Ionic liquid catalyzed Ritter reaction/Pd-catalyzed directed Ortho-arylation; facile access to diverse libraries of biaryl-amides from Aryl-nitriles

Article abstract of DOI:10.1016/j.tetlet.2020.152553

Diverse libraries of biaryl-amides bearing N-t-butyl and N-adamantyl groups were synthesized in two steps by the Ritter reaction of aryl-nitriles, using tBuOH and AdaOH as carbocation precursors, and employing [BMIM(SO₃H)][OTf] (neat or with [B

Full text of DOI:10.1016/j.tetlet.2020.152553

Journal Pre-proofs
Ionic Liquid Catalyzed Ritter Reaction/Pd-Catalyzed Directed Ortho-Aryla‐
tion; Facile Access to Diverse Libraries of Biaryl-amides from Aryl-nitriles
Suraj M. Sutar, Hemantkumar M. Savanur, Rajesh G. Kalkhambkar, Gabriela
L. Borosky, Gopalakrishnan Aridoss, Kenneth K. Laali
PII:
S0040-4039(20)31046-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152553
TETL 152553
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 August 2020
3 October 2020
8 October 2020
Please cite this article as: Sutar, S.M., Savanur, H.M., Kalkhambkar, R.G., Borosky, G.L., Aridoss, G., Laali,
K.K., Ionic Liquid Catalyzed Ritter Reaction/Pd-Catalyzed Directed Ortho-Arylation; Facile Access to Diverse
Libraries of Biaryl-amides from Aryl-nitriles, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152553
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1
Ionic Liquid Catalyzed Ritter Reaction/Pd-Catalyzed Directed Ortho-
Arylation; Facile Access to Diverse Libraries of Biaryl-amides from Aryl-
nitriles
Suraj M. Sutar,[a]Hemantkumar M. Savanur,[b]Rajesh G. Kalkhambkar,[a]*Gabriela L. Borosky,[c]
Gopalakrishnan Aridoss,[d]*, Kenneth K. Laali [e]*
[a]Department of Chemistry, Karnatak University’s Karnatak Science College, Dharwad
Karnatak 580001, India; Tel. +91 8362215403, Fax. +91 8362744334
E-mail: rgkalkhambkar@gmail.com (R. G. Kalkhambkar)
[b]Department of Studies and Research in Chemistry, P. C. Jabin Science College, Hubli,
Karnatak 580021, India
[c] INFIQC, CONICET and Departamento de Química Teórica y Computacional, Facultad de Ciencias
Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba 5000, Argentina.
[d] Department for Management of Science and Technology Development, Ton Duc Thang
University, Ho Chi Minh City, Vietnam and Faculty of Applied Sciences, Ton Duc Thang
University, Ho Chi Minh City, Vietnam. E-mail: Gopalakrishnan.aridoss@tdtu.edu.vn (G.
Aridoss)
[e]Department of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, Florida
32224, USA; Tel.: +1 904 620 1503; Fax: +1 904 620 3535.
E-mail: Kenneth.Laali@UNF.edu (K.K. Laali) (senior corresponding author)

