Isothiocyanate-Directed Ortho-Selective Halogenation of Arenes via C–H Functionalization

Article abstract of DOI:10.1007/s10562-017-2234-y

Abstract: Ortho-selective halogenation of arenes via C–H functionalization has been described under mild reaction conditions. In this reaction Cu(II)X₂ was used as a halide source. It is a simple, general and efficient method for the synthesis of 2-halo aromatic isothiocyanates. All the reactions are carried out under optimized reaction conditions to provide their respective desired products in good to high yield. Graphical Abstract: We have developed a general, simple and efficient method for the synthesis of 2-halo arylisothiocyanates from isothiocyanates through ortho-selective halogenation under mild reaction conditions. Cu(II)X₂ was used as a halide source for this methodology. All the reactions are carried out under optimized reaction conditions to provide their respective desired products in good to high yield. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-017-2234-y

Catalysis Letters
https://doi.org/10.1007/s10562-017-2234-y
Isothiocyanate-Directed Ortho-Selective Halogenation of Arenes
via C–H Functionalization
Usharani Mandapati1 · Srinivasarao Pinapati1 · Ramana Tamminana2 · Rudraraju Rameshraju1
Received: 10 August 2017 / Accepted: 20 October 2017
© Springer Science+Business Media, LLC 2017
Abstract
Ortho-selective halogenation of arenes via C–H functionalization has been described under mild reaction conditions. In
this reaction Cu(II)X2 was used as a halide source. It is a simple, general and efficient method for the synthesis of 2-halo
aromatic isothiocyanates. All the reactions are carried out under optimized reaction conditions to provide their respective
desired products in good to high yield.
Graphical Abstract
We have developed a general, simple and efficient method for the synthesis of 2-halo arylisothiocyanates from isothiocyanates
through ortho-selective halogenation under mild reaction conditions. Cu(II)X2 was used as a halide source for this method-
ology. All the reactions are carried out under optimized reaction conditions to provide their respective desired products in
good to high yield.
Keywords Copper catalyst · Ortho halogenations · 2-Halo isothiocyanates · Room temperature · C–H Activation
1 Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-017-2234-y) contains
In recent years, the functionalization of C–H bonds have
been developed towards the synthesis of heterocyclic com-
pounds using transition-metal-catalysis (For recent reviews
on directed C–H activation, see [1–9]). Especially, the
selective activation of particular C–H bond has been devel-
oped through incorporation of directing group on aryl ring
(For examples of diverse directing groups, see [10–31]).
Recently, many researchers have developed selective
supplementary material, which is available to authorized users.
* Rudraraju Rameshraju
rudrarajurameshraju716@gmail.com
1
Department of Chemistry, Acharya Nagarjuna University,
Nagarjuna Nagar, Guntur 522510, India
2
Department of Chemistry, GITAM University, NH-207,
Doddaballapur Taluk, Bengaluru, Karnataka 561203, India
Vol.:(0123456789)
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U. Mandapati et al.
Table 1 Optimization for ortho-chlorination
ortho-halogenation due to incorporation of a directing group
on aryl ring via C–H bond activation [32–38].
NCS
Cl
NCS
Isothiocyanate is an essential structural motif in many
compounds that are important in biological and medicinal
sciences. For example, the compounds having isothiocyanate
core structure exhibit antiinflammatory, antiasthmatic, anti-
viral, antineoplastic, cognition disorder, and antibiotic prop-
erties [39–42]. These compounds could be synthesized by
most regular methods [43–46] and recent ancient methods
[40, 47–64]. However, most of the methods have drawbacks
such as not readily available starting material, rigorous or
hazardous conditions, intractable side reactions, evolved
toxic gases, using expensive reagents, longer reaction time
and required several steps. The development of a straightfor-
ward protocol for the direct ortho-halogenation of isothiocy-
anate on aryl ring is thus highly desirable.
