Metal-free photocatalytic thiol-ene/thiol-yne reactions

Article abstract of DOI:10.1039/c8ob02313a

The organic photocatalyst (9-mesityl-10-methylacridinum tetrafluoroborate) in the presence of visible light is used to initiate thiol-ene and thiol-yne reactions. Thiyl radicals are generated upon quenching the photoexcited catalyst with a range of thiols

Full text of DOI:10.1039/c8ob02313a

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Metal-free photocatalytic thiol–ene/thiol–yne
reactions†
Cite this: DOI: 10.1039/c8ob02313a
Sarbjeet Kaur, Gaoyuan Zhao, Evan Busch and Ting Wang
*
The organic photocatalyst (9-mesityl-10-methylacridinum tetrafluoroborate) in the presence of visible
light is used to initiate thiol–ene and thiol–yne reactions. Thiyl radicals are generated upon quenching the
photoexcited catalyst with a range of thiols. The highlighted mild nature of the reaction conditions allows
a broad substrate scope of the reactants. Relying on this efficient metal-free condition, both thiol–ene
and thiol–yne reactions between carbohydrates and peptides could be realized in excellent yields.
Received 18th September 2018,
Accepted 10th October 2018
DOI: 10.1039/c8ob02313a
rsc.li/obc
The formation of a carbon–sulfur bond (C–S) is important acridinium tetrafluoroborate14 (Scheme 1). This photoredox
because organosulfur moieties are widely represented within process driven by the organic photocatalyst is synthetically
natural products, pharmaceuticals and modern materials.1,2 complementary to both traditional (using UV irradiation or
Among the various strategies of C–S bond formation, radical thermolysis of a radical initiator) and transition metal cata-
thiol–ene and thiol–yne reactions have been widely carried out lyzed approaches. In particular, the metal-free process could
in areas of bioconjugate chemistry, polymer science and potentially benefit peptide and glycoprotein chemistry, since
pharmaceutical chemistry.3,4 The atom economic process pro- certain polypeptide sequences and proteins have been shown
vides efficient access to sulfur containing products, fulfilling to interfere with transition metal mediated processes.15
the “click” chemistry concept.5 Traditionally, the radical thiol–
ene/thiol–yne reaction is promoted by UV light or a radical
initiator. However, it requires either stoichiometric reagents or
a specialized UV photo-apparatus. Recently, visible-light photo-
redox catalysis6 has been a leading efficient approach for
forming C–S bonds.7 In 2013, Yoon developed a transition
metal based photocatalytic thiol–ene reaction, where house-
hold visible light sources were used as a convenient alternative
to UV irradiation.8 One year later, Stephenson reported a
similar photocatalytic thiol–ene reaction by using the tri-
chloromethyl radical as a radical mediator.9 In addition to the
2+
Ru(bpy)3 catalysts, other types of catalysts, both metal-based
and metal-free catalysts, were also applied for the visible-light-
mediated thiol–ene reaction.10 Moreover, Ananikov reported
the first visible-light-mediated metal-free radical thiol–yne
reaction using Eosin Y as the photocatalyst, furnishing a range
of vinyl sulfides in good yields and selectivity.11 The visible
light photoredox catalysis provided a significantly milder
approach, which makes the thiol–ene/thiol–yne reaction
potentially useful in bioconjugation and polymer synthesis.12
Continuing our interest in organic photocatalysis,13 we report
herein a visible-light-mediated thiol–ene/thiol–yne reaction
initiated by the organic photocatalyst 9-mesityl-10-methyl-
Department of Chemistry, University at Albany, State University of New York,
1400 Washington Ave, Albany, New York 12222, USA. E-mail: twang3@albany.edu
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02313a
Scheme 1 Radical thiol–ene/thiol–yne reactions.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization studies for the thiol–ene reaction of benzyl mer-
We initiated our studies by examining the thiol–ene reac-
tion between benzyl mercaptan 1 and allyl alcohol 2. After an
investigation of organic photocatalysts and reaction solvents,
we were delighted to find that several catalysts could success-
fully initiate the photocatalytic thiol–ene reaction under blue
light-emitting diode (LED) irradiation in a variety of solvents
(Table 1, entries 1–14). Among them, 9-mesityl-10-methyl-
acridinium tetrafluoroborate (A) in acetonitrile has given the
best outcome, providing 90% isolated yield of the thiol–ene
adduct 3 (Table 1, entry 3). It is worth noting that only
minimum excess (1.2 equiv.) of the alkene substrate is
required for the complete conversion of thiol to the corres-
ponding product. Control experiments (Table 1, entries 15 and
16) confirmed that both the catalyst and light irradiation are
essential.
