Visible light photoredox-catalyzed hydrothiolation of enamides and enecarbamates

Article abstract of DOI:10.1016/j.tetlet.2020.152201

An efficient visible light photoredox-catalyzed, Markovnikov selective, hydrothiolation reaction of enamides and enecarbamates is presented. This protocol is mild and operationally simple. This process provides access to N,S-acetal products from available

Full text of DOI:10.1016/j.tetlet.2020.152201

Journal Pre-proofs
Visible Light Photoredox-Catalyzed Hydrothiolation of Enamides and Ene‐
carbamates
Eliezer Barman, Jason Hourezadeh, Daniel Lim
PII:
S0040-4039(20)30666-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152201
TETL 152201
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 May 2020
28 June 2020
29 June 2020
Please cite this article as: Barman, E., Hourezadeh, J., Lim, D., Visible Light Photoredox-Catalyzed
Hydrothiolation of Enamides and Enecarbamates, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/
j.tetlet.2020.152201
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Visible Light Photoredox-Catalyzed Hydrothiolation of Enamides and
Enecarbamates
Eliezer Barman, Jason Hourezadeh, and Daniel Lim
Department of Chemistry, Yeshiva University, 500 W 185th St, New York, NY 10033, USA.
Phone: 212-960-5414
Fax: 212-960-5400
Email: dlimychemistry@gmail.com
Keywords
Photoredox
Hydrothiolation
Markovnikov
Enamides
Enecarbamates
N, S-Acetal
Graphical Abstract
3
N
N
3
Blue
LED
R1
HN
O
N
N
Ru2+
R1
HN
O
N
S
R2
HS
N
R2
+
ACN
2 Cl- · 6 H O
2
Abstract
An efficient visible light photoredox-catalyzed, Markovnikov selective,
hydrothiolation reaction of enamides and enecarbamates is presented. This protocol is mild
and operationally simple. This process provides access to N, S-acetal products from available thiols
and a variety of enamides and enecarbamates.
Introduction
Hydrothiolation reactions directly couple a thiol and an alkene, two common and
abundant building blocks, to form a thioether via a new C−S and C−H bond.1-3 This strategy
toward C−S bond formation is highly valuable because organosulfur compounds are common
synthetic intermediates and components of many sulfur-containing natural products.4-7 Among
various hydrothiolation reactions, the thiol–ene reaction, a radical addition of thiols to olefins, is
1

arguably one of the most powerful current methods because of its widespread employment in
areas of bioconjugate chemistry, polymer science, and pharmaceutical chemistry.8,9 Since the
first transition metal-catalyzed hydrothiolation by Ogawa, organometallic chemists have
designed catalytic systems capable of selectively synthesizing C−S bonds from alkynes and
allenes.10-12 On that note, transition metal-catalyzed hydrothiolations of alkenes is relatively
underdeveloped.13,14 Ogawa demonstrated the Pd-catalyzed hydrothiolation of alkenes bonded
directly to heteroatoms, such as vinyl ethers and vinyl lactams.15 This was followed by the recent
disclosure of the Au-catalyzed anti-Markovnikov hydrothiolation of terminal olefins to afford
linear C−S bonds.16 Recently, Hull published a rhodium-catalyzed regiodivergent
hydrothiolation of allyl amines and imines.17 Compared to other hydrofunctionalization methods,
visible-light mediated photoredox-catalyzed hydrothiolation reactions have been relatively
underexplored. Yoon has employed photoredox catalysis to achieve the anti- Markovnikov
hydrothiolation of alkenes via a thiol−ene reaction.18 Using this protocol, the hydrothiolation of a
variety of styrenes, simple alkenes, and alkynes could be performed.18,19 Following this
methodology, a handful of hydrothiolation reactions or thiol−ene reactions, employing
photoredox catalysis have been presented in both functionalization of styrenes or terminal
alkenes present in small molecules or polymers.20-24 In addition, there have been reports of
aqueous anti-Markovnikov addition of thiols to unactivated alkenes.25 We demonstrate here a
very simple hydrothiolation reactions of enamides and enecarbamates driven by visible light and
a photoredox catalyst
Although many advances in the visible light photoredox-catalyzed thiol-ene reaction have
been made, the we noticed that in general, the substrate scope with regards to alkenes were
limited to the anti-Markovnikov hydrothiolation product.26 This observation from the literature
propelled our interest in determining if the use of enamides and enecarbamates, as
unsymmetrical alkene substrates, would lead to regiodivergent visible light photoredox-catalyzed
hydrothiolation products. More specifically, we grew interest in determining if we could develop
regioselective visible light photoredox-catalyzed hydrothiolation reaction methodologies. We
began to explore and develop a visible light-mediated photoredox-catalyzed hydrothiolation
methodology to regioselectively functionalize enamides and enecarbamates.
2

