A base-free, one-pot diazotization/cross-coupling of anilines with arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2010.11.099

Pd-catalyzed one-pot diazotization/cross-coupling is realized for the synthesis of biaryls directly from anilines and arylboronic acids.

Full text of DOI:10.1016/j.tetlet.2010.11.099

Tetrahedron Letters 52 (2011) 518–522
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A base-free, one-pot diazotization/cross-coupling of anilines with
arylboronic acids
⇑
Fanyang Mo, Di Qiu, Yubo Jiang, Yan Zhang, Jianbo Wang
Beijing National Laboratory of Molecular Sciences (BNLMS), and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd-catalyzed one-pot diazotization/cross-coupling is realized for the synthesis of biaryls directly from
anilines and arylboronic acids.
Received 14 October 2010
Revised 9 November 2010
Accepted 19 November 2010
Available online 24 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pd-catalyzed
Suzuki–Miyaura coupling
Diazotization
Aryl amine
Suzuki–Miyaura cross-coupling is a powerful tool for the con-
struction of C–C bonds.1 In general, aryl halides or triflates are used
as coupling partners. The search for alternative electrophilic
coupling partner continues to attract interests among the synthetic
organic community.2 Arenediazonium salts represent an attractive
alternative due to their high reactivity and easy availability from
aniline derivatives.3–7 The first utilization of the aryldiazonium
salts as electrophiles in palladium-catalyzed Suzuki–Miyaura
cross-couplings was achieved independently by Genet4 and Seng-
upta.5 These investigations allow biaryls synthesis with moderate
to good yields by coupling of aryldiazonium tetrafluoroborates
and arylboronic acids in the presence of catalytic amounts of
Pd(OAc)2 and without adding base and ligands. In 2001, Andrus
and Song reported a palladium-imidazolium carbene catalyst sys-
tem for the cross-coupling of arylboronic acid with aryldiazonium
tetrafluoroborates. The reaction could be carried out at low tem-
perature (0 °C or room temperature) and afforded the coupling
products with high yields.6
Although aryldiazonium tetrafluoroborates have been well
established as coupling partners in Pd-catalyzed reactions, there
are some drawbacks. First, aryldiazonium tetrafluoroborates are
generally unstable and only few of them are commercially
available. Therefore, they should be newly prepared before use.
However, the procedure for the preparation of aryldiazonium tet-
rafluoroborates is hazardous and tedious due to the use of fluoro-
boric acid and recrystallization in separation process.8 As a result,
the reaction usually gives low yield especially when carried out in
a small scale. Consequently, the advantage of easy availability of
aniline starting materials may be counteracted by the lack of effi-
ciency and flexibility in the preparation of aryldiazonium
tetrafluoroborates.
We conceived that
a one-pot diazotization/cross-coupling
would circumvent these setbacks. Such an approach has been pur-
sued first by Fujiwara and coworkers in 1980,9 although in their
seminal work stoichiometric amount of Pd(OAc)2 was required in
order to obtain good yields. Almost at the same time, Matsuda
and coworkers described the same coupling reaction but using al-
kyl nitrite as diazotizing agent and catalytic amounts of
Pd2(dba)3.10 Andrus and Song have also demonstrated the one-
pot diazotization/cross-coupling in their catalytic system with pal-
ladium-imidazolium carbene as catalyst.6 Encouraged by these
developments, we wish to report in this Letter an efficient Pd-
catalyzed base-free cross-coupling of arylamines and arylboronic
acids with tert-butyl nitrite as diazotizating agent.11 The reaction
does not need to use BF3ꢀOEt2 as in the case of Andrus’s system.
Initial screening of the reaction conditions with aniline 1a,
p-tolylboronic acid 2a, and tert-butyl nitrite revealed that the usual
Suzuki–Miyaura coupling protocol [DME, Pd(PPh3)4, aqueous
Na2CO3] failed to afford any desired product. After some experi-
mentations, it was concluded that the desired cross-coupling prod-
uct 3a could be obtained in 36% GC–MS yield under a condition
with 5 mol % Pd(PPh3)4 in CH3CN at 90 °C (Table 1, entry 1).
Encouraged by this initial result, we further proceeded to optimize
the reaction conditions. First, different solvents were examined
and it was concluded that DMF afforded the best yield of 64%
⇑
Corresponding author.
E-mail address: wangjb@pku.edu.cn (J. Wang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.099