Encouraged by these results, we next evaluated the scope of
the photocatalytic thiol–ene reaction. Scheme 2 summarizes
experiments probing a variety of thiols (4) and olefins (5).
Under the optimized reaction conditions, primary thiols
(benzyl mercaptan, para-methoxy benzyl mercaptan, methyl
thioglycolate, and cysteine derivative) reacted with allyl alcohol
efficiently to generate hydrothiolated products (3, 7, 8, and 9)
in high yields (82%–90%). To our delight, more steric hindered
secondary thiols and tertiary thiols also produced thiol–ene
adducts (10–13) successfully in good yields (77%–90%). In
addition, aromatic thiols could also be converted into the
corresponding aryl thioether (14) in high yield (88%). The
method was then applied to the reaction to different alkenes
captan with allyl alcohola
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
B
CH2Cl2
THF
MeCN
DMF
1,4-Dioxane
PhMe
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
62
90
49
53
83
55
83
69
80
0
30
33
0
0
0
9
C
10
11
12
13
14
15
16c
Rhodamine 6G
Riboflavin
Eosin Y
Rose Bengal
Methylene blue
None
A
a Reactions conducted by irradiating 1 (0.5 mmol), 2 (0.6 mmol), and
photocatalyst (1 mol%) in MeCN (1 mL) with two 12 W, 450 nm light-
emitting diode (LED) flood lamps for 6 h. b Isolated yield. c Reaction
conducted in the dark.
Scheme 2 Scope of the thio-ene reaction.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 3 Photocatalytic thiol–ene conjugations.
(5). We were delighted to find that both styrenes and aliphatic cosyl thiols and an aspartic acid derivative, giving the corres-
alkenes could react smoothly to afford the corresponding pro- ponding S-linked glycoconjugates (24–27) in good yields (73%–
ducts (15–19) in good yields (76%–87%). Moreover, this radical 85%).19 Moreover, glucosyl thiols could also be efficiently
thiol–ene process is compatible with a variety of functional coupled with carbohydrate derivatives, nucleoside derivatives,
groups, such as ester (20, 86%), formyl amide (21, 82%), and N-terminus functionalized dipeptides, affording S-linked
alcohol (22, 85%), and silane (23, 80%). In all cases, high anti- carbohydrate mimic 28, S-linked glyconucleoside 29 and glyco-
Markovnikov regioselectivity was observed, which is consistent peptide 30 in yields of 91%, 78% and 79%, respectively.19
with the proposed radical reaction process.
These examples further demonstrated the potential utility of
Having demonstrated the high efficiency of this thiol–ene this synthesis method for bioconjugation. The reverse fashion
reaction, we next focused on the applicability of this chemistry of coupling between a variety of alkenes and a cysteine deriva-
to the synthesis of glycoconjugates from glycosyl thiols tive also provided excellent yields of the conjugated products
(Scheme 3). Glycoconjugates are important tools for the (Scheme 3b, 31–35, 75%–90%).