Copper source (1 eq)
solvent, additive (3 eq)
RT, 6 h
(0.5 mmol)
Entry Copper source
Solvent Additive
–
Conversion (%)a
1
CuCl, NCS (1 eq) DCE
n.d
n.d
<10
<10
<15
80
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17b
18
CuCl, NCS (1 eq) CH3CN
CuCl2, NCS (1 eq) CH3CN
–
–
–
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
–
CH3CN
CH3CN BHT (1 eq)
CH3CN BHT (3 eq)
CH3CN BHT (2 eq)
THF
Toluene BHT
DCE
DCM
THF
THF
THF
THF
THF
THF
THF
In addition, aryl halides have been used as very precious
starting materials for the synthesis of organometallic rea-
gents and to construct carbon–carbon and carbon- heter-
oatom bonds via cross-coupling reactions (For examples, see
[65–67]) towards the synthesis of heterocyclic compounds,
that are biologically and medicinally active (For biological
activity of halogen-containing compounds, see [68]). There-
fore some conventional methods were used for the construc-
tion of aryl halides [69–71], however, they have suffered
due to overhalogentaion and low regioselectivity [20, 27,
72–76]. Thus, considerable efforts have been recently made
for the development of new methods for the regioselective
C–H halogenation of arenes, employing directing groups
in the presence of transition metal catalysis [32–38]. Pal-
ladium-based catalytic systems have been studied for the
halogenation of arenes, employing carboxylic acid, amide,
nitrile, and pyridine as the directing groups [32–37], while
the rhodium-based systems have been demonstrated with
amides and esters [38]. A few studies have been focused on
the copper-catalyzed C–H functionalization reactions [72,
77–80]. Herein, we wish to report isothiocyanate-directed
ortho-selective halogenation of arenes utilizing CuX2
(X = Cl, Br) as a halogen source. This protocol is simple,
general, and effective at moderate temperature to afford the
target products in moderate to high yield.
45
87
n.d
40
43
BHT
BHT
BHT
CH3COOAg 30
4-t-BuPhenol 52
PTSA
TFA
BHT
BHT
BHT
50
55
n.d
46
n.d
CuCl2
NCS (1 eq)
Bold indicate best condition for this reaction
Reaction conditions: Phenyl isothiocyanate (0.5 mmol), copper
source (1 eq), solvent (2 ml), additive (3 eq), rt, 6 h
aconversion based on diagnostic peaks integration in 1H NMR of
crude reaction mixture
bCuCl2 (0.5 eq) was used. (BHT: 2,6-bis(1,1-dimethylethyl)-4-meth-
ylphenol)
Later, the reaction was conducted with CuCl2, however
the reaction could give target product in less conversion
(Table 1, entries 3–4). When we incorporate the addi-
tive (BHT, 1 eq) into the reaction, the conversion of the
reaction was slightly improved (Table 1, entry 5). Very
interestingly the conversion of the reaction was dramati-
cally improved, when the reaction was performed with
3 eq BHT (Table 1, entry 6). The reaction was tested with
less amount of additive, but unfortunately it gave target
product in moderate conversion (Table 1, entry 7). Among
the set of solvents tested, THF gave desired product in
good conversion (Table 1, entry 8), while CH3CN, DCM
and DCE were found to be less effective in affording the
target product in 40–80% and toluene was failed to pro-
duce target product (Table 1, entry 9). In case of various
additives, BHT gave best results, whereas other additives
2 Results and discussion
First, the optimization of the reaction conditions for chlo-
rination was carried out using phenyl isothiocyanate as a
model substrate. Initially the reaction was done with CuCl
and NCS (N-Chloro succinimide) in the presence of DCE
and CH3CN at 60 °C (Table 1, entries 1–2). Unfortunately,
no reaction could give target product and the starting mate-
rial was recovered.
1 3

Isothiocyanate-Directed Ortho-Selective Halogenation of Arenes via C–H Functionalization
such as CH3COOAg, 4-t-BuPhenol, PTSA and TFA
gave inferior results. Finally the control experiment con-
firmed that the reaction couldn’t give target product in the
absence of copper source and the starting material was
recovered intact (Table 1, entry 16). Lowering of catalyst
afforded target product in 46% conversion (Table 1, entry
17). The reaction was also checked with NCS (N-Chloro
succinimide) in the absence of copper source, however the
reaction failed to obtain target product (Table 1, entry 18).
