Generation of Alkyl Radicals from Thiols via Zinc Thiolates: Application for the Synthesis of gem-Difluorostyrenes

Article abstract of DOI:10.1002/adsc.202100088

Reaction of thiols with α-(trifluoromethyl)styrenes under photocatalytic conditions leading to desulfurative allylic fluorine substitution is described. The reaction is performed by treatment of thiols with benzyl zinc chloride to generate zinc thiolates

Full text of DOI:10.1002/adsc.202100088

UPDATES
DOI: 10.1002/adsc.202100088
Generation of Alkyl Radicals from Thiols via Zinc Thiolates:
Application for the Synthesis of gem-Difluorostyrenes
Vyacheslav I. Supranovich,a Vitalij V. Levin,a Vladimir A. Kokorekin,a and
Alexander D. Dilmana,*
a
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
Fax: +7 499 135–53-28
E-mail: adil25@mail.ru
Manuscript received: January 21, 2021; Revised manuscript received: March 14, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100088
which undergoes cleavage of the CÀ S bond with
Abstract: Reaction of thiols with α-(trifluorometh-
concomitant formation of strong P=S bond. The
resulting radical rapidly abstracts a hydrogen atom
yl)styrenes under photocatalytic conditions leading
to desulfurative allylic fluorine substitution is
from the starting thiol leading to the product of
described. The reaction is performed by treatment
reductive desulfurization (path a). Indeed, the facile
of thiols with benzyl zinc chloride to generate zinc
hydrogen atom transfer (HAT) between thiols and alkyl
thiolates followed by visible light induced desulfur-
radicals is a key problem for trapping of the latter
ization by means of triphenylphosphine. Radicals
radical by external π-systems (path b).[10] Successful
formed after the CÀ S bond cleavage react with the
examples of such process were described for thiols
double bond affording gem-difluorostyrenes.
generating electrophilic radicals (such as α-carbonyl-
substituted),[11] which may exhibit favorable selectivity
profile for alkene addition vs. HAT.
Keywords: Fluorine; Radicals; Photocatalysis; Alke-
Herein we describe a novel approach to generate
nesThiols
alkyl radicals directly from unprotected thiols without
Free radicals are important intermediates in organic
chemistry, and radical reactions have been widely used
for a long time.[1,2] Radicals are usually generated at
the carbon atom connected to a certain substituent such
as halogen or hydroxy group derivatized with sulfur-
based reagents.[2] Concerning cleavage of the CÀ S
bond, various derivatives of thiols have been used in
radical processes. For example, xanthates provide
ample opportunities for group transfer reactions
triggered by radical initiators.[3] We have also shown
that sulfides bearing a fluorinated aromatic group can
be used to generate alkyl radicals.[4] Recently, a
derivatization strategy based on the conversion of the
thiol group by means of an iodine (III) regent followed
by photoredox initiated radical relay process was
reported.[5,6]
The generation of radicals directly from thiol was
achieved by single electron oxidation with subsequent
Scheme 1. Generation of radicals from thiols.
interaction of the thiyl radical with phosphines or
phosphites[7,8] (Scheme 1). The reaction is believed to
proceed through short-lived neutral four-coordinate
intermediate A (known as phosphoranyl radical[8,9]),
Adv. Synth. Catal. 2021, 363, 1–6
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
their conversion into a separate organic derivative. We
Concerning the mechanism of radical generation,
propose conditions allowing to switch off the side two pathways should be considered. First, the zinc
HAT pathway. This leads to intrinsically wider scope thiolate may be oxidized by photocatalyst to give S-
of alkyl radicals, which can be involved in C,C bond centered radical, which can interact with phosphine
forming reactions. Our concept is based on in situ leading to neutral species A.[8] An alternative pathway
conversion of thiols to metal thiolates, which interact involves single electron oxidation of phosphine into
with a phosphine upon single electron oxidation. This phosphonium radical cation, which can then attack the
would allow generation of intermediate A followed by thiolate with concomitant expulsion of zinc chloride
its fragmentation. The absence of free thiol makes cation. Phosphinyl radical cations have long been
possible further productive transformations of the alkyl known,[15] but only within the last few years they have
radical such as interaction with alkenes.
