A simple, rapid and efficient protocol for the synthesis of methylthiomethyl esters under Swern oxidation conditions

Article abstract of DOI:10.1016/j.tetlet.2007.02.036

A rapid, mild and high yielding method for the synthesis of methylthiomethyl esters is reported from the corresponding aliphatic, aromatic and unsaturated carboxylic acids under Swern oxidation conditions using dimethylsulfoxide, oxalyl chloride and triet

Full text of DOI:10.1016/j.tetlet.2007.02.036

Tetrahedron Letters 48 (2007) 2485–2487
A simple, rapid and efficient protocol for the synthesis of
methylthiomethyl esters under Swern oxidation conditions
Sunil B. Jadhav and Usha Ghosh*
Department of Medicinal Chemistry, Nicholas Piramal Research Centre, 1, Nirlon Complex, Off Western Express Highway,
Goregaon (East), Mumbai 400 063, India
Received 10 January 2007; revised 30 January 2007; accepted 8 February 2007
Available online 13 February 2007
Abstract—A rapid, mild and high yielding method for the synthesis of methylthiomethyl esters is reported from the corresponding
aliphatic, aromatic and unsaturated carboxylic acids under Swern oxidation conditions using dimethylsulfoxide, oxalyl chloride and
triethylamine at low temperature.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The methylthiomethyl (MTM) group is a useful carbox-
ylic acid protecting group, which can be cleaved under
neutral non-hydrolytic conditions.1 This property of
the MTM group has made it a suitable carboxyl protect-
ing group in peptide synthesis.2 MTM esters also show
interesting chemistry under photochemical conditions
involving electron transfer processes.3 MTM esters have
been utilised as easily absorbable pro-drugs of non-
steroidal anti-inflammatory agents,4 flavour additives
for foods, especially dairy products5 and are also present
in essential oils.6 The routine use of MTM protecting
groups has been restricted primarily due to the lack of
sufficiently mild and convenient methods which give
consistently good yields.
with an excess of these reagents, oxidation of hydroxy
acids gives keto acids only and no MTM ester formation
has been observed.
In an ongoing project involving the synthesis of pharma-
ceutical intermediates, we required ring-substituted
phthaldehydic acids/esters. We speculated that, these
could easily be obtained by Swern oxidation of a suit-
ably substituted benzyl alcohol. Lactone 1 on hydrolysis
under controlled pH, gave substituted hydroxymethyl
benzoic acid 2 (Scheme 1). When 2 was reacted under
O
O
MeO
MeO
OH
O
H
OR
MeO
MeO
Methylthiomethyl esters are usually prepared by the
reaction of carboxylic acid salts with chloromethyl
methyl sulfide.7 Dimethylsulfoxide (DMSO) when acti-
vated by reagents such as t-butyl bromide,8 N-chloro-
succinimide,9 dicyclohexylcarbodiimide10 and chlorine
or sulfuryl chloride11 reacts with carboxylate salts under
various conditions to produce mainly MTM esters. Acti-
vation of dimethyl sulfide (DMS) or DMSO by various
reagents occurs during the well-known Corey–Kim12
and Swern oxidations.13 Amongst the various reagents
used to activate DMSO, oxalyl chloride appeared to
be the best suited and most widely used in alcohol oxi-
dations. Swern and co-workers13 have shown that even
OH
O
3
4
X
Swern's reagents
(1 - 2.2 equiv.)
O
O
MeO
MeO
MeO
MeO
pH > 7
pH < 7
OH
OH
O
1
2
Swern's reagents
( 2.2 equiv.)
O
O
MeO
MeO
MeO
O
H
SMe
O
+
Keywords: Swern oxidation; Carboxylic acids; Methylthiomethyl
esters.
MeO
5
1
O
*
Corresponding author. Tel.: +91 22 3081 8311; fax: +91 22 3081
8036; e-mail: ughosh@nicholaspiramal.co.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.036

