Fe2O3-catalyzed Pummerer rearrangement of acyl chlorides and sulfoxides: Facile synthesis of alkylthiomethyl ester

Article abstract of DOI:10.1016/j.tetlet.2017.04.053

A simple, effective approach for the Pummerer rearrangement of acyl chlorides with sulfoxides by using a low-cost and more abundant Fe catalyst has been described. The alkylthiomethyl ester products were prepared in good to excellent yields for a range of different substrates including asymmetrical sulfoxides and acyl chlorides with a variety of functional groups under mild reaction conditions. The reaction features short reaction time, simple manipulation, cheap reagents and a broad substrate scope. Single crystal X-ray analysis of a representative methylthiomethyl (MTM) group containing product was also reported.

Full text of DOI:10.1016/j.tetlet.2017.04.053

Accepted Manuscript
Fe2O3-catalyzed Pummerer Rearrangement of Acyl Chlorides and Sulfoxides:
Facile Synthesis of Alkylthiomethyl Ester
Haotian Xing, Long Chen, Yimin Jia, Zhongxing Jiang, Zhigang Yang
PII:
S0040-4039(17)30493-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.053
TETL 48845
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2017
13 April 2017
18 April 2017
Please cite this article as: Xing, H., Chen, L., Jia, Y., Jiang, Z., Yang, Z., Fe2O3-catalyzed Pummerer Rearrangement
of Acyl Chlorides and Sulfoxides: Facile Synthesis of Alkylthiomethyl Ester, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.04.053
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2
Tetrahedron Letters
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Fe2O3-catalyzed Pummerer Rearrangement
of Acyl Chlorides and Sulfoxides: Facile
Synthesis of Alkylthiomethyl Ester
Leave this area blank for abstract info.
Haotian Xing, Long Chen, Yimin Jia, Zhongxing Jiang* and Zhigang Yang∗

Tetrahedron Letters
journal homepage: www.els evier.com
Fe2O3-catalyzed Pummerer Rearrangement of Acyl Chlorides and Sulfoxides:
Facile Synthesis of Alkylthiomethyl Ester
Haotian Xing, Long Chen, Yimin Jia, Zhongxing Jiang* and Zhigang Yang∗
Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals and Wuhan University School of Pharmaceutical Sciences,
Wuhan 430071, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple, effective approach for the Pummerer rearrangement of acyl chlorides with sulfoxides
by using a low-cost and more abundant Fe catalyst has been described. The alkylthiomethyl
ester products were prepared in good to excellent yields for a range of different substrates
including asymmetrical sulfoxides and acyl chlorides with a variety of functional groups under
mild reaction conditions. The reaction features short reaction time, simple manipulation, cheap
reagents and a broad substrate scope. Single crystal X-ray analysis of a representative
methylthiomethyl (MTM) group containing product was also reported.
Received in revised form
Accepted
Available online
Keywords:
Iron catalysis
Sulfoxide
2009 Elsevier Ltd. All rights reserved.
Acyl chloride
Organosulfur
Pummerer rearrangement
Introduction
studied and established itself as a very useful method that
involves addition of a nucleophile to the thionium ion for C-O
bond construction.13a-d
The incorporation of sulfurized residues into complex
molecular architectures has become almost ubiquitous in
pharmaceuticals, materials, agricultural chemicals and organic
