Cobalt-Catalyzed Biaryl Couplings via C-F Bond Activation in the Absence of Phosphine or NHC Ligands

Article abstract of DOI:10.1021/acs.joc.6b02354

A highly general and selective Co-catalyzed biaryl coupling through C-F cleavage under phosphine or NHC-free conditions was described. A broad range of aryl fluorides including unactivated fluorides as well as those with sensitive functionalities could couple with various Ti(OEt)₄-mediated aryl Grignard reagents with high selectivity under the catalysis of CoCl₂/DMPU. Importantly, selective C-F bond activation couplings between two types of fluorines (difluorinated aromatics and on two different coupling partners) and in the presence of C-Cl or C-Br bonds could also be achieved.

Full text of DOI:10.1021/acs.joc.6b02354

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Featured Article
Cobalt-catalyzed Biaryl Couplings via C#F Bond
Activation in the Absence of Phosphine or NHC Ligands
Juan Wei, Kun-ming Liu, and Xin-Fang Duan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02354 • Publication Date (Web): 25 Oct 2016
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Page 1 of 27
The Journal of Organic Chemistry
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Cobaltꢀcatalyzed Biaryl Couplings via C－F Bond
Activation in the Absence of Phosphine or NHC Ligands
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Juan Wei, KunꢀMing Liu, and XinꢀFang Duan*
College of Chemistry, Beijing Normal University, Beijing, 100875, China
xinfangduan@vip.163.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
O
CF3
O
HO
Phosphine
or NHC free !
77%
EtOOC
73%
Ar
F
7
.5 mol% CoCl2
unactivated fluoride
high chemoselectivity
15 mol% DMPU
1.0 equiv
6
0 mol% Ti(OEt)4
O
+
NH2
HOOC
HO
F
THF, 50 o
C
ArMgX
.5 equiv
1
F
46 examples
up to 94% yield
X = Cl, 70%
X = Br, 68%
diflunisal 85%
X
selective C-F cleavage in
the presence of C-Cl or C-Br
selective C-F cleavage between
two types of C-F bonds
ABSTRACT. A highly general and selective Coꢀcatalyzed biaryl coupling through C－F cleavage under
phosphine or NHC free conditions was described. A broad range of aryl fluorides including unactivated
fluorides as well as those with sensitive functionalities could couple with various Ti(OEt) ꢀmediated
4
aryl Grignard reagents with high selectivity under the catalysis of CoCl /DMPU. Importantly, selective
2
C−F bond activation couplings between two types of fluorines (difluorinated aromatics and on two
different coupling partners) and in the presence of C−Cl or C−Br bonds could also be achieved.
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1
. INTRODUCTION
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Fluorineꢀcontaining organic compounds have become increasingly important in a wide range of areas
1
such as medicine, agrochemistry, catalysis, materials science and biochemistry. The development of
2
undocumented reactions for functionalization of carbonꢀfluorine bonds are of high significance
because: a) the reactions will help in understanding of the activation of highly stable bonds and in
searching for highly reactive catalyst systems; b) selective carbonꢀcarbon formation couplings via C−F
cleavage of polyfluorinated molecules also provide an attractive way to make new fluorineꢀcontaining
0
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compounds; and c) the conversions of fluorides via C−F cleavage to versatile building blocks such as
3
organoborons are a stimulating way to derivatize the organoflorides. In this context, numerous
4
transition metalꢀcatalyzed crossꢀcouplings of fluorinated compounds with Grignard reagents,
5
6
organozinc reagents and organoboron reagents have been developed recently. Similar to the coupling
reactions of aryl iodides, bromides, chlorides, and triflates, the catalysts in known couplings of C−F
2
cleavage are mainly dominated by palladium and nickel complexes. Great efforts have been devoted to
developing or
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The Journal of Organic Chemistry
Scheme 1 Two means to activate CꢀF bonds in the reported Pd/Niꢀcatalyzed couplings and Coꢀcatalyzed
1
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7
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9
1
1
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5
6
C－F activation biaryl couplings in this work
4
c,4e,5a,6c
4a,6b
identifying highly effective phosphine
or NHC
ligands for Pd or Ni catalyst to activate the
0
1
2
3
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5
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0
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0
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9
0
highly stable C−F bonds of aryl fluorides (Scheme 1A). On the other hand, a series of functional groups
6a
6c
5b
6d
6e
such as 2(4)ꢀNO , 2ꢀpyridyl, 2ꢀC=NR, 2ꢀC(R)=O, 2ꢀoxazoline etc. can usually function as an
2
activating group to help to split the C−F bonds in the related Pd or Niꢀcatalyzed coupling reactions
(Scheme 1A). Up to now the reports on Pd or Niꢀcatalyzed biaryl couplings between aryl fluorides and
aryl metal reagents without using the aboveꢀmentioned two means (activating groups and
phosphine/NHC ligands) were rare.
Recently various Coꢀcatalyzed crossꢀcoupling reactions have been intensely and extensively
7
investigated. Although Coꢀmediated C−F bond activation in a stoichiometric manner has been
8
reported, there is only one report concerning the Coꢀcatalyzed crossꢀcouplings of aryl fluorides with
aryl metal reagents, where an ortho carbonyl group in the fluorides functioned as a key activating
9
group. To the best of our knowledge, there has been no report on Coꢀcatalyzed biaryl couplings
between aryl fluorides and aryl metal reagents in the absence of both activating groups and
phosphine/NHC ligands to date. Herein, we report a general and facile Coꢀcatalyzed crossꢀcouplings of
aryl fluorides with aryl Grignard reagents in the presence of substoichiometric Ti(OEt) (40 mol % to
4
ArMgX) (Scheme 1B). Salient features of this C−F bond activation reaction lie in the elimination of the
need for phosphine/NHC ligands or activating groups. Importantly, selective C−F bond cleavage
couplings in the presence of C−Cl or C−Br bonds and between two types of fluorines (difluorinated
aromatics and on two different coupling partners) could also be achieved.
2
. RESULTS AND DISSCUSSION
We started our study with the optimization of reaction conditions using the mode cross coupling
reaction of ethyl 2ꢀfluorobenzoate (1a) with PhMgBr (2a). The results were outlined in Table 1. It can
be seen from Table 1 that the Pdꢀcatalyzed reactions hardly gave the desired product while the Niꢀ
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catalyzed reaction could occur in a 32% yield (Entries 1ꢀ3). The reactions catalyzed by CoCl /PR (R =
2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
2
2
2
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5
5
5
5
5
5
5
5
5
5
6
1
0a
Me, nꢀBu and Cy) proceeded well to afford the product in over 80% yields (Entries 10ꢀ12). With no
a
Table 1 Optimization studies
CO Et
CO
2
Et
2
Catalyst (7.5 mol%)
Ligand
F + PhMgBr
Ti(OEt)4
Ph
+
Solvent
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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9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
a
3aa
1
a
1.5 equiv
n equiv
1.0 equiv
n
Yield
(%)
b
o
Entry
Catalyst/Ligand
NiCl /PBu
(equiv)
Solvent
THF
T ( C)
1
0.6
0.6
2
3
5
5
0
0
32
2
3
4
Pd(PPh3)4
THF
trace
trace
12
PdCl /PBu
0.6
0.6
THF
THF
50
50
2
3
CoCl2
5
6
7
8
9
1
1
CoCl /isoquinoline
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
THF
THF
THF
THF
THF
THF
THF
THF
50
50
50
50
50
50
50
50
7
2
CoCl /bipyridine
19
25
32
58
84
80
82
2
CoCl /tmeda
2
CoCl /PPh
2
3
CoCl /dppp
2
0
1
CoCl /PBu
2
3
CoCl /PMe
2
3
12
13
CoCl /PCy
2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
3
c
c
0.6
0.6
0.6
0.6
0.6
0.6
0
DMPU/THF
NMP/THF
50
83
21
35
29
48
78
11
30
82
67
85
1
1
1
1
1
1
4
5
6
7
8
9
50
DMPU/ether
DMPU/PhMe
DMPU/THF
DMPU/THF
DMPU/THF
DMPU/THF
DMPU/THF
DMPU/THF
50
50
25
reflux
50
d
d
20
0.3
0.9
1.5
0.6
50
2
1
50
22
50
e
2
3
DMPU/THF
50
a
b
The reaction was carried out on a 2 mmol scale. Unless indicated otherwise, the catalyst metals were charged in 7.5
mol % with 15 mol % (monodentate), 7.5 mol % (bidentate) ligand or 15 mol % TMEDA, DMPU and NMP.