found applications for the activation of alcohols and
The proposed mechanistic scenario is shown in carboxylic acids,[16] and other reactions.[17]
Scheme 2. First, thiols 1 are treated with benzyl zinc
Cyclohexylthiol 1a and styrene 2a were selected as
chloride with the formation of zinc thiolates. Indeed, model substrates and their reaction was evaluated
the zincation of thiols is rapid, and is likely to be (Table 1). The mixture of the thiol, triphenylphosphine
compatible with many functional groups by virtue of and a photocatalyst was first treated with a tetrahy-
mild reactivity profile of organozincs.[12] Interaction of drofuran solution of benzyl zinc chloride for 10 min
the zinc thiolate with triphenylphosphine in the affording a heterogeneous system, presumably due to
presence of oxidative photocatalyst generates neutral precipitation of zinc thiolate. Styrene 2a and a co-
sulfur-phosphorus intermediate A, which gives the solvent were added to give 0.25 M solution, and the
alkyl radical. As alkenes, we considered α-CF3- mixture was irradiated with blue LED. Among various
susbtituted styrenes.[13,14] After radical addition at the solvent, dichloromethane gave best result with
C=C bond, the CF3-substituted benzyl radical B is acetonitrile and DMF being inefficient (entries 2 and
reduced by the photocatalyst followed by elimination 3). The use of substoichiometric amount of
of fluoride anion affording gem-difluorinated products chlorotrimethylsilane (0.25 equiv.) was essential for
3.
reproducibility. The precise role of TMSCl is not clear
Table 1. Optimization studies.
#
Deviation from standard cndts.
Y. of 3a, %[a]
1
2
3
4
5
6
7
8
None
64[b]
trace
trace
31
45
–
–
trace
–
MeCN instead of CH2Cl2
DMF instead of CH2Cl2
1.3 equiv. of PPh3
PBu3 instead of PPh3
P(OEt)3 instead of PPh3
[Ir(dtbbpy)(ppy)2]PF6
Ir(ppy)3
9
No light
10
No Ir(III)
–
[a] Determined by 19F NMR using PhCF3 as internal standard.
[b] Isolated yield.
Scheme 2. Proposed mechanistic concept.
Adv. Synth. Catal. 2021, 363, 1–6
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
at present. Presumably, the silane may scavenge (3x). The reaction was typically complete within
fluoride anion originating from the trifluoromethyl 4 hours. However, for 1-naphthyl-substituted alkene,
group. In the absence of light or photocatalyst, no 24 hours of irradiation were required. The decreased
product was formed. Tributylphosphine was notably reactivity of this substrate may be attributed to the
less efficient, while triethylphosphite did not promote steric effect of the 1-naphthyl group, which attenuates
the reaction at all.
conjugative stabilization of radical forming at the
Under the optimized conditions, a series of thiols radical addition step. The reaction was unsuccessful
were combined with CF3-susbtituted styrenes with 4-methoxy-substituted styrene 1 furnishing an
(Scheme 3). The reaction worked with thiols generat- inseparable mixture of the expected product and the
ing primary and secondary alkyl radicals. Various hydroalkylation by-product (sequential addition of the
functional groups such as ester, PMP-protected cyclohexyl and hydrogen atom at the double bond).
hydroxy group, and phosphite were tolerated. Notably, This is presumably associated with electron-donating
ethyl ester of N-benzoylated cysteine also gave the effect of the MeO-group disfavoring SET reduction of
expected product 3k with acidic NÀ H fragment radical B (see Scheme 2), which instead undergoes
remaining unaffected. The styrene component may hydrogen atom transfer.
contain halogen (products 3q, r) and a boryl group
[a]
Scheme 3. Synthesis of difluorinated styrenes 3. Isolated yields are shown. Small amount of DMF was added to dissolve the
intermediate zinc thiolate. [b] Reaction time 24 h using 60 W LED.
Adv. Synth. Catal. 2021, 363, 1–6
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Concerning the mechanism of the alkyl radical
formation, the pathway involving the oxidation of the
phosphine seems to be more probable for the following
reasons. Measurement of oxidation potentials sug-
gested that triphenylphosphine (+0.78 V vs. SCE) is
oxidized more readily than the zinc thiolate (cyclo-
hexylSZnCl, +1.48 V vs. SCE). Moreover, ethyl
phosphite P(OEt)3, which is known to react with thiyl
radicals,[8] was ineffective under our conditions (Ta-
ble 1, entry 6). In further agreement, the Stern-Volmer
studies demonstrated fluorescence quenching of the
iridium photocatalyst by triphenylphosphine, but not
by the zinc thiolate.
In summary, a mechanistic scenario for the gener-
ation of alkyl radicals from thiols under the conditions
excluding undesired hydrogen atom transfer is de-
scribed. This is achieved by using an organozinc
reagent to completely remove the thiol hydrogen. The
phosphine serves as a recipient of sulfur, thereby
providing driving force for the cleavage of the carbon-
phosphorus bond.
