Rapid and efficient thiocyanation of phenols, indoles, and anilines in 1,1,1,3,3,3-hexafluoro-2-propanol under ultrasound irradiation

Article abstract of DOI:10.1080/00397911.2017.1390139

An efficient ultrasound-promoted thiocyanation of phenols, indoles, and anilines in the presence of N-chlorosuccinimide and NH₄SCN using 1,1,1,3,3,3-hexafluoro-2-propanol as the solvent has been developed. The major features of the present protocol include the mild reaction conditions, short reaction times, good to excellent yields, and broad substrate scope. Moreover, scale-up synthesis can be achieved and the solvent can be easily recovered and reused.

Full text of DOI:10.1080/00397911.2017.1390139

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Rapid and efficient thiocyanation of phenols,
indoles and anilines in 1,1,1,3,3,3-hexafluoro-2-
propanol under ultrasound irradiation
Zhonghao Wang, Liang Wang, Qun Chen & Ming-yang He
To cite this article: Zhonghao Wang, Liang Wang, Qun Chen & Ming-yang He (2017): Rapid and
efficient thiocyanation of phenols, indoles and anilines in 1,1,1,3,3,3-hexafluoro-2-propanol under
ultrasound irradiation, Synthetic Communications, DOI: 10.1080/00397911.2017.1390139
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1390139
View supplementary material
Accepted author version posted online: 23
Oct 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [UAE University]
Date: 24 October 2017, At: 06:01

Rapid and efficient thiocyanation of phenols, indoles and
anilines in 1,1,1,3,3,3-hexafluoro-2-propanol under
ultrasound irradiation
Zhonghao Wang
School of Petrochemical Engineering and Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, Changzhou University, Changzhou, P. R. China
Liang Wang
School of Petrochemical Engineering and Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, Changzhou University, Changzhou, P. R. China
Qun Chen
School of Petrochemical Engineering and Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, Changzhou University, Changzhou, P. R. China
Ming-yang He
School of Petrochemical Engineering and Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, Changzhou University, Changzhou, P. R. China
1

Address correspondence to Qun Chen, School of Petrochemical Engineering and Jiangsu Key
Laboratory of Advanced Catalytic Materials & Technology, Changzhou University, Changzhou
213164, P. R. China. Tele: + 86-519-86330263. Fax: + 86-519-86330251. E-mail:
lwcczu@126.com
Address correspondence to Ming-yang He, School of Petrochemical Engineering and Jiangsu
Key Laboratory of Advanced Catalytic Materials & Technology, Changzhou University,
Changzhou 213164, P. R. China. Tele: + 86-519-86330263. Fax: + 86-519-86330251. E-mail:
hemingyangjpu@yahoo.com
ABSTRACT
An efficient ultrasound-promoted thiocyanation of phenols, indoles and anilines in the
presence of N-chlorosuccinimide (NCS) and NH4SCN using 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) as the solvent has been developed. The major features of the present protocol include the
mild reaction conditions, short reaction times, good to excellent yields and broad substrate scope.
Moreover, scale-up synthesis can be achieved and the solvent can be easily recovered and reused.
GRAPHICAL ABSTRACT
2

KEYWORDS: 1,1,1,3,3,3-hexafluoro-2-propanol; thiocyanation; ultrasound irradiation; green
chemistry
1. Introduction
Aryl thiocyanates have been receiving considerable attention since thiocyano groups
widely exist in natural products and pharmaceutical ingredients.[1,2] The thiocyano groups often
serve as useful blocks for the preparation of valuable sulfur-containing compounds, and can be
readily transformed into other useful functional groups.[3–13] Thereby, the introduction of a
thiocyano group into a molecule is of great importance and still remains a challenge. Over the past
decades, a series of synthetic protocols have been developed for thiocyanation of arenes.[14–25]
However, the reported procedures still associated with some disadvantages such as the use of a
large excess of strong oxidizing agents, the use of the expensive metal catalysts, long reaction
times or unsatisfactory yields.
Recently, we focused on developing mild, efficient and green electrophilic thiocyanation
protocols.[26] The utilization of N-thiocyanatosuccinimide, XSCN (X＝halogen), which was
generated in situ from from N-halosuccinimide and an inorganic thiocyanate has proven to be
successful.[27,28] However, for the cheap and readily available NCS/NH4SCN combination, it
showed relatively lower reactivity compared with the NBS/NH4SCN combination. This
phenomenon may be ascribed to the strong N—Cl bond. An additive such as thiourea was thus
required to accelerate the reaction rate through hydrogen bonding. It is well known that HFIP has
3