c
d
Increasing the amount of DMPU and NMP from 15 mol% to 100 mol% gave the similar results. In these reactions,
e
the products of the addition of PhMgBr to the ester group were found. The mixture of 1.5 equiv of PhMgBr with 0.6
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The Journal of Organic Chemistry
o
equiv of Ti(OEt) was added in two portions, 1.0 equiv was added at first, after twoꢀhour reaction at 50 C, the
4
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5
6
7
8
9
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1
1
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1
1
1
1
1
1
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2
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2
2
2
2
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4
4
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5
5
5
5
5
5
5
5
5
5
6
remaining 0.5 equiv was added.
or other selected ligands, the Coꢀcatalyzed reactions gave unsatisfactory results (Entries 4ꢀ9). To our
delight, 7.5 mol% CoCl2 with 15 mol% of DMPU (1,3ꢀdimethylꢀ3,4,5,6ꢀtetrahydroꢀ2(1H)ꢀ
1
0b,c
pyrimidinone)
could catalyze the reaction equally well with those using PR ; whereas NMP as a coꢀ
3
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
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6
7
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9
0
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3
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5
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9
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2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
solvent gave a very low yield (Entries 13 and 14). A transitionꢀmetalꢀcatalyzed C−F activation reaction
in the absence of NHC or phosphine ligands is noteworthy, therefore we focused on further optimization
of the reaction conditions using CoCl /DMPU. Other solvents such as ether, toluene gave disappointing
2
yields (Entries 15 and 16). The reaction at room temperature could not proceed to completion and
afforded the product only in a 48%, while the reaction at a higher temperature did not give an improved
yield (Entries 17 and 18). The amount of Ti(OEt) had a remarkable influence on the reaction: when
4
Ti(OEt) was loaded below 0.6 equivalent (40 mol% based on the amount of PhMgBr), the products
4
resulted from the addition of PhMgBr to the ester group were formed and the yield of crossꢀcoupling
product was rather low; on the other hand, increasing the amount of Ti(OEt) over 0.9 equivalent (60
4
mol% to PhMgBr) also resulted in a lowered yield (Entries 19ꢀ22). It is worth mentioning that titanate
complexes [RTi(OR) ·M, M = Li or MgX] have been used as a simple means to modify the reactivity of
4
1
0a,11
Grignard or lithium reagents for a long time, however, their structures have not been ascertained.
The species of (hetero)aryl Grignard reagents tuned by substoichiometric titanates (40 mol% to ArMgBr)
10a
also exhibit reactivity and selectivity distinct from Grignard reagents while their structures wait for
further elucidation. Besides, it was found that adding the mixture of PhMgBr and Ti(OEt) in two
4
portions would facilitate the stirring and resulted in a yield rise (to 85%, Entry 23). This improvement
became even more obvious in the reactions when activeꢀhydrogenꢀcontaining substrates (for example 1f,
1
g, 1tꢀ1x in Table 2) were used.
With optimized reaction conditions in hand, we then investigated the generality of this cobaltꢀ
catalyzed C−F activation coupling. The results were outlined in Table 2. This phosphine or NHCꢀfree
Coꢀcatalyzed biaryl coupling via C−F bond cleavage proved to be quite general and could go to
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completion in 6ꢀ8 hours. Without an activating group, unactivated aryl fluorides such as PhF, 4ꢀ
1
2
3
4
5
6
7
8
9
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
MeOC H F, 1ꢀC H F, mꢀC H F could all couple with various aryl Grignard reagents smoothly (Table
6
4
10
7
6
4 2
a
Table 2 Coꢀcatalyzed C－F activation biaryl couplings under phosphine or NHC free conditions
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
Entry
1
ArF
Ar′
Product
Entry
15
ArF
Ar′
Product
3ia 75%
3je 72%
d
4ꢀMeOC H4
2a
6
1b
2b
3bb 65%
3bc 55%
1i
4
ꢀ
b,d
2
3
1b
EtOOCC H
16
17
2d
2a
6
4
b
2
c
1j
O
1b
1b
2ꢀNCC H
6
4
3ka
90%
3bd
5%
b
F
2
d
1k
5
2
2e
ꢀPby
4
18
2a
3be 65%
3la 65%
1
l
5
6
Ph
2a
19
20
4ꢀMeC H
6
4
c
1
c
3bb 50% (78%)
1m
O
2g
3mg 85%
3nb 82%
O
2b
S
F
N
3
db 77%
2b
1
d
1
n
O
NMe2
7
8
1d
4ꢀMe NC H
21
3ꢀF CC H
3 6 4
2
6
4
2
f
3df 70%
2i
OHC
CF3
1
o
3oi 63%
2
ꢀthioꢀ
3ꢀMeOC H4
22
23
phenyl
2j
6
1e
2g
1p
3pj 67%
3
eg 65%
4eb 79%
d
9
1e
2b
2b
1q
3qb 75%
10
e
1f
2b
24
25
26
2i
3fb 79%
3fb 72%
1r
3ri 76%
Me2N
O
3ꢀPy
2k
F
1
1
1
2
2b
1
1
f′
1s
3sk 76%
e
d
2h
2d
3td
92%
g
3
gh 91%
1t
d
1
1
3
4
2h
3gh 89%
27
28
2a
1
1
g′
1u
3ua 86%
d
2a
1ꢀNaphthyl
d
h
1v
2l
3vl 78%
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The Journal of Organic Chemistry
3
ha 88%
1
2
3
4
5
Table 2 (Continued)
6
7
8
9
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
Entry ArF
Ar′
Product
Entry
32
ArF
Ar′
Product
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
d
29
2b
2a
1
y
3ya 84%
1w
3wb 86%
3xb 78%
O
d
3
0
1
2b
33
34
2c
2a
HO
F
1
y′
3je 82%
EtOOC
1
x
d
3
1x
2i
3xi
3%
7
1z
3za 94%
a
b
All reactions were carried out on a 2 mmol scale. Pyridyl and aryl Grignard reagents with FG (CN, COOEt, etc.)
c
were prepared via bromine or iodineꢀmagnesium exchange using iꢀPrMgCl or iꢀPrMgClꢁLiCl. 0.3 equiv of Ti(OEt)4
d
e
was used. 2.5 equiv. Ar′MgBr and 0.6 equiv. Ti(OEt) were used. 3.5 equiv of Ar′MgBr and 0.6 equiv of Ti(OEt)
4
4
were used.
2
, Entries 1ꢀ9). Fluoroanilines are a class of deactivated fluorides, and the presence of a free amino
12
group may also lead to C−N formation side reaction; remarkably, 2ꢀfluoroanine and 3ꢀfluoroanine
underwent smooth couplings based on our present procedure with no C−N forming reaction being
observed (Table 2, Entries 10 and 12). The corresponding couplings of the protected fluoroanilines (3ꢀ
FC H N=CHPh and 2ꢀFC H N=CHPh) also proceeded equally well (Table 2, Entries 11 and 13).
6
4
6
4
Similarly, 2ꢀfluorophenol and 4ꢀfluorophenol also participated in the coupling to afford the desired
products in 88% and 75% yields respectively (Table 2, Entries 14 and 15). Also, the present C−F bond
activation reaction exhibited high functional group compatibility, and the fluorides bearing sensitive
functional groups such as ketone, ester, amide, imine, sulfonamide, sulfonate, free carboxylic acid, etc.
could couple facilely (Table 2, Entries 16ꢀ28). Although the similar functional group compatibility has
been demonstrated in our previously reported Fe or Coꢀcatalyzed cross couplings of aryl Grignard
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1
0,13
o
reagents in the presence of substoichiometric titanates,
those couplings were conducted at ꢀ10 C or
1
2
3
4
5
6
7
8
9
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
room temperature. Such high functional group tolerance was observed for the first time under the heated
conditions.
6d,9
5b
9
As aforeꢀmentioned, an ketone,
imine (C=NR) and ester functionality usually act as an ortho
position activating group in C−F bond activation, therefore, the C−F bond cleavage couplings beyond
the orthoꢀpositions of these groups have been investigated rarely. Our experiments clearly showed that
the couplings at meta or para position to these groups could also take place smoothly (Table 2, Entries
16ꢀ22). Furthermore, the couplings of two series of 2, 3 or 4ꢀsubstituted aryl fluorides further
demonstrated that the present reactions could proceed well beyond the ortho position of an activation
group (Table 2, Entries 23ꢀ28). Besides, highly functionalized fluorides without an ortho group such as
ethyl 5ꢀfluoroꢀ2ꢀhydroxybenzoate and ethyl 5ꢀfluoroꢀ2ꢀhydroxyꢀ3ꢀpropionylbenzoate could also couple
with aryl Grignard reagents to give the crossꢀcoupling products in good yields (Table 2, Entries 29ꢀ31).
