Superelectrophilic Activation of Crotonic/Methacrylic Acids: Direct Access to Thiochroman-4-ones from Benzenethiols by Microwave-Assisted One-Pot Alkylation/Cyclic Acylation

Article abstract of DOI:10.1021/acs.orglett.5b03172

An efficient microwave-assisted protocol for the synthesis of 2-/3-methylthiochroman-4-ones by superacid-catalyzed alkylation followed by cyclic acylation (cyclization via intramolecular acylation) is described. Using easily accessible benzenethiols and crotonic acid/methacrylic acid with triflic acid (as catalyst of choice for needed optimal acidity), the reaction was tuned toward the formation of the cyclized products in good selectivity and yield. A mechanism involving the formation of carbenium-carboxonium superelectrophilic species is suggested.

Full text of DOI:10.1021/acs.orglett.5b03172

Letter
pubs.acs.org/OrgLett
Superelectrophilic Activation of Crotonic/Methacrylic Acids: Direct
Access to Thiochroman-4-ones from Benzenethiols by Microwave-
Assisted One-Pot Alkylation/Cyclic Acylation
Habiba Vaghoo,*,† G. K. Surya Prakash,*,‡ Arjun Narayanan,‡ Rohit Choudhary,‡ Farzaneh Paknia,‡
Thomas Mathew,*,‡ and George A. Olah‡
†Department of Chemistry and Biochemistry, Colorado College, Colorado Springs, Colorado 80903-3243, United States
‡Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California
90089-1661, United States
S
* Supporting Information
ABSTRACT: An efficient microwave-assisted protocol for the
synthesis of 2-/3-methylthiochroman-4-ones by superacid-
catalyzed alkylation followed by cyclic acylation (cyclization via
intramolecular acylation) is described. Using easily accessible
benzenethiols and crotonic acid/methacrylic acid with triflic
acid (as catalyst of choice for needed optimal acidity), the
reaction was tuned toward the formation of the cyclized
products in good selectivity and yield. A mechanism involving
the formation of carbenium−carboxonium superelectrophilic
species is suggested.
hiochroman-4-ones have become valuable synthons and
Timportant precursors in organic synthesis. As reagents in
heterocyclic synthesis, they have shown versatility and
convenient application in many areas.1 These compounds have
also played vital roles in the synthesis of certain bioactive
antiproliferative agents2 as well as demonstrated direct
bioactivity by themselves in the form of antifungal properties.3−5
Recently, studies on the cytotoxic effect of a few thiochroman-4-
one derivatives on tumor cells in vitro have been reported.6
Results from such studies suggest that thiochromanone
derivatives, such as (Z)-3-(chloromethylene)-6-fluorothiochro-
man-4-one, can kill tumor cells by inducing tumor cell apoptosis
by increasing apoptosis-related factors.7 Many substituted
thiochromanones have been designated as effective “bioreductive
alkylating agents” as demonstrated by compound B (Figure 1),
Figure 1. Some biologically active thiochromanone derivatives.
an inhibitor of Ehrlich ascites tumor growth.8 Therefore,
investigation of the properties, synthetic routes, and applications
of thiochroman-4-ones is steadily gaining much attention
recently.
one-pot method for making these intriguing molecules directly
from simple substrates such as thiophenols and crotonic/
methacrylic acids. Thus, we were interested in designing a one-
pot, superacid-catalyzed synthesis of thiochroman-4-ones from
easily accessible and viable thio and keto precursor units
thiophenols and crotonic/methacrylic acids.
In our previous studies, we found that trifluoromethylated
acrylic acids undergo superacidic activation in triflic acid, and
their reaction with arenes under thermal conditions gave
trifluoromethylated coumarins and indanones in good yields.16
The thiochromanone family of heterocycles has not been
studied as thoroughly as their oxygen counterparts, the
chromanones, of which flavonones are a major subset. Thiochro-
man-4-ones have been prepared via several routes such as
palladium-catalyzed carbonylative heteroannulation of iodothio-
phenols with allenes and carbon monoxide,9 base-catalyzed
cyclization of β-halopropanoic acids with arylthiophenols,10−12
base-catalyzed condensation of β-propiolactone with 2-ethyl-
thiophenol followed by acid-promoted cyclization,13 and intra-
molecular Friedel−Crafts acylation with Lewis acids14 as well as
methanesulfonic acid.15 To the best of our knowledge, there is no
Received: November 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Therefore, initially, we conducted the triflic-acid-mediated
condensation of crotonic acid (2a) with benzenethiol (1a)
under thermal conditions (55 °C, 24 h) (Scheme 1).