Results and Discussion
In our preliminary studies, we chose to screen the reaction of thiophenol (1) and N-
vinyl acetamide (2) with Tris(2,2'-bipyridyl)ruthenium(II) chloride hexahydrate (3) as the
photoredox catalyst with a variety of organic and aqueous solvents (Table 1, entries 1-12). To our
surprise we could identify and isolate the two regiodivergent thiol-ene addition products, 4 and 5
(Table 1). In all the reactions done in aqueous solutions thioether 4, the expected anti-Markovnikov
product was the only product and was isolated in moderate yields. We were able to further
investigate these reaction conditions to develop a metal-free, anti-Markovnikov selective,
hydrothiolation reaction of enamides and enecarbamates in an aqueous medium.27 In
contrast, we observed that when the reaction was done in acetonitrile or methylene chloride the
only product was the N,S-acetal 5, which was isolated in moderate to good yields. The N, S-acetal
functionality in 5 is of interest because N, S-acetals are found in a number of biologically active
compounds and natural products and overall their role as biologically active molecules have been
underexplored (Figure 1).We subsequently decided to explore the reaction conditions associated
with the Markovnikov, N,S-acetal product. During the process of optimizing the reactions
conditions for the N, S -acetal product 5, we saw that more efficient reactions could be produced
when 1.1 equivalents of 1 was used and we discovered that the catalyst loading of 3 could be
lowered to 1% without deviating from our best recorded isolated yield (Table 2, entries 1-4). We
also determined that the visible light photoredox-catalyzed reaction to prepare 5, can also be done
on the 10 mmol scale with minimal change in efficiency (Table 2, entry 4). We were also able to
determine that in the absence of catalyst, with and without Blue LED light, that there is a slower
background reaction that favors the formation of anti-Markovnikov product 4 (Table 2, entry 5
and 6). Previous reactions were all done open to air, when the reaction was run with rigorously
degassed solvent in an inert atmosphere we observed that the rate of the reaction with repsect to
the formation of compound 5 decreased along with the formation of anti-Markovnkov product 4
(Table 2, entry 7).
3

Table 1: Initial and optimized reaction conditions.
3
N
N
N
N
Ru2+
N
3
Blue
LED
O
O
N
O
SH
S
S
NH
N
NH
H
+
2 Cl- · 6 H O
ACN
2
1
2
4
5
Entrya
% Catalyst
3
Solvent
% Yield 4b
% Yield 5b
1
2
3
4
5
6
7
8
9
5 %
5 %
5 %
5 %
5 %
5 %
2.5 %
2.5 %
1%
ACN
DCM
THF
0 %
0 %
75 %
45 %
35 %
25 %
0 %
0 %
60 %
0 %
25 %
25 %
50 %
55 %
0 %
50 %
0 %
55 %
0 %
MeOH
10 X PBS
H2O
ACN
H2O
ACN
H2O
ACN
H2O
80 %
0 %
0 %
10
11
12
1%
0 %
0 %
55 %
0 %
a.) Reactions run with 1 mmol of 1 and 2 in 0.2M solvent for 18 hr with Blue LED light and
monitored by TLC. b.) Isolated yield after column chromatography.
4

Figure 1. Biologically active Sulfur-containing compounds.
O
S
H
N
Cl
O
S
Cl
Cl
S
Cl
N
S
O
O
N
H
NH
Ph
Fusaperazinc A
HIV-1 RTI
Inhibitor
TRPA1 Activator
O
S
H
Ph
NH
O
S
N
O
N
COOH
O
Sedative
Penicillin G
O
5

