One-pot Suzuki-Miyaura cross-coupling followed by reductive monoalkylation of the resulting nitro biaryl system utilizing Pd/C as catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.06.128

Conditions for one-pot Suzuki-Miyaura cross-coupling between aryl boronic acids and bromo-nitrobenzene followed by reductive monoalkylation of the nitro functionality of the biaryl cross-coupling product utilizing hydrogen over Pd/C as the catalyst and aldehydes as alkylation agent are described.

Full text of DOI:10.1016/j.tetlet.2013.06.128

Accepted Manuscript
One-pot Suzuki-Miyaura cross-coupling followed by reductive monoalkylation
of the resulting nitro biaryl system utilizing Pd/C as catalyst
Lena Pedersen, Mohamed F. Mady, Magne O. Sydnes
PII:
S0040-4039(13)01113-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.128
TETL 43181
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 April 2013
13 June 2013
26 June 2013
Pleasecitethisarticleas:Pedersen, L., Mady, M.F., Sydnes, M.O., One-potSuzuki-Miyauracross-couplingfollowed
by reductive monoalkylation of the resulting nitro biaryl system utilizing Pd/C as catalyst, Tetrahedron Letters
(2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.128
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One-pot Suzuki-Miyaura cross-coupling
followed by reductive monoalkylation of the
resulting nitro biaryl system utilizing Pd/C
as catalyst
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Lena Pedersen, Mohamed F. Mady, Magne O. Sydnes

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot Suzuki-Miyaura cross-coupling followed by reductive monoalkylation of the
resulting nitro biaryl system utilizing Pd/C as catalyst
Lena Pedersen,a Mohamed F. Mady,a,b Magne O. Sydnesa*
a Faculty of Science and Technology, Department of Mathematics and Natural Science, University of Stavanger, N-4036 Stavanger, Norway.
b Department of Green Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Conditions for one-pot Suzuki-Miyaura cross-coupling between aryl boronic acids and bromo-
nitrobenzene followed by reductive monoalkylation of the nitro functionality of the biaryl cross-
coupling product utilizing hydrogen over Pd/C as the catalyst and aldehydes as alkylation agent
is described.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Catalysis
Pd/C
Suzuki-Miyaura cross-coupling
Reductive monoalkylation
One-pot reactions, where several steps are performed in the
same reaction vessel, have gained significant attention from
chemists working towards conducting synthesis in a more
sustainable fashion.1 The development of such reactions are
therefore important as chemists aim to minimize the use of
reagents, catalysts, and solvent, as well as reducing the number
of isolation steps which generate additional waste.
Nitro aryls are an important class of compounds due to their
easy formation from a range of aromatic starting materials2 and
their ready conversion into aromatic amines.3 Primary aryl
amines are vital starting materials for the preparation of
secondary amines found in numerous products, such as
pharmaceuticals.4 However, the selective conversion of primary
amines into secondary amines in high yields still remains a
challenge. Several one-pot strategies for the selective synthesis of
secondary amines have been reported5 including our own efforts
towards this end.6
The use of Pd/C for ligand free Suzuki-Miyaura cross-
coupling reactions has been pioneered by Sajiki and co-
workers.7,8 Mild conditions are now available for the cross-
coupling of boronic acids or boronates with aryl halides (Br, I).7,9
In continuation of our work in which Pd/C (10%) was utilized as
a catalyst for the reductive monoalkylation of nitro aryls under an
atmosphere of hydrogen6 we herein report the Suzuki-Miyaura
cross-coupling reaction of 1-bromo-4-nitrobenzene prior to
reductive monoalkylation of the resulting nitro biaryl compound
in the same pot.
reductive monoalkylation of nitro aryls, it was envisaged that
the cross-coupling reaction could be conducted prior to the
reductive monoalkylation of the nitro functionality in the Suzuki-
Miyaura cross-coupling product. As a starting point for our
investigation, the reaction sequence outlined in Scheme 1 was
chosen. Based on the work of Sajiki et al.,7b it was envisaged that
their conditions for the Pd/C catalyzed Suzuki-Miyaura cross-
coupling would be a good starting point for our optimization of
the first part of the reaction sequence. Utilizing the same solvent
system (EtOH/H2O, 1:1) and base (Na2CO3) as Sajiki and co-
workers, and heating the reaction mixture at reflux resulted in
expedient cross-coupling, as judged by TLC analysis, over the
course of three hours, however, the following reductive
monoalkylation sequence conducted at room temperature
utilizing ten equivalents of acetaldehyde and hydrogen gas (1
atm) as the reducing agent, failed to proceed over three days
according to TLC analysis (entry 1, Table 1). The situation was
improved when the water content in the solvent system was
reduced (EtOH/H2O, 3:1) resulting in the isolation of the desired
secondary amine 3a in 51% yield in addition to 34% of the
corresponding primary amine after 48 hours under a hydrogen
atmosphere (entry 2, Table 1). Further reduction of the water
content (EtOH/H2O, 12:1) resulted in the cross-coupling reaction
still proceeding smoothly (3 hours), followed by reductive
monoalkylation of the nitro biaryl when ten equivalents of
acetaldehyde were used, thus resulting in the isolation of the
desired product 3a in 95% yield after column chromatography
(entry 3, Table 1). Utilizing the latter reaction conditions, but
reducing the concentration of acetaldehyde (entries 4 and 5,
Table 1) resulted in longer reaction times. After 48 h the
predominant product in the reaction mixture was the primary
amine together with small amounts of compound 3a according to
TLC analysis.
Based on the aforementioned successful Suzuki-Miyaura
cross-coupling catalyzed by Pd/C, and our earlier reports on
____
*Corresponding author. Fax: +47 51831750
E-mail address: magne.o.sydnes@uis.no