Table 1. Synthesis of 2-Methylthiochroman-4-ones
Scheme 1. Reaction of Crotonic Acid with Benzenethiol
GC-MS analysis of the crude mixture after workup showed
that the desired product 2-methylthiochroman-4-one 3a did
indeed form, but side products (diphenyl sulfide 4 and diphenyl
disulfide 5) had formed in significant amounts. The diphenyl
sulfide was formed through an acid-mediated SNAr reaction,
while the disulfide was formed by air oxidation during the
reaction or during the workup. This became clear when we found
that the formation of the disulfide could be suppressed by
performing the reaction under an inert (N2) atmosphere. In our
attempt to stop the formation of the sulfide, we thought that
since the sulfide formation is kinetically rather slow, the side
reaction could also be suppressed by using microwave irradiation
and higher temperatures. Microwave heating has recently
become very popular in organic synthesis, and several reviews
have been published.17
To our delight, the desired 2-methylthiochroman-4-one 3a
was easily obtained in pure form after column chromatography. It
should be noted that the microwave-promoted reaction was
cleaner than the corresponding thermal reaction (the separation
by SiO2 flash column chromatography was much easier due to a
significant decrease in side products). The yield was further
improved by using dry dichloromethane as a cosolvent. Using
this protocol, a series of benzenethiols was reacted with crotonic
acid (Table 1) to afford the corresponding 2-methylthiochro-
man-4-ones.
a
Reactions were carried out with crotonic acid 2a (2 mmol) and
thiophenol (2 mmol) in dry CH2Cl2 (1 mL) and CF3SO3H (2 mL).
starting materials. In CF3COOH medium, the major product
observed (by GC analysis) was the trifluoroacetyl thioester.
This methodology was also extended to methacrylic acid 2b
for the synthesis of 3-methylthiochroman-4-ones 6a−h′ (Table
2). In the case of methacrylic acid 2b, the reactions were carried
out using commercially available dry CH2Cl2 but did not require
inert conditions.
A probable mechanism is proposed as follows. Initial
protonation of the crotonic acid by triflic acid gives the
carboxonium ion 7. Further protosolvation by the superacidic
medium results in a small equilibrium amount of the carbenium−
carboxonium superelectrophile 8, which is immediately
quenched by the nucleophilic attack of sulfur of thiophenol,
forming 9 and subsequently the carboxonium ion 10. This then
undergoes intramolecular Friedel−Crafts acylation, resulting in
the ring closure to yield the thiochroman-4-one product 3a.
Reaction of methacrylic acid also can be explained as following a
similar mechanistic pathway.
It is quite evident from the product that the alkylation step
occurs first rather than the acylation driving the acylation to
occur ortho to the thio functionality (acylation is generally
extremely regioselective for the para position when conducted
with o/p directing substituents). In addition, when 3,5-
bis(trifluoromethyl)benzenethiol was used as a substrate, no
cyclization product was obtained. Instead, both 19F and 1H NMR
support the formation of the corresponding arylpropanoic acid.
This suggests that the benzene ring with the two CF3 groups is
The reactions of the various benzenethiols with crotonic acid
proceeded cleanly, with few side products (SiO2 flash column
purification involved separation of unreacted thiol or minor
amounts of disulfide from the product). Activated aromatic rings
generally gave higher yields, and the presence of a para directing
group para to the site of acylation improved the yield of product
further. However, with more deactivating substituents (such as
−Br and −NO2), the reaction was found to be sluggish and the
product could not be formed cleanly. Interestingly, in contrast to
our expectation, 2,4-dimethylbenezenethiol 1e only gave the
desired product in 40% yield; substitution ortho to the sulfur was
not well tolerated, likely due to steric or unfavorable electronic
factors (the site of acylation is meta to both methyl groups).
2-Thionaphthol 1j proved too reactive (GC-MS analysis of the
crude revealed a very complex mixture of products), and 4-
methoxythiophenol 1i yielded an intractable solid that was
insoluble in common solvents. 4-Aminothiophenol also failed to
give any product, probably due to the highly deactivating nature
of the ammonium group (in the highly acidic medium, −NH2 is
+
completely protonated to −NH3 ).
When 4-hydroxythiophenol was used as a substrate,
cyclization failed to take place, and instead, the thioester was
obtained as the major product. When the reaction was conducted
in weaker acids (CF3COOH, CH3SO3H), GC analysis of the
crude reaction mixtures revealed poor conversion (<5%) of the
B
DOI: 10.1021/acs.orglett.5b03172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
zenethiols with both electron-donating and electron-with-
drawing groups are tolerated, affording the desired products in
moderate to high yields in most cases.
Table 2. Synthesis of 3-Methylthiochroman-4-ones
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03172.
Experimental procedures and full characterization of new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: habiba.vaghoo@coloradocollege.edu.
*E-mail: gprakash@usc.edu.
*E-mail: tmathew@usc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support by the Loker Hydrocarbon Research Institute is
gratefully acknowledged. H.V. thanks Colorado College for
granting pretenure sabbatical leave.
REFERENCES
■
(1) Bondock, S.; Metwally, M. A. J. Sulfur Chem. 2008, 29, 623.
(2) Dalla Via, L.; Marciani Magno, S.; Gia, O.; Marini, A. M.; Da
Settimo, F.; Salerno, S.; La Motta, C.; Simorini, F.; Taliani, S.; Lavecchia,
A.; Di Giovanni, C.; Brancato, G.; Barone, V.; Novellino, E. J. Med.
