Ruthenium(II)-Catalyzed Positional Selective C-H Oxygenation of N-Aryl-2-pyrimidines

Article abstract of DOI:10.1021/acs.joc.8b00714

Efficient Ru-catalyzed regioselective C-H oxygenation of N-aryl-2-pyrimidines is described with aryl carboxylic acids in the presence of AgSbF₆ as an additive and Ag₂CO₃ as an oxidant. The reaction can be extended to alkyl

Full text of DOI:10.1021/acs.joc.8b00714

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Article
Ruthenium(II)-Catalyzed Positional Selective
C-H Oxygenation of N-Aryl-2-pyrimidines
Tanumay Sarkar, Sourav Pradhan, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00714 • Publication Date (Web): 15 May 2018
Downloaded from http://pubs.acs.org on May 15, 2018
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Ruthenium(II)-Catalyzed Positional Selective C-H Oxygenation of N-Aryl-2-
pyrimidines
Tanumay Sarkar, Sourav Pradhan and Tharmalingam Punniyamurthy*
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Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, 781039, India.
ABSTRACT: Efficient Ruꢀcatalyzed regioselective CꢀH oxygenation of Nꢀarylꢀ2ꢀpyrimidines is
described with aryl carboxylic acids in the presence of AgSbF
6
2 3
as an additive and Ag CO as an
oxidant. The reaction can be extended to alkyl, heteroaryl and
α,β
ꢀunsaturated carboxylic acids.
The regioselectivity, broad substrate scope and functional group tolerance are the significant
practical advantages.
INTRODUCTION
The transitionꢀmetalꢀcatalyzed directed C–H bond functionalization has emerged as a reliable
synthetic toolbox to revolutionize the development of versatile carbogenic scaffolds, owing to the
1
proximityꢀdriven reactivity and selectivity that is aided by a chelating group. In this regard, the
2
direct CꢀH oxygenation forms a very integral constituent of C−H functionalization, due to the
3
prevalence of CꢀO bonds in pharmaceuticals, agrochemicals and material science. In 2004,
Sanford and coꢀworkers reported an oximeꢀdirected Pdꢀcatalyzed acetoxylation of CꢀH bonds
2
a
2
using PhI(OAc) as an acylating agent, while Yu and coꢀworkers demonstrated an oxazoline
directed Pdꢀcatalyzed acetoxylation of methyl CꢀH bond utilizing acid anhydride as an acyl
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source. Several studies on oxygenation of CꢀH bonds have been subsequently reported
4
5b,6b
employing Pd and Cuꢀbased catalytic systems with PhI(OAc)
2
, anhydride,
tertꢀbutyl
6c
6d
6e
peroxyacetate, acid halide and sodium carboxylate as a carboxyl source (Scheme 1a).
2
However, the direct oxygenation of C(sp )ꢀH bonds with aryl carboxylic acid as an acyl source is
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2b
7b
7e
7d,g
7c
7a
limited, and oxazoline, carboxamide, sulfoximine, pyridyl,
triazole and anilide based
directing groups are studied utilizing Pd, Rh, Ru, Cu and Coꢀbased catalytic systems (Scheme 1b).
This strategy is attractive as they are atom economical and can lead to diverse ester scaffolds.
8
Being a recurring moiety in bioꢀactive molecules, pyrimidine based σꢀcoordinating group is
Scheme 1. Methods for Directed Regioselective C-H Oxygenation of Arenes
Previous studies
DG
DG
O
Me
Pd, Cu
a)
b)
acetyl source
O
acetoxylation: well studied DG
DG
DG
O
Ar
Rh, Pd, Ru, Cu, Co
ArCOOH
O
benzoxylation: limited studies
DG = oxazoline, carboxamide, sulfoximine, pyridyl,
triazole,anilide
c) This study
-pym
2
2-pym
NH
NH
Ru
O
R
pym = pyrimidyl
RCO H
O
2
Advantages: R = aryl, alkyl, heteroaryl
functional group diversity
gram-scale synthesis
9
employed as directing group for the CꢀH functionalization. In continuation of our studies on
10
11,12
directed CꢀH functionalization, we here report an efficient Ruꢀcatalyzed
orthoꢀselective
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oxygenation of Nꢀarylꢀ2ꢀpyrimidines with benzoic acids (Scheme 1c). The reaction can be
extended to alkyl, heteroaryl and α,βꢀunsaturated carboxylic acids to furnish the respective esters
in high yields. The reaction is scalable, and the broad substrate scope and functional group
diversity are the important practical features.
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RESULTS AND DISCUSSION
Our optimization studies commenced using Nꢀphenylpyrimidinꢀ2ꢀamine 1a and 4ꢀchlorobenzoic
acid 2i as the model substrates with [RuCl
and additives (Table 1). To our delight, the reaction occurred to produce the ester 3i in 39% yield
when the substrates were stirred employing 5 mol % [RuCl (pꢀcymene)] , 20 mol % AgOTf and 2
equiv Ag CO at 110 °C for 15 h in 1,2ꢀdichloroethane under nitrogen atmosphere (entry 1).
2 2
(pꢀcymene)] as a catalyst in the presence of oxidants
2
2
2
3
Subsequent screening of AgSbF
AgBF and KPF produced 25 and 43% yields, respectively (entries 2ꢀ4). In a set of oxidants
screened, Ag CO , Cu(OAc) , K , AgOAc and Ag O, the former produced the best results
entries 5ꢀ8). 1,2ꢀDichloroethane was found to be the solvent of choice, whereas 1,4ꢀdioxane,
THF, MeOH and DMF produced inferior results (entries 9ꢀ12). The reactions using RuCl and
6
as an additive led to an enhancement in yield to 72%, whereas
4
6
2
3
2
S
2 2
O
8
2
(
3
RuCl
Co(OAc)
experiments confirmed that the absence of AgSbF
suggests that Ag CO and AgSbF are crucial for the transformation (entries 18ꢀ19).
2
(PPh
3
)
3
were not effective, affording 3i in <18% yield (entries 13ꢀ14). In addition,
and Pd(OAc) failed to catalyze the reaction (entries 15ꢀ17). Control
and Ag CO led to no CꢀH oxygenation, which
2
, Cu(OAc)
2
2
6
2
3
2
3
6
Having optimized the reaction condition, the scope of the procedure was studied for the
coupling of a series of aryl and alkyl carboxylic acids (Scheme 2). Benzoic acid 2a underwent
reaction to produce 3a in 72% yield. The reaction of benzoic acids bearing 2ꢀbromo 2b, 2ꢀchloro
2c, 2ꢀmethyl 2d, 2ꢀacetoxy 2e, 3ꢀchloro 2f and 3ꢀnitro 2g functional groups produced 3b-g in 61ꢀ
71% yields. In addition, benzoic acids containing the substitution at the 4ꢀposition with bromo 2h,
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Table 1. Optimization of Reaction Conditions
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entry
additive
AgOTf
oxidant
solvent
yield (%)
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5
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8
9
Ag
Ag
Ag
Ag
2
2
2
2
CO
CO
CO
3
3
3
(CH
(CH
(CH
2
2
2
Cl)
Cl)
Cl)
2
2
2
39
AgBF
KPF
AgSbF
AgSbF6
4
25
6
43
6
CO
3
(CH
2
Cl)
2
72
Cu(OAc)2
(CH Cl)2
0
2
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
6
6
6
6
6
K
2
S
2
O
8
(CH
(CH
(CH
2
2
2
Cl)
Cl)
Cl)
2
2
2
27
AgOAc
21
Ag
Ag
Ag
2
2
2
O
12
CO
3
3
1,4ꢀdioxane
THF
59
10
CO
64
11
AgSbF6
Ag CO3
MeOH
DMF
23
2
12
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
6
6
6
6
6
6
Ag
Ag
Ag
Ag
Ag
Ag
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
47
c
13
14
15
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
Cl)
Cl)
Cl)
Cl)
Cl)
2
2
2
2
2
0
d
18
e
0
f
16
0
g
1
1
7
8
0
AgSbF6
ꢀ
ꢀ
(CH Cl)2
0
0
2
19
Ag
2
CO
3
2 2
(CH Cl)
a
Reaction conditions: 1a (0.2 mmol), 2i (0.24 mmol), [RuCl (pꢀcymene)] (5 mol %), additive
2
2
b
c
(
20 mol %), oxidant (0.4 mmol), solvent (2.0 mL), 110 °C, 15 h, N
2
. Isolated yield. RuCl
3
d
e
f
g
used. RuCl
2
(PPh
3
)
3
used. Co(OAc)
2
used. Cu(OAc)
2
used. Pd(OAc)
2
used.
