Decatungstate as a direct hydrogen atom transfer photocatalyst for synthesis of trifluromethylthioesters from aldehydes

Article abstract of DOI:10.1016/j.cclet.2021.03.070

We have developed a versatile, mild protocol for trifluoromethylthiolation reactions of aldehydes with catalysis by a decatungstate hydrogen atom transfer photocatalyst under redox-neutral conditions. The protocol is highly selective, operationally simple, and compatible with a wide array of sensitive functional groups. It can be used for late-stage functionalization of bioactive molecules, which makes it convenient for drug discovery.

Full text of DOI:10.1016/j.cclet.2021.03.070

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Decatungstate as a direct hydrogen atom transfer photocatalyst for
synthesis of trifluromethylthioesters from aldehydes$
Xiaochen Wanga, Jianyang Donga, Yuxiu Liua, Hongjian Songa, Qingmin Wanga,b,
*
a
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
b
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
A R T I C L E I N F O
A B S T R A C T
Article history:
We have developed a versatile, mild protocol for trifluoromethylthiolation reactions of aldehydes with
catalysis by a decatungstate hydrogen atom transfer photocatalyst under redox-neutral conditions. The
protocol is highly selective, operationally simple, and compatible with a wide array of sensitive functional
groups. It can be used for late-stage functionalization of bioactive molecules, which makes it convenient
for drug discovery.
Received 21 January 2021
Received in revised form 19 March 2021
Accepted 25 March 2021
Available online xxx
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Aldehydes
Decatungstate photocatalyst
Redox-neutral
Hydrogen atom transfer
Trifluoromethylthiolation
Organofluorine compounds are of great importance in the fields
of medicine, agricultural chemistry, and functional materials [1,2].
The trifluoromethylthio (–SCF3) group is of particular interest
because its highly tunable lipophilicity, metabolic stability, and
strongly electron-withdrawing nature (Hansch parameter
has recently attracted much interest among synthetic chemists [8].
The Glorius group [9] reported an elegant method for obtaining
trifluoromethylthioesters from aldehydes via a hydrogen atom
transfer (HAT) process (Scheme 1B), but a noble metal photoredox
catalyst and a HAT mediator are required. The direct use of an
inexpensive HAT photo catalyst would be a more reagent- and
redox-economical strategy. More recently, the Wang group [10]
p
R = 1.44) [3] make it useful for fine-tuning the pharmacological
and pharmacokinetic properties of drug candidates [4,5]. Conse-
quently, reagents and methods for efficiently incorporating
trifluoromethylthio groups into target molecules have attracted
considerable interest in recent years [6]. However, the number of
methods for synthesis of trifluoromethylthioesters is rather
limited. In pioneering work, the groups of Man [7a], Yagupolskii
[7b], and Chen and Weng [7c] showed that trifluoromethylth-
ioesters can be synthesized by reactions of acid chlorides with Hg
(SCF3)2, NMe4SCF3, or (bpy)CuSCF3 (Scheme 1A). Because Hg
(SCF3)2 is highly toxic, NMe4(SCF3) is relatively unstable, and
stoichiometric amounts of metallic reagents are required, the
scope and utility of these reactions are limited.
reported
a method for visible-light-promoted synthesis of
trifluoromethylthioesters from aldehydes, but heat and a stoichio-
metric amount of a radical initiator are needed to trigger the
radical process, making the reaction relatively harsh (Scheme 1B).
Because aldehydes are economical and readily available, we
explored their trifluoromethylthiolation under mild conditions
using inexpensive and readily available metal photocatalysts
(Scheme 1C).
