Lewis acid-promoted site-selective cyanation of phenols

Article abstract of DOI:10.1039/d0ob00737d

An efficient Lewis acid-promoted site-selective electrophilic cyanation of 3-substituted and 3,4-disubstituted phenols has been developed. The cyanation reactions using MeSCN as the cyanating reagent proceeded efficiently to afford a wide range of 2-hydroxybenzonitriles with high efficiency and excellent regioselectivity. This protocol could provide a practical method for the synthesis and modification of biologically active molecules.

Full text of DOI:10.1039/d0ob00737d

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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/D0OB00737D
ARTICLE
Lewis acid-promoted site-selective cyanation of phenols
Wu Zhang, Wen Yang* and Wanxiang Zhao*
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient Lewis acid-promoted site-selective electrophilic cyanation of 3-substituted and 3,4-disubstituted phenols has
been developed. The cyanation reactions using MeSCN as the cyanating reagent proceeded efficiently to afford a wide range
of 2-hydroxybenzonitriles with high efficiency and excellent regioselectivity. This protocol could provide a practical tool for
the synthesis and modification of biologically active molecules.
DOI: 10.1039/x0xx00000x
and high desirability to develop efficient and practical cyanation
methods. Given the abundance and significance of phenols and
diverse transformations of nitriles, we believe that the
cyanation of phenols could play an important role in the
synthesis and modification of phenol-containing biologically
active molecules, especially pharmaceuticals.
Introduction
Phenols as abundant feedstocks are key structural scaffolds in
natural products, pharmaceuticals, agrochemicals, materials,
and catalysts, and often employed as useful synthetic
intermediates for their preparation (Fig. 1a).1 As a result, many
efforts from chemists and pharmaceutical scientists were
devoted to the modification of phenols at their ortho-, meta-,
and para- positions, and significant advances have been
achieved, with the direct C−H functionalization being the most
popular because of its high efficiency in synthesis of complex
organic molecules from readily available starting materials.1c,2
However, to the best of our knowledge, the examples of
cyanation of phenols are very rare,3,4 despite that aromatic
nitriles are versatile building blocks in organic and fine chemical
synthesis, especially in the drug synthesis.5 For example, phenol
derivatives bearing cyano functional group with excellent
biological activities are numerous, such as epanolol as a
selective β1-blocker in the treatment of angina pectoris and mild
hypertension,5b febuxostat as an antihyperuricemic agent used
to treat gout,5c and azoxystrobin as a broad spectrum pesticide
used in cultivation (Fig. 1b).5d
Aromatic nitriles can be readily converted to a variety of
valuable synthons, such as amines, ketones, aldehydes, amides,
and carboxylic acids, which made them the important role in
synthetic chemistry.6 Conventionally, the preparation of
aromatic nitriles mainly relies on transition-metal catalyzed
electrophilic cyanation of aromatic compounds7 or the coupling
of aryl halides with nucleophilic cyanating reagents (NaCN,
CuCN, Zn(CN)2, TMSCN, etc),8 and the coupling of aryl
organometallic reagents (ArB(OR)2, ArMgBr, ArLi, etc) with
electrophilic cyanating reagents (BrCN, ClCN, BtCN, etc).9
However, these methods may suffer from toxic cyanating
reagents, expensive catalysts, poor functional group tolerance,
and/or harsh reaction conditions. Thus, it is still of great interest
Fig. 1 Representative natural products and pharmaceuticals.
Despite many methods for aromatic nitriles have been
reported,7-10 the C−H cyanation of phenols still remains
underdeveloped.3 Sugasawa described a BCl3-promoted ortho
cyanation of phenols with MeSCN (Scheme 1a).3a In the seminal
work, preliminary investigation with just a few substrate
examples was disclosed, and the regioselectivity-control in the
cyanation process was not completed. Very recently, we
reported a Lewis-mediated α-cyanation of 2-naphthols using
NCTS as the cyanating reagent (Scheme 1b).3c Although
regioselective α-cyanation process was achieved for special
substrates (2-naphthols), the regioselectivity-control with
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha, Hunan 410082, P. R.