Having the optimal conditions in hand, we studied
the scope of the protocol for the chlorination of a wide
range of aryl isothiocyanate derivatives (Table 2). The
reaction with unsubstituted phenyl isothiocyanate gave
target product 1a in 80% isolated yield (Table 2, entry
1). The substrates having electron donating groups
Table 2 Substrate scope for
NCS
NCS
the synthesis of 2-chloroaryl
Cl
CuCl2 (1 eq), THF
BHT (3 eq), rt, 6 h
isothiocyanate
R
R
(0.5 mmol)
Entry
Substrate
NCS
Product
NCS
Isolated yield (%)a
Cl
1a
1
80
NCS
NCS
1b
Cl
NCS
2
3
81
83
Me
Me
NCS
1c
Cl
MeO
MeO
NCS
NCS
NCS
1d
Cl
NCS
1e
Cl
4
5
75
77
Cl
F
Cl
F
Cl
NCS
NO2
NCS
1f
6b
78
75
NC
NC
Cl
NCS
NCS
NO2
7b
1g
Me NCS
Me
Me NCS
Me
8b
Cl
75
77
Me
Me
1h
NCS
NCS
Me
Cl
Me
9b
1i
Me
Me
Reaction conditions: Aryl isothiocyanate (0.5 mmol), CuCl2 (1 eq), THF (2 ml), BHT (3 eq), rt, 6 h
aIsolated yield
bReaction time was 10 h. (BHT: 2,6-bis(1,1-dimethylethyl)-4-methylphenol)
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U. Mandapati et al.
4-Me and 4-OMe substituents on both aryl rings readily
reacted to obtain their target products 1b and 1c in 81%
and 83% yields, respectively (Table 2, entries 2–3). The
substrates bearing weak electron withdrawing group’s
4-Cl and 4-F readily underwent the reaction to get their
respective desired products 1d and 1e in 75 and 77%
yields, respectively (Table 2, entries 4–5). However, the
substrates contain strong electron withdrawing groups
4-CN and 2-NO2 required slightly longer reaction time
to give their respective desired products 1f and 1g in good
yield (Table 2, entries 6–7). Finally, we have also tried
the reactions with the substrates having bulkier groups
like 2-tBu and disubstituted groups such as 2,4-DiMe, as
a result, both the substrates took longer reaction time to
Table 3 Substrate scope for
NCS
NCS
the synthesis of 2-bromoaryl
Br
CuBr2 (1 eq), THF
BHT (3 eq), rt, 6 h
isothiocyanate
R
R
(0.5 mmol)
Entry
Substrate
NCS
Product
NCS
Isolated yield (%)a
Br
1
78
2a
NCS
NCS
2b
2
3
4
75
81
79
Cl
MeO
Me
Br
NCS
Cl
NCS
NCS
2c
Br
MeO
Me
NCS
2d
Br
Br
NCS
NCS
5
79
2e
NC
NC
Br
NCS
NCS
NO2
NO2
6b
72
74
2f
NCS
NCS
2g
7
F
F
Br
NCS
Me
NCS
Me
Br
Me
8b
71
72
2h
Me
Br
NCS
NCS
2i
9
Br
Br
Reaction conditions: Aryl isothiocyanate (0.5 mmol), CuBr2 (1 eq), THF (2 ml), BHT (3 eq), rt, 6 h
aIsolated yield
bReaction time was 10 h. (BHT: 2,6-bis(1,1-dimethylethyl)-4-methylphenol)
1 3

Isothiocyanate-Directed Ortho-Selective Halogenation of Arenes via C–H Functionalization
+CuIIX2
-CuIX
-H
N C S
X
N C S
X
Electron
transfer
-CuIX
N C SH
I
N C S
Cu
II
Cu
Halide transfer
Electron transfer
Deprotanation
X
X
H
b
c
a
X
X
X = Cl, Br
N C S
CuIIX2
Scheme 1 Proposed mechanism
obtain their respective final products 1 h and 1i (Table 2,
entries 8–9). It might be occurred due to steric effect at
reactive site on aryl ring.
