Transition-metal-free regioselective thiocyanation of phenols, anilines and heterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.12.043

An expedient direct and regioselective thiocyanation of phenols, anilines and heterocycles is described. Transformation is realized via the direct C[sbnd]H functionalization under transition metal free conditions at ambient temperature in excellent yields. Method proved to be monoselective and variety of functional groups tolerated the reaction conditions. The practicality of the protocol is demonstrated in gram scale synthesis of a precursor of PPAR δ agonist in excellent yield.

Full text of DOI:10.1016/j.tetlet.2016.12.043

Accepted Manuscript
Transition-Metal-Free Regioselective Thiocyanation of Phenols, Anilines and
Heterocycles
Trimbak B. Mete, Tushar M. Khopade, Ramakrishna G. Bhat
PII:
S0040-4039(16)31689-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.043
TETL 48455
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 November 2016
16 December 2016
18 December 2016
Please cite this article as: Mete, T.B., Khopade, T.M., Bhat, R.G., Transition-Metal-Free Regioselective
Thiocyanation of Phenols, Anilines and Heterocycles, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.12.043
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Transition-Metal-Free Regioselective Thiocyanation of
Phenols, Anilines and Heterocycles
Trimbak B. Mete, Tushar M. Khopade and Ramakrishna G. Bhat*

1
Tetrahedron Letters
Transition-Metal-Free Regioselective Thiocyanation of Phenols, Anilines and
Heterocycles
Trimbak B. Mete, Tushar M. Khopade, Ramakrishna G. Bhat*
Department of Chemistry, Indian Institute of Science Education and Research (IISER), Pune, 411008, Maharashtra, India, E-mail: rgb@iiserpune.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An expedient direct and regioselective thiocyanation of phenols, anilines and heterocycles is
described. Transformation is realized via the direct C-H functionalization under transition metal
free conditions at ambient temperature in excellent yields. Method proved to be monoselctive
and variety of functional groups tolerated the reaction conditions. The practicality of the
protocol is demonstrated in gram scale synthesis of a precursor of PPAR δ agonist in excellent
yield.
Available online
Keywords:
Thiocyanation
Transition-Metal-free
Persulphate
2009 Elsevier Ltd. All rights reserved.
Radical cation
Radical Scavenger
1. Introduction
heavy metal waste is the real drawback of these methods. Most of
these thiocyanation methods were focused on limited substrates,
Organosulfur derivatives are very important class of compounds
with biological importance. Hence, efforts have been devoted to
synthesize organosulfur compounds by directly introducing the
sulfur moieties into the organic scaffolds. Among these, direct
thiocyanation of aromatic and heteroaromatics is one of the most
important and convenient methods for carbon-sulfur bond
formation. Many aryl thiocyanates exhibit potent biological and
pharmacological activities and they are the building blocks of
many biologically active heterocycles and agrochemicals.1
Moreover, aryl thiocyantes are versatile precursors for making
various useful organosulfur compounds such as thiols,2
thioethers,3 thioesters,4 thiocarbamates,5 disulfides,6 sulfur
containing heterocycles7 and many pharamceuticals.1a Owing to
the importance, efforts were made to access the thiocyanates by
different methods.8 Usually, thiocyanates are obtained by direct
electrophilic thiocyanation of arenes or nucleophilic substitution
reaction of the corresponding organic molecules. Even though
some of these traditional methods contributed to the various
synthetic transformations, however, use of toxic transition metal
reagents, corrosive molecular halogen and halogen based
reagents, harsher reaction conditions impede their wide utility.
Certainly, these are the limiting factors for the successful and
wider applications. Some of the reagents that have been explored
for the thiocyanation under various conditions are antimony (V)
mostly on electron rich indoles and closely related N-bearing
heterocycles which are of high reactivity. Some of these methods
are also accompanied by low regio- and chemo-selectivity. In the
recent years, efforts have been made to improvise these classic
protocols using specialized reagents. Some of these methods are
thiocyanation of aryl organometallic compounds,15 copper
promoted thiocyanation of aryl iodides,16 direct cyanation of
organosulfur compounds17 thiocyanation of arylboronic acids.18
However, these methods are not devoid of the use of transition
metals or harsh reaction conditions and they generate metal waste
in the process. Efforts have also been focused on the metal free
and visible light promoted thiocyanation in an elegant way.19
However, most of the protocols of thiocyanation available in the
literature are executed on indoles, imidazoheterocycles and
nitrogen containing activated heterocycles.8a-g,12,19 Also,
thiocyanation of aromatic amines and nitrogen heterocycles are
reported to be facile. On the other hand, interestingly
thiocyanation of phenols are less explored20 and not studied
extensively possibly due to its intrinsic electronic nature.
Practical use of some of these available methods are seriously
limited due to the use of toxic Pb(SCN)2, molecular halogen, and
formation of side products. Thiocyanation of phenols are not
facile especially with electron withdrawing groups and have
limited substrate scope. Practical, efficient and highly selective
transition metal free transformations are gaining great importance
for the last few years.21 Synthetic organic chemists have been
focusing on the approaches that are transition metal free in nature
and they are increasingly becoming popular. Hence, efforts are
being made for the transition metal free direct C-H
functionalization of organic molecules. Phenol and heterocycle
scaffolds are core to many bioactive molecules and
chloride/lead
(II)
thiocyanate,9
arylthallium
bistrifluoroacetate/potassium thiocyanate,10 Zn(SCN)2/Cl2,11 ceric
ammonium nitrate (CAN)/ammonium thiocyante,8c Mn(OAc)3,12
Cu(SCN)2/Cl2,13 NaSCN/Br2, . These methods greatly rely either
14
on the use of heavy and toxic transition metals, or on corrosive
halogen and stronger oxidants. Use of these stoichiometric
reagents, oxidants and in turn generation of a large amount of