some unique properties such as high hydrogen bonding donor ability, high ionizing power, low
nucleophilicity and good solvation capability with water, making them popular as green solvent in
organic transformations.[29,30] We envisioned that HFIP can activate NCS via hydrogen bonding,
thereby facilitating the cleavage of N—Cl bond and the formation of ClSCN. In another aspect, the
utilization of ultrasound irradiation in organic synthesis has been received much attention since it
involves energy conservation and generates minimal waste. Particularly, better yields and
chemoselectivity can be achieved under milder reaction conditions within shorter reaction
times.[31–35] Herein, we report a rapid and efficient thiocyanation protocol using NCS/NH4SCN
combination in HFIP under ultrasound irradiation (Scheme 1).
2. Results and Discussion
Initially, phenol 1a and ammonium thiocyanate were selected as the substrates to optimize
the reaction conditions. The results are summarized in Table 1. The solvents were vital for this
reaction. Reactions in acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
1,4-dioxane, and methanol afforded the product 2a in only trace yield. Switching the solvent to
tetrahydrofuran (THF), dichloromethane (DCM), ethyl acetate (EtOAc) and 2,2,2-trifluoroethanol
(TFE) afforded the desired products in 60%, 86%, 52%, and 81% yield, respectively (entries 2, 3,
7 and 9). Pleasingly, it was found that the reaction proceeded very quickly in HFIP under ultrasonic
irradiation, giving the desired product in 90% yield after 5 minutes (entry 10). These results
suggested that both dissolving capacity and hydrogen bonding donor ability of the solvent played
4

important roles in this reaction. Further increasing the amounts of ammonium thiocyanate and
NCS to 1.5 equivalents led to a full conversion of phenol, giving the desired product 2a in almost
quantitative yield (entry 11). Moreover, slight decrease in the product yield was observed for when
ammonium thiocyanate was replaced by NaSCN or KSN (entries 12 and 13). Expectedly, 2a was
not observed in the absence of NCS, indicating N-thiocyanatosuccinimide was the key
intermediate (entry 14). Particularly, the reaction selectively took place at the para position, and
nearly no chlorinated phenol was observed as the by-product. This results indicated that the
reaction between NCS and NH4SCN was much faster than the chlorination of phenol. Finally, only
37% yield of 2a was obtained in the absence of ultrasonic irradiation (entry 15). This phenomenon
was attributed that ultrasonic irradiation could greatly enhance the reaction rates via increasing the
mixing between reactants and accelerating the diffusion of reactants and products.[36]
The thiocyanation reaction of various phenols under the optimized reaction conditions was
then examined (Table 2). To our delight, phenols with electron-donating groups such as methyl,
tert-butyl and methoxyl underwent the reaction smoothly to afford the corresponding products in
excellent yields (90~99%). Anisole also showed good activity to give product 2k in 95% yield.
Notably, the thiocyanation reaction exclusively occurred at the para position. For the meta-
substituted phenols, excellent yields could be obtained by prolonging the reaction time (2g and
2h). Substrate bearing electron-withdrawing group such as bromo also survived the reaction
conditions, delivering the desired product 2f in 72% yield after 30 min. Moreover, the
5

