Mn/Cu catalyzed addition of arylboronic acid to nitriles: Direct synthesis of arylketones

Article abstract of DOI:10.1016/j.tetlet.2018.09.021

A direct and efficient synthesis of arylketones via arylboronic acid addition to nitriles in presence of inexpensive Mn/Cu catalytic system is reported. The use of non-precious Mn and Cu salts has been found to be highly advantageous both in terms of accessibility as well as cost effectiveness. A series of arylboronic acids as well as nitriles were used to synthesize a variety of symmetrical and unsymmetrical arylketones. Based on the literature studies, the reaction mechanism is anticipated to go through an aryl radical intermediate which reacted with the copper activated nitrile to give the desired arylketones after the hydrolysis of the imine intermediate.

Full text of DOI:10.1016/j.tetlet.2018.09.021

Accepted Manuscript
Mn/Cu catalyzed addition of arylboronic acid to nitriles: Direct synthesis of
arylketones
Dina Moustafa, Chelsea Sweet, Hyun Lim, Brenda Calalpa, Parminder Kaur
PII:
S0040-4039(18)31102-X
https://doi.org/10.1016/j.tetlet.2018.09.021
TETL 50260
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 August 2018
3 September 2018
7 September 2018
Please cite this article as: Moustafa, D., Sweet, C., Lim, H., Calalpa, B., Kaur, P., Mn/Cu catalyzed addition of
arylboronic acid to nitriles: Direct synthesis of arylketones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.09.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Mn/Cu catalyzed addition of arylboronic acid to nitriles: Direct synthesis of
arylketones
Dina Moustafa,# Chelsea Sweet,# Hyun Lim, Brenda Calalpa and Parminder
Kaur*
1
Affiliations: College of Science and Health, Department of Chemistry, William
Paterson University, 300 Pompton Road, Wayne, NJ-07470 United States
Corresponding Author’s Email: kaurp6@wpunj.edu, Tel: (973)-720-2706
# co-authors contributed equally
Abstract
A direct and efficient synthesis of arylketones via arylboronic acid addition to
nitriles in presence of inexpensive Mn/Cu catalytic system is reported. The use of
non-precious Mn and Cu salts has been found to be highly advantageous both in
terms of accessibility as well as cost effectiveness. A series of arylboronic acids
as well as nitriles were used to synthesize a variety of symmetrical and
unsymmetrical arylketones. Based on the literature studies, the reaction
mechanism is anticipated to go through an aryl radical intermediate which
reacted with the copper activated nitrile to give the desired arylketones after the
hydrolysis of the imine intermediate.
Introduction
Arylketones are significant building blocks in various fields such as medicine,
agriculture, natural products and material chemistry.1 Arylketones are also
important building blocks for nucleic acid chemistry and are associated with
increased biological activity attributed to the presence of C=O bond leading to
extra binding interactions.1 Hence, there is a growing interest in developing new
methodologies for the synthesis of arylketones. The classical methods

documented in the literature for their synthesis mainly involve oxidation of
corresponding secondary alcohols using various oxidizing agents such as
chromates, permanganate salts under harsh reaction conditions.2 Other methods
for the synthesis of arylketones involve the use of classical Friedel-Craft
acylation,3 acylation of pre-metalated precursors4 and Pd-catalyzed cross-
coupling with boronic acids.5
In recent years, the use of transition metal-catalyzed methodologies has been
one of the most popular approach to synthesize arylketones directly from nitriles
exhibiting promising results in terms of yields and overall potential of the
reaction.6 Various reports, from Larock and co-workers, have been documented
using palladium to carry out the synthesis of arylketones.7 The group has
reported
palladium-catalyzed annulation of internal alkynes with 2-
iodobenzonitriles.7a-c Later, the same group reported the addition of arene C-H
bond as well as arylboronic acids to nitriles.7d-e In these reports, Larock and
group mentioned the palladium catalyzed C-H activation followed by the
carbopalaldation of the nitrile. The electrophilic metalation of the C-H bond by the
Pd(II) catalyst was anticipated that led to the formation of the arylpalladium
intermediate. And finally, the carbopalladation of the nitrile led to the imine-Pd (II)
complex which generated the desired arylketone upon protonation. A palladium-
catalyzed intramolecular addition of vinylpalladium to nitriles was reported by Lu
and group.8a Later, Lu et al. also reported the palladium-catalyzed addition of
arylboronic acids to nitriles.8b-c Miyaura and group reported a rhodium-catalyzed
addition of arylboronic acid to nitriles for the synthesis of arylketones.9 Murakami
and group reported the synthesis of arylketoesters through a rhodium catalyzed
reaction of cyanoformate with arylboronic acid.10 Very recently, Jain and
coworkers reported Pd-catalyzed synthesis of arylketones via CO insertion
reaction.11 Although, these above-mentioned methods present elegant
approaches for the synthesis of arylketones, they suffer from certain limitations
such as use of harsh chemicals, longer reaction times and/or use of expensive
catalysts.