China. Email: zhaowanxiang@hnu.edu.cn; yangwen@hnu.edu.cn.
†
Electronic Supplementary Information (ESI) available: Experimental details and
spectral data. See DOI: 10.1039/x0xx00000x
general 3,4-disubstituted phenols is
a significant and
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challenging work and remains unsolved. For our persistent MeSCN were investigated. As illustrated, the yield or/and
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interest in the synthesis and application of 2-hydroxy aromatic regioselectivity declined with the decreDaOseI: 1o0f.10th39e/Da0mOoB0u0n7t37oDf
nitriles,3c,11 herein, we would like to develop an efficient and BF3•OEt2 or AlCl3 (Table 1, entries 15−20). In contrast, both the
practical Lewis acid-promoted site-selective C−H ortho yield and regioselectivity were improved when the amount of
cyanation of 3-substituted and 3,4-disubstituted phenols MeSCN was increased from 1.2 equivalents to 2.0 equivalents
bearing two different meta-positions, complementing the (Table 1, entries 21−23). Notably, the sole use of AlCl3 or
established approaches (Scheme 1c).
BF3•OEt2 all gave poor results (Table 1, entries 24−25). The
results indicate that the cyanation reaction requires working
together of BF3•OEt2 and AlCl3 to ensure high efficiency and
excellent regioselectivity.
Table 1 Optimization of the reaction conditionsa
MeSCN
(equiv.)
yield (%)b
2a 2a’
Entry
LA (equiv.)
solvent
t (h)
(
/
)
1
2
1.5
1.5
1.5
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.8
2.0
1.5
1.5
MgCl2 (1.2)
TiCl4 (1.2)
DCE
DCE
12
12
12
3
6 (1/2)
7 (1/1)
3
ZnCl2 (1.2)
DCE
20 (1/2)
68 (2.8/1)
75 (16/1)
54 (8/1)
30 (5/1)
--
4
BCl3 (1.2)
DCE
5
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (1.5)
BF3•OEt2 (1.0)
BF3•OEt2 (0.5)
BF3•OEt2 (0.2)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
BF3•OEt2 (2.0)
--
DCE
12
12
12
12
12
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
Scheme 1 Direct C-H ortho cyanation of phenols.
6
MeCN
dioxane
THF
Initially, we used 5,6,7,8-tetrahydronaphthalen-2-ol 1a as a
model and treated it with the optimal reaction conditions
previously reported by us and Sugasawa. As shown in Scheme 2,
7
8
in the present of BF3
provided 2a in low yield with good regioselectivity (31%,
2a 2a´= 5/1). When 1a was subjected to Sugasawa’s conditions,
the desired cyanated product of 2a was produced in 68% yield
but with poor regioselectivity (2a 2a´= 2.8/1).
• OEt2/AlCl3, the cyanation with NCTS
9
toluene
DCE
59 (10/1)
86 (17/1)
63 (10/1)
46 (3/1)
85 (16/1)
76 (15/1)
85 (16/1)
83 (16/1)
76 (15/1)
52 (4/1)
70 (15/1)
54 (10/1)
64 (15/1)
88 (18/1)
91 (21/1)
5 (1/1.8)
24 (2.5/1)
10
11c
12d
13e
14f
15
16
17
18
19g
20h
21
22
23
24
25i
/
DCE
/
DCE
DCE
DCE
DCE
DCE
DCE
Scheme 2 Initial results.
DCE
Next, we turned our attention to further optimize various
reaction parameters, and the results are summarized in Table 1.
A variety of Lewis acid were tested (Table 1, entries 1−5), and
BF3•OEt2 was found to be the best Lewis acid which promoted
the cyanation reaction smoothly to afford product 2a in 75%
DCE
DCE
DCE
DCE
yield with high regioselectivity (2a/2a´= 16/1, entry 5).
