Simultaneous reduction of nitro- to amino-group in the palladium-catalyzed Suzuki cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2008.02.082

An efficient method for palladium-catalyzed Suzuki cross-coupling reaction with simultaneous reduction of nitro- to amino-group has been developed. This method allows nitro-substituted aryl halides to readily react with arylboronic acids, to afford aryl substituted aniline in low to excellent yields. The reaction was catalyzed by Pd(OAc)₂ (3 mol %) at 150 °C under atmospheric pressure in the presence of K₂CO₃ (3 equiv) in DMF/H₂O (5/1).

Full text of DOI:10.1016/j.tetlet.2008.02.082

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2634–2637
Simultaneous reduction of nitro- to amino-group in the
palladium-catalyzed Suzuki cross-coupling reaction
a,
Heng-Shan Wang , Ying-Chun Wang a,b, Ying-Ming Pan a,
*
Shu-Lin Zhao a, Zhen-Feng Chen a
a Key Laboratory of Medicinal Chemical Resources and Molecular Engineering, College of Chemistry and Chemical Engineering,
Guangxi Normal University, Guilin 541004, China
b College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China
Received 25 September 2007; revised 11 February 2008; accepted 15 February 2008
Available online 19 February 2008
Abstract
An efficient method for palladium-catalyzed Suzuki cross-coupling reaction with simultaneous reduction of nitro- to amino-group has
been developed. This method allows nitro-substituted aryl halides to readily react with arylboronic acids, to afford aryl substituted ani-
line in low to excellent yields. The reaction was catalyzed by Pd(OAc)2 (3 mol %) at 150 °C under atmospheric pressure in the presence of
K2CO3 (3 equiv) in DMF/H2O (5/1).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Palladium; Suzuki cross-coupling; Reduction; Aryl substituted aniline
The palladium-catalyzed Suzuki cross-coupling reaction
is probably one of the most powerful and well-known
chemical tools for the selective construction of carbon–
carbon bonds.1 A variety of improvements have been made
for the reaction conditions since the first discovery in 1981
by Suzuki and co-workers to prepare biaryls.2 However,
there are no published data for palladium-catalyzed Suzuki
cross-coupling reaction with the simultaneous reduction of
nitro- to amino-group to date. On the other hand, many
methods have been reported for the reduction of aromatic
nitro compounds to the corresponding aromatic amines,
including most popular catalytic hydrogenation and
metal-mediated reduction. Many valuable sources of
hydrogen such as hydrazine,3 CO/H2O,4 formate,5
NaBH4,6 and amine boranes7 have been used. Reported
herein is the discovery of a novel Pd(OAc)2/DMF/H2O
catalytic system for Suzuki cross-coupling reaction accom-
panied by the reduction of a nitro-group to an amine.
As part of our experimental goal to synthesize some chi-
ral fluorescence reagents from methyl 12-bromo-13-nitro-
7-oxo-dehydrodeisopropylabietate 1a, we are interested in
developing a general method to prepare methyl 12-aryl
substituted-13-amino-7-oxo-dehydrodeisopropylabietates.
In the course of our experiments of Pd-catalyzed Suzuki
cross-coupling of 1a with 4-biphenylboronic acid 2a and
2-naphthylboronic acid 2b, respectively, we found that
Suzuki cross-coupling reaction and nitro reduction reac-
tion synchronously occurred without affecting the other
reducible ester and carbonyl groups. Methyl 12-(4-biphen-
yl)-13-amino-7-oxo-dehydrodeisopropylabietate
3
and
methyl 12-(2-naphthyl)-13-amino-7-oxo-dehydrodeisopro-
pylabietate 4 were prepared in a single one-pot reaction
in moderate isolated yields (70% and 75%, respectively)
after 24 h (Scheme 1). The reaction took place under atmo-
spheric pressure at 150 °C in a mixture of DMF and H2O
(5/1) in the presence of 3 mol % Pd(OAc)2, and 3 equiv
of K2CO3.
*
Crystals of 3 and 4 were grown from a saturated petro-
leum ether/ethyl acetate solution by slow evaporation at
Corresponding author. Tel./fax: +86 773 580 3930.
E-mail address: wang_hengshan@yahoo.com.cn (H.-S. Wang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.082

H.-S. Wang et al. / Tetrahedron Letters 49 (2008) 2634–2637
2635
Br
Ar
12
13
NO
2
NH
2
H C
3
H C
3
Pd(OAc) (3 mol %)
2
K CO (3 eq.)