2486
S. B. Jadhav, U. Ghosh / Tetrahedron Letters 48 (2007) 2485–2487
1
Swern conditions13 with 1 equiv of reagents, we
obtained only lactone 1 with no trace of aldehyde 3 or
hydroxy lactone 4. However, with 2 equiv of Swern
reagent, two products were isolated, namely: lactone 1
(25%) and methylthiomethyl 2-formyl-4,5-dimethoxy-
benzoate14 5 (75%). We did not obtain 2-formyl-4,5-
dimethoxybenzoic acid 3 or its cyclised product 4 under
these conditions.
formed as judged from the H NMR spectrum of the
crude reaction mixture. Although oxidation of the alco-
hol was marginally faster, the protocol appeared prom-
ising for preparing MTM esters of carboxylic acids at
low temperature. In this Letter, we present the synthesis
of MTM esters of carboxylic acids under mild condi-
tions with high yields using Swern conditions.
Carboxylic acids with diverse structures were selected to
determine the scope of the present MTM esterification
protocol. The results are summarised in Table 1. Both
aliphatic and aromatic carboxylic acids gave the corre-
sponding MTM esters in near quantitative yields. Cin-
namic acid8 (Table 1, entry 3) gave the desired product
without isomerisation of the double bond. The N-pro-
tected amino acid, N-Z-Gly also gave the corresponding
This indicated that MTM ester formation competes with
alcohol oxidation. This was further confirmed by a com-
petitive experiment. On subjecting a 1:1 mixture of benz-
oic acid and benzyl alcohol under Swern conditions
using a quantity of reagents just sufficient to oxidise benz-
yl alcohol to benzaldehyde, a mixture of benzaldehyde
(65%) and methylthiomethyl benzoate (35%) was
Table 1. Conversion of carboxylic acids 6 to MTM esters 7
O
O
Me2SO, (COCl)2, CH2Cl2
Me
R
OH
R
O
S
Et3N, -60 oC, RT
30 min
6
7
Entry
1
Acid 6
MTM ester 7
Yielda (%)
99 Ref. 16
O
O
MeO
MeO
Me
OH
O
S
MeO
MeO
OMe
O
OMe
O
Me
2
99
OH
O
S
O
O
O
Me
Me
3
4
97 Ref. 8
OH
O
O
S
O
OH
S
96 Ref. 15
O2N
Me
O2N
O
O
O
Me
O
O
O
Me
5
6
97 Ref. 16
96
OH
O
S
O
O
Me
OH
O
S
Me
7
8
97 Ref. 5
OH
O
O
S
O
O
OH
O
S
95
O
N
H
N
H
Me
O
O
O
O
O
S
Me
9
95
OH
S
O
O
OH
O
10
80b
Me
O
OH
10
5
5
10
a Isolated yields. Spectral data for the products from entries 1, 3–5 and 7 are similar to those reported.5,8,15,16
b 2.2 equiv of reagents were used.