2
pharmaceuticals. In this regard, development of transition metal
free, more efficient and practical protocol for the direct
thiocyanation of diverse phenol, aniline and heterocycle
derivatives is highly desirable. Herein, we report novel, practical
and direct transition metal free regioselective thiocyanation of
phenols, aromatic amines and heterocycles with inexpensive
NH4SCN under mild conditions. This method has several
advantages such as broad substrate scope and transition metal
free reaction condition.
Reaction proceeded in acetonitrile affording 3a in 85% yield.
Gratifyingly, when solvent DCM was used, the reaction
proceeded smoothly by affording 3a in excellent yield (95%) in 4
hours at room temperature.
Notably, the reaction also proceeded in water yielding 3a in 68%.
DCM was found to be the best solvent after screening the
reaction in few other solvents. Based on further investigation, we
observed that both (NH4)2S2O8 and Na2S2O8 were effective for
the direct thiocyanation of the 1a. Further studies revealed that 2
equivalents of K2S2O8 were crucial for the transformation and for
the higher yield. However, we observed the incomplete
conversion, when the amount of K2S2O8 was reduced to 1-1.5
equivalents. Importantly, reaction did not work in the absence of
oxidant K2S2O8 (entry 15). The oxidants such as molecular
oxygen and TBHP did not facilitate the reaction. With the
optimized reaction conditions in hand, to generalize the
methodology, the substrate scope of this metal free direct
thiocyanation was investigated (Table 2).
Results and Discussions
At the outset of our investigation, we selected 2,6-dimethyl
phenol 1a and ammonium thiocyanate 2 as model substrates. In
order to optimize the reaction conditions different oxidants,
solvents, and conditions were explored. In presence of 2 equiv. of
oxone in DCE at room temperature, reaction afforded trace
amount of the expected product. Several solvents such as
CH3CN, THF, DCM were screened; however, reaction did not
afford the expected product. Later, the reaction of 1a and 2 in
presence of K2S2O8 in acetic acid at room temperature afforded
the thiocyanated product 3a in 70 % yield (entry 4).
Table 2 Direct Regioselective Thiocyanation of Phenol derivativesa
Table 1 Optimization of the reaction conditionsa
Entry
Oxidanta
Solvent
Time (h)
Yieldb (%)
1
2
Oxone
TBHP
12
12
12
12
12
4
trace
NR
NR
70
DCM
DCM
3
O2
DCM
4
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)S2O8
Na2S2O8
No Reagent
Acetic
Acetonitril
DCM
5
85
6
95
7
4
93
DCE
aReaction conditions: Substituted phenols and Anisoles (0.1 mg).
NH4SCN (1.5 equiv), DCM, (2 mL), reaction time (4 h), Isolated yields after
column chromatography given in brackets. rt (24 oC)
8
12
6
50
THF
9
68
water
To our delight, various substrates underwent a facile direct
and regioselective thiocyanation under optimized reaction
conditions by affording the desired products in good to excellent
yields.22 Various phenol and anisole derivatives with electron
donating and withdrawing groups reacted efficently under the
optimized reaction conditions to afford the corresponding desired
products (entry 3a-3m, Table 2). It is noteworthy that direct
thiocyanation exclusively occurred at the para position. The
reaction found to be facile, monoselective and did not form any
disubstituted products. Phenols bearing electron withdrawing
groups such as iodo, bromo, cyano, aldehyde resulted in
relatively lower yields of the corresponding products (3g-3j).
However, cyano and aldehyde functional groups tolerated the
reaction conditions. While the o-nitrophenol did not react under
the optimized reaction condition. The thiocyanate functional
group was confirmed by the characteristic IR absorption peak
10
11
12
13
14
15
12
12
12
4
73
Methanol
60
1,4-
trace
94
DMF
DCM
DCM
DCM
4
93
12
NR
aReaction conditions: 1a (0.1 g), 2 (1.5 equiv), Oxidant (2 equiv, 1.64 mmol),
solvent (2 mL), rt (24 oC), 4 h, bIsolated yield

