Aqueous metal-free hydrothiolation of enamides and enecarbamates

Article abstract of DOI:10.1016/j.tetlet.2019.150951

An efficient and metal-free, anti-Markovnikov selective, hydrothioaltion reaction of enamides and enecarbamates in an aqueous medium is presented. This protocol is operationally simple, mild, and atom-economical. This process provides access to thioethers

Full text of DOI:10.1016/j.tetlet.2019.150951

Accepted Manuscript
Aqueous Metal-Free Hydrothiolation of Enamides and Enecarbamates
Eliezer Barman, Jason Hourezadeh, Daniel Lim
PII:
S0040-4039(19)30699-9
https://doi.org/10.1016/j.tetlet.2019.150951
150951
DOI:
Article Number:
Reference:
TETL 150951
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 June 2019
12 July 2019
16 July 2019
Please cite this article as: Barman, E., Hourezadeh, J., Lim, D., Aqueous Metal-Free Hydrothiolation of Enamides
and Enecarbamates, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.150951
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Aqueous Metal-Free 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
Metal-Free
Hydrothiolation
Anti-Markovnikov
Thiol-Ene
Graphical Abstract
O
R1
HN
O
S
HS R2
+
R1
N
R2
H
H2O
Abstract
An efficient and metal-free, anti-Markovnikov selective, hydrothioaltion reaction
of enamides and enecarbamates in an aqueous medium is presented. This protocol is
operationally simple, mild, and atom-economical. This process provides access to thioethers 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
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-catalysed 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-catalysed hydrothiolations of alkenes is relatively
underdeveloped.13,14 Ogawa demonstrated the Pd-catalysed 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-catalysed anti-Markovnikov hydrothiolation of terminal olefins to afford
linear C−S bonds.16 Recently, Hull recently published a rhodium-catalysed regiodivergent
hydrothiolation of allyl amines and imines.17 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 contrast, there have
been reports of aqueous anti-Markovnikov addition of thiols to unactivated alkenes 25 We
demonstrate here a very simple and green procedure for anti-Markovnikov addition of thiols to
enamides and enecarbamates in water without the use of any additives.
Results and Discussion
Our initial interest in hydrothiolation reactions stem from recent advances in the field
of photocatalyzed redox intermolecular difunctionalization of alkenes and the different
approaches developed.26 These advances have allowed photoredox catalysis to be
considered a suitable process to improve the overall performance of this kind of reaction
compared to classic radical initiation conditions.26 In our preliminary studies, we chose to
screen the reaction of thiophenol (1) and N-vinyl acetamide (2) with rhodamine 6G (3) as
the photoredox catalyst with a variety of organic and aqueous solvents (Table 1, entries 1-
10). To our surprise, we could identify and isolate the two regiodivergent hydrothiolation
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
to good yields. In contrast, when the reaction was done in organic solvents a mixture of
thioether 4 and N,S-acetal 5, were isolated in low yields. We subsequently decided to
explore the reaction conditions associated with the anti-Markovnikov hydrothiolation
product. We viewed the potential for a metal free aqueous hydrothiolation reaction as an
important and useful methodology for synthetic chemists. In exploring the aqueous
hydrothiolation reaction that provided the anti-Markovnikov product 4, we saw that this
reaction was neither visible light nor photoredox catalyst dependent (Table 1, entries 5-
10). This data correlates with work done by Ranu, where hydrothiolation reactions were

