1,3-Carbothiolation of 4-(trifluoromethyl)-p-quinols: A new access to functionalized (trifluoromethyl)arenes

Article abstract of DOI:10.1021/ol403096g

A new strategy, the 1,3-carbothiolation/aromatization, for the synthesis of functionalized (trifluoromethyl)arenes has been developed that enables the regioselective introduction of two different functional groups onto an aromatic ring in the meta-position to each other in a single step.

Full text of DOI:10.1021/ol403096g

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6242–6245
1,3-Carbothiolation of
4‑(Trifluoromethyl)‑p‑Quinols:
A New Access to Functionalized
(Trifluoromethyl)arenes
Xiao Liu, Ling Pan,* Jinhuan Dong, Xianxiu Xu, Qian Zhang, and Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun 130024, China
panl948@nenu.edu.cn; liuqun@nenu.edu.cn
Received October 29, 2013
ABSTRACT
A new strategy, the 1,3-carbothiolation/aromatization, for the synthesis of functionalized (trifluoromethyl)arenes has been developed that enables
the regioselective introduction of two different functional groups onto an “aromatic ring” in the meta-position to each other in a single step.
Organofluorine compounds have received increasing
interest because of their higher bioavailability compared
to that of the corresponding nonfluorinated analogues.1,2 Thus,
over the past two decades, (trifluoromethyl)trimethylsilane
(TMSCF3)3 has been widely applied since its first synthetic
application as a nucleophilic trifluoromethylating reagent.3b
Different from numerous methods for the synthesis of
trifluoromethylated arenes that rely on substitution of a
preexisting aromatic ring,4 in 1989, Stahly and Bell de-
scribed the monotrifluoromethylation of p-quinones to give
4-(trifluoromethyl)-p-quinols5a as precursors of (trifluoromethyl)-
arenes.5 More recently, Hu and co-workers revealed an
unprecedented vicinal trifluoromethylation/iodination of
arynes, which can introduce CF3 and I groups onto an
aromatic ring in a single step.6 Herein, a new reaction, the
1,3-carbothiolation/aromatization of 4-CF3-p-quinol deriva-
tives 1 (Figure 1), is described (Scheme 1). This reaction
allows the regioselective introduction of two different func-
tional groups onto an aromatic ring in the meta-position to
each other (meta-double functionalization) and therefore
enables the construction of functionalized CF3-arenes4ꢀ6
in a single operation with readily available 1 as the nonaro-
matic precursors and ketene dithioacetals 2 (Figure 1). The
latter are versatile intermediates in organic synthesis,7 both
as carbon and sulfur nucleophiles.7a,8a,8b
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
€
In the present research, the model reaction of
4-(trifluoromethyl)-p-quinol silyl ether 1a with 3,3-bis-
(methylthio)-1-phenylprop-2-en-1-one 2a (Figure 1) was
Rev. 2008, 37, 320. (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
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J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975. (d) Prakash, G. K. S.;
Jog, P. V; Batamack, P. T. D.; Olah, G. A. Science 2012, 338, 1324.
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Chem. Soc. 1989, 111, 393.
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Stahly, G. P.; Jackson, A. J. Org. Chem. 1991, 56, 5472. (c) Singh, R.;
Czekelius, C.; Schrock, R. R.; Muller, P.; Hoveyda, A. H. Organome-
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first investigated using CuBr2, Cu(OAc)2, SnCl4 5H2O,
3
SnCl4, AlCl3, TfOH (triflic acid), Pd(OAc)2, BF3 Et2O,
3
(6) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.; Zhao, J.; Hu, J. J. Am.
Chem. Soc. 2013, 135, 2955(10 examples, 35ꢀ86% yields), using excess
[AgCF3], CsF, TMP (2,2,6,6-tetramethylpiperidine), and 1-iodophenyl-
acetylene (as iodine source).
(7) For recent reviews, see: (a) Pan, L.; Bi, X.; Liu, Q. Chem. Soc. Rev.
2013, 42, 1251. (b) Pan, L.; Liu, Q. Synlett 2011, 1073. For recent reports,
see: (c) Xu, X.; Zhang, L.; Liu, X.; Pan, L.; Liu, Q. Angew. Chem., Int.
Ed. 2013, 52, 9271. (d) Li, Y.; Xu, X.; Tan, J.; Xia, C.; Zhang, D.; Liu, Q.
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Soc. 2012, 134, 18245.
r
10.1021/ol403096g
Published on Web 11/21/2013
2013 American Chemical Society