We envisioned that polyoxometalates (many of which have
high-energy excited states and can accomplish the required CÀÀH
abstraction) [11] would be ideal HAT catalysts. We were
particularly interested in tetrabutylammonium decatungstate
(TBADT, (nBu4N)4[W10O32]), a highly efficient HAT photocatalyst
that is widely used for dehydrogenation, oxidation, and conjugate
addition reactions of unactivated aliphatic CÀÀH bonds [12]. We
recently developed a protocol for photoredox deuteration and
difluoromethylthiolation reactions of aldehydes mediated by
TBADT, which is responsible for the generation of an acyl radical
[13]. Herein we report that we have succeeded in developing a
protocol that uses TBADT as a HAT photocatalyst for efficient
We speculated that trifluoromethylthioesters could be synthe-
sized by a method involving the use of photoredox catalysis which
$
Dedicated this paper to the 100th anniversary of Chemistry at Nankai University.
* Corresponding author at: State Key Laboratory of Elemento-Organic Chemistry,
Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China.
E-mail address: wangqm@nankai.edu.cn (Q. Wang).
https://doi.org/10.1016/j.cclet.2021.03.070
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: X. Wang, J. Dong, Y. Liu et al., Decatungstate as a direct hydrogen atom transfer photocatalyst for synthesis of
trifluromethylthioesters from aldehydes, Chin. Chem. Lett., https://doi.org/10.1016/j.cclet.2021.03.070

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Chinese Chemical Letters xxx (xxxx) xxx–xxx
Table 1
Optimization of the reaction conditionsa.
b
Entry
Reagent
Base
Solvent
Yield (%)
1
2
3
4
5
6
6a
6a
6a
6a
6a
6b
6c
6a
6a
6a
6a
6a
6a
6a
Na2HPO4
Na2HPO4
DBU
CH3CN
CH3CN
CH3CN
CH3OH
Acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
41
28
Á
12H2O
NR
NR
11
NR
10
52
65
70
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
—
7
Scheme 1. Trifluoromethylthiolation reactions.
8c
9c,d
10c,d,e
11c,d,e,f
12h
13
synthesis of trifluoromethylthioesters by direct functionalization
reactions of aldehydic C(O)ÀÀH bonds.
82 (77g)
NR
NR
NR
The proposed mechanism for the reaction is shown in Scheme 2.
The reaction is initiated by photoexcitation of TBADT (2) followed
by intersystem crossing to produce triplet excited state 3, which
has a lifetime of 55 ns [14] and serves as the HAT catalyst. Excited
state 3 selectively abstracts the formyl H atom of 4-methylben-
zaldehyde (1a) to afford singly reduced decatungstate 4 and
nucleophilic formyl radical 5. Radical 5 then readily reacts with the
electrophilic N-(trifluoromethylthio)phthalimide (PhthSCF3, 6a) to
afford desired product 1 upon elimination of a phthalimide radical
Phthꢀ (7). Finally, with Na2HPO4 as a base, 7 is reduced by
decatungstate 4 to 8, with simultaneously regeneration of the
active HAT photocatalyst 2.
We began our study by using 1a and 6a as model substrates to
optimize the reaction conditions (Table 1). We were pleased to find
that in the presence of 4 mol% TBADT and 1.5 equiv. of disodium
phosphate as a base, irradiation of an acetonitrile solution of 1a
and 6a with a 390 nm blue LED at room temperature under argon
provided a 41% yield of desired product 1 (entry 1). Screening of
14i
Na2HPO4
NR = no reaction.
a
General conditions, unless otherwise noted: 1a (0.2 mmol),
6
(0.4 mmol),
TBADT (0.008 mmol), base (0.3 mmol), solvent (1 mL), Ar, r.t., 48 h.
b
Determined by 19F NMR spectroscopy with fluorobenzene as an internal
standard.
c
d
e
f
Amount of TBADT, 0.016 mmol.
Amount of 6a, 0.6 mmol.
CH3CN volume, 0.5 mL.
Reaction time, 96 h.
Isolated yield.
g
h
i
No TBADT.
No light.
With satisfactory conditions (Table 1, entry 11) in hand, we
explored the scope of the reaction with respect to the aldehyde
(Scheme 3). First, we tested aldehyde substrates with various
substituents on the aromatic ring and found that we could obtain
the corresponding trifluoromethylthioesters. For example, para-
substituted aryl aldehydes gave target products 1 and 9–20 in 24%–
94% yields, and meta-substituted aldehydes gave 21–25 in yields of
35%–75%. In general, substrates with electron-donating groups
gave better yields than those with electron-neutral groups.
