Lewis Acid-Mediated Cyanation of Phenols Using N-Cyano-N-phenyl-p-toluenesulfonamide

Article abstract of DOI:10.1002/adsc.201900813

Lewis acid-mediated cyanation of phenol derivatives with N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) has been developed. The reaction proceeded efficiently with high regioselectivity to produce aromatic nitriles in moderate to excellent yields, which provides a direct and practical access to valuable products. (Figure presented.).

Full text of DOI:10.1002/adsc.201900813

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DOI: 10.1002/adsc.201900813
Lewis Acid-Mediated Cyanation of Phenols Using N-Cyano-N-
phenyl-p-toluenesulfonamide
Wu Zhang,a Tao Li,a Qingli Wang,a,* and Wanxiang Zhaoa,*
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha, Hunan 410082, People’s Republic of China
E-mail: zhaowanxiang@hnu.edu.cn; qingliwang@hnu.edu.cn
Manuscript received: July 3, 2019; Revised manuscript received: August 27, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900813
NCTS in 2011.[4d] In addition, Rh-catalyzed CÀ H bond
Abstract: Lewis acid-mediated cyanation of phenol
cyanation has also been well developed in the presence
derivatives with N-cyano-N-phenyl-p-toluenesulfo-
namide (NCTS) has been developed. The reaction
of NCTS.[4g] As part of our interest in CÀ O bond
cleavage of 2-cyanophenols,[6] we envisioned whether
proceeded efficiently with high regioselectivity to
it is possible to produce 2-cyanophenols via direct
produce aromatic nitriles in moderate to excellent
CÀ H bond cyanation of phenols using NCTS as the
yields, which provides a direct and practical access
to valuable products.
cyanating reagent.
Traditionally, 2-cyanophenol derivatives are synthe-
sized via dehydration of 2-hydroxy aromatic
Keywords: Cyanation; Lewis acid; Phenols; N-
Cyano-N-phenyl-p-toluenesulfonamide
aldehydes,[7a–b] oximes[7c] and amides.[7d] Transition-
metal-catalyzed cyanation of 2-halo phenol
derivatives[8] is also an efficient method access to 2-
cyanophenols. In 1990, Sugasawa disclosed an ap-
Aromatic nitriles are wildly present in a variety of proach to covert phenols into 2-cyanophenols using a
natural products, pharmaceuticals, dyes, agrochemi- toxic and stinking cyanation reagent CH3SCN in the
cals, materials and cosmetics.[1] In addition, nitriles are presence of stoichiometric amount of BCl3 and
crucial building blocks in synthetic chemistry as they AlCl3.[9] Therefore, it is still highly desirable to develop
can be efficiently converted into amine, ketone, a green, safe, eco-friendly and efficient cyanation
aldehyde, amide and carboxylic acid.[2] To date, under mild reaction conditions. Herein, we describe a
numerous methods for the synthesis of aromatic Lewis acid-mediated cyanation of phenols using low
nitriles have been developed, and they can be divided toxic, stable, eco-friendly and readily available NCTS
into three categories according to cyanating reagent: as the cyanating reagent, which produces a range of o-
nucleophilic-,[3]
electrophilic-[1a,4]
and
radical-
cyanation.[5] The cyanides used in nucleophilic cyana-
tion include KCN,[3d] CuCN,[3e] NaCN,[3f] K4[Fe
(CN)6],[3g] etc (Scheme 1a), which have the risk of
generating hazardous HCN and leading to environ-
mental pollution. On the other hand, the cyanating
reagents employed in electrophilic cyanation (Sche-
me 1b), such as 1-cyanobenzotriazole (BtCN)[4a–b] and
PhOCN,[4c] are usually prepared from ClCN or BrCN
that possess safety issue. The examples of radical
cyanation are rare. Therefore, the use of safe, user- and
eco-friendly reagents for cyanation is highly desirable.