synthesis.1 In particular, methylthiomethyl (MTM) esters have
special chemical property under photochemical conditions
involving electron transfer processes.2 The MTM group could
also serve as an important carboxyl protecting group according to
its property.3 The pro-drugs of nonsteroidal anti-inflammatory
agents that contain MTM esters groups are more easily
absorbable,4 and some dairy and oil products use MTM esters as
the flavor additives.5 Furthermore, the MTM group could be used
in some reductive amination reactions, which would then
undergo intramolecular cyclization.6 Consequently, the
development of methods for the construction of MTM group is of
great interest for both academic and industrial chemists.
Since the first report in 1909, there are many practical
methods to prepare methylthiomethyl esters.7 Wade reported an
approach for the introduction of a valuable methylthiomethyl
group that utilized the carboxylic acid react with chloromethyl
methyl sulfide in 1978.8 To get MTM esters, many reagents were
used to activate dimethyl sulfoxide such as tert-butyl bromide9
and N-chlorosuccinimide.10 The activated dimethyl sulfoxide
could then react with carboxylic acid under different conditions
to provide the MTM esters.11
Different nucleophiles, such as arenes, alkenes, amides and
phenols were used to attack the thionium ions in numerous
Pummerer reactions.14 Moreover, it is an available synthetic strat-
egy to prepare natural and complex heterocyclic compounds15.
However, most of traditional Pummerer rearrangement require
harsh reaction conditions, such as low or high reaction
temperature, photolysis and application of microwave. These
conditions lead to some limitations on the large scale preparation
of MTM ester derivatives. Therefore, the development of low
cost and more efficient as well as facile large scale preparation
protocols for alkylthiomethyl ester is still desirable and
challenging.13-16 We disclose here a simple and effective method
for the iron catalyzed17 Pummerer rearrangement of acyl
chlorides and sulfoxides, providing a facile route for the
synthesis of alkylthiomethyl ester.
Results and discussion
The Pummerer rearrangement of benzoyl chloride 1a with
dimethyl sulfoxide (DMSO) 2a was chosen at the beginning of
our investigation as a model reaction. Firstly, the reaction was
carried out in the absence of base and metal catalyst in toluene at
room temperature under an argon atmosphere for 2 h. But no
product was observed (Table 1, entry 1). When 1.0 equiv.
triethylamine was added as a base, the desired product was
obtained in 20% yield (Table 1, entry 2). Subsequently,
During the Pummerer rearrangement, the sulfoxides can be
activated by harsh acidic initiators, such as acid anhydride and
acyl chloride to generate the thionium ion intermediates. The
thionium ions usually act as electrophilic reagents to react with
some nucleophiles,12 which can expand the synthetic utility of the
optimization of the reaction conditions was aimed at exploring
the effectiveness of metal catalyst. A similar yield of 3a was also
obtained when copper powder was used as a catalyst (Table 1,
reaction. Therefore, the Pummerer process has been extensively
———
∗ Corresponding author. Tel.: +(86)-027-68759220; fax: +(86)-027-68759850; E-mail: zxjiang@whu.edu.cn, zgyang@whu.edu.cn

