °C under O2 atmosphere (1 atm) for 24 h.
b Yields and conversions were determined by 1H NMR with nitrobenzene as an internal standard.
c Isolated yield.
d Pd-black was observed.
The results shown in Table 2 indicate that secondary acy- to allylic alcohol such as cinnamyl alcohol (1n), leading
clic benzylic alcohols were converted to the correspond- to cinnamaldehyde (2n) in 82% yield (entry 14). It is im-
ing ketones smoothly in excellent yields (95–98%, entries portant to note that thiourea ligand L1 can be recovered
1–5) while the oxidation of cyclic benzylic alcohol 1f was after the oxidation reaction by column chromatography.
less efficient (70% yield, entry 6). Primary benzylic alco-
The X-ray crystal structure of L1 is shown in Figure 1. It
hols 1g–i were readily oxidized to the corresponding alde-
is noteworthy that L1 exhibits a C2-symmetry,15 with the
hydes in good yields (75–85%, entries 7–9). In addition,
symmetry axis along the thiourea C=S bond. In addition,
the oxidation of secondary aliphatic alcohols remains
the orientation of N-aryl substituents of L1 is found out-
of-plane to that of the thiourea moiety, which might be
general to afford aliphatic ketones in high yields (entries
10–13). Importantly, this catalyst system was applicable
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M. Yang et al.
LETTER
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Figure 1 X-ray crystal structure of thiourea ligand L1
important in maintaining an appropriate steric bulkiness
as well as enhancing the stability of L1–Pd complex.
In summary, we have demonstrated that cyclic thiourea
ligand L1, with bulky tert-butyl groups on the aryl moi-
ety, is an efficient ligand in the palladium-catalyzed oxi-
dation of alcohols under aerobic condition. Cyclic
thiourea ligand L1 exhibits good tolerance to oxidizing
agents and efficiently stabilizes palladium from aggrega-
tion, the major pathway of catalyst decomposition. This
new catalyst system has been applied to the oxidation of a
wide variety of substrates such as benzylic alcohols, ali-
phatic secondary alcohols and allylic alcohol, producing
the corresponding carbonyl compounds in good to excel-
lent yields. Further investigation to develop asymmetric
catalysis based on chiral thiourea ligands is currently un-
der way in our laboratory.
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General Procedure for Palladium/Thiourea-Catalyzed Oxida-
tion of Alcohols
To a 5-mL round-bottomed flask equipped with a stir bar were add-
ed Pd(dba)2 (0.04 mmol), thiourea ligand L1 (0.16 mmol) and dry
toluene (1 mL). The mixture was stirred for 0.5 h at r.t. Then alcohol
1a (244 mg, 2 mmol) and NaOAc (10 mol%) were added sequen-
tially. The reaction flask was sealed with a rubber septum, connect-
ed with an oxygen balloon and heated to 85 °C. After 24 h, the
reaction mixture was cooled, filtered through a short pad of silica
gel (Et2O as eluent) and concentrated in vacuo. Nitrobenzene (0.123
mL, 1 mmol) was added as an internal standard and the yield of ox-
idation product was determined by 1H NMR analysis. Pure products
can be obtained by flash column purification with Et2O–pentane as
the eluent.
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Acknowledgment
This work was supported by the University of Hong Kong and the
Hong Kong Research Grants Council. D.Y. acknowledges the Bri-
stol-Myers Squibb Foundation for an Unrestricted Grant in Synthe-
tic Organic Chemistry.
(12) Komano, T.; Iwasawa, T.; Tokunaga, M.; Obora, Y.; Tsuji,
Y. Org. Lett. 2005, 7, 4677.
(13) L1 is a highly efficient ligand for Heck reactions; see ref.
11a. L2–4 were prepared following the similar procedures.
(14) Other reaction parameters, including palladium sources,
solvents, and bases, were examined and the reported
conditions were found optimal. The effect of 3 Å molecular
sieves was found to give deleterious effect on yields because
of serious Pd-black formation.
References and Notes
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Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. In
(15) Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
Synlett 2006, No. 18, 3057–3060 © Thieme Stuttgart · New York