A direct conversion of carboxylic acids to methylthiomethyl esters using a microwave-assisted pummerer rearrangement with dimethylsulfoxide

Article abstract of DOI:10.1016/j.tetlet.2012.06.136

A simple microwave-assisted method for the conversion of carboxylic acids to MTM esters is presented. This new process allows for rapid introduction of an MTM ester protecting group to a variety of carboxylic acids including alkyl, electron-rich aromatic,

Full text of DOI:10.1016/j.tetlet.2012.06.136

Tetrahedron Letters 53 (2012) 4782–4784
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A direct conversion of carboxylic acids to methylthiomethyl esters using a
microwave-assisted pummerer rearrangement with dimethylsulfoxide
⇑
Allison McCarthy, Russell Spatney, Madhuri Manpadi, Brian J. Myers, Jake R. Zimmerman
Department of Chemistry and Biochemistry, Ohio Northern University, Ada, OH 45810, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple microwave-assisted method for the conversion of carboxylic acids to MTM esters is presented.
This new process allows for rapid introduction of an MTM ester protecting group to a variety of carboxylic
acids including alkyl, electron-rich aromatic, and long chain unsaturated carboxylic acids. The products
isolated from this reaction are very pure after a simple extraction, which eliminates the need for further
purification. The reaction has also been carried out on 1.50 g without deterioration of product yields or
purity.
Received 15 June 2012
Revised 27 June 2012
Accepted 28 June 2012
Available online 6 July 2012
Keywords:
Methylthiomethyl ester
Carboxylic acid
Ó 2012 Elsevier Ltd. All rights reserved.
Pummerer rearrangement
Protecting group
Microwave
Dimethyl sulfoxide (DMSO)
Methylthiomethyl (MTM) esters have been utilized as protect-
ing groups for carboxylic acids for nearly four decades.1 Although
this protection strategy has been realized in the literature for a
long period of time, the synthetic preparation for the MTM ester
has seen very little change over the past thirty years.2 Two tradi-
tional routes for converting carboxylic acids to MTM esters involve
reacting a carboxylate anion with methylthiomethyl chloride
(MTM-Cl)1c or treating carboxylic acids with t-butyl bromide in di-
methyl sulfoxide (DMSO).1d,e The former method uses known toxic
reagents, MTM-Cl and 18-crown-6.3 For example, upon exposure, it
is known that crown ethers are readily absorbed through the skin,
which can ultimately lead to CNS effects.4 The latter procedure re-
quires a large excess (10 equiv) of a halogenated hydrocarbon, t-
butyl bromide, which has been found to be a carcinogen.3 While
MTM esters have mostly been employed as protecting groups, they
have also been used in the synthesis of chloromethyl esters,2c and
for ortho-thiomethylation of arylacetic acid derivatives.5 In this re-
port, we present a simple direct transformation of carboxylic acids
to MTM esters via a microwave-assisted Pummerer rearrangement
with DMSO (Scheme 1). While the Pummerer rearrangement has
been known in the literature for over one hundred years,6 to our
knowledge, there are no reports of a Pummerer reaction on DMSO
to functionalize carboxylic acids using a microwave-assisted proto-
col.7–9
Our experiments began by evaluating the reaction of benzoic
acid with DMSO in a conventional microwave.10 Initially we found
that after 3 min. of microwave irradiation in an open reaction vial,
63% of MTM ester 2a was obtained (Table 1, entry 1). Although, the
yield was modest, the product was very pure (>95%) after a simple
extraction, and therefore, no further purification was needed. We
then evaluated the same reaction using more traditional heating
conditions (entry 2). After a 4 h reflux in DMSO, 27% of 2a was iso-
lated. Since the microwave-assisted method was found to be supe-
rior to traditional heating in both reaction time and product yield,
we expanded our studies on this microwave process and focused
⇑
Corresponding author. Tel.: +1 419 772 2342; fax: +1 419 772 2985.
E-mail address: j-zimmerman.3@onu.edu (J.R. Zimmerman).