Table 2: Reaction optimization for compound 5.
3
Blue
LED
O
O
SH
S
NH
NH
+
ACN
1
2
5
Entry
% Catalyst
3
Equiv
Equiv
2
Rxn Time % Yield 4a % Yield 5a
(Hr)
1
1
2
3
1 %
1 %
1 %
1 %
0 %
0 %
1 %
1.1
2.0
4.0
1.1
1.1
1.1
1.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2
2
2
0 %
0 %
0 %
90 %
88 %
84 %
86 %
0 %
4b
5c
6d
7e
2
0 %
24
24
24
25 %
25 %
35 %
0 %
50 %
All reactions run in 0.2 M ACN and monitored by TLC. a.) Isolated yields after column
chromatography. b.) Reaction run at 10 mmol scale. c.) Reaction run with Blue LED and no
catalyst. d.) Reaction run with no catalyst in the dark. e.) Reaction run with degassed solvent
under inert atmosphere.
6

Next, we proceeded to explore and expand the substrate scope of the currently optimized
visible light photoredox-catalyzed Markovnikov hydrothiolation procedure. We discovered in the
following experiments that thiophenol (1) was a suitable thiol for efficient Markovnikov
hydrothiolation to a variety of enamides and enecarbamates (Table 3). In all examples, the
Markovnikov hydrothiolation N,S-acetal products were isolated in moderate to very good yields.
7

Table 3. Results for the hydrothiolation of different enamides and enecarbamates with
thiophenol (1).
3
Blue
LED
O
R1
O
R1
NH
SH
S
NH
+
ACN
1
6
Entry
1
R
S
Product
% Yield
90 %
NHBoc
6a
O
2
3
6b
93 %
86 %
S
N
6c
O
S
NH
4
6d
75 %
O
S
N
H
Reactions were run with 1.1 mmol of 1 and 1.0 mmol Enamide or Enecarbamate in 0.2 M ACN
with Blue LED light for 18 hr and monitored by TLC. Isolated yields after column
chromatography.
8

Next, we turned our attention to explore the reaction substrate scope with respect to variations
in thiols with varying encarbamates and enamides (Table 4). Benzyl mercaptan was determined
to be a suitable thiol for the Markovnikov hydrothiolation reaction with various enamides (Table
4, 7a and 7b). Again, these N,S-acetal products can be isolated in very good yields. We then
explored the use of para-functionalized aromatic thiols (Table 4, 7c-7f), with an N-Boc derived
enecarbamate. We were pleased to discover that the visible light photoredox-catalyzed
Markovnikov hydrothiolation products could be isolated in moderate to very good yields (Table
4, 7a-f). Although the initial thiols used in the reaction screening process were aromatic. The lab
began to investigate the use of 3-mercaptopropionic acid methyl ester with benzoic acid derived
enamides. (Table 4, 7e and 7g). Both Markovnikov hydrothiolation N,S-acetal products 7e and
7g are isolated in good yields. Again, we can demonstrate that this protocol is quite compatible
with a varying degree of substrates that provide the possibility for further transformations.
Unfortunately, when these conditions were applied to reactions using simple alkyl thiols, only
the bis addition products 8a and 8b were isolated (Table 5).
9

Table 4. Results for the hydrothiolation of different enamides and enecarbamates with
various thiols.
3
Blue
LED
R1
HN
O
R1
HN
O
S
R2
HS
R2
+
ACN
7
Entry
1
R
Product
7a
% Yielda
90 %
O
S
NH
O
2
7b
92 %
S
S
N
NHBoc
NHBoc
NHBoc
3
4
5
7c
7d
7e
88 %
80 %
78 %
Br
S
HO
S
HO
O
O
6
7f
70 %
S
NH
H2N
O
O
7
8
7g
7h
88 %
85 %
O
S
N
H
O
O
Br
O
S
N
H
Reactions were run with 1.1 mmol of Thiol and 1.0 mmol Enamide or Enecarbamate in 0.2 M
ACN with Blue LED light for 18 hr and monitored by TLC. a.) Isolated yields after column
chromatography.
10

