Reduction of ethanethiol esters to aldehydes

Article abstract of DOI:10.1055/s-2002-31969

Reduction of ethanethiol esters of α-amino acids to α-amino aldehydes by triethylsilane and catalytic palladium-on-carbon is described. α-Amino aldehydes with Boc, Cbz, or Fmoc protection could be obtained without racemization in high yield.

Full text of DOI:10.1055/s-2002-31969

PRACTICAL SYNTHETIC PROCEDURES
1121
Reduction of Ethanethiol Esters to Aldehydes
Practical
S
ynthetic
i
Proced
d
ures: Reduc
e
tion of Etha
t
nethio
o
l
Esters to
A
s
Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
PSP
Received 26 March 2002; revised 5 April 2002
No
2
Abstract: Reduction of ethanethiol esters of -amino acids to -amino aldehydes by triethylsilane and catalytic palladium-on-carbon is
described. -Amino aldehydes with Boc, Cbz, or Fmoc protection could be obtained without racemization in high yield.
Key words: reductions, aldehydes, thiol esters, amino aldehydes
1) ClCO2i-Bu
NHCbz
OH
Et3N, CH2Cl2
0 °C, 10 min
NHCbz
SEt
Ph
Ph
Procedure 1
2) EtSH, Et3N
O
O
1
2
Et3SiH
10% Pd/C
NHCbz
SEt
NHCbz
H
Ph
Ph
Procedure 2
acetone, rt
O
O
2
3
Scheme 1
Conversion of carboxylic acids to aldehydes has been the Table 1. Esters, silyl ethers, sulfides, acetals, and amides
subject of intense investigation among synthetic organic were tolerated in this transformation. Although some of
chemists. With a few exceptions, derivatives of acids, the less substituted olefins were reduced during the reduc-
such as acid chlorides, amides, and esters, are usually con- tion, tri-substituted olefins were not affected.
verted to aldehydes by selective reduction. Alternatively,
In addition, one of the advantages of the reduction of the
the most frequently employed procedure is the reduction
thiol esters is the simplicity of the reaction and work-up
of acids or their derivatives followed by mild oxidation of
protocol. Thus, after completion of the reaction, simple
the resulting alcohols. In the case of the reduction using
filtration through a pad of Celite is enough to remove the
aluminum reagents, care must be taken to remove the alu-
catalyst, and the resulting aldehydes can be used without
minum residue from the crude product in the work-up pro-
further purification. If needed, recrystallization or silica
cedure. Herein we describe a practical method for
gel column chromatography affords the pure aldehyde in
preparation of aldehydes from carboxylic acids via their
high yield.
ethanethiol esters.
-Amino aldehydes have been used as useful chiral syn-
Ethanethiol esters are easily derived from the correspond-
thons and hence several synthetic methods have been de-
ing carboxylic acids via their mixed anhydrides, or utiliz-
veloped.2 However, since -amino aldehydes tend to
ing various dehydrating agents, such as DCC. The
easily racemize under acidic or basic conditions and even
resulting ethanethiol esters can be reduced with triethylsi-
during purification by silica gel column chromatography,
lane in the presence of palladium-on-carbon to afford al-
treatment of the compounds should be performed careful-
dehydes.1 Due to the mild conditions of the procedures,
ly. The mild conditions of the present procedure and sim-
various functional groups are compatible as shown in
ple work-up after the reduction proved particularly useful
for the preparation of -amino aldehydes. Thus, by means
of these procedures various -amino acids can be trans-
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1121,1123,ftx,en;Z05102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1122
H. Tokuyama et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Reduction of Ethanethiol Esters with Triethylsilane and Pd/C
Thiol ester
Aldehyde (% yield)a
91b,c
Thiol ester
Aldehyde (% yield)
84
MeO
COSEt
O
Ph
COSEt
OAc
94
97
88
COSEt
Ph
COSEt
OTBS
MeO
75c,e
COSEt
PhS
COSEt
O
N
H
93d
92
CO2Me
O
O
O
O
COSEt
O
O
COSEt
t-Bu
a Isolated yields after chromatographic purification. Pd/C (2 mol%) and Et3SiH (3 equiv) in acetone were used unless noted otherwise.
b Et3SiH (2 equiv) was used.
c Isolated as tosylhydrazone.
d 5.8-g-scale reaction. Pd/C (0.5 mol%) and Et3SiH (1.5 equiv) were used. CH2Cl2 was used as a solvent.
e4 mol% of Pd/C was used.
formed into the corresponding -amino aldehydes without when the reduction was performed in the presence of 1.5
racemization3 (Table 2).
equiv of 2,6-lutidine.