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a,b
Scheme 2. Reaction of Aryl and Alkyl Carboxylic Acids 2a-w with 1a
[
Ru(p-cymene)Cl]2
5 mol %)
(
2-pym
2-pym
NH
NH
AgSbF (20 mol %)
6
O
R
H
R CO H
+
2
Ag CO (2.0 equiv)
2
3
O
R= aryl, alkyl
(CH Cl) , 110 °C
2
2
1
1
1
1
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1a
2a-w
3a-w
aryl carboxylic acids
-pym
2
2-pym
2-pym
NH
NH
NH
O
O
O
Y
O
O
X
O
Y= Cl, 3f, 71%, 15 h
3
a, 72%, 15 h
X= Br, 3b, 63%, 16 h
X= Cl, 3c, 65%, 16 h
X= Me,3d, 69%, 14 h
X= OCOMe, 3e, 66%, 17 h
Y= NO , 3g, 61%, 16 h
2
2
-pym
Z
NH
O
2
-pym
Me
2-pym
NH
NH
O
O
O
Me
Z= Br, 3h, 67%, 14 h
Z= F, 3j, 65%, 17 h
Z= Me, 3k, 73%, 14 h
Z= OMe, 3l, 68%, 15 h
O
O
3p, 64%, 16 h
3
o, 63%, 15 h
Z= CF , 3m, 59%, 18 h
3
Z= Ph, 3n, 67%, 15 h
alkyl carboxylic acids
2-pym
2-pym
2-pym
NH
NH
2-pym
NH
Me
Me
NH
O
Me
O
O
O
Me
Me
O
O
O
O
3q, 73%, 14 h
3r, 62%, 15 h
3s, 69%, 15 h
3t, 65%, 18 h
2-pym
2-pym
NH
2-pym
NH
NH
O
O
O
Ph
O
O
O
OMe
3u, 63%, 17 h
3v, 66%, 15 h
3w, 67%, 16 h
a
Reaction conditions: 1a (0.2 mmol), 2a-w (0.24 mmol), [RuCl
2
2 6
(pꢀcymene)] (5 mol %), AgSbF
b
(
20 mol %), Ag CO (0.4 mmol), (CH Cl) (2.0 mL), 110 °C, N . Isolated yield.
2
3
2
2
2
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6
a ,b
Scheme 3. Reaction of Heteroaryl and α,β-Unsaturated Carboxylic Acids 2x-ad with 1a
0
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Reaction conditions: 1a (0.2 mmol), 2x-ad (0.24 mmol), [RuCl
2
2 6
(pꢀcymene)] (5 mol %), AgSbF
b
(20 mol %), Ag
2
CO
3
(0.4 mmol), (CH
2
Cl)
2
(2.0 mL), 110 °C, N
2
. Isolated yield.
fluoro 2j, methyl 2k, methoxy 2l, trifluoromethyl 2m and phenyl 2n groups underwent
oxygenation to give the esters 3h-n in 59ꢀ73% yields. Further, 3,4ꢀdimethyl substituted benzoic
acid 2o and 1ꢀnaphthoic acid 2p reacted to give the oxygenated products 3o and 3p in 63 and 64%
yields, respectively. Interestingly, these reaction conditions can be extended to the coupling of
alkyl carboxylic acids. For examples, acetic acid 2q, propionic acid 2r, pivalic acid 2s and the
sterically hindered 1ꢀadamantanecarboxylic acid 2t can be reacted to produce esters 3q-t in 62ꢀ
7
3% yields. Furthermore, 2ꢀphenylacetic acid 2u, 2ꢀ(4ꢀmethoxyphenyl)acetic acid 2v and 1ꢀ
naphthylacetic acid 2w efficiently participated in directed CꢀH oxygenation to convey the
corresponding esters 3u-w in 63ꢀ67% yields.
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a,b
Scheme 4. Reaction of N-Containing Heterocycles 1b-o with Benzoic Acid 2a
[
Ru(p-cymene)Cl2]2
DG
R
O
OH
(5 mol %)
DG
R
NH
NH
AgSbF (20 mol %)
6
O
Ph
+
Ag CO (2.0 equiv)
2
3
(CH Cl) , 110 °C
O
2
2
1
b-o
2a
2-pym
3ae-ar
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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0
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0
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0
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0
1
2
3
4
5
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7
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9
0
2
-pym
2-pym
2-pym
NH
NH
Br
NH
NH
Me
O
Ph
O
Ph
O
Ph
O
Ph
O
O
O
O
Cl
F
3
ae, 65%, 14 h
3af, 63%, 15 h
3ag, 62%, 15 h
3
ah, 57%, 18 h
2-pym
2-pym
2-pym
2-pym
NH
NH
NH
NH
O
Ph
O
Ph
O
Ph
O
Ph
O
O
O
O
Cl
I
ai, 67%, 14 h
CF3
Me
3
3aj, 66%, 15 h
3ak, 52%, 15 h
3al, 71%, 14 h
unsucessfull substrates
-pym
2-pym
2
2-pym
NH
NH
NH
O
Ph
O
Ph
O
Ph
O
O
O
O N
2
COMe
CN
3am, 0%
3an, 0%
3ao, 0%
Reaction with other N-containing groups
N
Me
NH
Me
O
NH
N
NH
N
Me
O
Ph
O
O
Ph
O N
N
N
O
O
Ph
3ap, 0%
3aq, 63%, 15 h
3ar, 0%
a
Reaction conditions: 1b-o (0.2 mmol), 2a (0.24 mmol), [RuCl (pꢀcymene)] (5 mol %), AgSbF
2
2
6
b
(
20 mol %), Ag
2
CO
3
(0.4 mmol), (CH
2
Cl)
2
2
(2.0 mL), 110 °C, 15 h, N . Isolated yield.
The scope of the procedure was further investigated for the reaction of heteroaryl and α,βꢀ
unsaturated carboxylic acids (Scheme 3). The reaction of 2ꢀthiophenyl 2x and 2ꢀfuranyl 2y
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carboxylic acids readily occurred to produce the esters 3x and 3y in 62 and 65% yields,
respectively. However, 2ꢀpicolinic acid 2z was an unsuccessful substrate, which may be due to the
complex formation with the Ru species. Further, the reaction of cinnamic acid 2aa occurred to
furnish 3aa in 68% yield. The reaction of (E)ꢀ3ꢀ(benzo[d][1,3]dioxolꢀ5yl)acrylic acid 2ab
produced 3ab in 65% yield, whereas butꢀ2ꢀenoic acid 2ac gave the ester 3ac in 63% yield as a 5:1
mixture isomers. Moreover, methacrylic acid 2ad underwent reaction to afford 3ad in 69% yield.
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9
0
The reaction of a series of Nꢀarylꢀ2ꢀpyrimidines 1b-l was next screened using benzoic acid 2a as
a standard substrate (Scheme 4). The substrate 1b bearing substitution at the 2ꢀposition of the aryl
ring with methyl group underwent reaction to give 3ae in 65% yield. The reaction of the substrates
bearing the substitution at the 4ꢀposition of the aryl ring with bromo 1c, chloro 1d, fluoro 1e, iodo
1f, methyl 1g and trifluoromethyl 1h groups produced the esters 3af-ak in 52ꢀ67% yields. In
addition, the substrate 1i having substitution at the 3ꢀposition of the aryl ring with chloro group
underwent oxygenation to furnish 3al in 71% yield. In contrast, the reactions of the substrates
bearing 3ꢀnitro 1j, 4ꢀcyano 1k and 4ꢀacetyl 1l groups were unsuccessful to furnish the oxygenated
products. Similar results were observed with the substrates having oxazoline 1m and tetrazole 1o
directing groups, which may be due to the chelation of these functional groups to the Ruꢀcomplex.
However, the substrate 1n containing pyridyl directing group can be oxygenated to provide 3aq in
63% yield.
Scheme 5. Gram-Scale Synthesis
Scheme 6. Intermolecular Competition Experiments
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1
a
2
-pym
F 2-pym
Me
[
Ru(p-cymene)Cl2]2
5 mol %)
AgSbF (20 mol %)
CO H
CO H
NH
NH
2
2
(
O
O
6
(
a)
Ag CO (2.0 equiv)
O
O
2
3
(CH Cl)2
2
F
Me
2k
110 °C, 12 h
2j
3j, 6%
3k, 41%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
5
5
5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
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0
1
2
3
4
5
6
7
8
9
0
CO H
2
1a
2-pym
2-pym
[
Ru(p-cymene)Cl2]2
CO H
NH
NH
2
(
5 mol %)
O
Ph
O
Ph
AgSbF (20 mol %)
6
(b)
Ag CO (2.0 equiv)
O
O
2
3
(CH Cl)2
110 °C, 12 h
2
3a, 27%
3aa, 38%
2a
2aa
2a
2
-pym
2-pym
2-pym
2-pym
[
Ru(p-cymene)Cl2]2
NH
O
NH
F
NH
NH
(5 mol %)
Ph
O
Ph
AgSbF (20 mol %)
6
(
c)
O
O
Ag CO (2.0 equiv)
2
3
(
CH Cl)2
2
F
Me
Me
3aj, 33%
1
10 °C, 12 h
1e
1g
3ah, 24%
Scheme 7. Mechanistic Investigations
(
a) H/D Exchange Experiment
8
5% D
[
Ru(p-cymene)Cl2]2
5 mol %)
AgSbF (20 mol %)
2-pym
D/H
2-pym
D/H
(
NH
NH
6
H/D
O
1
a
2a
Ag CO (2.0 equiv)
CH Cl) /D O (1.8:0.2)
2 2 2
2
3
O
(
85% D [Dn]
-1a
1
10 °C, 15 h
80% D [D ]-3a
n
(12%)
(65%)
[
Ru(p-cymene)Cl2]2
5 mol %)
AgSbF (20 mol %)
(
6
no deuterium incorporation
1a
Ag CO (2.0 equiv)
(CH Cl) /D O (1.8:0.2)
2
3
2
2
2
110 °C, 15 h
(
b) Intermolecular Kinetic Isotope Experiment
2i
[
Ru(p-cymene)Cl2]2
2-pym
Cl
2
-pym
NH
NH
(5 mol %)
AgSbF (20 mol %)
D/H
O
D/H
H/D
6
Ag CO (2.0 equiv)
2
3
O
(
CH Cl)2
k /k = 5.25
H D
2
1
a/[D ]-1a
110 °C, 3 h
3i/[D ]-3i
n
2
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6
The scaleꢀup of the reaction was investigated using 1a and 2i as the representative examples
(Scheme 5). The reaction took place efficiently to provide the target oxygenated product 3i in 68%
yield. These results suggest that the reaction can be scale up to produce the oxygenated compound
in good yield.
