A mixed anhydride approach to the preparation of sulfinate esters and allylic sulfones: Trimethylacetic p-toluenesulfinic anhydride

Article abstract of DOI:10.1016/j.tetlet.2017.06.074

A reagent combination of toluenesulfinic acid and trimethylacetyl chloride affords a putative trimethylacetic p-toluenesulfinic anhydride. This reagent has been used to prepare a series of sulfinate esters from primary and secondary alcohols. In addition, the reagent was used to convert Baylis-Hillman substrates into allylic sulfones. Attempts to use the reagent to convert amines to sulfinamides were unsuccessful. In contrast, the use of 2-pyrrolidinone afforded N-p-toluenesulfinyl pyrrolidinone in 64% yield. The use of a chiral 4-benzyl-1,3-oxazolidinone or 4-benzyl-1,3-oxazolidine-2-thione led to the isolation of S-p-tolyl p-toluenethiosulfonate.

Full text of DOI:10.1016/j.tetlet.2017.06.074

Accepted Manuscript
A mixed anhydride approach to the preparation of sulfinate esters and allylic
sulfones: Trimethylacetic p-toluenesulfinic anhydride
Eric Jacobsen, Mihir K. Chavda, Kokou M Zikpi, Stephanie L. Waggoner,
Daniel J. Passini, Jesse A. Wolfe, Robert Larson, Chelsea Beckley, Christopher
G. Hamaker, Shawn R. Hitchcock
PII:
S0040-4039(17)30812-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.074
TETL 49066
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 May 2017
11 June 2017
23 June 2017
Please cite this article as: Jacobsen, E., Chavda, M.K., Zikpi, K.M., Waggoner, S.L., Passini, D.J., Wolfe, J.A.,
Larson, R., Beckley, C., Hamaker, C.G., Hitchcock, S.R., A mixed anhydride approach to the preparation of sulfinate
esters and allylic sulfones: Trimethylacetic p-toluenesulfinic anhydride, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.06.074
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A mixed anhydride approach to the preparation of
sulfinate esters and allylic sulfones: Trimethylacetic
p-toluenesulfinic anhydride
Eric Jacobsen, Mihir K. Chavda, Kokou M Zikpi, Stephanie L. Waggoner, Daniel J. Passini,
Jesse A. Wolfe, Robert Larson, Chelsea Beckley, Christopher G. Hamaker,
and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160
Abstract: A reagent combination of toluenesulfinic acid and trimethylacetyl chloride affords a
putative trimethylacetic p-toluenesulfinic anhydride. This reagent has been used to prepare a
series of sulfinate esters from primary and secondary alcohols. In addition, the reagent was used
to convert Baylis-Hillman substrates into allylic sulfones. Attempts to use the reagent to convert
amines to sulfinamides were unsuccessful. In contrast, the use of 2-pyrrolidinone afforded N-p-
1

toluenesulfinyl pyrrolidinone in 64% yield. The use of a chiral 4-benzyl-1,3-oxazolidinone or 4-
benzyl-1,3-oxazolidine-2-thione led to the isolation of S-p-tolyl p-toluenethiosulfonate.
Key words: Trimethylacetic sulfinic anhydride, sulfinate ester, Baylis-Hillman, allylic sulfones,
sulfinamide
Introduction
Sulfinate esters (1) are versatile synthetic intermediates that have been used in the
preparation of chiral sulfoxides1-3 and sulfinamides (Scheme 1).4-6 These compounds have also
been recently employed as highly selective probes for thiol bioimaging.7 The synthesis of
sulfinate esters has been achieved through a variety of methods including esterification of aryl-
and alkylsulfinates in presence of sulfuric acid,8 treatment of sulfinyl chlorides with alcohols,9 or
DCC coupling of sulfinic acids with alcohols10a-c, and other methods.10d,e A less common method
for the preparation of sulfinate esters that has not been explored is that of the reaction of mixed
anhydrides of sulfinic acid reacting with alcohols. Kobayashi and coworkers11 explored the
synthesis of mixed anhydrides containing a p-toluenesulfinyl moiety, but did not fully explore
the possibility of using these compounds as tools for the preparation of sulfinate esters.
Scheme 1. Sulfinate ester synthesis and utility.
2

