Lewis acid-catalyzed borono-minisci reactions of arylboronic acids and heterocycles

Article abstract of DOI:10.3987/COM-16-13506

A Lewis acid-catalyzed Minisci reaction between arylboronic acids and heterocycles has been developed. This radical-coupling reaction was demonstrated employing several different heterocycles as well as electron-rich arylboronic acids. Quinoline substrates afforded modest regioselectivity for substitution at the 4-position under the reaction conditions, in contrast to previously reported Br?nsted acid-mediated reactions with quinoline substrates that favored substitution at the 2-position.

Full text of DOI:10.3987/COM-16-13506

HETEROCYCLES, Vol. 92, No. 9, 2016
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HETEROCYCLES, Vol. 92, No. 9, 2016, pp. 1687 - 1697. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 24th May, 2016, Accepted, 1st July, 2016, Published online, 15th July, 2016
DOI: 10.3987/COM-16-13506
LEWIS ACID-CATALYZED BORONO-MINISCI REACTIONS OF
ARYLBORONIC ACIDS AND HETEROCYCLES
Joyce L. Biaco, Savannah L. Jones, and Timothy J. Barker*
Department of Chemistry and Biochemistry, College of Charleston, 66 George St.,
Charleston, SC 29424, USA; E-mail: barkertj@cofc.edu
Abstract – A Lewis acid-catalyzed Minisci reaction between arylboronic acids
and heterocycles has been developed. This radical-coupling reaction was
demonstrated employing several different heterocycles as well as electron-rich
arylboronic acids. Quinoline substrates afforded modest regioselectivity for
substitution at the 4-position under the reaction conditions, in contrast to
previously reported Brønsted acid-mediated reactions with quinoline substrates
that favored substitution at the 2-position.
The Minisci reaction has been a powerful reaction for the derivatization of heterocycles.1 The Minisci
reaction is broadly defined as the addition of a radical to a heterocycle and subsequent rearomatization of
the heterocycle. While many radical precursors have been demonstrated to work in this reaction,
arylboronic acids have only recently been identified as convenient sources of aryl radical precursors.2 One
of the remaining drawbacks to the Minisci reaction is the lack of regioselectivity. The regioselectivity in
these radical reactions is determined by the inherent reactivity of the substrate.3 We hypothesized that
Lewis acids could promote regioselective Minisci reactions by sterically blocking access to the
electrophilic 2-position of heterocycles.
Alternative methods have been developed to provide heterocycle-aryl coupling.4-7 An approach that
attracted our interest was precoordination of a Lewis acid to the heterocycle followed by addition of a
Grignard or zinc ionic nucleophile that provided one regioisomer of the coupled product.8 Typically in a
Minisci reaction the heterocycle is activated by a Brønsted acid. We sought to examine whether Lewis
acids would be effective catalysts in radical Minisci reactions and to evaluate the regioselectivity in these
reactions to determine if the Lewis acid coordination could overcome the inherent reactivity of the
heterocycle.
Lewis acids have previously been employed in Minisci reactions.9,10 These reactions occur under forcing
thermal conditions, making the possibility for a regioselective reaction unlikely. The coupling between

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HETEROCYCLES, Vol. 92, No. 9, 2016
arylboronic acids and heterocycles would provide a reaction system that favors monoarylation and
proceeds under mild reaction conditions, creating the possibility of a Lewis acid-catalyzed regioselective
Minisci reaction.
In order for this approach to work, the Lewis acid must be effective in an aqueous solvent mixture. There
have been reports of Lewis acids being effective in aqueous solvent mixtures which was a concern given
that a biphasic reaction medium is required for the Brønsted acid-mediated Minisci coupling between
heterocycles and arylboronic acids.11,12,2a Baran’s coupling of zinc sulphinate salts with heterocycles that
generate alkyl radicals does not require the addition of Brønsted acids in biphasic solvent systems,
suggesting the Zn metal may be activating the heterocycle as a Lewis acid.13 Given this precedent, Lewis
acids were considered to be a viable activator for the electron deficient heterocycles in Minisci reactions
in biphasic solvent systems.