On the other hand, aryl Grignard reagents bearing various sensitive groups such as COOEt (Table 2,
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
Entry 2), CN (Table 2, Entries 3 and 26) and CF (Table 2, Entries 21, 24 and 31) could also undergo
3
this Coꢀcatalyzed coupling. Moreover, heteroaryl Grignard reagents such as 2ꢀthiophenyl (Table 2,
Entry 22) and pyridyl (Table 2, Entries 4, 16 and 25) magnesium reagents were also good coupling
substrates. Noteworthily, pyridyl fluorides could also undergo the C−F bond activation couplings,
leading to the desired pyridine compounds in high yields (Table 2, Entries 32ꢀ34).
Selective functionalization of C−F bonds of polyfluorinated molecules is a research area of high interest
because it helps to identify the intrinsic factors for cleaving C−F bonds, and it also provides an
alternative approach to new fluorocompounds. As illustrated in Table 2 (Entry 8), a selective
monoarylation through C−F bond activation of mꢀdifluorobenzene was achieved based on our present
procedure, leading to 3ꢀphenyl fluorobenzene product in a 65% yield. While ortho selective
functionalization of C−F bonds of a range of polyflorinated compounds has been well achieved in the
5b
6d,9
6e
4d
literature utilizing a directing group such as C=NR, COR, 2ꢀoxazoline, OH and etc., herein we
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The Journal of Organic Chemistry
have achieved highly orthoꢀselective arylations of difluoroaromatics bearing a free amino or carboxylic
1
2
3
4
5
6
7
8
9
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
group using this Coꢀcatalyzed C−F activation reaction (Table 3, entries 1ꢀ3). To the best of our
Table 3 Selective C−F activation couplings in the presence of C−F, C−Cl and C−Br bonds
Entry
ArF
Ar′MgX
(Ar′)
Product
Yield
%)
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
(
a
1
4ꢀMeC H4
90
6
5ag
a
2
4ꢀMeOC H4
67
81
6
5
bb
b
3
2ꢀF CC H
4
3
6
5
cm
1
ꢀNaphthyl
c,d
4
85
88
5dl
c,d
5
2ꢀMeOC H4
6
5
em
NH2
F
a,d
6
4ꢀMeOC H4
70
68
6
5
fb
Cl
a,d
7
4ꢀMeOC H4
6
5gb
a
b
3.0 equiv of Ar′MgBr and 0.4 equiv. Ti(OEt) were used. 2.0 equiv of Ar′MgBr and 0.4 equiv. Ti(OEt) were used.
4
4
c
d
1
.0 equiv of Ar′MgBr and 0.4 equiv. Ti(OEt) were used. The diarylated products and those resulting from CꢀCl or Cꢀ
4
Br vs CꢀF cleavage were not observed.
knowledge, these were the first examples that a free amino or carboxylic group functioned as an orthoꢀ
directing group in the Coꢀcatalyzed selective C−F bond activation. Based on these findings, we then
investigated the orthoꢀselective C−F bond activation in the presence of C−Cl or C−Br bonds. To
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selectively cleave a highly strong bond (C−F) over a relatively weak bond (C−Cl or C−Br) is a
remarkably challenging task. Another challenge is that our previous investigation has showed that aryl
bromides or aryl chlorides could undergo the crossꢀcouplings with titanateꢀmediated aryl Grignard
1
2
3
4
5
6
7
8
9
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
10a
regents under the cobalt catalysis. Despite these challenges, the orthoꢀselective CꢀF bond activation in
the presence of C−Cl or C−Br bonds were achieved successfully under the catalysis of CoCl /DMPU
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
2
(Table 3, entries 4ꢀ7).
Remarkably, a selective C−F bond activation between two types of C−F bonds on two coupling
substrates was also achieved based on this present Coꢀcatalyzed reaction, which was outlined in Scheme
2
. In the couplings, the C−F bonds of 5ꢀfluoroꢀ2ꢀhydroxybenzoic acid and its ethyl ester were highly
selectively replaced by the aryl group without any activating groups at ortho positions, whereas the two
1
4
fluorine atoms in 2,4ꢀdifluorophenylmagnesium bromide were left untouched. It is worth mentioning
that the reported methods to yield new fluorinated compound via C−F bond cleavage are mainly based
2
d
on the selective C−F functionalization of polyfluorinated substrates. Our selective C−F bond activation
illustrated in Scheme 2 provides a new approach to make new fluorineꢀcontaining molecules. It can be
15
seen that our couplings facilely afforded an antiꢀinflammatory agent, diflunisal and its ethyl ester in
high yields.
Scheme 2 Synthesis of diflunisal and its ethyl ester via selective C−F bond activation
Mechanistically, we assume that the cobalt/titanium bimetallic cooperativity plays an important role in
the present reaction. As in a tentative transition state (Figure 1), the bimetallic complex promoted the
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The Journal of Organic Chemistry
4
c,4e,16
C−F bond cleavage in a synergetic manner.
complexes are underway in our laboratories.
Further studies for the cobalt/titanium bimetallic
1
2
3
4
5
6
7
8
9
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
Figure 1 Proposed transition state for the Co/Ti cooperative oxidative addition step
3
. CONCLUSION
In conclusion, we have developed an unexpectedly facile Coꢀcatalyzed biaryl crossꢀcoupling reaction
via C−F bond cleavage. In sharp contrast to the related reported reactions that are dominantly catalyzed
by Pd or Ni complexes with NHC or phosphine ligand, and often in the presence of an activating group
on the aryl fluorides; the present coupling reaction of C−F bond activation was catalyzed simply by
CoCl /DMPU and proved to be quite general. Remarkably, highly selective C−F activation couplings in
2
the presence of C−F, C−Cl and C−Br bonds could be achieved. We believe that these findings will be
helpful to the further development of CꢀF bond activation reactions and highly effective cobalt catalysts.
4
. EXPERIMENTAL SECTIONS
1
13
General Information IR spectra were recorded using a FTIR spectrophotometer. H NMR and C
13
NMR spectra were recorded on 400 MHz spectrometer (100 MHz for C spectroscopy) using TMS as
an internal standard. High resolution mass spectra (HRMS) were obtained with a microTOF (ESI).
Melting points recorded on a microscopic instrument and are uncorrected.
All reagents and solvents used for aryl magnesium reagents or lithium reagents and reactions were
freshly dehydrated and distilled before use. Ti(OEt) was distilled under vacuum before use. The
4
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o
corresponding glassware was oven dried (120 C) and cooled under a stream of argon gas. Aryl
Grignard reagents such as phenyl magnesium or 4ꢀmethoxyphenyl magnesium were prepared according
to standard procedure. Pyridyl Grignard reagents were prepared via bromineꢀmagnesium exchange
using iꢀPrMgCl while functionalized aryl Grignard reagents such as 2ꢀcyanophenylmagnesium chloride
or 4ꢀ(ethoxycarbonyl)phenyl magnesium chloride were prepared via iodineꢀmagnesium exchange using
1
2
3
4
5
6
7
8
9
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
7
18
iꢀPrMgClꢁLiCl according to Knochel’s method. All the Grignard reagents were titrated before use.
Typical procedure for Co-catalyzed biaryl couplings via C−F cleavage (3aa)
Under Ar atmosphere, a solution of PhMgBr in THF (3.0 mmol, 1.0 M in THF) was added dropwise to
a solution of Ti(OEt) (273.6 mg, 1.2 mmol) in 10 mL THF under the magnetic stirring at room
4
temperature. After addition, the stirring was continued for 0.5 h.
Under Ar atmosphere, to another threeꢀnecked roundꢀbottom flask were added CoCl (19.5 mg, 0.015
2
mmol), DMPU (38 mg, 0.03 mmol), 2ꢀfluorobenzoic acid ethyl ester (308 mg, 2 mmol) and 10 mL
o
THF. The resulting mixture was heated to 50 C under the magnetic stirring, and about 2/3 volume of
the aboveꢀprepared mixture of PhMgBr and Ti(OEt) were added dropwise. After addition, the mixture
4
o
was stirred at 50 C for about 3 h. The remaining mixture of PhMgBr and Ti(OEt) were added dropwise
4
o
and the resulting mixture was stirred at 50 C until the completion of the reaction. The reaction was
quenched with 30 mL distilled water and the product was taken up with CH Cl (50 mL × 4). The
2
2
organic layer was dried over Na SO and concentrated to yield the crude compound, which was purified
2
4
by column chromatography to yield the desired product 3aa (180 mg, 85% yield).
Note
For the reactions where the fluorinated substrates contain active hydrogen(s) (for example, 3fb, 3gh,
3ha, 3ia, 3td and etc.), after CoCl , DMPU, the fluorinated substrate and THF were added in the flask,
2
one or two equivalents of ArꞌMgX was added dropwise to the mixture to neutralize the active
o
hydrogen(s). After that, the mixture was heated slowly to 50 C. The other operations were conducted as
described in typical procedure.