Recently, a great amount of interest has been evolved in the area of non-
precious metal-catalyzed reactions.12 In 2010, Cheng and co-workers reported
the use of first row transition metal for the first time to carry out the direct
synthesis of arylketones. They reported the nickel catalyzed addition of
arylboronic acid to nitriles for the direct synthesis of various symmetrical and
unsymmetrical.13 The reaction was done in presence of Lewis acid, ZnCl2 and
H2O and all the arylketones were obtained in good to excellent yield. The NiII(OH)
intermediate formed during the reaction was proposed to undergo
transmetalation with arylboronic acid to give the arylnickel intermediate. The
coordination of phenylbrornic acid with nickel center followed by 1,2-addition of
the coordination aryl group to nitrile which eventually gives the arylketone on
13
hydrolysis using water. In 2012, Tseng and coworkers also reported the direct
synthesis of ketones from nitriles using nickel-catalyzed intermolecular insertion
of aryl iodides to nitriles.14 Later, in 2013, Liu and group reported the copper-
catalyzed regioselective reaction of internal alkynes and diaryliodonium salts for
the synthesis of aryl ketones.15 The reaction protocol mentioned by Liu and group
worked under mild conditions with good regioselectivity and, unlike Au-catalyzed
reactions, no extra oxidant or a large excess of arylation reagent was needed.
The iodonium salt used during the reaction actually acted as both an oxidant and
arylation reagent. The products were obtained in moderate to good yields from
arylpropargylic alcohols or aryl alkyl alkynes under mild conditions.15In a recent
report by Rahaim and group, the use of a dual Ni/Ti catalyst system was
discussed for the synthesis of ketones via a cross-coupling of organobromides
and nitriles.16
In our continuing efforts of exploring new catalytic systems, we are describing
here the use of Mn/Cu bimetallic catalyst system for the direct synthesis of
arylketones from nitriles in presence of bathophenanthroline (Bphen) as nitrogen
donor ligand. The reaction was carried out overnight under mild conditions and
the corresponding ketones were obtained in good to excellent yields. This
approach provides a direct method for the synthesis of symmetrical as well as
unsymmetrical ketones. Further, a series of substituted arylboronic acids and

aliphatic as well as aromatic nitriles were tested to give various arylketones in
good yields that showed the wide substrate scope of this method.
Result and Discussion
We started the optimization of the reaction by screening a series of manganese,
cobalt and copper salts as catalyst for the reaction of phenylboronic acid (1a)
with phenylacetonitrile (2a). As the model reaction, phenylboronic acid was
.
added to a solution of phenylacetonitrile in presence of MnCl2 H2O and 2,2’-
bipyridine ligand (3b) (Table 1, entry 1). The reaction was carried out in 1,4-
o
dioxane at 75 C for overnight (16 h) in presence of water. The reaction was
quenched and upon work-up, only traces of the desired product was obtained in
the crude mixture. A series of reaction conditions were then tested using various
metal salts, bimetallic systems such as CuCl2, Cu(OTf)2, Cu(OAc)2, Zn(OTf)2,
CoCl2, ZnCl2, NiCl2 and
Table 1. Effect of various metal salts on the addition reaction of phenylboronic
acid with phenylacetonitrilea
Entry Catalyst
Co-catalyst Ligand
Yield%
traces
21
1
2
3
4
5
6
7
8
9
3b
3b
3b
3a
3b
3a
3a
3b
3a
MnCl2. H2O
MnCl2. H2O
MnCl2. H2O
MnCl2. H2O
Mn(OTf)2. H2O
Mn(OTf)2. H2O
Mn(OTf)2. H2O
Mn(OTf)2. H2O
Mn(OAc)3.
-
CuCl2
ZnCl2
23
CuCl2
10
Co(OTf)2
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Co(OAc)2
14
6
26
32
30
2H2O