We started our investigations by examining quinoline and phenylboronic acid with the use of zinc triflate
(Zn(OTf)2) as a catalyst using similar biphasic conditions to those developed by Baran (Scheme 1).2
Zn(OTf)2 (0.2 equiv) was found to promote the reaction in 4 h at room temperature, providing the product
in 68% yield. Encouragingly, this reaction favored the 4-substituted product (1.5:1, C4:C2), in contrast to
the Brønsted acid-mediated reaction that favored the 2-substituted product reported by Baran (61%, 2:1
C2:C4). Control experiments revealed that catalytic amounts of zinc triflate and silver nitrate were both
required to maintain the reaction efficiency (entries 2 and 3). Next, the counterion on the Lewis acid
catalyst was substituted to determine if a more tightly coordinating counterion would improve the
regioselectivity in the reaction. In the reaction with ZnBr2, no product was observed after 12 h, indicating
that the ZnBr2 inhibits the AgNO3-catalyzed background reaction. The reaction employing Zn(OAc)2 as a
catalyst produced a 35% yield (1.5:1 C4:C2), but required 12 h to reach completion. These results suggest
a strongly coordinating counterion interfers with the Zn cation’s ability to coordinate and activate the
nitrogen heterocycle for radical addition. Transition metal cations of different sizes were then examined
to determine the effect on the yield and regioselectivity of the reaction. Sc(OTf)3 (Sc3+, 88.5 pm) and
La(OTf)3 (La3+, 117.2 pm) were competent catalysts under the reaction conditions providing the products
in 67% and 63% yields, respectively (entries 7 and 8) but both catalysts provided the same
regioselectivity (1.5:1, C4:C2) as the Zn(OTf)2-catalyzed reaction. A control experiment using a catalytic
amount of trifluoromethanesulfonic acid (0.4 equiv) revealed that it could not function as a catalyst,
providing only a 27% yield of the product. While the nature of the activation of the heterocycle by the
Zn(OTf)2 catalyst remains unclear at this time, this experiment demonstrates that Zn(OTf)2 was an
effective catalyst and superior in efficiency to catalytic amounts of the related Brønsted acid in the
biphasic solvent system. Given the success of Zn(OTf)2, AgOTf was evaluated as a catalyst to see if it
could serve the dual purpose of radical initiator and Lewis acid. While the reaction with just AgOTf

HETEROCYCLES, Vol. 92, No. 9, 2016
1689
provided the desired product and complete consumption of starting material, the yield was greatly
reduced (entry 10). The Zn(OTf)2-catalyzed reaction proved very sensitive to solvent, requiring both
dichloromethane and water. Use of more coordinating organic solvents such as DMSO and acetonitrile
completely shut down the reaction.
+
Zn(OTf)2 (0.2 equiv)
AgNO3 (0.2 equiv)
(NH4)2S2O8 (3 equiv)
N
1
B(OH)2
4:1 DCM:H2O
rt, 4 h
N
3
2
1.5 equiv
Entry Change from Standard Conditions
C4:C2 ratio Yield (%)
1
2
3
4
5
6
7
8
9
none
no AgNO3
no Zn(OTf)2
ZnBr2 (0.2 equiv) and no Zn(OTf)2
Zn(OAc)2 (0.2 equiv) and no Zn(OTf)2
Zn(OTf)2 (0.3 equiv)
Sc(OTf)3 (0.2 equiv) and no Zn(OTf)2
La(OTf)3 (0.2 equiv) and no Zn(OTf)2
CF3SO3H (0.4 equiv) and no Zn(OTf)2
1.5:1
NA
1:1
68
0
35
0
NA
1.5:1
1.5:1
1.5:1
1.5:1
1:1
2:1
2:1
1.5:1
NA
35 a
61a,b
67b
63b
27 c
35
15b
34
0
10 AgOTf (0.2 equiv) and no Zn(OTf)2 and no AgNO3
11 AgOTf (0.2 equiv) and no Zn(OTf)2
12 Zn(OTf)2 (0.1 equiv)
13 only DCM as solvent
14 DMSO instead of DCM
NA
0
15 MeCN instead of DCM
NA
0
aReaction time 12 h. b 1H NMR yield using 1,4-dimethoxybenzene as an internal standard.
c15% of the starting material was also recovered.
Scheme 1. Optimization of Reaction Conditions
With optimized conditions in hand, we examined other heterocycles in this reaction (Scheme 2).14 Given
the regioselectivity obtained in the reaction of quinoline, several 6-substituted quinolines were employed
as substrates. The 6-substituted methyl ester provided an excellent yield (90%) of the product 3b and a
ratio of 1.6:1 C4:C2 regioselectivity, similar to that observed with quinoline. The 6-methyl and
6-bromoquinoline substrates also provided modest regioselectivity for the C4-substituted products 3c and
3d. Examination of substituted pyridines revealed that electron-deficient pyridines performed best in this
Lewis acid-catalyzed reaction. Reactions employing 4-cyano and 3-cyanopyridines both provided the
desired products in good yields. A limitation was that 2-substituted pyridines such as 2-cyanopyridine
provided none of the desired product under the standard conditions, similar to previous findings.2 Despite
the altered regioselectivity observed with quinoline and substituted quinolines, the regioselectivity
observed with substituted pyridines was similar to that reported with Brønsted acid-mediated coupling,
indicating that the Lewis acid was unable to overcome the inherent selectivity in pyridine substrates.3 The
reaction using 4-tert-butylpyridine did not go to completion under these conditions and provided only a

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HETEROCYCLES, Vol. 92, No. 9, 2016
21% yield of product 3j, showing the limitations of this Zn(OTf)2-catalyzed reaction.