In the context of employing an anhydride based methodology, we became interested in
determining if such a reagent could be prepared and successfully used in the preparation of
sulfinate esters. We opted to pursue the use of the synthesis and application of a mixed anhydride
reagent in which the p-toluenesulfinyl group would be the favored group for nucleophilic attack.
This inspired the use of trimethylacetyl (pivaloyl) group as based on its success in amide bond
formation.12 Thus, the proposed trimethylacetic p-toluenesulfinic anhydride reagent was
prepared by the addition of trimethylacetyl chloride to a methylene chloride solution of
anhydrous sodium p-toluenesulfinate (Scheme 2). The solution was initially heterogeneous with
the suspended sulfinate salt, but became an opaque, homogeneous solution within an hour. This
solution was stirred for a total of 5 hours, and an alcohol substrate was added in addition with
triethylamine (scavenger base). The reaction was then stirred for 12-15 hrs and the sulfinate ester
product was isolated in 57 to 82% yield (Table 1). The alcohol substrates included primary and
secondary alcohols, including L-menthol. In the case of the sterically hindered L-menthol, the
compound S-p-tolyl p-toluenethiosulfonate (6) also formed as a byproduct (~4%) (Scheme 3).
13
The identity of 6 was confirmed by spectroscopy (1H, C NMR, IR) and X-ray crystallography
(Figure 1). It is proposed that this material originated from a disproportionation of the anhydride
4 when there is no suitable nucleophile present. Kobayashi and coworkers11 proposed a pathway
for this disproportionation that involves the formation of a variety of species in solution (Scheme
4).
3

Scheme 2. Synthesis and application of the Trimethylacetic p-toluenesulfinic anhydride.
Table 1. Isolated yields for the synthesis of the sulfinate esters.
product
entry
1
alcohol substrate
C6H5CH2CH2OH
yielda
71%
5a
5b
5c
5d
5e
5f
2
3
4
5
6
BrC6H4CH2OH
73%
79%
73%
63%
82%
ClC6H4CH2OH
MeC6H4CH2OH
NO2C6H4CH2OH
rac-C6H5(CH3)CHOH
5g
5h
7
8
sec-butyl alcohol
65%
L-menthol
57%b
b
aIsolated chemical yields were determined after flash chromatography. The crude product was
obtained as a 66:34 ratio of diastereomers. The purified product was obtained as a 74:26 mixture of
diastereomers.
4

The thiosulfonate 6 has been proposed to originate from the disproportionation that forms
p-toluenesulfinic anhydride 9 which then undergoes a rearrangement to a labile intermediate
thioxosulfonate 9’ that ultimately forms the observed thiosulfonate 6.
Scheme 3. S-p-tolyl p-toluenethiosulfonate (6)
Figure 1. S-p-Toluenesulfinyl p-toluenesulfonate formation.
Based on the Kobayashi disproportionation, the sulfinylating agent could be anhydride 4 or
the sulfinyl chloride 7, having been formed in situ via the putative anhydride. Regardless of the
identity of the agent, there was an interest in applying this reagent combination to the synthesis
of allylic sulfones derived from allylic alcohols sourced from the Baylis-Hillman (BH) reaction.
In 2009, Tian and coworkers developed an expeditious route to allylic sulfones from Baylis-
5

Hillman adducts by direct reaction of phenylsulfinyl chloride (PhSOCl) with MBH derived
allylic alcohols.13 In addition to this work, Tian and coworkers also developed a methodology in
which MBH derived sulfonamides could be converted into allylic sulfones.14 More recently, in
2010 and 2011, Yadav and coworkers15a,b developed a method for the preparation of these
compounds by the use of p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of the
ionic liquid 1-n-hexyl-3-methyl-imidazolium bisulfuate. Finally, Reddy and coworkers
developed a method for the preparation of MBH allylic sulfones by using p-toluenesulfonyl
cyanide.16
Scheme 4. The disproportionation proposed by Kobayashi and coworkers.
To pursue the alternate methodology of the trimethylacetic p-toluenesulfinic anhydride,
Baylis-Hillman adducts 10a-e were prepared using the method of Aggarwal and coworkers
(Table 2).17 These adducts were then reacted with 4 and stirred for 12-15 hrs. This process
yielded the targeted allylic sulfones 11a-e in fair to good yield (59-98%). In all cases, the
6