thiocyanation of 1-naphthol took place at the 8-position of the naphthalene ring, resulting in
product 2j in 93% yield. Interestingly, a stable oxathioimine 2i was isolated as the major product
in 84% yield when using p-methylphenol as the substrate.[37]
Encouraged by these results, we next investigated the thiocyanation of indoles and anilines
(Table 3). As seen from the results, a series of indoles and anilines showed good activities to
provide the corresponding products in good to excellent yields. For indole derivatives, functional
groups such as halo, alkoxy, alkyl, ester and nitro were well tolerated under the standard
conditions, albeit substrates with electron-withdrawing groups afforded relatively lower yields
(5c~5g). N-methyl indole also reacted smoothly to deliver the desired product in 93% yield, while
N-Boc indole gave only trace amount of the desired product. Interestingly, when 3-methyl-1H-
indole was employed as the substrate, both products 5l and 5m were observed in 24% and 47%
yields, respectively. Generally, electrophilic thiocyanation at 3-position of 3-methyl-1H-indole
could deliver product 5l.[24,38] Meanwhile the thiocyanation reaction could also occur at the 2-
position due to the steric hindrance. The 2-thiocyanated indole could be further attacked by
succinimide anion or Clˉ to lose a CNˉ. Then the generated 3-methyl-1H-indole-2-thiolate was
protonated and rearranged to give the product 5m.[26] Different aniline derivatives were then
checked and excellent yields were obtained. It was worth noting that the thiocyanation reaction
was regioselectively occurred at the para position. Similar with ortho-substituted phenols, the
benzo[d]thiazol-2-amines 6g and 6h were isolated as the major products when using para-
6

substituted anilines as the substrates. This result was attributed that that ortho-thiocyanation
reaction occurs at the first step, followed by the addition of hydroxyl or amino group to the
thiocyanato group.[37] Moreover, N-substituted aniline derivatives such as N-methylaniline and
acetanilide also showed good activities, affording the desired products 6f and 6i in good yields.
Furthermore, gram-scale synthesis of product 2a was performed to show the practical
application of the present protocol (Scheme 2). The reaction reacted well and afforded 2a in 95%
yield (10 mmol scale). Moreover, the solvent HFIP could be recovered via evaporation.
Some control experiments were then conducted to gain insight into this reaction. For
example, when a radical inhibitor 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) was added to the
mixture, the reaction still proceeded smoothly without obviously decreasing of the yield of 2a,
indicating that the reaction did not involve a radical pathway. According to previous literature and
our experiment results,[26–28] a plausible reaction mechanism was proposed in Scheme 3. First,
+
reaction of NCS and NH4SCN generated N-thiocyanatosuccinimide. The addition of SCN to
phenol provided intermediate A, which was attacked by B to deliver the final product 2a via
deprotonation. In these processes, HFIP was a good solvent, and meanwhile, could activate NCS
via hydrogen bonding to accelerate the formation of N-thiocyanatosuccinimide, namely the SCN
cation. In another aspect, the utilization of ultrasonic irradiation also greatly enhanced the reaction
rate.
3. Conclusion
7

In summary, we have developed a facile and efficient thiocyanation reaction of phenols,
indoles and anilines using NCS/NH4SCN combination in HFIP under ultrasonic irradiation. In the
present protocol, HFIP not only worked as a good solvent but also greatly accelerated the formation
of SCN cation via activation of NCS through hydrogen bonding. Mild reaction conditions, good
to excellent yields, as well as broad substrate scope were the major features of the present protocol.
Moreover, gram-scale synthesis could be achieved, demonstrating its practical use in organic
synthesis.
4. Experimental
4.1 Apparatus and analysis
All reagents were obtained from local commercial suppliers and used without further
purification. The progress of the reaction was monitored by TLC using analytical-grade silica gel
plates (GF254) under UV light. 1H NMR and 13C NMR spectra were recorded CDCl3 or DMSO-
d6 at 300 MHz and 75 MHz (Bruker Avance) instrument respectively, using TMS as internal
standard. Chemical shifts are given in parts per million (δ, ppm) and the coupling constants J are
given in Hz. Mass spectrometry was performed on an LCMS-2010 EV (Shimadzu) instrument
with an ESI source. High-resolution mass spectrometry (HRMS) was performed on a TOF MS
instrument with an ESI source. The sonication was performed in a CD-4831 ultrasonic cleaner
(with a frequency of 50 kHz and a nominal power 170 W; Codyson Co. Ltd., China). The reaction
temperature of the water bath was controlled at room temperature (25 oC).
8