benzyl, or n-butyl groups on the ketene dithioacetyl moiety.
It was noted that the reaction of 1a with R-cinnamoyl ketene
dithioacetal 2i showed a good tolerance for the cinnamoyl
group giving 30ai in high yield. Moreover, all reactions were
completed within 0.4ꢀ2.4 h except for the reaction of 1a
with R-cyano ketene dithioacetal 2h, which led to p-quinol
and 4-hydroxy-4-(trifluoromethyl)cyclohexa-2,5-dienone in
70% yield, instead of 3ah. Thus, the desired sulfide 3ah was
prepared under identical conditions as above but catalyzed
by SnCl4 5H2O. In products 3/30, 30ag, 30ai, and 30akꢀ30am
3
exist primarily in their enol forms, whereas others, except for
3ah, in the tautomeric ketoꢀenol forms.10
All of the functionalized (trifluoromethyl)arenes 3/30
show that an (alkylthiocarbonyl)methyl and an alkylthio
group can be introduced into the ortho and para positions
of the electron-deficient (trifluoromethyl)benzene ring.
This efficient domino sequence comprises a fundamentally
new way to synthesize (trifluoromethyl)arenes having high
structural complexity.1,4ꢀ6 Fortunately, the scope of the
synthesisof functionalized (trifluoromethyl)arenes4 under
optimized conditions (Scheme 1, for products 4aa) gave
further powerful support for the efficiency of the double
functionalization/aromatization reaction.
The corresponding functionalized (trifluoromethyl)-
arenes 4aaꢀag, 4ai, 4aj, 4ba, 4ca, 4da, 4dg, 4ea, and4akꢀam
were synthesized in high-to-excellent yields (except for 4ea in
40% yield due to the steric hindrance of the bulky t-Bu
group) under similar reaction conditions as the synthesis of
3 but in the presence of TMSCl (Scheme 1). Similar to the
preparation of 3ah, 4ah was obtained in high yield under
Figure 1. Selected 4-(trifluoromethyl)-p-quinols and ketene
dithioacetals.
and In(OTf)3 as the catalysts, respectively.7,8 After careful
screening of the reaction conditions (for details, see the
Supporting Information), it was found that, when cata-
lyzed by In(OTf)3, a mixture of (trifluoromethyl)arenes
3aa/30aa(inthetautomericketoꢀenol form) wereobtained
in 95% overall yields by reaction in DCE (1,2-dichlor-
oethane, Scheme 1), whereas, in the presence of TMSCl
(trimethylsilyl chloride) and catalyzed by In(OTf)3,
(trifluoromethyl)arene 4aa was produced in 92% yield
(Scheme 1). However, under identical conditions for 6 h
but promoted only by TMSCl (2.0 equiv), no reaction
occurred for reaction of 1a with 2a (Table S1, entry 14,
Supporting Information), and no transformation of
3aa/30aa to 4aa was observed. These results indicate that
TMSCl can accelerate the reaction.
identical conditions but catalyzed by SnCl4 5H2O in the
3
absence of TMSCl. For the formation of CF3-arenes 4, the
electron-donating alkyl substituents on the p-quinol ring of
substrates 1b, 1c, and 1e did not affect the regioselectivity
of the reaction (Scheme 1). In addition, 4-(trifluoromethyl)-
4-(trimethylsilyloxy)naphthalen-1(4H)-one 1d was also
proved to be the suitable substrate (Scheme 1, products
4da and 4dg). Clearly, our new method based on the
tandem 1,3-carbothiolation/aromatization sequence is
flexible and opens up new possibilities for the construction
of valuable polyfunctionalized arenes.
Thus, (trifluoromethyl)arenes 3 and 4, which also share
structural features of aryl sulfides, R-aryl ketones, R-aryl
nitriles, and related structural motif,11ꢀ14 are obtained
selectively under controllable conditions with or without
the addition of TMSCl. In addition, products 3 also have
the β-ketothioester motif, allowing straightforward access,
in principle, to a series of functional groups such as ketones,
The successful construction of CF3-bearing aryl sulfides
3aa/30aa and 4aa significantly extends the synthetic utility
of the readily available 4-(trifluoromethyl)-p-quinol
derivatives5 and adds a new entry to the chemo- and
regioselective construction of polyfunctionalized arenes
from readily available nonaromatic precursors.4ꢀ6,9
Therefore, the scope of the meta-double-functionalization
of 4-CF3-p-quinol derivatives 1 with ketene dithioacetals 2
was next examined. As a result, under optimal conditions
(Scheme 1, for products 3aa/30aa and 4aa), a series of
functionalized CF3-arenes was prepared, and the results
are summarized in Scheme 1.
According to the experimental results (Scheme 1),
methyl aryl sulfides 3aa/30aaꢀ3ac/30ac with phenacyl sub-
stituents on the aryl ring were obtained in excellent yields
from reactions of 1a with 2aꢀc, respectively. Similarly,
alkyl aryl sulfides 3ad/30ad and 3af/30af with ethylthio and
benzylthio groups were prepared in high yields from
reactions of 1a with 2d and 2f. Similarly, sulfides 30ag
and 30akꢀ30am were prepared in high yield from the
reactions of 1a with the corresponding R-acetyl ketene
dithioacetals 2g and 2kꢀm having two methyl, ethyl,
(10) CCDC 906801 (30aa) and CCDC 896680 (4aa) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ddcd.cam.ac.uk/data_request/cif.
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Org. Lett., Vol. 15, No. 24, 2013
6243