Notably, reaction of an aldehyde bearing a tertiary CÀÀH bond
selectively gave 10 (67% isolated yield), the product of CÀÀH
trifluoromethylthiolation at the aldehydic C(O)ÀÀH bond; no
products of CO dissociation were observed [15]. Aryl aldehydes
containing alkyl groups (1, 9–11), ethers (13–18), phenyl groups
(12 and 22), and an ester (30) were found to be compatible with the
reaction conditions, giving the corresponding products in moder-
ate to high yields. Interestingly, several relatively sensitive yet
versatile functional groups—boronic esters (19 and 25) and an
alkene (20)—tolerated the trifluoromethylthiolation conditions
well, which shows the potential utility of this protocol for
medicinal and synthetic chemistry applications. Polysubstituted
aldehydes were also suitable substrates (26–31), and naphthalde-
hydes afforded target products 32 and 33 in yields of 37% and 55%,
respectively. Aware of the important role of heteroaromatic
moieties in drug compound scaffolds, we were pleased to find
that under our trifluoromethylthiolation conditions, N-heterocy-
clic substrates were also tolerated, giving 34 and 35 in 42% and 32%
yield. However, our experiments uncovered a limitation of this
reaction: substrates containing electron-withdrawing groups or
ortho substituents on the phenyl ring were incompatible with the
various alternative bases revealed that Na2HPO4 12H2O gave a low
Á
yield, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) failed to
afford any of the target product (entries 2 and 3). Methanol and
acetone proved to be inferior solvents to CH3CN (entries 4 and 5).
Other SCF3 sources (6b and 6c) gave lower yields than 6a (entries 6
and 7). We also varied the catalyst loading, SCF3 reagent
stoichiometry, solvent volume, and reaction time (entries 8–11)
gratifyingly, these experiments greatly improved the yield (entry
11). Control experiments demonstrated that TBADT, base, and light
were all essential for the success of the reaction (entries 12–14).
Scheme 2. Proposed mechanism of the trifluoromethylthiolation reaction.
2

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X. Wang, J. Dong, Y. Liu et al.
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Scheme 3. Substrate scope with respect to the aldehyde.
reaction conditions, possibly because of the steric bulk of TBADT
and its tendency to react with nucleophilic sites.
Because of the biological relevance of fluoroalkylthio groups
[16,4b], a mild, selective method for late-stage introduction of
trifluoromethylthio groups into complex molecules is highly
desirable for drug modification studies. We found that our
protocol could readily be used for trifluoromethylthiolation of
aromatic aldehydes such as fenbufen and ibuprofen derivatives to
afford 36 and 37 (Scheme 4A). The successful late-stage
functionalization of these two drug derivatives, which contain
ester and carbonyl groups and a tertiary CÀÀH bond, demonstrates
the high chemoselectivity and functional group tolerance of our
method.
Scheme 5. Mechanistic experiments.
To demonstrate the viability of the method for preparative
purposes, we carried out a gram-scale trifluoromethylthiolation
reaction of p-anisaldehyde (5 mmol) under the standard con-
ditions, except that the amount of catalyst was reduced to 4 mol%;
the reaction was complete within 96 h and gave 13 in 71% yield
(Scheme 4B).
Next we conducted some mechanistic studies (Scheme 5) in
support of the proposed pathway shown in Scheme 2. When
TEMPO ((tetramethylpiperidin-1-yl)oxyl) or 1,1-diphenylethylene
was used as a radical scavenger, the formation of 13 was
completely inhibited. TEMPO adduct 2,2,6,6-tetramethylpiperi-
din-1-yl 4-methoxybenzoate (38) was isolated in 21% yield, and
radical trapping product 1-(4-methoxyphenyl)-3,3-diphenylprop-
2-en-1-one (39) was detected by mass spectrometry. These results
suggest that acyl radical 5 was generated, and they clearly point to
a radical pathway. Moreover, a light/dark experiment showed that
product 13 did not form in the dark (Supporting information),
which implies that light was essential and that any chain
propagation process was short-lived.