Table 5. Results for the hydrothiolation of 2 with alkyl thiols.
3
Blue
LED
O
O
HN
S
R2
HS
HN
R2
+
ACN
2
8
Entry
1
R
O
Product
8a
% Yielda
40 %
S
NH
S
O
2
8b
45 %
S
NH
S
Reactions were run with 1.1 mmol of Thiol and 1.0 mmol Enamide or Enecarbamate in 0.2 M
ACN with Blue LED light for 18 hr and monitored by TLC. a.) Isolated yields after column
chromatography.
11

Having developed two different and regiodivergent hydrothiolation protocols, we looked
to apply these procedures toward the regioselective hydrothiolation of N-vinyl amide 9 (Figure
1).27 We found that the anti-Markovnikov hydrothiolation product (10) for the reaction of
thiophenol (1) to N-vinyl amide (9) in water was isolated in 80% yield after 18 hours (Figure 2).
When thiophenol (1) and N-vinyl amide (9) were reacted with photoredox catalyst 3 in
acetonitrile with blue LED light, the Markovnikov hydrothiolation N,S-acetal product 11 was
isolated in 85% yield after 18 hours (Figure 2).
12

Figure 2. Regiodivergent hydrothiolation of enamide 3 with thiophenol (1).
N3
N3
1
3
and
Blue
LED
O
1
H2O
O
O
S
N
H
S
NH
NH
ACN
N3
10
9
11
80% Yield
86% Yield
Reactions were run with 1.1 mmol of thiophenol (1) and 1.0 mmol enamide (3) in 0.2 M H2O
(10) for 18 hr or 0.2 M ACN with Blue LED light (11) for 18 hr and monitored by TLC. Isolated
yields after column chromatography.
13

Next, disubstituted E-N-vinyl-enamide 12 was exposed to previously disclosed conditions
with thiophenol (1) and photoredox catalyst 3. Pleasingly, this gave the N,S-acetal product 13a
in 92% isolated yield. We then explored the use of para-functionalized aromatic thiols (13b-13e),
with an E-N-vinyl-enamide 12. We were pleased to discover that the visible light photoredox-
catalyzed Markovnikov hydrothiolation products could be isolated in moderate to very good
yields (Table 6, 13a-13e). Unfortunately, there was no reaction when the thiol, 3-
mercaptopropionic acid methyl ester, was used as the thiol substrate (Table 6, 13f).
14

Table 6. Results for the hydrothiolation of different enamides and enecarbamates with
various thiols.
3
Blue
LED
R2
O
S
O
N
HS
R2
O
+
N
O
ACN
12
13
Entry
1
R
Product
13a
% Yielda
92 %
S
S
S
S
O
N
N
N
N
O
Br
2
3
4
5
13b
13c
13d
13e
90 %
80 %
70 %
73 %
O
O
OH
O
O
NH2
O
O
O
OH
S
S
O
N
N
O
O
6
13f
No Reaction
O
O
O
Reactions were run with 1.1 mmol of Thiol and 1.0 mmol Enamide in 0.2 M ACN with Blue
LED light for 18 hr and monitored by TLC. a.) Isolated yields after column chromatography.
15

Finally, we began to investigate the diastereoselectivity of the proposed visible light
photoredox-catalyzed hydrothiolation reaction. Thiophenol (1) we exposed to chiral enamide
derived Boc-proline with photoredox catalyst 3 in acetonitrile with blue LED light. NMR
analysis of the crude hydrothiolation N,S-acetal product 14a revealed a diastereomic ratio of 2:1.
Following column chromatography the N,S-acetal product 14a was isolated in 65% yield with
no change in the diastereomeric ratio (Table 7, 14a). Next, N-Boc-L-Cysteine methyl ester was
reacted under the same conditions with a variety of enamide and enecarbamate substrates (Table
7, 14b-14d). The diastereomeric ratio of the crude hydrothiolation N,S-acetal product 14b-14d
were determined by NMR. Again, isolated yields after column chromatography could be
obtained but with no change in the diastereomeric ratio. Unfortunately, the lauric acid and
pyrrolidinone derived enamides produced N,S-acetal products 14c and 14d with a 1:1
diastereomeric ratio. A slight increase in diastereoselectivity of 2:1 was observed when the N-
Boc-derived enecarbamate substrate was used (Table 7, 14b).
16