Chem. 2009, 52, 5429.
(3) Fang, B.; Ma, Z.; Yang, G.; Wang, G.; Tian, W.; Li, L. Int. J. Chem.
2010, 2, 143.
(4) Song, Y.-L.; Wu, F.; Zhang, C.-C.; Liang, G.-C.; Zhou, G.; Yu, J.-J.
Bioorg. Med. Chem. Lett. 2015, 25, 259.
(5) Geng, H.-J.; Xing, Z.-B.; Luo, W.; Cong, L.; Li, x-U.; Guo, C. Lett.
Drug Des. Discovery 2012, 9, 797.
(6) Xiao, W.-J.; Alper, H. J. Org. Chem. 1999, 64, 9646.
(7) Zhao, J.; Li, C.; Suo, H.; Wang, Y.; Yang, C.; Ma, Z.; Liu, Y. Global.
Adv. Res. J. Med. Med. Sci. 2014, 3, 240−250.
a
Reactions were carried out with methacrylic acid 2a (1.18 mmol) and
thiophenol (1.18 mmol) in CH2Cl2 (0.5 mL) and CF3SO3H (1.5 mL).
(8) Holshouser, M. H.; Loeffler, L. J.; Hall, I. H. J. Med. Chem. 1981, 24,
853−858.
too deactivated to participate in a Friedel−Crafts acylation.
Formation of the carbenium−carboxonium dication 8 is a crucial
step, which is possible under the superacidic condition provided
by triflic acid (Scheme 2).18
(9) Li, J.-T.; Li, H.-Y.; Li, H.-Z.; Xiao, L.-W. J. Chem. Res. 2004, 6, 394.
(10) Xiao, L.-W.; Li, H.-Z. Chin. J. Org. Chem. 2006, 26, 979.
(11) Chu, S.-L.; Chang, C.-C. Huaxue Xuebao 1958, 24, 87. Chu, S.-L.;
Chang, C.-C. Chem. Abstr. 1959, 53, 39911.
(12) (a) Sen, A. B.; Arora, S.L. J. Indian Chem. Soc. 1958, 35, 197.
(b) Sen, A. B.; Kulkarni, Y.D. J. Indian Chem. Soc. 1957, 34, 687.
(13) Cui, D.-M.; Kawamura, M.; Shimada, S.; Hayashi, T.; Tanaka, M.
Tetrahedron Lett. 2003, 44, 4007.
In summary, we have developed an efficient direct route to
both 2- and 3-methylthiochroman-4-ones (3 and 6) via
superacid-catalyzed sequential alkylation/cyclic acylation. Ben-
(14) Clayton, S. E.; Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M.
Tetrahedron 1993, 49, 939.
Scheme 2. Proposed Mechanism
(15) Dougherty, G.; Hammond, P. D. J. Am. Chem. Soc. 1935, 57, 117.
(16) (a) Prakash, G. K. S.; Paknia, F.; Vaghoo, H.; Rasul, G.; Mathew,
T.; Olah, G. A. J. Org. Chem. 2010, 75, 2219. (b) Prakash, G. K. S.;
Paknia, F.; Narayanan, A.; Rasul, G.; Mathew, T.; Olah, G. A. J. Fluorine
Chem. 2012, 143, 292.
(17) (a) Krystenansky, J. L.; Cotteril, I. Curr. Opin. Drug Discovery Dev.
2000, 3, 454. (b) Larhed, M.; Hallberg, A. Drug Discovery Today 2001, 6,
406. (c) Microwave Methods in Organic Synthesis; Larhead, M., Olofsoon,
K., Eds.; Springer: Berlin, 2006. (d) Dallinger, D.; Kappe, C. O. Chem.
Rev. 2007, 107, 2563. (e) Larhed, M.; Moberg, C.; Hallberg, A. Acc.
Chem. Res. 2002, 35, 717. (f) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res.
2005, 38, 653. (g) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008,
41, 629. (h) Microwaves in Organic Synthesis, 3rd ed.; de la Hoz, A.,
C
DOI: 10.1021/acs.orglett.5b03172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Loupy, A., Eds.; Wiley-VCH: Weinheim, 2012. (i) Ultrasound and
Microwaves: Recent Advances in Organic Chemistry, 1st ed.; Transworld
Research Network: Kerala, 2011. (j) Ameta, C.; Ameta, K. L.; Sharma, B.
K.; Ameta, R. Microwave-Assisted Organic Synthesis. A Need of the
Day. In Green Chemistry; Ameta, S. C., Ameta, R., Eds.; Academic Press:
New York, 2013; pp 283−315.
́
́
(18) (a) Olah, G. A.; Prakash, G. K. S.; Sommer, J.; Molnar, A.
Superacid Chemistry, 2nd ed.; Wiley: Hoboken, NJ, 2009. (b) Olah, G.
A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley-
Interscience: Hoboken, NJ, 2008.
D
DOI: 10.1021/acs.orglett.5b03172
Org. Lett. XXXX, XXX, XXX−XXX