R
N
R
N
Zn(OTf)2 (0.2 equiv)
AgNO3 (0.2 equiv)
(NH4)2S2O8 (3 equiv)
B(OH)2
+
4:1 DCM:H2O
rt, 4 h
2
1
3
1.5 equiv
O
Br
O
N
N
N
N
3d 56%
(C4:C2 1.3:1)
3a 68%
(C4:C2 1.5:1)
3b 90%
(C4:C2 1.6:1)
3c 67%
(C4:C2 1.2:1)
O
O
CN
NC
N
N
N
N
3f 68%
(C2:C3 2:1)
3g 74%
(C2:C6:C4
1.9:1.3:1)
3e 72%
(C2)
3h 64%a
(C2)
N
N
NC
N
N
3j 21%
3i 69%
3k 0%
(C2)
(C4:C2 5:1)
a1.3 equivalents of phenylboronic acid were employed to avoid double addition.
Scheme 2. Scope of Heterocycles
Next, varying the arylboronic acid component was examined. 4-Cyanopyridine was chosen as the
heterocycle to evaluate different arylboronic acids in this reaction (Scheme 3). Electron-rich substituents
were well tolerated. The regioselectivity with all substrates favored the 2-substituted product. Notably,
4-(N-Boc-amino)phenylboronic acid was effective in this reaction providing product 3n in 54% yield.
The Boc protecting group would potentially be incompatible with the TFA-mediated reaction conditions
Baran reported. p-Methoxyphenylboronic acid provided a 6% yield of an unusual minor side product, the
2,3-disubstituted cyanopyridine. Reactions employing less p-methoxyphenylboronic acid (1.2 equiv)
reduced but did not eliminate the presence of this side product. When using p-tolylboronic acid, a small
amount of the 2-substituted product was isolated as the 4-formylphenyl-substituted cyanopyridine. When
0.1 equiv of Zn(OTf)2 was employed, this side product was reduced, indicating the zinc catalyst was
responsible for this additional oxidation. No benzylic oxidation products were observed in the reaction
with 4-isopropylphenylboronic acid.

HETEROCYCLES, Vol. 92, No. 9, 2016
1691
Zn(OTf)2 (0.2 equiv)
B(OH)2
CN
CN
N
AgNO3 (0.2 equiv)
(NH4)2S2O8 (3 equiv)
+
4:1 DCM:H2O
rt, 4 h
R
N
R
4
5
3
1.5 equiv
CN
N
CN
N
CN
CN
N
NHBoc
Cl
N
3n 54%
(4:1 C2:C3)
3l 79%
(2.2:1 C2:C3)a
3m 73%
(2:1 C2:C3)
3c 68%
(2:1 C2:C3)
CN
CN
N
CN
OMe
N
N
O
3o 54%
(3:1 C2:C3)b
3p 61%
(2:1 C2:C3)
3q 81%
(2:1 C2:C3)
a16% of the 2-substituted product was isolated as the 4-formylphenyl addition product.
b6% was the 2,3-disubstituted product.
Scheme 3. Scope of Arylboronic Acids
We have developed a Lewis acid-catalyzed Minisci reaction between arylboronic acids and heterocycles.
Reactions employing quinoline substrates exhibited modest regioselectivity favoring the C4-substituted
products that is different than previously reported examples with stoichiometric Brønsted acid mediators
of this reaction that favor the C2-substituted products. A range of heterocycles as well as electron-rich
arylboronic acids including 4-(N-Boc-amino)phenylboronic acid were found to work in this reaction.
EXPERIMENTAL
Standard Procedure: Ammonium persulfate (3 equiv, 342 mg), phenylboronic acid (1.5 equiv, 91 mg),
silver nitrate (0.2 equiv, 17 mg), and zinc trifluoromethanesulfonate (0.2 equiv, 36 mg) were combined in
a 10 mL round bottom flask. A heterocycle (1 equiv, 0.5 mmol) was then added to the same flask and
solvated with water (0.4 mL) and CH2Cl2 (1.6 mL). The resulting mixture was sonicated for 10 sec and
placed on a stir plate to stir vigorously at room temperature for 4 h. The reaction was quenched with 28%
ammonium hydroxide (2 mL), diluted with water (10 mL), and extracted with CH2Cl2 (3 x 10 mL). The
organic layer was dried over sodium sulfate, filtered through cotton, and evaporated en vacuo. The
products were purified by column chromatography (SiO2, 5-20% EtOAc/hexanes). Products 3b, 3c, and
3d required further purification by crystallization as the trifluoromethanesulfonic acid salts and
recrystallization from THF/hexanes.

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HETEROCYCLES, Vol. 92, No. 9, 2016
3a 42 mg of 4-phenylquinoline as a colorless solid and 28 mg of 2-phenylquinoline as an orange oil were
isolated providing a combined yield of 68% in a 1.5:1 ratio (C4:C2). 2-phenylquinoline:14 1H NMR (400
MHz, CDCl3) δ 8.23 (dd, J = 8.6, 0.8 Hz, 1H), 8.20 – 8.15 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.83 (d, J =
1.6 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.59 – 7.42 (m, 4H); 4-phenylquinoline:15 1H NMR (400 MHz,
CDCl3) δ 8.95 (d, J = 4.4 Hz, 1H), 8.21 – 8.15 (m, 1H), 7.96 – 7.89 (m, 1H), 7.73 (ddd, J = 8.4, 6.8, 1.4
Hz, 1H), 7.59 – 7.43 (m, 6H), 7.34 (d, J = 4.4 Hz, 1H).