Recently,
N-cyano-N-phenyl-p-toluenesulfonamide
(NCTS)[4d–g] has received much attention in cyanation
reactions due to its low toxicity, stability and ready
availability. For instance, Wang developed an elegant
method for cyanation of indoles and pyrroles using
Scheme 1. Aromatic nitrile synthesis.
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Table 1. Optimization of the reaction conditions.[a]
Entry LA (equiv.) NCTS
(equiv.)
Base
Solvent Yield (%)
[b]
1
2
In(OTf)3
(0.1)
Sn(OTf)2
(0.1)
1.5
1.5
Et3N
Et3N
toluene 26
toluene 28
Scheme 2. SnCl4-mediated cyanation of 2-naphthol derivatives.
3
4
5
6
7
8
9
10
11
SnCl4 (0.5) 1.5
– 1.5
Et3N
Et3N
Et3N
Et3N
Et3N
Me3N
BnNMe2 toluene 18
DIPA
–
toluene 58
toluene 0
SnCl4 (0.5) 1.5
SnCl4 (0.5) 1.5
SnCl4 (0.5) 1.5
SnCl4 (0.5) 1.5
SnCl4 (0.5) 1.5
SnCl4 (0.5) 1.5
SnCl4 (0.5) 1.5
DCE
dioxane 10
MeCN
toluene 34
15
With the optimized conditions in hand, we then
examined the scope of 2-naphthols. As illustrated in
Scheme 2, the reaction of 2-naphthols with NCTS
proceeded smoothly to furnish the corresponding
products in moderate to good yields (Scheme 2, 2a–d).
Both electron-donating and electron withdrawing
groups were tolerated. However, we found that the
purification of products 2 is problematic. For ease of
isolation and characterization, the crude products 2
were then treated with NaOH and EtOH, which led to
the desulfonylation products 3 in high efficiency.
As shown in Scheme 3, a variety of 2-naphthols
reacted with NCTS efficiently to give the 1-naphthoni-
triles. Various functional groups were tolerated, such
as MeO, BnO and alkene. It is worth to mention that
TBS-protected naphthalene-2, 6-diol and naphthalene-
2, 7-diol all successfully participated in this cyanation
reaction to afford the corresponding desilylated naph-
0
toluene 63
toluene 0
toluene 76
toluene 96
toluene 98 (88)[d]
12[c] SnCl4 (0.5) 2.0
13[c] SnCl4 (0.5) 2.5
14[c] SnCl4 (0.5) 3.0
DIPA
DIPA
DIPA
[a] Reaction conditions: 1a (0.2 mmol), NCTS, base (4.0 equiv.),
°
solvent (2 mL), 16 h, 100 C. SnCl4 (1.0 M in dichloro-
methane). Me3N (2.0 M in THF). LA=Lewis acid. DCE=
1.2-dichloroethane. DIPA=diisopropylamine.
[b] 1H NMR yield using CH2Br2 as the internal standard.
[c] Reaction time was 24 h.
[d] Isolated yield.
cyanophenols with high efficiency and regioselectivity thonitriles (3h and 3i) in 97% and 92% yield,
(Scheme 1c). respectively. The substrates with halogens, including F,
We began our investigation with the evaluation of Cl and Br, are applicable in this transformation (3d–e,
Lewis acid using 7-methoxynaphthalen-2-ol 1a as the 3p–r). Noticeably, hetero-aromatic rings, such as
model substrate in the presence of NCTS (Table 1). We thiophene and furan, were also compatible.
