Unified Protocol for Cobalt-Catalyzed Oxidative Assembly of Two Aryl Metal Reagents Using Oxygen as an Oxidant

Article abstract of DOI:10.1021/acs.joc.5b01787

The first cobalt-catalyzed oxidative cross-coupling reaction of two aryl metal reagents is described. An equivalent amount of two aryl Grignard or lithium reagents, after mediation by an equivalent amount of simple ClTi(OEt)₃, was facilely assembled under the catalysis of 1 mol % of CoCl₂/10 mol % of DMPU using oxygen. The cross-couplings between various aryl metal reagents, especially between two structurally similar aryl Grignard reagents, proceeded smoothly and selectively and, thus, provided a highly general and efficient method for the construction of biaryl compounds.

Full text of DOI:10.1021/acs.joc.5b01787

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Featured Article
A Unified Protocol for Cobalt-catalyzed Oxidative Assembly
of Two Aryl Metal Reagents Using Oxygen as an Oxidant
Lian-Yan Liao, Kun-ming Liu, and Xin-Fang Duan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01787 • Publication Date (Web): 29 Sep 2015
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The Journal of Organic Chemistry
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A Unified Protocol for Cobaltꢀcatalyzed Oxidative
Assembly of Two Aryl Metal Reagents Using Oxygen
as an Oxidant
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LianꢀYan Liao, KunꢀMing Liu, and XinꢀFang Duan*
College of Chemistry, Beijing Normal University, Beijing, 100875, China
xinfangduan@vip.163.com
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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
N
N
COOEt
79%
Br
Cl
N
N
N
O
70%
1 mol % CoCl2
10 mol % DMPU
late-stage arylation of
natural product
tolerance to highly active
C-Br bond
ArM
+
CHO
ClTi(OEt)3
Ar'M
O2, -10 or 0 oC
87%
N
85%
MeO
equivalent
48 examples
up to 96%
EtOOC
high selectivity between two
similar metal reagents
high functional group tolerance
with broad scope
ABSTRACT. The first cobaltꢀcatalyzed oxidative crossꢀcoupling reaction of two aryl metal reagents is
described. An equivalent amount of two aryl Grignard or lithium reagents, after mediation by an
equivalent of simple ClTi(OEt)3, was facilely assembled under the catalysis of 1 mol % CoCl2 / 10
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Page 2 of 34
mol% DMPU using oxygen. The crossꢀcouplings between various aryl metal reagents, especially
between two structurally similar aryl Grignard reagents, proceeded smoothly and selectively, and thus
provided a highly general and efficient method for the construction of biaryl compounds.
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1. INTRODUCTION
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Oxidative couplings of metal reagents have now become a very attractive method to construct C－C
bonds.1 The prominent advantages of these couplings lie not only in that the rapid advances in
organometalllic chemistry provide a wide range of varoius metal reagents for this transformation;2 but
also that direct metalation of arenes enables this type of couplings using simple or functionalized
arenes.3 In transitionꢀmetalꢀcatalyzed reactions, catalysts are usually expensive not only because of the
use of expensive transitionꢀmetal as catalyst centers, but also owing to the requirement of complex
ligands to sustain the activity of catalyst. In this regard, an oxidative coupling may eliminate the use of
special ligands because it proceeds through double transmetallation without the use of an aryl halide or
pseudohalide as well as the process of oxidative addition that usually requires a special ligand for
unreactive halides.4 As illustrated in Scheme 1, under the catalysis of inexpensive and simple catalyst
system as well as with molecular oxygen as an oxidant, an ideal oxidative coupling will provide the
desired products with peroxide inorganic salts as only side products under mild conditions. Despite
these advantages, the undesired homocoupling side reactions of two metal reagents remain a serious
problem to be controlled in the oxidative crossꢀcoupling reactions. As such, only few examples of the
oxidative crossꢀcoupling have been described to date, most of which are achieved between different
hybridized carbon atoms such as C(sp)－C(sp2);5 C(sp)－C(sp3);6 C(sp2)－C(sp3),7 and usually with
one of the metal reagents in large excess. The examples of oxidative arylꢀaryl cross couplings are very
rare.5b,8 Obviously, the similar reactivity of the organometallic reagents makes the arylꢀaryl oxidative
cross couplings remarkably challenging due to the homocoupling side reactions. On the other hand, due
to the high cost of palladium and the high toxicity of nickel catalysts, cobalt salts or complexes are
viable alternatives. Recently intense research has been conducted on cobaltꢀcatalyzed coupling
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reactions,9,10 however, to the best of our knowledge, there has been no report on cobaltꢀcatalyzed
oxidative crossꢀcouplings between two aryl metal reagents to date.
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Scheme 1 Comparison of an ideal oxidative crossꢀcoupling with the cobaltꢀcatalyzed oxidative
assembly of titanateꢀmediated two aryl metal reagents.
Recently we have reported a highly selective ironꢀcatalyzed arylꢀaryl oxidative crossꢀcoupling
reaction of titanateꢀmediated aryl metal reagents.11 We have also observed a remarkable synergetic
effect of Co and Ti in the Coꢀcatalyzed biaryl crossꢀcouplings.12 Prompted by these findings, we
decided to develop a facile Coꢀcatalyzed oxidative biaryl crossꢀcoupling reaction of aryl metal reagents,
on which we would like to present our full investigations herein. Meanwhile, a series of ironꢀcatalyzed
crossꢀcouplings of this type was also examined for comparison. This Coꢀcatalyzed reaction represents
one of most desirable oxidative crossꢀcouplings between two aryl metal reagents, and meets almost all
the requirements of the ideal oxidative crossꢀcouplings (Scheme 1). Importantly, low loading of catalyst
cobalt salt (1 mol% CoCl2) as well as simple ligand (DMPU) showed a high catalytic effect.
2. RESULTS AND DISSCUSSION
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Table 1 Optimization studiesa
1
N
2
3
4
5
6
7
8
9
Me
Li
N
N
[Co ]
ligand
3a
Me
N
N
N
ClTi(OR)3
Ph Ph
Ph
+
PhMgBr
PhTi(OR)3
+
N
O2, solvent
N
Me
Me
Biimdazoe
1a
Biphenyl
4aa
10
11
12
13
14
15
16
17
18
19
20
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22
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Entry
1
Catalystb
(mol%)
Ligand
(mol%)
Titanate
Yield
of 4aa
(%)
Yield of
biimdazoe
(%)
Yield of
biphenyl
(%)
Time
(1.0 equiv)
ClTi(OEt)3
ClTi(OEt)3
（h）
FeCl3 (8)
TMEDA (20)
TMEDA (20)
6
78
trace
11
2
3
4
CoCl2 (10)
3
4
4
40
25
35
10
6
38
55
46
CoCl2 (10)
CoCl2 (10)
Bu3P (20)
Cy3P (20)
ClTi(OEt)3
ClTi(OEt)3
8
CoCl2 (10)
CoCl2 (10)
CoCl2 (10)
CoCl2 (10)
CoCl2 (10)
CoCl2 (10)
BPYc (20)
PTLd (20)
ClTi(OEt)3
ClTi(OEt)3
ClTi(OEt)3
ClTi(OEt)3
ClTi(OPri)3
TBEPCf
4
4
4
4
4
4
4
4
20
18
60
61
45
62
15
12
12
13
15
10
22
8
53
51
23
28
30
25
65
70
5
6
DMPUe (20)
DMPU (10)
DMPU (10)
Bu3P (20)
7
8
9
10
11
12
Co(acac)2 (10) Cy3P (20)
Co(acac)2 (10) BPYc (20)
ClTi(OEt)3
ClTi(OEt)3
12
8
13
CoCl2 (5)
CoCl2 (3)
CoCl2 (3)
CoCl2 (1)
ꢀꢀꢀꢀꢀ
DMPU (10)
DMPU (10)
DMPU (5)
DMPU (10)
ꢀꢀꢀꢀꢀ
ClTi(OEt)3
ClTi(OEt)3
ClTi(OEt)3
ClTi(OEt)3
ClTi(OEt)3
4
5
5
6
6
72
78
72
82
6
7
10
9
14g,h
15
3
5
12
8
16
trace
2
17
23
aThe reaction was conducted on 5 mmol scale at 0 C unless indicated otherwise. 3a was prepared by lithiation of 1ꢀ
o
b
methylimidazole using TPMLi at 0 oC. c2,2’ꢀbipyridine. d1,10ꢀphenanthroline. e1,3ꢀdimethylꢀ3,4,5,6ꢀtetrahydroꢀ2(1H)ꢀ
pyrimidinone. ClTi(OPri)(OCH2CH2OCH2CH2O)11. The coupling reactions could not occur when conducted in
f
g
toluene and hexane under these conditions. hLowering the temperature to ꢀ5 or ꢀ10 oC did not improve the yield of 4aa.
At the outset of our studies, we investigated the oxidative crossꢀcoupling of titatnateꢀmediated
PhMgBr (1a) and 1ꢀmethylꢀimidazolylꢀ2ꢀlithium (3a) with the selected examples being shown in Table
1. Compared with iron catalysis,11 the Coꢀcatalyzed reaction under similar conditions gave low yield of
crossꢀcoupling product (entries 1 and 2). The screening of ligands indicated that the simple phosphine
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ligands such as PBu3, PCy3 and bidentate nitrogen ligands such as 2,2ꢀbipyridine (BPY) and 1,10ꢀ
phenanthroline (PTL) were not as effective as expected (entries 3ꢀ6). To our delight, the use of an
inexpensive ligand, DMPU13 could promote the oxidative crossꢀcoupling reactions more efficiently
(entries 7 and 8). We also examined the influence of different titanates (entries 9 and 10). While the use
of ClTi(OPri)3 resulted in a lower yield, ClTi(OEt)3 and TBEPC11 gave almost the same results, which
was in contrast with the corresponding ironꢀcatalyzed reactions.11 It was also found that the type of
cobalt salts was sensitive to the reaction, and Co(acac)2 only resulted in very low yields of crossꢀ
coupling product (entries 11 and 12).
1
2
3
4
5
6
7
8
9
10
11
12
13
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17
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After careful observation, we found that the oxidative couplings occurred much more rapidly under
the catalysis of 10 mol % CoCl2 / 10 mol % DMPU than those catalyzed by FeCl3/TMEDA (entry 1 and
the examples in the ref. 11). We deduced that lowering the loading of the cobalt catalyst to slow down
the coupling reaction might help to improve the selectivity of the crossꢀcoupling. As expected, the
crossꢀcoupling occurred in a 82 % yield when CoCl2 was loaded in 1 mol% (entries 13ꢀ16). The crossꢀ
coupling hardly occurred in the absence of CoCl2 (entry 17). Besides, the reaction conducted in toluene
o
or hexane did not proceed, and further lowering the reaction temperature (to ꢀ5 or ꢀ10 C) did not
improve the yield of the crossꢀcoupling. Thus, a highly selective Coꢀcatalyzed oxidative crossꢀcoupling
with the low loading of cobalt salt (1 mol% CoCl2) and simple ligand (10 mol% DMPU) was
established using oxygen as an oxidant in single THF solvent at 0 oC.