2
3
7
+
ArB(OH)
2
o
3
DMF/H O (5/1),150 ºC
O
H
2
H
H C
3
H C
COOCH
3
COOCH
3
2a Ar = 4-biphenyl
2b Ar = 2-naphthyl
3 Ar = 4-biphenyl
4 Ar = 2-naphthyl
1a
Scheme 1. Synthesis of compounds 3 and 4 from methyl 12-bromo-13-nitro-7-oxo-dehydrodeisopropylabietate 1a.
any ligands, 1-bromo-2-nitro-benzene in a mixed solvent
of DMF and H2O (5/1) reacted with 4-biphenylboronic
acid in the presence of 3 mol % Pd(OAc)2, and 3 equiv of
K2CO3 at 150 °C to give 2-amino-p-terphenyl 5 in 78%
yield after 16 h (entry 1). Then we turned our attention
to optimize reaction conditions using 1b and 2a as a model
reaction. A number of parameters were evaluated and, all
the reactions were carried out under air. Temperature
appeared to be crucial to the reaction. Below 80 °C, it affor-
ded only starting materials even after a reaction time of
two days (entry 2). The reaction conducted at 120 °C also
gave good result but it was necessary to use longer reaction
time (24 h) (entry 3). Although the reaction rate was faster
at 180 °C, the conversion was not enhanced, and in fact,
the yield of 2-amino-p-terphenyl was reduced to 70% (entry
4), which may be due to the decomposition of the aryl-
boronic acids. The use of DABCO (triethylenediamine)
as a ligand led to higher yield for this reaction (entry 5 vs
entry 1), similar to previous reports, in which DABCO
was employed as a highly efficient ligand for palladium-
catalyzed coupling reaction.8 But there was no significant
improvement when TBAB, CTMAB, and PPh3 were used
Fig. 1. Crystal structures of compound 3 and 4.
room temperature (Fig. 1). All hydrogen atoms are omitted
for clarity.
Encouraged by these results, we extended the system to
the reaction of 1-bromo-2-nitro-benzene 1b and 4-
biphenylboronic acid 2a. As shown in Table 1, without
Table 1
Reaction of 1-bromo-2-nitro-benzene 1b with 4-biphenylboronic acid 2a in various conditionsa
3 mol %Pd(OAc) , ligand
2
Br
B(OH)
2
+
K CO , solvent, T (OC)
2
3
NO
NH
2
2
1b
2a
Ligand
5
Entry
Solvent
Temperature (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
a
DMF–H2Oc
DMF–H2Oc
DMF–H2Oc
DMF–H2Oc
DMF–H2Oc
DMF–H2Oc
DMF–H2Oc
DMF–H2Oc
DMF
0
0
0
0
150
80
16
48
24
10
12
16
16
24
24
24
24
24
24
78
0
120
180
150
150
150
150
150
150
150
150
150
76
70
87
79
76
72
0
0
0
0
0
DABCO
TBAB
CTMAB
PPh3
DABCO
DABCO
DABCO
DABCO
DABCO
Toluene
DME–H2Od
DMSO
DMSO–H2Oe
Unless otherwise indicated, the reaction conditions were as follows: 1b (1 mmol), 2a (1.5 mmol), Pd(OAc)2 (3 mol %), ligand (6 mol %), K2CO3
(3 equiv), and solvent (6 ml).
b
Isolated yields.
c
The mixture of DMF (5 ml) and H2O (1 ml) was used as a solvent.
The mixture of DME (5 ml) and H2O (1 ml) was used as a solvent.
The mixture of DMSO (5 ml) and H2O (1 ml) was used as a solvent.
d
e

2636
H.-S. Wang et al. / Tetrahedron Letters 49 (2008) 2634–2637
(entries 6–8). In the presence of DABCO, different solvents,
including DMF, toluene, DME/H2O, DMSO, and DMSO/
H2O, were tested, but no desired product 5 was obtained in
the absence of DMF–water system (entries 9–13). These
results suggest that the solvent plays a key role for the suc-
cess of the reduction of the nitro-group to an amine. Addi-
tionally, 1.5 equiv of 4-biphenylboronic acid was required
for the completion of 1-bromo-2-nitro-benzene, and an
increase in the amount of 4-biphenylboronic acid did not
reduce the reaction time or improve the yields.