F. Mo et al. / Tetrahedron Letters 52 (2011) 518–522
519
Table 1
Pd-catalyzed cross-coupling of aniline 1a and p-tolylboronic acid 2aa
cat. + ligand
tBuONO
NH2
+
B(OH)2
additive
solvent, 5 h
1a
3a
2a
Entry
Cat. (mol %)
Solvent (mol %)
Additive
Temp (°C)
Yieldb (3a, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
—
Pd(PPh3)4(5)
PdCl2(PPh3)2(5)
Pd(PtBu)3(5)
Pd(OAc)2(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
MeCN
DCE
Toluene
DMSO
DMF
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
—
—
—
—
—
—
90
90
90
90
90
90
90
90
90
90
90
90
90
90
36
8
17
52
64
0
K2CO3 (200)
—
—
—
8
12
32
17
49
70
74
91
—
AcOH (100)
—
AcOH (100)
Pd2dba3(2.5)/P(2-furyl)3(15)
Pd2dba3(2.5) P(2-furyl)3(15)
DMF
DMF
a
Reaction conditions: aniline 1a (0.5 mmol); 1a:2a:tBuONO = 1:1.3:1.2; solvent 2 mL, under N2.
GC–MS yield using mesitylene as internal standard.
b
Tab1e 2
The scope of the one-pot diazotization-coupling reactiona
Pd2dba3 (2.5 mol%)
P(2-furyl)3 (20%)
NH2
+
MeO
B(OH)2
tBuONO (1.3 equiv)
AcOH (1.0 equiv)
DMF, 90 oC, 8 h
R
1a-n (1 equiv)
2b (1.2 equiv)
OMe
R
3a'-n
Entry
1
Arylamines 1a–n
NH2
Products 3a0–n
Yieldb (%)
81
OMe
1a
3a'
NH2
OMe
2
3
77
73
1b
3b
NH2
NH2
OMe
OMe
1c
3c
4
5
52
75
1d
3d
Cl
Cl
NH2
Cl
Cl
OMe
OMe
1e
3e
Cl
Cl
NH2
6
56
1f
3f
(continued on next page)

520
F. Mo et al. / Tetrahedron Letters 52 (2011) 518–522
Tab1e 2 (continued)
Entry
Arylamines 1a–n
Products 3a0–n
Yieldb (%)
56
MeO
NH2
MeO
OMe
OMe
7
8
1g
3g
O2N
NH2
O2N
O2N
56
48
1h
3h
O2N
NH2
OMe
9
1i
3i
3j
NC
NH2
NC
OMe
10
11
70
50
1j
AcHN
AcHN
OMe
AcHN
AcHN
NH2
1k
3k
NH2
OMe
12
13
63
1l
3l
AcO
AcO
NH2
OMe
52
50
1m
EtO2C
3m
EtO2C
OMe
NH2
14
3n
1n
a
Reaction were carried out in 1 mmol scale, DMF 4 mL under N2 atmosphere.
Isolated yield.
b
(entries 2–5). Control experiment indicated that without palla-
dium catalyst, the reaction failed to give any coupling product (en-
try 6). Besides, the reaction could not be improved by adding a base
(entry 7). Next, we examined other palladium catalysts; however,
the reaction could not be improved (entries 8–10). The reaction be-
came sluggish when the temperature decreased from 90 to 70 °C.
To our delight, it was noted that the reaction could be significantly
improved when catalyzed by a combination of Pd2dba3 (2.5 mol %)
and P(2-furyl)3 (15 mol %) (entry 13). Finally, adding 1 equiv of
acetic acid was found to further improve the reaction (entry 14).
The positive effect of acetic acid in one-pot diazotization-coupling
reaction has also been observed by Matsuda10 and Beller.12 We rea-
soned that acetic acid not only accelerated the diazotization pro-
cess but also influenced the transmetallation step by anion
The yields of this one-pot diazotization/coupling reaction were
moderate to good and the main byproduct is homo coupling of
arylboronic acids. Control experiment showed that tert-butyl ni-
trite could function as an oxidant in homo coupling of arylboronic
acid catalyzed by Pd(0). The advantage of this one-pot reaction lies
in its operational simplicity and convenience. It is important to
note that the aryldiazonium salts are formed very quickly for some
substrates, such as ethyl p-aminobenzoate. For this type of sub-
strates, we have applied an alternative procedure in which the
diazotization is carried out first and the cross-coupling with boro-
nic acid is then performed upon the completion of the diazotiza-
tion, namely a one-pot, two-step process. This procedure was
then applied to the coupling of arylboronic acids with arylamines
(Table 3). In a typical experiment, arylamine and tert-butyl nitrite
were first mixed with a ratio of 1:1.05 and set to react at room
temperature. The diazotization was complete within 5 min as
monitored by TLC analysis. Then Pd(0) catalyst, P(furyl)3, and boro-
nic acid were added and the reaction was carried out at 90 °C. For a
wide range of arylboronic acids, the reaction afforded products
3o–z in moderate yields.
t
exchange with BuOꢁ.
With Pd2dba3/P(2-furyl)3 catalytic system, the scope of the one-
pot diazotization/coupling reaction was examined by a series of
arylamines 1a–n and 4-methoxyphenylboronic acid 2b13 The re-
sults are summarized in Table 2. For a wide range of arylamines,
the reaction afforded the biaryl products 3a0–n in moderate to
good yields. Substrates with weak electronic effect generally gave
good yields, as shown by methyl and halide substituted arylamines
(entries 1–5). However, it was noted that the steric hindrance sig-
nificantly diminished the yield (entry 4). It is also worthy to note
that the reaction tolerates a wide range of subtituents, wheather
it is of electron withdrawing or electron donating.
The mechanism of this diazotization-coupling is proposed to be
the standard oxidative addition–reductive elimination mechanism
of Pd-catalyzed cross-coupling (Scheme 1). The first-step is diazo-
tization of arylamine to form corresponding aryldiazonium salt. It
is known that aryldiazonium salt cations can coordinate transition
metals to give species like A, in which the metal has increased its