2
Graphical Abstract
O
o
1) acidic-IL;
50 - 70 C
N
C
R
N
R
OH
Ar-1
Ar-1
+
H
2) H2O
X
o C
0
steps 1&2
then
9
X
-
0
8
Pd(OAc)2, IL
AgOAc
80 - 90 oC
Ar-2
c
Ar-2
A
O
g
X = I, Br
R = tBu; adamantyl
A
L
I
[BMIM(SO3H)][OTf]/[BMIM][PF6]
,
2
)
c
[TMG][CF3COO]
[TMG][EtOSO3]
A
IL
O
O
(
d
R
P
N
Ar-1
H
Ar-2
Abstract
Diverse libraries of biaryl-amides bearing N-t-butyl and N-adamantyl groups were synthesized in
two steps by the Ritter reaction of aryl-nitriles, using tBuOH and AdaOH as carbocation
precursors, and employing [BMIM(SO3H)][OTf] (neat or with [BMIM][PF6] as co-solvent) or
tetramethyl guanidinium-ILs [TMG][X] (X = CF3COO, EtOSO3) as dual catalyst/solvent,
followed by a Pd-catalyzed directed regioselective ortho-C-H arylation of the Ritter amides with
Ar-X (X = I, Cl). The feasibility to perform the two-steps in sequence is also demonstrated, and
potential for recycling/reuse of the ILs is also shown. Preference for [Pd] coordination to the
amide carbonyl versus amide nitrogen is borne out by DFT computations.
Keywords: Biarylamides from arylnitriles; Ritter reaction; Pd-catalyzed directed ortho-arylation;
imidazolium and guanidiniumILs
Functionalized biaryls are high value small molecules that serve as building blocks in
medicinal and natural products chemistry as well as in material science.1,2 There is a vast
literature on transition-metal catalyzed cross-coupling reactions in which Ar-M couples to ArX
to yield biaryls.1Another strategy for the synthesis of biaryls is direct arylation involving
coupling of ArH to ArX.1-3

3
Metal-mediated directed C-H arylation enables the biaryl moiety to be assembled in a
regioselective manner by introducing the aryl moiety selectively ortho to a directing substituent
to which the metal pre-coordinates. Among various directing groups that have been employed,
the amide functionality has played an important role.4-8 Apart from simple primary benzamides
and aryl-acetamides,4-5 bidentate versions of sec-benzamides in which -CO-N(H)-Ph-NHR or -
CO-N(H)-Ph-pyrazole moieties provide additional metal coordination sites have also been
utilized.6-8 Reactions were catalyzed by Pd(OAc)2 with Ag or Mn salts as additive in acetic acid
or toluene as solvent at high temperatures. The PIP (2-pyridylisopropyl) group in -CO-N(H)-PIP
acted as a removable auxiliary for directed ortho-arylation in Ni (II) catalyzed reactions using
triethoxy(aryl)silanes, KF and other additives.9
In continuation of our studies on metal-mediated cross-coupling reactions in ILs10-18 and
our earlier report on synthesis of amides via the Ritter chemistry in ILs,19 we report here a facile
method for the synthesis of diverse libraries of biaryl-amides from arylnitriles.
Expanding upon our earlier report,19 libraries of arylnitriles were synthesized by the
Ritter reaction, using tBuOH and AdaOH as carbocation precursors, in imidazolium as well as in
tetramethylguanidium (TMG) ILs (Figure 1 and Table 1).
R2
O
N
N
IL
C
C
R2
H2O
R2
OH
N
R1
+
R1
R1
50 - 70 o
3 - 18 h
C
H
[BMIM(SO H)][OTf]/
[BMIM][PF6]
3
R2 = tBu; Adamantyl
[TMG][CF3COO]
[TMG][EtOSO3]
IL
Figure 1. Synthesis of Ritter amides in ILs
Isolated yields of the amides when using fresh [BMIM(SO3H)][OTf], [TMG][CF3COO],
and [TMG][EtOSO3] were in 92% to 89% range (for R = tBu), and 90% to 84% range (for R =
Ada) respectively. Slightly lower yields were obtained by using
[BMIM(SO3H)][OTf]/[BMIM][PF6]. The use of this IL mixture was advantageous allowing
lesser quantities of the Brønsted acidic IL to be used. The isolated yields gradually decreased
when recycled/reused ILs were employed in subsequent runs (Table 1). The feasibility to

