Nickel-Catalyzed Deoxycyanation of Activated Phenols via Cyanurate Intermediates with Zn(CN)2: A Route to Aryl Nitriles

Article abstract of DOI:10.1021/acs.orglett.8b00974

A novel, and efficient nickel-catalyzed deoxycyanation of phenolic compounds using relatively nontoxic Zn(CN)₂ as the cyanide source was developed. The reaction of C-O bond activated phenolic compounds by 2,4,6-trichloro-1,3,5-triazine with Zn(CN)₂ in the presence of a nickel precatalyst afforded the aromatic nitriles in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.8b00974

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Deoxycyanation of Activated Phenols via Cyanurate
Intermediates with Zn(CN)2: A Route to Aryl Nitriles
Majid M. Heravi,*,† Farhad Panahi,*,†,‡ and Nasser Iranpoor‡
†Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran
‡Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran
S
* Supporting Information
ABSTRACT: A novel, and efficient nickel-catalyzed deoxy-
cyanation of phenolic compounds using relatively nontoxic
Zn(CN)2 as the cyanide source was developed. The reaction of
C−O bond activated phenolic compounds by 2,4,6-trichloro-
1,3,5-triazine with Zn(CN)2 in the presence of a nickel
precatalyst afforded the aromatic nitriles in good to excellent
yields.
cyanating agents, the cyanation of aryl C−O electrophiles has
been largely overlooked (Scheme 1).9−12
cyanation reaction toward synthesis of aromatic nitriles
Aplays a key role in organic synthesis because this building
block exist in the structure of many natural products,1
pharmaceuticals (Figure 1),2 agricultural chemicals, and
advanced materials.3
Noticeably, the aryl C−O electrophiles derived from phenols
are more commercially available and more readily accessible
than their aryl halides counterparts.13 The direct employment
of phenol derivatives (as a chemical feedstock) instead of aryl
halides as the aryl C−O electrophile is favorable from both
Scheme 1. Metal-Catalyzed Cyanation of Aryl Halides and
Aryl C−O Electrophiles
Figure 1. Chemical structures of some important pharmaceuticals
containing an aryl nitrile moiety: (A) rilpivirine, an anti-HIV agent;
(B) citalopram, Cipramil (Promonta Lundbeck), a central nervous
system (CNS) drug; (c) periciazine, Aolept (Bayer), a antipsychotic
agent; (D) RU-58841, a nonsteroidal receptor antagonist.
More importantly, the nitrile group located on the aryl
moiety can be readily converted to other important functional
groups in organic synthesis, such as aldehyde, carboxylic acid,
ketone, esters, amine, amide, etc.4 Conventionally, there are
two routes for the synthesis of aryl nitriles: (a) the classical
diazotization of anilines followed by the Sandmeyer reaction5
and (b) the Rosenmund−von Braun reaction,6 which suffers
from the requirement of a stoichiometric amount of CuCN at
temperatures as high as 150 °C to convert aryl iodides to aryl
nitriles. Thus, both of these conventional methods require
harsh reaction conditions and tedious workup procedures and
experience limited substrate scope.
Transition-metal-catalyzed cyanation of aryl halides, as
another important approach, has made many progress in
terms of efficiency and practicality.7,8 Despite much progress in
metal-catalyzed cyanation of aryl halides with different
Received: March 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00974
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Organic Letters
Letter
synthetic and environmental points of view.14 In this light,
various C−O bond-activating agents have been developed for
the preparation of different aryl C−O electrophiles for use in
the appropriate organic transformations.13,14 Furthermore, it
has been found that nickel species are superior catalysts in the
aryl C−O electrophile coupling reactions due to their high
capability in oxidative addition, as well as their low price relative
to Pd species counterparts.15
a
Table 1. Optimization of the Reaction Conditions
It has been reported that 2,4,6-trichloro-1,3,5-triazine (TCT)
can effectively activate C−O bonds in phenols in order to be
used in nickel-catalyzed coupling reactions.16 Prompted by
these reports and our interest in Ni-catalyzed organic
transformations,17 in this paper, we disclose that TCT can
offer direct conversion of activated phenolic compounds to
aromatic nitriles via a Ni-catalyzed process. To the best of our
knowledge, this is the first example of the Ni-catalyzed
deoxycyanation of phenolic compounds activated by TCT
(Scheme 2).