0
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0
To gain insight into the reaction pathway, intermolecular competitive experiments were pursued.
Benzoic acid bearing electron rich 4ꢀmethyl substituent 2k exhibited greater reactivity compared
to that having electron withdrawing 4ꢀfluoro group 2j (Scheme 6a). Similarly, the less acidic α,βꢀ
unsaturated carboxylic acid 2aa showed enhanced reactivity in comparison to more acidic benzoic
acid 2a (Scheme 6b). These results suggest that the carboxylic acids having higher pKa showed
superior reactivity to that of containing lower pKa, which might be attributed to the greater
nucleophilicity of the conjugate base of less acidic carboxylic acids 2k and 2aa that may assist in
the rapid generation of active Ruꢀcarboxylate species. In addition, Nꢀarylꢀ2ꢀpyrimidine having
electron donating 4ꢀmethyl group 1g was more reactive than the substrate containing electron
withdrawing 4ꢀfluoro functionality 1e, which suggests that intramolecular electrophilic
substitutionꢀtype CꢀH metalation may be involved (Scheme 6c). Further, the reaction using D
a coꢀsolvent displayed a significant H/D scrambling at the orthoꢀposition of the reꢀisolated starting
material [D ]ꢀ1a and the ester [D ]ꢀ3a (Scheme 7a), whereas the H/D exchange experiment in the
2
O as
n
n
absence of carboxylic acid 2a, exhibited no deuterium incorporation. These results suggest that a
reversible CꢀH metalation phenomenon may be involved. The intermolecular KIE study of 1a and
[
D
2
]ꢀ1a with 2i produced k
H
/k
D
= 5.25 (Scheme 7b), which indicates that the CꢀH bond cleavage
(pꢀcymene)] with
6
and carboxylic acid may generate Ru complex a (Scheme 8). Subsequent reversible coꢀ
might be involved in the rateꢀdetermining step. Thus, the reaction of [RuCl
2
2
7b,f
AgSbF
ordination with substrate 1 can lead to the formation of b, which can undergo intramolecular CꢀH
metalation to produce Ru metallacycle c. Reductive elimination followed by Ag CO mediated
2
3
oxidation can furnish 3 with the regeneration of active Ru species to complete the catalytic cycle.
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Scheme 8. Plausible Catalytic Cycle
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
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0
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0
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 9. Acid Hydrolysis of 3i
Finally, we attempted the removal of the directing group using 3i as a representative example
9d
(Scheme 9). However, our effort was not successful and the hydrolysis of both the pyrimidyl and
ester groups was observed with aq. HCl under microwave irradiation to produce 2ꢀaminophenol 4
in 71% yield.
CONCLUSIONS
In summary, we have demonstrated a Ruꢀcatalyzed positional selective CꢀH oxygenation of Nꢀ
arylꢀ2ꢀpyrimidines using carboxylic acids as acyl source. The reaction of a broad range of aryl
carboxylic acids has been accomplished with diverse functional groups. These reaction conditions
can be extended to the coupling of alkyl, heteroaryl and
α,βꢀunsaturated carboxylic acids. The
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6
broad substrate scope, functional group diversity, gram scale synthesis and regioselectivity are the
important practical features.
EXPERIMENTAL SECTION
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9
0
2 2 3 2 3 3
General Information. [RuCl (pꢀcymene)] (97%), RuCl (45ꢀ55%), RuCl (PPh ) (97%),
Co(OAc) (99.99%), Cu(OAc) (98%), Pd(OAc) (99.9%), AgSbF (98%) and Ag CO (99%)
2
2
2
6
2
3
9a,b
were purchased from Aldrich and used as received. NꢀArylꢀ2ꢀpyrimidines 1a-l,
Nꢀ
9b
10a
phenylpyridinꢀ2ꢀamine 1n, 1ꢀ(2,6ꢀdimethylphenyl)ꢀNꢀ(pꢀtolyl)ꢀ1Hꢀtetrazolꢀ5ꢀamine 1o and Nꢀ
3
c
phenylꢀ4,5ꢀdihydrooxazolꢀ2ꢀamine 1m were prepared according to literature. SRL silica gel
G/GF 254 plates were used for analytical TLC and SRL silica gel (100ꢀ200 mesh) was used for
column chromatography. NMR spectra were recorded with Varian DRXꢀ400, Bruker Ascend 400
3 6
and Bruker Avance III 600 MHz spectrometers using CDCl or DMSOꢀd as solvent and TMS as
an internal standard. Chemical shifts (δ) and spinꢀspin coupling constant (J) are reported in ppm
and in Hz, respectively, and other data are reported as follows: s = singlet, d = doublet, t = triplet,
m = multiplet, q = quartet, dd = doublet of doublets. Melting points were determined using a
Büchi Bꢀ540 apparatus and are uncorrected. FTꢀIR spectra were collected on Perkin Elmer IR
spectrometer. QꢀTof ESIꢀMS instrument (model HAB 273) was used for recording mass spectra.
Single crystal Xꢀray data were collected on a Bruker SMART APEX equipped with a CCD area
detector using Mo/Kα radiation and the structure was solved by direct method using SHELXLꢀ14
(Göttingen, Germany). Microwave reaction was carried out in sealed vessel using CEM Discover
Microwave reactor fitted with external IR sensor that monitors the surface temperature of the
reaction vessel.
General Procedure for the C-H Oxygenation of Arenes with Carboxylic acids. NꢀArylꢀ2ꢀ
pyrimidine (0.2 mmol), carboxylic acid (0.24 mmol), [RuCl
2 2
(pꢀcymene)] (5.0 mol %, 6 mg),
AgSbF (20 mol %, 13.7 mg) and Ag CO (0.4 mmol, 110 mg) were stirred at 110 °C in 1,2ꢀ
6
2
3
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dichloroethane (2.0 mL) under N . The progress of the reaction was monitored by TLC using
2
hexane and ethyl acetate as an eluent. The reaction mixture was cooled to room temperature,
diluted with dichloromethane (10 mL) and passed through a short pad of celite using
dichloromethane (50 mL). Evaporation of the solvent gave a residue that was purified on silica gel
column chromatography using ethyl acetate and hexane as eluent.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
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3
3
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0
2-(Pyrimidin-2-ylamino)phenyl benzoate 3a. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
f
= 0.52; colorless solid; mp 136ꢀ137 °C; yield 72% (42 mg); H NMR (400
3
) δ 8.38ꢀ8.37 (m, 3H), 8.20 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.51 (t, J =
.6 Hz, 2H), 7.32ꢀ7.28 (m, 1H), 7.27ꢀ7.24 (m, 1H), 7.22 (s, 1H), 7.15ꢀ7.10 (m, 1H), 6.70 (t, J =
7
4
1
3
3
.8 Hz, 1H); C NMR (150 MHz, CDCl ) δ 164.8, 160.1, 158.1, 140.9, 134.1, 131.8, 130.5,
ꢀ1
129.1, 128.9, 126.6, 123.4, 122.6, 122.0, 113.1; FTꢀIR (KBr) 3408, 1726 cm . HRMS (ESI) m/z
+
[
M+H] calcd for C17
14
H N
3
O
2
: 292.1086, found: 292.1083.
2-(Pyrimidin-2-ylamino)phenyl 2-bromobenzoate 3b. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
.53 (s, 1H), 7.43ꢀ7.38 (m, 2H), 7.33ꢀ7.29 (m, 2H), 7.13ꢀ7.11 (m, 1H), 6.71 (t, J = 4.2 Hz, 1H);
f
= 0.48; colorless solid; mp 119ꢀ120 °C; yield 63% (47 mg); H NMR (600
3
) δ 8.43ꢀ8.39 (m, 3H), 7.96 (dd, J = 7.2, 2.4 Hz, 1H), 7.73 (dd, J = 7.8, 1.8 Hz, 1H),
7
1
3
3
C NMR (150 MHz, CDCl ) δ 164.4, 160.2, 158.1, 140.6, 134.7, 133.5, 132.1, 131.7, 131.3,
ꢀ1
1
27.6, 126.7, 123.1, 122.3, 122.2, 121.9, 113.1; FTꢀIR (KBr) 3402, 1725 cm . HRMS (ESI) m/z
+
[M+H] calcd for C17
H13BrN
3
O
2
: 370.0191, found: 370.0198.