3.1 Experimental Section
3.1.1 General Information
Next, the bromination of the substituted aryl isothiocy-
anate derivatives was studied CuBr2 as a bromine source
(Table 3). All the substrates having both electron donating
and electron with.
CuBr2 (99%), CuCl2 (99%) and CuCl (98%), NCS,
CH3COOAg, 4-t-BuPhenol, PTSA, TFA and BHT were
purchased from Aldrich and used without further purifica-
tion. The solvents were purchased and dried according to
standard procedure prior to use [64]. 1H NMR (400 MHz)
spectra were recorded with a Varian 400 spectrometer.
Infrared (IR) spectra recorded on a Perkin Elmer Spectrum
one FT-IR spectrometer. Aromatic isothiocyanates have
been synthesized by our recent reported literature [63].
drawing groups readily underwent the reaction under
optimized reaction conditions to provide their target prod-
ucts 2a–2i in 71–81% yields.
Based on experimental results and literature reports
the mechanism is proposed (Scheme 1). The reaction may
proceed via single-electron transfer pathway [81] which
we shown in below scheme 1. Phenyl isothiocyanate
reacts with CuX2 to provide intermediate a, which gives
another intermediate c via b through consecutive single
electron transfer from phenyl ring and halide transfer.
Electron transfer from intermediate c to Cu(II) species
and followed by deprotonation to afford desired prod-
uct as 2-halo phenylisothiocyanate. Not yet confirm any
intermediate, which we shown in mechanism. Still many
experiments need to be performed to confirm and propose
the actual mechanism. For that mechanism studies are
under process in our laboratory.
3.1.2 General Procedure for 2-haloarylisothiocyanate
To a stirred solution of THF (2 ml), respective isothio-
cyanate (0.5 mmol) was added in slowly and followed by
CuX2 (1 eq) and BHT (3 eq) were added slowly and the
reaction mixture was stirred for 6 h at room temperature.
The progress of the reaction was investigated by TLC (5%
ethylacetate in hexane). After finish the reaction, the reac-
tion mixture was washed with water (4 ml) and ethylac-
etate (6 ml) for 3 times. Both organic and aqueous layers
were separated and the organic layer was concentrated by
using rotary evaporator and the crude mixture was purified
by silica gel (60–120 mesh) column chromatography using
Ethylacetate in Hexane as eluent to obtain a 2-halophenyl
isothiocyanate as oily liquid
3 Conclusion
In conclusion we have developed general and efficient
ortho-selective halogenation of arenes using Cu(II) halide
as halide source under mild reaction conditions. The use
of cheap, readily available and air stable copper source
give a good method for the synthesis 2-halo isothiocy-
anates, which are good intermediates for the synthesis of
hetero cyclic compounds. In addition the reaction exhibit
good functional group tolerance in attaining product with
good yield and high selectivity.
Acknowledgements The authors thankful to Department of Chemistry,
Acharya Nagarjuna University, Nagarjuna Nagar, Guntur for providing
work space and thanks to UGC-BSR for providing research fellowship
and the authors are grateful to Icon Pharmaceutical Lab for providing
instrumental support.
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U. Mandapati et al.