Scheme 1. Preparation of MTM esters.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.136

A. McCarthy et al. / Tetrahedron Letters 53 (2012) 4782–4784
4783
Table 1
parameters on the synthesizer were adjusted including reaction
time, microwave power, and pressure (not all data shown), yet
product yields were consistently lower than irradiating for
10 min. with an open reaction vial in a conventional microwave
(1380 W).
MTM ester synthesis of carboxylic acid derivatives via
rearrangement with DMSO
a microwave Pummerer
With the optimized conditions in hand, we explored a series of
carboxylic acids in order to determine the scope of this reaction
(Table 2). It was observed that aliphatic acids such as hydrocinnam-
ic and octanoic acid give superior yields to simple aromatic acids
such as benzoic (see entries 1, 4 and 5). Electron rich aromatic car-
boxylic acids gave excellent yields of the MTM-ester product (see
entries 6 and 7), while electron deficient acids resulted in low yields
of the desired product (entries 8 and 9). This procedure was also
found to be very efficient for converting long chain unsaturated
fatty acids, such as oleic acid, to the corresponding MTM ester (entry
11). Branched carboxylic acids including 2-phenylbutyric acid and
ibuprofen also proved to give excellent yields of the desired product
(entries 10 and 12). In general, lower yields of the reactions were
due to incomplete reaction conversion as indicated by TLC of the
reaction mixture. In the case of the electron deficient aromatic acids
we suspected that decarboxylation11,8b may have occurred since we
observed some over pressurization in the microwave synthesizer
using a sealed reaction vessel. Albeit, when completing the reaction
on m-chlorobenzoic acid (entry 9) using our method, 38% of the
MTM ester (2i) and 58% of m-chlorobenzoic acid was obtained for
a total of 96% recovery of material. Thus, it is likely that only a small
amount of decarboxylation may be occurring under the reaction
conditions employed here.
Finally, we wanted to test whether this methodology was ame-
nable for larger scale reactions. Therefore, we carried out reactions
on 1.50 g scale with 2-phenylbutanoic acid (1j), oleic acid (1k), and
ibuprofen (1l) (Scheme 2). The results from the scale-up reactions
were very similar to the previously reported reactions.15 Again, all
products were obtained pure after a simple extraction, which elim-
inated the need for further purification.
A possible mechanism for this microwave-assisted MTM ester
synthesis of carboxylic acids is shown in Figure 1.16 Initially DSMO
reacts with the acid to give the acylated DMSO adduct 4. Elimina-
tion yields the thionium intermediate 5, which undergoes addition
with the carboxylate anion to yield the MTM ester product 6. An
alternate mechanistic route would involve anhydride formation
from the dimerization of two carboxylic acids. Once formed, the
Entry
–X
Time (min)
Concn. (M)
Yielda (%)
1
2
3
4
5
6
7
8
9
–OH
–OH
3
N/A
3
<1
3
2
3.3
2
2
2
2
2
1
4
63
27b
83
–O2CPh
–Cl
–OCH3
–NH2
–OH
–OH
–OH
–OH
–OH
Decomp.c
N.R.d
N.R.d
71
3
10
10
10
15
7
71
62
10
11
2
2
65
49e
a
b
c
Isolated yields.
Reaction was refluxed for 4 h.
Reaction mixture decomposed.
No reaction was observed.
d
e
Carried out in a microwave reactor at 150 °C (150 W, max. of 140 psi) for 7 min.
our attention on evaluating other carboxylic acid derivatives. Ben-
zoic anhydride gave an excellent yield of 2a, again with good purity
after extraction. Methyl benzoate and benzamide resulted in no
product formation (entries 5 and 6), and benzoyl chloride decom-
posed under the microwave reaction conditions (entry 4). Next, we
evaluated both reaction time and concentration. It was discovered
that 10 min. of microwave irradiation was optimal at either 1 or
2 M concentrations (see entries 7 and 8). Longer reaction times
and higher concentrations did not improve product yields (see en-
tries 9 and 10). Finally, we explored this method in a microwave
synthesizer using a sealed reaction vessel (entry 11). A variety of
Table 2
Carboxylic acid screening for microwave-assisted MTM ester synthesis12
Entry
Product
R
Yielda (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph–
PhCHCH–
PhCH2–
PhCH2CH2–
CH3(CH2)6–
p-CH3-Ph–
3,4-Dimethoxy-Ph–
p-CHO-Ph–
m-Cl-Ph–
71
65
69
88
91
82
94
20
38
10
11
2j
9213
95
2k
12
2l
9414
a
Isolated yields.