promoted in water via hydrogen bonding interactions that increase the thiol
nucleophilcty.26 We also observed that the addition of additives like PBS made the
reaction worse (Table 1, entry 8). We also found that better yields can be achieved with a
slight excess of thiol 1 (Table 1, entry 10). We have determined that we can prepare the
anti-Markovnikov hydrothiolation product in water without the use of visible light and a
photoredox catalyst.
Table 1. Initial and optimized reaction conditions.
O
O
NH
O
SH
S
NH
S
3
NH
+
+
1
2
4
5
3 = Rhodamine 6G
% Yield 4b % Yield 5b
% Catalyst Blue
Entrya
Solvent
3
LED
ACN
DCM
THF
1
2
3
4
5
6
7
8
9
Yes
Yes
Yes
Yes
Yes
Yes
No
30%
30%
25%
22%
50%
55%
15%
50%
80%
85%
35%
30%
35%
25%
0%
5%
5%
5%
5%
5%
5%
0%
0%
0%
0%
DMF
10xPBS
H2O
0%
ACN
10xPBS
H2O
0%
No
0%
No
0%
10c
No
0%
H2O
a. Reactions were run with 1 mmol of 1 and 2 in 0.2 M solvent for
18 hr and monitored by TLC. b. Isolated yields after column
chromatography. c. Reaction was run with 1.2 mmol of 1 and 1.0
mmol 2 in 0.2 M H2O for 18 hr and monitored by TLC.

Next, we proceeded to explore and expand the substrate scope of the currently optimized
aqueous anti-Markovnikov hydrothiolation methodology. We discovered in the following
experiments that thiophenol (1) was a suitable thiol for efficient anti-Markovnikov
hydrothiolation to a variety of enamides and enecarbamates in water (Table 2). In all examples,
the anti-Markovnikov hydrothiolation products were isolated in moderate to very good yields.
This protocol is compatible with the N-Boc-derived enecarbamate (6a) and secondary enamide
(6b), along with primary enamides of varying functionalities from aryl to amino acid derived
(6c-6f). It should be noted that the reaction is quite compatible with a varying degree of
substrates that provide the possibility for further transformations.
Table 2. Results for the hydrothiolation of different enamides and enecarbamates with
thiophenol (1).
O
R1
O
SH
S
NH R1
+
NH
H2O
1
6
O
O
N
HN
O
S
S
6b, 83%
6a, 88%
O
O
HN
HN
S
S
Br
6c, 85%
6d, 78%
O
O
O
O
S
NH
O
NH
S
N
NH
6e, 75%
O
6f, 72%
Reactions were run with 1.2 mmol of 1 and 1.0 mmol Enamide or
Enecarbamate in 0.2 M H2O for 18 hr at RT and monitored by TLC.
Isolated yields after column chromatography.

Next we turned our attention to explore the reaction substrate scope with respect to variations
in the aromatic thiols (Table 3). Benzyl mercaptan was determined to be a suitable thiol for the
anti-Markovnikov hydrothiolation reaction with various enamides (7a-7e). Again these thioether
products can be isolated in very good yields. We then explored the use of functionalized
aromatic thiols such as bromine (7f), with an N-Boc derived enecarbamate. We were pleased to
discover that the anti-Markovnikov hydrothiolation products could be isolated in moderate to
very good yields (Table 3, 7a-f). Again, we can demonstrate that this protocol is quite
compatible with a varying degree of substrates that provide the possibility for further
transformations.
Table 3. Results for the hydrothiolation of different enamides and enecarbamates with
varying aromatic thiols.
R1
HN
O
R1 NH
O
HS R2
S
R2
+
H2O
7
O
O
O
HN
N
HN
S
S
S
7a, 88%
7b, 83%
7c, 82%
O
O
HN
O
HN
O
S
S
7d, 88%
Br
7e, 82%
Reactions were run with 1.2 mmol of Thiol and 1.0 mmol Enamide or
Enecarbamate in 0.2 M H2O for 18 hr at RT and monitored by TLC.
Isolated yields after column chromatography.