With optimized reaction conditions in hand, we then explored the generality of this cobaltꢀcatalyzed
oxidative crossꢀcoupling. Since Nꢀheteroarylꢀcontaining biaryls are widely presented in bioactive and
related compounds, the reactions between aryl and Nꢀheteroaryl metal reagents were first investigated
with the results being outlined in Table 2. It can be seen that this reaction was quite general and
exhibited a high tolerance for various sensitive functional groups. Almost all common Nꢀheteroarenes
including pyridine, (iso)quinolone, imidazole, benzoimidazole, benzothiazole, aryloxazole, quinoxaline
and caffeine were all readily amenable to this Coꢀcatalyzed crossꢀcoupling. In general, the yields of
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Table 2 Cobaltꢀcatalyzed crossꢀcouplings between titanateꢀmediated Nꢀheteroaryl and aryl metal
1
2
3
reagents with molecule oxygena
4
5
6
7
8
9
Entry
1
ArMgX
ArNM
Product
Entry
11
ArMgX
ArNM
Product
MgBr
10
11
12
13
14
15
16
17
18
19
20
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22
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MgBr
N
S
N
MgBr
N
S
N
M
1a
3bb
4ab 90% (Co)
1d
3if
4di
95% (Fec)
77% (Co)
CN
MeO
MgBr
OMe
MgBr
N
N
N
N
2
3
12
13
4hi
M
MgX
1b
3b
4bb 96% (Co)
1h
3if
81% (Co)
CN
96% (Fec)
MgBr
N
N
N
N
M
MgBr
OMe
MeO
MgBr
N
4cc 84% (Co)
N
1c
3cb
55% (Fed)
1b
3jf
4bj 85% (Co)
S
N
M
CN
MgX
MgBr
N
MeO
N
4
14
N
MgBr
N
S
MeO
MeO
N
3db
4dd 75% (Co)
15% (Fec)
NC
1d
1h
3jf
60% (Fed)
4hj 76% (Co)
N
N
MgBr
MgBr
MgBr
M
MeO
5
6
15
16
N
N
N
N
3cb
3db
4cd 85% (Co)
1g
3kf
3af
4gk 80% (Co)
N
N
S
N
Li
Br
Cl
Cl
MgBr
MgBr
MgBr
N
S
N
Br
Br
N
1e
3eb
4ee 70% (Co)
1d
4da 86% (Co)
N
Br
MgBr
N
Me
F3C
MgBr
N
Li
Me
17
7
4ffN 83% (Co)
45% (Fec)
4ia 78% (Co)
35% (Fec)
CF3
N
N
1f
3fb
58% (Fed)
1i
3af
58% (Fed)
MgBr
N
N
F
F
MgBr
18
19
M
N
S
8
9
N
M
S
1c
3ge
4cg 73% (Co)
1g
3lg
4gl 80% (Co)
N
F
OMe
F
MgBr
MgBr
1a
N
O
N
3ge
M
N
Ph
1g
1f
4gg 77% (Co)
3mg
4am 82% (Co)
O
N
N
N
3nf
10
N
Me
M
20
3hf
O
M
4fh 80% (Co)
1j
4jn 79% (Co)
aThe reaction was conducted on 3 mmol scale unless indicated otherwise. For the Coꢀcatalyzed reaction: 1 mol% CoCl2
/ 10 mol% DMPU, ClTi(OEt)3, 0 oC. For the Feꢀcatalyzed reaction: 8 mol% FeCl3 / 20 mol% TMEDA, ClTi(OEt)3 or
b
c
TBEPC, RT. The Grignard reagents were prepared through bromineꢀmagnesium exchange using iꢀPrMgCl. In these
d
e
Feꢀcatalyzed reactions, ClTi(OEt)3 was used. In these Feꢀcatalyzed reactions, TBEPC was used. The reagent was
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f
prepared through deprotonative metalation using BF3·Et2O/TMPMgCl·LiCl. The reagent was prepared through
deprotonative metalation using TMPMgCl·LiCl or TMPLi. gThe reagent was prepared through deprotonative
metalation using EtMgBr.
1
2
3
4
5
6
7
8
9
the present crossꢀcouplings under the catalysis of 1 mol% CoCl2 and 10 mol% DMPU with the
mediation of simple ClTi(OEt)3 were comparable to or even better than those catalyzed by 10 mol%
FeCl3 and 20 mol% TMEDA with the mediation of TBEPC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Although iron or cobaltꢀcatalyzed the coupling reactions of 2ꢀpyridyl moiety have been well
developed,14 the corresponding crossꢀcouplings using 3ꢀpyridyl species often show disappointing results.
Our investigations clearly indicated that the Co or Feꢀcatalyzed oxidative crossꢀcouplings using both 2ꢀ
pyridyl and 3ꢀpyridyl Grignard reagents were achieved facilely (Table 2, entries 1ꢀ7). While the ironꢀ
catalyzed couplings of 2ꢀpyridyl Grignard reagents proceeded equally well using ClTi(OEt)3 and
TBEPC (Table 2, entries 1 and 2); the corresponding couplings of 3ꢀpyridyl Grignard reagents showed a
significant difference between the two titanates, where the couplings using TBEPC resulted in higher
yields (Table 2, entries 3 and 4). Nevertheless, the cobaltꢀcatalyzed couplings of 3ꢀpyridyl Grignard
reagents mediated with simple ClTi(OEt)3 proceeded equally well compared with those of 2ꢀpyridyl
moiety (entries 3ꢀ7), demonstrating the broad scope and robustness of the cobalt catalysis. Noteworthily,
two highly similar 3ꢀpyridyl Grignard reagents were also selectively assemble to yield 4cd in a 85%
yield (Table 2, entry 5). The tolerance of C－Cl, C－Br bonds, especially the highly active C－Br bond
at the C2 position of pyridyl ring, offers an attractive and useful feature for this oxidative crossꢀcoupling
(Table 2, entries 6 and 7), for the chlorine or bromine handle can be derivatized to afford other
products.15 Since the deprotonative metalation has been well established,3 the present oxidative crossꢀ
couplings could be achieved using simple (hetero)arenes. For example, 2ꢀquinolinyl metal reagents was
facilely prepared from quinoline using BF3·Et2O/TMPMgCl·LiCl,16 and oxidatively coupled with
Grignard reagents in 73% and 77% yields (Table 2, entries 8 and 9). Meanwhile, isoquinoline, 2ꢀ
phenylpyridine and quinoxaline were all directly metalated using TMPMgCl·LiCl or TMPLi, and
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Table 3 Cobaltꢀcatalyzed oxidative assembly of titanateꢀmediated oxazoline or imineꢀcontaining aryl
1
2
3
4
5
metal reagents and aryl Grignard reagents using oxygena
ArGM
1 mol% CoCl2
10 mol% DMPU
O2, THF, 0 oC to rt
ArMgX
ClTi(OEt)3
5
Ar ArG
ArG[ArTi(OEt)3]M
ArMgX
ArTi(OEt)3
6
7
8
9
6
1
Entry
1
ArMgX
ArGM
Product
Entry
ArGM
Product
O
O
N
O
M
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
N
MgBr
S
6ge 85% (Co)
45% (Fec)
F
MgBr
MgBr
M
S
9
6da
N
1d
1g
1a
5ee
73% (Fed)
5ab
80% (Co)
O
CHO
O
NPh
F
MgBr
MgBr
N
N
2
3
6ga
MgX
10
M
75% (Co)
35% (Fec)
68% (Fed)
5fe
6af 84% (Co)
1g
1f
60% (Fec)
F
5ab
O
O
CHO
O
M
COOEt
MgX
NPh
MgX
5fe
N
N
Me
11
MeO
MeO
6fb 77% (Co)
EtOOC
1ke
5bb
26% (Fec)
6kf 87% (Co)
MgBr
NPh
O
N
N
6ca
CHO
EtOOC
N
EtOOC
F3C
MgX
72% (Co)
4
5
12
13
6jg 82% (Co)
M
1c
1je
5ge
73% (Fed)
5ab
MgX
Ph
NH2
CF3
O
O
N
CN
MgBr
N
6hb
MeO
MgX
MgX
1he
MeO
M
6ih 79% (Co)
28% (Fec)
5he
5bb
67% (Co)
1i
51% (Fed)
NC
O
Ph
NH2
O
Me
N
6ac
78%
(Co)
N
N
MgBr
MgBr
6
7
14
15
16
MgX
1a
M
Me
5he
5ie
5ie
6lh 78% (Co)
5cb
F
1l
F
O
Ph
MgBr
O
O
H2N
MgX
Cl
Cl
N
Me
MgBr
MgX
N
N
M
5de
6fd 83% (Co)
1f
1e
6ei 82% (Co)
O
Ph
EtOOC
N
MgX
N
1je
6mi 73% (Co)
N
8
M
EtOOC
5de
1m
34% (Fec)
6jd 80% (Co)
aThe reaction was conducted on 3 mmol scale unless indicated otherwise. For the Coꢀcatalyzed reaction: 1 mol% CoCl2
/ 10 mol% DMPU, ClTi(OEt)3, 0 oC. For the Feꢀcatalyzed reaction: 8 mol% FeCl3 / 20 mol% TMEDA, ClTi(OEt)3 or
b
c
TBEPC, RT. The reagent was prepared through deprotonative metalation using TMPMgCl·LiCl. In these Feꢀ
d
e
catalyzed reactions, ClTi(OEt)3 was used. In these Feꢀcatalyzed reactions, TBEPC was used. The Grignard reagents
were prepared through iodineꢀmagnesium exchange using iꢀPrMgCl·LiCl.
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coupled with various Grignard reagents including functionalized or heteroaryl ones to give the desired
products in 76ꢀ85% yields (Table 2, entries 10ꢀ14). Similarly, various imidazole, benzoimidazole,
benzothiazole and aryloxazole derivatives which are often found in pharmaceutical compounds were
prepared in 78ꢀ86% yields (Table 2, entries 15ꢀ19). Additionally, a mild arylation of caffeine could also
be achieved, demonstrating a convenient lateꢀstage functionality of natural product (Table 2, entry 20).