2-(Pyrimidin-2-ylamino)phenyl 2-chlorobenzoate 3c. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R = 0.50; colorless solid; mp 157ꢀ158 °C; yield 65% (42 mg); H NMR (400 MHz,
f
3
CDCl ) δ 8.45ꢀ8.40 (m, 3H), 8.01ꢀ7.99 (m, 1H), 7.54ꢀ7.50 (m, 2H), 7.48ꢀ7.46 (m, 1H), 7.40ꢀ7.36
13
(
m, 1H), 7.33ꢀ7.29 (m, 2H), 7.14ꢀ7.10 (m, 1H), 6.72 (t, J = 4.8 Hz, 1H); C NMR (150 MHz,
CDCl
3
) δ 163.9, 160.2, 158.1, 140.5, 134.3, 133.6, 132.3, 131.7, 131.5, 129.2, 127.1, 126.7, 123.1,
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2
2
2
2
2
2
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3
3
3
3
3
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5
5
5
6
ꢀ
1
+
1
22.3, 121.8, 113.1; FTꢀIR (KBr) 3413, 1723 cm . HRMS (ESI) m/z [M+H] calcd for
17 3 2
C H13ClN O
: 326.0696, found: 326.0695.
2-(Pyrimidin-2-ylamino)phenyl 2-methylbenzoate 3d. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.54; thick liquid; yield 69% (42 mg); H NMR (400 MHz, CDCl
3
) δ 8.40ꢀ
0
1
2
3
4
5
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8
9
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1
2
3
4
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7
8
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8
.38 (m, 3H), 8.17ꢀ8.15 (m, 1H), 7.51ꢀ7.47 (m, 1H), 7.33ꢀ7.24 (m, 5H), 7.15ꢀ7.11 (m, 1H), 6.71 (t,
13
J = 4.8 Hz, 1H), 2.66 (s, 3H); C NMR (150 MHz, CDCl ) δ 165.3, 160.2, 158.1, 141.9, 141.0,
3
1
3
33.2, 132.2, 131.9, 131.4, 128.1, 126.4, 126.2, 123.3, 122.6, 122.0, 113.0, 22.2; FTꢀIR (neat)
ꢀ1
+
16 3 2
435, 1740 cm . HRMS (ESI) m/z [M+H] calcd for C18H N O : 306.1243, found: 306.1250.
2
-(Pyrimidin-2-ylamino)phenyl 2-acetoxybenzoate 3e. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.42; thick liquid; yield 66% (46 mg); H NMR (400 MHz, CDCl
3
) δ 8.42ꢀ
8.38 (m, 3H), 8.20ꢀ8.17 (m, 1H), 8.67ꢀ7.62 (m, 1H), 7.40ꢀ7.35 (m, 1H), 7.32ꢀ7.28 (m, 2H), 7.23ꢀ
13
7
1
1
.17 (m, 2H), 7.13ꢀ7.08 (m, 1H), 6.72ꢀ6.69 (m, 1H), 2.28 (s, 3H); C NMR (150 MHz, CDCl
3
) δ
70.1, 162.8, 160.1, 158.1, 151.2, 140.3, 135.0, 132.4, 131.8, 129.2, 126.8, 126.5, 124.2, 123.2,
ꢀ1
+
22.6, 121.9, 113.1, 21.2; FTꢀIR (neat) 3435, 1765, 1745 cm . HRMS (ESI) m/z [M+H] calcd for
: 350.1141, found: 350.1124.
19 16 3 4
C H N O
2
-(Pyrimidin-2-ylamino)phenyl 3-chlorobenzoate 3f. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
8.0, 1.2 Hz, 1H), 7.46ꢀ7.42 (m, 1H), 7.33ꢀ7.29 (m, 1H), 7.25ꢀ7.12 (m, 3H), 6.71 (t, J = 4.8 Hz,
f
= 0.48; colorless solid; mp 155ꢀ156 °C; yield 71% (46 mg); H NMR (400
3
) δ 8.38ꢀ8.31 (m, 1H), 8.138ꢀ8.134 (m, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.61 (dd, J =
13
1H); C NMR (150 MHz, CDCl
3
) δ 163.7, 160.2, 158.2, 141.1, 135.0, 134.1, 131.7, 130.9, 130.4,
ꢀ1
1
30.2, 128.5, 126.8, 123.7, 122.56, 122.54, 113.1; FTꢀIR (KBr) 3429, 1740 cm . HRMS (ESI) m/z
+
[
M+H] calcd for C17
H13ClN
3
O
2
: 326.0696, found: 326.0703.
2
-(Pyrimidin-2-ylamino)phenyl 3-nitrobenzoate 3g. Analytical TLC on silica gel, 1:5 ethyl
1
f 3
acetate/hexane R = 0.44; thick liquid; yield 61% (41 mg); H NMR (400 MHz, CDCl ) δ 8.97ꢀ
8
.96 (m, 1H), 8.49ꢀ8.46 (m, 2H), 8.37ꢀ8.35 (m, 2H), 8.28ꢀ8.26 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H),
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7
.36ꢀ7.32 (m, 1H), 7.27ꢀ7.25 (m, 1H), 7.21ꢀ7.15 (m, 2H), 6.72ꢀ6.69 (m, 1H); C NMR (100 MHz,
CDCl ) δ 162.9, 160.2, 158.2, 148.5, 141.2, 135.9, 131.5, 131.0, 130.1, 128.4, 127.1, 125.3, 124.0,
123.0, 122.4, 113.2; FTꢀIR (neat) 3433, 1746, 1531, 1350 cm . HRMS (ESI) m/z [M+H] calcd
: 337.0937, found: 337.0924.
3
ꢀ1
+
13 4 4
for C17H N O
1
1
1
1
1
1
1
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1
2
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2
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7
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9
0
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8
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8
9
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2
3
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5
6
7
8
9
0
2-(Pyrimidin-2-ylamino)phenyl 4-bromobenzoate 3h. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R = 0.46; brown solid; mp 153ꢀ154 °C; yield 67% (49 mg); H NMR (400 MHz,
f
CDCl
3
) δ 8.37ꢀ8.32 (m, 3H), 8.04ꢀ8.01 (m, 2H), 7.65ꢀ7.61 (m, 2H), 7.33ꢀ7.29 (m, 1H), 7.26ꢀ7.23
13
(
m, 2H), 7.15ꢀ7.11 (m, 1H), 6.70 (t, J = 4.8 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ 164.1, 160.1,
1
3
58.1, 141.0, 132.2, 131.8, 131.7, 129.3, 128.0, 126.7, 123.5, 122.5, 122.3, 113.1; FTꢀIR (KBr)
ꢀ1
+
3 2
440, 1740 cm . HRMS (ESI) m/z [M+H] calcd for C17H13BrN O : 370.0191, found: 370.0195.
2
-(Pyrimidin-2-ylamino)phenyl 4-chlorobenzoate 3i. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
CDCl
7.25ꢀ7.23 (m, 1H), 7.15ꢀ7.12 (m, 2H), 6.71 (t, J = 4.8 Hz, 1H); C NMR (150 MHz, CDCl
64.0, 160.1, 158.1, 141.0, 140.6, 131.8, 131.7, 129.2, 127.6, 126.7, 123.6, 122.5, 122.3, 113.1;
f
= 0.48; yellow solid; mp 156ꢀ157 °C; yield 72% (46 mg); H NMR (600 MHz,
3
) δ 8.38ꢀ8.33 (m, 3H), 8.12 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.32ꢀ7.29 (m, 1H),
1
3
3
) δ
1
ꢀ1
+
FTꢀIR (KBr) 3430, 1740 cm . HRMS (ESI) m/z [M+H] calcd for C H ClN O : 326.0696,
1
7
13
3
2
found: 326.0699.
2
-(Pyrimidin-2-ylamino)phenyl 4-fluorobenzoate 3j. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
.20ꢀ7.11 (m, 4H), 6.71 (t, J = 4.8 Hz, 1H); C NMR (150 MHz, CDCl ) δ 167.3 (J = 254.2
f
= 0.52; colorless solid; mp 121ꢀ122 °C; yield 65% (40 mg); H NMR (400
3
) δ 8.38ꢀ8.35 (m, 3H), 8.22ꢀ8.19 (m, 2H), 7.33ꢀ7.29 (m, 1H), 7.25ꢀ7.23 (m, 1H),
1
3
7
3
CꢀF
Hz), 163.9, 160.1, 158.1, 141.0, 133.16 (JCꢀF = 9.4 Hz), 131.7, 126.7, 125.4, 123.5, 122.5, 122.2,
19
ꢀ
1
3
16.2 (JCꢀF = 22.0 Hz), 113.1; F NMR (377 MHz, CDCl ) δ ꢀ103.7; FTꢀIR (KBr) 3419, 1732 cm
1
+
.
HRMS (ESI) m/z [M+H] calcd for C17
H13FN
O
3 2
: 310.0992, found: 310.0998.
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-(Pyrimidin-2-ylamino)phenyl 4-methylbenzoate 3k. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
f
= 0.51; colorless solid; mp 139ꢀ140 °C; yield 73% (44 mg); H NMR (400
3
) δ 8.40ꢀ8.37 (m, 3H), 8.09 (d, J = 8.4 Hz, 2H), 7.31ꢀ7.23 (m, 5H), 7.13ꢀ7.09 (m,
13
1
1
3
H), 6.69 (t, J = 4.8 Hz, 1H), 2.44 (s, 2H); C NMR (150 MHz, CDCl
3
) δ 164.8, 160.1, 158.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
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3
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6
7
8
9
0
45.0, 140.9, 131.8, 130.5, 129.6, 126.4, 126.3, 123.2, 122.6, 121.8, 113.0, 21.9; FTꢀIR (KBr)
ꢀ1
+
450, 1735 cm . HRMS (ESI) m/z [M+H] calcd for C H N O : 306.1243, found: 306.1255.