10
11
3a
3b
Mn(OAc)3.
2H2O
Cu(OAc)2
Cu(OAc)2
26
54
Mn(OAc)3.
2H2O
12
13
14
3b
3b
3b
MnBr2
CuBr2
NiBr2
CoBr2
28
41
39
MnBr2
MnBr2
aAll reactions were carried out with boronic acid (1.0 mmol), nitrile (0.5 mmol), Mn salt (5.0 mol%), Cu salt
(5.0 mol%), ligand (10 mol%) and H2O (0.5 mmol).
use of ligands. The results are summarized in the Table 1. While screening
.
various conditions, it was found that the use of MnCl2 H2O in presence of CuCl2
and ligand 3b, gave 21% of the desired product (Table 1, entry 2). With this
promising result in hand, we started exploring the bimetallic systems to carry out
this reaction. After testing various combinations, it was discovered that with the
.
combination of Mn(OTf)2 H2O and Cu(OTf)2 in presence of 2,2’-dipyridine (3b)
and water at 75oC, 32%
Table 2. Effect of ligand on the addition reaction of phenylboronic acid with
phenylacetonitrilea
C N
O
B(OH)2
+
Mn(OAc)3. 2H2O/Cu(OAc)2/ligand
1,4-dioxane, H2O, 75 °C, 8 h
1a
2a
4a
Entry
Catalyst
Co-catalyst Ligand Yield%b
1
2
3
4
5
6
7
3a
3c
3d
3e
3d
3e
-
Mn(OAc)3. 2H2O
Mn(OAc)3. 2H2O
Mn(OAc)3. 2H2O
Mn(OAc)3. 2H2O
Mn(OAc)3. 2H2O
Mn(OAc)3.2H2O
Mn(OAc)3. 2H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Zn(OAc)2
Zn(OAc)2
-
21
38
64
82
39
23
NRc

NRc
8
Cu(OAc)2
-
-
aAll reactions were carried out with boronic acid (1.0 mmol), nitrile (0.5 mmol), Mn salt (5.0 mol%), Cu salt
(5.0 mol%), ligand (10 mol%) and H2O (0.5 mmol). bIsolated yields. cNR = No reaction.
of the product was obtained (Table 1, entry 8). However, when the reaction was
carried out in presence of 3b as ligand, using Mn(OAc)3. 2H2O and Cu(OAc)2
bimetallic system, 54% of the product was obtained (Table 1, entry 11).
With an aim to further improve the product yield, the reaction was tested
with and without the presence of different mono-, bi- and tridendate nitrogen
ligands, such as, 1,2-Bis(phenylamino)ethane (3a), 2,2’-bipyridine (3b), 2,2’-
dipyridylamine (3c),1,10-phenanthroline (3d) and bathophenanthroline (3e)
(Figure 1). The results of screening various ligands are summarized in Table 2.
It was found that the product yield is better when ligand 3d and 3e (Table 2,
entry 3
NH
N
N
N
H
N
N
N
H
3a
3b
3c
N
N
N
N
3d
Figure 1. Ligands screened during the reaction
3e
and 4) were used with the Mn(OAc)3. 2H2O and Cu(OAc)2 bimetallic system.
When the reaction was carried out in presence of Bathophenanthroline (ligand
3e) with Mn(OAc)3. 2H2O and Cu(OAc)2 catalyst system in 1,4-dioxane, the
reaction yield was further increased to 82% (Table 2, entry 4). It was found that
most of the bimetallic systems screened were not very effective except the
Mn(OAc)3.2H2O : Cu(OAc)2 system in presence of Bphen (3e) as a nitrogen

donor ligand. Also, it was found that the presence of Cu salt is necessary for the
reaction to proceed. When the reaction was carried out only with Mn(OAc)3.
2H2O and in absence of Cu(OAc)2 and any nitrogen donor ligand, no product was
obtained (Table 2, entry 7) that confirms the critical role of Cu salt in the
reaction. In order to see the effect of Mn:Cu on minimizing the formation of
homocoupling side product, we screened various ratios of Mn:Cu such as 3:1,
2:1, 1:2 and 1:3. Unfortunately in each case an appreciable amount of
homocoupling product (ranging from 20%-34%) was observed. The least amount
of homocoupling product was observed when 1:1 Mn:Cu was used (8% incase of
entry 1, Table 2). We also tried the reaction using lesser quantities of boronic
acid (1 equivalents) but the product yield declined exponentially. And hence the
2:1 ratio of boronic acid:nitrile was used.
To further improve the product yield, the reaction was carried out in various
solvents such as DMF, toluene, and acetonitrile. However, only poor reaction
yields were obtained when reaction was carried out in DMF (23%), toluene (27%)
and acetonitrile (31%).and it was found that 1,4-dioxane is the solvent of choice.
With these reaction conditions in hand, we carried out the reaction at elevated
temperature to see the effect of temperature on the reaction yield. The reaction
was initially carried out at 75 oC and slowly the temperature is increased to 85 oC
o
and then finally to 90 C. It was found that the reaction yield was increased from
o
82% to 88% when the reaction was carried out at 90 C for a longer period of
time (overnight instead of 8 h).
During the optimization, it was also interestingly observed that the
presence of water is necessary to obtain the final ketone product in good yield. It
was found that at least one equivalent of the water is required for the reaction
and any decrease in the amount of water affected the reaction yield adversely.
After obtaining the above optimizations, we proceeded with the reaction
conditions using boronic acid (1.0 mmol), nitrile (0.5 mmol), Mn(OAc)3. 2H2O (5.0
mol%), Cu(OAc)2 (5.0 mol%), Bphen (3e, 10 mol%) and H2O (0.5 mmol). The
o
reaction was carried out in 1,4-dioxane at 90 C for overnight and after