Based on the above findings, we further extended the scope of the Coꢀcatalyzed oxidative crossꢀ
couplings to the reactions between two aryl metal reagents, one of which contained an oxazoline or
imine group. The results were illustrated in Table 3. Oxazolines are usually used as protecting groups,
directing groups for metalation, chiral ligands or auxiliaries, and therefore are a class of important
structural blocks for crossꢀcouplings. Taking advantage of ortho deprotonative metalation of oxazolines
using TMPMgCl·LiCl,17 a series of aryloxazolines was arylated in 67ꢀ80% yields based on this Coꢀ
catalyzed oxidative crossꢀcoupling (Table 3, entries 1ꢀ6). Relatively, the corresponding ironꢀcatalyzed
reaction mediated with TBEPC gave a comparable yield while those using ClTi(OEt)3 resulted in low
yields (Table 3, entries 2 and 3). The sterically hindered oxazoline products such as 6ca and 6hb were
conveniently prepared as well. It is worthy to note that the oxidative arylation at the position meta or
para to the oxazoline group proceeded equally well (Table 3, entries 7ꢀ9), which can function as a
complementary protocol to the existing Ruꢀcatalyzed ortho arylation of 2ꢀaryloxazolines.18
1
2
3
4
5
6
7
8
9
10
11
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The imine group is also an important functionality in organic chemistry, and is often used as
protecting groups for primary amines, aldehydes and ketones.19 As illustrated in Table 3 (entries 10ꢀ16),
various Grignard reagents containing an imine group (derivatized from amines or aldehydes) were
oxidatively coupled with another aryl Grignard reagent under the present Coꢀcatalyzed conditions to
afford the desired products in 73ꢀ87% yields. Once again, while the Coꢀcatalyzed reactions using
ClTi(OEt)3 proceeded well, the ironꢀcatalyzed couplings using ClTi(OEt)3 gave lower yields relative to
those using TBEPC (Table 3, entries 10, 12, 13 and 16). To date, although the Coꢀcatalyzed arylation,
alkenylation and alkylation of ketimines and aldimines have been well established at the positions ortho
to carbonyl group,9c,d;10 the corresponding arylation ortho to amine group has relatively rarely been
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Table 4 Cobaltꢀcatalyzed oxidative assembly of titanateꢀmediated two structurally similar aryl Grignard
1
2
reagents using oxygen as oxidanta
3
4
5
1 mol% CoCl2
Ar'MgX
1
10 mol% DMPU
ArMgX
Ar'[ArTi(OEt)3]MgX
Ar Ar'
7
O2, THF, -10 oC to rt
1
6
7
8
Entry
ArMgX
Ar′MgX
Product
9
N
MeO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1b
1b
1n
7bn 79% (Co);85% (Cod)
56% (Fec); 79% (Fed)
Me
MeO
2
1f
7bf 78% (Co); 86% (Cod)
50% (Fec); 79% (Fed)
F
MeO
3
4
1b
1b
1g
1i
7bg 81% (Co)
MeO
7bi 81% (Co)
CF3
84% (Fed)
N
5
1c
1n
7cn 77% (Co)
Cl
6
7
1e
1i
7ei 73% (Co)
CF3
COOEt
1ke
1l
1he
7kh
83% (Co)
NC
Me
8b
9b
1oe
1pe
7lo
78% (Co)
Me2NOC
1l
7lp
76% (Co)
10b
11b
12b
1qe
1pe
1re
1a
1f
7aq
74% (Co)
7fp
76% (Co)
85% (Cod)
1a
7ar 85% (Co)
aThe reaction was conducted on 3 mmol scale unless indicated otherwise. For the Coꢀcatalyzed reaction: 1 mol% CoCl2
o
/ 10 mol% DMPU, ClTi(OEt)3, ꢀ10 C. For the Feꢀcatalyzed reaction: 8 mol% FeCl3 / 20 mol% TMEDA, ClTi(OEt)3
or TBEPC, 0 oC. bIn these reactions, the Coꢀcatalyzed reaction was performed at 0 oC while the Feꢀcatalyzed reaction at
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c
d
RT. In these Feꢀcatalyzed reactions, ClTi(OEt)3 was used. In these Co or Feꢀcatalyzed reactions, TBEPC was used.
1
2
3
eThe Grignard reagents were prepared through iodineꢀmagnesium exchange using iꢀPrMgCl·LiCl.
4
5
6
7
8
9
investigated. With Grignard reagent 5h, this oxidative coupling reaction produced the 2ꢀarylated
anilines in good yields (Table 3, entries 13 and 14). Notably, the arylations beyond the ortho position of
imine group also proceeded well (Table 3, entries 12, 15 and 16). Based on our present procedure, two
structurally similar Grignard reagents as well as sterically hindered Grignard reagents were all facilely
assembled (Table 3, entries 11, 12 and 14).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Selective oxidative crossꢀcouplings of two structurally similar aryl metal reagents is remarkably
challenging because a similar reactivity of the organometallic reagents makes the homocoupling side
reactions very difficult to be controlled. As illustrated in aforeꢀmentioned examples (Table 2, entry 5;
Table 3, entries 5, 11 and 12), a few of such selective crossꢀcouplings have already been achieved
successfully. To further extend the generality of this coupling reaction, additional Coꢀcatalyzed
oxidative crossꢀcouplings between two structurally similar aryl metal reagents were examined, and the
results were summarized in Table 4. To our delight, two common structurally highly similar aryl
Grignard reagents were coupled to give the crossꢀcoupling product in 79% yield (Table 4, entries 1ꢀ3),
demonstrating the high amenability to various aryl metal reagents as well as the robustness of this Coꢀ
catalyzed oxidative crossꢀcoupling. Importantly, this oxidative crossꢀcoupling reaction still showed
broad scope with remarkable selectivity over homocouplings, and at the same time sensitive functional
groups such as ester, amide and nitrile were tolerated. While the Coꢀcatalyzed couplings using
ClTi(OEt)3 and TBEPC showed a slight difference, the Feꢀcatalyzed ones showed a significant
difference (Table 4, entries 1, 2, 11). Sterically hindered biaryls could still be assembled smoothly
(Table 4, entries 7ꢀ11). Besides, not only the couplings between electronically different aryl Grignard
reagents occurred with good yields (Table 4, entries 3, 4, 5, 8, 9, 10), the couplings between
electronically similar aryl Grignard reagents also proceeded equally well (Table 4, entries 1, 2, 6 and 7).
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Mechanistically, we assume that a cobaltꢀtitanium bimetallic cooperativity in this oxidative crossꢀ
coupling suppresses the formation of the symmetrical diaryl cobalt complex [Co(Ar)2 or Co(Ar′)2] and
the consequent undesired homocouplings. The preparation and isolation of the cobaltꢀtitanium
bimetallic complexes are being carried out in our laboratories. This oxidative coupling seemed not to
proceed through a radical mechanism since it was not inhibited by the addition of a radical scanvengner
(TMPO). Besides, the peroxide group from the expected peroxide salt [Scheme 1; MOOM, M = Li,
MgX, Ti(OEt)3] was also detected by potassium iodideꢀstarch solution after the quench of the reactions.
Further mechanistic studies are being investigated in our laboratories.
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5
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7
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10
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3. CONCLUSION
The first Coꢀcatalyzed oxidative crossꢀcoupling reaction between titanateꢀmediated two aryl metal
reagents using oxygen has been developed. It represents one of most desirable oxidative crossꢀcouplings
between two aryl metal reagents because it can highly selectively assemble two various aryl Grignard or
lithium reagents in equivalent amount with peroxide salts as side products. Attractive features include
the use of lowꢀloading CoCl2 as well as inexpensive ligand DMPU; simple ClTi(OEt)3 as titanate,
oxygen as greenest oxidant, broad generality, high selectivity over homocouplings, remarkable
functional group tolerance, mild conditions and single THF solvent. Besides, the mediation of titanates
only requires simple combination of titanates with metal reagents. Meanwhile, titanium is a nonꢀtoxic,
abundant and environmentally safe element.20 Therefore, the present crossꢀcoupling reaction provides
an ecoꢀfriendly, simple and efficient method to access various biaryl compounds.
4. EXPERIMENTAL SECTIONS
1
General Information IR spectra were recorded using a FTIR spectrophotometer. H NMR and 13C
13
NMR spectra were recorded on 400 MHz or 500 MHZ spectrometer (100 MHz or 125 MHz for C
spectroscopy) using TMS as an internal standard. High resolution mass spectra (HRMS) were obtained
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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
1
2
3
4
5
6
o
freshly dehydrated and distilled before use. The corresponding glassware was oven dried (120 C) and
7
8
9
cooled under a stream of argon gas. Aryl Grignard reagents such as phenyl magnesium or 4ꢀmethoxyꢀ
phenyl 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; 4ꢀ(ethoxycarbonyl)phenyl magnesium chloride, 4ꢀ(4,4ꢀ
dimethylꢀ4,5ꢀdihydrooxazolꢀ2ꢀyl)phenyl magnesium chloride and 2ꢀ(phenylimino)methylphenylꢀ
magnesium chloride were prepared via iodineꢀmagnesium exchange using iꢀPrMgClꢁLiCl according to
Knochel’s method.21 All the Grignard reagents were titrated before use.22 ClTi(OEt)3 and TBEPC were
prepared according to the reported method.11
10
11
12
13
14
15
16
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21
22
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60
Typical procedure for 4dd (Table 2, entry 4)
Under Ar atmosphere, to a solution of ClTi(OEt)3 (654 mg, 3 mmol) in 10 mL THF was added dropwise
o
2ꢀthiophenylmagnesium bromide (3 mL, 1 M in THF) at 0 C. The resulting mixture was stirred for 2h
o
at room temperature. The mixture was cooled to 0 C, and to it was added dropwise a solution of 6ꢀ
methoxypyridinꢀ3ꢀylmagnesium bromide (3 mL, 1 M in THF, prepared from 5ꢀbromoꢀ2ꢀmethoxyꢀ
o
pyridine through bromineꢀmagnesium exchange using iꢀPrMgCl23) and stirred for 40 min at 0 C. The
solution of CoCl2 (3.9 mg, 0.03 mmol), DMPU (38.4 mg, 0.3 mmol) in THF (5 mL) was added in at one
portion. The Ar atmosphere was changed into O2 atmosphere (applied by a balloon filled with
dioxygen). The thusꢀobtained mixture was stirred at 0 oC until the completion of the reaction (monitored
by TLC). The reaction was quenched with saturated aqueous Na2CO3 solution and diluted with CH2Cl2.
After being filtered, the mixture was extracted with CH2Cl2 (50 mL × 4). The organic layer was dried
over Na2SO4 and concentrated to yield the crude compound, which was purified by column
chromatography to yield the desired product 4dd.
Note 1: For the reactions where the metal reagents were unstable at room temperature (for example, 1h,
1j and etc.), the combination of the metal reagents with ClTi(OEt)3 was performed at –30 or –40 oC. The
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temperature was then allowed to come to room temperature over 2 h, and the mixture was stirred for 2h
at that temperature.
1
2
3
4
5
6
o
Note 2: For the reactions where the Nꢀheteroaryl metal reagents were prepared at –30 or –40 C (for
7
8
9
example, 3j, 3n and etc.), the combination of the Nꢀheteroaryl metal reagents with the aryl titanium
reagents was also conducted at –30 or –40 oC. The following operations were conducted as described in
typical procedure.
10
11
12
13
14
15
16
17
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22
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54
55
56
57
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59
60
Note 3: The reactions catalyzed by FeCl3/TMEDA were performed according to the reported
procedure.11
Typical procedure for 6af (Table 3, entry 10)
Under Ar atmosphere, to a solution of ClTi(OEt)3 (654 mg, 3 mmol) in 10 mL THF was added dropwise
o
phenylmagnesium bromide (3 mL, 1 M in THF) at 0 C. The resulting mixture was stirred for 2h at
room temperature.