1
8
16
3
2
2-(Pyrimidin-2-ylamino)phenyl 4-methoxybenzoate 3l. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
.98ꢀ6.95 (m, 2H), 6.69 (t, J = 4.8 Hz, 1H), 3.88 (s, 3H); C NMR (150 MHz, CDCl
164.3, 160.1, 158.1, 140.9, 132.6, 131.9, 126.3, 123.2, 122.6, 121.8, 121.3, 114.1, 113.0, 55.7; FTꢀ
f
= 0.38; colorless solid; mp 125ꢀ126 °C; yield 68% (44 mg); H NMR (400
3
) δ 8.39ꢀ8.36 (m, 3H), 8.15ꢀ8.13 (m, 2H), 7.31ꢀ7.23 (m, 3H), 7.13ꢀ7.09 (m, 1H),
13
6
3
) δ 164.5,
ꢀ1
+
IR (KBr) 3440, 1730 cm . HRMS (ESI) m/z [M+H] calcd for C18
16 3 3
H N O : 322.1192, found:
322.1199.
2-(Pyrimidin-2-ylamino)phenyl 4-(trifluoromethyl)benzoate 3m. Analytical TLC on silica gel,
1
1:5 ethyl acetate/hexane R
f
= 0.52; colorless solid; mp 117ꢀ118 °C; yield 59% (42 mg); H NMR
(400 MHz, CDCl ) δ 8.38ꢀ8.28 (m, 5H), 7.78 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.28ꢀ
3
13
7
.26 (m, 1H), 7.15 (t, J = 7.2 Hz, 2H), 6.71 (t, J = 4.8 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ
163.7, 160.1, 158.2, 141.0, 135.5 (JCꢀF = 32.5 Hz), 132.455, 132.451, 131.6, 130.8, 126.9, 125.95
1
9
(JCꢀF = 3.7 Hz), 124.5 (JCꢀF = 271.0 Hz), 123.7, 122.58, 122.51, 113.2; F NMR (377 MHz,
ꢀ1
+
CDCl
3 13 3 3 2
) δ ꢀ63.2; FTꢀIR (KBr) 3453, 1742 cm . HRMS (ESI) m/z [M+H] calcd for C18H F N O :
360.0960, found: 360.0967.
2-(Pyrimidin-2-ylamino)phenyl [1,1'-biphenyl]-4-carboxylate 3n. Analytical TLC on silica gel,
1
1:5 ethyl acetate/hexane R
f
= 0.43; colorless solid; mp 145ꢀ146 °C; yield 67% (49 mg); H NMR
(400 MHz, CDCl
3
) δ 8.41ꢀ8.38 (m, 3H), 8.27 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.66 (d,
J = 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.44ꢀ7.41 (m, 1H), 7.35ꢀ7.26 (m, 3H), 7.16ꢀ7.13 (m, 1H),
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3
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.70 (t, J = 4.4 Hz, 1H); C NMR (100 MHz, CDCl ) δ 164.7, 160.2, 158.2, 146.8, 140.9, 139.9,
3
131.8, 131.0, 129.2, 128.5, 127.8, 127.58, 127.55, 126.6, 123.4, 122.6, 122.0, 113.1; FTꢀIR (KBr)
ꢀ1
+
3434, 1738, 1728 cm . HRMS (ESI) m/z [M+H] calcd for C23
18 3 2
H N O : 368.1399, found:
368.1392.
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9
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9
0
2-(Pyrimidin-2-ylamino)phenyl 3,4-dimethylbenzoate 3o. Analytical TLC on silica gel, 1:5
1
ethyl acetate/hexane R = 0.48; colorless solid; mp 178ꢀ179 °C; yield 63% (40 mg); H NMR (400
f
MHz, CDCl
3
) δ 8.39ꢀ8.37 (m, 3H), 7.95ꢀ7.91 (m, 2H), 7.31ꢀ7.28 (m, 2H), 7.26ꢀ7.23 (m, 2H),
13
7
.14ꢀ7.10 (m, 1H), 6.70 (t, J = 4.8 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H); C NMR (150 MHz,
3
CDCl ) δ 165.1, 160.1, 158.1, 143.7, 141.0, 137.3, 131.9, 131.4, 130.1, 128.1, 126.6, 126.4, 123.3,
ꢀ1
+
1
22.6, 121.9, 113.0, 20.3, 19.8; FTꢀIR (KBr) 3440, 1728 cm . HRMS (ESI) m/z [M+H] calcd for
C H N O : 320.1399, found: 320.1393.
19
18
3
2
2
-(Pyrimidin-2-ylamino)phenyl 1-naphthoate 3p. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
CDCl
f
= 0.47; colorless solid; mp 111ꢀ112 °C; yield 64% (44 mg); H NMR (400 MHz,
3
) δ 9.04 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 7.2 Hz, 1H), 8.41ꢀ8.35 (m, 3H), 8.11 (d, J = 8.0 Hz,
H), 7.93 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 6.8 Hz, 1H), 7.58ꢀ7.52 (m, 2H), 7.43 (s, 1H), 7.34 (t, J =
1
7
1
1
13
.6 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.67 (t, J = 4.4 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
65.3, 160.2, 158.1, 141.1, 134.9, 134.1, 132.0, 131.6, 128.9, 128.5, 126.7, 126.6, 125.9, 125.3,
ꢀ1
+
24.7, 123.4, 122.7, 122.2, 113.1; FTꢀIR (KBr) 3450, 1733 cm . HRMS (ESI) m/z [M+H] calcd
: 342.1243, found: 342.1246.
16 3 2
for C21H N O
2
-(Pyrimidin-2-ylamino)phenyl acetate 3q. Analytical TLC on silica gel, 1:4 ethyl
1
acetate/hexane R = 0.52; colorless liquid; yield 73% (33 mg); H NMR (400 MHz, CDCl ) δ 8.43
f
3
(d, J = 4.8 Hz, 2H), 8.37ꢀ8.35 (m, 1H), 7.28ꢀ7.23 (m, 1H), 7.16ꢀ7.14 (m, 2H), 7.09ꢀ7.04 (m, 1H),
13
6
.74 (t, J = 4.8 Hz, 1H), 2.35 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 169.0, 160.1, 158.2, 140.7,
ꢀ1
1
31.5, 126.4, 123.2, 122.4, 121.9, 113.1, 21.2; FTꢀIR (neat) 3434, 1767 cm . HRMS (ESI) m/z
+
[
M+H] calcd for C12
H
12
N
3
O
2
: 230.0930, found: 230.0932.
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-(Pyrimidin-2-ylamino)phenyl propionate 3r. Analytical TLC on silica gel, 1:4 ethyl
1
acetate/hexane R
f
= 0.48; colorless liquid; yield 62% (33 mg); H NMR (400 MHz, CDCl
3
) δ 8.41
(d, J = 4.6 Hz, 2H), 8.33ꢀ8.31 (m, 1H), 7.27ꢀ7.22 (m, 2H), 7.16ꢀ7.13 (m, 1H), 7.09ꢀ7.04 (m, 1H),
13
6.73 (t, J = 4.8 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H); C NMR (100 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
) δ 172.5, 160.1, 158.1, 140.8, 131.5, 126.3, 123.2, 122.4, 121.9, 113.0, 27.9, 9.30; FTꢀIR
ꢀ1
+
(neat) 3432, 1764 cm . HRMS (ESI) m/z [M+H] calcd for C H N O : 244.1086, found:
13 14 3 2
244.1110.
2-(Pyrimidin-2-ylamino)phenyl pivalate 3s. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.48; colorless liquid; yield 69% (34 mg); H NMR (400 MHz, CDCl
3
) δ 8.41
(d, J = 4.8 Hz, 2H), 8.27ꢀ8.24 (m, 1H), 7.27ꢀ7.23 (m, 1H), 7.12ꢀ7.06 (m, 2H), 7.00 (s, 1H), 6.72 (t,
13
J = 5.2 Hz, 1H), 1.38 (s, 9H); C NMR (100 MHz, CDCl ) δ 176.6, 160.3, 158.2, 141.4, 131.6,
3
ꢀ1
126.3, 123.5, 122.35, 122.33, 113.0, 39.5, 27.4; FTꢀIR (neat) 3375, 1756 cm . HRMS (ESI) m/z
+
[
M+H] calcd for C15
18
H N
3
O
2
: 272.1399, found: 272.1401.
2-(Pyrimidin-2-ylamino)phenyl (3r,5r,7r)-adamantane-1-carboxylate 3t. Analytical TLC on
1
silica gel, 1:4 ethyl acetate/hexane R
f
= 0.54; colorless liquid; yield 65% (45 mg); H NMR (400
MHz, CDCl ) δ 8.40 (d, J = 4.8 Hz, 2H), 8.27ꢀ8.25 (m, 1H), 7.26ꢀ7.21 (m, 1H), 7.10ꢀ7.04 (m, 3H),
3
13
6
.71 (t, J = 4.8 Hz, 1H), 2.09ꢀ2.06 (m, 9H), 1.76 (s, 6H); C NMR (100 MHz, CDCl
3
) δ 175.6,
160.3, 158.1, 141.2, 131.6, 126.2, 123.4, 122.3, 122.1, 112.9, 41.4, 38.9, 36.5, 28.0; FTꢀIR (neat)
ꢀ1
+
3432, 1748 cm . HRMS (ESI) m/z [M+H] calcd for C21
24 3 2
H N O : 350.1869, found: 350.1887.