exploration of many biological processes.16 Particularly,
We next tested this catalytic system on a thiol–yne reaction
S-linked glycoconjugates have become useful analogs of glyco- (Scheme 4). Ideally, the first hydrothiolation between thiol (36)
peptides and glycoproteins because of their improved chemi- and alkyne (37) would provide a vinyl sulfide product 38a,
cal stability and enzymatic resistance.17,18 To our delight, the which could react with another molecule of thiol (36) to
thiol–ene reaction occurred smoothly between a variety of gly- furnish the double hydrothiolation product 38b (Scheme 4,
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 4 Photocatalytic thiol–yne reactions. a Reactions irradiated with two 12 W, 450 nm light-emitting diode (LED) flood lamps for 14 h.
b Reactions irradiated with two 12 W, 450 nm light-emitting diode (LED) flood lamps for 2 h.
Scheme 5 Photocatalytic thiol–yne conjugations.
eqn (a)). However, we found that the double hydrothiolation stoichiometric amounts of thiol (36) were used in the reaction,
products were favored when less steric hindered thiols were a mixture of 38a and 38b was still obtained. However, the vinyl
used in the reaction, providing corresponding adducts 39–42 sulfides (38a) could be synthesized selectively when more steri-
in good yields (72%–95%). It is difficult to make the reaction cally hindered thiols were used as starting materials, affording
stay in the first hydrothiolation stage. Even though less than a mixture of E/Z isomers of the resulting vinyl sulfides 43–46
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 6 Proposed mechanism.
in good yields (70%–83%). In the case of thiophenol, the reac- molecule of oxygen. In the thiol–yne reaction, the photo-
tion process could be controlled by reaction time and reagent catalytic-generated thiol radical reacted with alkyne to generate
amount. Vinyl sulfide 47 could be isolated in 63% after a vinyl radical, which would abstract a hydrogen atom from
2 hours of irradiation of blue LED light with stoichiometric thiol to furnish the hydrothiolation product 58A. This vinyl
amounts of thiophenol. Extended reaction time (14 hours) and sulfide could react with another thiol radical to give the
excess thiophenol (4 equiv.) would result in a double hydro- double hydrothiolation product 58B (Scheme 6b).
thiolation product 48 in 96% yield (Scheme 4, eqn (b)).
In summary, we have reported a visible light promoted
We then applied this efficient chemistry to the synthesis of radical thiol–ene and thiol–yne reaction using catalytic
glycoconjugates between glycosyl thiols and amino acid deriva- amounts of 9-mesityl-10-methylacridinium tetrafluoroborate (A).
tives (Scheme 5).
These highly efficient reactions have shown great scope gener-
To our delight, the thiol–yne reaction occurred smoothly ality. Through the successful model glycoconjugates, this
between glucosyl thiol and a range of alkyne-containing amino radical reaction demonstrates promise for future glycoprotein
acids (glycine, valine, cysteine, aspartic acid, tyrosine, and studies.
serine derived terminal alkyne), affording the corresponding
S-linked glycoconjugates in good yields (49–54, 61%–73%).19
The mild conditions are compatible with both Boc-protected Conflicts of interest
amino groups and Fmoc-protected amino groups, which
would make this method useful in the context of both Boc-
There are no conflicts to declare.
SPPS and Fmoc-SPPS chemistry. Moreover, the method could
be expanded to the coupling of glycosyl thiol with dipeptide,
affording the corresponding glycoconjugate 55 in 65% yield.
Acknowledgements
A possible mechanism for the thiol–ene reaction is outlined
in Scheme 6a. Upon photoexcitation of catalyst A, the strongly
oxidizing state (A*) could oxidize a thiol to generate the thiyl
radical cation and one electron reduced acridinium 57.14,20
We are grateful to the University at Albany, State University of
New York, for financial support.
Deprotonation of the radical cation followed by coupling with
the alkene results in the C–S bond formation with anti-
References
Markovnikov selectivity. The resulting alkyl radical then
abstracts a hydrogen atom from another molecule of thiol to
afford the thiol–ene product and generates another equivalent
of the thiyl radical. However, light irradiation is necessary for
the reaction to reach completion based on our experimental
results.13a The catalyst is likely to be regenerated by reducing a
1 P. Chauhan, S. Mahajan and D. Enders, Chem. Rev., 2014,
114, 8807.