4
employ recycled BMIM-ILs and TMG-ILs was gauged by repeating selected model reactions
from Tables 1 and 2, and the data are shown in graphical format in Figures S1-S3.
With a library of the arylamides at hand, attention was then focused on the ortho-
arylation
step.
Reactions
were
carried
out
in
[BMIM(SO3H)][OTf],
[BMIM(SO3H)][OTf]/[BMIM][PF6], [TMG][CF3COO], and [TMG][EtOSO3] solvents, with
aryl-iodides and aryl-bromides, and with Pd(OAc)2 as catalyst and AgOAc as additive, under
mild heating (Figure 2 and Table 2), with isolated yields in 67%-54% range when fresh ILs were
used. Use of recycled/reused ILs resulted in gradual decrease in conversions.
X
O
O
R2
Pd(OAc)2, IL
AgOAc
R2
N
N
R3
X = Br, I
+
R1
R1
H
H
80-90 o
C
R3
R2 = tBu; Adamantyl
Figure 2. Synthesis of biarylamides by regioselective ortho-arylation
The next phase of the study focused on developing a sequential version (Figure 3). At the
onset, a comparative study was undertaken to determine relative efficacy of various IL systems
in a model reaction (Table 3), showing neat [BMIM(SO3H)][OTf] to be most effective (run 1).
Adding small volumes of [BMIM][PF6] to [BMIM(SO3H)][OTf] resulted in small yield
reductions (runs 6-7), but use of excess [BMIM][PF6] resulted in drastic drop in yields (runs 9-
12). Based on this survey, [BMIM(SO3H)][OTf]/[BMIM][PF6] (2:1) was selected for the
sequential reactions, allowing the recovered [BMIM][PF6] from the Ritter step to be used in the
arylation step. Table 4 summarizes these reactions, with isolated yields based on two steps in the
47% to 39% range.
X
X = Br, I
R3
O
O
AgOAc
Pd(OAc)2,
[BMIM(SO3H)][OTf]
fresh [BMIM][PF6]
N
R2
R2
C
recovered [BMIM][PF6]
N
N
R2
OH
R1
R1
R1
+
H
H
50 - 70 o
C
[BMIM(SO3H)][OTf]
80-90 o
C
R3
R2 = tBu; Adamantyl
Figure 3. Sequential Ritter reaction/ortho arylation in ILs

5
To shed light on the relative preference for Pd coordination to carbonyl oxygen versus
amide nitrogen, structures of the corresponding complexes and the intermediates were studied by
density functional theory (DFT) computations using N-t-butyl-benzamide as model (Table 1, run
1). For both pairs, Pd coordination to carbonyl oxygen was favored (Figure 4). This preference
increased when acetic acid was used as solvent by polarized continuum model (PCM)
calculations. These findings are in line with those reported for aryl-acetamides (ref.5). The DFT-
optimized structures are shown in Figure S4.
In summary, the N-t-butyl- and N-adamantyl-arylamides prepared from aryl-nitriles by
the Ritter reaction in imidazolium and guanidinium ILs undergo Pd-catalyzed directed ortho-
arylation to furnish libraries of biaryl-amides in good yields. A sequential version of this
chemistry is feasible albeit in moderate yields. The recycling and reuse of the ILs employed in
this study was also demonstrated. DFT computations using N-t-butyl-benzamide as model
suggested that the complex formed by Pd coordination to the carbonyl oxygen and the resulting
Pd-insertion intermediate are energetically favored over those arising from amide-nitrogen
coordination.
O
O
O
Pd
H
N
O
O
O
Pd
N
Complex
O
O
H
O
O
G = 4.49 kcal/mol [6.32 kcal/mol]
G = 0.0 kcal/mol
Intermediate
O
O
H
N
O
Pd
O
Pd
N
H
O
O
G = 0.0 kcal/mol
G = 6.80 kcal/mol [9.25 kcal/mol]
Relative free energies [PCM acetic acid]