42. Nastruzzi C, Cotesi R, Eaposito E, Menegatti E, Leoni O, Iori R,
Palmier SJ (2000) Agric Food Chem 48:3572
43. Larsen C, Stelliou K, Harpp DN (1978) J Org Chem 43:337
44. Larsen C, Harpp DN (1981) J Org Chem 46:2465
45. Kim S, Yi KY (1985) Tetrahedron Lett 26:1661
46. Gottfried R (1966) Angew Chem Int Ed 5:963
47. Boas U, Jakobsen MH (1995) Chem Commun 19:1995
48. Boas U, Pedersen B, Christensen JB (1998) Synth Commun
28:1223
References
1. Engle KM, Mei TS, Wasa M, Yu JQ (2012) Acc Chem Res
45:788
2. Lyons TW, Sanford MS (2010) Chem Rev 110:1147
3. Li CJ (2009) Acc Chem Res 42:335
4. Ackermann L, Vicente R, Kapdi AR (2009) Angew Chem Int Ed
48:9792
5. Alberico D, Scott ME, Lautens M (2007) Chem Rev 107:174
6. Hickman AJ, Sanford MS (2012) Nature Rev 484:178
7. Yeung CS, Dong VM (2011) Chem Rev 111:1215
8. Colby DA, Bergman RG, Ellman JA (2010) Chem Rev 110:624
9. Chen X, Engle KM, Wang DH, Yu JQ (2009) Angew Chem Int
Ed 48:5094
49. Boas U, Pedersen HG, Christensen JB, Heegaard PMH (2004)
Tetrahedron Lett 45:269
50. Molina P, Alajarin M, Tamiaki H (1982) Synthesis 1982:596
51. Munch H, Hansen JS, Pittelkow M, Christensen JB, Boas U (2008)
Tetrahedron Lett 49:3117
52. Hodgkins JE, Reeves WP (1964) J Org Chem 29:3098
53. Nath J, Jamir L, Patel BK (2011) Green Chem Lett Rev 4:34
54. Ghosh H, Yella R, Nath J, Patel BK (2008) Eur J Org Chem
2008:6189
10. Boele MDK, Strijdonck GPFV, Vries JGD, Leeuwen PWNM
(2002) J Am Chem Soc 124:1586
11. Thu HY, Yu WY, Che CM (2006) J Am Chem Soc 128:9048
12. Xiao B, Fu Y, Xu J, Gong TJ, Dia JJ, Yi J, Liu L (2010) J Am
Chem Soc 132:468
55. Yella R, Ghosh H, Murru S, Sahoo SK, Patel BK (2010) Synth
Comm, 40:2083
13. Lu Y, Wang DH, Engle KM, Yu JQ (2010) J Am Chem Soc
132:5916
56. Ghosh H, Yella R, Ali AR, Sahoo SK, Patel BK (2009) Tetrahe-
dron Lett 50:2407
14. Yoo EJ, Ma S, Mei TT, Chan SL, Yu JQ (2011) J Am Chem Soc
133:7652
57. Ali AR, Ghosh H, Patel BK (2010) Tetrahedron Lett 8:1674
58. Zhang Z, Wu HH, Ya-Jun Tan YJ (2013) RSC Adv 3:16940
59. Zhu J, Han L, Diao Y, Ren X, Xu M, Xu L, Li S, Li Q, Dong D,
Huang J, Liu X, Zhao Z, Wang R, Zhu L, Xu Y, Qian X, Li H
(2015) J Med Chem 58:1123
15. Chan WW, Lo SF, Zhou Z, Yu WY (2012) J Am Chem Soc
134:13565
16. Padala K, Jeganmohan M (2011) Org Lett 13:6144
17. Dia HX, Stepan AF, Plummer MS, Zhang DHX, Stepan AF, Plum-
mer MS, Zhang YH, Yu JQ (2011) J Am Chem Soc 133:7222
18. Rubia AG, Arrayas RG, Carretero JC (2011) Angew Chem Int
Ed 50:10927
60. Wong R, Dolman SJ (2007) J Org Chem 72:3969
61. Chen Y, Su L, Yang X, Pan W, Fang H (2015) Tetrahedron
71:9234
62. Mohan S, Bajivali SK, Prasad rao K (2016) Synthetic comm
46:1759
19. Wang C, Chen H, Wang Z, Chen J, Huang Y (2012) Angew
Chem Int Ed 51:7245
63. Srinivasarao P, Usharani M, Rameshraju R (2017) ChemistrySe-
lect 2:295
20. Nishino M, Hirano K, Satoh T, Miura M (2012) Angew Chem