Under Ar atmosphere, a solution of iꢀPrMgCl·LiCl (3 mmol, 1.0 M in THF) was added dropwise to a
solution of Nꢀ(2ꢀiodobenzylidene)aniline (921 mg, 3 mmol) in 10 ml THF at –40 oC and stirred for 2h at
that temperature, and a solution of the aboveꢀprepared titanium reagent was added dropwise to it at ꢀ40
o
oC. The resulting solution was allowed to come to 0 C, and stirred for 40 min at the temperature. The
solution of CoCl2 (3.9 mg, 0.03 mmol), DMPU (38.4 mg, 0.3 mmol) in THF (5 mL) was added in at one
portion. The Ar atmosphere was changed into O2 atmosphere (applied by a balloon filled with
o
dioxygen). The resulting mixture was stirred at 0 C until the completion of the reaction (monitored by
o
TLC). The reaction was quenched with HCl aqueous solution (2M, 15mL) and stirred for 4h at 40 C.
o
After the temperature was cooled to 25 C, the mixture was extracted with CH2Cl2 (50 mL × 3). The
organic layer was dried over Na2SO4 and concentrated to yield the crude compound, which was purified
by column chromatography to yield a light yellow solid.
Note 1: The postꢀtreatment of the reactions for 6ih, 6lh, 6ei, 6mi was performed as following: the
reaction was quenched with HCl aqueous solution (2M, 25 mL) and stirred for 4h at 40 oC. The mixture
was extracted the mixture with ether (50 mL × 3). To the aqueous phase, was added saturated aqueous
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Na2CO3 solution to make the solution alkaline (PH ＞ 9). This aqueous phase was then extracted with
1
2
3
4
5
6
CH2Cl2 (50 mL × 3). The combined CH2Cl2 was dried over Na2SO4 and concentrated to yield the crude
compound, which was purified by column chromatography.
7
8
9
Note 2: The reactions catalyzed by FeCl3/TMEDA were performed according to the reported
procedure.11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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Typical procedure for 7bn (Table 4, entry 1)
Under Ar atmosphere, a solution of 4ꢀMeOC6H4MgBr (3 mmol, 1.0 M in THF) was added dropwise to a
solution of ClTi(OEt)3 (654 mg, 3 mmol) in 10 mL THF at 0 oC and stirred for 2h at that temperature.
To this mixture was added dropwise 4ꢀdimethylaminophenylmagnesium bromide (3 mmol, 1.0 M in
o
THF). The resulting mixture stirred at 0 C for 1h and then cooled to ꢀ10 oC. A mixture of CoCl2 (3.9
mg, 0.03 mmol), DMPU (38.4 mg, 0.3 mmol) in THF (5 mL) was added in at one portion. The Ar
atmosphere was changed into O2 atmosphere (applied by a balloon filled with dioxygen). The thusꢀ
obtained mixture was stirred at ꢀ10 oC until the completion of the reaction (monitored by TLC). The
reaction was quenched with saturated aqueous Na2CO3 solution and diluted with CH2Cl2. After being
filtered, the mixture was extracted with CH2Cl2 (50 mL × 3). The organic layer was dried over Na2SO4
and concentrated to yield the crude compound, which was purified by column chromatography to yield
the desired product 7bn as a whitish solid (538 mg, 79% yield).
Note 1: The reactions of Aryl Grignard reagents bearing amide groups were carried out at 0 oC.
Note 2: The reactions catalyzed by FeCl3/TMEDA were performed according to the reported
procedure.11
2ꢀPhenylpyridine (4ab). The product was prepared as described in typical procedure for 4dd and
isolated as a colorless oil in 90% yield (396 mg); Rf = 0.33 (petroleum ether/ethyl acetate = 10:1); IR
(cmꢀ1, KBr): 1592, 1565, 693; 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.67 (d, J = 4.8 Hz, 1H), 7.98 (d, J
= 7.2 Hz, 2H), 7.67ꢀ7.66 (m, 2H), 7.46ꢀ7.40 (m, 2H), 7.38ꢀ7.36 (m, 1H), 7.17ꢀ7.13 (m, 1H);
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13C{1H}NMR (CDCl3, 100 MHz) δ (ppm): 157.4, 149.7, 139.4, 136.7, 129.0, 128.8, 127.0, 122.1,
120.5. Data was consistent with that reported in the literature.24
1
2
3
4
5
6
7
8
2ꢀ(4ꢀMethoxyphenyl)pyridine (4bb). The product was prepared as described in typical procedure for
4dd and isolated as a whitish solid in 96% yield (516 mg ); m.p. = 52.5ꢀ53.5 °C; Rf = 0.20 (petroleum
9
1
ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 2926, 1609, 1587, 1516, 1462, 1040, 782, 744; H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
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25
26
27
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29
30
31
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60
(CDCl3, 400 MHz) δ (ppm): 8.65 (dd, J = 5.0 Hz, J = 0.6 Hz, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.73ꢀ7.66
13
(m, 2H), 7.19ꢀ7.15 (m, 1H), 7.00 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H); C{1H}NMR (CDCl3, 100 MHz) δ
(ppm): 160.5, 157.1, 149.5, 136.7, 132.0, 128.2, 121.4, 119.8, 114.1, 55.3. Data was consistent with that
reported in the literature.25
3ꢀ(Naphthalenꢀ1ꢀyl)pyridine (4cc). The product was prepared as described in typical procedure for
4dd and isolated as a pale yellow oil in 84% yield (517 mg); Rf = 0.20 (petroleum ether/ethyl acetate =
1
10:1); IR (cmꢀ1, KBr): 3096, 2933, 2856, 1587, 1471, 1173, 1024, 797; H NMR (400 MHz, CDCl3) δ
(ppm): 8.75ꢀ8.74 (m, 1H), 8.66 (dd, J = 4.9 Hz, J = 1.6 Hz, 1H), 7.89 (t, J = 8.0 Hz, 2H), 7.80ꢀ7.77 (m,
2H), 7.54ꢀ7.50 (m, 2H); 7.46ꢀ7.43 (m, 1H), 7.41ꢀ7.38 (m, 2H); 13C{1H}NMR (125 MHz, CDCl3) δ
(ppm): 150.5, 148.5, 137.4, 136.5, 136.3, 133.9, 131.5, 128.62, 128.56, 127.5, 126.6, 126.2, 125.5,
125.3, 123.3; Data was consistent with that reported in the literature.26
2ꢀMethoxyꢀ5ꢀ(thiophenꢀ2ꢀyl)pyridine (4dd). The product was isolated as a pale yellow solid in 75%
o
yield (430 mg), m.p. = 72 C; Rf = 0.43 (petroleum ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 2923,
1601, 1493, 1285, 1020, 833; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.40 (d, J = 2.2 Hz, 1H), 8.22 (dd, J
= 5.0 Hz, J = 1.9 Hz, 1H), 7.91 (dd, J = 8.6Hz, J = 2.4Hz, 1H), 7.65 (dd, J = 7.3 Hz, J = 1.9 Hz, 1H),
13
7.04 (dd, J = 7.3 Hz, J = 5.0 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.03 (s, 3H); C{1H}NMR (125 MHz,
CDCl3) δ (ppm): 163.6, 144.5, 137.1, 128.1, 126.9, 124.7, 122.9, 117.2, 111.1, 53.6; Data was
consistent with that reported in the literature.27
6ꢀMethoxyꢀ3,3'ꢀbipyridine (4cd). The product was prepared as described in typical procedure for 4dd
o
and isolated as a white solid in 85% yield (576 mg); m.p. = 46ꢀ48 C; Rf = 0.43 (petroleum ether/ethyl
1
acetate = 10:1); IR (cmꢀ1, KBr): 2924, 1604, 1583, 1456, 1374, 1285, 1022, 757; H NMR (400 MHz,
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CDCl3) δ (ppm): 8.80 (m, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 2.5 Hz, 1H), 7.84ꢀ7.77 (m, 2H),
7.40ꢀ7.37 (m, 1H), 7.39 (dd, J = 7.9 Hz, J = 4.9 Hz, 1H), 3.99 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3)
δ (ppm): 164.2, 146.4, 147.6, 145,1, 137.3, 134.1, 133.7, 126.7, 123.7, 111.3, 53.7; Data was consistent
with that reported in the literature.27
1
2
3
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5
6
7
8
9
2ꢀBromoꢀ5ꢀ(4ꢀchlorophenyl)pyridine (4ee). 6ꢀBromopyridinꢀ3ꢀylmagnesium bromide was prepared
via bromineꢀmagnesium exchange from 2,5ꢀdibromopyridine using iꢀPrMgCl. The product was
prepared as described in typical procedure for 4dd and isolated as a light yellow solid in 70% yield (564
mg), m.p. = 112 oC; Rf = 0.55 (petroleum ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 3034, 1588, 1546,
1452, 1427, 1350, 1084, 997; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.0 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H),
10
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7.56 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H); 7.43 (d, J = 8.5 Hz, 1H); C{1H}NMR (125 MHz,
CDCl3) δ (ppm): 155.1, 147.8, 135.8, 135.2, 134.5, 129.4, 129.1, 128.2, 128.1; Data was consistent with
that reported in the literature.28
3ꢀBromoꢀ5ꢀ(pꢀtolyl)pyridine (4ff). 5ꢀBromopyridinꢀ3ꢀylmagnesium bromide was prepared via bromineꢀ
magnesium exchange from 3,5ꢀdibromopyridine using iꢀPrMgCl. The product was prepared as
described in typical procedure for 4dd and isolated as a white solid in 83% yield (583 mg); m.p. = 90
oC; Rf = 0.56 (petroleum ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 2920, 1614, 1515, 1472, 1384,
1026, 796, 712; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.83 (s, 1H), 8.56 (d, J = 4.2 Hz, 1H), 7.87 (d, J =
13
7.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 2.41 (s, 3H); C{1H}NMR (100 MHz,
CDCl3) δ (ppm): 147.9, 145.4, 138.1, 134.8, 134.3, 129.8, 126.9, 123.6, 115.5, 21.1; Data was
consistent with that reported in the literature.29