1
products were primarily obtained as the (Z)-diastereomer (Z:E, ~ 95:5) as determined by H
NMR spectroscopy.
Table 2. Preparation of allylic sulfones via the trimethylacetic p-toluenesulfinic anhydride.
yield (%)a
yield (%)a
entry
Aldehyde
C6H5CHO
adduct
10a
Allylic sulfone
1
70
74
11a
2
p-NO2C6H4CHO
62
65
10b
11b
11c
3
4
m-CH3OC6H4CHO
p-Cl-C6H4CHO
80
34
88
59
10c
10d
11d
7

5
1-C8H7CHO
31
98
10e
11e
aIsolated chemical yield after purification.
The stereochemistry of the product was confirmed by X-ray crystallography of allylic sulfone
11e (Figure 2). Mechanistically, it is proposed that the BH adduct undergoes formation of the p-
toluenesulfinate ester which then rearranges to the sulfone. This argument is proposed based on
the work of Tian and coworkers13 wherein the use of phenylsulfinyl chloride was employed to
initially create the sulfinate ester as a transient intermediate in the formation of the sulfone target.
Figure 2. X-ray crystal structure for 11e.
We were gratified to learn that the synthesis of the allylic sulfones was viable. This inspired
further study with the trimethylacetic p-toluenesulfinic anhydride in reacting with amines.
Attempts to employ benzylamine (12) in the reaction of the anhydride 4 failed to produce the
8

expected sulfinamide, but afforded the pivalamide as part of a mixture of products (Scheme 5).
This was an interesting observation in connection with the Kobayashi disproportionation
(Scheme 3). If a p-toluenesulfinyl chloride entity was present in significant amount, the facile
formation of the sulfinamide would have been predicted. Reaction of 2-pyrrolidinone with
anhydride 4 was successfual and afforded the product in 64% yield. It is proposed that the
reduced nucleophilicity of the amide as compared to the benzylamine contributed to the success
of the reaction. The success of this reaction prompted the use of oxazolidinone 16a and
oxazolidine-2-thione 16b in this process. The reaction generated the thiosulfonate 6 and the
oxazolidinone and oxazolidine-2-thione unchanged. The failure of the coupling reaction was
attributed to the steric hindrance associated with the appendant C4-benzyl substituent structure.
Scheme 5. Reaction of anhydride 4 with nitrogen based nucleophiles.
A new reagent mixture based on the reaction of trimethylacetyl chloride and sodium p-
toluenesulfinate has been investigated. The utility of the method described in this work has been
9

demonstrated in the synthesis of a series of sulfinate esters derived from primary and secondary
alcohols. In addition, the reagent has been used to synthesize allylic sulfones from Baylis-
Hillman adducts. Finally, the reagent does not readily react with amines, but does with 2-
pyrrolidinone.
Acknowledgements
The authors wish to thank Tejas Idate for his technical assistance. The authors also thank the
Department of Chemistry of Illinois State University for support of this research.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at…
References
1.
Lenstra, D. C.; Vedovato, V.; Ferrer Flegeau, E.; Maydom, J.; Willis, M. C. Org. Lett.
2016, 18, 2086-2089.
2.
(a) Chelouan, A.; Recio, R.; Alcudia, A.; Khiar, N.; Fernandez, I. Eur. J. Org. Chem.
2014, 6935-6944. (b) Khiar, N.; Araujo, C. S.; Alcudia, F.; Fernandez, I. J. Org. Chem.
2002, 67, 345-356. (c) Khiar, N.; Alcudia, F.; Espatero, J.-L.; Rodriguez, L.; Fernandez,
I. J. Am. Chem. Soc. 2000, 122, 7598-7599.
3.
4.
Ridley, D. D.; Smal, M. A. J. Chem. Soc., Chem. Comm. 1981, 505-506.
Robak, M. T.; Herbarge, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600-740.
10