4.2 General procedure for thiocyanation of phenols, indoles and anilines
To a solution of N-chlorosuccinimide NCS (1.5 mmol, 200.3 mg) in HFIP (5 mL) was
added ammonium thiocyanate (1.5 mmol, 114.2 mg) at room temperature. The mixture was stirred
for 5 min. Then phenol (indole or aromatic amine) (1 mmol) was added immediately, and the
mixture was placed in an ultrasound bath (monitored by TLC). After reaction, the HFIP was
removed via evaporation. The residue was extracted with ethyl acetate and washed with water.
The combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatography on silica gel with petroleum
ether/ethyl acetate to afford the pure desired product. (CAUTION: HFIP is highly toxic and
corrosive. It should be used in a fume cupboard with all appropriate precautions taken.)
4.3 Selected spectral data
5-methylbenzo[d][1,3]oxathiol-2-imine (2i):
1H NMR (300 MHz, CDCl3) δ 7.06 (s, 1H), 6.99 (d, J = 1.0 Hz, 2H), 2.33 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 166.5, 149.0, 134.2, 127.5, 123.6, 121.9, 110.7, 21.0. HRMS (ESI) calcd. for
C8H8NOS [M + H] + 166.0321, found 166.0329.
8-Thiocyanatonaphthalen-1-ol (2j):
1H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.34 – 8.17 (m, 2H), 7.88 (d, J = 8.1 Hz,
1H), 7.77 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.62 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 6.98 (d, J = 8.1 Hz,
9

13
1H); C NMR (75 MHz, DMSO-d6) δ 157.3, 136.6, 133.8, 128.7, 125.9, 125.8, 124.3, 123.3,
112.4, 108.7, 107.5. HRMS (ESI) calcd. for C11H8NOS [M + H] + 202.0321, found 202.0315.
Acknowledgements
We gratefully acknowledge the National Natural Science Foundation of China (21302014),
the Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110), and
the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions for
the financial support.
References
[1] Guy, R. G. The Chemistry of Functional Groups, Syntheses and Preparative Applications of
Thiocyanates. In Interscience, Patai, S., Ed.; John Wiley: New York, 1977; p 833, ch. 18.
[2] Castanheiro, T.; Suffert, J.; Donnard, M.; Gulea, M. Chem. Soc. Rev. 2016, 45, 494–505.
[3] Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091–4094.
[4] Varela, J. A.; Castedo, L.; Saa, C. J. Org. Chem. 2003, 68, 8595–8598.
[5] Zhang, Z.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331–4333.
[6] Kamiya, I.; Kawakami, J.; Yano, S.; Namoto, A.; Ogawa, A. Organometallics 2006, 25,
3562–3564.
[7] Wu, F.-Y.; Li, Y.; Feng, H.; Wu, Q.; Jiang, B.; Shi, F.; Tu, S.-J. Synthesis 2011, 43, 2459–
2465.
[8] Melzig, L.; Rauhut, C. B.; Naredi-Rainer, N.; Knochel, P. Chem. Eur. J. 2011, 17, 5362–
5372.
[9] Wang, F.; Chen, C.; Deng, G.; Xi, C. J. Org. Chem. 2012, 77, 4148–4151.
[10] Lu, X.; Wang, H.; Gao, R.; Sun, D.; Bi, X. RSC Adv. 2014, 4, 28794–28797.
[11] Pawliczek, M.; Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, 17, 1716–1719.
[12] Brown, S. P.; Smith, A. B., III. J. Am. Chem. Soc. 2015, 137, 4034–4037.
10