In summary, the procedures described here provide an ef-
ficient and convenient route for preparation of a variety of
aldehydes from carboxylic acids. Especially, these mild
procedures have been extended to the preparation of race-
mization-prone -amino aldehydes. The general applica-
bility of this reactions has been fully demonstrated in a
total synthesis of (+)-neothramycin A methyl ester1 and
Leinamycin4 as well as in the recent total syntheses of
complex natural products.5
Table 2 Formation of Ethanethiol Esters from -Amino Acids, and
Reduction with Triethylsilane and Pd/C Leading to -Amino Alde-
hydes
a-Amino Acid
Thiol ester
(% yield)a
Aldehyde
(% yield)a,b
NHR
89 (R = Boc)
89 (R = Cbz)
86 (R = Fmoc)
93 (R = Boc)c
91 (R = Cbz)
83 (R = Fmoc)
Ph
CO2H
Herein, we describe typical procedures of the simple and
convenient transformation from carboxylic acid to alde-
hyde by way of the thiol ester. In Procedure 1, we report
the preparation of thiolester Cbz-L-phenylalanine
ethanethiol ester (2) starting from Cbz-L-phenylalanine
(1) via its mixed anhydride without racemization. In the
second procedure (Procedure 2), the reduction of the thio-
lester was performed to give Cbz-L-phenylalaninal (3) in
69–70% yield (Scheme 1).
90 (R = Boc)
81 (R = Cbz)
87 (R = Boc)
96 (R = Cbz)
R
N
CO2H
85
82
79
93c
92c
84
NHBoc
Me
CO2H
NHBoc
CO2H
NHBoc
CO2H
MeO2C
CbzHN
Cbz-L-Phenylalanine Ethanethiol Ester (2)
An oven-dried, 500 mL, round-bottomed flask was equipped with a
magnetic stirring bar, and a three-way stopcock attached to an Ar
balloon. The flask was charged with Cbz-L-phenylalanine (1) (22.0
g, 73.5 mmol) and anhyd CH2Cl2 (150 mL) with cooling in an ice-
water bath. To the flask were added dropwise isobutyl chlorofor-
mate (10.5 mL, 80.9 mmol) and Et3N (10.2 mL, 73.5 mmol) via sy-
ringe at 0 °C, successively. After stirring vigorously for 10 min,
ethanethiol (12.0 mL, 162 mmol) and Et3N (10.2 mL, 73.5 mmol)
were added and immediately the color of the solution turned pink.
The mixture was diluted with Et2O (50 mL) to cause precipitation
of triethylamine hydrochloride. The salt was filtered off and the fil-
ter cake was washed with Et2O (100 mL). The combined Et2O solu-
tion was evaporated on a rotary evaporator. The residue was
a Isolated yields after chromatographic purification.
b Pd/C (5 mol%) and Et3SiH (2 equiv) in acetone were used unless not-
ed otherwise.
c 2,6-Lutidine (1.5 equiv) was added.
The Cbz group turned out to be the best protective group
for the amino group, and Fmoc group could also be em-
ployed. In the case of the Boc group, however, a by-prod-
uct was formed in some cases to lower the yield.
Formation of the by-product was completely suppressed,
Synthesis 2002, No. 8, 1121–1123 ISSN 0039-7881 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Reduction of Ethanethiol Esters to Aldehydes
1123
dissolved in EtOAc (50 mL) and transferred to a 300 mL separating
funnel. The solution was diluted with Et2O (100 mL ), and washed
with aq 1 M HCl (50 mL), water (50 mL), 1 M aq NaOH (50 mL),
H2O (20 mL), and brine (50 mL). The organic extracts were dried
(Na2SO4), filtered, and concentrated on a rotary evaporator. After
azeotropic distillation of the crude oil with hexane, a white solid
was obtained and recrystallized (EtOAc–hexane, 10 mL:200 mL) to
afford white crystals.
13C NMR (100 MHz, CDCl3): = 35.3, 61.0, 67.1, 127.2, 128.1,
128.2, 128.5, 128.8, 129.3, 135.4, 136.1, 155.9, 198.8.