DCE
Encouraged by this fascinating serendipity, we then shifted our
efforts to examine solvents, and found 1,2-dichloroethane (DCE)
was superior to other solvents (Table 1, entries 6−9). Pleasingly,
the yield was improved to 86% with a slightly higher ratio
DCE
BF3•OEt2 (2.0)
DCE
a Conditions: i) 1a (1.0 mmol, 1.0 equiv.), MeSCN, AlCl3 (1.0 equiv.),
LA, solvent (1.0 mL). ii) NaOH (4 M aq. 3.3 mL), 80 °C for 0.5 h. LA =
(2a/2a´= 17/1) when the reaction time was prolonged to 24 h
Lewis acid. TiCl4 (1.0
M in dichloromethane). BCl3 (1.0 M in
(Table 1, entry 10). In addition, both the yield and the product
ratio were decreased at either higher or lower reaction
temperature (Table 1, entries 11−12). The concentration was
also screened, but no better result was obtained (Table 1,
entries 13−14). Finally, the amounts of BF3•OEt2, AlCl3, and
dichloromethane). b Yields and ratios were determined by 1H NMR
using CH2Br2 as internal standard. Numbers in parentheses are the
f
ratio of 2a
/
2a´
.
c 60 °C. d 100 °C. e DCE (0.5 mL). DCE (2.0 mL). g AlCl3
(0.5 equiv.). h AlCl3 (0.2 equiv.). I Without AlCl3.
2 | J. Name., 2012, 00, 1-3
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Table 2 Scope of the site-selective cyanation of phenolsa
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DOI: 10.1039/D0OB00737D
a Reaction conditions: i)
mL), 80 °C for 0.5 h. b BCl3.
1 (1.0 mmol), MeSCN (2.0 mmol), AlCl3 (1.0 mmol), BF3•OEt2 (2.0 mmol), DCE (1 mL), 80 °C for 24 h. ii) NaOH (4 M aq, 3.3
With the optimized conditions in hand, we next explored the transetherification of 3c with (+)-fenchol led to chiral ether 3d
substrate scope of the site selective cyanation reaction (Table in a good yield.11 The hydrolysis of 3c under different reaction
2). A wide range of 3-substituted or 3,4-disubstituted phenols
were examined, generally furnishing the desired 2- amide 3f, respectively.11,14 Moreover, according to the known
hydroxybenzonitriles
in good to excellent yields. It is procedure,15 an antitumor agent 3g was efficiently synthesized
1
conditions efficiently provided the corresponding acid 3e and
2
noteworthy that excellent regioselectivities (2/2'>20/1) were in two simple steps, using 2-hydroxybenzonitrile 2g as the
observed in all cases, which were determined by 1H NMR starting material, which can be readily prepared on gram-scale
analysis of the crude reaction mixtures. Alkyl, alkoxy, hydroxyl, from 3-methoxyphenol 1g by this cyanation method.
and aryl groups (1a
−k
,
1o
−
w) are all viable substituents.
However, m-halophenols 1l
−n were found to be less efficient
under the standard conditions, probably because the halogen
substituents reduce the electron richness of phenol ring.
Fortunately, with slight modification of the conditions (BCl3
instead of BF3•OEt2), the desired cyanated products 2l−2n were
successfully obtained in good to high yields (76-92%).
Heterocycles, such as furane and thiophene, could be
incorporated into the products (2x−y) with good efficiency.
Notably, this method is also suitable for the cyanation of
phenol-containing complex molecules. For example, the
installation of a cyano group into estrone- and estradiol-derived
Scheme 3 Gram-scale synthesis of 2c and its synthetic transformations.
Reaction conditions: i) (S)-2-Amino-3,3-dimethylbutan-1-ol, ZnCl2, PhCl,
131 °C , 72 h; ii) α-Bromoacetophenone, K2CO3, acetone, reflux, 8 h; iii)
MeI, K2CO3, DMF, 60 °C , 5 h; iv) (+)-Fenchol, KOtBu, dioxane, rt,
overnight; v) 34% aq. KOH, EtOH, 80°C , overnight, for 3e; vi) KOH(s),
substrates (1z, 1aa) was achieved with good efficiency (74% and
73% yield, respectively). It shows that our method can be
applied to the modification of natural products and
pharmaceuticals.
tBuOH, 60 °C, overnight, for 3f
.