[13] Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J. Angew. Chem. Int. Ed. 2015, 54,
5753–5756.
[14] Zolfigol, M. A.; Khazaei, A.; Mokhlesi, M.; Vahedi, H.; Sajadifar, S.; Pirveysian, M. Sulfur
Silicon Relat. Elem. 2012, 187, 295–304.
[15] Khazaei, A.; Zolfigol, M. A.; Mokhlesi, M.; Pirveysian, M. Can. J. Chem. 2012, 90, 427–
432.
[16] Jana, S.; Chattopadhyay, S. Inorg. Chem. Commun. 2013, 35, 160–163.
[17] Fan, W.; Yang, Q.; Xu, F.; Li, P. J. Org. Chem. 2014, 79, 10588–10592.
[18] Ali, M.; Zarchi, K.; Banihashemi, R. Phosphorus, Sulfur Silicon Relat. Elem. 2014, 189,
1378–1390.
[19] Venkatesham, N.; Reddy, K. R.; Rajanna, K. C.; Veerasomaiah, P. J. Sulfur Chem. 2014,
35, 606–612.
[20] Kokorekin, V. A.; Sigacheva, V. L.; Petrosyan, V. A. Tetrahedron Lett. 2014, 55, 4306–
4309.
[21] Sun, N.; Che, L.; Mo, W.; Hu, B.; Shen, Z.; Hu, X. Org. Biomol. Chem. 2015, 13, 691–696.
[22] Khalili, D. Chin. Chem. Lett. 2015, 26, 547–552.
[23] Khalili, D. New J. Chem. 2016, 40, 2547–2553.
[24] Wang, L.; Wang, C.; Liu, W.; Chen, Q.; He, M. Tetrahedron Lett. 2016, 57, 1771–1774.
[25] Mete, T. B.; Khopade, T. M.; Bhat, R. G. Tetrahedron Lett. 2017, 58, 415–418.
[26] Wang, C.; Wang, Z.; Wang, L.; Chen, Q.; He, M. Chin. J. Chem. 2016, 34, 1081–1085.
[27] Zhang, H.; Wei, Q.; Wei, S.; Qu, J.; Wang, B. Eur. J. Org. Chem. 2016, 2016, 3373–3379.
[28] Chen, Q.; Lei, Y.; Wang, Y.; Wang, C.; Wang, Y.; Xu, Z.; Wang, H.; Wang, R. Org. Chem.
Front. 2017, 4, 369–372.
[29] Khaksar, S.; Talesh, S. M. J. Fluorine Chem. 2012, 140, 95–98.
[30] Khaksar, S. J. Fluorine Chem. 2015, 172, 51–61.
[31] Mason, T. J.; Lorimer, J. P. Sonochemistry: Theory, Application and Uses of Ultrasound in
Chemistry; John Wiley and Sons: New York, 1988.
[32] Einhorn, C.; Einhorn, J.; Luche, J.-L. Synthesis 1989, 1989, 787–813.
[33] Li, J. T.; Wang, S. X.; Chen, G. F.; Li, T. S. Curr. Org. Synth. 2005, 2, 415–436.
11

[34] Mason, T. J. Ultrasonics Sonochem. 2007, 14, 476–483.
[35] Wang, L.; Keyume, A.; Feng, J. Ultrasonics Sonochem. 2015, 22, 113–118.
[36] Cella, R.; Stefani, H. A. Tetrahedron 2009, 65, 2619–2641.
[37] Castanheiro, T.; Suffert, J.; Gulea, M.; Donnard, M. Org. Lett. 2016, 18, 2588–2591.
[38] Muniraj, N.; Dhineshkumar, J.; Prabhu, K. Chem. Select 2016, 5, 1033–1038.
12

Table 1. Optimization of reaction conditions for thiocyanation of phenol.a
Entry
Solvent
SCN source
(equiv)
NCS (equiv)
Time
(min)
Yield (%)b
1
2
CH3CN
THF
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.2)
NH4SCN (1.5)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
30
30
15
30
30
30
30
30
15
5
trace
60
3
DCM
86
4
DMF
trace
trace
trace
52
5
DMSO
dioxane
EtOAc
MeOH
CF3CH2OH
HFIP
6
7
8
trace
81
9
10
11
90
HFIP
5
> 99
13

12
13
14
15
HFIP
HFIP
HFIP
HFIP
NaSCN (1.5)
KSCN (1.5)
1.5
1.5
-
5
5
93
95
NH4SCN (1.5)
NH4SCN (1.5)
30
15
no reaction
37c
1.5
a Reaction conditions: the mixture of 1a (1 mmol), thiocyanate salt and NCS in a solvent (5 mL) was reacted under ultrasonic
irradiation at room temperature. b Isolated yield. c In the absence of ultrasonic irradiation.
14

Table 2. Reaction scope for phenols.a
a Reaction conditions: 1 (1 mmol), NH4SCN (1.5 mmol), NCS (1.5 mmol), HFIP (5 mL), room temperature, ultrasonic
irradiation, 5 min, isolated yields.
15

Table 3. Thiocyanation of indoles and anilines.a
a Reaction conditions: 3 or 4 (1 mmol), NH4SCN (1.5 mmol), NCS (1.5 mmol), HFIP (5 mL), room temperature, ultrasonic
irradiation, 5 min, isolated yields.
16

Scheme 1. Ultrasound-promoted thiocyanation reactions in HFIP.
17

Scheme 2. Gram-scale synthesis of 2a.
18

Scheme 3. Plausible mechanism.
19