Palladium on charcoal-catalyzed Fukuyama coupling reaction

Article abstract of DOI:10.1016/S0040-4039(00)01984-5

The Pd/C-catalyzed coupling reactions of thiol esters 1 with a zinc reagent 2 were accomplished in the presence of DMF leading to the polyfunctional ketones 3 in good yields under mild reaction conditions. The protocol was applied to the coupling reaction of a thiolactone 4c with a zinc reagent 2 to provide, after dehydration, a dehydrobiotin derivative 5c in 94% yield.

Full text of DOI:10.1016/S0040-4039(00)01984-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 429–432
Palladium on charcoal-catalyzed Fukuyama coupling reaction
Toshiaki Shimizu and Masahiko Seki*
Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku,
Osaka 532-8505, Japan
Received 29 September 2000; revised 1 November 2000; accepted 2 November 2000
Abstract—The Pd/C-catalyzed coupling reactions of thiol esters 1 with a zinc reagent 2 were accomplished in the presence of
DMF leading to the polyfunctional ketones 3 in good yields under mild reaction conditions. The protocol was applied to the
coupling reaction of a thiolactone 4c with a zinc reagent 2 to provide, after dehydration, a dehydrobiotin derivative 5c in 94%
yield. © 2001 Elsevier Science Ltd. All rights reserved.
Palladium-catalyzed cross-coupling reactions have re-
ceived considerable attention as versatile and reliable
methods for synthesizing valuable compounds such as
drugs and natural products.1 The use of heterogeneous
catalysts is much more important especially for a prac-
tical large scale preparation than the homogeneous
counterparts because of low cost, stability, and ease of
operation and recovery.2 Recent papers in this context
have shown that homogeneous palladium catalysts can
be replaced by heterogeneous palladium on charcoal
(Pd/C) in the Suzuki,3c,h Stille,3d,g Negishi,3e and Sono-
gashira couplings3a,f of aryl or alkenyl halides with aryl,
alkenyl or alkynyl compounds of various metals (B, Sn,
Zn, Cu). The use of the supported palladium catalysts
involving Pd/C was also found in the Heck arylation of
a vinyl ether.3b However, any couplings of sp3-based
organometallics in the presence of Pd/C have never
been reported.
We have recently developed a novel synthesis of (+)-bio-
tin via the Fukuyama coupling reaction4 between a
thiolactone 4c and a zinc reagent 2 in the presence of a
homogeneous catalyst, PdCl2(PPh3)2.5 A pioneering
work by Fukuyama and co-workers has shown that
reduction of thiol esters to aldehydes (CꢀH bond form-
ing reaction) with triethylsilane takes place in the pres-
ence of Pd/C.6 These findings have led us to investigate
Pd/C-catalyzed Fukuyama coupling reaction (CꢀC
O
COSEt
Pd/C (1.5 mol%)
CO2Et
Solvent
20°C, 22 h
MeO
MeO
1a
3a
+
Solvent
Yield (%)a
IZn-(CH2)4-CO2Et
68
79
85
87
THF-toluene
2
THF-toluene-DMAb
THF-toluene-NMPb
THF-toluene-DMFb
(2 equiv)
a: Isolated yield, the compound 3a was
characterized by 1H, 13C NMR, IR and
MS analysis; b: 4% (v/v) of DMA, NMP
or DMF was added.
Scheme 1.
Keywords: palladium and compounds; sulfur compounds; zinc and compounds; vitamins.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01984-5

