Organophotoredox assisted cyanation of bromoarenes: via silyl-radical-mediated bromine abstraction

Article abstract of DOI:10.1039/d0cc00163e

The insertion of a nitrile (-CN) group into arenes through the direct functionalization of the C(sp²)-Br bond is a challenging reaction. Herein, we report an organophotoredox method for the cyanation of aryl bromides using the organic photoredox catalyst 4CzIPN and tosyl cyanide (TsCN) as the nitrile source. A photogenerated silyl radical, via a single electron transfer (SET) mechanism, was employed to abstract bromine from aryl bromide to provide an aryl radical, which was concomitantly intercepted by TsCN to afford the aromatic nitrile. A range of substrates containing electron-donating and -withdrawing groups was demonstrated to undergo cyanation at room temperature in good yields.

Full text of DOI:10.1039/d0cc00163e

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Organophotoredox Assisted Cyanation of Bromoarenes via Silyl-
Radical-Mediated Bromine Abstraction
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
Maniklal Shee, Sk. Sheriff Shah and N. D. Pradeep Singh*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Insertion of nitrile (-CN) group to arenes through direct In the last decade, photoredox catalysis has been exploited for
2
11
functionalization of C(sp )-Br bond is a challenging reaction. the synthetically challenging reactions. Notably, facile
Herein, we report an organophotoredox method for the cyanation generations of reactive intermediates such as arene radical
of aryl bromides using organic photoredox catalyst 4CzIPN and cations, α-carbonyl radicals, trifluoromethyl radicals, enone
Tosyl cyanide (TsCN) as the nitrile source. Photogenerated silyl radical anions, iminium ions via SET under photocatalytic
1
2
radical, via single electron transfer (SET) mechanism, was condition ease the synthesis of complex molecules.
employed to abstract bromine from aryl bromide to provide aryl
radical, which concomitantly intercepted by TsCN to afford the
aromatic nitrile. A range of substrates containing electron-
donating and -withdrawing groups, were demonstrated to
undergo cyanation at room temperature in good yield.
The presence of aromatic nitriles in pharmaceuticals,
agrochemicals, natural products, pesticides, and fine chemicals
1
reflects their utmost importance. Cyanoarenes are treated as
valuable functional group precursors for the late stage
2
3
4
installation of acids, aldehydes or amines, ketones or imines,
5
and amides. Aromatic nitriles are synthesized by numerous
methods such as Sandmeyer reaction using diazonium salt,
6
Rosenmund–von Braun reaction from aryl halides and copper
7
catalyst. In addition to classic approaches several transition
metal catalyzed cross-coupling of aryl halides and cyano
8
precursors are utilized for the synthesis of cyanoarenes.
Primarily copper and palladium catalysts are used to couple
aryl halides with cyanating reagents to provide cyanoarenes (a,
Scheme 1).9 Buchwald's works on palladium-and copper-
1
0
catalyzed cyanation of aryl halides are noteworthy. Although
these methods are efficient, the requirement of toxic reagents,
high temperature, expensive metal catalysts, and ligands are
serious drawbacks. Development of a transition metal free
method at room temperature for the direct conversion of aryl
halides to aryl nitriles would be attractive. This motivated us to
focus on the photocatalytic method to synthesize aromatic
nitriles.
Scheme 1. Cyanation Methods for Aromatic Ring.
Interestingly, photocatalytic cyanation of organic molecules is
a synthetically viable method. In 2015, Fu and Peter groups
developed photoinduced copper-catalyzed cyanation of
unactivated secondary alkyl chlorides at room temperature in
1
3
the presence of UV light. Later on, several decarboxylative
cyanation of carboxylic acids using visible light has been
1
4a-c
developed.
Recently, König and co-workers achieved
cyanation of aliphatic carboxylic acids via decarboxylation
a. Department of Chemistry, Indian Institute of Technology Kharagpur, 721302 method using tosyl cyanide as a cyanating agent and Flavin as
Kharagpur, West Bengal, India. E-mail: ndpradeep@chem.iitkgp.ac.in
Electronic Supplementary Information ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
14d
a photocatalyst. These photocatalytic cyanation restricted to
aliphatic systems. Nicewicz et al. reported cyanation of arenes
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
by direct functionalization of C-H bonds assisted by an To implement our hypothesized photocatalytViciewcAyrtaicnleaOtniloinne
acridinium based photoredox catalyst and nucleophile reaction, we focused on the cyanDatOioI:n10.1o03f9/Dm0eCtCh0y0l1634E-
trimethylsilyl cyanide (TMSCN) under aerobic condition (b, bromobenzoate 6 (Table 1).