Although the initial thiols used in the reaction screening process were aromatic. The lab began
to investigate the use of alkyl thiols containing various functional groups. Table 4 presents our
initial attempts at applying the aqueous anti-Markovnikov hydrothiolaton methodology using N-
Boc-Cysteine methyl ester (8) and an N-Boc-derived enecarbamate (9) (Table 4).Using our
previous conditions, initial attempts resulted in poor yields of the desired anti-Markovnikov
product 10 (Table 4, entry 1). We decided to explore the effects of extended reaction times and
increasing the temperature of the reaction conditions. We found that with an extended reaction
time (Table 4, entry 2) there was a slight increase in the isolated yields. However, with gradual
increase in the reaction temperature we discovered that moderate to good yields of 10 can be
obtained (Table 4, entries 3-5). Notably that at both 57°C (18 hr) and 70°C (2 hr) similar yields
of 10 can be isolated depending on the reaction temperature and reaction time chosen. We
continued to explore the vinyl amide substrate scope of this hydrothiolation reaction with N-Boc-
Cysteine methyl ester (8) at 57°C. Table 5 presents the scope of enamide and enecarbamate
substrates that were reacted with N-Boc-Cysteine methyl ester (8). Again, we found that the anti-
Markovnikov hydrothiolation products can be isolated in moderate to good yields from an N-
Boc-derived enecarbamate (10), a secondary enamide (11a), and from primary enamides of
varying functionalities from aryl to amino acid derived (11b-11d). Unfortunately, when the
reaction conditions were applied to reactions using simple alkyl thiols, no desired products were
isolated, even with the assistance of elevated temperatures (Table 6, Entries 1-6).
Table 4. Initial and optimized reaction conditions.
O
O
O
O
NH
O
O
O
SH
+
O
O
S
NH
H2O
NH
NH
O
8
9
10
O
O
Entrya
% Yield 4b
Time
Temperature
1
2
3
4
5
18 hr
48hr
18 hr
18 hr
2 hr
RT
10%
35%
65%
75%
75%
RT
37°C
57°C
75°C
a. Reactions were run with 1.2 mmol of 8 and 1.0 mmol of 9 in 0.2 M
H2O and monitored by TLC. b. Isolated yields after column
chromatography.

Table 5. Results for the hydrothiolation of varying enamides and enecarbamates with N-
Boc-Cysteine methyl ester (8).
R1
O
O
O
NH
R1
O
O
O
SH
NH
O
O
S
+
NH
NH
NH
H2O
NH
8
11
O
O
O
O
NH
O
N
O
S
O
S
O
O
O
O
NH
10, 75%
11a, 73%
O
O
O
O
NH
O
NH
O
O
S
O
O
S
O
NH
O
O
Br
11b, 78%
11c, 69%
O
NH
O
O
O
S
O
NH
N
O
O
11d, 72%
Reactions were run with 1.2 mmol of 8 and 1.0 mmol Enamide or
Enecarbamate in 0.2 M H2O for 18 hr at 57 °C and monitored by
TLC. Isolated yields after column chromatography.
Table 6. Reactions with alkyl thiols.
R1
NH
O
O
O
R1
S
SH
H2O
+
NH
O
9
Entrya
R1
% Yield 4
Temperature
1
2
3
4
5
6
Ethyl
RT
RT
NR
NR
NR
NR
NR
NR
Isopropyl
Octyl
RT
Ethyl
75°C
75°C
75°C
Isopropyl
Octyl
a. Reactions were run with 1.2 mmol of 8 and 1.0 mmol of 9 in 0.2 M
H2O and monitored by TLC.