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Ethyl biphenylꢀ2ꢀcarboxylate (3aa). The product was prepared as described in typical procedure and
1
2
3
4
5
6
7
8
9
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
isolated as a colorless oil in 85% yield (384 mg); R = 0.50 (petroleum ether/ethyl acetate = 20:1, v/v);
f
ꢀ1
1
IR (cm , KBr): 1710, 1601, 1258, 698; H NMR (CDCl , 400 MHz) δ (ppm): 7.82 (dd, J = 7.6 Hz, J =
3
0
.9 Hz, 1H), 7.55ꢀ7.50 (m, 1H), 7.43ꢀ7.31 (m, 7H), 4.08 (q, J = 7.1 Hz, 2H), 0.99 (t, J = 7.1 Hz, 3H);
1
3
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 168.8, 142.4, 141.6, 134.3, 131.4, 131.1, 130.6, 129.7,
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
3
1
9
1
28.4, 128.0, 127.1, 60.9, 13.6. Data was consistent with that reported in the literature.
4
ꢀMethoxybiphenyl (3bb). The product was prepared as described in typical procedure and isolated as
o
o
a white solid in a 78% yield (287 mg); mp = 85ꢀ86 C (lit., 85ꢀ87 C); R = 0.55 (petroleum ether). IR
f
ꢀ1
1
(
cm , KBr): 3025, 2918,1605, 1487, 834, 760, 683; H NMR (CDCl , 400 MHz) δ (ppm): 7.59ꢀ7.55 (m,
3
1
3
1
4
H), 7.44 (t, J = 6.0 Hz, 2H), 7.34ꢀ7.28 (m, 1H), 7.01 (d, J = 6.8 Hz, 2H), 3.88 (s, 3H); C{ H}NMR
(CDCl , 100 MHz) δ (ppm): 159.2, 140.8, 133.8, 128.7, 128.2, 126.8, 126.7, 114.2, 55.4. Data was
3
20
consistent with that reported in the literature.
Ethyl biphenylꢀ4ꢀyl carboxylate (3bc). The product was prepared as described in typical procedure
and isolated as a colorless oil in a 55% yield (249 mg); R = 0.51 (petroleum ether/ethyl acetate = 20:1,
f
ꢀ1
1
v/v). IR (cm , KBr): 3027, 2975, 1705, 1600, 1257, 701; H NMR (CDCl , 400 MHz) δ (ppm): 8.12 (d,
3
J = 8.3 Hz, 2H)，7.67ꢀ7.62 (m, 4H)，7.49ꢀ7.45 (m, 2H), 7.39 (t, J = 7.2 Hz, 1H), 4.40 (q, J = 7.2 Hz,
13
1
2
H), 1.42 (t, J = 7.1 Hz, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 166.5, 145.5, 140.1, 130.1,
3
2
1
129.3, 128.9, 128.1, 127.3, 127.0, 61.0, 14.4. Data was consistent with that reported in the literature.
Biphenylꢀ2ꢀcarbonitrile (3bd). The product was prepared as described in typical procedure and
ꢀ1
isolated as a colorless oil in a 55% yield (197 mg); R = 0.48 (petroleum ether). IR (cm , KBr): 3046,
f
1
2225, 1599, 1480, 760; H NMR (CDCl , 400 MHz) δ (ppm): 7.80 (d, J = 6.2 Hz, 1H), 7.69ꢀ7.66 (m,
3
1
3
1
1
H), 7.60 (d, J = 5.8 Hz, 2H), 7.56ꢀ7.51 (m, 3H), 7.48 (t, J = 5.6 Hz, 2H); C{ H}NMR (CDCl , 100
3
MHz) δ (ppm): 145.5, 138.2, 133.8, 132.9, 130.1, 128.79, 128.77, 127.6, 127.2, 118.8, 111.3. Data was
2
2
consistent with that reported in the literature.
2ꢀPhenylpyridine (3be). The product was prepared as described in typical procedure and isolated as
ꢀ1
a yellow oil in a 65% yield (202 mg); R = 0.58 (petroleum ether/ethyl acetate = 20:1, v/v). IR (cm ,
f
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1
KBr): 3056, 1592, 1565, 693; H NMR (CDCl , 400 MHz) δ (ppm): 8.67 (d, J = 4.8 Hz, 1H), 7.99ꢀ7.97
3
1
2
3
4
5
6
7
8
9
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
1
3
1
(
m, 2H), 7.67ꢀ7.66 (m, 2H), 7.46ꢀ7.40 (m, 2H), 7.38ꢀ7.36 (m, 1H), 7.17ꢀ7.14 (m, 1H); C{ H}NMR
(CDCl , 100 MHz) δ (ppm): 157.4, 149.7, 139.4, 136.7, 129.0, 128.8, 126.9, 122.1, 120.5. Data was
3
23
consistent with that reported in the literature.
1
ꢀ(4ꢀMethoxyphenyl)naphthalene (3db). The product was prepared as described in typical
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
procedure and isolated as a white solid in a 77% yield (360 mg); mp = 116.5ꢀ118 °C (lit. 116ꢀ117 °C);
ꢀ1
R = 0.45 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 3028, 2987, 1601, 1514, 1104,
f
1
756; H NMR (CDCl , 400 MHz) δ (ppm): 7.93ꢀ7.81 (m, 3H), 7.52ꢀ7.39 (m, 6H), 7.04–7.01 (m, 2H),
3
13
1
3
.88 (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm) 159.0, 140.0, 133.9, 133.2, 131.9, 131.1, 128.3,
3
1
27.3, 127.0, 126.1, 125.9, 125.7, 125.4, 113.8, 55.4. Data was consistent with that reported in the
2
4
literature.
N,Nꢀdimethylꢀ4ꢀ(naphthalenꢀ1ꢀyl)aniline (3df). The product was prepared as described in typical
procedure and isolated as a white solid in a 70% yield (346 mg); mp = 108ꢀ110 °C. (lit. 109ꢀ112 °C); Rf
ꢀ1
= 0.40 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 3045, 2851, 1394, 1352, 1198, 799,
1
7
75; H NMR (CDCl , 400 MHz) δ (ppm): 8.01 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.80 (d, J
3
1
3
1
=
8.0 Hz, 1H), 7.51ꢀ7.39 (m, 6H), 6.87 (d, J = 7.9 Hz, 2H), 3.02 (s, 6H,); C{ H}NMR (CDCl , 100
3
MHz) δ (ppm): 149.8, 140.6, 134.1, 131.0, 129.0, 128.4, 128.1, 127.0, 126.9, 126.5, 125.9, 125.7, 125.6,
25
1
12.5, 40.8. Data was consistent with that reported in the literature.
3ꢀFluoroꢀ3'ꢀmethoxybiphenyl (3eg). The product was prepared as described in typical procedure and
isolated as a pale yellow oil in a 65% yield (263 mg); R = 0.58 (petroleum ether/ethyl acetate = 10:1,
f
ꢀ1
1
v/v). IR (cm , KBr): 3073, 2998, 2965, 2938, 2839, 1608, 1587, 700; H NMR (CDCl , 400 MHz): δ
3
(ppm): 7.37ꢀ7.32 (m, 3H), 7.28ꢀ7.25 (m, 1H), 7.15ꢀ7.12 (m, 1H), 7.09ꢀ7.08 (m, 1H), 7.04ꢀ6.99 (m, 1H),
13
1
6
.91ꢀ6.88 (m, 1H)，3.83 (s，3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 163.4 (d, J = 243.9 Hz),
3
160.3, 143.6 (d, J = 7.5 Hz), 141.5 (d, J = 2.1 Hz), 130.4 (d, J = 8.3 Hz), 130.1, 123.0 (d, J = 2.4 Hz),
19
1
19.7, 114.3 (d, J = 21.0 Hz), 114.1 (d, J = 21.9 Hz), 113.4, 113.1, 55.2; F NMR (376 MHz, CDCl ) δ
3
2
6
(ppm): ꢀ113.1. Data was consistent with that reported in the literature.
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The Journal of Organic Chemistry
1
,3ꢀBis(4ꢀmethoxyphenyl)benzene (4eb). The product was prepared as described in typical procedure
1
2
and isolated as a white solid in a 79% yield (458 mg); mp = 203ꢀ205 °C (lit., 203ꢀ204 °C); R = 0.47
f
3
4
5
6
7
8
9
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
1
(petroleum ether/ethyl acetate = 10:1, v/v). IR (cmꢀ1, KBr): 1685, 1571, 1498, 1321, 759; H NMR
(
CDCl , 400 MHz) δ (ppm): 7.72 (t, J = 1.8 Hz, 1H), 7.58 (d, J = 8.9 Hz, 4H), 7.51ꢀ7.46 (m, 3H), 7.00
3
1
3
1
(
d, J = 8.8 Hz, 4H), 3.86 (s, 6H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 159.2, 141.3, 133.8, 129.1,
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
3
2
7
1
28.3, 125.3, 125.2, 114.2, 55.4. Data was consistent with that reported in the literature.