2 (a) J. Clayden and P. MacLellan, Beilstein J. Org. Chem.,
2011, 7, 582; (b) Sulphur-Containing Drugs and Related
Organic Compounds, ed. L. A. Damani, Wiley, New York,
1989; (c) D. Jacob, Nat. Prod. Rep., 2006, 23, 851.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
3 For the utility of thiyl radicals in organic synthesis, see:
F. Dénès, M. Pichowicz, G. Povie and P. Renaud, Chem.
Rev., 2014, 114, 2587.
(i) M. Singh, A. K. Yadav, L. D. S. Yadav and R. K. P. Singh,
Tetrahedron Lett., 2017, 58, 2206–2208.
11 S. S. Zalesskiy, N. S. Shlapakov and V. P. Ananikov, Chem.
Sci., 2016, 7, 6740–6745.
4 For selective reviews on the applications of the thiol–ene/
thiol–yne reaction, see: (a) C. E. Hoyle, T. Y. Lee and 12 For recent examples of biomolecule conjugation and bio-
T. Roper, J. Polym. Sci., Part A: Polym. Chem., 2004, 42, 5301;
(b) E. Sletten and C. R. Bertozzi, Angew. Chem., Int. Ed.,
2009, 48, 6974; (c) C. E. Hoyle and C. N. Bowman, Angew.
Chem., Int. Ed., 2010, 49, 1540; (d) A. Dondoni and
molecule-compatible reaction induced by visible light, see:
(a) D. A. Fancy and T. Kodadek, Proc. Natl. Acad. Sci. U. S.
A., 1999, 96, 6020; (b) Y. Chen, A. S. Kamlet, J. B. Steinman
and D. R. Liu, Nat. Chem., 2011, 3, 146; (c) S. Sato and
H. Nakamura, Angew. Chem., Int. Ed., 2013, 52, 8681;
(d) C. Hu and Y. Chen, Tetrahedron Lett., 2015, 56, 884;
(e) H. Huang, G. Zhang, L. Gong, S. Zhang and Y. Chen,
J. Am. Chem. Soc., 2014, 136, 2280; (f) J. Yang, J. Zhang,
L. Qi, C. Hu and Y. Chen, Chem. Commun., 2015, 51, 5275.
A.
Marra,
Chem.
Soc.
Rev.,
2012,
41,
573;
(e) R. Hoogenboom, Angew. Chem., Int. Ed., 2010, 49, 3415;
(f) A. Massi and D. Nanni, Org. Biomol. Chem., 2012, 10,
3791; (g) A. B. Lowe, C. E. Hoyle and C. N. Bowman,
J. Mater. Chem., 2010, 20, 4745; (h) I. P. Beletskaya and
V. P. Ananikov, Chem. Rev., 2011, 111, 1596; 13 (a) G. Zhao, S. Kaur and T. Wang, Org. Lett., 2017, 19, 3291;
(i) R. Castarlenas, A. Di Giuseppe, J. J. Perez-Torrente and
L. A. Oro, Angew. Chem., Int. Ed., 2013, 52, 211;
( j) A. B. Lowe, Polymer, 2014, 55, 5517.
5 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew.
Chem., Int. Ed., 2001, 40, 2004; (b) M. G. Finn and
V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1231.