On the basis of the above results and related literature, we believe that water has a
specific role in this reaction (Scheme 1).18,19,25 In our initial reactions we found that the anti-
Markovnikov hydrothiolation product (4) for the reaction of thiophenol (1) to N-vinyl acetamide
(2) in acetonitrile was isolated in 15% yield after 18 hours (Table 1, entry 7). In contrast, when
the reaction is run in water for 18 hours the anti-Markovnikov hydrothiolation product (4) is
isolated in 80% yield (Table 1, entry 9). In order to explore the mechansim in more depth a series
of reactions were done. Initial reactions were set up to explore the possibility of a radical based
mechansim (Table 7, Entries 1 and 2). Under standard AIBN condition the anti-Markovnikov
hydrothiolation product (4) was isolated at 45% yield. When the control experiment without
AIBN was done only 12% of 4 was isolated. Reactions run in other organic solvents without
radical initators and light were explored. Hydrothiolation product 4 was isolated in poor to
moderate yield in these entries (Table 7, Entries 3-7) likely by a standard alkene addition
mechanism. None of these entries (Table 7, Entries 3-7) performed as well as when water was
the solvent (Table 7, Entries 10). It was also determined that acidic and basic aqueous conditions
resulted in no reation (Table 7, Entries 8 and 9). A competition experiment was also done
between a 1:1 mixture thiophenol and 4-bromo-thiophenol (Table 8). We found that both anti-
Markovnikov hydrothiolation product 4 and 7e can be isolated in a 4:1 ratio. From these results
we believe that water has a specific and important role in improving this reaction. We also
looked at other possible nucleophiles with similar pKa profiles to thiophenol (1). Unfortunately,
when the reaction conditions were applied to these potential nucleophiles, no desired products
were isolated (Table 9, Entries 1-3). A plausible mechanism involves water promoting the
reaction through hydrogen bond formation with the hydrogen of the thiol, thus increases the
nucleophilicity of the thiolate ion. It may be further speculated that addition of the thiolate anion
to the enamide takes place in a concerted manner with steric factors controlling the
regioselectivity leading to the anti-Markovnikov product (Scheme 1).25

Table 7. Reactions to explore the hydrothiolation mechansim.
O
O
SH
S
NH
NH
+
1
2
4
Entrya
% Yield 4b
Additives
Solvent
40%
15%
25%
15%
35%
55%
45%
NR
Toluene
Toluene
THF
1
2
AIBN
None
None
None
None
None
None
None
None
None
3
DMF
4
MeOH
ACN
5
6
DCM
7
2M NaOH
3M HCl
H2O
8
NR
9
85%
10
a. Reaction was run with 1.2 mmol of 1 and 1.0 mmol 2 in 0.2 M
H2O for 18 hr and monitored by TLC. b. Isolated yields after column
chromatography.
Table 8 . Competition reaction.
O
O
O
NH
SH
SH
S
S
NH
NH
+
+
Br
Br
2
1
4
7e
Entrya
% Yield 4
% Yield 7e
Solvent
H2O
1
64%
16%
a. Reaction was run with 1.2 mmol of 1 and 1.0 mmol 2 in 0.2 M
H2O for 18 hr and monitored by TLC. b. Isolated yields after column
chromatography.

Table 9 . Hydrothiolation reaction with other nucleophiles.
R1
NH
O
O
R1
S
X
H2O
+
NH
O
2
Entrya
% Yield 4
X
Temperature
1
2
3
Phenol
Aniline
RT
RT
RT
NR
NR
NR
MeO-Ala-NH2 HCl
a. Reactions were run with 1.2 mmol of 8 and 1.0 mmol of 9 in 0.2 M
H2O and monitored by TLC.
O
O
O
R1 NH
O
R1 NH
HS R2
H2O
R1 NH
R1 NH
H
H
S
S
R2
R2
S
R2
H
O
H
H
O
H
Scheme 1. Proposed mechanism for the aqueous hydrothiolation reaction.
Conclusion
In conclusion, we have developed a very simple and efficient metal-free methodology for
the addition of thiols to enamides and enecarbamates in water without any additives producing
the anti-Markovnikov thioether products. The significant advantages offered by this method are
simple operation, mild and environmentally friendly experimental conditions that are compatible
with various functionalities, anti-Markovnikov regioselectivity, and moderate to very good yields
of isolated thioether products. This methodology thus provides a very convenient and
synthetically useful approach to preparing chemically useful thioethers. Further studies on the
application of this methodology to the thiol selective conjugation of enamides and enecarbamates
to Cysteine containing peptides and proteins are currently in progress.