Scheme 1. Synthesis of Functionalized (Trifluoromethyl)arenesa,b
a Conditions for 3/30: 1 (0.60 mmol), 2 (0.50 mmol), In(OTf)3 (20 mol %), DCE (2 mL), 70 °C, 0.4ꢀ2.4 h. b Conditions for 4: 1 (0.60 mmol), 2
(0.50 mmol), In(OTf)3, (30 mol %), TMSCl (2.0 equiv), DCE (2 mL), 70 °C, 0.5ꢀ2.0 h. c Catalyzed by SnCl4 5H2O (30 mol %) and reacted for 10 h.
3
d Catalyzed by SnCl4 5H2O (30 mol %) in THF (2.0 mL) in the absence of TMSCl and reacted for 24 h.
3
aldehydes, esters, amides and R-hydroxy-β-ketothioesters
upon a single transformation.15,16 Fortunately, the chemo-
selective oxidation of 4ag, 4dg, and 4am to the correspond-
ing aryl aldehydes 5 was also successful (Scheme 2).17
On the basis of the above results (Scheme 1), a mechan-
ism for the formation of 3 and 4 is proposed (Scheme 3,
with 3aa and 4aa as an example). The overall process
involves (1) hydrolysis of ketene dithioacetal 2a to release
methanethiol under acidic conditions in the presence of
water (moisture);7a,e,18 (2) formation of complex I from 1a,
In(OTf)3 and methanethiol;8a (3) addition of methanethiol
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6244
Org. Lett., Vol. 15, No. 24, 2013

Scheme 2. Synthesis of (Trifluoromethyl)aryl Aldehydes 5
Scheme 3. Proposed Mechanism for Formation of 3 and 4
at the carbonyl group of I in a pseudointramolecular
manner to give intermediate II;8a,14,19 (4) attack of the
nucleophilic R-C of 2a at II in a SN20 manner,7a,b,8a,20 along
with the release of water to produce thionium III; and
finally, (5) further transformation involving intramolecu-
lar thiophilic attack of the silyloxy oxygen (III to IV),21
elimination of trimethyl(methylthio)silane (IV to V) and
subsequent aromatization to give 3aa or further to give 4aa
in the assistance of TMSCl.
Clearly, the above transformation would benefit from
reincorporation of the ketene dithioacetals 2 into the
products in the form of an efficient recycling of the
alkylthiol and trimethyl(methylthio)silane generated in
situ to enable further transformations. Accordingly, the
synthesis of functionalized CF3-arenes described in this
study represents a new carbothiolation reaction,22,23 the
catalytic intermolecular 1,3-carbothiolation, through
meta-double functionalization of the nonaromatic precursors.
Significantly, the 1,3-carbothiolation enables two different
functional groups to be introduced into the aromatic ring in
the ortho and para positions to an electron-withdrawing
trifluoromethyl group, which has been a tough challenge in
chemistry.
In summary, a new strategy for the synthesis of functio-
nalized trifluoromethyl arenes with readily available
4-(trifluoromethyl)-p-quinol derivatives as the nonaromatic
precursors has been developed. The reactions can be carried
out under mild reaction conditions to afford a series of
(trifluoromethyl)arenes with important structural features,
including aryl sulfides, R-arylated carbonyl and nitrile
compounds, and β-ketothioesters in good to excellent
yields in most cases in a single operation via a tandem
1,3-carbothiolation/aromatization sequence. Further inves-
tigations to demonstrate the utility of the intermolecular
1,3-carbothiolation reaction are in progress.
Acknowledgment. Financial support of this research by
the National Natural Sciences Foundation of China
(21072027, 21172030, 21272034, and 21202015) is greatly
acknowledged.
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Nature 2012, 490, 208.
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ꢀ
Supporting Information Available. Experimental pro-
cedures and analytical and spectral data for all the new
compounds. CCDC 906801 (30aa) and CCDC 896680
(4aa). This material is available free of charge via the
Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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