observed that SnCl4 promoted the CÀ H bond cyanation
Although the cyanation of 2-naphthols provided a
of 1a to afford 1-cyano-7-methoxynaphthalen-2-yl 4- range of 2-hydroxy naphthonitriles in the presence of
methylbenzenesulfonate 2a with OH being protected SnCl4, NCTS and base, low yield was obtained when
by Ts in moderate yield, although Sn(OTf)2 and In 1-naphthol was employed as the substrate. Pleasantly,
(OTf)3 can also be used as a promoter (Table 1, entries we found that the combination of AlCl3 and
[10]
1–3). It is worth noting that no desired product was BF3 ·OEt2
was efficient for the cyanation of 1-
observed in the absence of Lewis acid (Table 1, naphthol, and afforded the 1-hydroxy-2-naphthonitrile
entry 4). Other solvents were also examined, but all in 87% yield. It is notable that the substrates resulting
resulted in either low or no conversion (Table 1, entries in low yields (1t and 1u) or no reaction (1v) when
5–7). We then paid attention to the base. As shown, SnCl4 was employed, all worked well when AlCl3 and
diisopropylamine gave the best yield among the bases BF3 ·OEt2 employed to produce the naphthonitriles in
examined (Table 1, entries 8–10). Notably, no product good yields (Scheme 4, 3t–3v). It is worth noting that
2a was formed in the absence of base (Table 1, the tosylated product 3u was isolated in 26% when
entry 11), indicating the important role of the base in naphthalene-2,7-diol was used as the substrate, which
this cyanation. Pleasingly, we found the yield was was generated via Ts transfer from the NCTS to the 3h
improved to 76% with prolonged reaction time in the presence of NaOH.[11] Furthermore, phenol
(Table 1, entry 12), and the highest yield was obtained derivatives also reacted smoothly with NCTS to
when 3 equivalents of NCTS was employed (Table 1, provide the corresponding benzonitriles in moderate to
entry 14).
good yields (Scheme 4, 3w–3z), although the SnCl4
can not catalyze the cyanation of these substrates.
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Scheme 5. Proposed mechanism.
(eq. 1). Additionally, we found that the Ts group can
transfer from the NCTS to 3b, resulting in the
formation of 2b (eq. 2).[11] Based on these results, a
proposed mechanism for this cyanation is demon-
strated in Scheme 5.[12] Initially, the intermediate I
generated from SnCl4, base and phenol derivative
reacts with NCTS via a six-membered transition state
II to give the intermediate III, which then undergoes
the elimination of PhNSnTs (IV) to give the product V.
The subsequent tautomerization leads to the formation
of desired cyanation product, which could further react
with NCTS in the presence of base to generate product
2. In addition, the tin exchange between the intermedi-
ate IV and phenol derivative regenerates the intermedi-
ate I and completes the catalytic cycle.
Scheme 3. SnCl4-mediated cyanation for the synthesis of 2-
hydroxy naphthonitriles.
To demonstrate the utility of this cyanation reac-
tion, 2-hydroxy naphthonitrile synthesized from a gram
scale reaction of 2-naphthol with NCTS was employed
as a platform for synthesis of various useful building
blocks (Scheme 6). First, an antibacterial compound
4a was prepared in 88% yield from 3b and 2-
bromoacetophenone via intermolecular cyclization.[13]
Besides, the chiral alcohol, (+)-Fenchol, can be
incorporated into naphthalene via our reported alcohol
exchange reaction.[6] We then investigated the synthesis
Scheme 4. BF3 ·OEt2-mediated cyanation of phenol derivatives.
To get more mechanistic information, we carried of chiral oxazoline ligand from 3b and chiral amino
out a series of control experiments. First, we treated alcohol, and found the desired product was formed in
the sulfonyl-protected naphthol, 2-methoxynaphtha- the presence of ZnCl2 albeit with 48% yield.[14] Finally,
lene, and 2-naphthylamine with the standard reaction the Ni-catalyzed coupling of 2-methoxy-1-naphthoni-
conditions, and no cyanation product was observed trile with methylmagnesium bromide was carried out,
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21702056, 21971059
and 21605070), the National Program for Thousand Young
Talents of China and the Fundamental Research Funds for the
Central Universities.
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[10] In the BF3 ·OEt2/AlCl3-mediated cyanation, the reaction
produced compound 5 first in the presence of Lewis acid,
which then underwent elimination in the presence of
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Lewis Acid-Mediated Cyanation of Phenols Using N-Cyano-
N-phenyl-p-toluenesulfonamide
Adv. Synth. Catal. 2019, 361, 1–6
W. Zhang, T. Li, Q. Wang*, W. Zhao*