(b) K. Wu, Y. Du and T. Wang, Org. Lett., 2017, 19, 5669;
(c) G. Zhao and T. Wang, Angew. Chem., Int. Ed., 2018, 57,
6120; (d) K. Wu, C. Fang, S. Kaur, P. Liu and T. Wang,
Synthesis, 2018, 50, 2897; (e) Y. Du, Z. Wei and T. Wang,
Synthesis, 2018, 50, 3379; (f) K. Wu, Y. Du, Z. Wei and
T. Wang, Chem. Commun., 2018, 54, 7443.
6 For selected reviews, see: (a) C. K. Prier, D. A. Rankic and 14 (a) S. Fukuzumi, H. Kotani, K. Ohkubo, S. Ogo,
D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322;
(b) M. N. Hopkinson, B. Sahoo, J. L. Li and F. Glorius,
Chem. – Eur. J., 2014, 20, 3874; (c) M. D. Kärkäs, J. A. Porco
Jr. and C. R. J. Stephenson, Chem. Rev., 2016, 116, 9683;
(d) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51,
6828; (e) T. P. Yoon, ACS Catal., 2013, 3, 895;
N. V. Tkachenko and H. Lemmetyinen, J. Am. Chem. Soc.,
2004, 126, 1600; (b) A. C. Benniston, K. J. Elliott,
R. W. Harrington and W. Clegg, Eur. J. Org. Chem., 2009,
253; (c) A. Joshi-Pangu, F. Léveque, H. G. Roth, S. F. Oliver,
L. Campeau, D. A. Nicewicz and D. A. DiRocco, J. Org.
Chem., 2016, 81, 7244.
(f) D. A. Nicewicz and T. M. Nguyen, ACS Catal., 2014, 4, 15 (a) H. Takashima, S. Shinkai and I. Hamachi, Chem.
355; (g) S. Fukuzumi and K. Ohkubo, Org. Biomol. Chem.,
2014, 12, 6059; (h) D. P. Hari and B. König, Chem.
Commun., 2014, 50, 6688; (i) N. A. Romero and
Commun., 1999, 2345; (b) S. H. Hewitt, M. H. Filby,
E. Hayes, L. T. Kunh, A. P. Kalverda, M. E. Webb and
A. J. Wilson, ChemBioChem, 2017, 18, 223.
D. A. Nicewicz, Chem. Rev., 2016, 116, 10075; ( j) J.-R. Chen, 16 (a) A. Varki, Glycobiology, 2017, 27, 3; (b) R. A. Dwek, Chem.
X.-Q. Hu, L.-Q. Lu and W.-J. Xiao, Chem. Soc. Rev., 2016, 45,
2044; (k) J.-R. Chen, X.-Q. Hu, L.-Q. Lu and W.-J. Xiao, Acc.
Chem. Res., 2016, 49, 1911; (l) J.-R. Chen, X.-Y. Yu and
W.-J. Xiao, Synthesis, 2015, 604; (m) Y. Liu, R. Song and
J. Li, Sci. China: Chem., 2016, 59, 161.
7 A. Wimmer and B. König, Beilstein J. Org. Chem., 2018, 14,
54.
8 E. L. Tyson, M. S. Ament and T. P. Yoon, J. Org. Chem.,
2013, 78, 2046.
Rev., 1996, 96, 683; (c) B. G. Davis, Chem. Rev., 2002, 102,
579; (d) A. Helenius and M. Aebi, Science, 2001, 291, 2364;
(e) P. M. Rudd, T. Elliot, P. Cresswell, I. A. Wilson and
R. A. Dwek, Science, 2001, 291, 2370; (f) R. Kannagi, Curr.
Opin. Struct. Biol., 2002, 12, 599; (g) J. B. Lowe, Cell, 2001,
104, 809.
17 D. Horton and J. D. Wander, Carbohydrates: Chemistry and
Biochemistry, Academic Press, New York, 1990, vol. 4B,
p. 799.