completion the reaction was quenched followed by the aqueous workup to isolate
the crude product.
Using these standard conditions, we screened various arylboronic acids
for the reaction with phenylacetonitrile to give the corresponding arylketones. The
boronic acids with electron withdrawing group such as 3-nitrophenylboronic acid
and 4-nitrophenylboronic acid gave good product yields upon reaction with
benzylnitrile (Table 3, entry 11 and 12). When 2-tolylboronic acid and 4-
hydroxyboronic acid were treated with phenylacetonitrile, excellent yields 83%
and 89% of corresponding ketones were obtained respectively (Table 3, entry 2
and 7). Comparable yields were obtained (81% and 86%) when 2- and 4-
anisylboronic acids were reacted with phenylacetonitrile (Table 3, entry 4 and 5).
It was found that the reaction worked great with both the electron withdrawing as
well as electron donating groups on boronic acids. It was also found that the
reaction worked great with bulkier boronic acid such as with groups like 1-
naphthyl (Table
Table 3. Substrate scope for the addition reaction between arylboronic acid (1a)
and phenylacetonitrile (2a)a
C N
O
B(OH)2
Mn(OAc)3. 2H2O/Cu(OAc)2/ 3e
+
1,4-dioxane, H2O, 90 °C, overnight
R1
R1
1a-1m
2a
4a-4n
Entry
R1
Product Yield%
1
2
3
4
5
6
7
8
H (1a)
4a
4b
4c
4d
4e
4f
88
83
84
81
86
79
89
82
2-methyl (1b)
4-methyl (1c)
2-methoxy (1d)
4-methoxy (1e)
4-dimethylamine (1f)
4-hydroxy (1g)
2-chloro (1h)
4g
4h

9
4-bromo (1i)
4-fluoro (1j)
3-nitro (1k)
4i
79
88
86
82
80
78
10
11
12
13
14
4j
4k
4l
4-nitro (1l)
1-Naphthyl (1m)
4-pyridyl (1n)
4m
4n
aboronic acid (1.0 mmol), benzylnitrile (0.5 mmol), Mn(OAc)3. 2H2O (5.0 mol%), Cu(OAc)2 (5.0 mol%),
o
Bphen (10 mol%) and H2O (0.5 mmol). The reaction was carried out in 1,4-dioxane at 90 C for overnight.
Isolated yields are reported.
3, entry 13). The presence of halogens on the boronic acid did not affect the
reaction adversely and good yields were obtained with 2-chloro-, 4-bromo- and 4-
fluorophenylboronic acids (Table 3, entry 8, 9 and 10). However, a
comparatively low yield (65%) was obtained when heteroaromatic boronic acid
such as 4-pyridyl boronic acid was used to synthesize the corresponding
arylketone (Table 3, entry 14).
The Mn/Cu catalyzed reaction was then further extended to various
substituted arylnitriles as well as aliphatic nitriles. For example, benzonitrile was
reacted successfully with phenylboronic acid to give the corresponding ketone in
excellent yields (82%, Table 4, entry 1). Other nitriles such as 4-
acetylbenzonitrile (2c) as well as butyronitrile (2d) were tested and the
corresponding ketones were obtained in good to moderate yields (Table 4, entry
5-8). Upon reaction of cyclohexylnitrile (2f) with phenylboronic acid, the
corresponding ketone was obtained in excellent yield (89%, Table 4, entry 10).
The above reactions confirmed the wide substrate scope of this catalytic system
in terms of direct synthesis of symmetrical and unsymmetrical ketones under mild
conditions.
Table 4. Substrate scope for the addition reaction between different arylboronic
acid and nitrilesa