2
Tetrahedron Letters
entry 3). To our delight, the yield was improved to 70% when
Table 2. Scope of acyl chlorides.a,b
iron powder was utilized instead of copper powder (Table 1,
entry 4). Encouraged by these initial results, we further optimized
the reaction conditions by using different iron catalysts in
different solvents at room temperature. As an alternative iron
catalyst, FeCl2 was ineffective for the Pummerer rearrangement,
and the yield decreased dramatically (Table 1, entry 5). For
comparison, other ferrous catalysts such as Fe(OAc)2, Fe(acac)2
and Fe(OTf)2 afforded product 3a in 47-61% yields, respectively
(Table 1, entries 6-8). It was further found that the valence of the
iron salts is an important factor for the yield of the reaction.
FeCl3 gave the product in 60% yield (Table 1, entry 9). Notably,
when Fe2O3 wasemployed as the catalyst, the reactivity was
improved significantly (81% yield, Table 1, entry 10), and Fe3O4
provided a similar result. Other bases, such as DMAP, DIPEA,
pyridine and inorganic base, were investigated. But no superior
result was obtained (see the Supporting Information). A short
survey on solvents indicated that the property of solvents was
crucial for this transformation. Reactions in polar, aprotic
solvents such as dioxane, EtOAc, CHCl3, DMSO and THF
afforded low yields (Table 1, entries 12-16). No desired product
was observed when protonic solvent methanol was used and an
unexpected byproduct methyl benzoate was detected in
quantitative yield (Table 1, entry 17). It was noteworthy that the
reaction was very sensitive to the reaction temperature. High
temperature could decrease the reactivity.
Table 1. Optimization of the reaction conditions.a
O
O
Catalyst (5 mol%)
Et3N (1.0 equiv.)
O
S
Cl
O
S
Solvent (1.0 mL)
Ar, rt, 2 h
1a
2a
3a
Entry
Catalyst
―
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Yield (%)b
N.R.d
1c
2
3
4
5
6
7
8
9
―
20
Cu
19
Fe
70
FeCl2
Fe(OAc)2
Fe(acac)2
Fe(OTf)2
FeCl3
10
61
50
47
60
10
Fe2O3
Toluene
81
11
12
13
14
15
16
17
Fe3O4
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Toluene
Dioxane
EtOAc
CHCl3
DMSO
THF
75
60
65
41
42
57
0
aReaction conditions: Acyl chlorides 1 (0.5 mmol), dimethyl sulfoxide 2a (2.5
mmol, 5.0 equiv.), Fe2O3 (5 mol%) and Et3N (0.5 mmol, 1.0 equiv.) in
toluene (1.0 mL) at rt for 2 h. bIsolated yield.
fluoro and alkoxyl into the ortho-positions of the phenyl ring, the
corresponding products 3b-3d were obtained with high yields
(71-88%). It is interesting that the substituents on meta-position
of the aromatic ring had a limited influence on the reactivity
(Table 2, 3e-f). Remarkably, the para-position of the phenyl ring
bearing different functional group such as halogen, ester, alkane,
ether, amide and sulfide were also suitable substrates for the
reaction, and afforded the desired products 3g-3p in high yields.
When the substitutes were halogen atoms such as fluorine and
bromine, the products 3g-3h can be achieved in 62-70% yields.
The methyl ester as an electron-withdrawing group which was
substituted on the phenyl ring could also lead the corresponding
product 3i in good yield (65%). The structure of compound 3i
was further confirmed by X-ray diffraction of its single crystal.18
The X-ray structure indicates that two molecules 3i were stacked
together bya weak face-to-face (F-tape) π-π stacking interaction
MeOH
aReaction conditions: 1a (0.5 mmol), 2a (2.5 mmol, 5.0 equiv.), catalyst (5
mol%) and Et3N (0.5 mmol, 1.0 equiv.) in solvent (1.0 mL) at rt for 2 h.
bDetermined by 1H NMR analysis with 1,3,5-trimethoxybenzene as an
internal standard. cWithout Et3N. dNo reaction.
Under the optimized conditions (Table 1, entry 10), a study on
the substrate scope of the Fe-catalyzed Pummerer rearrangement
was carried out. The results were summarized in Table 2. First,
with DMSO as the sulfoxide, various aromatic and alkyl acyl
chlorides were then examined. In general, the reactions took
place efficiently with good yields (60–93%). This catalyst system
was efficient when introducing various substituents such as