In summary, we have developed a versatile photoredox-
mediated HAT protocol for direct trifluoromethylthiolation of
aldehydes. The mild reaction occurred at room temperature with
the aldehyde as the limiting reagent, tolerated various functional
groups, and had a broad substrate scope. Commercially available,
stable aldehydes were used as the carbonyl source, and the HAT
photocatalyst was TBADT, an inexpensive complex of an earth-
abundant metal. This expedient alternative to traditional methods
of synthesizing trifluoromethylthioesters can be expected to be
Scheme 4. Applications of the protocol.
3

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X. Wang, J. Dong, Y. Liu et al.
Chinese Chemical Letters xxx (xxxx) xxx–xxx
useful for late-stage functionalization of natural products and drug
molecules.
[7] (a) E.H. Man, D.D. Coffman, E.L. Muetterties, J. Am. Chem. Soc. 81 (1959) 3575–
3577;
(b) M.M. Kremlev, W. Tyrra, D. Naumann, Y.L. Yagupolskii, Tetrahedron Lett. 45
(2004) 6101–6104;
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgments
(c) M. Zhang, J. Chen, Z. Chen, Z. Weng, Tetrahedron 72 (2016) 3525–3530.
[8] (a) J.M.R. Narayanam, C.R.J. Stephenson, Chem. Soc. Rev. 40 (2011) 102–113;
(b) C.K. Prier, D.A. Rankic, D.W.C. MacMillan, Chem. Rev. 113 (2013) 5322–
5363;
(c) J. Xuan, Z.G. Zhang, W.J. Xiao, Angew. Chem. Int. Ed. 54 (2015) 15632–
15641;
(d) N.A. Romero, D.A. Nicewicz, Chem. Rev. 116 (2016) 10075–10166;
(e) Q.Q. Zhou, Y.Q. Zou, L.Q. Lu, W.J. Xiao, Angew. Chem. Int. Ed. 58 (2019) 1586–
1604;
We are grateful to the National Natural Science Foundation of
China (Nos. 21732002, 22077071) for generous financial support
for our programs.
(f) R.S.J. Proctor, R.J. Phipps, Angew. Chem. Int. Ed. 58 (2019) 13666–13699.
[9] S. Mukherjee, T. Patra, F. Glorius, ACS Catal. 8 (2018) 5842–5846.
[10] M. Wang, X. Zhu, X. Zhang, et al., Org. Biomol. Chem. 18 (2020) 5918–5926.
[11] F. Scandola, C.A. Bignozzi, M.T. Indelli, Photosensitization and Photocatalysis
Using Inorganic and Organometallic Compounds, Kluwer Academic,
Dordrecht, The Netherlands, 1993.
Appendix A. Supplementary data
[12] (a) R.F. Renneke, C.L. Hill, J. Am. Chem. Soc. 108 (1986) 3528–3529;
(b) R.F. Renneke, C.L. Hill, Angew. Chem. Int. Ed. Engl. 27 (1988) 1526–1527;
(c) D. Ravelli, S. Protti, M. Fagnoni, Acc. Chem. Res. 49 (2016) 2232–2242;
(d) D.M. Schultz, F. Levesque, D.A. DiRocco, et al., Angew. Chem. Int. Ed. 56
(2017) 15274–15278;
Supplementarymaterialrelatedto thisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2021.03.070.