O
B(OH)2
Mn(OAc)3. 2H2O/Cu(OAc)2/ 3e
1,4-dioxane, H2O, 90 °C, overnight
R2
+
R2-CN
2b-2e
R1
1a, 1c, 1i, 1l
R1
4o-4x
2b: R2 = Ph
2c: R2 = 4-COMe-C6H4
2d: R2 = (CH2)2-CH3
2e: R2 = CH-(CH3)2
2f: R2 = cyclohexyl
Entry Boronic acid Nitrile
Product
Yield%
1
1a
2b
82
4o
4p
4q
4r
2
3
4
5
1c
1i
2b
2b
2b
2c
80
82
80
79
1l
1a
4s
6
7
8
9
1c
1a
1c
1a
2c
2d
2d
2e
74
76
83
85
4t
4u
4v
4w
4x
10
1a
2f
89
aboronic acid (1.0 mmol), nitrile (0.5 mmol), Mn(OAc)3. 2H2O (5.0 mol%), Cu(OAc)2 (5.0 mol%), Bphen (10
o
mol%) and H2O (0.5 mmol). The reaction was carried out in 1,4-dioxane at 90 C for overnight. Isolated
yields are reported.
To confirm the broader applicability of the current methodology, the synthesis of
5, a core scaffold that has proven to be an important structural component for

various bioactive compounds with anti-malarial and anti-viral activities,17 was
carried out. The direct synthesis of quinolinecarboxyl derivatives (such as 5)
would give a broader scope for further derivatization of the molecules to
introduce different functionalizations on this important scaffold. For the synthesis,
4-phenylboronic acid (1i, 4 mmol) along with 2-quinolinecarbonitrile (2g, 1 mmol)
was used. The reaction was carried out in presence of Mn(OAc)3. 2H2O (5.0
mol%), Cu(OAc)2 (5.0 mol%), Bphen (3e, 10 mol%) and H2O (0.5 mmol) in 1,4-
o
dioxane at 90 C for overnight. The desired product was isolated in 62% yield,
with the formation of homocoupling side product. The higher concentration of
boronic acid (4 equivalents) was needed to carry out the reaction successfully.
Scheme 1. Synthesis of biologically important scaffold, 5
Based on the reported literature,18 it is anticipated that the Mn(OAc)3. 2H2O
facilitate the formation of the aryl radical from aryl boronic acid which reacts with
the Cu-Bphen activated nitrile intermediate to give the imine intermediate. The
imine intermediate upon hydrolysis with water leads to the formation of the
desired arylketone product. Further studies regarding the exact mechanistic
pathway and future scope of this catalyst system are under way.
Conclusion
In conclusion, we have reported an inexpensive Mn/Cu bimetallic catalyst system
for the direct synthesis of arylketones by reacting various arylboronic acids with
aromatic as well as alkyl nitriles. The reaction proceeded with good to excellent
yields of the product under mild conditions with inexpensive and non-toxic metal
catalysts. This method provides a simpler approach for the synthesis of
symmetrical and unsymmetrical arylketones. The catalysts system worked best
with an equimolar quantities of Mn(OAc)3.2H2O and Cu(OAc)2 in presence of

bidentate nitrogen donor ligand, Bphen. It is anticipated that reaction pathway
proceeded through the generation of aryl radical from arylboronic acid which
reacts with the Cu-activated nitrile intermediate to give the desired arylketones.
Further studies regarding the exact mechanistic pathway and future scope of this
catalyst system are under way.
Notes
The authors declare no competing financial interest.
Acknowledgments
We would like to thank Department of Chemistry, College of Science and Health,
William Paterson University (WPU) for providing the start-up funds. We would
also like to thank WPU for providing the necessary facilities to carry out this
study. H.L., D.M., and C.S. would like to thank Garden State–Louis Stokes
Alliance for Minority Participation (GS-LSAMP) for the financial support. P.K.
would like to thank Center for Research Summer award, WPU for summer
award.
References:
1. a) hm, M.; Mitsch, A.; Wissner, P.; Sattler, I.; Schlitzer, M. J. Med.
Chem. 2001, 44, 3117. (b) Husain, S. S.; Nirthanan, S.; Ruesch, D.; Solt,
K.; Cheng, Q.; Li, G.- D.; Arevalo, E.; Olsen, R. W.; Raines, D. E.;
Forman, S. A.; Cohen, J. B.; Miller, K. W. J. Med. Chem. 2006, 49, 4818.
(c) Chan, J. H.; Freeman, G. A.; Tidwell, J. H.; Romines, K. R.; Schaller, L.
T.; Cowan, J. R.; Gonzales, S. S.; Lowell, G. S.; Andrews, C. W.;
Reynolds, D. J., St; Clair, M.; Hazen, R. J.; Ferris, R. G.; Creech, K. L.;
Roberts, G. B.; Short, S. A.; Weaver, K.; Koszalka, G. W.; Boone, L. R. J.
Med. Chem. 2004, 47, 1175. (d) Tsuji, J. Transition Metal Reagents and
Catalysts; Wiley: New York, 2004. (e) Diederich, F.; Stang, P. J. Metal-
Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, Germany,

