About the reaction of aryl fluorides with sodium sulfide: Investigation into the selectivity of substitution of fluorobenzonitriles to yield mercaptobenzonitriles via SNAr displacement of fluorine

Article abstract of DOI:10.1016/j.tetlet.2012.03.032

In this report we describe a simple synthesis of mercaptobenzonitriles from the reaction of fluorobenzonitriles with Na₂S in DMF at room temperature and following direct treatment with Zn/HCl. Significantly, 2- and 4-fluorobenzonitriles substituted with chlorine or bromine, but not iodine, undergo selective substitution of fluorine at room temperature to yield synthetically useful halo-substituted mercaptobenzonitriles.

Full text of DOI:10.1016/j.tetlet.2012.03.032

Tetrahedron Letters 53 (2012) 2548–2551
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Tetrahedron Letters
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About the reaction of aryl fluorides with sodium sulfide: investigation into
the selectivity of substitution of fluorobenzonitriles to yield
mercaptobenzonitriles via SNAr displacement of fluorine
⇑
Tony Taldone , Pallav D. Patel, Hardik J. Patel, Gabriela Chiosis
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In this report we describe
a simple synthesis of mercaptobenzonitriles from the reaction of
Received 22 February 2012
Revised 4 March 2012
Accepted 8 March 2012
Available online 15 March 2012
fluorobenzonitriles with Na2S in DMF at room temperature and following direct treatment with Zn/HCl.
Significantly, 2- and 4-fluorobenzonitriles substituted with chlorine or bromine, but not iodine, undergo
selective substitution of fluorine at room temperature to yield synthetically useful halo-substituted
mercaptobenzonitriles.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Mercaptobenzonitrile
Aryl fluoride
SNAr
Selectivity
Sodium sulfide
Aryl thiols are an important class of compounds as intermedi-
ates in the synthesis of biologically active natural products and
pharmaceutical drugs. Unfortunately, because of their tendency
to oxidize relatively few aryl thiols are available commercially.
As a result, they are generally synthesized and used as required.
Despite recent advances in transition metal catalyzed methods
for their synthesis,1 aryl thiols are still commonly prepared using
classical methods such as Newman–Kwart and Schonberg rear-
rangement,2 Grignard reaction with sulfur,3 and reduction of aryl
sulfonyl chlorides4 or aryl disulfides.5 These reactions typically re-
quire harsh conditions and suffer from a limited scope of substrate.
As a result, the development of efficient methods for the synthesis
of aryl thiols is always welcome.
with Na2S, we obtained 4-bromo-2-mercaptobenzonitrile (6B)
cleanly and in 81% yield at room temperature, with no evidence
of the desired product (Scheme 1). This result, including the mild
conditions required, led us to investigate SNAr displacement of aro-
matic fluorides with Na2S as a method to yield substituted
mercaptobenzonitriles.
Although there is much precedent in the use of aryl fluorides
possessing strong electron withdrawing groups in the o- or p-posi-
tions to prepare aryl sulfides,7 their use in synthesizing aryl thiols is
much less common.8 In one instance 4-mercaptobenzonitrile was
reportedly obtained as a minor component along with disulfide
and sulfide sideproducts following the reaction of 4-fluorobenzoni-
trile with K2S (1.1 equiv) at 50–55 °C in DMF for 21 h.8d However, it
was not isolated but used directly in the further synthesis of methyl
4-mercaptobenzoate. That there are only a few reports describing
such a synthesis of aryl thiols is understandable in light of the fact
that SNAr substitution of aromatic fluorides typically requires two
In the course of our drug discovery efforts we required a series of
mercaptobenzonitriles as intermediates in the synthesis of thio-
ethers. A convenient synthesis of a limited number of 4-merca-
ptobenzonitriles from 4-bromo- and chlorobenzonitriles in
a
single step with Na2S has been reported.6 This reaction requires
heating the bromide or chloride in NMP at high temperatures. Using
a modification of this procedure we obtained 4-mercaptobenzonit-
rile in 51% yield by heating a mixture of 4-bromobenzonitrile and
Na2S in DMF at 130 °C for 3.5 h and following reduction with Zn/
HCl. However, when we attempted to prepare 2-fluoro-4-merca-
ptobenzonitrile by reacting 4-bromo-2-fluorobenzonitrile (6A)
SH
CN
Br
Br
F
F
SH
CN
CN
⇑
Corresponding author. Tel.: +1 646 888 2238; fax: +1 646 422 0416.
E-mail addresses: taldonet@mskcc.org (T. Taldone), pallavpatel85@gmail.com
6A
6B
81%
(P.D. Patel), PatelH3@mskcc.org (H.J. Patel), chiosisg@mskcc.org (G. Chiosis).
Scheme 1. Reagents and condition: Na2S, DMF, rt, 1 h.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.032