9 M. H. Keylor, J. E. Park, C.-J. Wallentin and 18 (a) N. Floyd, B. Vijayakrishnan, J. R. Koeppe and
C. R. J. Stephenson, Tetrahedron, 2014, 70, 4264.
B. G. Davis, Angew. Chem., Int. Ed., 2009, 48, 7798;
(b) R. T. Dere and X. Zhu, Org. Lett., 2008, 10, 4641;
(c) G. J. L. Bernards, E. J. Grayson, S. Thompson,
J. M. Chalker, J. C. Errey, F. El Oualid, T. D. W. Claridge
and B. G. Davis, Angew. Chem., Int. Ed., 2008, 47, 2244;
(d) G. J. L. Bernardes, D. P. Gamblin and B. G. Davis,
Angew. Chem., Int. Ed., 2006, 45, 4007; (e) D. P. Gamblin,
P. Garnier, S. van Kasteren, N. J. Oldham, A. J. Fairbanks
and B. G. Davis, Angew. Chem., Int. Ed., 2004, 43, 827;
(f) S. B. Cohen and R. L. Halcomb, J. Am. Chem. Soc., 2002,
124, 2534; (g) D. A. Thayer, H. N. Yu, M. C. Galan and
C. H. Wong, Angew. Chem., Int. Ed., 2005, 44, 4596;
(h) Y. Zhu and W. A. van der Donk, Org. Lett., 2001, 3, 1189;
10 (a) E. L. Tyson, Z. L. Niemeyer and T. P. Yoon, J. Org. Chem.,
2014, 79, 1427; (b) V. T. Bhat, P. A. Duspara, S. Seo,
N. S. B. Abu Bakar and M. F. Greaney, Chem. Commun.,
2015, 51, 4383; (c) C. A. DeForest and K. S. Anseth, Nat.
Chem., 2011, 3, 925; (d) C. A. DeForest and K. S. Anseth,
Angew. Chem., Int. Ed., 2012, 51, 1816; (e) H. Shih and
C. C. Lin, Macromol. Rapid Commun., 2013, 34, 269;
(f) H. Shih, A. K. Fraser and C. C. Lin, ACS Appl. Mater.
Interfaces, 2013, 5, 1673; (g) D. Limnios and C. G. Kokotos,
Adv. Synth. Catal., 2017, 359, 323; (h) O. O. Fadeyi,
J. J. Mousseau, Y. Feng, C. Allais, P. Nuhant, M. Z. Chen,
B. Pierce and R. Robinson, Org. Lett., 2015, 17, 5756–5759;
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
(i) Y. Zhu, M. D. Gieselman, H. Zhou, O. Averin and
W. A. van der Donk, Org. Biomol. Chem., 2003, 1, 3304;
( j) X. Zhu, K. Pachamuthu and R. R. Schmidt, J. Org.
Chem., 2003, 68, 5641; (k) X. Zhu and R. R. Schmidt, Chem.
– Eur. J., 2004, 10, 875; (l) M. Fiore, A. Marra and
A. J. Dondoni, Org. Chem., 2009, 74, 4422; (m) J. R. Rich,
A. Szpacenko, M. M. Palcic and D. R. Bundle, Angew.
1989, 190, 3; (r) J. P. Issa, D. Lloyd, E. Steliotes and
C. S. Bennett, Org. Lett., 2013, 15, 4170; (s) P. Acharya,
K. N. Baryal, C. Reno and J. Zhu, Carbohydr. Res., 2017,
448, 103; (t) K. N. Barayl and J. Zhu, Org. Lett., 2015, 17,
4530; (u) K. N. Barayl, D. Zhu, X. Li and J. Zhu, Angew.
Chem., Int. Ed., 2013, 52, 8012; (v) P. L. Durette and
T. Y. Shen, Carbohydr. Res., 1980, 81, 261.
Chem., Int. Ed., 2004, 43, 613; (n) H. Driguez, Top. Curr. 19 The assignments of 1,2-trans thioglycosides were based on
Chem., 1997, 187, 85; (o) L. Szilagyi and O. Varela, Curr. isolated products.
Org. Chem., 2006, 10, 1745; (p) H. Driguez, ChemBioChem, 20 The proposed preference of oxidizing thiols over alkenes
2001, 2, 311; (q) D. Crich and T. J. Ritchie, Carbohydr. Res.,
relies on their differences in reduction potentials.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.