b
ligand
T
yield
(%)
entry
[Ni] (mol %)
(mol %)
solvent
(°C)
1
2
NiCl2 ·5H2O (5)
NiCl2·5H2O (5)
NiCl2·5H2O (5)
NiCl2·5H2O (5)
NiCl2·5H2O (5)
NiCl2·5H2O (5)
NiCl2·5H2O (5)
NiBr2 (5)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
110
110
110
110
110
110
110
110
110
110
0
0
PPh3 (20)
dppe (10)
dppf (10)
dcype (10)
dmg (10)
dme (10)
dcype (10)
dcype (10)
dcype (10)
3
<10
35
70
60
25
63
90
75
4
5
6
7
8
Scheme 2. Ni-Catalyzed Deoxycyanation of Phenols Using
TCT as C−O Bond-Activating Agent
9
Ni(COD)2 (5)
10
Ni(PPh3)2(CO)2
(5)
11
12
13
14
15
16
17
18
19
20
21
22
Ni(COD)2 (7)
Ni(COD)2 (3)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
dcype (14)
dcype (6)
dioxane
dioxane
dioxane
toluene
DMF
110
110
110
110
110
110
80
89
58
74
80
45
50
35
dcype (5)
dcype (10)
dcype (10)
dcype (10)
dcype (10)
dcype (10)
dcype (10)
dcype (10)
dcype (10)
THF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
To find the optimal reaction conditions, p-cresol was selected
as a model phenolic compound and initially activated by TCT
to provide the corresponding TAT [2,4,6-tris(p-tolyloxy)-1,3,5-
triazine; 2a], which was then treated with different source of
nitriles such as Zn(CN)2, KCN, and TMSCN in the presence
of Ni precursor as catalyst under diverse reaction conditions to
obtain 4-methylbenzonitrile 3a (Table 1).
c
110
110
110
110
110
88
d
52
e
72
f
70
0
a
Reaction conditions: 2a (0.35 mmol), Zn(CN)2 (1.5 mmol), solvent
(5 mL). GC yield. 2 mmol of Zn(CN)2. KCN was used. TMSCN
was used. K4[Fe(CN)6] was used.
b
c
d
e
In the presence of NiCl2 as precatalyst in dioxane at 110 °C,
no product was observed (Table 1, entry 1). With addition of
PPh3 as ligand in the reaction media, no change in the result
was detected (Table 1, entry 2). About 10% of the desired
product was detected when dppe was used as ligand along with
NiCl2 precatalyst (Table 1, entry 3). Having observed this
result, we started screening other ligands. The reaction yield
was enhanced to 35% by use of dppf as ligand (Table 1, entry
4). A satisfactory yield of 70% was observed when dcype was
used as ligand under the same reaction conditions (Table 1,
entry 5). Interestingly, an acceptable yield of 60% (Table 1,
entry 6) was obtained when dmg was used as a nonphosphine
ligand; however, in the presence of dme the reaction yield was
decreased to 25% (Table 1, entry 7). Considering the high yield
of product obtained when dcype ligand was used, the other
reaction parameters were optimized based on this ligand. Then,
different type of Ni sources were examined, and the maximum
yield of product (90%) by use of Ni(COD)2 was obtained
(Table 1, entries 8−10). No improvement in the reaction yields
was observed by increasing of the catalyst loading up to 7.0 mol
%, while the reaction yield was decreased when 3.0 mol % of
the catalyst was used; thus, 5.0 mol % of catalyst was selected as
the optimum catalyst loading (Table 1, entries 11 and 12).
Decreasing the amount of ligand to 5.0 mol % (related to 5.0
mol % of Ni source) also decreased the reaction yield to 74%
(Table 1, entry 13). Other solvents were also screened, but no
superiority was observed in the reaction outcome (Table 1,
entries 14−16). By decreasing the reaction temperature to 80
f
°C, the yield was significantly decreased to 35% (Table 1, entry
17). When 2.0 equiv of Zn(CN)2 was used, no improvement in
the reaction yield was observed (Table 1, entry 18). Among the
tested cyanides sources, Zn(CN)2 was found to be the reagent
of choice in terms of giving higher yield and shorter reaction
time (Table 1, entries 19−21). It should be mentioned that in
the absence of Ni catalyst no product was observed under the
optimized reaction conditions, demonstrating that this is a Ni-
catalyzed process and Zn(CN)2 could not perform this process
alone (Table 1, entry 22).
Having these secured optimal reaction conditions in hand,
direct conversion of a wide range of phenolic compounds to
their corresponding aryl nitriles using TCT as C−O bond
activating agent in the presence of Ni species was successfully
investigated. To study the substrate scope and establishing the
generality of our novel method, differently substituted phenols
(bearing electron-releasing and electron-withdrawing groups)
were also fruitfully converted to their corresponding nitriles
(Scheme 3).