3
Tetrahedron Letters
hindered moiety of sulfoxides. The corresponding alkylthioalkyl
esters 4c-d were observed with excellent regioselectivity favoring
the 1H NMR spectroscopy. Finally, under the similar reaction
conditions, aryl sulfoxides were tested. Likewise, either the
electronic nature or the position of the substituents on the
aromatic ring of aryl sulfoxides had a limited influence on the
reactivity. The desired adducts 4e-j were obtained in satisfactory
yields.
Fig. 1. Single crystal X-ray structure of 3i.
(Fig. 1). When the phenyl ring bearing electron-donating groups,
such as alkyl, alkoxyl, methylthio and dimethylamino, were
compatible with the reaction conditions affording the corres-
ponding products with excellent yields (Table 2, 3j-p, 62-93%).
It is interesting that difluoro and dichloro substituted benzoyl
chlorides were suitable for the reaction and the desired products
3q-3r were observed with satisfactory yields (80-85%). Finally,
alkyl acyl chlorides were examined for the Pummerer rearran-
gement. Cyclic substrates such as cyclopropylformyl chloride
and cyclohexaylformyl chloride could be smoothly converted to
MTM ester derivatives 3s-t with 90% and 65% yield, respective-
ly. Aliphatic branched and linear acyl chlorides also proceeded
smoothly in the reaction leading to the corresponding adducts 3u-
v in 68-90% yields.
Scheme 1. Proposed reaction mechanism for the formation of
compound 3a.
On the basis of the above results and related publications, a
plausible mechanism of this transformation is proposed (Scheme
1).15-16, 19-20 Initially, benzoyl chloride 1a was activated by an iron
catalyst to produce iron acylium ion A, which attacks DMSO 2a
to generate the acylated dimethylsulfoxide adduct B. Further
decomposition of intermediate B affords the thionium salt C and
hydrochloric acid that was scavenged by the base Et3N. Finally,
the thionium intermediate C recombines with the carboxylate
anion to provide the final methylthiomethyl ester 3a.
Table 3. Scope of sulfoxides.a,b
In conclusion, we have established a simple and practical
protocol to construct alkylthiomethyl ester via an iron promoted
Pummerer rearrangement of acyl chlorides with sulfoxides under
mild reaction conditions. The alkylthiomethyl ester products
were prepared with a variety of functional groups in good to high
yields (up to 93%). The advantage of the current method
compared to the previous method is that it uses the inexpensive
and widely utilized Fe2O3 as the catalyst. Thus, potentially, it will
afford a general method for the construction of any desired
alkylthiomethyl ester building blocks. Application of this
property of iron catalyst on other type of reactions and further
investigation of the reaction mechanism are underway in our
laboratory.
Acknowledgments
We gratefully acknowledge financial support from the National
Key Research and Development Program of China (grant No.
2016YFC1304704) and the National Natural Science Foundation
of China (grant No. 21402144, 21372181 and 21572168).
References and notes
1. (a) Lin, D. Y.; Zhang, S. Z.; Block, E.; Katz, L. C. Nature 2005, 434, 470;
(b) Mishra, A.; Ma, C. Q.; Bäuerle, P. Chem. Rev. 2009, 109, 1141; (c)
Sulfur Compounds: Advances in Research and Application; Acton, A. Q.,
Ed.; Scholarly Editions: Atlanta, GA, 2012; (d) Joyce, N. I.; Eady, C. C.;
Silcock, P.; Perry, N. B.; van Klink, J. W. J. Agric. Food Chem. 2013, 61,
1449; (e) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem. 2014,
57, 2832; (f) Takimiya, K.; Osaka, I.; Mori, T.; Nakano, M. Acc. Chem.
Res. 2014, 47, 1493; (g) He, C. Y.; Wu, C. Z.; Zhu Y. L.; Zhang X.
Chem. Sci. 2014, 5, 1317; (h) Qiao, Z.; Jiang, X. Org. Lett. 2016, 18,
1550; (i) Wei, J.; Li, Y.; Jiang X. Org. Lett. 2016, 18, 340.
aReaction conditions: Benzoyl chloride 1a (0.5 mmol), sulfoxides 2 (2.5
mmol, 5.0 equiv.), Fe2O3 (5 mol%) and Et3N (0.5 mmol, 1.0 equiv.) in
toluene (1.0 mL) at rt for 2 h. bIsolated yield.
To further expand the scope of sulfoxides, various alkyl and
aromatic sulfoxides were tested under the optimized conditions to
afford the corresponding products, including alkylthioalkyl and
arylthioalkyl esters, in good yields from 57% to 73%. The
reactions of benzoyl chloride with symmetric alkyl sulfoxides
such as diethyl and dipropyl sulfoxides occurred smoothly after 2
h at room temperature to give the products 4a-b in 65% and 60%
yield, respectively. Remarkably, when asymmetric alkyl sulfoxi-
des were used as substrates, the reaction occurred in the less
2. Dossena, A.; Palla, G.; Marchelli, R.; Lodi, T. Int. J. Pept. Protein Res.
1984, 23, 198.
3. (a) Ho, T.-L.; Wong, C. M. J. Chem. Soc., Chem. Commun. 1973, 224; (b)
Kim, S.; Park, Y. H.; Kee, I. S. Tetrahedron Lett. 1991, 32, 3099.
4. Griesbeck, A. G.; Oelgemöller M.; Lex, J. J. Org. Chem. 2000, 65, 9028.
5. Loftsson, T.; Kaminski, J. J.; Bodor, N. J. Pharm. Sci. 1981, 70, 743.