Scheme 2. Scaled-up reactions to form MTM esters.

4784
A. McCarthy et al. / Tetrahedron Letters 53 (2012) 4782–4784
Chem. Soc., Perkin Trans. 1 1981, 2737–2739; (e) Dossena, A.; Marchelli, R.;
O
Casnati, G. J. Chem. Soc., Chem. Commun. 1979, 370–371.
O
2. For recent modifications to MTM ester preparation, see: (a) Ghosh, U.; Jadhav,
S. B. Tetrahedron Lett. 2007, 48, 2485–2487; (b) Liu, J.-S.; Tao, Y. Tetrahedron
1992, 48, 6793–6798; (c) Ragan, J. A.; Ide, N. D.; Cai, W.; Cawley, J. J.; Colon-
Cruz, R.; Kumar, R.; Peng, Z.; Vanderplas, B. C. Org. Process Res. Dev. 2010, 14,
1402–1406.
DMSO
– H2O
R
O
S
R
O
OH
3
4
3. See the MSDS (Aldrich) for methoxythiomethyl chloride, 18-crown-6, and/or t-
butyl bromide toxicity information.
– RCO2H
4. Hendrixson, R. R.; Mack, M. P.; Palmer, R. A.; Ottolenghia, A.; Ghirardellia, R. G.
Toxicol. Appl. Pharmacol. 1978, 44, 263–268.
5. (a) Bourgaux, M.; Gillet-Berwart, A.-F.; Marchand-Brynaert, J.; Ghosez, L. Synlett
1995, 113–115; (b) Jaroskova, L.; Bourgaux, M.; Wenkin, I.; Ghosez, L.
Tetrahedron Lett. 1998, 39, 3157–3160.
RCO2
S
R
O
S
6
5
6. 6. For seminal publications see: (a) Pummerer, R. Berichte 1909, 42, 2282–2291;
(b) Pummerer, R. Berichte 1910, 43, 1401–1412; For reviews of the Pummerer
Rearrangement see: (c) Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis
1997, 1353–1357; (d) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401–2432;
(e) de Lucchi, O.; Miotti, U.; Modena, G. Org. React. 2004, 157–405.
7. A recent publication reports a microwave-assisted triple process that includes a
Pummerer rearrangement as one step of this multi-component reaction. Islas-
Jácome, A.; González-Zamora, E.; Gámez-Montaño, R. Tetrahedron Lett. 2011,
52, 5245–5248.
Figure 1. Proposed mechanism for microwave-assisted MTM ester synthesis from
carboxylic acids and DMSO.
anhydride would also produce the activated DMSO intermediate 4
and ultimately yield desired product 6.
8. A thermal (215 °C, 3 h) KOH catalyzed esterification of dehydroabietatic acid
with DMSO to give a methylthiomethyl ester was recently reported: (a) Shi, Z.;
Wan, Y.; Yao, X. Adv. Mat. Res. 2012, 1694–1996. The synthesis of
methylthiomethyl esters under thermal conditions was also reported; (b)
Chen, C.-T.; Wang, C.-H. Bull. Ins. Chem., Acad. Sinica 1971, 19, 79–83.
9. Some relevant aromatic substitution reactions via a Pummerer rearrangement
on DMSO under thermal conditions include: (a) Liu, J.; Wang, X.; Guo, H.; Shi,
X.; Ren, X.; Huang, G. Tetrahedron 2012, 68, 1560–1565; (b) Guzei, I. A.;
Zimmerman, H. E.; Shorunov, A.; Spencer, L. C. J. Chem. Crystallogr. 2009, 39,
399–406; (c) Doucet, J.; Gagnaire, D.; Robert, A. Synthesis 1971, 556.
10. This procedure uses a 1380 W conventional microwave. Results using a 725 W
microwave did not yield product under the optimized conditions outlined in
the procedure.