3b 73 mg of methyl 4-phenylquinoline-6-carboxylate as a colorless solid and 46 mg of methyl
2-phenylquinoline-6-carboxylate as a colorless solid were isolated providing a combined yield of 90% in
a 1.6:1 ratio (C4:C2). methyl 4-phenylquinoline-6-carboxylate:16 1H NMR (400 MHz, CDCl3) δ 9.01 (d,
J = 4.4 Hz, 1H), 8.68 (dd, J = 1.9, 0.6 Hz, 1H), 8.30 (dd, J = 8.8, 1.9 Hz, 1H), 8.20 (dd, J = 8.8, 0.6 Hz,
1H), 7.59 – 7.49 (m, 5H), 7.40 (d, J = 4.4 Hz, 1H), 3.92 (s, 3H); methyl
2-phenylquinoline-6-carboxylate:17 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.9 Hz, 1H), 8.33 – 8.29
(m, 2H), 8.21 – 8.18 (m, 3H), 7.95 (d, J = 8.6 Hz, 1H), 7.59 – 7.47 (m, 3H), 4.01 (s, 3H).
3c 40 mg of 6-methyl-4-phenylquinoline as a colorless solid and 33 mg of 6-methyl-2-phenylquinoline as
a colorless solid were isolated providing a combined yield of 67% in a 1.2:1 ratio (C4:C2).
6-methyl-4-phenylquinoline:18 1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 4.4 Hz, 1H), 8.07 (d, J
= 8.6 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.59 – 7.46 (m, 6H), 7.29 (d, J = 4.4 Hz, 1H), 2.47 (s, 3H);
6-methyl-2-phenylquinoline:19 1H NMR (400 MHz, CDCl3) δ 8.18 – 8.12 (m, 3H), 8.08 (d, J = 8.6 Hz,
1H), 7.84 (d, J = 8.6 Hz, 1H), 7.60 – 7.49 (m, 4H), 7.45 (t, J = 6.7 Hz, 1H), 2.55 (s, 3H).
3d 45 mg of 6-bromo-4-phenylquinoline as a colorless solid and 35 mg of 6-bromo-2-phenylquinoline as
a colorless solid were isolated providing a combined yield of 56% in a 1.3:1 ratio (C4:C2).
6-bromo-4-phenylquinoline:20 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 4.4 Hz, 1H), 8.07 – 8.02 (m,
2H), 7.80 (dd, J = 9.0, 2.2 Hz, 1H), 7.59 – 7.46 (m, 5H), 7.36 (d, J = 4.4 Hz, 1H);
6-bromo-2-phenylquinoline:21 1H NMR (400 MHz, CDCl3) δ 8.18 – 8.12 (m, 3H), 8.04 (d, J = 9.0 Hz,
1H), 7.99 (d, J = 2.2 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.79 (dd, J = 9.0, 2.2 Hz, 1H), 7.56 – 7.46 (m,
3H).
3e 79 mg of 4-methyl-2-phenylquinoline as a yellow solid was isolated providing a 72% yield.
4-methyl-2-phenylquinoline:15 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.0 Hz, 1H), 8.05 – 7.94 (m,
1H), 7.72 (d, J = 1.2 Hz, 1H), 7.53 (s, 1H), 2.77 (d, J = 1.0 Hz, 2H).
3f 43 mg of 4-cyano-2-phenylpyridine and 22 mg of 4-cyano-3-phenylpyridine were isolated as pale
yellow solids providing a combined yield of 68% in a 2:1 ratio (C2:C3). 4-cyano-2-phenylpyridine:2b 1
H
NMR (400 MHz, CDCl3) δ 8.85 (dd, J = 4.9, 1.0 Hz, 1H), 8.04 – 7.96 (m, 2H), 7.94 (t, J = 1.2 Hz, 1H),
7.57 – 7.47 (m, 3H), 7.44 (dd, J = 5.0, 1.4 Hz, 1H). 4-cyano-3-phenylpyridine:2b 1H NMR (400 MHz,
CDCl3) δ 8.87 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 5.0 Hz, 1H), 7.61 – 7.49 (m, 5H).