S. B. Jadhav, U. Ghosh / Tetrahedron Letters 48 (2007) 2485–2487
2487
9. Vilasmaier, E.; Dittrich, K. H.; Sprugel, W. Tetrahedron
¨
MTM ester (Table 1, entry 8) in very good yield. p-
Nitrobenzoic acid15 and an d-keto acid (Table 1, entries
4 and 9) also gave the corresponding MTM esters in
excellent yields. Contrary to Swern’s observation,13
12-hydroxystearic acid, on treatment with 2 equiv of
reagents, gave the corresponding keto methylthiomethyl
ester in 80% yield (Table 1, entry 10) along with ꢀ15–
20% of a keto acid where only the hydroxy group had
been oxidised. When this experiment was carried out
according to the reported conditions by Swern13 (at
À10 ꢁC), similar results to those above were obtained.
Lett. 1974, 3601–3604.
10. Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87,
5661–5670.
11. Ho, T.-L. Synth. Commun. 1979, 9, 267–270.
12. Corey, E. J.; Kim, C. U. Tetrahedron Lett. 1974, 287–
290.
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480–2482.
14. Spectral data on methylthiomethyl-2-formyl-4,5-di-
methoxybenzoate 5: mp 90–92 ꢁC, 1H NMR (300 MHz,
CDCl3): d 2.33 (3H, s, CH3S), 3.99 (3H, s, OCH3), 4.00
(3H, s, OCH3), 5.44 (2H, s, CH2S), 7.47 (1H, s, Ar), 7.51
(1H, s, Ar), 10.66 (1H, s, CHO); 13C NMR (125 MHz,
CDCl3): d 190.97, 165.51, 152.39, 152.17, 131.35, 125.59,
In summary, we report a very mild and effective proto-
col using Swern’s reagent for the synthesis of MTM
esters of aliphatic, aromatic, unsaturated carboxylic
and N-protected amino acids.
112.60, 109.73, 69.77, 56.37, 56.31, 15.89; IR (KBr, cmÀ1
)
1721, 1675, 1590, 1521, 1359, 1287, 1210, 1134; MS (CI,
70 eV) m/z 271 (M++H); HRMS calcd for C12H14O5S,
270.0556; found, 270.0556; Anal. Calcd for C12H14O5S: C,
53.32; H, 5.22; S, 11.86. Found: C, 53.47; H, 5.18; S,
11.58.
In a typical procedure, DMSO (1.56 ml, 22 mmol) in
dichloromethane (10 ml) was added dropwise to a
stirred solution of oxalyl chloride (0.96 ml, 11 mmol)
in dichloromethane (15 ml) at À60 to À65 ꢁC under an
inert atmosphere. After 5 min, the carboxylic acid (solid/
neat) (10 mmol) was added to the reaction mixture
and stirring was continued for 15 min. Triethylamine
(6.97 ml, 50 mmol) was added dropwise and after
5 min, the reaction mixture was allowed to attain room
temperature and then diluted with dichloromethane
(20 ml). Water (30 ml) was added to the reaction mix-
ture and the aqueous layer was extracted with dichloro-
methane (50 ml). The combined organic extract was
washed with water (30 ml), then brine (30 ml) and dried
over anhydrous sodium sulfate. The solvent was evapo-
rated and the residue was purified by silica gel column
chromatography/crystallization. All the products17 have
15. (a) Kukla, M. J. Tetrahedron Lett. 1982, 23, 4539–4540;
(b) Sumio, I.; Seiji, A.; Kenjiro, T. Yuki Gosei Kagaku
Kyokaishi 1968, 26, 375–380; Sumio, I.; Seiji, A.; Kenjiro,
T. Chem. Abstr. 1968, 69, 35641.
16. Claus, P.; Vavra, N.; Schilling, P. Monatsh. Chem. 1971,
102, 1072–1080.
17. Spectroscopic data for novel products: (Table 1, entry 2):
1
Oil; H NMR (300 MHz, CDCl3): d 2.31 (3H, s, CH3S),
3.91 (3H, s, OCH3), 5.36 (2H, s, CH2S), 6.97–7.02 (2H, m,
Ar), 7.48 (1H, t, J = 6 Hz, Ar), 7.83 (1H, d, J = 6 Hz, Ar);
13C NMR (125 MHz, CDCl3): d 165.69, 159.42, 133.93,
131.83, 120.15, 119.54, 112.04, 68.49, 55.99, 15.48; MS
(EI, 70 eV), m/z 212 (M+); IR (neat, cmÀ1) 1731, 1600,
1491, 1288, 1238; HRMS calcd for C10H12O3S, 212.0514;
found, 212.0515; (Table 1, entry 6): oil; 1H NMR
(300 MHz, CDCl3): d 2.31 (3H, s, CH3S), 5.38 (2H, s,
CH2S), 5.39 (1H, d, J = 9 Hz), 5.87 (1H, d, J = 18 Hz),
6.75 (1H, dd, J = 18, 9 Hz), 7.47 (2H, d, J = 8.4 Hz, Ar),
8.02 (2H, d, J = 8.4 Hz, Ar); 13C NMR (75 MHz, CDCl3):
d 166.04, 142.29, 135.97, 130.08, 128.91, 126.19, 116.76,
68.80, 15.53; IR (neat, cmÀ1) 1720, 1607, 1260, 1087; MS
(EI, 70 eV) m/z 208 (M+); Anal. calcd for C11H12O2S: C,
63.43; H, 5.81; S, 15.40; found C, 63.29; H, 6.00; S, 15.72;
(Table 1, entry 8): oil turns solid on keeping, mp 40–42 ꢁC;
1H NMR (300 MHz, CDCl3): d 2.25 (3H, s, CH3S), 4.02
(2H, d, J = 5.4 Hz, NHCH2CO), 5.12 (2H, S, OCH2Ph),
5.24 (2H, s, CH2S), 5.34 (1H, bs, NH), 7.35 (5H, s, Ar);
13C NMR (75 MHz, CDCl3): 169.86, 156.27, 136.16,
128.57, 128.25, 128.14, 69.42, 67.19, 42.89, 15.51; IR
(neat, cmÀ1) 1722, 1525, 1260, 1171; HRMS calcd for
C12H15NO4S, 269.0709; found, 269.0710; (Table 1, entry
9): mp 50–52 ꢁC; 1H NMR (300 MHz, CDCl3) d 2.06–2.16
(2H, m, PhCOCH2CH2), 2.24 (3H, s, CH3S), 2.50 (2H, t,
J = 7.2 Hz, PhCOCH2), 3.08 (2H, t, J = 7.2 Hz,
CH2CH2CO), 5.15 (2H, s, CH2S), 7.44–7.50 (2H, m, Ar),
7.55–7.61 (1H, m, Ar), 7.96–7.99 (2H, m, Ar); 13C NMR
(75 MHz, CDCl3): d 199.31, 172.92, 136.77, 133.14,
128.63, 128.03, 68.16, 37.28, 33.39, 19.28, 15.45; MS(EI)
m/z 253 (M++H); HRMS calcd for C13H16O3S, 252.0813;
found, 252.0814; (Table 1, entry 10), oil turns solid on
keeping, mp 44–46 ꢁC; 1H NMR (300 MHz, CDCl3): d
0.87 (3H, t, J = 6.2 Hz, CH3CH2), 1.25–1.40 (18H, m,
9 · CH2), 1.54–1.67 (6H, m), 2.31 (3H, s, CH3S), 2.32–2.42
(6H, m, CH2CH2CO), 5.12 (2H, m, CH2S); 13C NMR
(75 MHz, CDCl3): 211.83, 173.53, 67.92, 42.84, 42.81,
34.35, 31.62, 29.69, 29.38, 29.25, 29.21, 29.05, 28.94, 24.86,
23.86, 22.50; IR (neat, cmÀ1) 2920, 2850, 1734, 1463, 1417;
HRMS calcd for C20H38O3S, 358.2507; found, 358.2508.
1
been fully characterised by H NMR, 13C NMR and
mass spectroscopy, and by mp and elemental analysis.
Acknowledgements
The authors would like to thank the analytical depart-
ment of Nicholas Piramal Research Centre for spectral
services and elemental analysis.
References and notes
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