3
(~2160 cm-1) and 13C NMR data. We did not observe the
formation of any isothiocyanates. Reactions of naphthalene
derivative (1n) and 3,4-dimethyl phenol (1o) under the reaction
conditions resulted in the corresponding stable oxathioimines
(3n, 3o).
optimized reaction condition on a 3g scale in excellent yield
(94%, eq 4). Easy, practical and metal free reaction conditions
demonstrated the practical utility of this method for the direct
thiocyanation.
Scheme 1 Thiocyanation on a Gram Scalea
Encouraged by the success, we turned our attention towards the
relatively more reactive anilines and heterocycles. Different
indole derivatives (4a-4g) under the optimized conditions
underwent direct C-3 thiocyanation easily in excellent yields (5a-
5g, Table 3). Indoles bearing –CN, -NO2, -Br groups reacted
regioselectively to afford the corresponding thiocyanted products
(5c-5e) in good to excellent yields. Notably, 2, 2’-bithiophene
(4h) reacted with ease to afford the C-2 mono thiocyanated
product 5h in excellent yield. Later, we explored the reactivity of
various aniline derivatives. All the aniline derivatives under the
reaction conditions afforded thiocyanted products (5i-5n) in good
to excellent yields.
Table
3 Direct and Regioselective Thiocyanation of Anilines and
Heterocyclesa
aReaction conditions: Phenol, Aniline and Indole (2 g), K2S2O8 ( 2 equiv),
DCM (20 mL), rt (24 oC), time (6 h), 2-methyl phenol, 1p (3 g, 30 mL)
In order to gain further insight into the mechanism, we treated the
reaction mixture with the radical scavenger TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxyl). The thiocyanation reaction did
not proceed even after prolonged reaction time and this indicated
that most likely free radical pathway might have been involved
during the course of the reaction. K2S2O8 is known to generate a
•-
strong, short-lived oxidant-sulphate radical anion (SO4 ) easily.
The sulphate radical anion (Eo = 2.6 V) is known to generate
radical cation on interaction with the low ionization potential
aromatics.23
In order to investigate further the formation of a radical cation
intermediate, we carried out UV−Vis spectroscopy studies. We
observed an intense UV absorption band in the visible region
between 400 to 500 nm during the reaction of phenol 1a with
K2S2O8 at rt (see supporting Information). This study strongly
favours the formation of radical cation intermediate during the
reaction and is in accordance with the previous literature
findings.24
aReaction conditions: Substituted Aromatic amines and Heterocycles (0.1 g).
NH4SCN (1.5 equiv), DCM, (2 mL), reaction time (4 h), rt (24 C), Isolated
yields after column chromatography given in brackets.
o
It is very important to note that direct thiocyanation was highly
regioselective and occurred at para position. Substrates bearing
electron withdrawing groups afforded the thiocyanated products
in excellent yields. However, para substituted anilines resulted in
the formation of the corresponding stable azathioimines (5o, 5p)
via ortho thiocyanation.
Scheme 2 Proposed Mechanism for the direct Thiocyanation
In order to make this approach more practical and for the future
development, we extended this method on gram scale (Scheme
1). 2,6-dimethyl phenol 1a, 2,6-dimethyl aniline 4i and indole 4a
afforded the corresponding thiocyanated products (3a, 5i, 5a, eq.
1-3) in excellent yields. GW501516 is a well known, most potent
and selective peroxisome proliferator-activator receptor
δ
(PPARδ) agonist. Compound 3p (Scheme 1), precursor of
GW501516 was earlier synthesized using NaSCN and molecular
bromine.2 Using our protocol we synthesized compound 3p under