HETEROCYCLES, Vol. 92, No. 9, 2016
1693
3g 21 mg of 6-phenylnicotinonitrile (white solid), 30 mg of 2-phenylnicotinonitrile (white solid) and 16
mg of 4-phenylnicotinonitrile (white solid) were isolated providing a 67% combined yield of the products
in a 1.9:1.3:1 ratio (C2:C6:C4). 6-phenylnicotinonitrile:22 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 1.3
Hz, 1H), 8.08 – 8.02 (m, 2H), 8.00 (dd, J = 8.4, 2.2 Hz, 1H), 7.85 (dd, J = 8.3, 0.9 Hz, 1H), 7.54 – 7.48
(m, 3H). 2-phenylnicotinonitrile:23 1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J = 4.9, 1.8 Hz, 1H), 8.08
(dd, J = 7.9, 1.8 Hz, 1H), 7.96 – 7.91 (m, 2H), 7.58 – 7.51 (m, 3H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H).
4-phenylnicotinonitrile:24 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.82 (d, J = 5.2 Hz, 1H), 7.68 –
7.59 (m, 2H), 7.57 – 7.53 (m, 3H), 7.48 (d, J = 5.2 Hz, 1H).
3h Employing 1.3 equivalents (79 mg) of phenylboronic acid, 68 mg of methyl 2-phenylisonicotinate as a
colorless oil was isolated providing a 64% yield. methyl 2-phenylisonicotinate:25 1H NMR (400 MHz,
CDCl3) δ 8.84 (dd, J = 5.0, 0.9 Hz, 1H), 8.30 (dd, J = 1.5, 0.9 Hz, 1H), 8.12 – 7.99 (m, 2H), 7.77 (dd, J =
5.0, 1.5 Hz, 1H), 7.62 – 7.35 (m, 3H), 3.99 (s, 3H).
3i 50 mg of 4-phenylpyrimidine and 4 mg of 2-phenylpyrimidine as colorless oil were isolated providing
a 69% yield of products in a 5:1 ratio (C4:C2). 4-phenylpyrimidine:2b 1H NMR (400 MHz, CDCl3) δ
9.27 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 5.3 Hz, 1H), 8.24 – 8.01 (m, 2H), 7.72 (dd, J = 5.4, 1.5 Hz, 1H),
7.60 – 7.46 (m, 3H). 2-phenylpyrimidine:2b 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 4.9 Hz, 2H), 8.45
(ddt, J = 4.8, 3.6, 1.4 Hz, 2H), 7.59 – 7.44 (m, 3H), 7.22 – 7.15 (m, 1H).
3j 22 mg of 2-phenyl-4-tert-butylpyridine as a clear oil (21% yield) was isolated along with 7 mg of
recovered starting material (10%). 2-phenyl-4-tert-butylpyridine:2a 1H NMR (400 MHz, CDCl3) δ 8.62
– 8.59 (m, 1H), 8.02 – 7.94 (m, 2H), 7.71 (dd, J = 1.8, 0.6 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.45 – 7.38 (m,
1H), 7.25 (dd, 1H), 1.38 (s, 9H).
3l 45 mg of 2-(p-tolyl)isonicotinonitrile as a pale yellow solid and 33 mg of an inseparable mixture of
3-(p-tolyl)isonicotinonitrile and 2-(4-formylphenyl)isonicotinonitrile were isolated in a 1:0.4 ratio
providing a combined yield of 79%. 2-(p-tolyl)isonicotinonitrile:2b 1H NMR (400 MHz, CDCl3) δ 8.82
(dd, J = 5.0, 1.0 Hz, 1H), 7.91 – 7.89 (m, 2H), 7.88 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 4.9, 1.4 Hz, 1H),
7.33 – 7.28 (m, 2H), 2.42 (s, 3H); 3-(p-tolyl)isonicotinonitrile and 2-(4-formylphenyl)-
isonicotinonitrile:2b 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 0.4H), 8.91 (dd, J = 5.0, 0.9 Hz, 0.4H), 8.85
(d, J = 0.9 Hz, 1H), 8.72 (d, J = 5.0 Hz, 1H), 8.19 (d, J = 8.4 Hz, 0.8H), 8.06 – 7.99 (m, 1.2H), 7.60 (dd, J
= 5.0, 0.8 Hz, 1H), 7.53 (dd, J = 4.9, 1.4 Hz, 0.4H), 7.48 (d, J = 8.2 Hz, 2H), 7.35 (dt, J = 7.8, 0.8 Hz, 2H),
2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 191.8, 157.4, 151.1, 151.0, 148.5, 142.7, 139.9, 138.9, 137.4,
131.7, 130.4, 130.0, 128.8, 127.7, 126.2, 124.3, 122.7, 121.7, 118.8, 116.6, 116.5, 21.4; IR (neat) v =
3790, 3662, 2254, 1709, 1596, 1548, 1479, 1382, 903, 722, 649 cm-1.
3m 50 mg of 2-(4-chlorophenyl)isonicotinonitrile and 28 mg of 3-(4-chlorophenyl)isonicotinonitrile were
isolated as yellow solids providing a combined yield of 73% in a 2:1 ratio (C2:C3).