Table 7. Results for the hydrothiolation of chiral enamides and enecarbamates with
various thiols.
3
Blue
LED
R1
HN
O
R1
HN
O
S
R2
HS
R2
+
ACN
14
Entry
1
R
Product Diastereomer
%
Ratioa
Yieldb
65 %
14a
2:1
O
N
Boc
S
NH
2
3
14b
14c
2:1
1:1
72 %
80 %
O
O
S
NHBoc
BocHN
O
O
S
N
O
BocHN
O
O
4
14h
1:1
70 %
N
S
O
H
NHBoc
Reactions were run with 1.1 mmol of Thiol and 1.0 mmol Enamide or Enecarbamate in 0.2 M
ACN with Blue LED light for 18 hr and monitored by TLC. a.) Diastereomer ratio of the crude
product determined by NMR. b.) Isolated yields after column chromatography with no change in
the diastereomer ratio.
17

A plausible mechanism (Scheme 1) that we propose begins with the visible-light
2+
irradiation of Ru(bpy)32+ to form a strongly reducing species *Ru(bpy)3 , which performs a
single-electron transfer (SET) to generate a thiolate anion 16 and a hydrogen atom 17 which
directly adds to the electron-rich β-position of enamide or enecarbamate (18). Hydrogen atom
addition generates radical 19 which performs a single-electron transfer (SET) to oxidize and
3+
regenerate the Ru(bpy)32+ from Ru(bpy)3 . The resulting cation 20 can be directly trapped by
thiolate anion 16 to provide the N,S-acetal product 21.
18

visible
light
*
Ru2+
Ru2+
S
S
H
NHCOR1
NHCOR1
R
SH
R
16
R
-1e-
20
21
15
+1e-
H
Ru3+
NHCOR1
18
NHCOR1
S
+
H
R
16
17
19
H
Scheme 1. Proposed mechanism for the visible light photoredox-catalyzed hydrothiolation
reaction.
19

Conclusion
In conclusion, we have developed a simple and efficient visible light photoredox-
catalyzed methodology for the addition of thiols to enamides and enecarbamates producing the
Markovnikov N,S-acetal products. The significant advantages offered by this method are simple
operation and mild experimental conditions that are compatible with various functionalities,
Markovnikov regioselectivity, and moderate to very good yields of isolated N,S-acetal products.
This methodology thus provides a very convenient and synthetically useful approach to
preparing chemically useful N,S-acetals. Further studies on the mechanism and application of
this methodology to the thiol selective conjugation of enamides and enecarbamates to Cysteine
containing peptides and proteins are currently in progress.
20

Acknowledgments
The authors wish to thank Yeshiva University for financial support.
Supplementary Data
Supplementary data associated with this article can be found, in the online version, at
21

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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
22

Visible Light Photoredox-Catalyzed Hydrothiolation of Enamides and
Enecarbamates
Eliezer Barman, Jason Hourezadeh, and Daniel Lim
Department of Chemistry, Yeshiva University, 500 W 185th St, New York, NY 10033, USA.
Phone: 212-960-5414
Fax: 212-960-5400
Email: dlimychemistry@gmail.com
Highlights
 An efficient visible light photoredox-catalyzed thiol-ene reaction.
 Markovnikov selective thiole-ene reaction.
 Hydrothioaltion reaction of enamides and enecarbamates.