2ꢀ(Naphthalenꢀ1ꢀyl)quinoline (4cg). 2ꢀQuinoline metal reagent was prepared from quinoline using
o
BF3·Et2O and TMPMgCl·LiCl16,30 and combined with the titanium reagent at –40 C. The magnesium
o
o
reagents and titanium reagent were mixed at ꢀ40 C, after that the temperature was raised to 0 C. The
coupling reaction was conducted as described in typical procedure for 4dd. The product was isolated as
o
a pale yellow solid in 73% yield (557 mg); m.p. = 95ꢀ96 C, Rf = 0.46 (petroleum ether/ethyl acetate =
1
5:1); IR (cmꢀ1, KBr): 3316, 2949, 2866, 1604, 1489, 1385, 1303, 1225, 1033, 789, 748; H NMR (400
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MHz, CDCl3) δ (ppm): 8.08ꢀ8.08 (m, 1H), 7.97ꢀ7.95 (m, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.69ꢀ7.66 (m,
1H), 7.55ꢀ7.54 (m, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.36ꢀ7.32 (m, 2H), 7.18ꢀ7.13 (m, 2H), 6.88 (m, 2H),
1
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13
6.43 (d, J = 7.8 Hz, 1H); C{1H}NMR (125 MHz, CDCl3) δ (ppm): 154.9, 150.1, 148.0, 143.1, 136.0,
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132.5, 130.0, 129.4, 129.1, 128.4, 127.5, 127.0, 126.1, 125.5, 124.9, 123.2, 121.9, 117.0, 114.0; Data
was consistent with that reported in the literature.31
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2ꢀ(4ꢀFluorophenyl)quinoline (4gg). The coupling was conducted as described in 4cg. The product was
isolated as a pale yellow solid in 77% yield (515 mg); m.p. = 94ꢀ96 oC, Rf = 0.25 (petroleum ether/ethyl
1
acetate = 5:1); IR (cmꢀ1, KBr): 2957, 2924, 2854, 1602, 1496, 1385, 1225, 1157, 822, 750; H NMR
(400 MHz, CDCl3) δ (ppm): 8.22ꢀ8.14 (m, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.54ꢀ7.45 (m, 4H), 7.20 (t, J =
13
8.6 Hz, 1H), 7.14ꢀ7.12 (m, 2H); C{1H}NMR (125 MHz, CDCl3) δ (ppm): 163.4, 161.5, 156.3, 148.2,
136.9, 136.4, 129.7 (d, J = 19.3 Hz), 129.4 (d, J = 8.2 Hz), 128.7 (q, J = 7.9 Hz), 127.3 (q, J = 58.3 Hz),
126.4, 118.6, 115.7 (q, J = 9.3 Hz); Data was consistent with that reported in the literature.32
1ꢀ(4ꢀMethylphenyl)isoquinoline (4fh). 1ꢀIsoquinoline metal reagent was prepared from isoquinoline
o
using TMPMgCl·LiCl33 and combined with the titanium reagent at 0 C. The coupling reaction was
conducted as described in typical procedure for 4dd. The product was isolated as a pale yellow solid in
o
80% yield (526 mg); m.p. = 70ꢀ72 C; Rf = 0.35 (petroleum ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr):
3064, 2955, 1604, 1550, 1502, 1387, 1257, 1177, 1022 , 833, 770; 1H NMR (400 MHz, CDCl3) δ (ppm):
8.60 (d, J = 5.7 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.69
(d, J = 5.6 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 6.97 (d, J = 7.0 Hz, 2H), 2.47 (s,
3H); 13C{1H}NMR (125 MHz, CDCl3) δ (ppm): 160.8, 154.5, 141.2, 138.8, 137.0, 130.4, 129.8, 129.1,
127.9, 127.4, 126.9, 120.3, 115.4, 21.3; Data was consistent with that reported in the literature.34
2ꢀ(2ꢀ(Thiophenꢀ2ꢀyl)phenyl)pyridine (4di). 2ꢀ(Pyridinꢀ2ꢀyl)phenyl magnesium reagent was prepared
o
from 2ꢀphenylpyridine using TMPMgCl·LiCl33 and combined with titanium reagent at 0 C. The
coupling reaction was conducted as described in typical procedure for 4dd and the product was isolated
as a pale yellow oil in 77% yield (466 mg); Rf = 0.15 (petroleum ether/ethyl acetate = 10:1); IR (cmꢀ1,
KBr): 3058, 1585, 1466, 1420, 1260, 1022, 848, 745, 712; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.71 (d,
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J = 5.3 Hz, 1H), 7.67ꢀ7.63 (m, 1H), 7.57ꢀ7.55 (m, 1H), 7.48ꢀ7.46 (m, 1H), 7.25ꢀ7.22 (m, 1H), 7.20ꢀ7.18
(m, 2H), 6.92ꢀ6.88 (m, 1H), 6.81 (d, J = 7.7 Hz, 2H), 6.71 (dd, J = 3.5 Hz, J = 1.0 Hz, 1H);
13C{1H}NMR (125 MHz, CDCl3): 159.1, 149.3, 142.8, 139.6, 135.7, 133.1, 130.7, 130.5, 128.6, 128.1,
127.1, 127.0, 125.8, 125.1, 121.9; Data was consistent with that reported in the literature.35
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2'ꢀ(Pyridinꢀ2ꢀyl)ꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarbonitrile (4hi). The product was prepared as described in 4di
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and isolated as a pale yellow solid in 81% yield (622 mg); m.p. = 138ꢀ140 C; Rf = 0.11 (petroleum
ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 2922, 2223, 1589, 1467, 1010, 759; H NMR (400 MHz,
1
CDCl3) δ (ppm): 7.73 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.61ꢀ7.55 (m, 2H), 7.53ꢀ7.52 (m, 1H), 7.47ꢀ7.43
(m, 1H), 7.35ꢀ7.28 (m, 1H), 7.21ꢀ7.19 (m, 1H), 7.11 (dd, J = 7.6 Hz, J = 1.5 Hz, 1H), 6.98ꢀ6.96 (m,
1H), 6.87ꢀ6.83 (m, 1H); 6.78 (dd, J = 8.0 Hz, J = 0.9 Hz, 1H); 13C{1H}NMR (125 MHz, CDCl3) δ
(ppm): 160.7, 149.2, 145.0, 141.6, 139.8, 136.2, 133.6, 133.0, 130.6, 130.3, 129.8, 129.3, 128.3, 124.5,
124.0, 122.6, 117.7, 112.3; HRMS calcd. for C18H13N2 [M+H]+: 257.1079; found: 257.1074.
+
2ꢀ(4ꢀMethoxyphenyl)quinoxaline (4bj). Quinoxalinꢀ2ꢀylmagnesium chloride was prepared from
36
o
quinoxaline using TMP2Mg·LiCl2 and combined with the titanium reagent at 0 C. The coupling
reaction was conducted as described in typical procedure for 4dd and the product was isolated as a pale
yellow solid in 85% yield (602 mg); m.p. = 94ꢀ95 oC; Rf = 0.52 (petroleum ether/ethyl acetate = 5:1); IR
(cmꢀ1, KBr): 2934, 1602, 1584, 1286, 1252, 1176, 1028, 763; 1H NMR (400 MHz, CDCl3) δ (ppm): 9.30
(s, 1H), 8.19ꢀ8.17 (m, 2H), 8.14 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 8.11 (dd, J = 8.2 Hz, J = 1.2 Hz, 1H);
7.80ꢀ7.70 (m, 2H); 7.10ꢀ7.07 (m, 2H); 3.90 (s, 3H); C{1H}NMR (125 MHz, CDCl3) δ (ppm): 161.5,
13
151.6, 142.8, 142.3, 130.5, 129.4, 129.3, 129.1, 128.7, 116.2, 114.8, 114.6, 55.8; Data was consistent
with that reported in the literature.37
2ꢀ(Quinoxalinꢀ2ꢀyl)benzonitrile (4hj). The product was prepared as described in 4bj and isolated as a
pale yellow solid in 76% yield (527 mg); m.p. = 158ꢀ160 oC; Rf = 0.38 (petroleum ether/ethyl acetate =
5:1); IR (cmꢀ1, KBr): 2225, 1544, 1487, 1246, 1155, 1091, 958, 760; H NMR (400 MHz, CDCl3) δ
1
(ppm): 8.57 (dd, J = 8.0 Hz, J = 1.1 Hz, 1H); 8.31 (d, J = 8.2 Hz, 1H); 8.25ꢀ8.23 (m, 1H), 7.83ꢀ7.79 (m,
1H), 7.64ꢀ7.60 (m, 1H), 7.52ꢀ7.49 (m, 1H), 7.33ꢀ7.29 (m, 3H); 13C{1H}NMR (125 MHz, CDCl3) δ
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(ppm): 162.1, 153.7, 147.8, 144.3, 137.3, 133.6, 132.9, 131.8, 130.6, 129.8, 129.2, 124.9, 122.8, 117.5,
1
2
3
+
112.5; HRMS calcd. for C15H10N3 [M+H]+: 232.0875; found: 232.0871.
4
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6
2ꢀ(4ꢀFluorophenyl)ꢀ1ꢀmethylꢀ1Hꢀbenzoimidazole (4gk). Benzoimidazole lithium reagent was
7
8
o
prepared from Nꢀmethyl benzoimidazole using TMPLi at 0 C and combined with the titanium reagent
9
at 0 oC. The coupling reaction was conducted as described in typical procedure for 4dd and the product
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was isolated as a pale yellow solid in 80% yield (542 mg); m.p. = 95ꢀ97 C; Rf = 0.45 (ethyl acetate );
IR (cmꢀ1, KBr): 2941, 2875, 1604, 1509, 1384, 1221, 1157, 1052, 836; H NMR (400 MHz, CDCl3) δ
1
(ppm): 8.22ꢀ8.19 (m, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.41ꢀ7.39 (m, 3H), 7.11ꢀ7.03 (m, 2H), 2.30 (s, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ (ppm): 153.8, 142.9, 136.6, 130.2, 129.7, 129.5, 128.7, 122.8,
122.4, 119.8, 109.6, 31.7. Data was consistent with that reported in the literature.38
1ꢀMethylꢀ2ꢀ(thiophenꢀ2ꢀyl)ꢀ1Hꢀimidazole (4da).39 The coupling reaction was conducted as described
in 4gk and the product was isolated as a pale yellow oil in 86% yield (423 mg); Rf = 0.15 (ethyl acetate );
IR (cmꢀ1, KBr): 3103, 1655, 1560, 1508, 1471, 1406, 1285, 1140, 849, 716; H NMR (400 MHz,
1
CDCl3) δ (ppm): 7.35 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.08 (t, J = 3.9 Hz, 1H), 7.05 (s, 1H),
6.90 (s, 1H), 3.79 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ (ppm): 142.1, 136.7, 128.2, 127.5, 126.5,
125.7, 122.6, 34.6.
1ꢀMethylꢀ2ꢀ(3ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀimidazole (4ia). The product was prepared as described in
4da and isolated as a pale yellow oil in 78% yield (529 mg); Rf = 0.24 (ethyl acetate ); IR (cmꢀ1, KBr):
1
2950, 1619, 1472, 1328, 1167, 1125, 1069, 808, 703; H NMR (400 MHz, CDCl3) δ (ppm): 7.89 (s,
1H), 7.80 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.11 (s, 1H), 6.99 (s,
1H); 3.74 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ (ppm): 146.4 (d, J = 122.2 Hz), 131.6, 130.9,
+
129.2, 129.1, 128.4, 128.1, 125.2 (q, J = 3.7 Hz), 123.0, 122.5, 32.2; HRMS calcd. for C11H10F3N2
[M+H]+: 227.0796; found: 227.0801.