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HETEROCYCLES, Vol. 92, No. 9, 2016
2-(4-chlorophenyl)isonicotinonitrile:2b 1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 5.0, 1.0 Hz, 1H),
7.98 – 7.91 (m, 2H), 7.89 (t, J = 1.2 Hz, 1H), 7.47 (s, 1H), 7.46 – 7.41 (m, 2H). 3-(4-chlorophenyl)-
isonicotinonitrile:2b 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.77 (d, J = 5.0 Hz, 1H), 7.63 (dd, J =
5.0, 0.8 Hz, 1H), 7.52 (s, 4H).
3n 63.6 mg of tert-butyl (4-(4-cyanopyridin-2-yl)phenyl)carbamate as an off-white solid and 16.6 mg of
tert-butyl (4-(4-cyanopyridin-3-yl)phenyl)carbamate as a brown oil were isolated for a combined yield of
54%. tert-butyl (4-(4-cyanopyridin-2-yl)phenyl)carbamate: 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J
= 5.0, 0.9 Hz, 1H), 7.89 δ 7.84 (m, 2H), 7.80 (t, J = 1.2 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.30 (dd, J =
13
5.0, 1.4 Hz, 1H), 6.66 (s, 1H), 1.46 (s, 9H); C NMR (101 MHz, CDCl3) δ 158.2, 152.4, 150.6, 140.6,
131.8, 127.9, 122.9, 121.5, 121.2, 118.6, 116.9, 81.1, 28.4. IR (neat) v = 3790, 3661, 2254, 1597, 1548,
1526, 1502, 1467, 1385, 903, 722, 650 cm-1; HRMS-ESI (m/z) [M + Na]+ calcd for C17H17N3O2Na,
318.1219; found, 318.1227. tert-butyl (4-(4-cyanopyridin-3-yl)phenyl)carbamate: 1H NMR (400 MHz,
CDCl3) δ 8.76 (d, J = 0.8 Hz, 1H), 8.63 (d, J = 5.0 Hz, 1H), 7.52 (dd, J = 5.0, 0.8 Hz, 1H), 7.47 (d, J = 4.8
13
Hz, 3H), 6.69 (s, 1H), 1.47 (s, 10H); C NMR (101 MHz, CDCl3) δ 152.6, 151.0, 148.4, 140.0, 138.4,
129.7, 128.8, 126.2, 118.9, 118.6, 116.6, 81.2, 28.4; IR (neat) v = 3791, 3662, 2254, 1588, 1529, 1480,
1382, 902, 722, 650 cm-1; HRMS-ESI (m/z) [M + Na]+ calcd for C17H17N3O2Na, 318.1219; found,
318.1229.
3o 38.9 mg of 2-(4-methoxyphenyl)isonicotinonitrile as a yellow-orange solid and 21.4 mg of an
inseparable mixture of 3-(4-methoxyphenyl)isonicotinonitrile and 2,3-bis(4-methoxyphenyl)-
isonicotinonitrile were isolated as a light-yellow solid in a 2:1 ratio for a combined 54% yield in a 3:1
ratio (C2:C3) with the double addition by-product comprising 6% of the total yield.
2-(4-methoxyphenyl)isonicotinonitrile:2b 1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J = 5.0, 1.0 Hz, 1H),
7.89 (d, J = 8.9 Hz, 2H), 7.80 (t, J = 1.2 Hz, 1H), 7.30 (dd, J = 5.0, 1.4 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H),
3.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.6, 158.5, 150.6, 130.0, 128.5, 122.4, 121.4, 121.2, 117.0,
114.6, 55.6; IR (neat) v = 3791, 3662, 2254, 1599, 1530, 1468, 1382, 902, 722, 650 cm-1; LC-MS
Expected [M + H]+ 211 found 211. 3-(4-methoxyphenyl)isonicotinonitrile2b and 2,3-bis(4-
1
methoxyphenyl)isonicotinonitrile: H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.76 (d, J = 4.9 Hz,
0.5H), 8.69 (d, J = 5.1 Hz, 1H), 7.59 (dd, J = 5.0, 0.8 Hz, 1H), 7.56 – 7.47 (m, 2.5H), 7.25 (d, J = 8.9 Hz,
1.5H), 7.16 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.8 Hz,
13
1H), 3.88 (s, 3H), 3.83 (s, 1.5H), 3.78 (s, 1.5H); C NMR (101 MHz, CDCl3) δ 160.9, 160.02, 159.98,
159.0, 151.0, 148.5, 148.2, 138.6, 137.2, 131.4, 131.3, 130.6, 130.3, 128.0, 126.8, 126.2, 124.0, 122.3,
118.6, 116.8, 116.7, 114.8, 114.4, 113.6, 55.6, 55.39, 55.36; IR (neat) v = 3791, 3662, 2254, 1610, 1516,
1479, 1382, 1252, 903, 722, 650 cm-1; HRMS-ESI (m/z) [M + Na]+ calcd for C20H16N2O2Na, 339.1110;
found, 339.1098.

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3p 45 mg of 2-(4-isopropylphenyl)isonicotinonitrile as a pale yellow solid and 23 mg of
3-(4-isopropylphenyl)isonicotinonitrile as an orange oil were isolated providing a combined yield of 61%.