arylboronic acids in a 5:1 mixture of DMF and water using
DABCO as the ligand, and the results are summarized in
Table 2. As already observed, 1-iodo-4-nitro-benzene 1c
and nitro-substituted aryl bromides, regardless of the nitro
group in the ortho-, para- or meta-position, were readily
converted to the corresponding aryl-substituted anilines
in excellent yields (entries 1–4). It is worth noting that
the reaction of 1-chloro-4-nitro-benzene 1f and 2a was car-
ried out smoothly to afford 4-amino-p-terphenyl 6 in 56%
yield (entry 5). However, this catalytic system is less effec-
tive for the reaction of phenylboronic acid. Only a 40%
yield of 2-aminobiphenyl 8 was obtained after 20 h of
The scope of the catalytic system was evaluated by the
reaction of a series of nitro-substituted aryl halides and
Table 2
Reaction of nitro-substituted aryl halides or 1a with arylboronic acids catalyzed by the Pd(OAc)2/DABCO/DMF/H2O catalytic systema
1a or
Pd(OAc)2 (3 mol %)
K2CO3 (3 eq.)
ArB(OH)2
+
Ar
X
DMF/H2O (5/1), 150 oC
H N
2
O2N
1b-1f
2a-2f
5-12
Entry
1
Substrate
Br
NO2
ArB(OH)2
Time (h)
12
Yieldb (%)
B(OH)2
B(OH)2
87 (5)
(2a)
(1b)
O2N
I
2
3
10
12
89 (6)
85 (7)
(2a)
(1c)
Br
B(OH)2
B(OH)2
B(OH)2
(2a)
(2a)
(2a)
O2N
O2N
(1d)
Br
4
12
90 (6)
(1e)
O2N
Cl
5
6
16
20
56 (6)
40 (8)
(1f)
Br
NO2
Br
NO2
Br
NO2
B(OH)2
(2c)
(1b)
H CO
3
B(OH)
2
7
20
45 (9)
(2d)
(1b)
(1b)
H3COC
B(OH)2
8
9
20
48
52 (10)
28 (11)
B(OH)2
1a
1a
(2c)
10
24
79 (12)
B(OH)2
(2f)
a
Unless otherwise indicated, the reaction conditions were as follows: nitro-substituted aryl halides or 1a (1 mmol), arylboronic acids (1.5 mmol),
Pd(OAc)2 (3 mol %), DABCO (6 mol %) and K2CO3 (3 equiv) in DMF (5 ml) and H2O (1 ml) at 150 °C.
b
Isolated yields.

H.-S. Wang et al. / Tetrahedron Letters 49 (2008) 2634–2637
2637
stirring at 150 °C (entry 6), the reaction of activated phen-
Supplementary data
ylboronic acid (electron-rich) 2d with 1b afforded 45% yield
of product 9 (entry 7), and electron-poor phenylboronic
acid (entry 8) also gave a low yield (52%). We also
explored the reaction of 1a with phenylboronic acid 2c
and 1-naphthylboronic acid 2f, the reaction of 1a with 2f
resulted in a moderate yield after 24 h (entry 10), but only
28% yield of methyl 12-phenyl-13-amino-7-oxo-dehydrode-
isopropylabietate 11 was isolated after 48 h (entry 9).
It is known that DMF–water system is widely used as a
solvent in the Suzuki–Miyaura cross-coupling reaction.9 In
addition, DMF, when heated with water, can generate
hydrogen gas with or without the use of a suitable cata-
lyst.10 It is reasonable to believe that the DMF–water sys-
tem probably served as a hydrogen source in this reaction.
Although, to the best of our knowledge there is no litera-
ture precedent for the Pd-mediated reduction of aromatic
nitro compounds to the corresponding aromatic amines
employing DMF/H2O as a hydrogen source. Thus, we tried
to use DMF/H2O as the hydrogen source to reduce nitro-
benzene in the presence of 3 mol % of Pd(OAc)2, 6 mol %
of DABCO, and 3 equiv of K2CO3. Unfortunately, under
the present reaction conditions, no hydrogenation was
observed after one or two days either under atmospheric
pressure or in the Teflon-lined stainless steel Parr bomb.
As a result, at the moment we cannot offer a definitive
explanation for the process of the reaction and investi-
gations in this reaction are currently underway in our
laboratory.
In conclusion, we have developed a novel and efficient
Pd(OAc)2/DMF/H2O catalyzed Suzuki cross-coupling
reaction with simultaneous reduction of nitro- to amino-
group for synthesizing aryl substituted anilines, especially
polycyclic aromatic amines, which can be prepared
directly from the corresponding nitro-substituted aryl
halides and arylboronic acids in a single step, one-pot
reaction in low to excellent yields. We have also found
that the additive DABCO has a beneficial effect on the
rate and the yield of the reaction. Further efforts to
extend the application of the catalytic system are under-
way in our laboratory.