4
'ꢀMethoxybiphenylꢀ3ꢀamine (3fb). The product was prepared as described in typical procedure and
o
isolated as a pale yellow solid in a 79% yield (314 mg); mp = 89ꢀ91 °C, (lit., 91 C); R = 0.48
f
ꢀ1
(
petroleum ether/ethyl acetate = 5/1, v/v). IR (cm , KBr): 3367, 3022, 1612, 1523, 1296,1243, 1032,
1
8
36, 758, 698; H NMR (CDCl , 400 MHz) δ (ppm): 7.49 (d, J = 8.8 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H),
3
13
1
6.96ꢀ6.94 (m, 3H), 6.88ꢀ6.87 (m, 1H), 6.65ꢀ6.63 (m, 1H), 3.84 (s, 3H); C{ H}NMR (CDCl , 100
3
MHz) δ (ppm): 159.1, 146.7, 142.1, 134.0, 129.6, 128.1, 117.4, 114.1, 113.57, 113.55, 55.3. Data was
2
8
consistent with that reported in the literature.
4'ꢀMethylbiphenylꢀ2ꢀamine (3gh). The product was prepared as described in typical procedure and
isolated as a pale yellow oil in a 91% yield (333 mg); R = 0.62 (petroleum ether/ethyl acetate = 10/1,
f
ꢀ1
1
v/v). IR (cm , KBr): 3381, 1614, 1492, 1295, 820, 748, 733; H NMR (CDCl , 400 MHz) δ (ppm): 7.34
3
(
d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.15ꢀ7.10 (m, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 8.0
13
1
Hz, 1H), 3.71 (br, 2H), 2.39 (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 143.9, 137.1, 136.9,
3
130.8, 129.8, 129.3, 128.7, 128.0, 119.0, 116.0, 21.5. Data was consistent with that reported in the
2
9
literature.
ꢀPhenylphenol (3ha). The reaction was quenched with 2M HCl aqueous solution and the product
was isolated as a white solid in an 88% yield (299 mg); mp = 58ꢀ59 °C. (lit. 56ꢀ58 °C); R = 0.49
2
f
ꢀ1
1
(
(
(
petroleum ether/ethyl acetate = 10/1, v/v). IR (cm , KBr): 3513, 1608, 1511, 825, 740, 688; H NMR
CDCl , 400 MHz) δ (ppm): 7.54ꢀ7.50 (m, 4H), 7.44 (t, J = 5.4 Hz, 1H), 7.32ꢀ7.28 (m, 2H), 7.05ꢀ7.02
3
1
3
1
m, 2H), 5.24 (br, 1H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 152.5, 137.2, 130.3, 129.3, 129.23,
3
30
1
29.18, 128.2, 127.9, 120.9, 115.9. Data was consistent with that reported in the literature.
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4
ꢀPhenylphenol (3ia). The reaction was quenched with 2M HCl aqueous solution and the product was
1
2
3
4
5
6
7
8
9
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
o
isolated as a white solid in a 75% yield (255 mg); mp = 164 C (lit., 163ꢀ165 °C); R = 0.55 (petroleum
f
ꢀ1
1
ether/ethyl acetate = 10/1, v/v). IR (cm , KBr): 3422, 1613, 1523, 836, 758, 698; H NMR (CDCl , 400
3
MHz) δ (ppm): 7.56 (d, J = 6.1 Hz, 2H), 7.51 (d, J = 6.6 Hz, 2H), 7.45ꢀ7.42 (m, 2H), 7.34ꢀ7.31(m, 1H),
1
3
1
6
.93 (d, J = 6.7 Hz, 2H), 4.81 (br, 1H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 155.1, 140.8, 134.1,
3
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
3
1
1
28.7, 128.4, 126.7, 115.6. Data was consistent with that reported in the literature.
Ethyl 4ꢀ(pyridinꢀ2ꢀyl)benzoate (3je). The product was prepared as described in typical procedure
and isolated as a white solid in a 72% yield (327 mg); mp = 50.5ꢀ51.5 °C (lit. 50.5ꢀ52.0 °C); R = 0.45
f
ꢀ1
(
petroleum ether/ethyl acetate = 5/1, v/v). IR (cm , KBr): 3056, 2983, 1708, 1607,1585, 1468, 1363,
1
1
281, 1018, 870; H NMR (CDCl , 400 MHz) δ (ppm): 8.73 (d, J = 4.6 Hz, 1H), 8.16–8.06 (m, 4H),
3
7.79 (d, J = 3.8 Hz, 2H), 7.31–7.27 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H);
13
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 166.4, 156.2, 149.8, 143.4, 136.9, 130.7, 130.0, 126.8,
3
3
2
1
22.8, 121.0, 61.0, 14.3. Data was consistent with that reported in the literature.
Biphenylꢀ2ꢀyl propanone (3ka). The product was prepared as described in typical procedure and
ꢀ1
isolated as a yellow oil in a 90% yield (378 mg); R = 0.35 (petroleum ether). IR (cm , KBr): 3060,
f
1
2
975, 2937, 2877, 1681, 1605, 1423, 778, 755, 690; H NMR (CDCl , 400 MHz) δ (ppm): 7.45ꢀ7.39
3
(
m, 2H), 7.38ꢀ7.29 (m, 5H), 7.27ꢀ7.25 (m, 2H), 2.18 (q, J = 7.3 Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H);
13
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 207.7, 140.1, 139.7, 138.9, 129.3, 129.1, 127.8, 127.6,
3
3
3
126.8, 126.6, 126.4, 35.1, 7.5. Data was consistent with that reported in the literature.
Biphenylꢀ4ꢀyl ethanone (3la). The product was prepared as described in typical procedure and
o
o
isolated as a white solid in a 65% yield (255 mg); mp = 121ꢀ122 C (lit., 121ꢀ123 C); R = 0.50
f
ꢀ1
1
(petroleum ether/ethyl acetate = 20:1, v/v). IR (cm , KBr): 1682, 1601, 1263, 961, 764; H NMR
(
CDCl , 400 MHz) δ (ppm): 8.04 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.64ꢀ7.62 (m, 2H), 7.48
3
13
1
(
t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 2.64 (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm):
3
1
97.7, 145.8, 139.9, 135.9, 129.0, 128.9, 128.2, 127.3, 127.2, 26.7. Data was consistent with that
34
reported in the literature.
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The Journal of Organic Chemistry
Ethyl 4'ꢀmethylbiphenylꢀ4ꢀyl sulfonate (3mg). The product was prepared as described in typical
1
2
o
procedure and isolated as a white solid in a 85% yield (469 mg); mp = 132ꢀ133 C (lit., 131ꢀ133 °C); R
f
3
4
5
6
7
8
9
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
ꢀ
1
1
= 0.52 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 1595, 1483, 1358, 808, 794, 636; H
NMR (CDCl , 400 MHz) δ (ppm): 7.96 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.1
3
Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H);
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
3
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 146.6, 138.8, 136.1, 134.5, 129.8, 128.3, 127.5, 127.2, 67.0,
3
10a
2
1.2, 14.8. Data was consistent with that reported in the literature.
3
5
4ꢀ(4'ꢀmethoxybiphenylꢀ4ꢀylsulfonyl)morpholine (3nb). The product was prepared as described in
o
typical procedure and isolated as a white solid in a 82% yield (572 mg); mp = 198ꢀ199 C; R = 0.48
f
ꢀ1
1
(
petroleum ether/ethyl acetate = 3:1, v/v). IR (cm , KBr): 1597, 1485, 1108, 945, 766; H NMR
(CDCl , 400 MHz) δ (ppm): 7.78 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H),
3
13
1
7
.02 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.76 (t, J = 4.7 Hz, 4H), 3.04 (t, J = 4.6 Hz, 4H); C{ H}NMR
(
CDCl , 100 MHz) δ (ppm): 160.2, 145.6, 132.9, 131.5, 128.5, 128.4, 127.1, 114.6, 66.1, 55.4, 46.0.
3
3
'ꢀ(Trifluoromethyl)biphenylꢀ3ꢀcarbaldehyde (3oi). The reaction was postꢀtreated as described in the
1
0b
literature and the product was isolated as a yellow solid in a 63% yield (315 mg); mp = 142.5ꢀ144 °C.