2
Tetrahedron Letters
Scheme 1. Outline of the one-pot reaction sequence (Method A).
Table 1. Optimization of reaction conditions.
Timea
Yield
Entry
Solvent
Equiv.
acetaldehyde
3a
-
51%c
b
1
2
3
4
5
EtOH/H2O (1:1)
EtOH/H2O (3:1)
EtOH/H2O (12:1)
EtOH/H2O (12:1)
EtOH/H2O (12:1)
10
10
3 h, 96 h
3 h, 48 h
3 h, 48 h
3 h, 48 h
3 h, 48 h
10
95%
d
1.5
-
d
3.3
-
aThe first time is the time for the Suzuki-Miyaura cross-coupling and the
b
second time reported is the time used for the reductive monoalkylation; No
secondary amine was observed by TLC analysis; c34% of the primary amine
d
was also isolated; Small amounts of compound 3a were observed by TLC
analysis.
During our optimization experiments (Table 1) it was obvious
that the water content in the solvent system played an important
role during the imine forming step of the reaction. The imine
formation did not take place when the EtOH/water ratio is 1:1
(entry 1, Table 1) and slowly improved when the water content
was reduced (entries 2 and 3, Table 1). Based on literature reports
it is obvious that the sensitivity to water during the imine forming
process is substrate dependent,10 and, as described in our work,
small quantities of water are acceptable.
With suitable reaction conditions in hand we embarked upon
determining the scope of the one-pot reaction. A range of
saturated aldehydes were chosen as alkylating agents together
with a few arylboronic acids (see Table 2). Conducting the
reaction sequence utilizing saturated aldehydes gave good to
excellent yields of the desired products (entries 1-10, Table 2).
The reductive monoalkylation process was run until the reaction
had reached completion, as judged by TLC analysis, or for a
maximum of 48 hours.

3
Table 2 One-pot formation of secondary biaryl amines from 1-bromo-4-nitrobenzene utilizing Method A.a
Entry
Boronic acid
Aldehyde
Product
Timeb
3 h,
Yield
76%
1
CH3(CH2)4CHO
48 h
1a
1a
2
3
4
CH3(CH2)8CHO
3 h,
80%
89%
70%
23 h
3 h,
46 h
CH3CHO
3 h,
48 h
1b
1b
5
6
CH3(CH2)4CHO
3 h,
85%
24 h
3 h, 16 h
88%
7
8
HCHO
(formaldehyde
solution, 37 wt% in
water)
4 h,
99%
75%
95%
98%
23%
24 h
1c
1c
1c
1a
CH3CHO
7.75 h, 48 h
9
CH3(CH2)4CHO
4 h,
24 h
10
11
4 h,
24 h
3 h,
36 h
aSolvent (EtOH/H2O, 12:1), Suzuki-Miyaura cross-coupling was conducted at reflux, and the reductive monoalkylation was conducted at rt with 10 equiv. of
aldehyde (see also Scheme 1); bThe times given correspond to the following reactions: Suzuki-Miyaura cross-coupling, reduction + imine formation + reduction.