F. Mo et al. / Tetrahedron Letters 52 (2011) 518–522
521
Table 3
tBuONO
HOAc
Cross-coupling of arylamines with arylboronic acids by one-pot, two-step process14
Ar N N Pd
ArNH2
Ar
N
N OAc
OAc
1) tBuONO (1.05 equiv)
AcOH (1.0 equiv)
DMF, RT, 5 min
N2
A
Ar NH2
Ar Ar'
Pd(0)Ln
OAc
Ar Pd
2) Pd2dba3 (2.5 mol%)
P(2-furyl)3 (20%), Ar'B(OH)2
DMF, 90 oC, 10 h
B
Ar'B(OH)2
Ar Ar'
Ar Pd Ar'
Entry
1
Arylamine 1
Boronic acid 2
Yielda (3, %)
C
EtO2C
NH2
NH2
B(OH)2
2c
Scheme 1. Possible reaction mechanism.
3o, 50
3p, 52
1n
azonium salt to afford Pd(II) intermediate. Extrusion of dinitrogen
from intermediate A leads to the formation of complex B, from
which transmetallation to form C. Reductive elimination is fol-
lowed to afford the final biaryl product.
In conclusion, we have developed a convenient Pd-catalyzed
one-pot diazotization/cross-coupling of arylamines and arylbo-
ronic acids. Since arylamines are abundant and easily available,
this transformation provides an efficient and economic approach
for the preparation of biaryl products.
Cl
Cl
EtO2C
B(OH)2
2
1n
2d
EtO2C
NH2
NH2
B(OH)2
3
4
3q, 51
3r, 50
1n
2e
2f
EtO2C
Br
B(OH)2
Acknowledgments
1n
MeO
The project is generously supported by Natural Science Founda-
tion of China (Grant Nos. 20902005, 20832002, 20772003,
20821062), the Ministry of Education of China, and National Basic
Research Program of China (973 Program, No. 2009CB825300).
EtO2C
NH2
NH2
B(OH)2
5
6
7
3s, 54
3t, 58
3u, 55
1n
2g
B(OH)2
EtO2C
Supplementary data
1n
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.099.
2h
MeO
NH2
References and notes
B(OH)2
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EtO2C
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8
3v, 53
1o
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CN
2i
MeO
NH2
B(OH)2
10
2g
1p
NC
NH2
B(OH)2
11
12
3y, 48
3z, 65
1j
2d
AcHN
NH2
B(OH)2
S
2i
1k
a
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oxidation number by two units.15 Alternatively, this process could
also be considered as an oxidative addition of Pd(0)Ln with aryldi-

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Schlenk round bottle flask under nitrogen atmosphere. The system was
degassed four times by oil pump. Ethyl 4-aminobenzoate 1n (165 mg,
1 mmol) was weighed in another 25 mL Schlenk round bottle flask under
nitrogen atmosphere. DMF (2 mL), tBuONO (108 mg, 1.05 equiv), and HOAc
(60 mg, 1.0 equiv) were added in succession by syringe and this reaction
mixture was stirred for 5 min. Then the solution containing the newly
generated diazonium salt was transferred to the above Schlenk round bottle
by syringe. In the course of this transfer, another 2 mL DMF was added to
the reaction system. The resulting reaction solution was stirred at 90 °C for
10 h. The solution was then concentrated under reduced pressure and the
crude residue was purified by flash column chromatography (petroleum
ether/EtOAc = 30:1) to afford the product ethyl biphenyl-4-carboxylate 3o
(113 mg, 50%).
12. Beller, M.; Fischer, H.; Kühlein, K. Tetrahedron Lett. 1994, 35, 8773.
13. General procedure. Pd2dba3 (23 mg, 2.5 mol %), P (2-furyl)3 (46 mg, 20 mol %),
4-methoxybenzeneboronic acid 2b (182 mg, 1.2 equiv), and p-toluidine 1b
(107 mg, 1 mmol) were weighed in a 25 mL Schlenk round bottle flask under
nitrogen atmosphere. The system was degassed four times by oil pump. DMF
(4 mL), tBuONO (134 mg, 1.3 equiv), and HOAc (60 mg, 1.0 equiv) were then
added in succession by syringe. The resulting reaction mixture was allowed to
stir at 90 °C for 8 h. The solution was then concentrated under reduced
pressure and the crude residue was purified by flash column chromatography
with petroleum ether to give 4-methoxy-40-methylbiphenyl 3b (152 mg, 77%).
14. General procedure. Pd2dba3 (23 mg, 2.5 mol %), P (2-furyl)3 (46 mg, 20 mol %),
and benzeneboronic acid 2c (146 mg, 1.2 equiv) were weighed in a 25 mL
15. (a) Sutton, D. Chem. Rev. 1993, 93, 995; (b) King, R. B. J. Organomet. Chem. 1995,
500, 187.