ꢀ1
(
lit. 143ꢀ144 °C); R = 0.39 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 3025, 2998,
f
1
1
692, 1598, 1580, 1336, 1165, 825, 790, 761, 700; H NMR (CDCl , 400MHz) δ (ppm): 10.11 (s, 1H),
3
13
1
8.15 (t, J = 1.5 Hz, 1H), 7.93ꢀ7.90 (m, 2H), 7.69ꢀ7.65 (m, 2H), 7.57ꢀ7.45 (m, 3H); C{ H}NMR
(
CDCl , 100 MHz) δ (ppm): 192.1, 143.9, 140.6, 137.1, 133.0, 131.1 (q, J = 34.8 Hz, 1C), 129.9, 129.8,
3
3
6
1
29.5, 129.2, 128.0, 124.8, 123.3, 120.9. Data was consistent with that reported in the literature.
4ꢀ(Thiophenꢀ2ꢀyl)benzaldehyde (3pj). The reaction was postꢀtreated as described in the literature
and the product was isolated as a yellow solid in a 67% yield (252 mg); mp = 68–69 °C (lit. 69.0–69.5
1
0b
ꢀ1
°
C); R = 0.52 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 3011, 1701, 1604, 1276, 792;
f
1
H NMR (CDCl , 400 MHz) δ (ppm): 10.0 (s, 1H), 7.90 (d, J = 1.8 Hz, 2H), 7.89ꢀ7.78 (m, 2H), 7.77 (d,
3
13
1
J = 5.0 Hz, 2H), 7.48ꢀ7.46 (m, 1H), 7.41ꢀ7.39 (m, 1H), 7.15ꢀ7.13 (m, 1H); C{ H}NMR (CDCl , 100
3
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Page 18 of 27
MHz) δ (ppm): 191.5, 142.8, 140.1, 135.1, 130.5, 128.5, 126.9, 126.1, 125.1. Data was consistent with
1
2
3
4
5
6
7
8
9
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
3
7
that reported in the literature.
N, Nꢀdimethyl 4'ꢀmethoxybiphenylꢀ2ꢀcarboxamide (3qb). The product was prepared as described in
typical procedure and isolated as a yellow oil in a 75% yield (383 mg); R = 0.45 (petroleum ether/ethyl
f
ꢀ1
1
acetate = 1:1, v/v). IR (cm , KBr): 3051, 2970, 1624, 1427, 1286, 768, 759; H NMR (CDCl , 400
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
3
MHz) δ (ppm): 7.45ꢀ7.34 (m, 6H), 6.93 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H), 2.88 (s, 3H), 2.41 (s, 3H);
13
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 171.6, 159.2, 132.39, 132.35, 131.2, 131.1, 130.9, 129.6,
3
+
2
+
127.4, 127.2, 113.8, 55.2, 38.29, 38.27; HRMS calcd for C H NO [M+H] 256.1332, Found
1
6
18
2
56.1327.
N, NꢀDimethyl 3'ꢀ(trifluoromethyl)biphenylꢀ3ꢀcarboxamide (3ri). The product was prepared as
described in typical procedure and isolated as a pale yellow solid in a 76% yield (445 mg); mp = 108ꢀ
o
ꢀ1
1
09 C; R = 0.48 (petroleum ether/ethyl acetate = 3:1, v/v). IR (cm , KBr): 1597, 1485, 1108, 945, 766;
f
1
H NMR (CDCl , 400 MHz) δ (ppm): 7.84 (s, 1 H), 7.77 (d, J = 7.6 Hz, 1H), 7.66ꢀ7.61 (m, 3H), 7.56 (t,
3
J = 7.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 3.14 (s, 3H), 3.03 (s, 3H);
13
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 171.1, 141.1, 139.9, 137.2, 131.1 (q, J = 32.0 Hz, 1C),
3
1
3
30.4, 129.4, 129.0, 128.1, 126.4, 125.8, 124.2 (q, J = 3.7 Hz, 1C), 123.8 (q, J = 3.8 Hz, 1C), 122.7,
+
+
9.4, 35.2; HRMS calcd for C H F NO [M+H] 294.1100, Found 294.1101.
1
6
15 3
N, Nꢀdimethyl 4ꢀpyridinꢀ3ꢀylbenzamide (3sk). The product was prepared as described in typical
o
procedure and isolated as a white solid in a 76% yield (344mg); mp = 95 C (lit., 94ꢀ96 °C); R = 0.32
f
ꢀ1
1
(
petroleum ether/ethyl acetate = 1/1, v/v). IR (cm , KBr): 1638, 1562, 1395, 1084; H NMR (CDCl ,
3
4
00 MHz) δ (ppm): 8.87 (s, 1H), 8.64 (s, 1H), 7.90 (d, J = 6.2 Hz, 1H), 7.63 (d, J = 6.6 Hz, 2H), 7.55 (d,
1
3
1
J = 6.8 Hz, 2H), 7.41 (s, 1H), 3.15 (s, 3H), 3.05 (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm):
3
1
71.1, 148.7, 148.1, 138.9, 136.1, 136.0, 134.6, 128.0, 127.1, 123.7, 39.6, 35.4. Data was consistent
1
0a
with that reported in the literature.
2'ꢀCyanobiphenylꢀ2ꢀcarboxylic acid (3td). The reaction was quenched with 2M HCl aqueous
solution and the product was isolated as a white solid in a 92% yield (410 mg); mp = 170.4ꢀ172.3 °C
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Page 19 of 27
The Journal of Organic Chemistry
ꢀ1
(
lit., 170–172 °C); R = 0.48 (petroleum ether/ethyl acetate/acetic acid = 5:1:0.01, v/v/v). IR (cm , KBr):
f
1
2
3
4
5
6
7
8
9
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
1
3
433, 3267, 3051, 2229, 1701, 1602, 1433, 1384, 1095, 692, 521; H NMR (CDCl , 400 MHz) δ (ppm):
3
1
3
1
8.12 (d, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.35ꢀ7.31 (m, 2H), 7.28ꢀ7.24 (m, 4H); C{ H}NMR
(
CDCl , 100 MHz) δ (ppm) 171.0, 135.0, 134.9, 133.7, 132.2, 132.1, 130.2, 130.0, 128.6, 128.54,
3
3
8
1
28.49, 127.9, 119.2, 117.6. Data was consistent with that reported in the literature.
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
Biphenylꢀ3ꢀcarboxylic acid (3ua). The reaction was quenched with 2M HCl aqueous solution and
o
o
the product was isolated as a white solid in a 86% yield (341 mg); mp = 163ꢀ165 C (lit., 160ꢀ161 C);
ꢀ1
R = 0.32 (petroleum ether/ethyl acetate/acetic acid = 5:1:0.01, v/v/v). IR (cm , KBr): 1708, 1693, 1584,
f
1
1
277, 745, 701; H NMR (CDCl , 400 MHz) δ (ppm): 8.37 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.85 (d, J =
3
7
.8 Hz, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.3
13
1
Hz, 1H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 171.8, 141.7, 140.0, 132.5, 129.8, 129.02, 128.98,
3
39
1
28.96, 128.9, 127.9, 127.2. Data was consistent with that reported in the literature.
4
ꢀNaphthalenꢀ1ꢀylbenzoic acid (3vl). The reaction was quenched with 2M HCl aqueous solution and
o
the product was isolated as a white solid in a 78% yield (387 mg); mp = 234ꢀ236 C (lit., 235.2ꢀ236.1
o
ꢀ1
C); R = 0.47 (petroleum ether/ethyl acetate/acetic acid = 5:1:0.01, v/v/v). IR (cm , KBr): 1685, 1571,
f
1
1
498, 1321, 759; H NMR (CDCl , 400 MHz) δ (ppm): 8.29ꢀ7.89 (m, 5H), 7.66ꢀ7.50 (m, 6H);
3
1
3
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 171.8, 146.6, 139.0, 133.8, 131.9, 131.7, 131.2, 130.29,
3
1
30.27, 128.4, 127.0, 126.4, 126.0, 125.6, 125.3. Data was consistent with that reported in the
4
0
literature.
Ethyl 4ꢀhydroxyꢀ4'ꢀmethoxybiphenylꢀ3ꢀcarboxylate (3wb). The reaction was quenched with 2M HCl
aqueous solution and the product was isolated as a white solid in an 86% yield (468 mg); mp = 120ꢀ122
o
ꢀ1
C; R = 0.62 (petroleum ether/ethyl acetate = 10/1, v/v). IR (cm , KBr): 3138, 1712, 1485, 1439, 1210,
f
1
7
66, 590; H NMR (CDCl , 400 MHz) δ (ppm): 10.81 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.6
3
Hz, J = 2.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 4.44 (q,
1
3
1
J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H) ; C{ H}NMR (CDCl , 100 MHz) δ (ppm):
3
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1
70.2, 160.7, 159.0, 134.0, 132.6, 132.1, 127.7, 127.6, 117.9, 114.3, 112.7, 61.5, 55.3, 14.2; HRMS
1
2
3
4
5
6
7
8
9
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
+
+
calcd for C H O [M+H] 273.1121, Found 273.1120.