2-(Pyrimidin-2-ylamino)phenyl 2-phenylacetate 3u. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R = 0.51; thick liquid; yield 63% (38 mg); H NMR (400 MHz, CDCl ) δ 8.39 (d,
f
3
J = 4.8 Hz, 2H), 8.29ꢀ8.27 (m, 1H), 7.37ꢀ7.34 (m, 4H), 7.32ꢀ7.30 (m, 1H), 7.25ꢀ7.21 (m, 2H),
13
7.12ꢀ7.09 (m, 1H), 7.06ꢀ7.02 (m, 1H), 6.71 (t, J = 4.8 Hz, 1H), 3.89 (s, 2H); C NMR (150 MHz,
CDCl
3
) δ 169.6, 160.1, 158.1, 140.8, 133.3, 131.4, 129.4, 129.1, 127.6, 126.4, 123.2, 122.2, 122.0,
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ꢀ
1
+
1
13.0, 41.5; FTꢀIR (neat) 3427, 1760 cm . HRMS (ESI) m/z [M+H] calcd for C H N O :
18 16 3 2
306.1243, found: 306.1257.
2
1
8
2
-(Pyrimidin-2-ylamino)phenyl 2-(4-methoxyphenyl)acetate 3v. Analytical TLC on silica gel,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
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4
4
4
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5
5
5
5
5
5
6
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
:5 ethyl acetate/hexane R
f 3
= 0.51; thick liquid; yield 66% (44 mg); H NMR (400 MHz, CDCl ) δ
.39 (d, J = 4.8 Hz, 2H), 8.31ꢀ8.29 (m, 1H), 7.31ꢀ7.27 (m, 2H), 7.25ꢀ7.21 (m, 1H), 7.12ꢀ7.08 (m,
1
3
H), 7.05ꢀ7.01 (m, 1H), 6.91ꢀ6.88 (m, 2H), 6.72 (t, J = 4.8 Hz, 1H), 3.83 (s, 2H), 3.80 (s, 3H); C
NMR (100 MHz, CDCl
122.2, 121.8, 114.5, 113.1, 55.4, 40.7; FTꢀIR (neat) 3434, 1758 cm . HRMS (ESI) m/z [M+H]
calcd for C19 : 336.1348, found: 336.1373.
3
) δ 169.9, 160.1, 159.1, 158.1, 140.7, 131.5, 130.4, 126.4, 125.3, 123.1,
ꢀ1
+
18 3 3
H N O
2-(Pyrimidin-2-ylamino)phenyl 2-(naphthalen-1-yl)acetate 3w. Analytical TLC on silica gel,
1
1:4 ethyl acetate/hexane R
f
= 0.46; colorless liquid; yield 67% (47 mg); H NMR (400 MHz,
CDCl
3
) δ 8.34 (d, J = 4.8 Hz, 2H), 8.24ꢀ8.21 (m, 1H), 8.08ꢀ8.06 (m, 1H), 7.88ꢀ7.86 (m, 1H), 7.82
(
d, J = 8.0 Hz, 1H), 7.56ꢀ7.42 (m, 4H), 7.23ꢀ7.18 (m, 1H), 7.09ꢀ7.05 (m, 2H), 7.02ꢀ6.98 (m, 1H),
13
6
.68ꢀ6.65 (m, 1H), 4.32 (s, 2H); C NMR (100 MHz, CDCl
3
) δ 169.6, 160.1, 158.0, 141.0, 134.1,
1
32.1, 131.4, 129.8, 129.0, 128.6, 128.3, 126.9, 126.4, 126.0, 125.7, 123.6, 123.2, 122.2, 122.1,
ꢀ1
+
18 3 2
113.0, 39.3; FTꢀIR (neat) 3411, 1761 cm . HRMS (ESI) m/z [M+H] calcd for C22H N O :
356.1399, found: 356.1408.
2-(Pyrimidin-2-ylamino)phenyl thiophene-2-carboxylate 3x. Analytical TLC on silica gel, 1:5
1
ethyl acetate/hexane R
f
= 0.47; colorless solid; mp 137ꢀ138 °C; yield 62% (37 mg); H NMR (400
MHz, CDCl ) δ 8.39ꢀ8.36 (m, 3H), 7.98 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 4.4 Hz, 1H), 7.32ꢀ7.26
3
13
(
m, 3H), 7.17 (t, J = 4.4 Hz, 1H), 7.13ꢀ7.09 (m, 1H), 6.71 (t, J = 4.8 Hz, 1H); C NMR (150
MHz, CDCl
13.1; FTꢀIR (KBr) 3403, 1717 cm . HRMS (ESI) m/z [M+H] calcd for C15
found: 298.0659.
3
) δ 160.1, 158.1, 140.5, 135.2, 134.1, 132.3, 131.8, 128.4, 126.6, 123.2, 122.5, 121.9,
ꢀ1
+
1
12 3 2
H N O S: 298.0650,
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-(Pyrimidin-2-ylamino)phenyl furan-2-carboxylate 3y. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
f
= 0.50; colorless solid; mp 148ꢀ149 °C; yield 65% (36 mg); H NMR (400
3
) δ 8.41ꢀ8.39 (m, 3H), 7.67 (s, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.32ꢀ7.26 (m, 3H), 7.10
1
3
(t, J = 7.6 Hz, 1H), 6.72 (t, J = 4.8 Hz, 1H), 6.59 (s, 1H); C NMR (150 MHz, CDCl
3
) δ 160.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
158.1, 156.4, 147.6, 143.6, 139.9, 131.8, 126.7, 123.1, 122.4, 121.8, 120.2, 113.1, 112.5; FTꢀIR
ꢀ1
+
(
KBr) 3411, 1736 cm . HRMS (ESI) m/z [M+H] calcd for C H N O : 282.0879, found:
15 12 3 3
282.0890.
2-(Pyrimidin-2-ylamino)phenyl cinnamate 3aa. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
MHz, CDCl
4H), 7.30ꢀ7.23 (m, 2H), 7.12ꢀ7.08 (m, 1H), 6.72 (t, J = 4.8 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H); C
NMR (150 MHz, CDCl ) δ 165.0, 160.1, 158.1, 147.6, 140.5, 134.1, 131.7, 131.0, 129.1, 128.5,
26.3, 123.1, 122.4, 121.7, 116.7, 113.0; FTꢀIR (KBr) 3452, 1737 cm . HRMS (ESI) m/z [M+H]
calcd for C19 : 318.1243, found: 318.1247.
-(Pyrimidin-2-ylamino)phenyl (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylate 3ab. Analytical TLC
f
= 0.42; colorless solid; mp 112ꢀ113 °C; yield 68% (43 mg); H NMR (400
3
) δ 8.41ꢀ8.38 (m, 3H), 7.90 (d, J = 16.0 Hz, 1H), 7.58ꢀ7.56 (m, 2H), 7.45ꢀ7.41 (m,
1
3
3
ꢀ1
+
1
16 3 2
H N O
2
on silica gel, 1:5 ethyl acetate/hexane R = 0.38; colorless solid; mp 169ꢀ170 °C; yield 65% (47
f
1
mg); H NMR (400 MHz, CDCl
3
) δ 8.41 (s, 3H), 7.80 (d, J = 16.0 Hz, 1H), 7.31ꢀ7.20 (m, 3H),
7.08ꢀ7.04 (m, 3H), 6.84 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 6.49 (d, J = 15.6 Hz, 1H), 6.03 (s, 2H);
1
3
C NMR (150 MHz, CDCl
3
) δ 165.2, 160.1, 158.1, 150.3, 148.6, 147.3, 140.5, 131.7, 128.6,
ꢀ
126.3, 125.3, 123.0, 122.4, 121.6, 114.5, 113.0, 108.8, 106.8, 101.9; FTꢀIR (KBr) 3439, 1745 cm
1
+
.
HRMS (ESI) m/z [M+H] calcd for C H N O : 362.1141, found: 362.1153.
20 16 3 4
2-(Pyrimidin-2-ylamino)phenyl but-2-enoate 3ac. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.50; thick liquid; dr = 5:1; yield 63% (32 mg); H NMR (400 MHz, CDCl
3
) δ
8.41ꢀ8.34 (m, 3H), 7.53 (s, 1.04H), 7.27ꢀ7.15 (m, 3.21H), 7.07 (t, J = 7.6 Hz, 1.06H), 6.73 (s,
1.08H), 6.10 (d, J = 15.6 Hz, 1.02H), 5.88 (d, J = 15.2 Hz, 0.21H), 1.96 (d, J = 6.4 Hz, 2.91H),
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7
8
9
1
3
1
.91 (d, J = 6.8 Hz, 0.59H); C NMR (150 MHz, CDCl ) δ 170.2, 164.4, 160.0, 158.1, 148.0,
3
145.8, 140.6, 131.6, 126.2, 123.1, 123.0, 122.4, 121.8, 121.7, 112.9, 18.4, 18.2; FTꢀIR (neat)
ꢀ1
+
3437, 1736 cm . HRMS (ESI) m/z [M+H] calcd for C14
H
14
N
3
O
2
: 256.1086, found: 256.1099.