1998. (f) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; John Wiley & Sons: Weinheim, Germany, 2004.
2. (a) Larock, R. C. ComprehensiVe Organic Transformations; VCH: New
York, 1989; p 591. (b) Hudlicky, M. In Oxidations in Organic Chemistry;
ACS Monograph 186; American Chemical Society: Washington, DC,
1990.
3. (a) Zimmerman, H. E.; Paskovich, D. H. J. Am. Chem. Soc. 1964, 86,
2149. (b) Osman, M. Helv. Chim. Acta 1982, 65, 2448. (c) Ianni, A.;
Waldvogel, S. R. Synthesis 2006, 5, 2103. (d) Heitzler, F. R.; Hopf, H.;
Jones, P. G.; Bubenitschek, P.; Lehne, V. J. Org. Chem. 1993, 58, 2781.
(e) Li, C.; Liu, W.; Zhao, Z. Catal. Commun. 2007, 8 (11), 1834. (f)
Kowalski, K.; Zakrzewski, J.; Jerzykiewicz, L. J. Organomet. Chem. 2005,
690, 1474.
4. (a) Duplais, C.; Bures, F.; Sapountzis, I.; Korn, T. J.; Cahiez, G.; Knochel,
P. Angew. Chem., Int. Ed. 2004, 43, 2968. (b) Reddy, C. K.; Knochel, P.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1700. (c) Eberle, M. K.; Kahle, G.
G. Tetrahedron Lett. 1980, 21, 2303. (d) Labadie, J. W.; Stille, J. K. J. Am.
Chem. Soc. 1983, 105, 669.
5. (a) Xin, B.; Zhang, Y.; Cheng, K. J. Org. Chem. 2006, 71, 5725. (b)
Blangetti, M.; Rosso, H.; Prandi, C.; Deagostino, A.; Venturello, P.
Molecules 2013, 18, 1188.
6. (a) Ishiyama, T.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 12043. (b)
Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J. Org.
Chem. 1998, 63, 4726. (c) Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A.
Tetrahedron Lett. 1993, 34, 7595. (d) Liebeskind, L. S.; Srogl, J. J. Am.
Chem. Soc. 2000, 122, 11260. (e) Hirao, T.; Misu, D.; Agawa, T. J. Am.
Chem. Soc. 1985, 107, 7179. (f) Satoh, T.; Itaya, T.; Miura, M.; Nomura,
M. Chem. Lett. 1996, 823. (g) Pucheault, M.; Darses, S.; Genet, J.-P. J.
Am. Chem. Soc. 2004, 126, 15356, and references therein.
7. (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999, 121,
3238. (b) Pletnev, A. A.; Larock, R. C. Tetrahedron Lett. 2002, 43, 2133.