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

1. Castarlenas, R., DiꢀGiuseppe, A., Pérez-Torrente, J. J. and Oro, L. A., Angew. Chem. Int. Ed.,
2013, 52, 211.
2. Kondo, T, Mitsudo, Chemical Reviews, 2000, 100, 3205.
3. Beletskaya, I. P., Ananikov, V. P., Eur. J. Org. Chem., 2007, 3431.
4. Denmark, S.E., Cresswell, A.J., The Journal of Organic Chemistry, 2013, 78, 12593.
5. Sabarre , A., Love, J, Organic Letters, 2008, 10, 3941.
6. Trost, B.M., Bridges, A.J., Journal of the American Chemical Society, 1976, 98, 5017.
7. McGrath, N.A., Brichacek, M., Njardarson, J.T., Journal of Chemical Education, 2010, 87,
1348.
8. Hoyle, CharlesꢀE. and Bowman, ChristopherꢀN., Angewandte Chemie International Edition,
2010, 49, 1540.
9. Hoyle, C. E., Lee, T. Y. and Roper, T., J. Polym. Sci. A Polym. Chem., 42, 5301.
10. Kuniyasu, H., Ogawa, A., Sato, K., Ryu, I., Kambe, N., Sonoda, N., Journal of the American
Chemical Society, 1992, 114, 5902.
11. Pritzius, A. B., Breit, B., Angew. Chem. Int. Ed., 2015, 54, 3121.
12. Di Giuseppe, A., Castarlenas, R., Pérez-Torrente, J.J., Crucianelli, M., Polo, V., Sancho, R.,
Lahoz, F.J., Oro, L.A., \Journal of the American Chemical Society, 2012, 134, 8171.
13. Screttas, C.G., Micha-Screttas, M, The Journal of Organic Chemistry, 1979, 44, 713.
14. Weïwer,M., Coulombel, L., Duñach, E., Chem. Commun., 2006, 10, 332.
15. Tamai, T., Ogawa, A., The Journal of Organic Chemistry, 2014, 79, 5028.
16. Tamai, T., Fujiwara, K., Higashimae, S., Nomoto, A., Ogawa, Organic Letters, 2016, 18,
2114.
17. Kennemur,J.L., Kortman, G.D., Hull, K.L, Journal of the American Chemical
Society, 2016, 138, 11914.
18. Tyson, E.L., Ament, M.S., Yoon, T.P, The Journal of Organic Chemistry, 2013, 78, 2046.
19. Tyson, E.L., Ament, M.S., Yoon, T.P., The Journal of Organic Chemistry, 2014, 79, 1427.
20. Fadeyi, O.O., Mousseau, J.J., Feng, Y., Allais, C., Nuhant, P., Chen, M.Z., Pierce, P.,
Robinson, R., Organic Letters, 2015, 17, 5756.
21. Xu, J., Boyer, C., Macromolecules 2015, 48, 520.
22. Gao, X.F., Du, J.J., Liu, Z., Guo, J., Organic Letters, 2016, 18, 1166.
23. Zhao, G., Kaur, S., Wang, T., Organic Letters, 2017, 19, 3291
24. Liu, H., Chung, H., ACS Sustainable Chemistry & Engineering , 2017, 5, 9160.
25. Ranu, B.C., Mandal, T., Synlett 2007, 6, 0925.
26. Prier, C.K., Rankic, D.A., MacMillan, D.W., Chemical Reviews, 2013, 113 , 5322.

Aqueous Metal-Free 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 and metal-free thiol-ene reaction.
 Anti-Markovnikov selective thiole-ene reaction.
 Hydrothioaltion reaction of enamides and enecarbamates in an aqueous medium is
presented.


This protocol is operationally simple, mild, and atom-economical.
This process provides access to thioethers from available thiols and a variety of enamides and
enecarbamates.