Scheme 1).15 This procedure was successful with electron rich
arenes and showed regioselectivity problem. Limited access to
Table 1. Optimization of Reaction Conditions.a
synthesize aromatic nitriles led us to develop a direct
cyanation method under visible light irradiation. With this
2
intention, we were interested to functionalize C(sp )-Br bond
of aryl bromide via radical mediated Br abstraction to generate
aryl radical, which would then intercept by TsCN as a cyanating
agent to produce desire aromatic nitrile (c, Scheme 1).
entry
conditions
as shown
as shown
as shown
as shown
as shown
TMSCN
1 equivTsCN
2 equivTsCN
4CzTPN as PC
4DPAIPN as PC
solvent
CH CN
DMF
DMSO
DME
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
yield (%)[b]
1
2,14,15
Inspired by the literature reports,
we hypothesized that
1
2
3
4
5
3
48
14
19
5
71
<5
63
75
55
0
43
9
0
0
0
the visible-light promoted cyanation of aryl bromide based on
our methodology proceed following the photocatalytic cycle
depicted in the Scheme 2.
c
6
7
8
9
1
0
d
1
1
TMS
3
SiH
1
1
1
1
1
2
3
4
5
6
Presence of air
no PC
3
no (TMS) SiOH
no visible light
no TsCN
0
aReaction conditions: Aryl bromide 6 (0.25 mmol, 1 equiv), 4CzIPN (5 mol %),
TsCN (0.30 mmol, 1.2 equiv), base (107 mg, 0.50 mmol, 2 equiv), (TMS) SiOH
0.375 mmol, 1.5 equiv), solvent (3 mL), irradiated under inert condition with
3
(
b
c
blue LEDs for 12 h at room temperature. Isolated products. TMSCN used instead
of TsCN as a -CN source. 1.5 equiv of TMS
d
3
SiH used in place of (TMS)
3
SiOH.
A reaction mixture of 6 (1 equiv), organic photocatalyst 4CzIPN
5 mol %), silyl radical source (TMS) SiOH, and cyanating agent
TsCN were added to CH CN under N atmosphere and exposed
to blue LED for 12 h at room temperature. The desired nitrile-
bearing product 12 was obtained in 48 % yield (Table 1, entry
Scheme 2. Proposed mechanism for silyl radical mediated cyanation of aryl
(
3
bromides via photoredox catalysis.
3
2
The catalytic cycle will follow the sequence as, (i) Visible-light
excitation of photocatalyst (PC) 4CzIPN [1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene] (1) will produce
excited state species (2), (ii) the excited photocatalyst (2) [Ered
1
). Solvent screening showed that acetone afforded the cyano
product with maximum yield (Table 1, entry 5). Further studies
revealed that the use of 4CzTPN [2,3,5,6-Tetra(carbazol-9-
yl)terephthalonitrile] as an organic photocatalysts provided
satisfactory yield whereas 4DPAIPN [1,3-Dicyano-2,4,5,6-
tetrakis(diphenylamino)-benzene] found to be ineffective
photocatalyst (Table 1, entries 9, 10). When we used TMSCN
as a cyanating reagent trace amount of product was formed
1
6
(
(
[
PC*/PC‾) = +1.43 V vs SCE in CH
trimethylsilyl) silanol (supersilanol,
SiOH /(TMS) SiOH] = +1.54 V vs SCE in MeCN] via SET
3
CN] will then oxidize tris-
4)
[Ered
+•
17
(TMS)
3
3
mechanism to generate reduced form of the photocatalyst (3),
iii) oxidized form of supersilanol will then generate silicon-
centered radical (5), after deprotonation followed by radical
(
1
8
Brook rearrangement, (iv) silyl radical (5), known as potent
(Table 1, entry 6). Further, change in the reaction parameters
2
19,20
abstractor of bromine atom from C(sp )-Br bonds
1
(k ≈ 5×
like substrate and reagents’ concentrations and catalyst
loading had an adverse impact on the yield of the product
6
−1 −1
8
−1 −1
21
0 M s to 1.1 × 10 M s for bromobenzene) will result
in the formation of aryl radical (7), (v) weakly nucleophilic aryl
radicals will then attack the highly electrophilic TsCN (8) to
furnish the expected key intermediate (9), which then affords
(
Table 1, entry 7, 8). Under aerobic condition cyanation
reaction provided drastically reduced product yield due to
interference of O with the catalytic cycle (Table 1, entry 12).
2
the desired nitrile compound (12) through Barton nitrile
Control experiments revealed that photocatalyst, silanol, TsCN,
and visible light were all individually necessary for the success
of the reaction (Table 1, entries 13−16, 0% yield). Additionally,
the exclusion of base resulted in lower product yield
transfer1
4a,b
along with the formation of p-toluenesulfonyl
•
radical (Ts , 10), (vi) finally, the reduced photocatalyst (PC‾)
1
6
[
E
red (PC‾/PC) = −1.24 V vs SCE in CH
3
CN] will donate single
•
•
−
22
electron to Ts [Ered (Ts /Ts ) = −0.50 V vs SCE in CH
3
CN] to
(supporting information, SI, Figure S2, entry 6, 32% yield).