5.
6.
Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.; Suarez, J. R.;
Unthank M. G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482-3484.
(a) Hans, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Su, X; Wilkinson, H. S.; Lu,
Z.-H.; Magiera, D.; Senanayake, C. H. Tetrahedron 2005, 61, 6386-6408. (b) Hans, Z.;
Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. J. J. Am. Chem. Soc. 2002,
124, 7880-7881. (c) Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.;
Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977-5985.
7.
8.
9.
Malwal, S. R.; Labade, A.; Andhalkar, A. S.; Sengupta, K.; Chakrapani, H. Chem.
Comm. 2014, 50, 11533-11535.
Tranquilino, A.; Andrade, S. R. C. P.; Da Silva, A. P. M.; Menezes, P. H.; Oliveira, R. A.
Tetrahedron Lett. 2017, 58, 1265-1268.
(a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646-2650. (b) Evans, J. W.;
Fierman M. B.; Miller, S.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 8134-8135. (c)
Peltier, H. M.; Evans, J. W.; Ellman, J. A. Org. Lett. 2005, 7, 1733-1736. (d) Whitesell, J.
K.; Wong, M. S. J. Org. Chem. 1991, 56, 4552-4554. (e) Klunder, J.; Sharpless, K. B. J.
Org. Chem. 1987, 30, 91-96. (f) Furukawa, M.; Okawara, T.; Noguchi, Y.; Nishikawa,
M. Synthesis 1978, 6, 441-442. (g) Douglass, I. B. J. Org. Chem. 1965, 30, 633-635.
(a) Hajipour, A. R.; Falahati, A. R.; Ruoho, A. E. Tetrahedron Lett. 2006, 47, 2717-2719.
(b) Furukawa, M.; Ohkawara, T.; Noguchi, Y.; Nishikawa, M.; Tomimatsu, M. Chem.
Pharm. Bull. 1980, 28, 134-141. (c) Miyaji, Y.; Minato, H.; Kobayashi, M. Bull. Chem.
Soc. Jap. 1971, 44, 862-863. (d) Li, H.-J.; Wang, R.; Gao, J.; Wang, Y.-Y.; Luo, D.-H.;
Wu, Y.-C. Adv. Synth. Catal. 2015, 1393-1397. (e) Harpp, D. N.; Back, T. G. J. Org.
Chem. 1973, 38, 4328-4334.
10.
11

11.
12.
(a) Kobayashi, M.; Terao, M. Bull. Chem. Soc. Jpn. 1966, 39, 1292-1296. (b) Kobayashi,
M.; Bull. Chem. Soc. Jpn. 1966, 39, 967-970. (c) Kobayashi, M.; Yamamoto, A. Bull.
Chem. Soc. Jpn. 1966, 39, 961-967.
(a) Gill, M. A.; Manthorpe, J. M. Synth. Comm. 2013, 43, 1460-1468. (b) Joullie, M. M.;
Lassen, K. M. ARKIVOC 2010, 189-250. (c) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004,
60, 2447-2467.
13.
14.
Li, H.-H.; Dong, D.-J.; Jin, Y.-H.; Tian, S.-K. J. Org. Chem. 2009, 74, 9501-9504.
Liu, C.-R.; Li, M.-B.; Cheng, D.-J.; Yang, C.-F.; Tian, S.-K. Org. Lett. 2009, 11, 2543-
2545.
15.
(a) Yadav, J. S.; Subba Reddy, B. V.; Singh, A. P.; Majumder, N. Tetrahedron Lett.
2010, 51, 2291-2294. (b) Garima; Srivastava, V. P.; Yadav, L. D. S. Tetrahedron Lett.
2011, 52, 4622-4626.
16.
17.
Reddy, L. R.; Hu, B.; Prashad, M.; Prasad, K. Angew. Chem. Int. Ed. 2008, 48, 172-174.
Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692-700.
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Highlights
“A mixed anhydride approach to the preparation of sulfinate esters
and allylic sulfones: Trimethylacetic p-Toluenesulfinic anhydride”
Eric Jacobsen, Mihir K. Chavda, Kokou M Zikpi, Stephanie L. Waggoner, Daniel J. Passini,
Jesse A. Wolfe, Robert Larson, Chelsea Beckley, Christopher G. Hamaker,
and Shawn R. Hitchcock*
 A new putative reagent tirmethylacetic p-toluenesulfinic anhydride has been prepared
 The reagent has been used to synthesize sulfinate esters
 Sulfones were prepared from Baylis-Hillman derived alcohols
 The reagent has been used to prepare a N-p-toluenesulfinylamide.
13