(c) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276.
(d) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302. (e) Zhou,
C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
8. (a) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343. (b) Zhao, B.;
Lu, X. Tetrahedron Lett. 2006, 47, 6765. (c) Zhao, B.; Lu, X. Org. Lett.
2006, 8, 5987.
9. Ueura, K.; Miyamura, S.; Satoh, T.; Miyaura, M. J. Organomet. Chem.
2000, 595, 31.
10.Shimizu, H.; Murakami, M. Chem. Commun. 2007, 2855.
11.Sharma, P.; Rohilla, S.; Jain, N. J. Org. Chem. 2017, 82, 1105−1113.
12.(a) Zweig, J. E.; Kim, D. E.; Newhouse, T. R. Chem. Rev., 2017, 117,
11680-11752. (b) Miao, J.; Ge, H. Eur. J. Org. Chem. 2015, 36, 7859-
7868. (c) Filonenko, G. A.; Putten, R.; Hensen, E. J. M.; Pidko, E. A.
Chem. Soc. Rev., 2018, 47, 1459-1483. (d) Peng, J. -B.; Wu, F.-P.; Wu,
X.-F. Chem. Rev. 2018, ASAP, 10.1021/acs.chemrev.8b00068.
13.Wong, Y.-C.; Parthasarthy, K.; Cheng, C.-H. Org. Lett. 2010, 12, 1736-
1739.
14.Hsieh, J.-C.; Chen, Y.-C.; Cheng, A.-Y.; Tseng, H.-C. Org. Lett. 2012, 14,
1282-1285.
15.Xu, Z.-F.; Cai, C. X.; Liu, J.-T. Org. Lett. 2013, 15, 2096-2099.
16.Chenniappan, V. K.; Silwal, S.; Rahaim, R. J.; ACS catalysis, 2018, 8,
4539-4544.
17.(a) Nqoro, X.; Tobeka, N.; Aderibigbe, B. A. Molecules 2017, 22, 2268. (b)
Sevene, E.; Gonzalez, R.; Menendez, C. Expert Opin. Pharmacother.
2010, 11, 1277–1293.
18.(a) Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.; Lu, P.; Wang, Y. Tetrahedron Lett.,
2014, 55, 1271. (b) Demir, A.S.; Reis, Q.; Emrullahoglu, M. J. Org. Chem.
2003, 68, 578. (c) Pye, D.R.; Cheng, L. -J.; Mankad, N. P. Chem. Sci.
2017, 8, 4750.
19.General procedure for the synthesis of arylketones: In a 25mL round
bottom flask (oven-dried overnight) was added the phenyl boronic acid

(1a, 1.0 mmol) followed by the addition of 1,4-dioxane (6 mL). To this
solution, manganese (III) acetate. dihydrate (5 mol%), Bphen (3e, 10
mol%), Cu(OAc)2 (5 mol%), nitrile (0.5 mmol) and water (0.5 mmol) were
added sequentially. The reaction was then stirred at room temperature for
10 min and slowly brought to 90 oC under air. The reaction was allowed to
run for overnight at the same temperature. After the completion, the
reaction mixture was quenched and extracted with ethyl acetate and
water. The organic layer was collected, and the aqueous layer was again
extracted with ethyl acetate for three more times. The combined organic
layer was further washed with sodium bicarbonate and brine solution. The
organic layer was then dried over sodium sulfate, filtered and evaporated
using rotavap. The crude compound obtained was further purified using
column chromatography (EA:hexane 10:90). The pure product (4a) was
obtained as thick oil. The 1-H and 13-C data for some of the lesser known
1
products are listed below. Compound 4f: H NMR (400 MHz, CDCl3): δ
7.78 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.24 (d, J = 7.0 Hz, 2H),
7.02 (t, J = 6.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 2H), 4.22 (s, 2H, CH2), 3.10
13
(s, 6H). C NMR (100 MHz, CDCl3): δ 198.2, 155.9, 135.6, 128.4 2C),
127.2, 124.6, 117.6 (2C), 44.4, 41.6 (2C). GC-MS: C16H17NO m/z
1
239.0214 ([M]+) (Exact mass: 239.2312); Compound 4m: H NMR (400
MHz, CDCl3): δ 8.58 s, 1H), 8.21 d, J = 8.0 Hz, 1H), 8.05-8.00 (m, 2H),
7.83 (d, J = 7.8 Hz, 1H), 7.60-7.67 (m, 2H), 7.27 (t, J = 8.0 Hz, 2H), 7.24
13
(d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 4.08 (s, 2H, CH2). C NMR
(100 MHz, CDCl3): δ 196.2, 136.2, 134.8, 132.8 2C), 129.5 2C), 129.2
(2C), 128.5, 128.3, 127.6, 127.2, 126.5, 124.6, 44.8. GC-MS: C18H14O m/z
1
246.3264 ([M]+) (Exact mass: 246.0622); Compound 4n: H NMR (400
MHz, CDCl3): δ 8.40 (d, J = 8.2 Hz, 2H), 7.94 (t, J = 6.8 Hz, 2H), 7.74 (d, J
= 8.0 Hz, 2H), 7.52 (t, J = 7.31 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 4.18 (s,
13
2H, CH2). C NMR (100 MHz, CDCl3): δ 191.2, 150.9 (2C), 135.6, 128.4
(2C), 127.2 (2C), 124.6, 124.4, 117.6 (2C), 44.4. GC-MS: C13H11NO m/z
1
197.0478 ([M]+) (Exact mass: 197.2316); Compound 4r: H NMR (400