4
Tetrahedron Letters
6. Vandenbosch, S.; Van’t Land, E.; Stoffelsma, J. Pat. Appl. EP 7673,
1980.
Supplementary Material
7. Ghosh, U.; Bhattacharyya, R.; Keche, A. Tetrahedron 2010, 66, 2148.
8. Liu, J.; Wang, X.; Guo, H.; Shi, X.; Ren, X.; Huang, G. Tetrahedron
2012, 68, 1560.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
9. Wade, L. G.; Gerdes, J. M.; Wirth, R. P. Tetrahedron Lett. 1978, 731.
10. Dossena, A.; Marchelli, R.; Casnati, G. Chem. Commun. 1979, 370.
11. Vilasmaier, E.; Dittrich, K. H.; Sprugel, W. Tetrahedron Lett. 1974,
3601.
12. Jadhav, S. B.; Ghosh, U. Tetrahedron Lett. 2007, 48, 2485.
13. Ito, S.; Kubota, Y.; Asami, M. Chem. Lett. 2015, 45, 16.
14. For selected recent reviews see: (a) Fedorov, N. V.; Anisimov, A. V.;
Viktorova, E. A. Chem. Heterocycl. Compd. 1989, 25, 1083; (b) de
Lucchi, O.; Miotti, U.; Modena, G., The Pummerer Reaction of Sulfinyl
Compounds, Organic Reactions 2004, 40, 157; (c) Padwa, A.; Gunn Jr.,
D. E.; Osterhout, M. H. Synthesis 1997, 1353; (d) Padwa, A.; Bur, S. K.;
Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett. 2002, 851; (e) Bur, S. K.;
Padwa, A. Chem. Rev. 2004, 104, 2401; (f) Feldman, K. S. Tetrahedron
2006, 62, 5003; (g) Akai, S.; Kita, Y. Top. Curr. Chem. 2007, 274, 35; (h)
Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. T. Angew.
Chem., Int. Ed. 2010, 49, 5832.
15. (a) McAllister, L. A.; McCormick, R. A.; Brand, S.; Procter, D. J. Angew.
Chem., Int. Ed. 2005, 44, 452; (b) Feldman, K. S.; Karatjas, A. G. Org.
Lett. 2006, 8, 4137; (c) Ovens, C.; Martin, N. G.; Procter, D. J. Org. Lett.
2008, 10, 1441; (d) Zhang, Y.; Lee, J. H.; Danishefsky, S. J. J. Am. Chem.
Soc. 2008, 130, 14964; (e) Feldman, K. S.; Nuriye, A. Y. Tetrahedron
Lett. 2009, 50, 1914; (f) Feldman, K. S.; Nuriye, A. Y. Org. Lett. 2010,
12, 4532.
16. (a) McCarthy, A.; Spatney, R.; Manpadi, M.; Myers, B. J.; Zimmerman,
J. R. Tetrahedron Lett. 2012, 53, 4782; (b) Beddoes, R. L.; MacLeod, D.;
Moorcroft, D.; Quayle, P.; Zhao, Y.; Davies, G. M. Tetrahedron Lett.
1992, 33, 417.
17. Selected examples of Fe catalyzed transformations: (a) Benito-Garagorri,
D.; Kirchner, K. Acc. Chem. Res. 2008, 41, 201; (b) Bauer, I.; Knölker,
H.-J. Chem. Rev. 2015, 115, 3170; (c) Morris, R. H. Acc. Chem. Res.
2015, 48, 1494; (d) Chirik, P. J. Acc. Chem. Res. 2015, 48, 1687; (e)
Chakraborty, S.; Bhattacharya, P.; Dai, H.; Guan, H. Acc. Chem. Res.
2015, 48, 1995; (f) McNeill, E.; Ritter, T. Acc. Chem. Res. 2015, 48,
2330; (g) Pan, J.; Li, J.; Huang, R.; Zhang, X.; Shen, H.; Xiong, Y.; Zhu,
X. Tetrahedron 2015, 71, 5341; (h) Jin, M.; Adak, L.; Nakamura M. J.
Am. Chem. Soc. 2015, 137, 7128; (i) Chakraborty, S.; Leitus, G.;
Milstein, D. Angew. Chem., Int. Ed. 2017, 56, 2074.
18. Crystal data of 3i: Crystallographic data (excluding structure data
factors) for the structures in this letter have been deposited with the
Cambrige Crystallographic Data Centre as supplementary publication
number CCDC 1534089. Copies of the data can be obtained free of
charge on an application to CCDC, 12 Union Road, Cambrige CB21 EZ,
UK [fax: +44 1223336033 or e-mail: deposit@ccdc.cam.ac.uk].
19. Zhu, D.; Chang, D.; Gan, S.; Shi, L. RSC Adv. 2016, 6, 27983.
20. Fujita, J.; Matsuda, H.; Yamamoto, K.; Morii, Y.; Hashimoto, M.;
Okuno, T.; Hashimoto, K. Tetrahedron 2004, 60, 6829.

5
Tetrahedron Letters
(1) A Fe2O3-catalyzed Pummerer rearrangement
was explored.
(2) Applications of the method led to a series of
important alkylthiomethyl molecules.
(3) The product structure was further confirmed by
X-ray analysis of its single crystal.