4
Tetrahedron
Price, K. E.; McQuade, D. T. Org. Biomol. Chem., 2005, 3, 2899; d) Platon,
Not surprisingly, utilizing 2-furaldehyde as the alkylation
M.; Amardeil, R.; Djakovitch, L.; Herso, J.-C. Chem. Soc. Rev. 2012, 41,
3929; e) Wende, R. C.; Schreiner, P. R. Green Chem. 2012, 14, 1821.
2. Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York, 2001;
pp 3-9.
agent under the standard conditions (Method A) resulted in a low
yield (23%) of the desired product 3l (entry 11, Table 2).
Furaldehydes are known to be readily reduced over hydrogen on
Pd/C, thus generating
a
range of products including
3. Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York, 2001;
pp 170-172.
tetrahydrofuran.11 However, by utilizing the reaction conditions
for the reductive monoalkylation developed in our previous
work,6b thus conducting the imine formation under an atmosphere
of air followed by reduction under an atmosphere of hydrogen,
Method B (Scheme 2), it was possible to improve the yield of the
desired compound 3l to 49% (entry 1, Table 3). These conditions
also facilitated the formation of the furan-2-ylmethyl compounds
3m and 3n in 54% and 59% isolated yields, respectively (entries
2 and 3, Table 3). Although the yields for these conversions were
moderate, the method described herein represents an easy way to
generate these compounds.
4. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785.
5. a) Xiaojian, Z.; Zuwang, W.; Li, L.; Guijuan, W.; Jiaping, L. Dyes Pigm.
1998, 36, 365; b) Bae, J. W.; Cho, Y. J.; Lee, S. H.; Yoon, C.-O. M.; Yoon,
C. M. Chem. Commun. 2000, 1857; c) Sajiki, H.; Ikawa, T.; Hirota, K. Org.
Lett. 2004, 6, 4977; d) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Process Res.
Dev. 2005, 9, 219; e) Nacario, R.; Kotakonda, S.; Fouchard, D. M. D.;
Tillekeratne, L. M. V.; Hudson, R. A. Org. Lett. 2005, 7, 471; f) Fouchard, D.
M. D.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis 2005, 17; g) Reddy,
C. R.; Vijeender, K.; Bhusan, P. B.; Madhavi, P. P.; Chandrasekhar, S.
Tetrahedron Lett. 2007, 48, 2765; h) Byun, E.; Hong, B.; De Castro, K. A.;
Lim, M.; Rhee, H. J. Org. Chem. 2007, 72, 9815-9817; i) Lee, C.-C.; Liu, S.-
T. Chem. Commun. 2011, 47, 6981; j) del Pozo, C.; Corma, A.; Iglesias, M.;
Sánchez, F. J. Catal. 2012, 291, 110; k) Sreedhar, B.; Rawat, V. S. Synth.
Commun. 2012, 42, 2490; l) Xie, Y.; Liu, S.; Liu, Y.; Wen, Y.; Deng, G.-J.
Org. Lett. 2012, 14, 1692; m) Ikawa, T.; Fujita, Y.; Mizusaki, T.; Betsuin, S.;
Takamatsu, H.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Org. Biomol. Chem.
2012, 10, 293; n) Li, H.; Dong, Z.; Wang, P.; Zhang, F.; Ma, J. React. Kinet.
Mech. Cat. 2013, 108, 107.
6. Sydnes, M. O.; Isobe, M. Tetrahedron Lett. 2008, 49, 1199; b). Sydnes, M.
O.; Kuse, M.; Isobe, M. Tetrahedron 2009, 64, 6406.
7. a) Kitamura, Y.; Sako, S.; Udzu, T.; Tsutsui, A.; Maegawa, T.; Monguchi,
Y.; Sajiki, H. Chem. Commun. 2007, 5069; b) Maegawa, T.; Kitamura, Y.;
Sako, S.; Udzu, T.; Sakurai, A.; Tanaka, A.; Kobayashi, Y.; Endo, K.; Bora,
U.; Kurita, T.; Kozaki, A.; Monguchi, Y.; Sajiki, H. Chem. Eur. J. 2007, 13,
5937; c) Kitamura, Y.; Sakurai, A.; Udzu, T.; Maegawa, T.; Monguchi, Y.;
Sajiki, H. Tetrahedron 2007, 63, 10596; d) Kitamura, Y.; Sako, S.; Tsutsui,
A.; Monguchi, Y.; Maegawa, T.; Kitade, Y.; Sajiki, H. Adv. Synth. Catal.
2010, 352, 718; e) Monguchi, Y.; Fujita, Y.; Hashimoto, S.; Ina, M.;