Supplementary data contains experimental procedure,
X-ray crystallographic files (CIF) for 3 and 4, analytical
data, NMR (1H and 13C NMR), and MS spectrum. Sup-
plementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.02.082.
References and notes
1. For reviews see for example: (a) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457; (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998; (c) Llord-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145;
´
(d) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1395; (e) Bellina, F.; Carpita, A.; Rossi, R.
Synthesis 2004, 15, 2419; (f) Dugger, R. W.; Ragan, J. A.; Ripin, D.
H. B. Org. Process Res. Dev. 2005, 9, 253; (g) Corbet, J.-P.; Mignani,
G. Chem. Rev. 2006, 106, 2651; (h) Yin, L. X.; Liebscher, J. Chem.
Rev. 2007, 107, 133.
2. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
3. (a) Furst, A.; Berlo, R. C.; Hooton, S. Chem. Rev. 1965, 65, 51; (b)
Han, B. H.; Jang, D. G. Tetrahedron Lett. 1990, 31, 1181.
4. (a) Tafesh, A. M.; Weiguny, J. Chem. Rev. 1996, 96, 2035; (b) Liu, X.-
Z.; Liu, S.-W. J. Mol. Catal. A: Chem. 2004, 212, 127.
5. Nacario, R.; Kotakonda, S.; Fouchard, D. M. D.; Tillekeratne, L. M.
V.; Hudson, R. A. Org. Lett. 2005, 7, 471.
6. (a) Capecchi, T.; Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin
Trans. 1 2000, 16, 2681; (b) Johnson, T. A.; Curtis, M. D.; Beak, P.
Org. Lett. 2002, 4, 2747; (c) Wilkinson, H. S.; Tanouty, G. J.; Wald, S.
A.; Senanayake, C. H. Tetrahedron Lett. 2002, 42, 167.
7. Beaudin, J.; Bourassa, D. E.; Bowles, P.; Castaldi, M. J.; Clay, R.;
Couturier, M. A.; Karrick, G.; Makowski, T. W.; McDermott, R. E.;
Meltz, C. N.; Meltz, M.; Phillips, J. E.; Ragan, J. A.; Ripin, D. H.;
Singer, R. A.; Tucker, J. L.; Wie, L. Org. Process Res. Dev. 2003, 7,
873.
8. For examples, see: (a) Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809;
(b) Li, J.-H.; Hu, X.-C.; Liang, Y.; Xie, Y.-X. Tetrahedron 2006, 62,
31; (c) Li, J.-H.; Liu, W.-J.; Xie, Y.-X. J. Org. Chem. 2005, 70, 5409;
(d) Li, J.-H.; Liang, Y.; Wang, D.-P.; Liu, W.-J.; Xie, Y.-X.; Yin,
D.-L. J. Org. Chem. 2005, 70, 2832; (e) Li, J.-H.; Zhang, X.-D.; Xie,
Y.-X. Synthesis 2005, 804; (f) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Eur.
J. Org. Chem. 2005, 4256; (g) Li, J.-H.; Deng, C.-L.; Liu, W.-J.; Xie,
Y.-X. Synthesis 2005, 3039; (h) Li, J.-H.; Wang, D.-P.; Xie, Y.-X.
Synthesis 2005, 2193.
9. For examples, see: (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org.
Chem. 1995, 60, 7508; (b) Conlon, D. A.; Pipik, B.; Ferdinand, S.;
LeBlond, C. R.; Sowa, J. R.; Izzo, B. Adv. Synth. Catal. 2003, 345,
931; (c) Stevens, P. D.; Fan, J. D.; Gardimalla, H. M. R.; Yen, M.;
Gao, Y. Org. Lett. 2005, 7, 2085; (d) Mino, T.; Shirae, Y.; Sakamoto,
M.; Fujita, T. J. Org. Chem. 2005, 70, 2191; (e) Miao, G.-B.; Ye, P.;
Yu, L.-B.; Baldino, C. M. J. Org. Chem. 2005, 70, 2332; (f) Ishiyama,
T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508; (g) Kim,
J.-H.; Kim, J.-W.; Shokouhimehr, M.; Lee, Y.-S. J. Org. Chem. 2005,
70, 6714.
Acknowledgements
We thank the National Natural Science Foundation of
China (Nos. 20362002 and 20762001), and the Natural
Science Foundation of Guangxi Province (Nos. 0575046
and 0575049).
10. Yu, J. Y.; Shreiner, S.; Vaska, L. Inorg. Chim. Acta 1990, 170, 145.