430
T. Shimizu, M. Seki / Tetrahedron Letters 42 (2001) 429–432
bond forming reaction) to ensure an economical access
to (+)-biotin. Reported herein are the successful results
to permit an efficient synthesis of (+)-biotin as well as
other polyfunctional compounds by the use of the
Pd/C-catalyzed Fukuyama coupling reaction.
DMA, NMP or DMF per total volume of the solvent
(4% (v/v)), the coupling product 3a was obtained in
much improved yields (79, 85 and 87%,9 respectively).
The protocol using Pd/C in the presence of DMF was
successfully applied to the coupling reactions of other
aliphatic or aromatic thiol esters 1b–g with the zinc
reagent 2 (Table 1). Remarkably the reaction can be
extended to various functionalized thiol esters 1c–g
carrying a thiophene, a chlorophenyl, an ester or a
ketone to give the corresponding coupling products
3c–g in good yields without accompanying a problem
of catalytic poison (Table 1, Entries 2–6).
Our initial study was focused on the coupling reaction
of a thiol ester 1a7 with the zinc reagent 25 (Scheme 1).
It was found that the coupling reaction in the presence
of Pd/C (1.5 mol%) took place in 68% yield by the
treatment of 1a with 2 (2 equiv.) in a mixed solvent of
THF and toluene. To the best of our knowledge, this
represents the first example of the coupling of sp3-based
organometallics in the presence of heterogeneous Pd/C.
In order to improve the yield, addition of an aprotic
polar solvent to the reaction mixture was tested because
the zinc reagent might be activated by the solvent
possibly by dissociation of the stabilized chelated struc-
ture.8 As expected, when the reaction was conducted in
the presence of DMA, NMP or DMF (4% volume of
The coupling reaction with cyclic thiol esters (thiolac-
tones) 4a–c was the next subject for our investigation
(Table 2). Treatment of a five-membered thiolactone 4a
with the zinc reagent 2 (2 equiv.) in the presence of 1.5
mol% of Pd/C provided, after dehydration, correspond-
ing vinyl sulfide 5a in 57% yield as a mixture of endo-
Table 1.
IZn-(CH2)4-CO2Et (2) (2 equiv)
Pd/C (1.5 mol%)
O
RCOSEt
R
CO2Et
THF, toluene, DMF (4% (v/v))
20°C, 22 h
1b-i
3b-i
Product (3)
Thiol ester (1)
Entry
1
Yield (%)a
O
COSEt
91
CO2Et
1b
3b
O
S
67
90
76
2
3
CO2Et
COSEt
S
3c
1c
O
COSEt
Cl
Cl
CO2Et
3d
1d
1e
O
MeO2C
4
5
6
COSEt
MeO2C
CO2Et
3e
O
COSEt
70
74
CO2Et
CO2Et
MeO2C
1f
MeO2C
3f
O
COSEt
O
1g
O
3g
a: Isolated yield, all compounds were characterized by 1H, 13C NMR, IR and MS analyses.

T. Shimizu, M. Seki / Tetrahedron Letters 42 (2001) 429–432
i) IZn-(CH2)4-CO2Et (2)
431
Table 2.
Catalyst, THF, toluene
DMF (4% (v/v)), 25°C, 18 h
R
R
O
CO2Et
S
ii) p-TsOH, toluene
S
20°C, 18 h
5a-c
4a-c
Yield (%)a
Entry
2 (equiv)
Product (5)
Thiolactone (4)
Catalyst (mol%)
1
2
Pd/C (1.5)
Pd/C (5)
57
49
2.0
2.5
S
O
S
4a
CO2Et
CO2Et
5ab
38
Pd/C (1.5)
2.0
3
S
O
S
5b
4b
O
O
45
5c
6
86
80
34
94
PdCl2 (PPh3)2 (10)
PdCl2 (PPh3)2 (10)
PdCl2 (PPh3)2 (10)
3.0
6.0
2.5
2.5
BnN
NBn
BnN
NBn
CO2Et
Pd/C (5)
7
O
S
S
5c
4c
a: Isolated yield, all compounds were characterized by 1H, 13C NMR, IR and MS analyses; b: the product
was obtained as a mixture of endo- and exo-isomers (contained E- and Z-isomers); c: the reaction was
conducted without DMF.
O
and exo-isomers (contained E- and Z-isomers) (Table
2, Entry 1). When a six-membered thiolactone 4b was
allowed to the coupling reaction, the coupling product
5b was obtained in poor yield (38%) as an endo-isomer
(Table 2, Entry 3). These results might reflect the order
of the reactivity of Pd(0) toward 4a and 4b to form the
possible palladacyclic intermediates 6a and 6b, respec-
tively. The six-membered palladacycle 6a should be
generated more easily than the seven-membered deriva-
tive 6b to result in the better yield of 5a than 5b. The
coupling reaction was then applied to the synthesis of
(+)-biotin. The C-2 side-chain of (+)-biotin was effi-
ciently introduced to the bicyclic five-membered thio-
lactone 4c by the use of 5 mol% of Pd/C and 2.5 equiv.
of the zinc reagent 2 to provide the dehydrobiotin
derivative 5c in 94% yield (Table 2, Entry 7). This result
is superior to those obtained under homogeneous cata-
lytic conditions (Table 2, Entry 7 versus Entries 45–6).
The excellent yield of the coupling reaction with 4c
(Table 2, Entry 7 versus Entry 2) should arise from the
stabilization of the six-membered palladacycle 6c by
means of the favorable conformational effect of the
N-benzyl-2-imidazolidinone ring.12
R
Pd
S
6a-c
O
6a: R = -(CH2)3-
6b: R = -(CH2)4-
6c: R =
BnN
NBn
CH-
-CH2
filtered through Celite, and the filtrate was evaporated
and digested with aqua resia to provide a sample for
the measurement. Only a small amount of the palla-
dium (5.8% relative to the initially added Pd/C or 0.29
mol% relative to the initially added 4c) was found in
the filtrate and thus most of the palladium remained in
the filter cake. The coupling reaction did not proceed to
any appreciable extent in the presence of such a small
amount of palladium catalyst (0.29 mol% of Pd/C or
PdCl2(PPh3)2). The observations suggest that the cou-
pling reaction should take place on the surface of the
Pd/C and, after the reaction, most of the catalyst might
be recovered by the simple filtration. Further investiga-
tion on the re-use of the recovered catalyst is under
current investigation.
To make sure the possibility of the recovery of the
catalyst, we measured the palladium in the reaction of
4c with 2 by employing atomic absorption spectroscopy
(initially added Pd/C: 5 mol% relative to 4c).13 Thus,
after the reaction was completed, the mixture was
In conclusion, Pd/C-catalyzed Fukuyama coupling re-
action was accomplished. The Pd/C-catalyzed reaction
was successfully applied to the synthesis of various