Int Ed 51:6993
64. Usharani M, Srinivasarao P, Rameshraju R (2017) Tetrahedron
Lett 58:125
21. Gandeepan P, Cheng CH (2012) J Am Chem Soc 134:5738
22. Li W, Xu Z, Sun P, Jiang X, Fang M (2011) Org Lett 13:1286
23. Ros A, Rodriguez RL, Estepa B, Lvarez EA, Alvarez E, Fernandez
R, Lassaletta JM (2012) J Am Chem Soc 134:4573
24. Lee DH, Kwon KH, Yi CS (2012) J Am Chem Soc 134:7325
25. Tang C, Jiao N (2012) J Am Chem Soc 134:18924
26. Li H, Li P, Wang L (2012) Org Lett 15:620
27. Tran LD, Popov I, Daugulis O (2012) J Am Chem Soc
134:18237
65. Crampton MR (2007) In: Knipe AJ Organic reaction mechanism.
Wiley, New York
66. Nicolaou KC, Bulger PG, Sarlah D (2005) Angew Chem Int Ed
44:4442
67. Rout L, Sen TK, Punniyamurthy T (2007) Angew Chem Int Ed
46:5583
68. Butler A, Walker JV (1993) Chem Rev 93:1937
69. Taylor R (1990) Electrophilic aromatic substitution. John Wiley,
New York
28. Yoshikai N, Matsumoto A, Norinder J, Nakamura E (2009) Angew
Chem Int Ed 48:2925
70. Barluenga J, Rasul G, Olah GA (2004) J Am Chem Soc 126:15770
71. Merkushev EB (1988) Synthesis 1988:923
72. Chen X, Hao XS, Goodhue CE, Yu JQ (2006) J Am Chem Soc
128:6790
29. Seki M (2011) ACS Catal 1:607
30. Ye M, Edmunds A, Morris J, Sale D, Zhang Y, Yu JQ (2013)
Chem Sci 4:2374
31. Giri R, Maugel NL, Foxman BM, Yu JQ (2008) Organometallics
27:1667
73. Wendlandt AE, Suess AM, Stahl SS (2011) Angew Chem Int Ed
50:11062
32. Mei TS, Giri R, Maugel N, Yu JQ (2008) Angew Chem Int Ed
47:5215
74. Shang M, Sun SZ, Dai HX, Yu JQ (2014) J Am Chem Soc
136:3354
33. Kakiuchi F, Kochi T, Mutsutani H, Kobayashi N, Urano S, Sato
M, Nishiyama S, Tanabe T (2009) J Am Chem Soc 131:11310
34. Bedford RB, Haddow MF, Mitchell CJ, Webster RL (2011)
Angew Chem Int Ed 50:5524
75. Wang L, Priebbenow DL, Dong W, Bolm C (2014) Org Lett
16:2661
76. Shang M, Wang HL, Sun SZ, Dai HX, Yu JQ (2014) J Am Chem
Soc 136:11590
35. Wan X, Ma Z, Li B, Zhang K, Cao S, Zhang S, Shi Z (2006) J Am
Chem Soc 128:7416
77. Menini L, Gusevskaya EV (2006) Chem Commun 2006:209
78. Li Z, Bohle DS, Li CJ (2006) Proc Natl Acad Sci USA 103:8928
79. Mizuhara T, Inuki S, Oishi S, Fujii N, Ohno H (2009) Chem Com-
mun 2009:3413
36. Kalyani D, Anani WQ, Sanford MS (2006) Org Lett 8:2523
37. Du B, Jiang X, Sun P (2013) J Org Chem 78:2786
38. Schroder N, Wencel-Delord J, Glorius F (2012) J Am Chem Soc
134:8298
80. King AE, Huffman LM, Casitas A, Costas M, Ribas X, Stahl SS
(2010) J Am Chem Soc 132:12068
39. Mukerjee AK, Ashare R (1991) Chem Rev91:1
40. Stephensen H, Zaragosa F (1997) J Org Chem 62:6096
41. Fernandez JMG, Mellet CO, Blanco JLJ, Mota JF, Gadelle A,
Coste SA, Defaye J (1995) Carbohydr Res 268:57
81. Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (2004)
Vogel’s textbook of practical organic chemistry, 5th edn, Pearson
Education Pte. Ltd., Indian Branch, Delhi, pp 928–929
1 3