2ꢀ(4ꢀFluorophenyl)benzothiazole (4gl). Benzothiazolꢀ2ꢀylmagnesium bromide, which was prepared
from benzothiazole using EtMgBr at 10ꢀ15 C.40 The thus obtain mixture was combined with the
o
titanium reagent at 0 °C. The coupling reaction was conducted as described in typical procedure for 4dd
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and the product was isolated as a light yellow solid in 80% yield (550 mg); m.p. = 100ꢀ101 oC, Rf = 0.34
(petroleum ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 2966, 1669, 1601, 1454, 1288, 1216, 1160, 833;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.16ꢀ8.10 (m, 3H), 7.95 (d, J = 8.0Hz, 1H), 7.57ꢀ7.53 (m, 1H),
1
2
3
4
5
6
7.44 (t, J = 8.0 Hz, 1H), 7.25ꢀ7.21 (m, 2H); C{1H}NMR (125 MHz, CDCl3) δ (ppm): 166.8, 165.5,
7
8
13
9
163.5, 154.0, 135.0, 129.5 (d, J = 8.4 Hz), 126.5, 125.3, 123.2, 121.7, 116.2 (d, J = 22.0 Hz). Data was
consistent with that reported in the literature.41
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5ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀphenyloxazole (4am). The product was prepared as described in 4da and
isolated as a light yellow solid in 82% yield (617 mg); m.p. = 78ꢀ79 oC; Rf = 0.28 (petroleum ether/ethyl
1
acetate = 5:1); IR (cmꢀ1, KBr): 3022, 2965, 2823, 1625, 1501, 1244, 1176; H NMR (400 MHz, CDCl3)
δ (ppm): 8.56 (d, J = 2.2Hz, 1H), 8.10 (dd, J = 7.9 Hz, J = 2.4 Hz, 2H), 7.89 (dd, J = 8.6 Hz, J = 2.4 Hz,
1H), 7.50ꢀ7.47 (m, 4H), 7.38 (s, 1H), 6.85 (d, J = 8.6 Hz, 1H), 4.00 (s, 3H); 13C{1H}NMR (CDCl3, 125
MHz) δ (ppm): 164.0, 161.2, 148.9, 143.0, 134.8, 130.5, 128.9, 126.3, 122.7, 117.9, 111.4, 58.5; Data
was consistent with that reported in the literature.42
Ethyl 2ꢀ(1,3,7ꢀtrimethylꢀ2,6ꢀdioxoꢀ2,3,6,7ꢀtetrahydroꢀ1Hꢀpurinꢀ8ꢀyl)benzoate (4jn). The Grignard
reagent of caffeine was prepared as follows: to a solution of caffeine (480 mg, 3 mmol, 1 equiv) in THF
o
(10 ml) was added dropwise TMPMgCl·LiCl (3.6 mmol, 1.2 equiv) at ꢀ10 C and stirred for 2 h at this
o
temperature. The Grignard reagent of caffeine was combined with the titanium reagent at 0 C. The
coupling reaction was conducted as described in typical procedure for 4dd and the product was isolated
o
as a white solid in 79% yield (811 mg); m.p. = 174ꢀ175 C; Rf = 0.22 (ethyl acetate = 5:1); IR (cmꢀ1,
1
KBr): 2919, 2851, 1714, 1659, 1284, 1102, 744; H NMR (400 MHz, CDCl3) δ (ppm): 8.18 (d, J = 8.4
Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 4.62 (q, J = 7.1 Hz, 2H), 4.09 (s, 3H), 3.64 (s, 3H), 3.44 (s, 3H), 1.23
(t, J = 7.2 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ (ppm): 165.2, 155.6, 151.7, 150.9, 148.4, 132.5,
132.3, 130.0, 129.1, 109.0, 60.9, 34.0, 29.8, 28.0, 14.0. Data was consistent with that reported in the
literature.43
4,4ꢀDimethylꢀ2ꢀ(2ꢀ(thiophenꢀ2ꢀyl)phenyl)ꢀ4,5ꢀdihydrooxazole (6da). (2ꢀ(4,4ꢀDimethylꢀ4,5ꢀdihydroꢀ
oxazolꢀ2ꢀyl)phenyl)magnesium chloride was prepared from 4,4ꢀdimethylꢀ2ꢀphenylꢀ4,5ꢀdihydrooxazole
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using TMPMgCl·LiCl at 0 oC for 4h, and combined with titanium reagent at 0 oC. The coupling reaction
was conducted as described in typical procedure for 4dd and the product was isolated as a pale yellow
solid in 80% yield (617 mg); m.p. = 213ꢀ214 oC; Rf = 0.23 (petroleum ether/ethyl acetate = 5:1); IR (cmꢀ
1
2
3
4
5
6
1, KBr): 3063, 1648, 1585, 1462, 1425, 725, 700; H NMR (400 MHz, CDCl3) δ (ppm): 8.50 (d, J = 1.8
7
8
1
9
Hz, 1H), 8.44 (dd, J = 4.7 Hz, J = 1.2 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.24ꢀ7.20 (m, 2H), 6.80 (d, J =
8.9 Hz, 1H), 6.73ꢀ6.71 (m, 1H), 2.93 (s, 2H), 1.28 (d, J = 6.8 Hz, 6H); 13C{1H}NMR (CDCl3, 125 MHz)
δ (ppm): 163.5, 142.3, 134.2, 130.6, 130.4, 130.3, 128.4, 127.6, 127.1, 126.1, 125.8, 79.7, 67.7, 28.1;
Data was consistent with that reported in the literature.44
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2ꢀ(4'ꢀFluoroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ4,4ꢀdimethylꢀ4,5ꢀdihydrooxazole (6ga).45 The compound was
prepared as described in 6da and isolated as a colorless yellow oil in 75% yield (605 mg); Rf = 0.12
(petroleum ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 2952, 2833, 1640, 1510, 1454, 1234, 1179, 826,
1
734; H NMR (400 MHz, CDCl3) δ (ppm): 7.77 (d, J = 7.6 Hz, 1H), 7.53 (td, J = 7.5 Hz, J = 1.4 Hz,
1H), 7.43 (dd, J = 7.5 Hz, J = 1.2 Hz, 1H), 7.41ꢀ7.37 (m, 3H), 7.14ꢀ7.09 (m, 2H), 3.87 (s, 2H), 1.34 (s,
13
6H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 163.5 (d, J = 62.5 Hz), 161.3, 140.6, 137.1 (d, J = 3.4
Hz), 130.6, 130.2 (d, J = 8.1 Hz), 130.0 (d, J = 7.8 Hz), 128.1 (q, J = 8.1 Hz), 127.3, 115.0, 114.9, 79.6,
67.5, 28.0.
2ꢀ(5ꢀMethoxyꢀ4'ꢀmethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ4,4ꢀdimethylꢀ4,5ꢀdihydrooxazole (6fb). The compound
was prepared as described in 6da and isolated as a light yellow oil in 77% yield (682 mg); Rf = 0.40
(petroleum ether/ethyl acetate = 3:1); IR (cmꢀ1, KBr): 2967, 2839, 1644, 1610, 1513, 1256, 1172, 1083,
1029, 839; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.89 (d, J = 8.6 Hz, 2H), 7.02 (s, 2H), 6.87 (d, J = 8.6
13
Hz, 2H), 6.79 (s, 1H), 4.13 (s, 2H), 3.81 (s, 3H), 2.56 (s, 3H), 1.39 (s, 6H); C{1H}NMR (CDCl3, 125
MHz) δ (ppm): 163.1, 162.4, 158.0, 156.1, 153.8, 152.3, 130.3, 129.3, 119.6, 115.9, 113.9, 79.4, 67.3,
55.5, 28.4, 20.6; Data was consistent with that reported in the literature.46
4,4ꢀDimethylꢀ2ꢀ(2ꢀ(naphthalenꢀ1ꢀyl)phenyl)ꢀ4,5ꢀdihydrooxazole (6ca). The compound was prepared
as described in 6da and isolated as a pale yellow oil in 72% yield (555 mg); Rf = 0.10 (petroleum
1
ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 3057, 1653, 1589, 1462, 1435, 1259, 735; H NMR (400
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MHz, CDCl3) δ (ppm): 7.89ꢀ7.85 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H); 7.60 (d, J = 8.5 Hz, 1H), 7.54 (dd, J
= 7.5 Hz, J = 1.4 Hz, 1H), 7.51ꢀ7.49 (m, 1H), 7.48ꢀ7.42 (m, 4H), 7.41ꢀ7.38 (m, 1H), 3.47 (d, J = 8.0 Hz,
1H), 3.19 (d, J = 8.0 Hz, 1H), 1.0 (s, 3H), 0.95 (s, 3H); 13C{1H}NMR (CDCl3, 125 MHz) δ (ppm):
163.5, 140.2, 139.4, 133.3, 131.9, 131.3, 130.5, 129.7, 129.3, 128.1, 127.6, 127.5, 126.4, 126.0, 125.9,
125.6, 125.2, 79.3, 67.0, 27.72, 27.69; HRMS calcd. for C21H20NO+ [M+H]+: 302.1539; found:
302.1551.
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2'ꢀ(4,4ꢀDimethylꢀ4,5ꢀdihydrooxazolꢀ2ꢀyl)ꢀ5'ꢀmethoxyꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarbonitrile
(6hb).
The
product was prepared as described in 6da and isolated as a yellow solid in 67% yield (615 mg); m.p. =
o
215ꢀ220 C; Rf = 0.25 (petroleum ether/ethyl acetate = 3:1); IR (cmꢀ1, KBr): 2953, 2846, 2222, 1651,
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1635, 1504, 1256, 1179, 1060, 1029, 845; H NMR (400 MHz, CDCl3) δ (ppm): 8.06 (d, J = 8.8 Hz,
1H), 7.02ꢀ6.98 (m, 2H), 6.91 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H), 6.81ꢀ6.77 (m, 2H), 6.55 (d, J = 2.8 Hz,
13
1H), 3.70 (s, 3H), 3.49 (s, 2H), 1.16 (s, 3H), 1.12 (s, 3H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm):
160.4, 141.9, 134.2, 131.4, 130.2, 129.2, 128.9, 128.8, 126.8, 126.0, 124.6, 120.9, 120.7, 78.0, 68.7,
33.2, 19.3; HRMS calcd. for C19H19N2O2 [M+H]+: 307.1447; found: 307.1444.
+
2ꢀ(6ꢀFluoroꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ4,4ꢀdimethylꢀ4,5ꢀdihydrooxazole (6ac). The compound was
o
prepared as described in 6da and isolated as a yellow solid in 78% yield (629 mg); m.p. = 105ꢀ106 C;
Rf = 0.43 (petroleum ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 2787, 2671, 1649, 1502, 1456, 1361,
1
1234, 1193, 1080, 829, 746; H NMR (400 MHz, CDCl3) δ (ppm): 7.95ꢀ7.93 (m, 2H), 7.48ꢀ7.46 (m,
1H), 7.40ꢀ3.36 (m, 2H), 6.86ꢀ6.76 (m, 3H), 4.15 (s, 2H), 1.40 (s, 6H); 13C{1H}NMR (CDCl3, 125 MHz)
δ (ppm): 163.1, 157.5, 155.6, 153.2 (d, J = 1.5 Hz), 131.7, 128.5, 128.4, 127.3, 116.6 (d, J = 7.6 Hz),
115.8, 115.6, 79.3, 67.4, 28.3; HRMS calcd. for C17H17FNO+ [M+H]+: 270.1294; found: 270.1299.