References
(1) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990,
112, 7050.
(2) For a review on -amino aldehydes, see: Jurczak, J.;
Golebiowski, A. Chem. Rev. 1989, 89, 149.
Yield: 19.1 g, 76%; mp 69–70 °C (EtOAc–hexane).
(3) In Procedure 2, the optical purity of the resulting -amino
aldehyde was determined by the following procedure. An
amide was obtained via a three-step sequence: (a) NaBH4,
EtOH; (b) 10% Pd/C, H2, EtOH; (c) (R)-(+)-MTPA, DCC,
MeCN]. No peak due to N-Cbz-D-phenylalaninal ( = 3.29)
was detected (Scheme 2).
IR (CCl4): 3433, 3032, 2932, 1731, 1686, 1548, 1498, 1216 cm–1.
1H NMR (270 MHz, CDCl3): = 1.24 (t, J = 7.5 Hz, 3 H), 2.88 (q,
J = 7.5 Hz, 2 H), 3.07 (dd, J = 7.0, 13.8 Hz, 1 H), 3.16 (dd, J = 5.4,
13.8 Hz, 1 H), 4.67–4.74 (m, 1 H), 5.10 (s, 2 H), 5.13 (br d, 1 H),
7.12–7.35 (m, 10 H).
13C NMR (67.5 Hz, CDCl3): = 14.4, 23.4, 38.4, 61.3, 67.1, 127.2,
128.1, 128.5, 128.6, 128.8, 129.3, 135.4, 136.0, 155.6, 200.4.
H2
10% Pd/C
NHCbz
NaBH4
EtOH
NHCbz
OH
Anal. Calcd for C19H21NO3S: C, 66.44; H, 6.16; N, 4.08. Found. C,
66.26; H, 6.06; N, 3.85.
Ph
H
Ph
EtOH
O
Cbz-L-Phenylalaninal (3)
OMe
CF3
(R)-(+)-MTPA
DCC
Ph
HN
A 200 mL, two-necked, round-bottomed flask equipped with a pres-
sure-equalizing funnel fitted with an Ar balloon and a magnetic stir-
ring bar was charged with Cbz-L-phenylalanine ethanethiolester (20
g, 58.2 mmol), 10% Pd/C (3.1 g, 5 mol%), and acetone (58 mL). To
the suspension was added triethylsilane (13.9 mL, 87.3 mmol) over
1 h via addition funnel at r.t.. The completion of the reaction could
be checked by TLC. The solvent was carefully removed on a rotary
evaporator. The residue was suspended in Et2O (60 mL) and the cat-
alyst was filtered off through a Celite pad and rinsed with Et2O (6
20 mL). The filtrate was concentrated under reduced pressure to ob-
tain a crude product as a colorless oil, which solidified upon addi-
tion of hexane (30 mL). The solid was collected by filtration and
washed with cooled hexane (7 10 mL) to obtain analytically pure
product (11.3–11.6 g, 68.5–70.3%).
NH2
Ph
OH
O
CH3CN
Ph
OH
Scheme 2
(4) Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115,
8451.
(5) (a) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115,
4497. (b) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem.
Soc. 1993, 115, 11446. (c) Morimoto, Y.; Iwahashi, M.;
Nishida, K.; Hayashi, Y.; Shirahama, H. Angew. Chem. Int.
Ed. Engl. 1996, 35, 904. (d) Evans, D. A.; Trotter, B. W.;
Côté, B.; Coleman, P. J. Angew. Chem. Int. Ed. Engl. 1997,
36, 2741. (e) Smith, A. B. III; Chen, S. S.-Y.; Nelson, F. C.;
Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997,
119, 10935. (f) Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett
2000, 1667.
IR (CCl4): 3337, 3032, 2952, 1740, 1691, 1535, 1454, 1264, 1065,
738 cm–1.
1H NMR (400 MHz, CDCl3): = 3.15 (d, J = 6.6 Hz, 2 H), 4.53 (q,
J = 6.6 Hz, 1 H), 5.12 (s, 2 H), 5.30 (br d, 1 H), 7.13–7.39 (m, 10
H), 9.65 (s, 1 H).
Synthesis 2002, No. 8, 1121–1123 ISSN 0039-7881 © Thieme Stuttgart · New York