References
[1] a) M. Yan, J. C. Lo, J. T. Edwards, P. S. Baran, J. Am.
Chem. Soc. 2016, 138, 12692–12714; b) S. Z. Zard, Org.
Lett. 2017, 19, 1257–1269; c) K. J. Romero, M. S.
Galliher, D. A. Pratt, C. R. J. Stephenson, Chem. Soc.
Rev. 2018, 47, 7851–7866.
[2] a) Radicals in Organic Synthesis (Eds.: P. Renaud, M. P.
Sibi), Wiley-VCH, Weinheim, 2001; b) S. Z. Zard,
Radical Reactions in Organic Synthesis, Oxford Univer-
sity Press, New York, 2004.
[3] a) B. Quiclet-Sire, S. Z. Zard, Pure Appl. Chem. 2011,
83, 519–551; b) B. Quiclet-Sire, S. Z. Zard, Chem. Eur.
J. 2006, 12, 6002–6016; c) B. Quiclet-Sire, S. Z. Zard,
Top. Curr. Chem. 2006, 264, 201–236.
[4] a) M. D. Kosobokov, M. O. Zubkov, V. V. Levin, V. A.
Kokorekin, A. D. Dilman, Chem. Commun. 2020, 56,
9453–9456; b) M. O. Zubkov, M. D. Kosobokov, V. V.
Levin, V. A. Kokorekin, A. A. Korlyukov, J. Hu, A. D.
Dilman, Chem. Sci. 2020, 11, 737–741; c) L. I. Panfer-
ova, M. O. Zubkov, V. A. Kokorekin, V. V. Levin, A.
Dilman, Angew. Chem. Int. Ed. 2021, 60, 2849–2854;
d) B. A. van der Worp, M. D. Kosobokov, V. V. Levin,
A. D. Dilman, Adv. Synth. Catal. 2021, 363, 1152–1158.
[5] Y. Wang, L.-F. Deng, X. Zhang, Z.-D. Mou, D. Niu,
Angew. Chem. Int. Ed. 2021, 60, 2155–2159.
[6] For generation of radicals via substitution at sulfurs, see:
D. Crich, Helv. Chim. Acta 2006, 89, 2167–2182.
[7] a) F. W. Hoffmann, R. J. Ess, T. C. Simmons, R. S.
Hanzel, J. Am. Chem. Soc. 1956, 78, 6414–6414; b) C.
Walling, R. Rabinowitz, J. Am. Chem. Soc. 1957, 79,
5326–5326.
[8] a) W. G. Bentrude, Acc. Chem. Res. 1982, 15, 117–125;
b) W. G. Bentrude, in: Reactive Intermediates: Volume 3
(Ed.: R. A. Abramovitch), Springer US, Boston, MA,
1983, pp. 199–298.
[9] For recent reviews, see: a) J. A. Rossi-Ashton, A. K.
Clarke, W. P. Unsworth, R. J. K. Taylor, ACS Catal.
2020, 10, 7250–7261; b) X.-Q. Hu, Y.-X. Hou, Z.-K.
Liu, Y. Gao, Org. Chem. Front. 2020, 7, 2319–2324;
c) J. Maddigan-Wyatt, J. F. Hooper, Adv. Synth. Catal.
2021, 363, 924–936.
Experimental Section
Reaction of Thiols with α-trifluoromethyl Styrenes
(General Procedure)
Photocatalyst (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.4 mg, 0.25 mol%)
and triphenyl phosphine (262 mg, 1.0 mmol, 2.0 equiv.) were
placed in a tube (Duran cat. no 261351155, Roth cat. no
K248.1, outside diameter=12 mm). The tube was evacuated
and filled with argon. Thiol 1 (0.67 mmol 1.33 equiv.) was
added followed by benzyl zinc chloride (1.9 M in THF, 350 μL,
0.67 mmol, 1.33 equiv.), and the mixture was stirred for 10
minutes at room temperature. Then, Me3SiCl (16 μL,
0.125 mmol, 0.25 equiv.), dichloromethane (1.5 mL) and
styrene 2 (0.50 mmol) were successively added [for 3d, DMF
(200 μL) was added as a co-solvent to mitigate low solubility of
the corresponding zinc thiolate]. The tube was closed with a
screw cap and irradiated for 4 hours by a 450 nm LED chip
(Hontiey royal blue 100 W) operated at 40 Watt for 3a–s, u–x
or for 24 hours operated at 60 Watt for 3t. The distance
between LED chip and the reaction tube was 1 cm. The reaction
[10] Indeed, thiols are frequently used as sources of hydrogen
towards alkyl radicals. For examples, see: a) Y. Wang,
H. M. Carder, A. E. Wendlandt, Nature 2020, 578, 403–
408; b) J. Dong, X. Wang, Z. Wang, H. Song, Y. Liu, Q.