MHz, CDCl3): δ 8.03 d, J = 9.6 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.78 (d,
J = 8.6 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 2.86 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 198.4, 196.3, 145.3, 140.2, 138.9,
132.4, 130.3 (2C), 130.0 (2C), 128.4 (2C), 128.0 (2C), 27.2. GC-MS:
C15H12O2 m/z 224.0046 ([M]+) (Exact mass: 224.2414); Compound 4t: 1H
NMR (400 MHz, CDCl3): δ 7.92 d, J = 9.0 Hz, 2H), 7.67 (t, J = 7.8 Hz,
1H), 7.46 (d, J = 8.0 Hz, 2H), 2.86 (t, J = 8.0 Hz, 2H), 1.51-1.49 (m, 2H),
0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 199.9, 136.3,
133.3, 128.8 (2C), 128.2 (2C), 41.2, 18.2, 13.1. GC-MS: C10H12O m/z
1
148.1240 ([M]+) (Exact mass: 148.3213); Compound 4v: H NMR (400
MHz, CDCl3): δ 8.10 d, J = 9.0 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.52 (d, J
13
= 8.0 Hz, 2H), 3.22-3.20 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H). C NMR (100
MHz, CDCl3): δ 201.9, 136.0, 134.1, 130.0 2C), 129.2 2C), 37.0, 18.1
(2C). GC-MS: C10H12O m/z 148.3246 ([M]+) (Exact mass: 148.4523):
1
Compound 4w: H NMR (400 MHz, CDCl3): δ 8.05 d, J = 8.8 Hz, 2H),
7.67 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 2.98-2.92 (m, 1H), 1.64
(t, J = 7.8 Hz, 2H), 1.53-1.43 (m, 4H), 1.39 (t, J = 7.8 Hz, 2H), 1.35-1.30
13
(m, 2H). C NMR (100 MHz, CDCl3): δ 201.9, 138.8, 133.1, 129.2 2C),
128.6 (2C), 48.1, 28.8 (2C), 25.4 (2C), 25.2. GC-MS: C13H16O m/z
1
188.0287 ([M]+) (Exact mass: 188.2123). Compound 5: H NMR (400
MHz, CDCl3): δ 8.90 d, J = 8.8 Hz, 1H), 8.07 (d, J = 9.0 Hz, 2H), 7.99 (d,
J = 7.8 Hz, 1H), 7.86 (t, J = 8.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.38
(d, J = 8.8 Hz, 2H), 7.26 (d, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 197.4, 159.2, 151.2, 136.3 (2C), 131.9 (2C), 131.4 (2C), 130.2, 129.6
(2C), 127.9, 127.1, 126.9, 119.6. GC-MS: C16H10BrNO m/z 310.9913
([M]+) (Exact mass: 310.2025).

Mn/Cu catalyzed addition of arylboronic acid to nitriles: Direct synthesis of
arylketones
Dina Moustafa,# Chelsea Sweet,# Hyun Lim, Brenda Calalpa and Parminder
Kaur*
1
Affiliations: College of Science and Health, Department of Chemistry, William
Paterson University, 300 Pompton Road, Wayne, NJ-07470 United States
Corresponding Author’s Email: kaurp6@wpunj.edu, Tel: (973)-720-2706
#co-authors contributed equally
O
B(OH)2
Mn(OAc)3. 2H2O/Cu(OAc)2/ 3e
R2
R2-CN
2a-2e
+
1,4-dioxane, H2O, 90 °C, overnight
R1
R1
4a-4w
1a-1m
74%-89%
2a: R2 = PhCH2
2b: R2 = Ph
2c: R2 = 4-COMe-C6H4
2d: R2 = (CH2)2-CH3
2e: R2 = CH-(CH3)2
2f: R2 = cyclohexyl
R1 = H, Me, OMe,
NO2, OH, halogens,
Ph, N(CH3)2
NH
N
N
N
N
H
N
N
N
N
H
N
N
3a
3b
3c
3d
3e

Mn/Cu catalyzed addition of arylboronic acid to nitriles: Direct synthesis of
arylketones
Dina Moustafa,# Chelsea Sweet,# Hyun Lim, Brenda Calalpa and Parminder
Kaur*
1
Affiliations: College of Science and Health, Department of Chemistry, William
Paterson University, 300 Pompton Road, Wayne, NJ-07470 United States
Corresponding Author’s Email: kaurp6@wpunj.edu, Tel: (973)-720-2706
#co-authors contributed equally
Highlights
 Manganese-copper bimetallic system was developed and used for the first
time for arylketone synthesis
 One equivalent water is required for the reaction
 Bathophenanthroline (Bphen) was used as the nitrogen donor ligand
 Both symmetrical and unsymmetrical ketones were successfully
synthesized