Takahashi, T.; Ito, R.; Nozaki, K.; Maegawa, T.; Sajiki, H. Tetrahedron 2011,
67, 8628.
8. For recent reviews discussing the use of Pd/C in cross-coupling reactions,
see: a) Sydnes, M. O. Curr. Org. Synth. 2011, 8, 881; b) Mora, M.; Jimenez-
Sanchidrian, C.; Ruiz, J. R. Curr. Org. Chem. 2012, 16, 1128.
9. Sajiki et al. have also started utilizing palladium supported on a synthetic
adsorbent for ligand-free cross-coupling reactions, see: a) Monguchi, Y.;
Fujita, Y.; Endo, K.; Takao, S.; Yoshimura, M.; Takagi, Y.; Maegawa, T.;
Sajiki, H. Chem. Eur. J. 2009, 15, 834; b) Monguchi, Y.; Sakai, K.; Endo, K.;
Fujita, K.; Niimura, M.; Yoshimura, M.; Mizusaki, T.; Sawama, Y.; Sajiki, H.
ChemCatChem 2012, 4, 546.
Scheme 2. Outline of Method B.
In conclusion, we have developed simple conditions that
facilitate the Suzuki-Miyaura cross-coupling of aryl boronic acids
with 1-bromo-4-nitrobenzene prior to reductive monoalkylation
of the resulting biaryl nitro compounds in one-pot utilizing Pd/C
as catalyst and hydrogen gas (1 atm) as the reducing agent. These
conditions resulted in the formation of secondary amines in
predominantly good yields when saturated aldehydes were
utilized as the alkylation agent. In this one-pot procedure, four
sequential reaction steps, Suzuki-Miyaura cross-coupling,
reduction of the nitro functionality to the primary amine, imine
formation, and reduction of the imine to the corresponding
secondary amine occurred in one reaction flask with only one
simple purification step. Further work will focus on reducing the
equivalents of aldehyde needed for the reaction and also
switching the halide in the starting material from bromine to
chlorine.
10. a) Simion, A.; Simion, C.; Kanda, T.; Nagashima, S.; Mitoma, Y.;
Yamada, T.; Mimura, K.; Tashiro, M. J. Chem. Soc., Perkin Trans. 1 2001,
2071; b) Cody-Alcantar, C.; Yatsimirsky, A. K.; Lehn, J.-M. J. Phys. Org.
Chem. 2005, 18, 979; c) Saggiomo, V.; Lüning, U. Eur. J. Org. Chem. 2008,
25, 4329; d) Saggiomo, V.; Lüning, U. Tetrahedron Lett. 2009, 50, 4663.
11. a) Corma, A.; Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411; b)
Sitthisa, S.; Resasco, D. E. Catal. Lett. 2011, 141, 784.
Acknowledgments
Financial support from the University of Stavanger and the
research program, Green Production Chemistry is gratefully
acknowledged. M. M. is grateful for the provision of a ParOwn
grant from the Egyptian government. Thanks are also due to Dr.
Bjarte Holmelid, University of Bergen, for recording mass
spectra.
Supplementary Material
Supplementary material available: Experimental procedures,
experimental data and NMR spectra of new compounds. See
…….
References and notes
1. a) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl., 1993, 32, 131; b)
Tietze, L. F. Chem. Rev., 1996, 96, 115; c) Broadwater, S. J.; Roth, S. L.;

5
Table 3 One-pot formation of secondary biaryl amines with 2-furaldehyde utilizing Method B.a
Entry
1
Boronic acid
Product
Timeb
Yield
49%
1a
3 h, 1.5 h, 4 h, 24 h
2
3
1b
1c
3 h, 1.5 h, 4 h, 24 h
3 h, 1.5 h, 4 h, 24 h
54%
59%
aSolvent (EtOH), Suzuki-Miyaura cross-coupling was conducted at reflux, and the remaining steps were conducted at rt with 10 equiv. of 2-furaldehyde (see also
Scheme 2); bThe times given correspond to the following reactions: Suzuki-Miyaura cross-coupling, reduction to primary amine, imine formation (under an atm
of air), reduction to the secondary amine.