This protocol is operationally simple, mild, and atom-economical.
This process provides access to N,S-thioacetals from available thiols and a variety of enamides
and enecarbamates.
Table 1: Initial and optimized reaction conditions.
3
N
N
N
N
Ru2+
N
3
Blue
LED
O
O
N
O
SH
S
S
NH
N
NH
H
+
2 Cl- · 6 H O
ACN
2
1
2
4
5
23

Entrya
% Catalyst
3
Solvent
% Yield 4b
% Yield 5b
1
2
3
4
5
6
7
8
9
5 %
5 %
5 %
5 %
5 %
5 %
2.5 %
2.5 %
1%
ACN
DCM
THF
0 %
0 %
75 %
45 %
35 %
25 %
0 %
0 %
60 %
0 %
25 %
25 %
50 %
55 %
0 %
50 %
0 %
55 %
0 %
MeOH
10 X PBS
H2O
ACN
H2O
ACN
H2O
ACN
H2O
80 %
0 %
0 %
10
11
12
1%
0 %
0 %
55 %
0 %
b.) Reactions run with 1 mmol of 1 and 2 in 0.2M solvent for 18 hr with Blue LED light and
monitored by TLC. b.) Isolated yield after column chromatography.
24

Figure 1. Biologically active Sulfur-containing compounds.
O
S
H
N
Cl
O
S
Cl
Cl
S
Cl
N
S
O
O
N
H
NH
Ph
Fusaperazinc A
HIV-1 RTI
Inhibitor
TRPA1 Activator
O
S
H
Ph
NH
O
S
N
O
N
COOH
O
Sedative
Penicillin G
O
25

Table 2: Reaction optimization for compound 5.
3
Blue
LED
O
O
SH
S
NH
NH
+
ACN
1
2
5
Entry
% Catalyst
3
Equiv
Equiv
2
Rxn Time % Yield 4a % Yield 5a
(Hr)
1
1
2
3
1 %
1 %
1 %
1 %
0 %
0 %
1 %
1.1
2.0
4.0
1.1
1.1
1.1
1.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2
2
2
0 %
0 %
0 %
90 %
88 %
84 %
86 %
0 %
4b
5c
6d
7e
2
0 %
24
24
24
25 %
25 %
35 %
0 %
50 %
All reactions run in 0.2 M ACN and monitored by TLC. a.) Isolated yields after column
chromatography. b.) Reaction run at 10 mmol scale. c.) Reaction run with Blue LED and no
catalyst. d.) Reaction run with no catalyst in the dark. e.) Reaction run with degassed solvent
under inert atmosphere.
26

Table 3. Results for the hydrothiolation of different enamides and enecarbamates with
thiophenol (1).
3
Blue
LED
O
R1
O
R1
NH
SH
S
NH
+
ACN
1
6
Entry
1
R
S
Product
% Yield
90 %
NHBoc
6a
O
2
3
6b
93 %
86 %
S
N
6c
O
S
NH
4
6d
75 %
O
S
N
H
Reactions were run with 1.1 mmol of 1 and 1.0 mmol Enamide or Enecarbamate in 0.2 M ACN
with Blue LED light for 18 hr and monitored by TLC. Isolated yields after column
chromatography.
27

Table 4. Results for the hydrothiolation of different enamides and enecarbamates with
various thiols.
3
Blue
LED
R1
HN
O
R1
HN
O
S
R2
HS
R2
+
ACN
7
Entry
1
R
Product
7a
% Yielda
90 %
O
S
NH
O
2
7b
92 %
S
S
N
NHBoc
NHBoc
NHBoc
3
4
5
7c
7d
7e
88 %
80 %
78 %
Br
S
HO
S
HO
O
O
6
7f
73 %
S
NH
H2N
O
O
7
8
7g
7h
88 %
85 %
O
S
N
H
O
O
Br
O
S
N
H
Reactions were run with 1.1 mmol of Thiol and 1.0 mmol Enamide or Enecarbamate in 0.2 M
ACN with Blue LED light for 18 hr and monitored by TLC. a.) Isolated yields after column
chromatography.
28

Table 5. Results for the hydrothiolation of 2 with alkyl thiols.
3
Blue
LED
O
O
HN
S
R2
HS
HN
R2
+
ACN
2
8
Entry
1
R
O
Product
8a
% Yielda
40 %
S
NH
S
O
2
8b
45 %
S
NH
S
Reactions were run with 1.1 mmol of Thiol and 1.0 mmol Enamide or Enecarbamate in 0.2 M
ACN with Blue LED light for 18 hr and monitored by TLC. a.) Isolated yields after column
chromatography.
29