4,4ꢀDimethylꢀ2ꢀ(4'ꢀmethylꢀ[1,1'ꢀbiphenyl]ꢀ3ꢀyl)ꢀ4,5ꢀdihydrooxazole
(6fd).
3ꢀ(4,4ꢀDimethylꢀ4,5ꢀ
dihydrooxazolꢀ2ꢀyl)phenylmagnesium chloride was prepared via iodineꢀmagnesium exchange using iꢀ
PrMgCl·LiCl at ꢀ20 oC for 3h; and combined with titanium reagent at ꢀ20 oC. After that, the temperature
o
was raised to 0 C, and the coupling reaction was conducted as described in 6da. The product was
o
isolated as a white solid in 83% yield (660 mg); m.p. = 117ꢀ118 C, Rf = 0.44 (petroleum ether/ethyl
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acetate = 5:1); IR (cmꢀ1, KBr): 2962, 2921, 2885, 1642, 1608, 1497, 1313, 1194, 1069, 809; H NMR
(400 MHz, CDCl3) δ (ppm): 8.01 (d, J = 8.2 Hz, 2H), 7.63ꢀ7.61 (m, 2H) 7.53ꢀ7.51 (m, 2H), 7.27 (s, 1H),
7.25 (s, 1H), 4.15 (s, 2H), 2.40 (s, 3H), 1.42 (s, 6H); 13C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 162.1,
143.9, 137.8, 137.3, 129.6, 128.7, 127.0, 126.7, 126.5, 79.6, 67.2, 28.4, 21.1; HRMS calcd. for
C18H20NO+ [M+H]+: 266.1545; found: 266.1539.
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Ethyl 3'ꢀ(4,4ꢀdimethylꢀ4,5ꢀdihydrooxazolꢀ2ꢀyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀcarboxylate (6jd). The compound
was prepared as described in 6fd and isolated as a white solid in 80% yield (811 mg); m.p. = 158ꢀ160
oC, Rf = 0.38 (petroleum ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 2966, 2926, 1723, 1649, 1560, 1350,
1305, 1076, 1053, 966, 714; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.15 (d, J = 7.6 Hz, 2H), 7.95 (d, J =
7.7 Hz, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.7Hz, 1H), 7.42ꢀ7.40 (m, 2H), 4.41 (q, J = 7.0 Hz,
13
2H), 4.12 (s, 2H), 1.40 (s, 6H), 1.26 (q, J = 7.2 Hz, 3H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm):
166.3, 162.1, 144.3, 131.2, 130.2, 129.0, 128.3, 128.2, 128.0, 127.2, 126.4, 125.8, 79.1, 67.5, 61.1, 20.4,
+
14.3; HRMS calcd. for C20H22NO3 [M+H]+: 324.1600; found: 324.1597.
2ꢀ(4'ꢀFluoroꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ4,4ꢀdimethylꢀ4,5ꢀdihydrooxazole (6ge). The product was prepared
o
as described in 6fd and isolated as a white solid in 85% yield (686 mg); m.p. = 68ꢀ70 C, Rf = 0.55
(petroleum ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 2967, 2929, 1643, 1512, 1364, 1271, 1207, 1029,
961, 802; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.75 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 6.93ꢀ
6.89 (m, 2H), 6.79ꢀ6.76 (m, 2H), 4.14 (s, 2H), 1.40 (s, 6H); 13C{1H}NMR (CDCl3, 125 MHz) δ (ppm):
162.5, 157.6, 155.9, 152.6, 137.7, 129.9, 116.4, 115.9, 115.7, 79.5, 67.7, 28.3; HRMS calcd. for
C17H17FNO+ [M+H]+: 270.1294; found: 270.1289.
[1,1'ꢀBiphenyl]ꢀ2ꢀcarbaldehyde (6af). The product was isolated as a colorless oil in 84% yield (458
mg); Rf = 0.55 (petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 2868, 2848, 1692, 1597, 1454,
1
1196, 1058, 750, 702; H NMR (400 MHz, CDCl3) δ (ppm): 9.99 (s, 1H), 8.03 (dd, J = 7.8 Hz, J = 1.1
Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.48ꢀ7.44 (m, 4H), 7.40ꢀ7.37 (m, 2H), 7.33 (d, J = 4.4Hz, 1H);
13C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 192.4, 146.0, 137.8, 133.6, 130.8, 130.1, 128.5, 128.2, 127.8,
127.6, 125.7; Data was consistent with that reported in the literature.47
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The Journal of Organic Chemistry
Ethyl 2'ꢀformylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxylate (6kf). The product was prepared as described in typical
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procedure for 6af and isolated as a white solid in 87% yield (662 mg); m.p. = 44ꢀ45 C, Rf = 0.46
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(petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 2980, 1712, 1598, 1443, 1365, 1290, 1256, 1132,
1082, 1049, 756, 708; 1H NMR (400 MHz, CDCl3) δ (ppm): 10.05 (s, 1H), 7.93 (dd, J = 7.8 Hz, J = 1.1
Hz, 1H), 7.90ꢀ7.88 (m, 1H), 7.84 (s, 1H), 7.58ꢀ7.54 (m, 3H), 7.47 (td, J = 7.6 Hz, J =1.3 Hz, 1H), 7.36
(dd, J = 7.6 Hz, J = 0.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H); 13C{1H}NMR
(CDCl3, 125 MHz) δ (ppm): 192.2, 168.0, 142.7, 141.3, 136.2, 134.6, 131.5, 130.7, 130.3, 129.7, 128.6,
128.4, 127.9, 127.1, 61.0, 13.8; Data was consistent with that reported in the literature.48
Ethyl 4'ꢀformylꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀcarboxylate (6jg).11 The product was prepared as described in
typical procedure for 6af and isolated as a light yellow solid in 82% yield (624 mg); m.p. = 62ꢀ63 oC, Rf
= 0.45 (petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 2936, 1702, 1606, 1276, 1187, 1104, 771;
1H NMR (400 MHz, CDCl3) δ (ppm): 10.11 (s, 1H), 8.16ꢀ8.14 (m, 3H), 7.92–7.88 (m, 2H), 7.71–7.68
(m, 2H), 7.65 (t, J = 7.7 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H}NMR
(CDCl3, 100 MHz) δ (ppm): 192.0, 166.3, 143.9, 141.1, 137.1, 133.1, 130.3, 129.7, 128.2, 127.1, 61.1,
14.4.
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3'ꢀ(Trifluoromethyl)ꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀamine (6ih). The product was prepared as described in typical
procedure for 6af and isolated as a light yellow oil in 79% yield (561 mg); Rf = 0.36 (petroleum
ether/ethyl acetate = 10:1); IR (cmꢀ1, KBr): 3456, 3390, 1610, 1509, 1475, 1456, 1340, 1168, 1133,
1
1095, 1074; H NMR (400 MHz, CDCl3) δ (ppm): 7.34 (dd, J = 5.2 Hz, J = 1.0 Hz, 1H), 7.28 (dd, J =
7.5 Hz, J = 1.3 Hz, 1H), 7.20 (dd, J = 3.5 Hz, J = 1.0 Hz, 1H), 7.15 (td, J = 7.9 Hz, J = 1.5 Hz, 1H),
7.11 (dd, J = 5.1 Hz, J = 3.2 Hz, 2H), 6.82ꢀ6.78 (m, 2H), 4.09 (br, 2H); 13C{1H}NMR (CDCl3, 125
MHz) δ (ppm): 143.2, 140.3, 132.5, 130.4, 130.2, 129.3, 129.2, 128.8, 126.1, 126.0 (q, J = 3.8 Hz),
124.0 (q, J = 3.7 Hz), 119.0, 115.0. Data was consistent with that reported in the literature.49
2'ꢀMethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀamine (6lh). The product was prepared as described in typical procedure
for 6af and isolated as a light yellow oil in 78% yield (406 mg); Rf = 0.26 (petroleum ether/ethyl acetate
1
= 10:1); IR (cmꢀ1, KBr): 3028, 1611, 1448, 1294, 1234, 908; H NMR (400 MHz, CDCl3) δ (ppm):
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7.91ꢀ7.89 (m, 1H), 7.47ꢀ7.46 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.40ꢀ7.34 (m, 1H), 7.28ꢀ7.24 (m, 1H),
7.20 (d, J = 6.6 Hz, 1H), 7.17ꢀ7.14 (m, 1H), 7.11ꢀ7.10 (m, 1H), 2.30 (s, 3H); 13C{1H}NMR (CDCl3, 125
MHz) δ (ppm): 143.2, 137.9, 134.5, 133.1, 131.2, 130.5, 130.4, 129.0, 128.9, 126.5, 119.0, 115.9, 18.5;
Data was consistent with that reported in the literature.49
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4'ꢀChloroꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀamine (6ei). The product was prepared as described in typical procedure
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for 6af and was isolated as a light yellow solid in 82% yield (499 mg); m.p. = 132ꢀ133 C; Rf = 0.21
(petroleum ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 3356, 3440, 1610, 1588, 1520, 1466, 1367, 1254,
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1190, 1136, 1021, 789; H NMR (400 MHz, CDCl3) δ (ppm): 7.19ꢀ7.15 (m, 2H), 7.10ꢀ7.08 (m, 2H),
6.86ꢀ6.82 (m, 2H), 6.79 (d, J = 8.0 Hz, 2H), 4.00 (br, 2H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm):
13
143.0, 137.8, 133.2, 130.5, 129.0, 126.6, 119.1, 116.0; Data was consistent with that reported in the
literature.50
2'ꢀMethoxyꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀamine (6mi). The product was prepared as described in typical
procedure for 6af and isolated as a light yellow oil in 73% yield (436 mg); Rf = 0.27 (petroleum
ether/ethyl acetate = 5:1); IR (cmꢀ1, KBr): 3366, 1610, 1489, 1295, 1028, 820, 770; 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.60 (d, J = 7.7 Hz, 1H), 7.33 (t , J = 8.0 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 6.95ꢀ6.87
(m, 2H), 6.57 (d, J = 8.6 Hz, 2H), 3.90 (s, 3H), 3.66 (br, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ
(ppm): 155.9, 145.7, 133.6, 132.0, 128.7, 121.9, 116.8, 112.2, 111.7, 110.0, 56.2; Data was consistent
with that reported in the literature.51
4'ꢀMethoxyꢀN,Nꢀdimethylꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀamine (7bn). The product was isolated as a white solid in
85% yield (579 mg); m.p. = 155ꢀ156 C; Rf = 0.15 (petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1,
o
1
1
KBr): 2897, 1612, 1507, 1248, 1177, 1040, 810; H NMR (400 MHz, CDCl3) δ (ppm): H NMR (400
MHz, CDCl3) δ (ppm): 7.48ꢀ7.44 (m, 4H), 6.94 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 3.83 (s,
3H), 2.97 (s, 6H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 158.3, 149.5, 133.9, 129.4, 127.4, 127.3,
13
114.2, 113.1, 55.4, 40.8. Data was consistent with that reported in the literature.52