6
Figure 4. Computed relative energiesfor the [Pd] coordination complexes and the resulting
intermediates.
Table 1:Scope of the Imidazolium and Tetramethylguanidium ILs Catalyzed Ritter Reactiona
Time
(h)
Yieldb
(%)
Entry Aryl-nitrile
ROH
Aryl-amide
IL
O
N
90c
OH
1
[BMIM(SO3H)][OTf]
9
N
H
O
N
92c
N
H
OH
2
[TMG][CF3COO]
13
O
O
O
N
89c
91c
88d
OH
OH
OH
N
H
3
4
5
[TMG][EtOSO3]
[TMG][CF3COO]
[BMIM(SO3H)][OTf]
14
16
9
O
N
N
H
Cl
Cl
O
N
N
H
Br
Br
O
N
[BMIM(SO3H)][OTf]/
[BMIM][PF6]
6*
13
82c
OH
N
H
O
N
N
Cl
Cl
7
8
9
[TMG][CF3COO]
[BMIM(SO3H)][OTf]
[TMG][EtOSO3]
12
13
13
85d
81e
83d
OH
OH
N
H
O
Br
Br
N
H
O
N
O
O
OH
N
H

7
N
O
[BMIM(SO3H)][OTf]/
[BMIM][PF6]
10*
15
84c
N
H
HO
N
O
11
12
[BMIM(SO3H)][OTf]
[TMG][CF3COO]
16
16
81d
86c
N
H
O
HO
HO
O
N
O
N
H
N
O
[BMIM(SO3H)][OTf]/
[BMIM][PF6]
13*
14
18
17
76d
90c
N
H
Cl
HO
HO
Cl
N
O
[BMIM(SO3H)][OTf]
N
H
Br
Br
N
O
15
16
17
[TMG][CF3COO]
[TMG][EtOSO3]
22
20
18
67e
70e
84c
N
H
HO
HO
HO
N
N
Cl
O
O
O
Cl
Br
N
H
Br
[BMIM(SO3H)][OTf]
N
H
N
O
18
[TMG][EtOSO3]
22
86c
N
H
HO
O
aReaction Condition: Nitrile (1 mmol), tert-Alcohol (2 mmol), IL (6-7 mL), Oil bath temperature
o
b
c
d
(50-70 C), Isolated yield of pure product, Yield employing fresh IL; Yield using recycled IL
(2nd cycle); eYield using recycled IL (3rd cycle), *[BMIM(SO3H)][OTf] (5-6
mL)/[BMIM][PF6](2-3 mL).

8
Table 2: Regioselective Directed Ortho-Arylation of Benzamidesa
Time
(h)
Yieldb
(%)
Entry
Benzamide
Aryl Halide
Product
IL
O
I
O
N
H
1
[BMIM(SO3H)][OTf]
5
67c
N
H
O
I
O
N
H
O
N
H
2
3
4
[TMG][CF3COO]
[TMG][EtOSO3]
[TMG][CF3COO]
7
62c
55d
56d
O
O
I
O
N
H
N
10
19
H
O
O
Br
Br
I
N
H
N
H
Cl
Cl
O
O
N
H
N
H
5*
6
[BMIM(SO3H)][OTf]/[ 21
BMIM][PF6]
49d
Br
Br
O
O
N
H
N
[TMG][EtOSO3]
[TMG][CF3COO]
6
4
59c
55d
H
O
Br
O
O
N
H
O
N
H
7
O
I
O
O
Br
O
N
H
Br
65c
N
8
[BMIM(SO3H)][OTf]
19
H

9
O
O
I
N
H
N
9
[TMG][CF3COO]
8
5
62c
54c
H
O
O
I
O
[BMIM(SO3H)][OTf]/
[BMIM][PF6]
O
N
H
10*
N
H
O
O
O
I
O
N
H
11
12
13
[TMG][EtOSO3]
[TMG][EtOSO3]
[TMG][CF3COO]
8
60c
54d
47e
N
H
Br
Br
Br
O
O
N
H
11
22
N
H
Br
O
O
N
H
N
Cl
H
Cl
O
I
O
N
H
14
[BMIM(SO3H)][OTf]
20
56d
N
Br
H
Br
Br
Br
O
O
N
H
15
16
[BMIM(SO3H)][OTf]
[TMG][EtOSO3]
18
9
53e
46e
N
H
MeO
O
O
O
N
H
N
H