432
T. Shimizu, M. Seki / Tetrahedron Letters 42 (2001) 429–432
functionalized ketones involving chiral compound. The
C-2 side chain of (+)-biotin was efficiently installed into
the thiolactone derivative by the use of the protocol
using inexpensive Pd/C. The good yields, simple opera-
tions, mild reaction conditions and ease of the recovery
of the catalyst would permit a ready access to the
synthetically useful ketones for a practical large scale
preparation.
and CH3CN: (a) Seki, M.; Kondo, K.; Iwasaki, T. Synlett
1995, 315. (b) Seki, M.; Kondo, K.; Iwasaki, T. J. Chem.
Soc. Perkin Trans. 1 1996, 2851. (c) Seki, M.; Yamanaka,
T.; Kondo, K. J. Org. Chem. 2000, 65, 517.
8. Jackson, R. F. W.; Moore, R. J.; Dexter, C. S. J. Org.
Chem. 1998, 63, 7875.
9. A typical procedure (synthesis of 3a): Into a suspension
of zinc powder (activated according to Ref. 10) (590 mg,
9.03 mmol) in THF (1.35 ml) was added 1,2-dibromo-
ethane (20 ml, 0.16 mmol) and the mixture was heated to
reflux for 3 min. After cooling the mixture to 25°C,
TMS-Cl (20 ml, 0.23 mmol) was added, and the slurry
was stirred for 15 min. Ethyl 5-iodopentanoate6 (1.14 g,
4.45 mmol) was then added and the mixture was heated
to 35°C and stirred for 30 min to give the zinc reagent 2.
Into the zinc reagent 2 were added thiol ester 1a (500 mg,
2.23 mmol), toluene (2.5 ml), DMF (0.17 ml) and 10%
Pd/C11 (water content: 1.2 wt.%) (36 mg, 0.034 mmol),
and the mixture was stirred at 25°C for 22 h. The mixture
was filtered through Celite and the filtrate was evapo-
rated. Into the residue was added ether and the mixture
was washed successively with 1N HCl, sat. aq. NaHCO3
and brine, dried over MgSO4 and evaporated. The
residue was purified by silica-gel column chromatography
(hexane: AcOEt=10:1) to afford 3a (570 mg, 87%).
10. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
New York, London, Sydney: John Wiley and Sons, 1967;
Vol. 1, p. 1276.
11. The Pd/C catalyst (10 wt.% on activated carbon) used in
this study was purchased from Kawaken Fine Chemicals
Co., Ltd. The reproducibility of the coupling reaction
was confirmed by the use of other source of Pd/C (10
wt.% on activated carbon, Nacalai Tesque Co., Inc.).
12. The favorable conformational effect of an N-benzyl
group for the formation of the bicyclic ring of (+)-biotin
was reported: Deroose, F. D.; Clercq, P. J. D. J. Org.
Chem. 1995, 60, 321.
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13. The atomic absorption spectrum was measured using
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.
.