4
12. Pan, X-Q.; Lei, M-Y.; Zou, J-P.; Zhang, W. Tetrahedron Lett. 2009,
50, 347.
13. Kaufmann, H. P.; Kulchler, K. A. Eur J. Inorg. Chem. 1934, 67, 944.
14. Kaufmann, H. P.; Oehring, W. Eur J. Inorg. Chem. 1926, 59, 187.
15. Takagi, K.; Takachi, H.; Sasaki, K. J. Org. Chem. 1995, 60, 6552.
Based on these investigations and previous literature, the
plausible mechanism is proposed (Scheme 2). Potassium
persulphate would decompose to generate very strong oxidant
•-
sulphate radical anion (SO4 ), which in turn oxidizes the aromatic
compound to form radical cation intermediate I. Simultaneous
nucleophilic addition of thiocyanate anion to the cation
intermediate would lead to the formation of radical intermediate
II. Ultimately the loss of hydrogen radical from II would afford
the desired compound 3a. Alternatively, further oxidation of the
intermediate II will lead to the formation of cation intermediate
III. Finally, the elimination of H+ from this intermediate would
afford the desired product 3a.
16. Yang, Y. F.; Zhou, Y.; Wang, J. R.; Liu, L.; Guo, Q. X. Chin. Chem.
Lett. 2006, 17, 1283.
17. Still, I. W. J.; Watson, I. D. J. Synth. Commun. 2001, 31, 1355.
18. Sun, N.; Che, L.; Mo, W.; Hu, B.; Shen, Z.; Hu, X. Org. Biomol. Chem.
2015, 13, 691.
19. (a) Mitra, S.; Ghosh, M.; Mishra, S.; Hajra, A. (b) Fan, W.; Yang, Q.;
Xu, F.; Li, P. J. Org. Chem. 2014, 79, 10588.
20. (a)Kaufmann, H. P.; Oehring, W. Ber, 1926, 59B, 187;(b)
Likhosherstov, M. V.; Petrov, A. A. J. Gen. Chem. (USSR) 1933, 3,
183; (c) Kaufmann, H. P.; Kulchler, K. A. Ber, 1934, 67B, 944; (d)
Kita, Y.; Takeda, Y.; Okuno, T.; Egi, M.;IIo, K.;Kawaguchi, K.; Akai,
S. Chem. Pharm. Bull. 1997, 45, 1887; (c) Prakash, O.; Kaur, H.;
Pundeer, R.; Dhillon, R. S.; Singh, S. P. Synth. Commun. 2003, 33,
4037.
21. (a) Wang, H.; Guo, L-N; Duan, X-H. Org. Lett. 2013, 15, 5254; (b) Lin,
J-P.; Zhang, F-H.; Long, Y-Q. Org. Lett. 2014, 16, 2822; (c) Siddaraju,
Y.; Lamani, M.; Prabhu, K. R. J. Org. Chem. 2014, 79, 3856; (d)
Shichao, L.; Gong, Y.; Zhou, D. J. Org. Chem. 2015, 80, 9336; (e)
Yang, H; Duan, X-H.; Zhao, J-F.; Guo, L-N. Org. Lett. 2015, 17, 1998;
(e) Gesu, A.; Pozzoli, C.; Torre, E.; Aprile, S.; Pirali, T. Org. Lett.
2016, 18, 1992; (f) Yang, D.; Yan, K.; Wei, W.; Li, G.; Lu, S.; Zhao,
C.; Tian, L.; Wang, H. J. Org. Chem. 2015, 80, 11073.
22. General Procedure for the synthesis of Thiocyanatophenols,
Thiocyanatoindoles and Thiocyanatoanilines: In an oven dried round
bottom flask containing a mixture of 2,6-dimethyl phenol 1a (100 mg,
0.82 mmol), ammonium thiocyanate 2 (94 mg, 1.23 mmol) and
potassium persulphate (443 mg, 1.64 mmol) in DCM (2 mL) were
stirred for 4 h. Progress of the reaction was monitored by TLC. Upon
completion, the reaction mixture was filtered through sintered funnel
containing silica and sodium sulphate. The Filtrate was concentrated
under reduced pressure to afford the crude product 3a. This was purified
by column chromatography (EtOAc:Hexane) to furnish the pure
compound 3a as a white solid (139 mg, 95% yield). Similar procedure
was used for the thiocyanation of anisoles, anilines and heterocycles.
23. (a) Minisci, F.; Citterio, A. Acc. Chem. Res. 1983, 16, 27; (b) Hey, D.
H.; Jones, G. H.; Perkins, M. J. J. C. S. Perkin I, 1972, 118.
24. (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujata, S.; Mitoh, S.;
Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684. (b)
Sankararaman, S.; Haney, W. A.; Kochi, J. K. J. Am. Chem. Soc. 1987,
109, 7824.
Conclusions
In conclusion, we have demonstrated the transition-metal-free
regioselective and monoselective direct thiocyantion of phenols,
anilines and other aromatics under mild conditions. The use of
commercially available and inexpensive K2S2O8 has been
explored for the thiocyantion in an efficient manner. Most
importantly, this protocol proved to be scalable on a multi gram
quantity. The desired products were obtained in good to excellent
yields and a wide range of functional groups were tolerated.
Initial understandings suggested that reaction proceeded via
radical cation intermediate. This protocol presents a new and
viable path to access thiocyanated aromatics and precursors of
bioactive molecules.
Acknowledgments
T. B. M. and T. M. K thank CSIR, New Delhi for the fellowship.
Financial support from IISER-Pune is gratefully acknowledged
by the authors to carry out this research work.
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5
Highlights
 Transition metal free protocol
 Reaction is regioselective and
monoselective in nature
 Scalable-Multi Gram Synthesis
 Radical pathway
 28 examples up to 97% yield