2-(4-isopropylphenyl)isonicotinonitrile: 1H NMR (400 MHz, CDCl3) δ 8.82 (dd, J = 5.0, 1.0 Hz, 1H),
7.94 (s, 1H), 7.93 – 7.89 (m, 2H), 7.40 (dd, J = 5.0, 1.4 Hz, 1H), 7.38 – 7.35 (m, 2H), 3.15 – 2.85 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 158.9, 151.5, 150.6, 135.0, 127.3, 127.1, 122.9, 121.9, 121.2, 116.9,
34.1, 23.9; IR (neat) v = 3774, 3662, 2964, 2254, 1710, 1595, 1546, 1468, 1389, 903, 831, 723, 649, 545,
479 cm-1; HRMS-ESI (m/z) [M + Na]+ calcd for C15H14N2Na, 245.1055; found, 245.1051.
3-(4-isopropylphenyl)isonicotinonitrile: 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 0.9 Hz, 1H), 8.72 (d,
J = 5.0 Hz, 1H), 7.61 (dd, J = 5.0, 0.8 Hz, 1H), 7.54 – 7.50 (m, 2H), 7.43 – 7.38 (m, 2H), 3.08 – 2.90 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 151.1, 150.7, 148.5, 138.9, 132.0, 128.9, 127.4, 126.2, 118.8, 116.7,
34.1, 24.0; IR (neat) v = 3791, 3662, 2254, 1584, 1479, 1382, 903, 832, 722, 650, 591 cm-1; HRMS-ESI
(m/z) [M + Na]+ calcd for C15H14N2Na, 245.1055; found, 245.1064.
3q 71.2 mg of 2-(3-(benzyloxy)phenyl)isonicotinonitrile as a white solid and 45.2 mg of
3-(3-benzyloxy)phenyl)isonicotinonitrile as a brown oil were isolated for a combined 81% yield.
2-(3-(benzyloxy)phenyl)isonicotinonitrile: 1H NMR (400 MHz, CDCl3) δ 8.74 (dd, J = 4.9, 1.0 Hz, 1H),
7.81 (t, J = 1.2 Hz, 1H), 7.59 (dd, J = 2.6, 1.7 Hz, 1H), 7.46 (ddd, J = 7.7, 1.7, 1.0 Hz, 1H), 7.41 – 7.34
13
(m, 2H), 7.36 – 7.26 (m, 4H), 7.29 – 7.20 (m, 1H), 7.00 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 5.06 (s, 2H); C
NMR (101 MHz, CDCl3) δ 159.6, 158.5, 150.6, 138.8, 136.8, 130.2, 128.7, 128.2, 127.6, 123.4, 122.3,
121.3, 119.6, 117.1, 116.8, 113.4, 70.6; IR (neat) v = 3791, 3662, 2254, 1591, 1548, 1468, 1443, 1381,
1291, 1229, 1026, 902, 788, 722, 649 cm-1; HRMS-ESI (m/z) [M + H]+ calcd for C19H15N2O, 287.1184;
found, 287.1191. 3-(3-benzyloxy)phenyl)isonicotinonitrile: 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H),
8.67 (d, J = 5.0 Hz, 1H), 7.54 (dd, J = 5.0, 0.8 Hz, 1H), 7.42 – 7.28 (m, 5H), 7.31 – 7.22 (m, 1H), 7.12 –
13
7.07 (m, 2H), 7.07 – 7.02 (m, 1H), 5.07 (s, 2H); C NMR (101 MHz, CDCl3) δ 159.4, 151.0, 148.9,
138.7, 136.7, 135.8, 130.4, 128.8, 128.3, 127.7, 126.2, 121.6, 119.0, 116.4, 116.3, 115.4, 70.5; IR (neat) v
= 3791, 3662, 2254, 1710, 1600, 1480, 1382, 903, 786, 722, 650 cm-1; HRMS-ESI (m/z) [M + Na]+ calcd
for C19H14N2ONa, 309.1004; found, 309.0994.
ACKNOWLEDGEMENTS
The College of Charleston Undergraduate Research and Creative Activities office is acknowledged for
summer undergraduate research fellowship grants for SLJ and JAB. A grant from the Howard Hughes
Medical Institute to the College of Charleston as part of their 2012 Undergraduate Science Education
Competition is also acknowledged for a summer undergraduate research fellowship for SLJ. The College of
Charleston is also acknowledged for financial support. The NMR spectrometer at the College of Charleston

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HETEROCYCLES, Vol. 92, No. 9, 2016
is supported by the National Science Foundation under Grant No. 1429308. Dr. Beniam Berhane
(University of California, Irvine) is acknowledged for mass spectrometry data.
REFERENCES
1. (a) M. A. J. Duncton, Med. Chem. Commun., 2011, 2, 1135; (b) J. Tauber, D. Imbri, and T. Opatz,
Molecules, 2014, 19, 16190; (c) C. Punta and F. Minisci, Trends Heterocycl. Chem., 2008, 13, 1.