References
(e) S.D. Halperin, D. Kwon, M.E. Holmes, et al., Org. Lett. 17 (2015) 5200–5203;
(f) J.G. West, D. Huang, E.J. Sorensen, Nat. Commun. 6 (2015) 10093–10099;
(g) I.B. Perry, T.F. Brewer, P.J. Sarver, et al., Nature 560 (2018) 70–75;
(h) P.J. Sarver, V. Bacauanu, D.M. Schultz, et al., Nat. Chem. 12 (2020) 459–467;
(i) S. Esposti, D. Dondi, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed. 46 (2007)
2531–2534;
(j) M.D. Tzirakis, M. Orfanopoulos, J. Am. Chem. Soc. 131 (2009) 4063–4069;
(k) L. Capaldo, M. Fagnoni, D. Ravelli, Chem. Eur. J. 23 (2017) 6527–6530;
(l) M. Meanwell, J. Lehmann, M. Eichenberger, R.E. Martin, R. Britton, Chem.
Commun. 54 (2018) 9985–9988;
[1] (a) V.N. Boiko, Beilstein J. Org. Chem. 6 (2010) 880–921;
(b) F. Toulgoat, S. Alazet, T. Billard, Eur. J. Org. Chem. (2014) 2415–2428;
(c) X.H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 115 (2015) 731–764;
(d) C. Ni, J. Hu, Chem. Soc. Rev. 45 (2016) 5441–5454.
[2] (a) D.T. Wong, K.W. Perry, F.P. Bymaster, Nat. Rev. Drug Discov. 4 (2005) 764–
774;
(b) W.K. Hagmann, J. Med. Chem. 51 (2008) 4359–4369;
(c) K.L. Kirk, Org. Process Res. Dev. 12 (2008) 305–321;
(d) N.A. Meanwell, J. Med. Chem. 54 (2011) 2529–2591.
[3] (a) A. Leo, C. Hansch, D. Elkins, Chem. Rev. 71 (1971) 525–616;
(b) L.M. Yagupol’skii, A.Y. Ilchenko, N.V. Kondratenko, Russ. Chem. Rev. 43
(1974) 32.
(m) P. Fan, C. Zhang, Y. Lan, et al., Chem. Commun. 55 (2019) 12691–12694;
(n) Y. Kuang, H. Cao, H. Tang, et al., Chem. Sci. 11 (2020) 8912–8918;
(o) P. Fan, Y. Lan, C. Zhang, C. Wang, J. Am. Chem. Soc. 142 (2020) 2180–2186;
(p) P. Fan, C. Zhang, L. Zhang, C. Wang, Org. Lett. 22 (2020) 3875–3878.
[13] (a) J. Dong, X. Wang, Z. Wang, et al., Chem. Sci. 11 (2020) 1026–1031;
(b) J. Dong, F. Yue, X. Wang, et al., Org. Lett. 22 (2020) 8272–8277.
[14] V. De Waele, O. Poizat, M. Fagnoni, A. Bagno, D. Ravelli, ACS Catal. 6 (2016)
7174–7182.
[15] (a) C.M. Jensen, K.B. Lindsay, R.H. Taaning, et al., J. Am. Chem. Soc. 127 (2005)
6544–6545;
(b) S.A. Moteki, A. Usui, S. Selvakumar, T. Zhang, K. Maruoka, Angew. Chem. Int.
Ed. 53 (2014) 11060–11064.
[16] K. Larsson, L. Rosenhall, Clin. Exp. Allergy 26 (Suppl 4) (1996) 18–19.
[4] (a) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320–330;
̀
(b) J. Wang,M. Sanchez-Rosello’,J.L. Aceña, et al., Chem. Rev.114 (2014) 2432–2506.
[5] C. Hansch, A. Leo, R.W. Taft, Chem. Rev. 91 (1991) 165–195.
[6] (a) T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 115 (1993) 2156–2164;
(b) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem., Int. Ed. 46 (2007) 754–
757;
(c) F. Baert, J. Colomb, T. Billard, Angew. Chem., Int. Ed. 51 (2012) 10382–10385;
(d) B. Langlois, D. Montégre, N. Roidot, J. Fluorine Chem. 68 (1994) 63–66;
(e) C. KimmyCao, E. Tretyakov, C. Chen, Green Synth. Catal. 2 (2021) 62–65.
4