1
6
17
4
Ethyl 4ꢀhydroxyꢀ4'ꢀmethoxyꢀ5ꢀpropionyl biphenylꢀ3ꢀcarboxylate (3xb). The reaction was quenched
with 2M HCl aqueous solution and the product was isolated as a white solid in a 78% yield (512 mg);
o
ꢀ1
mp = 110ꢀ112 C; R = 0.45 (petroleum ether/ethyl acetate = 5:1, v/v). IR (cm , KBr): 3369, 1685, 1658,
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
f
1
1
8
439, 1251, 766, 699; H NMR (CDCl , 400 MHz) δ (ppm): 12.22 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H),
3
.15 (d, J = 2.5 Hz, 1H), 7.51ꢀ7.48 (m, 2H), 7.00ꢀ6,96 (m, 2H), 4.46 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H),
1
3
1
3.15 (q, J = 7.2 Hz, 2H)；1.44 (t, J = 7.2 Hz, 3H), 1.23(t, J = 7.2 Hz, 3H); C{ H}NMR (CDCl , 100
3
MHz) δ (ppm): 203.4, 169.1, 160.4, 159.3, 134.1, 133.1, 131.68, 131.64, 127.8, 125.8, 115.7, 114.4,
+
+
61.9, 55.4, 35.8, 14.2, 8.3; HRMS calcd for C H O [M+H] 329.1384, Found 329.1383.
1
9
21
5
Ethyl 4ꢀhydroxyꢀ5ꢀpropionylꢀ3'ꢀ(trifluoromethyl)biphenylꢀ3ꢀcarboxylate (3xi). The reaction was
quenched with 2M HCl aqueous solution and the product was isolated as a white solid in a 73% yield
o
ꢀ1
(534 mg); mp = 102ꢀ104 C; R = 0.45 (petroleum ether/ethyl acetate = 5:1, v/v). IR (cm , KBr): 3398,
f
1
1
1
683, 1667, 1447, 1249, 763, 700; H NMR (CDCl , 400 MHz) δ (ppm): 12.3 (s, 1H), 8.26ꢀ8.25 (m,
3
H), 8.21ꢀ8.20 (m, 1H), 7.79ꢀ7.74 (m, 2H), 7.63ꢀ7.56 (m, 2H), 4.49 (q, J = 7.1 Hz, 2H), 3.17 (q, J = 7.2
13
1
Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm):
3
2
02.7, 169.0, 161.3, 139.9, 134.6, 133.2, 131.3 (q, J = 32.1 Hz, 1C), 130.4, 130.0, 129.4, 126.3, 124.1
(q, J = 3.6 Hz, 1C), 123.4 (q, J = 3.7 Hz, 1C), 122.7, 115.7, 62.1, 36.1, 14.2, 8.2; HRMS calcd for
+
4
+
C H F O [M+H] 367.1152, Found 367.1150.
19
18
3
3
ꢀPhenylpyridine (3ya). The product was prepared as described in typical procedure and isolated as a
ꢀ1
colorless oil in a 81% yield (260 mg); R = 0.54 (petroleum ether/ethyl acetate = 5:1, v/v). IR (cm ,
f
1
KBr): 3038, 1603, 1521, 699; H NMR (CDCl , 400MHz) δ (ppm): 8.87 (d, J = 1.6 Hz, 1H), 8.61ꢀ8.60
3
(m, 1H), 7.90ꢀ7.87 (m, 1H), 7.60ꢀ7.58 (m, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.44ꢀ7.36 (m, 2H);
1
3
1
C{ H}NMR (CDCl , 100 MHz) δ (ppm): 148.4, 148.3, 137.8, 136.7, 134.4, 129.1, 128.1, 127.2,
3
41
1
23.6. Data was consistent with that reported in the literature.
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Methyl 6ꢀphenylnicotinate (3za). The product was prepared as described in typical procedure and
1
2
3
4
5
6
7
8
9
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
isolated as a white solid in a 92% yield (400 mg); mp = 117ꢀ118 °C (lit., 118 °C); R = 0.53 (petroleum
f
ꢀ1
1
ether/ethyl acetate = 20:1, v/v). IR (cm , KBr): 1716, 1596, 1288, 1117, 752, 698; H NMR (CDCl ,
3
4
3
1
00MHz) δ (ppm): 8.71 (s, 2H), 7.64 (d, J = 5.0 Hz, 1H), 7.47ꢀ7.39 (m, 3H), 7.35ꢀ7.32 (m, 2H), 3.70 (s,
1
3
1
H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 167.3, 151.4, 148.9, 137.7, 137.1, 136.0, 128.5, 128.4,
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
3
4
2
28.1, 122.5, 52.4. Data was consistent with that reported in the literature.
ꢀFluoroꢀ4'ꢀmethylbiphenylꢀ2ꢀamine (5ag). The product was prepared as described in typical
procedure and isolated as a colorless oil in a 90% yield (362 mg); R = 0.49 (petroleum ether/ethyl
5
f
ꢀ1
acetate = 10:1, v/v). IR (cm , KBr): 3422, 3375, 1712, 1599, 1487, 1241, 1168, 1034, 829, 814, 755,
1
6
97; H NMR (CDCl , 400 MHz) δ (ppm): 7.33 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.6 Hz, 2H), 6.88ꢀ6.83
3
1
3
1
(m, 2H), 6.70ꢀ6.67 (m, 1H), 3.59 (s, 2H), 2.40 (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 156.4
3
(
d, J = 234.7 Hz), 139.6 (d, J = 1.2 Hz), 137.4, 135.6 (d, J = 1.2 Hz), 129.6, 128.8, 116.7 (d, J = 22.2
19
Hz), 116.4 (d, J = 7.9 Hz), 114.6 (d, J = 22.2 Hz), 21.2; F NMR (376 MHz, CDCl ) δ (ppm): ꢀ127.0.
3
4
3
Data was consistent with that reported in the literature.
ꢀFluoroꢀ4'ꢀmethoxybiphenylꢀ2ꢀamine (5bb). The product was prepared as described in typical
procedure and isolated as a yellow oil in a 67% yield (291 mg); R = 0.31 (petroleum ether/ethyl acetate
4
f
ꢀ1
1
=
5:1, v/v). IR (cm , KBr): 3425, 3380, 1598 1480, 1167, 698; H NMR(400 MHz, CDCl ) δ (ppm):
3
7
.32 (d, J = 8.7 Hz, 2H), 7.25ꢀ7.00 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.51ꢀ6.42 (m, 2H), 3.84 (s, 3H);
1
3
1
C{ H}NMR (100 MHz, CDCl ) δ (ppm): 163.0 (d, J = 241.6 Hz), 158.9, 145.2 (d, J = 10.8 Hz), 131.6
3
(
d, J = 9.7 Hz), 130.9, 130.3, 123.3 (d, J = 2.7 Hz), 114.3, 105.0 (d, J = 21.2 Hz), 101.9 (d, J = 24.6 Hz),
19
5
5.3; F NMR (376 MHz, CDCl ) δ (ppm): ꢀ135.1. Data was consistent with that reported in the
3
4
4
literature.
5ꢀFluoroꢀ2'ꢀtrifluoromethylbiphenylꢀ2ꢀcarboxylic acid (5cm). The reaction was quenched with 2M
HCl aqueous solution and the product was isolated as a yellow solid in a 81% yield (460 mg); mp =
ꢀ1
1
3
64.5ꢀ165.4 °C; 81%; R = 0.49 (petroleum ether/ethyl acetate/acetic acid = 5:1:0.01). IR (cm , KBr):
f
1
421, 3066, 1692, 1600, 1435, 766; H NMR (CDCl , 400 MHz) δ (ppm): 8.33 (s, 1H), 7.57ꢀ7.53 (m,
3
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1
3
1
3
H), 7.46ꢀ7.42 (m, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 167.7, 167.1, 136.5, 134.4, 131.1,
3
1
2
3
4
5
6
7
8
9
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
1
9
1
29.7, 129.5, 127.2, 126.4, 125.4, 124.7, 124.1, 115.2, 110.7; F NMR (376 MHz, CDCl ) δ (ppm): ꢀ
3
1
0c
98.7, ꢀ104.6. Data was consistent with that reported in the literature.