To further demonstrate the utility of this protocol, we carried
out the gram-scale synthesis and product derivatizations
(Schemes 3 and 4). First, the gram-scale preparation of 2c was
performed well with no erosion in the yield (93%). Second,
based on facile transformations of cyano and hydroxyl groups,
product 2c was efficiently converted into diverse useful building
blocks. For example, in the presence of ZnCl2, 2c reacted
smoothly with (S)-2-amino-3,3-dimethyl-butan-1-ol to afford
chiral oxazoline ligand 3a in 88% yield.12 The construction of
benzofuran ring (3b) was achieved with high efficiency via
intermolecular cyclization of 2c with α-bromoacetophenone.13
Methyl ether 3c was obtained in 94% yield after methylation
with methyl iodide. By our previously reported method, the
Scheme 4 Synthesis of anticancer drug 3g.
To gain more mechanistic information, control experiments were
carried out. Firstly, 1-methoxy-3-methylbenzene was subjected to
the standard condition, and no cyanation product was detected (eq.
1). It indicates that the free hydroxyl group is crucial to this process.
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Additionally, the first step product 4 from 1c was obtained in 87%
isolated yield, and its structure was confirmed by NMR and HRMS.
Based on the observed results and previous study,3a,c we proposed a
similar plausible mechanism for this cyanation (Scheme 5). First, the
intermediate I is generated from phenol 1c and BF3•OEt2 with the
help of AlCl3. The role of AlCl3 is to activate BF3•OEt2 and improve its
Lewis acidity.16 Then it reacts with MeSCN though a six-membered
ring transition state II to form the intermediate III, which undergoes
tautomerization to give the key intermediate IV, which was
demonstrated by us. Due to the steric hindrance of substituent at the
meta-position, the formation of the transition state II' is unfavored,
which accounts for excellent regioselectivity. Finally, the treatment
of IV with NaOH aqueous solution followed by protonation leads to
the desired cyanation product 2.
Acknowledgements
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We gratefully acknowledge the financial suDpOpoI:r1t0f.1r0o3m9/tDh0eONB0a0ti7o3n7aDl
Natural Science Foundation of China (Grant No. 21702056, 21971059,
and 21702055), the National Program for Thousand Young Talents of
China and the Fundamental Research Funds for the Central
Universities.
Notes and references
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Scheme 5 Control experiments and proposed reaction mechanism.
Examples of C−H cyanation of phenols, see: (a) M. Adachi and
T.
Sugasawa,
Exclusive
ortho
cyanation
and
alkylthiocarbonylation of anilines and phenols using boron
trichloride, Synth. Commun., 1990, 20, 71; (b) A. R. Sardarian,
I. D. Inaloo, A. R. Modarresi-Alam, E. Kleinpeter and U. Schilde,
Conclusions
In conclusion, we have developed an efficient Lewis acid-
promoted site-selective direct cyanation of 3-substituted and
3,4-disubstituted phenols using commercially available
cyanating reagent MeSCN. The cyanation reactions proceeded
smoothly to afford a wide range of 2-hydroxybenzonitriles with
moderate to excellent yields and excellent regioselectivities.
Moreover, the practicality of this method was demonstrated by
the gram-scale preparation and various product
transformations. This process features broad substrate scope,
excellent regioselectivity, good functional group tolerance, and
easy gram-scale preparation. This protocol, as a new example
of electrophilic cyanation, may provide a practical tool to find
applications in the synthesis of key building blocks and the late-
stage modifications of biologically active complex molecules,
especially pharmaceuticals.
Metal-free regioselective monocyanation of hydroxy
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Conflicts of interest
There are no conflicts to declare.
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An efficient Lewis acid-promoted site-selective C−H ortho cyanation of 3-substituted and 3,4-DdOisIu: 1b0s.1t0i3tu9/tDe0dOBp0h0e73n7oDls
with MeSCN has been developed.