Scheme 3 also clearly shows that this protocol canbe used
with a wide range of phenolic compounds bearing different
functionalities, such as alkyl (3a), alkoxy (3b,k,m,n), amino
(3j,l), trifluoromethyl (3d), cyano (3e), and nitro (3f) groups,
aldehydic (3g,m) and ketonic (3h,v,w) carbonyls, ester moiety
(3i), halogeno (3o,p), and carboxylic (3n) groups, and
B
DOI: 10.1021/acs.orglett.8b00974
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Scheme 3. Ni-Catalyzed Deoxycyanation of Phenols Using
TCT as C−O Bond-Activating Agent
Scheme 4. Ni-Catalyzed Deoxycyanation of Different Aryl
C−O Electrophiles
a
proceed, and only a yield of 15% for deoxycyanation product
for 2-(p-tolyloxy)pyridine was obtained. In the case of using 3-
(p-tolyloxy)pyridine and 4-(p-tolyloxy)pyridine, no product
was even detected. These findings clearly show the key role of a
suitable compound containing nitrogen such as TCT as an
activating agent for the effective cleavage of C−O bond during
cyanation process. It seems reasonable to assume that the
coordination of N atom with Ni metal facilitates the
deoxycyanation process. In addition, the electron-deficient
nature of the used heterocycle is also important factor because
2-(p-tolyloxy)pyrimidine has a higher yield of 55%. More
importantly, for 5-(p-tolyloxy)pyrimidine no product was
detected, which clearly confirms the superior role of nitrogen
at ortho position for the activation of C−O bond due to the
electronic nature of the heterocycle ring. In accordance with the
already suggested catalytic cycle of transition-metal-catalyzed
cyanation reactions including aryl halides and metal cyanides, a
plausible reaction mechanism for this protocol is proposed, as
illustrated in Scheme 5.7a
a
All yields refer to isolated product.
Scheme 5. Proposed Mechanism for the Nickel-Catalyzed
Deoxycyanation of Activated Phenols with TCT
tolerates the reaction conditions to afford the respective aryl
nitriles 3a−x in good to excellent yields. Interestingly, good
chemoselectivity between C−O and C−halogen bond cleavage
under the optimized reaction conditions in the production of
compounds 3o and 3p was also observed. Sterically hindered
substrates also underwent the above-mentioned strategy to give
the desired products in satisfactory yields (3l−n). In addition,
polyaromatic phenol such as anthracene was successfully
subjected to cyanation by this protocol to give the
corresponding nitriles 3q in good yields. Using this method-
ology, heterocyclic substrates including pyridine, quinoline,
indole, and thiophene bearing an OH group also afforded
moderate to good yields of their corresponding nitrile
derivatives 3r−u. It is worth mentioning that we successfully
applied our methodology in conversion of biologically
important phenols such as xanthene and steroid estrone to
obtain the corresponding nitriles 3v and 3w, respectively.
Interestingly, the double bond is inactive under the reaction
conditions; thus, it is possible to use hydroxyl-functionalized
styrene in cyanation reactions before coupling with aryl halides
using palladium catalysis (3x). In order to show the
applicability of this method in the conversion of bis-hydroxyl
substrates to bis-functionalized nitriles, hydroquinone was
activated by TCT and underwent the reaction successfully to
give the expected bis-cyanation product 3e in 60% yield after 24
h. To prove the key role of triazine ring in accomplishment of
this reaction, the optimized reaction was used for other aryl C−
O electrophiles (Scheme 4).
The catalytic cycle is started with C−O oxidative addition of
the activated phenol by TCT to Ni(0) catalyst to generate II.12
The nitrogen 2 of triazine ring plays a key role in this step (the
results in Scheme 4 support this fact). Then nitrogen and
oxygen atoms of triazine ring can coordinate with Zn(CN)2 III
to facilitate the anion exchange between triazinolate and
cyanide to produce intermediate V. The produced part from
this stage (IV) can undergo another cycle through other
phenoxy groups. Finally, the produced intermediate V is
subjected into a reductive elimination to afford the arylnitrile
product.
In conclusion, we have developed a novel and efficient
deoxycyanation methodology for the conversion of phenolic
compounds to their corresponding aryl cyanides. This protocol
As shown in Scheme 4, under the optimized reaction
conditions, the conversion of unactivated p-cresol did not
C
DOI: 10.1021/acs.orglett.8b00974
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Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00974.
Experimental procedures, spectral data, and 1H, 13C
NMR spectra for synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mmheravi@alzahra.ac.ir.
*E-mail: panahi@shirazu.ac.ir.
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ORCID
Farhad Panahi: 0000-0003-0420-4409
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to the Iran Science Elites Federation for their
financial support. M.M.H. also acknowledges encouragement
by the Alzahra University Research Council.
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DOI: 10.1021/acs.orglett.8b00974
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