1
ꢀ(4ꢀChloroꢀ2ꢀ(naphthalenꢀ1ꢀyl)phenyl)ethanone (5dl). The product was prepared as described in
o
typical procedure and isolated as a white solid in a 85% yield (476 mg); mp = 118ꢀ120 C; R = 0.52
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
f
ꢀ1
(
petroleum ether/ethyl acetate = 20:1, v/v). IR (cm , KBr): 3061, 2998, 2937, 1682, 1608, 1421, 751,
1
6
98; H NMR (CDCl , 400 MHz) δ (ppm): 7.92 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (d, J
3
1
3
1
= 8.4 Hz, 1H), 7.54 ꢀ7.45 (m, 4H), 7.423ꢀ7.418 (m, 1H), 7.34ꢀ7.32 (m, 1H), 1.75 (s, 3H); C{ H}NMR
(
CDCl , 100 MHz) δ (ppm): 201.6, 141.0, 139.4, 137.4, 137.1, 133.6, 131.7, 131.5, 130.1, 128.9, 128.5,
3
+
+
1
28.1, 127.3, 126.9, 126.3, 125.33, 125.31, 29.7; HRMS calcd for C H ClO [M+H] 281.0728,
18 14
Found 281.0726.
(
2′ꢀMethoxyꢀbiphenylꢀ2ꢀyl) (4ꢀchlorophenyl) methanone (5em). The product was prepared as
o
described in typical procedure and isolated as a white solid in a 92% yield (592 mg); mp = 97ꢀ98 C; R
f
ꢀ1
1
= 0.38 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 1659, 1572, 1497, 1319, 758; H
NMR (CDCl , 400 MHz) δ (ppm): 7.68 (d, J = 8.5 Hz, 2H)，7.59ꢀ7.54 (m, 1H), 7.48ꢀ7.38 (m, 3H)，
3
1
3
1
7
.30ꢀ7.18 (m, 4H)，6.97ꢀ6.93 (m, 1H), 6.67 (d, J = 8.2 Hz, 1H), 3.38 (s, 3H); C{ H}NMR (CDCl ,
3
1
1
3
00 MHz) δ (ppm): 195.7, 155.2, 138.7, 138.5, 137.9, 135.7, 131.5, 131.3, 131.0, 130.8, 129.3, 129.1,
+
2
+
28.5, 128.2, 126.8, 121.0, 110.2, 54.4. HRMS calcd for C H ClO [M+H] 323.0833, Found
2
0
16
23.0831.
5ꢀChloroꢀ4'ꢀmethoxybiphenylꢀ2ꢀamine (5fb). The product was prepared as described in typical
procedure and isolated as a white solid in a 78% yield (326 mg); mp = 83.5ꢀ85.5 °C (lit., 84.5ꢀ85.5 °C);
Rf = 0.43 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cmꢀ1, KBr): 3463, 3372, 1608, 1487, 1241,
1
1168, 1034, 829, 814, 697; H NMR (CDCl , 400 MHz) δ (ppm): 7.34 (d, J = 8.6 Hz, 2H), 7.09ꢀ7.07
3
13
1
(
m, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.71ꢀ6.68 (m, 1H), 3.84 (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ
3
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(
ppm): 159.1, 142.3, 130.5, 130.1, 130.0, 128.7, 127.9, 123.1, 116.6, 114.4, 55.4. Data was consistent
1
2
3
4
5
6
7
8
9
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
4
5
with that reported in the literature.
5ꢀBromoꢀ4'ꢀmethoxybiphenylꢀ2ꢀamine (5gb). The product was prepared as described in typical
procedure and isolated as a white solid in a 68% yield (377 mg); mp = 89ꢀ91 °C (lit., 89.1ꢀ90.6 °C); R =
f
ꢀ1
0
.42 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 3458, 3369, 1598, 1477, 1290, 1168,
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
1
034, 814, 697; H NMR (CDCl , 400 MHz) δ (ppm): 7.33 (d, J = 8.8 Hz, 2H), 7.21ꢀ7.19 (m, 2H), 6.97
3
13
1
(d, J = 8.8 Hz, 2H), 6.63ꢀ6.61 (m, 1H), 3.84, (s, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 159.1,
3
142.9, 132.8, 130.7, 130.4, 130.1, 129.2, 117.0, 114.4, 110.1, 55.4. Data was consistent with that
4
6
reported in the literature.
Ethyl 2',4'ꢀdifluoroꢀ4ꢀhydroxybiphenylꢀ3ꢀcarboxylate (diflunisal ethyl ester). The reaction was
quenched with 2M HCl aqueous solution and the product was isolated as a pale yellow oil in a 92%
ꢀ1
yield (450 mg); R = 0.55 (petroleum ether/ethyl acetate = 10:1, v/v). IR (cm , KBr): 3137, 1679, 1485,
f
1
1
439, 1210,766; H NMR (CDCl , 400 MHz) δ (ppm): 10.9 (s, 1H), 7.98ꢀ7.97 (m, 1H), 7.59 (d, J = 8.7
3
Hz, 1H), 7.40ꢀ7.34 (m, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.97ꢀ6.88 (m, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.43
13
1
(t, J = 7.1 Hz, 3H); C{ H}NMR (CDCl , 100 MHz) δ (ppm): 170.0, 162.2 (dd, J = 247.2 Hz, J = 11.7
3
Hz, 1C), 161.3, 159.7 (dd, J = 248.0 Hz, J =11.7 Hz, 1C), 136.1 (d, J = 2.9 Hz, 1C), 131.1(dd, J = 9.4
Hz, J = 4.9 Hz, 1C), 130.1 (d, J = 2.7 Hz, 1C), 126.0, 124.2 (dd, J = 13.4 Hz, J = 3.7 Hz, 1C), 117.8,
19
1
12.7, 111.6 (dd, J = 21.0 Hz, J = 3.7 Hz, 1C), 104.4 (dd, J = 26.5 Hz, J =25.1 Hz, 1C), 61.7, 14.2. F
NMR (376 MHz, CDCl ) δ (ppm) ꢀ111.5 (d, J = 7.8 Hz, 1F), ꢀ113.7 (d, J = 7.4 Hz, 1F). Data was
3
4
7
consistent with that reported in the literature.
',4'ꢀDifluoroꢀ4ꢀhydroxybiphenylꢀ3ꢀcarboxylic acid (diflunisal). The reaction was quenched with 2M
HCl aqueous solution and the product was isolated as a white solid in an 87% yield (425 mg); mp =
10ꢀ212 °C (lit., 210ꢀ211 °C); R = 0.33 (petroleum ether/ethyl acetate / acetic acid = 10:1:0.01, v/v/v).
2
2
f
ꢀ1
1
IR (cm , KBr): 3098, 1682, 1600, 1496, 1467, 1326, 1162, 701; H NMR (CD SOCD , 400 MHz) δ
3
3
(ppm): 7.92 (s, 1H), 7.70ꢀ7.67 (m, 1H), 7.61ꢀ7.55 (m, 1H), 7.39ꢀ 7.33 (m, 1H), 7.21ꢀ7.16 (m, 1H), 7.08
13
1
(d, J = 8.6 Hz, 1H); C{ H}NMR (CD SOCD , 100 MHz) δ (ppm) 171.5, 160.7, 160.4 (dd, J = 245.1
3
3
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Hz, J =12.2 Hz, 1C), 158.9 (dd, J = 246.5 Hz, J = 12.3 Hz, 1C), 135.8 (d, J = 2.2 Hz, 1C), 131.5 (dd, J =
.5 Hz, J = 4.6 Hz, 1C), 130.2 (d, J = 3.1 Hz, 1C), 125.1, 123.7 (dd, J = 13.2 Hz, J = 3.7 Hz, 1C), 117.5,
1
2
3
4
5
6
7
8
9
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
9
1
9
113.1, 112.0 (dd, J = 20.9 Hz, J =3.6 Hz, 1C), 104.1 (t, J = 26.4 Hz, 1C); F NMR (376 MHz, CDCl ) δ
3
(ppm): ꢀ111.4 (d, J = 7.4 Hz, 1F), ꢀ114.2 (d, J = 7.4 Hz, 1F). Data was consistent with that reported in
4
8
the literature.
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
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4
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9
0
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*
Eꢀmail: xinfangduan@vip.163.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Science Foundation of China (21242006, 21372031,
2
1572022) and Beijing Municipal Commission of Education.
Supporting Information
1
13
19
Copies of HNMR, C NMR spectra for all products; F NMR spectra for the fluorineꢀcontaining
products and HRMS spectra for the new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
REFERENCES
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(
(
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1
1
1
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1
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2
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3
3
3
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
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9
0
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8
9
0
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J.; Ma, Y. Q.; Qiu, L. L.; Fang, J. X. Chem. Eur. J. 2012, 18, 446.
(
5) (a) Nakamura, Y.; Yoshikai, N.; Ilies, L.; Nakamura, E. Org. Lett. 2012, 14, 3316; (b) Sun, A. D.; Leung, K.;
Restivo, A. D.; LaBerge, N. A.; Takasaki, H.; Love, J. A. Chem. Eur. J. 2014, 20, 3162; (c) Zhu, F.; Wang, Z.
X. J. Org. Chem. 2014, 79, 4285.
(
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