−
provide Ts (11) and the photocatalyst (1).
2
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DOI: 10.1039/D0CC00163E
that heteroaryl bromides such as bromo derivatives of
pyridines, N-substituted indoles, and carbazole yielded cyano
products moderately (37−45, 41−56%). To our delight,
heterocycles e.g. benzodiazole, benzothiazole, thiophene,
furan attached to para postion of the aromatic bromides
delivered the cyano products under the presented
photocatalytic method (46−50, 47−61%). The reason for the
moderate yields is due the formation of dehalogenation
product. The dibromide substrates provided moderate to
lower yield along with minimum amount of dicyano products
(SI, for details).
To shed light on the reaction mechanism, we have carried out
some control experiments. Formation of the aryl radical
intermediate was checked by conducting the photocatalytic
cyanation reaction under the optimized reaction condition in
the presence of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)
(A, Scheme 4).
Scheme 4. Mechanistic studies on aryl radical.
As expected, the formation of aryl nitrile was completely
Scheme 3. Scope of the Cyanation Reaction of Aryl Bromides: Aryl bromide (0.5 mmol,
equiv), 4CzIPN (5 mol %), TsCN (0.60 mmol, 1.2 equiv), base (1.00 mmol, 2 equiv),
TMS)
SiOH (0.75 mmol, 1.5 equiv), solvent (6 mL), irradiated under inert condition 15% yield (see the SI for details). Further, the dehalogenation
suppressed, whereas aryl-TEMPO adduct (51) was obtained in
1
(
3
with blue LEDs for 12 h at room temperature. Isolated products yields were reported.
product (52) was obtained in 18% yield under the optimized
reaction condition due to hydrogen atom abstraction from
solvent (B, Scheme 4). When the same reaction was conducted
in acetone-d6, 11% deuterium incorporated product (53) was
observed. Furthermore, the standard reaction was carried out
Having optimized conditions in hand, we explored the scope
of this photocatalytic cyanation method with diverse aromatic
and hetero aromatic bromides (Scheme 3). Electronically
varied bromoarenes with para substitution provided good
product yields (12−27, 57−86%). ortho- and meta-substituted
substrates were well tolerated and gave moderate yields
2 2 8 6
using K S O as an oxidant instead of TsCN in acetone-d
solvent resulted in high incorporation of deuterium to the
arene (56% yield of 53), further supporting the intermediacy of
an aryl radical.
(28−31, 40−61%). Notably, substrates containing electron-
withdrawing groups (e.g. NO , CN) did not hinder the reaction
2
The utility of this method was shown by inserting -CN group to
and furnished good product yields (12−21, 57−75%). Similarly,
electron-donating group bearing substrates afforded high yield
of the desired products (23−28, 40−86%). Interestingly,
substrates containing other halogen (fluoro and chloro) groups
proceeded smoothly and furnished nitrile products with good
yields (17 and 18, 75% and 68%). Disubstituted aryl bromides
produced slightly lower product yields (32−34, 36−54%).
Bromonaphthalenes were suitable substrates for the cyanation
reactions (35 and 36, 61% and 68%). We were pleased to find
N-substituted bromo-phenothiazine (54) to
synthesize
compound 55 (Scheme 5). Nitrile containing phenothiazine
moiety constitute several drug molecules e.g. pericyazine and
1
a
cyamemazine which are antipsychotic drugs.
Cyano-
phenothiazine molecules exhibits strong luminescent property.
These redox-active chromophores also found application in
2
3
photocatalysis and dye-sensitized solar cells (DSSC).
Compound 55 shows strong yellow fluorescent color.
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Scheme 5. Direct insertion of -CN group to phenothiazine.
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mediated halogen abstraction strategy has been employed to
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CzIPN and cyanating reagent TsCN effectively accomplish the
reactions. A range of aryl and heteroaryl bromides were tested
successfully. The developed photocatalytic cyanation reaction
proceeded at room temperature and provided moderate to
good product yields. Wide variety of functional groups e.g.
ester, acid, amide, and protected amines were well tolerant
towards the proposed photocatalytic conditions. To the best of
our knowledge, this is the first time we have shown a metal-
free direct cyanation of (hetero)aryl bromides. Additionally,
the application of this direct cyanation was demonstrated by
incorporating -CN group to arene ring of phenothiazine. This
Mild and simple protocol can be used to synthesize
pharmaceuticals, organic precursors, and natural products.
We thank the DST (SERB) (Grant No. DIA/2018/000019) for
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Conflicts of interest
There are no conflicts to declare.
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