T. Taldone et al. / Tetrahedron Letters 53 (2012) 2548–2551
2549
Table 1
Table 2
Reaction of halo-substituted 2-fluorobenzonitriles with Na2S
Reaction of halo-substituted 4-fluorobenzonitriles with Na2S
X
X
F
SH
Na2S (1.1 eq)
DMF, rt, 1h
Na2S (1.1 eq)
DMF, rt, 1h
X
X
F
SH
CN
CN
CN
CN
X= Cl, Br, I
X= Cl, Br, I
Entry
Aryl fluoride
A
Product
B
Yield (%)
Entry
Aryl fluoride
A
Product
B
Yield (%)
Cl
Cl
F
SH
Cl
Cl
1
86
F
CN
Cl
SH
12
68
78
CN
Cl
CN
F
CN
SH
2
69
SH
F
CN
Cl
13
14
15
16
CN
Cl
Cl
Br
Cl
Br
CN
F
CN
SH
3
4
5
84
86
88
F
F
SH
SH
CN
CN
86
CN
F
CN
SH
Cl
Cl
CN
Br
CN
Br
77
Br
Br
F
CN
Br
SH
CN
SH
CN
F
CN
Br
66a
6
81
I
I
F
CN
Br
SH
CN
CN
CN
Br
a
Minor quantities of 4-fluro-2-mercaptobenzonitrile were formed.
7
8
72
77
F
F
SH
SH
thesized from fluorobenzonitriles through selective substitution
of fluorine with Na2S in good to excellent yields at room
temperature.
CN
CN
CN
Br
CN
I
Br
The cyano group is a strong electron withdrawing group and it
is well known that such groups activate the 2- and 4-positions to
nucleophilic substitution. Indeed, we found that the reaction of
chloro- and bromo-substituted 2- and 4-fluorobenzonitriles with
Na2S occurs with exclusive substitution of fluorine at room tem-
perature and is complete in less than 1 h to yield the corresponding
mercaptobenzonitrile in good to excellent yields (Tables 1 and 2;
entries 1–8 and 12–15).9 Exclusive substitution of fluorine was ob-
served irrespective of the position of the chlorine or bromine. How-
ever, in the case of iodo-substituted 2- and 4-fluorobenzonitriles
exclusive substitution of fluorine occurred only in the case of
10A, whereby the iodine is located meta to the cyano group, to give
10B in 86% yield. When the iodine was also in an activated position
(i.e. ortho or para to the cyano group) it could be substituted as well
and in the case of 9A and 11A resulted in a complex mixture
including both substitution products. It is of significance that in
contrast to all other 2- and 4-fluorobenzonitriles reacted, reaction
with 9A and 11A was not complete after 1 h. It is likely that a com-
bination of factors are responsible for the sluggishness of these two
substrates to react as well as the mixture of substitution products
obtained. These include the decreased activating effect of iodine
compared to chlorine or bromine, its placement meta to fluorine,
9
Mixturea
n.a.
F
CN
I
I
10
11
86
F
SH
CN
CN
Mixturea
n.a.
I
F
CN
n.a. not applicable.
a
Incomplete after 1 h and results in a complex mixture after 24 h.
electron-withdrawing groups, which limit the scope of this reac-
tion. However, in this report we show that synthetically useful
halo-substituted mercaptobenzonitriles can be conveniently syn-