Wang, Chem. Sci. 2020, 11, 1026–1031; c) Y. Y. Loh, K.
Nagao, A. J. Hoover, D. Hesk, N. R. Rivera, S. L.
Colletti, I. W. Davies, D. W. C. MacMillan, Science
2017, 358, 1182–1187.
[11] a) J. M. Lopp, V. A. Schmidt, Org. Lett. 2019, 21, 8031–
8036; b) L. Zhang, X. Si, Y. Yang, S. Witzel, K. Sekine,
M. Rudolph, F. Rominger, A. S. K. Hashmi, ACS Catal.
2019, 9, 6118–6123; c) Q. Qin, W. Wang, C. Zhang, S.
Song, N. Jiao, Chem. Commun. 2019, 55, 10583–10586.
[12] a) P. Knochel, N. Millot, A. L. Rodriguez, C. E. Tucker,
in Org. React., John Wiley & Sons, Inc., 2004; b) P.
Knochel, H. Leuser, L. Z. Gong, S. Perrone, F. F.
°
temperature was maintained in a range of 15–20 C by a cooling
bath. For the work-up, the mixture was poured into water
(10 mL) and extracted with hexanes (4×4 mL). The combined
organic phases were dried over Na2SO4, filtered, concentrated,
and the residue was purified by column chromatography on
silica gel.
Acknowledgements
This work was supported by the Russian Science Foundation
(project 20-13-00112).
Adv. Synth. Catal. 2021, 363, 1–6
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
Kneisel, in: The Chemistry of Organozinc Compounds
(Eds.: Z. Rappoport, I. Marek), John Wiley & Sons,
Chen, H. Yang, Org. Lett. 2019, 21, 2658–2662; g) Z.
Lin, Y. Lan, C. Wang, Org. Lett. 2019, 21, 8316–8322.
Chichester, U. K., 2006, pp. 287–394; c) A. D. Dilman, [15] a) H. Ohmori, T. Takanami, M. Masui, Tetrahedron Lett.
V. V. Levin, Tetrahedron Lett. 2016, 57, 3986–3992.
[13] F. Tian, G. Yan, J. Yu, Chem. Commun. 2019, 55,
13486–13505.
[14] For recent applications of α- CF3-styrenes as acceptors of
radicals, see: a) Y. Chen, N. Ni, D. Cheng, X. Xu,
Tetrahedron Lett. 2020, 61, 152425; b) Z. Lin, Y. Lan, C.
1985, 26, 2199–2200; b) S. Yasui, M. Tsujimoto, K.
Shioji, A. Ohno, Chem. Ber. 1997, 130, 1699–1707;
c) X. Pan, X. Chen, T. Li, Y. Li, X. Wang, J. Am. Chem.
Soc. 2013, 135, 3414–3417; d) F. Hirakawa, H. Nakaga-
wa, S. Honda, S. Ishida, T. Iwamoto, J. Org. Chem.
2020, 85, 14634–14642.
Wang, Org. Lett. 2020, 22, 3509–3514; c) R. J. Wiles, [16] a) E. E. Stache, A. B. Ertel, T. Rovis, A. G. Doyle, ACS
J. P. Phelan, G. A. Molander, Chem. Commun. 2019, 55,
7599–7602; d) H. Chen, D. Anand, L. Zhou, Asian J.
Org. Chem. 2019, 8, 661–664; e) Y. He, D. Anand, Z.
Catal. 2018, 8, 11134–11139; b) J. I. Martinez Alvarado,
A. B. Ertel, A. Stegner, E. E. Stache, A. G. Doyle, Org.
Lett. 2019, 21, 9940–9944.
Sun, L. Zhou, Org. Lett. 2019, 21, 3769–3773; f) P.-J. [17] For report from our group, see: a) V. V. Levin, A. D.
Xia, Z.-P. Ye, Y.-Z. Hu, D. Song, H.-Y. Xiang, X.-Q.
Dilman, Chem. Commun. 2021, 57, 749–752.
Adv. Synth. Catal. 2021, 363, 1–6
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

UPDATES
Generation of Alkyl Radicals from Thiols via Zinc Thiolates:
Application for the Synthesis of gem-Difluorostyrenes
Adv. Synth. Catal. 2021, 363, 1–6
Dr. V. I. Supranovich, Dr. V. V. Levin, Dr. V. A. Kokorekin,
Prof. Dr. A. D. Dilman*