10
I
O
O
N
17
[TMG][CF3COO]
10
8
49e
44e
H
N
H
O
I
O
[BMIM(SO3H)][OTf ]
/[BMIM][PF6]
N
H
18*
N
O
H
O
aReaction Condition: Benzamide (1 mmol), Aryl Halide (1.2 mmol), IL (5-7 mL), AgOAc (2
o
equiv.), Pd(OAc)2 (5 mol %), Oil bath temperature (80-90 C),bIsolated yield of pure product,
d
cYield employing fresh IL; Yield using recycled IL (2nd cycle);eYield using recycled IL(3rd
cycle).*[BMIM(SO3H)][OTf] (5-6 mL) + [BMIM][PF6](2-3 mL).
Table 3: Survey of ILs Efficacy for the ortho-arylation step
O
O
I
Pd(OAc)2
AgOAc
N
N
H
H
IL
Time
(h)
9
Yield
(%)
67
Entry
BrønstedAcidic IL(%)
[BMIM][PF6](%)
1
2
[BMIM(SO3H)][OTf] (100)
[TMG][CF3COO] (100)
[TMG][EtOSO3] (100)
--
--
--
13
12
10
19
11
11
11
11
11
11
15
52
55
NR
NR
60
60
52
39
31
19
19
3
--
4
100
100
20
40
50
70
80
90
90
5
--
6
[BMIM(SO3H)][OTf] (80)
[BMIM(SO3H)][OTf] (60)
[BMIM(SO3H)][OTf] (50)
[BMIM(SO3H)][OTf] (30)
[BMIM(SO3H)][OTf] (20)
[BMIM(SO3H)][OTf] (10)
[BMIM(SO3H)][OTf] (10)
7
8
9
10
11
12

11
Table 4: Sequential Ritter Reaction/ortho-Arylationa
Time
(h)
Yieldb
(%)
Entry
Ar-CN
ROH
Aryl-X
Biaryl-benzamide
O
I
N
N
H
OH
1
25
15
24
47
O
I
I
N
N
H
OH
OH
2
3
45
42
O
N
N
H
Cl
Cl
I
I
O
N
N
N
H
4
5
23
27
41
39
HO
HO
O
N
H
N
O
I
N
H
6
24
40
O
O
HO
aReaction conditions: Ar-CN (1 mmol),ROH (2 mmol),Ar-X (1.2 mmol), Pd(OAc)2 (5 mol %),
AgOAc (2 equiv.),Oil bath temperature (80-90oC), [BMIM(SO3H)][OTf] (5-6 mL),
[BMIM][PF6] (2-3 mL), bIsolated yield of pure product by using BMIM-PF6 recovered from the
1st step.

12
Supplemental Information
Experimental procedures, analytical and spectral data for the products, recycling feasibility
graphs, and DFT optimized structures for this article are gathered in the supplemental
information file.
Acknowledgements
K. K. L. thanks University of North Florida for the Outstanding Faculty Scholarship and
Presidential Professorship awards, Faculty scholarship and UNF Foundation Board grants, and
the Dean’s Leadership Council award. The authors at Karnatak Science College thank the
University Sophisticated Instrument Center, KUD for IR, GC, and GC-MS, They also thank
1
NMR Research Center, Indian Institute of Science, Bangalore for H NMR and 13C NMR.
Financial assistance through Project No. VGST-RGS/F-GRD-742/2017-18/2018- 19 by Vision
Group on Science and Technology, Govt. of Karnataka, Bangalore is gratefully acknowledged.
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Declaration of Interest Statement

14
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Highlights
Synthesis of diverse libraries of biaryl-amides from aryl-nitriles
IL-mediated Ritter reaction followed by Pd-catalyzed directed ortho-arylation
Use of [BMIM(SO3H)][OTf] (neat or diluted in BMIM-PF6) and tetramethyl guanidinium-ILs
[TMG][X] (X = CF3COO, EtOSO3) as dual catalysts/solvents
Feasibility for sequential reaction