2. (a) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L. Sobel, and P. S. Baran, J.
Am. Chem. Soc., 2010, 132, 13194; (b) J. Wang, S. Wang, G. Wang, J. Zhang, and X.-Q. Yu, Chem.
Commun., 2012, 48, 11769; (c) A. Deb, S. Manna, A. Maji, U. Dutta, and D. Maiti, Eur. J. Org.
Chem., 2013, 5251.
3. (a) F. O’Hara, D. G. Blackmond, and P. S. Baran, J. Am. Chem. Soc., 2013, 135, 12122; (b) T.
Brückl, R. D. Baxter, Y. Ishihara, and P. S. Baran, Acc. Chem. Res., 2012, 45, 826.
4. (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (b) A. Suzuki, J. Organomet. Chem.,
2002, 653, 83; (c) J. Hassan, M. Sévignon, C. Gozzi, E. Schulz, and M. Lemaire, Chem. Rev., 2002,
102, 1359.
5. S. Yanagisawa, K. Ueda, T. Taniguchi, and K. Itami, Org. Lett., 2008, 10, 4673.
6. (a) L. Ackermann and S. Fenner, Chem. Commun., 2011, 47, 430; (b) F. Gosselin, S. J. Savage, N.
Blaquiere, and S. T. Staben, Org. Lett., 2012, 14, 862; (c) Z. Wu, H. Song, X. Cui, C. Pi, W. Du, and
Y. Wu, Org. Lett., 2013, 15, 1270; (d) C. Zhu, M. Yi, D. Wei, X. Chen, Y. Wu, and X. Cui, Org.
Lett., 2014, 16, 1840; (e) G. Li, C. Jia, and K. Sun, Org. Lett., 2013, 15, 5198; (f) Z. Wu, C. Pi, X.
Cui, J. Bai, and Y. Wu, Adv. Synth. Catal., 2013, 355, 1971; (g) W. Mai, J. Yuan, Z. Li, G. Sun, and
L. Qu, Synlett, 2012, 23, 145.
7. L. Bering and A. P. Antonchick, Org. Lett., 2015, 17, 3134.
8. Q. Chen, X. M. du Jourdin, and P. Knochel, J. Am. Chem. Soc., 2013, 135, 4958.
9. G. Deng and C.-J. Li, Org. Lett., 2009, 11, 1171.
10. C. A. Correia, L. Yang, and C.-J. Li, Org. Lett., 2011, 13, 4581.
11. S. Kobayashi, S. Nagayama, and T. Busujima, J. Am. Chem. Soc., 1998, 120, 8287.
12. S. Kobayashi and C. Ogawa, Chem. Eur. J., 2006, 12, 5954.
13. (a) Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder, D. D. Dixon, R. A. Rodriguez, R. D. Baxter,
B. Herlé, N. Sach, M. R. Collins, Y. Ishihara, and P. S. Baran, Nature, 2012, 492, 95; (b) Y. Ji, T.
Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond, and P. S. Baran, Proc. Natl.
Acad. Sci. USA, 2011, 108, 14411.
14. A, Modvig, T. L. Andersen, R. H. Taaning, A. T. Lindhardt, and T. Skrydstrup, J. Org. Chem., 2014,
79, 5861.

HETEROCYCLES, Vol. 92, No. 9, 2016
1697
15. A. Wendlandt and S. Stahl, J. Am. Chem. Soc., 2014, 136, 11910.
16. I. Kinoyama, T. Miyazaki, Y. Koganemaru, T. Washio, and W. Hamaguchi, U.S. Patent
20,120,142,727, 2010.
17. I. Hyodo, M. Tobisu, and N. Chatani, Chem. Asian J., 2012, 7, 1357.
18. X. Zhang, X. Xu, Y. Wu, Z. Wang, L. Yu, Q. Zhao, and F. Shi, Synlett, 2015, 26, 1885.
19. P. P. Varma, B. S. Sherigara, K. M. Mahadevan, and V. Hulikal, Synth. Commun., 2010, 40, 2220.
20. J. Tummatorn, P. Poonsilp, P. Nimnual, J. Janprasit, C. Thongsornkleeb, and S. Ruchirawat, J. Org.
Chem., 2015, 80, 4516.
21. Z. Huo, I. D. Gridnev, and Y. Yamamoto, J. Org. Chem., 2010, 75, 1266.
22. P. Petiot and A. Gagnon, Eur. J. Org. Chem., 2013, 2013, 5282.
23. R. Ghosh, N. N. Adarsh, and A. Sarkar, J. Org. Chem., 2010, 75, 5320.
24. L.-L. Gundersen, F. Rise, and K. Undheim, Tetrahedron, 1992, 48, 5647.
25. J. Bostroem, L. Cheng, T. Fex, M. Karle, D. Pettersen, and P. Schell, U.S. Patent 61,167,224, 2009.
26. F. Xiong, C. Qian, D. Lin, W. Zeng, and X. Lu, Org. Lett., 2013, 15, 5444.