4ꢀMethoxyꢀ4'ꢀmethylꢀ1,1'ꢀbiphenyl (7bf). The product was prepared as described in the typical
o
procedure for 7bn and isolated as a white solid in 86% yield (511 mg); m.p. = 102ꢀ104 C; Rf = 0.48
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(petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 3030, 2965, 1608, 1300, 1270, 1214, 1180, 1011;
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1H NMR (400 MHz, CDCl3) δ (ppm): 7.61ꢀ7.58 (m, 2H), 7.54 (d, J = 6.4 Hz, 2H), 7.30 (d, J = 6.2 Hz,
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2H), 7.05ꢀ7.04 (m, 2H), 3.91 (s, 3H), 2.47 (s, 3H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 159.0,
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138.0, 136.4, 133.8, 129.5, 128.0, 126.6, 114.2, 55.4, 21.1; Data was consistent with that reported in the
literature.53
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4ꢀFluoroꢀ4'ꢀmethoxyꢀ1,1'ꢀbiphenyl (7bg). The product was prepared as described in the typical
o
procedure for 7bn and isolated as a white solid in 81% yield (491 mg); m.p. = 87ꢀ88 C; Rf = 0.65
1
(petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 1607, 1488, 1251, 833, 760, 690; H NMR (400
MHz, CDCl3) δ (ppm): 7.56ꢀ7.52 (m, 3H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.30 (d, J =
13
7.3 Hz, 1H), 6.99ꢀ6.96 (m, 2H), 3.85 (s, 3H); C{1H}NMR (CDCl3, 100 MHz) δ (ppm): 163.3, 160.9,
159.2, 137.0, 132.8, 127.5(q), 115.5 (d), 114.3, 55.3. Data was consistent with that reported in the
literature.52
4'ꢀMethylꢀ3ꢀ(trifluoromethyl)ꢀ1,1'ꢀbiphenyl (7bi). The product was prepared as described in the
typical procedure for 7bn and isolated as a light yellow oil in 81% yield (605 mg); Rf = 0.57 (petroleum
ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 2955, 1610, 1335, 1126, 798; 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.82 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.59–7.48 (m, 4H), 7.27 (d, J = 7.9 Hz, 2H), 2.41 (s, 3H);
13C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 141.9, 138.0, 131.3, 131.0, 130.2, 129.7, 129.2, 127.0, 124.7
(d), 124.0 (d), 123.7 (q), 21.1. Data was consistent with that reported in the literature.25,54
N,NꢀDimethylꢀ4ꢀ(naphthalenꢀ1ꢀyl)aniline (7cn). The product was prepared as described in the typical
o
procedure for 7bn and was isolated as a white solid in 77% yield (571 mg); m.p. = 68ꢀ69 C; Rf = 0.44
(petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 3383, 2991, 1606, 1504, 1394, 1242, 1175, 804,
1
781; H NMR (400 MHz, CDCl3) δ (ppm): 8.00 (dd, J = 8.3 Hz, J = 3.8 Hz, 1H), 7.87 (d, J = 8.0 Hz,
13
1H), 7.79 (d, J = 8.1Hz, 1H), 7.51ꢀ7.38 (m, 6H), 6.86 (d, J = 8.5 Hz, 2H), 3.02 (s, 6H); C{1H}NMR
(CDCl3, 125 MHz) δ (ppm): 149.8, 140.6, 134.0, 132.0, 130.9, 129.0, 128.3, 126.9, 126.8, 126.4, 125.8,
125.7, 125.6, 112.4, 40.8; Data was consistent with that reported in the literature.54
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4'ꢀChloroꢀ3ꢀ(trifluoromethyl)ꢀ1,1'ꢀbiphenyl (7ei). The product was prepared as described in the typical
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procedure for 7bn and isolated as a white solid in 73% yield (560 mg); m.p. = 98ꢀ99 C; Rf = 0.59
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(petroleum ether/ethyl acetate = 20:1); IR (cmꢀ1, KBr): 1485, 1440, 1338, 1275, 1132, 907, 702 ; H
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NMR (400 MHz, CDCl3) δ (ppm): 7.93 (s, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.70ꢀ7.68 (m, 2H), 7.66ꢀ7.62
(m, 2H); 13C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 141.2, 139.4, 131.3 (q, J = 32.0 Hz), 130.4, 129.4,
129.1 (d, J = 3.8 Hz), 128.3 (d, J = 5.6 Hz), 127.0, 124.3 (q, J = 3.5 Hz), 124.1 (q, J = 270.0 Hz), 123.9
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(q, J = 3.7 Hz); HRMS calcd. for C13H9ClF3 [M+H]+: 257.0345; found: 257.0342.
Ethyl 2'-cyano-[1,1'-biphenyl]-2-carboxylate (7kh). Both Grignard reagents were prepared via
iodineꢀmagnesium exchange using iꢀPrMgClꢁLiCl according to Knochel’s method. The titanium reagent
o
o
and the aryl magnesium reagent were mixed at ꢀ40 C. After that, the temperature was raised to ꢀ10 C,
and the coupling reaction was conducted as described in the typical procedure for 7bn. The product was
o
isolated as a white solid in 83% yield (625 mg); m.p. = 68ꢀ70 C; Rf = 0.59 (petroleum ether/ethyl
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acetate = 20:1); IR (cmꢀ1, KBr): 2988, 2223, 1719, 1614, 1485, 1301, 1276, 1107, 1028, 713; H NMR
(400 MHz, CDCl3) δ (ppm): 8.03 (d, J = 7.8Hz, 1H), 7.65ꢀ7.62 (m, 1H), 7.57ꢀ7.54 (m, 2H), 7.50ꢀ7.43
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(m, 2H), 7.37ꢀ7.24 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H); C{1H}NMR (CDCl3,
125 MHz) δ (ppm): 167.2, 143.3, 135.0, 132.3, 132.0, 131.3, 131.0, 130.2, 129.9, 129.5, 128.8, 127.5,
127.1, 112.4, 53.5, 13.7; Data was consistent with that reported in the literature.55
N, N, 2'ꢀTrimethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (7lo). 2ꢀ(Dimethylcarbamoyl)phenylmagnesium
o
chloride was prepared via iodineꢀmagnesium exchange using iꢀPrMgCl·LiCl at ꢀ40 C for 2h. The
titanium reagent was added to this mixture at ꢀ40 oC. After that, the temperature was raised to 0 oC, and
the coupling reaction was conducted at this temperature as described in the typical procedure for 7bn.
The product was isolated as a white solid in 78% yield (559 mg); m.p. = 58ꢀ60 oC; Rf = 0.44 (petroleum
ether/ethyl acetate = 3:1); IR (cmꢀ1, KBr): 2970, 1643, 1426, 1330, 1291, 1124, 796, 720; 1H NMR (400
MHz, DMSO) δ (ppm): 7.87 (dd, J = 8.0 Hz, J = 0.8 Hz, 1H), 7.57 (dd, J = 8.0 Hz, J = 0.8 Hz, 1H),
7.47 (td, J = 7.5 Hz, J = 1.0 Hz, 1H), 7.35ꢀ7.33 (m, 1H), 7.29 (dd, J = 7.4 Hz, J = 1.0 Hz, 1H), 7.25 (dd,
J = 7.8 Hz, J = 1.8 Hz, 1H), 7.18ꢀ7.15 (m, 1H), 7.13ꢀ7.11 (m, 1H), 3.02 (s, 3H), 2.74 (s, 3H), 2.35 (s,
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3H); 13C{1H}NMR (DMSO, 100 MHz) δ (ppm): 170.0, 143.3, 139.1, 137.7, 132.5, 131.6, 130.6, 128.9,
128.3, 128.1, 127.5, 124.7, 93.4, 38.2, 34.5, 22.9; HRMS calcd. for C16H18NO+ [M+H]+: 240.1388;
found: 240.1385.
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Nꢀ(2'ꢀMethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)benzamide (7lp). The product was prepared as described in 7lo and
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isolated as a white solid in 76% yield (655 mg); m.p. = 123ꢀ125 C; Rf = 0.33 (petroleum ether/ethyl
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acetate = 5:1); IR (cmꢀ1, KBr): 3342, 2924, 1655, 1518, 1468, 1156, 753, 703.; H NMR (400 MHz,
CDCl3) δ (ppm): 8.67 (d, J = 8.3 Hz, 1H), 7.79 (br, 1H), 7.56ꢀ7.50 (m, 3H), 7.45ꢀ 7.42 (m, 4H), 7.34 (d,
J = 7.0 Hz, 1H), 7.30 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.91ꢀ6.87 (m, 1H), 2.21
(s, 3H); 13C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 165.2, 137.0, 136.9, 135.3, 134.6, 131.9, 131.0,
130.8, 130.1, 129.7, 128.8, 128.7, 127.0, 126.7, 124.4, 120.6, 115.1, 19.8; HRMS calcd. for C20H18NO+
[M+H]+: 288.1388; found: 288.1383.
Nꢀ(4'ꢀMethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)benzamide (7fp).56 The compound was prepared as described in 7lo
and isolated as a white solid in 76% yield (654 mg); m.p. = 116ꢀ117 oC; Rf = 0.30 (petroleum ether/ethyl
acetate = 3:1); IR (cmꢀ1, KBr): 3266, 2886, 1667, 1582, 1522, 1469, 1310, 1242, 1114, 751; H NMR
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(400 MHz, CDCl3) δ (ppm): 8.13 (br, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.62ꢀ7.60
(m, 2H), 7.57 (d, J = 7.6 Hz, 2H); 7.52 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H); 7.20 (d, J = 8.0 Hz,
2H), 2.42 (s, 3H); C{1H}NMR (CDCl3, 125 MHz) δ (ppm): 165.8, 153.7, 138.9, 138.1, 134.3, 132.4,
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130.0, 129.5, 129.1, 128.5, 127.3, 126.9, 126.4, 122.1, 115.2, 20.6.
NꢀPhenylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (7aq). The compound was prepared as described in 7lo and
o
isolated as a white solid in 74% yield (606 mg); m.p. = 119ꢀ120 C; Rf = 0.35 (petroleum ether/ethyl
acetate = 3:1); IR (cmꢀ1, KBr): 3322, 3041, 1664, 1602, 1537, 1422, 1323; H NMR (400 MHz, CDCl3)
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δ (ppm): 7.61ꢀ7.58 (m, 1H), 7.56ꢀ7.52 (m, 2H); 7.44ꢀ7.42 (m, 2H), 7.22ꢀ7.18 (m, 4H), 7.14 (d, J = 7.9
Hz, 1H), 6.90ꢀ6.87 (m, 2H), 6.78 (d, J = 7.7 Hz, 2H); 6.14 (br, 1H); 13C{1H}NMR (CDCl3, 125 MHz) δ
(ppm): 159.3, 149.4, 142.9, 139.9, 135.6, 133.1, 130.7, 130.5, 128.5, 128.0, 127.1, 127.0, 125.7, 125.0,
121.8; Data was consistent with that reported in the literature.57
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