2
-(Pyrimidin-2-ylamino)phenyl methacrylate 3ad. Analytical TLC on silica gel, 1:4 ethyl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
f 3
acetate/hexane R = 0.46; colorless liquid; yield 69% (35 mg); H NMR (400 MHz, CDCl ) δ 8.41
(
d, J = 4.8 Hz, 2H), 8.35ꢀ8.32 (m, 1H), 7.28ꢀ7.24 (m, 1H), 7.18ꢀ7.16 (m, 2H), 7.10ꢀ7.06 (m, 1H),
13
6
.72 (t, J = 4.8 Hz, 1H), 6.378ꢀ6.372 (m, 1H), 5.79ꢀ5.77 (m, 1H), 2.06 (t, J = 1.2 Hz, 3H);
C
NMR (100 MHz, CDCl
121.9, 113.1, 18.6; FTꢀIR (neat) 3434, 1738 cm . HRMS (ESI) m/z [M+H] calcd for C14
56.1086, found: 256.1107.
3
) δ 165.4, 160.1, 158.1, 140.9, 135.6. 131.6, 128.1, 126.4, 123.3, 122.4,
ꢀ1
+
14 3 2
H N O :
2
3-Methyl-2-(pyrimidin-2-ylamino)phenyl benzoate 3ae. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.52; thick liquid; yield 65% (39 mg); H NMR (400 MHz, CDCl
3
) δ 8.24 (d,
J = 4.4 Hz, 2H), 7.97 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.29ꢀ
7
3
1
.25 (m, 1H), 7.23ꢀ7.21 (m, 1H), 7.18ꢀ7.16 (m, 1H), 6.60 (s, 1H), 6.54 (t, J = 4.4 Hz, 1H), 2.32 (s,
13
H); C NMR (100 MHz, CDCl
28.6, 128.4, 127.5, 120.6, 112.1, 18.6; FTꢀIR (neat) 3436, 1738 cm . HRMS (ESI) m/z [M+H]
: 306.1243, found: 306.1246.
3
) δ 164.9, 161.4, 158.3, 147.5, 138.1, 133.6, 130.2, 129.6, 129.4,
ꢀ1
+
16 3 2
calcd for C18H N O
5
-Bromo-2-(pyrimidin-2-ylamino)phenyl benzoate 3af. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
CDCl
f
= 0.46; colorless solid; mp 132ꢀ133 °C; yield 63% (46 mg); H NMR (400 MHz,
3
) δ 8.38ꢀ8.35 (m, 3H), 8.19 (d, J = 6.8 Hz, 2H), 7.66ꢀ7.65 (m, 1H), 7.54ꢀ7.52 (m, 2H), 7.42ꢀ
13
7
1
1
.40 (m, 2H), 7.19 (s, 1H), 6.74 (s, 1H); C NMR (150 MHz, CDCl ) δ 164.4, 159.8, 158.2,
3
40.9, 134.4, 131.2, 130.5, 139.5, 129.0, 128.6, 125.7, 122.7, 114.6, 113.5; FTꢀIR (KBr) 3430,
ꢀ1
+
3 2
746 cm . HRMS (ESI) m/z [M+H] calcd for C17H13BrN O : 370.0191, found: 370.0193.
5
-Chloro-2-(pyrimidin-2-ylamino)phenyl benzoate 3ag. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.45; colorless solid; mp 139ꢀ140 °C; yield 62% (40 mg); H NMR (400
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2
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3
3
3
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5
5
5
5
5
5
5
5
5
6
MHz, CDCl ) δ 8.39ꢀ8.38 (m, 3H), 8.19 (d, J = 7.6 Hz, 2H), 7.68ꢀ7.64 (m, 1H), 7.52 (t, J = 7.6
3
1
3
Hz, 2H), 7.29ꢀ722 (m, 3H), 6.73 (t, J = 4.8 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ 164.4, 159.9,
158.1, 140.9, 134.3, 130.7, 130.5, 129.0, 128.7, 127.6, 126.6, 122.9, 122.5, 113.4; FTꢀIR (KBr)
ꢀ1
+
3
3 2
436, 1744 cm . HRMS (ESI) m/z [M+H] calcd for C17H13ClN O : 326.0696, found: 326.0696.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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8
9
0
1
2
3
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8
9
0
5-Fluoro-2-(pyrimidin-2-ylamino)phenyl benzoate 3ah. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R = 0.47; colorless solid; mp 106ꢀ107 °C; yield 57% (35 mg); H NMR (400
f
MHz, CDCl
3
) δ 8.36 (d, J = 4.8 Hz, 2H), 8.22ꢀ8.19 (m, 1H), 8.16ꢀ8.14 (m, 2H), 7.64 (t, J = 7.6
13
Hz, 1H), 7.51ꢀ7.47 (m, 2H), 7.17 (br s, 1H), 7.07ꢀ7.01 (m, 2H), 6.69 (t, J = 4.8 Hz, 1H); C NMR
(150 MHz, CDCl
3
) δ 164.4, 160.3, 159.3 (JCꢀF = 242.8 Hz), 158.2, 142.2 (JCꢀF = 10.8 Hz), 134.2,
130.5, 128.9, 128.8, 128.0, 123.9 (JCꢀF = 8.7 Hz), 113.3 (JCꢀF = 21.7 Hz), 113.0, 110.6 (JCꢀF = 25.5
1
9
ꢀ1
Hz); F NMR (377 MHz, CDCl ) δ ꢀ117.2; FTꢀIR (KBr) 3442, 1741 cm . HRMS (ESI) m/z
3
+
[
M+H] calcd for C17
H13FN
3
O
2
: 310.0992, found: 310.0996.
5-Iodo-2-(pyrimidin-2-ylamino)phenyl benzoate 3ai. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.49; brown solid; mp 147ꢀ148 °C; yield 67% (56 mg); H NMR (400 MHz,
CDCl
3
) δ 8.40 (d, J = 4.4 Hz, 2H), 8.26 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 7.6 Hz, 2H), 7.67 (t, J =
13
7
.2 Hz, 1H), 7.60ꢀ7.57 (m, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.18 (s, 1H), 6.74 (t, J = 4.4 Hz, 1H); C
NMR (150 MHz, CDCl
28.6, 123.0, 113.5, 84.3; FTꢀIR (KBr) 3427, 1749 cm . HRMS (ESI) m/z [M+H] calcd for
: 418.0052, found: 418.0059.
3
) δ 164.5, 159.8, 158.1, 140.8, 135.5, 134.3, 132.0, 131.3, 130.5, 129.0,
ꢀ1
+
1
17 3 2
C H13IN O
5-Methyl-2-(pyrimidin-2-ylamino)phenyl benzoate 3aj. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R = 0.51; colorless solid; mp 121ꢀ122 °C; yield 66% (40 mg); H NMR (400
f
3
MHz, CDCl ) δ 8.35 (d, J = 4.8 Hz, 2H), 8.17ꢀ8.09 (m, 3H), 7.63 (t, J = 7.2 Hz, 1H), 7.49 (t, J =
13
7
.6 Hz, 2H), 7.12ꢀ7.08 (m, 3H), 6.66 (t, J = 4.8 Hz, 1H), 2.36 (s, 3H); C NMR (150 MHz,
CDCl
3
) δ 164.9, 160.4, 158.1, 141.5, 134.09, 134.01, 130.4, 129.2, 129.0, 128.8, 127.2, 123.1,
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ꢀ
1
+
1
22.9, 112.7, 21.0; FTꢀIR (KBr) 3449, 1732 cm . HRMS (ESI) m/z [M+H] calcd for
18 16 3 2
C H N O
: 306.1243, found: 306.1244.
2
-(Pyrimidin-2-ylamino)-5-(trifluoromethyl)phenyl benzoate 3ak. Analytical TLC on silica
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
gel, 1:5 ethyl acetate/hexane R
f
= 0.46; thick liquid; yield 52% (37 mg); H NMR (400 MHz,
CDCl ) δ 8.75 (d, J = 8.4 Hz, 1H), 8.46ꢀ8.44 (m, 2H), 8.23ꢀ8.21 (m, 2H), 7.71ꢀ7.66 (m, 1H), 7.58ꢀ
3
1
3
7
.53 (m, 4H), 7.45 (s, 1H), 6.81 (t, J = 4.8 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ 164.5, 159.5,
1
58.2, 139.2, 135.2, 134.5, 130.5, 129.0, 128.5, 124.9 (JCꢀF = 269.8 Hz), 124.3 (JCꢀF = 33.0 Hz),
19
3
123.75 (JCꢀF = 3.7 Hz), 120.4, 119.98 (JCꢀF = 3.9 Hz), 118.5, 114.1; F NMR (377 MHz, CDCl ) δ
ꢀ1
+
ꢀ
13 3 3 2
61.7; FTꢀIR (neat) 3433, 1746 cm . HRMS (ESI) m/z [M+H] calcd for C18H F N O :
360.0960, found: 360.0964.