In conclusion, we have reported a simple method for the prep-
aration of MTM esters from carboxylic acids using a microwave-as-
sisted protocol. This method is compatible with a variety of
carboxylic acids including alkyl, electron-rich aromatic, and long
chain unsaturated carboxylic acids. The procedure was also suc-
cessfully carried out on up to 1.50 g scale without deterioration
in yields or product purity. The products obtained from this meth-
od are very pure after a simple extraction, and therefore, the need
for further purification is not necessary.
11. (a) March, J. J. Chem. Educ. 1963, 40, 212–213; (b) Brown, B. R. Quart. Revs. 1951,
5, 131–146.
Acknowledgments
12. General Procedure for the preparation of MTM esters: The carboxylic acid
(2 mmol) and DMSO (1 mL) were added to a 5 dram 24-400 neck vial and
heated in a conventional microwave (1380 W) for 10 min. Once cool, the
solution was transferred into a separatory funnel with diethyl ether (50 mL)
and washed with water (2 Â 10 mL) and 0.5 M NaOH (2 Â 20 mL). The organic
layer was then dried over MgSO4, filtered and concentrated under reduced
pressure to afford the pure MTM ester product. Caution: This procedure should
be carried out in a hood as the MTM ester products have a strong odor.
13. Spectroscopic data for (methylthio)methyl 2-phenylbutanoate (2j): 92% yield; IR
Acknowledgment is made to the Donors of the American Chem-
ical Society Petroleum Research Fund for support of this research
(ACS PRF 49489-UNI). JRZ, MM, and RS thank the ONU Chemistry
and Biochemistry Signature Program for funding.
Supplementary data
(cmÀ1) 3063 (m), 2966 (s), 2962 (s), 2875 (m), 1736 (s), 1454 (m), 1146 (s); 1
H
NMR (200 MHz, CDCl3) d 7.33–7.31 (m, 5H), 5.11 (s, 2H), 3.51 (t, J = 8 Hz, 1H),
2.13 (quint, 1H), 2.08 (s, 3H), 1.84 (quint, 1H), 0.92 (t, J = 7.6 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 173.8, 140.0, 128.8, 128.2, 127.5, 68.5, 53.7, 26.8, 15.3, 12.3;
HRMS exact mass Calcd for C12H16O2SNa [M+Na]+: 247.0769. Found: 247.0765.
14. Spectroscopic data for (methylthio)methyl 2-(4-isobutylphenyl) propanoate (2l):
94% yield;: IR (cmÀ1) 3455 (m), 2953 (s), 2924 (s), 2868 (m), 1738 (m), 1512
(w), 1462 (m), 1420 (m), 1146 (s); 1H NMR (200 MHz, CDCl3) 1. 7.22 (d,
J = 8 Hz, 2H), 7.10 (d, J = 8 Hz, 2H), 5.12 (s, 2H), 3.73 (q, J = 7.0, 14.3 Hz, 1H),
2.45 (d, J = 8 Hz, 3H), 2.06 (s, 3H), 1.85 (sep, J = 6 Hz, 1H), 1.51(d, J = 7.3 Hz, 2H),
0.89 (d, J = 6.6 Hz, 6H); 13C NMR (50 MHz, CDCl3) d 174.5, 140.9, 137.7, 129.6,
127.4, 68.4, 45.4, 45.3, 30.4, 22.6, 18.5, 15.2; HRMS exact mass Calcd for
Supplementary data (1H and 13C NMR spectra of all the com-
pounds and other data) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.136.
References and notes
1. (a) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd Ed.;
Wiley: New York, 1999. p 389; For seminal publications using MTM esters as
carboxylic acid protecting groups, see: (b) Ho, T.-L.; Wong, C. M. J. Chem. Soc.,
Chem. Commun. 1973, 224–225; (c) Wade, L. G.; Gerdes, J. M.; Wirth, R. P.
Tetrahedron Lett. 1978, 8, 731–732; (d) Dossena, A.; Marchelli, R.; Casnati, G. J.
C
15H22O2SNa [M+Na]+: 289.1238. Found: 289.1224.
15. The reactions in Tables 1 and 2 were all run on 2 mmol scale.
16. Johnson, C. R.; Phillips, W. G. J. Am. Chem. Soc. 1969, 91, 682–687.