2550
T. Taldone et al. / Tetrahedron Letters 53 (2012) 2548–2551
Table 3
Table 4
Reaction of substituted 3-fluorobenzonitriles with Na2S
Reaction of arylfluorides with Na2S
X
X
F
SH
Na2S (1.1 eq)
DMF, rt, 1h
R
R
Na2S (1.1 eq)
DMF, rt, 1h
X
X
Y
Y
CN
CN
Y= C, N
X= CN, CF3, NO2
X= Cl, Br, I, CN
Entry
Aryl fluoride
A
Product
B
Yield (%)
Entry
Aryl fluoride
A
Product
B
Yield (%)
70a
Cl
F
Mixturea
n.a.
SH
22
17
F
CN
CN
CN
Br
F
F
23
24
No reactionb
18
19
Mixturea
n.a.
58b
CN
F
SH
CN
I
46c
85
75
76
SH
F
F
CN
F
CN
SH
CN
Br
CN
Br
F
SH
25
26
27
CF3
CF3
CN
SH
20
21
52c
70
CN
F
CN
CN
CN
CN
NC
F
NC
SH
NO2
F
NO2
SH
n.a. not applicable.
a
Incomplete after 1 h and results in a complex mixture after 24 h.
b
c
48 h.
24 h.
N
N
CN
CN
and the leaving ability of iodine. Iodo 16A yielded the fluoro-
substituted compound 16B as the major product, however, a minor
amount of 4-fluoro-2-mercaptobenzonitrile was detectable by ESI-
MS. Based on the results in Tables 1 and 2, the procedure described
here likely represents the best general method for the synthesis of
chloro- or bromo-substituted 2- or 4-mercaptobenzonitriles.
In the case of halo-substituted 3-fluorobenzonitriles we found
that reactions generally do not occur as readily and that each of
the 4-substituted halogens can compete with fluorine (Table 3; en-
tries 17–19). Reactions with chloro 17A and bromo 18A were
incomplete after 1 h at room temperature and after 24 h a complex
mixture was obtained that included both substitution products.
Interestingly, we found that iodo 19A results in exclusive substitu-
tion of iodine to yield 19B in 58% yield after 48 h at room temper-
ature (Table 3). In this case it appears that selective substitution of
iodine occurs as a result of a combination of factors including its
leaving ability and activation by two electron withdrawing groups.
When bromine was meta-substituted as in 20A selective substitu-
tion of fluorine was observed and 20B was isolated in 52% yield,
though the reaction was still sluggish and required 24 h. Installa-
tion of an additional meta-substituted cyano group as in 21A re-
stores reactivity and enables for convenient substitution of
fluorine to yield 21B in 70% yield after 1 h.
a
b
c
24 h.
48 h.
36 h.
fluorobenzonitriles (22A–24A, Table 4). Reactions with 2- and 4-
fluorobenzonitrile were not complete even after 24 and 36 h,
respectively, however, in both cases substantial amounts of prod-
uct were obtained. Heating either 22A or 24A at 50 °C for 3 h re-
sulted in complete consumption of starting material, however,
yield was not improved in either case as it is likely that competing
side reactions occur. Reaction with 3-fluorobenzonitrile at room
temperature does not occur appreciably, even after 48 h at room
temperature. As expected, the addition of an electron withdrawing
trifluoromethyl group in 25A enables substitution of the fluorine to
give 25B in 85% yield after 1 h at room temperature. The presence
of a stronger electron withdrawing group in 4-fluoro-nitrobenzene
(26A) enables for this reaction to occur readily at room tempera-
ture to give 26B in 75% yield after 1 h. Finally, pyridine derivative
27A also reacts readily to give heterocyclic thiol 27B in 76% yield
after 1 h.
In conclusion, we show that fluorobenzonitriles substituted
with electron withdrawing groups can undergo SNAr displacement
of fluorine with Na2S at room temperature to yield the correspond-
ing mercaptobenzonitrile in good to excellent yields following
In order to probe the reactivity and examine the scope of SNAr
displacement of aryl fluorides with Na2S as a method to produce
mercaptobenzonitriles, we examined the reaction of unsubstituted

T. Taldone et al. / Tetrahedron Letters 53 (2012) 2548–2551
2551
16, 2355; (e) Yi, J.; Fu, Y.; Xiao, B.; Cui, W.-C.; Guo, Q.-X. Tetrahedron Lett. 2011,
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treatment with Zn/HCl. One of the most significant results derived
from these studies is that 2- and 4-fluorobenzonitriles substituted
with chlorine or bromine undergo exclusive substitution of fluo-
rine to yield the corresponding thiol in good to excellent yields.
Reactions with iodo-substituted fluorobenzonitriles or with 3-flu-
orobenzonitriles are less predictable. The procedure described here
enables for the preparation of mercaptobenzonitriles in good to
excellent yields from appropriately substituted fluorobenzonitriles
in sufficient purity to be useful as important intermediates in syn-
thesis. It is hoped that the foregoing discussion provides a rational
framework for the synthesis of mercaptobenzonitriles and other
aryl thiols from SNAr reactions with aryl fluorides.
3. Gilman, H.; Fullhart, C. J. Am. Chem. Soc. 1949, 71, 1478.
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2011, 1143; (c) Liljenberg, M.; Brinck, T.; Herschend, B.; Rein, T.; Rockwell, G.;
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Acknowledgments
8. (a) Chancellor, D. R.; Davies, K. E.; De Moor, O.; Dorgan, C. R.; Johnson, P. D.;
Lambert, A. G.; Lawrence, D.; Lecci, C.; Maillol, C.; Middleton, P. J.; Nugent, G.;
Poignant, S. D.; Potter, A. C.; Price, P. D.; Pye, R. J.; Storer, R.; Tinsley, J. M.; van
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9. General procedure: Into an oven-dried flask equipped with a magnetic stir bar
was added aryl fluoride (1.00 g, 1.0 equiv), Na2S (1.1 equiv), and DMF (5 mL)
under argon. The reaction mixture was stirred at room temperature for 1 h. Then
1 M NaOH (50 mL) was added and washed with CH2Cl2 (2 Â 25 mL). The
aqueous layer was acidified to pH ꢀ1–2 with 6 N HCl and extracted with CH2Cl2
(2 Â 50 mL). The combined organic layer was washed with brine (50 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure to provide a
crude residue. To the residue was added 10% HCl (40 mL) and cooled with an
ice-water bath. Then zinc dust (4 g) was added and the mixture was stirred for
1 h. Then EtOAc (100 mL) was added and the mixture was stirred for an
additional 30 min. The organic layer was separated and washed with water
(40 mL) and brine (40 mL), dried over MgSO4, filtered, and concentrated to
provide the desired product with satisfactory purity.
T.T. is funded by Susan G. Komen for the Cure (KG091313) and
the Department of Defense, Breast Cancer Research Program (PDF-
BC093421). We also thank Dr. George Sukenick and Dr. Hui Liu of
the NMR Analytical Core Facility at MSKCC for expert mass spectral
analysis.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.03. 032.
References and notes
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