4
-Chloro-2-(pyrimidin-2-ylamino)phenyl benzoate 3al. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
CDCl
f
= 0.47; colorless solid; mp 137ꢀ138 °C; yield 71% (46 mg); H NMR (400 MHz,
3
) δ 8.65 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 4.8 Hz, 2H), 8.21ꢀ8.19 (m, 2H), 7.67 (t, J = 7.6 Hz,
H), 7.52 (t, J = 8.0 Hz, 2H), 7.30 (br s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.07ꢀ7.04 (m, 1H), 6.77 (t, J
1
13
=
4.8 Hz, 1H); C NMR (150 MHz, CDCl ) δ 164.6, 159.6, 158.1, 138.4, 134.3, 133.0, 131.8,
3
ꢀ1
130.5, 129.0, 128.8, 123.3, 122.4, 120.7, 113.7; FTꢀIR (KBr) 3435, 1750 cm . HRMS (ESI) m/z
+
[M+H] calcd for C17
H13ClN
3
O
2
: 326.0696, found: 326.0697.
2-(Pyridin-2-ylamino)phenyl benzoate 3aq. Analytical TLC on silica gel, 1:5 ethyl
1
acetate/hexane R
f
= 0.48; thick liquid; yield 63% (37 mg); H NMR (600 MHz, CDCl
3
) δ 8.15ꢀ
8
7
.13 (m, 3H), 7.77ꢀ7.76 (m, 1H), 7.64ꢀ7.61 (m, 1H), 7.49ꢀ7.45 (m, 3H), 7.28ꢀ7.26 (m, 2H), 7.15ꢀ
13
.12 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.73ꢀ6.71 (m, 1H), 6.50 (br s, 1H); C NMR (150 MHz,
CDCl
22.4, 115.6, 109.0; FTꢀIR (neat) 3444, 1740 cm . HRMS (ESI) m/z [M+H] calcd for
: 291.1134, found: 291.1122.
3
) δ 164.8, 155.8, 148.4, 142.6, 137.9, 134.0, 133.1, 130.4, 129.1, 128.8, 126.8, 123.9, 123.2,
ꢀ1
+
1
18 15 2 2
C H N O
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6
Gram-scale Synthesis of 3i. NꢀPhenylpyrimidinꢀ2ꢀamine 1a (513 mg, 3 mmol), pꢀchlorobenzoic
acid 2i (562 mg, 3.6 mmol), [RuCl
and Ag CO (1.65 g, 6 mmol) were stirred in 1,2ꢀdichloroethane (15 mL) at 110 °C for 16 h under
. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (50
2 2 6
(pꢀcymene)] (92 mg, 5 mol %), AgSbF (206 mg, 20 mol %)
2
3
N
2
0
1
2
3
4
5
6
7
8
9
0
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2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
mL) and passed through a short pad of celite using dichloromethane (100 mL). Evaporation of the
solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate
and hexane as an eluent to yield 3i in 68% yield (663 mg).
Competition Experiment using Acids 2j and 2k (Scheme 6a). NꢀPhenylpyrimidinꢀ2ꢀamine 1a
2 2
(17 mg, 0.1 mmol), 2j (14 mg, 0.1 mmol), 2k (13.6 mg, 0.1 mmol), [RuCl (pꢀcymene)] (3.0 mg,
5
.0 mol %), AgSbF
6
(7.0 mg, 20 mol %), Ag
2
CO
3
(55.2 mg, 0.2 mmol) and 1,2ꢀdichloroethane
o
(1.0 mL) were subjected to the reaction conditions described in the general procedure (110 C) for
12 h to produce 3j and 3k in 6 and 41% yields, respectively.
Competition Experiment using Acids 2a and 2aa (Scheme 6b). The reaction of Nꢀ
phenylpyrimidinꢀ2ꢀamine 1a (17 mg, 0.1 mmol) was performed with 2a (12.2 mg, 0.1 mmol) and
2aa (14.8 mg, 0.1 mmol) in the presence of [RuCl
2 2 6
(pꢀcymene)] (3.0 mg, 5.0 mol %), AgSbF (7.0
mg, 20 mol %) and Ag CO (55.2 mg, 0.2 mmol) for 12 h in 1,2ꢀdichloroethane (1.0 mL) as
2
3
described above to give 3a and 3aa in 27 and 38% yields, respectively.
Competition Experiment using N-Aryl-2-pyrimidines 1e and 1g (Scheme 6c). The reaction of
1
e (18.9 mg, 0.1 mmol) and 1g (18.5 mg, 0.1 mmol) with benzoic acid 2a (12.2 mg, 0.1 mmol)
was performed in the presence of [RuCl (pꢀcymene)] (3.0 mg, 5.0 mol %), AgSbF (7.0 mg, 20
mol %) and Ag CO (55.2 mg, 0.2 mmol) in 1,2ꢀdichloroethane (1.0 mL) as described above for
2
2
6
2
3
12 h to afford 3ah and 3aj in 24 and 33% yields, respectively.
H/D Exchange with D O. NꢀPhenylpyrimidinꢀ2ꢀamine 1a (34.2 mg, 0.2 mmol), benzoic acid 2a
(29.2 mg, 0.24 mmol), [RuCl (pꢀcymene)] (6.0 mg, 5.0 mol %), AgSbF (13.7 mg, 20 mol %)
Cl) :D O (1.8:0.2) under
2
2
2
6
and Ag
2
CO
3
(110 mg, 0.4 mmol) were stirred at 110 °C for 15 h in (CH
2
2
2
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N . The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL)
2
and passed through a short pad of celite using dichloromethane (25 mL). Drying (Na
evaporation of the solvent gave a residue that was purified using column chromatography on silica
gel to yield [D ]ꢀ1a in 12% (4 mg) and [D ]ꢀ3a in 65% (38 mg) yields.
2 4
SO ) and
n
n
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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Preparation of [D
cymene)] (6 mg, 5.0 mol %), AgSbF
Ag CO (110 mg, 0.4 mmol) were stirred at 110 °C for 3 h in (CH
The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL) and
passed through a short pad of celite using dichloromethane (50 mL). Drying (Na SO ) and
2
]ꢀ1a. NꢀPhenylpyrimidinꢀ2ꢀamine 1a (34.2 mg, 0.2 mmol), [RuCl
(13.7 mg, 20 mol %), AcOH (5.0 L, 50.0 mol %) and
Cl) :D O (1.8:0.2) under N
2
(pꢀ
2
6
ꢀ
2
3
2
2
2
2
.
2
4
evaporation of the solvent gave a residue that was purified using column chromatography on silica
gel to yield [D ]ꢀ1a in 57% yield (19 mg) as a colorless solid. Deuterium incorporation in the
2
1
orthoꢀposition was found to be 96% as estimated from 600 MHz H NMR.
Intermolecular Kinetic Isotope Experiment. NꢀPhenylpyrimidinꢀ2ꢀamine 1a (17 mg, 0.1
2
mmol), [D ]-1a (17.3 mg, 0.1 mmol), 2i (18.8 mg, 0.12 mmol), [RuCl
2 2
(pꢀcymene)] (3.0 mg, 5.0
mol %), AgSbF
6
(7.0 mg, 20 mol %) and Ag CO (55.2 mg, 0.2 mmol) were stirred in 1,2ꢀ
2
3
dichloroethane (1.0 mL) at 110 °C for 3 h under N . The resulting mixture was cooled to room
2
temperature, diluted with dichloromethane (10 mL) and passed through a short pad of celite using
dichloromethane (25 mL). Evaporation of the solvent gave a residue that was purified on silica gel
column chromatography using ethyl acetate and hexane as an eluent to afford a mixture of 3i and
1
[
D
n
]ꢀ3i as a colorless solid. The k
H
/k
D
was found to be 5.25, based on 600 MHz H NMR.
9d
Acid Hydrolysis of 3i. 2ꢀ(Pyrimidinꢀ2ꢀylamino)phenylꢀ4ꢀchlorobenzoate 3i (65 mg, 0.2 mmol)
and aqueous HCl (37%, 1 mL) were stirred at 150 °C for 3 h in microwave reactor sealed vial. The
reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL). The
resultant solution was treated with saturated NaHCO
3
until the pH was adjusted to 7. The aqueous
SO ) and evaporation of the solvent
layer was extracted with ethyl acetate (3 × 5 mL). Drying (Na
2
4
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gave a residue, which was purified on silica gel column chromatography to afford 2ꢀaminophenol
4 as a brown solid in 71% yield (15 mg). Analytical TLC on silica gel, 1:1 ethyl acetate/hexane R
f
1
= 0.48; mp 180ꢀ182 °C; H NMR (400 MHz, DMSOꢀd
6
) δ 8.92 (br s, 1H), 6.64ꢀ6.62 (m, 1H),
1
3
6
1
.58ꢀ6.51 (m, 2H), 6.40ꢀ6.36 (m, 1H), 4.44 (br s, 2H); C NMR (100 MHz, DMSOꢀd
6
) δ 144.4,
0
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ꢀ1
+
36.9, 119.9, 116.9, 114.9, 114.8; FTꢀIR (KBr) 3466, 3376, 3305 cm . HRMS (ESI) m/z [M+H]
calcd for C H NO: 110.0606, found: 110.0607.
6
8
ASSOCIATED CONTENT
Supporting Information
1
13
XꢀRay structure and NMR ( H and C) spectra of the products are available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*tpunni@iitg.ernet.in
ACKNOWLEDGMENT
We thank Science and Engineering Research Board (EMRꢀ2015ꢀ43) and Council of Scientific and
Industrial Research (02(0088)ꢀ12ꢀEMRꢀII) for the generous financial support. We also thank
Central Instrumental Facility, Indian Institute of Technology Guwahati for NMR and DSTꢀFIST
for HRMS and Xꢀray analysis.
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