Synthesis of a (piperazin-1-ylmethyl)biaryl library via microwave-mediated Suzuki-Miyaura cross-couplings

Article abstract of DOI:10.1016/j.tetlet.2011.05.025

Boc-protected (piperazin-1-ylmethyl)biaryls have been synthesised from (Boc-piperazin-1-ylmethyl)phenylboronic acid pinacol esters via a microwave-mediated Suzuki-Miyaura coupling with aryl bromides viz. 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nit

Full text of DOI:10.1016/j.tetlet.2011.05.025

Tetrahedron Letters 52 (2011) 3963–3968
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a (piperazin-1-ylmethyl)biaryl library via microwave-mediated
Suzuki–Miyaura cross-couplings
John Spencer a, , Christine B. Baltus a, Neil J. Press b, Ross W. Harrington c, William Clegg c
⇑
a School of Science at Medway, University of Greenwich, Chatham, ME4 4TB, UK
b Novartis Pharmaceuticals UK Ltd, Horsham, Sussex, RH12 5AB, UK
c School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Boc-protected (piperazin-1-ylmethyl)biaryls have been synthesised from (Boc-piperazin-1-ylmethyl)
phenylboronic acid pinacol esters via a microwave-mediated Suzuki–Miyaura coupling with aryl
bromides viz. 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nitropyridine. Judicial removal of the
protecting group on the piperazine, or facile reduction of the nitro group on the biaryl system enabled
the manipulation of two points of functionality in order to diversify the scope of the resulting biaryl library.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 March 2011
Revised 18 April 2011
Accepted 6 May 2011
Available online 20 May 2011
Keywords:
Suzuki–Miyaura coupling
Biaryl
Piperazine
Microwave
The biaryl unit is found in many natural and synthetic products
and as a privileged scaffold in medicinal chemistry. Undoubtedly,
the most important and efficient strategy for its construction is
the palladium-catalyzed Suzuki–Miyaura (SM) coupling reaction.1
The incorporation of a piperazine motif into a molecule is inter-
esting from a medicinal chemistry point of view since it produces
analogues that have a lower lipophilicity and enhances aqueous
solubility.2 Hence, piperazine units are found in many drugs with
a broad scope of actions such as antidepressants,3 antihistamines,4
antiretrovirals,5 anti-Parkinson’s,6 antianginals7 and antipsychot-
ics8 amongst others (Fig. 1).9–11
ylboronic acid pinacol esters with a range of N-, S- and O-nucleo-
philes.12 These were further reacted to afford a library of biaryls.
In certain instances, Boc-piperazine was used as an N-nucleophile
and the arylboronic esters obtained were found to be interesting
because the protecting group on the piperazine could be easily re-
moved to liberate an amine, allowing further functionalisation
prior to, or following, a Suzuki–Miyaura cross-coupling with vari-
ous aryl halides.
Herein, we describe the use of protected m- or p-substituted
(piperazin-1-ylmethyl)phenylboronic acid pinacol esters
1 as
useful synthons for the synthesis of a wide range of biaryls. As a
starting point, we have repeated or elaborated upon our previous
findings, in order to increase the scope of the SM coupling reaction
Recently, we reported the synthesis of an arylboronate library
using microwave-mediated SN2 reactions of (bromomethyl)phen-
N
O
NH
N
HN
N
N
N
N
O
O
O
N
N
N
S
N
N
N
H
HN
N
Cl
O
O
N
N
Sildenafil (viagra)
cGMP-specific
phosphodiesterase type 5 inhibitor
Cyclizine
Imatinib
tyrosine kinase inhibitor
Amoxapine
antihistamine drug with
antidepressant
anticholinergic effects
Figure 1. Examples of drugs containing the piperazine motif (in blue).
⇑
Corresponding author. Tel.: +44 2083318215; fax: +44 2083319805.
E-mail addresses: j.spencer@gre.ac.uk, J.Spencer@greenwich.ac.uk (J. Spencer).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.025

3964
J. Spencer et al. / Tetrahedron Letters 52 (2011) 3963–3968
Br
NO2
X
O
O
N
2
B
N
O
N
NO2
X = CH or N
O
N
X
O
O
Pd(OAc)2
Na2CO3
1
3
TBAB
1a
meta isomer
H2O
µw, 150 ºC
1b para isomer
NO2
O2N
NO2
O
O
O
O
O
N
N
N
N
N
N
O
3a
3b
3c
10 min
72%
10 min
87%
10 min
72%
NO2
O2N
NO2
NO2
N
N
N
N
N
N
N
O
N
O
N
O
O
O
O
O
O
3d
3e
3f
3g
20 min
85%
10 min
75%
10 min
81%
20 min
70%a
Scheme 1. SM reactions on compounds 1. Reaction yields given after purification by chromatography. Reaction times given in minutes (min). aPd(PPh3)4 used as precatalyst
(3 mol %), Na2CO3 (3 equiv) in toluene/EtOH/H2O (1:1:1), 150 °C, microwave irradiation (maximum power 300 W).
1) TFA
CH2Cl2
NO2
16 h
NO2
N
N
O
N
X
HN
X
2) K2CO3
H2O
O
X = CH or N
4
3
O2N
NO2
NO2
HN
N
HN
N
HN
N
4a
99%
4b
4c
93%
98%
O2N
NO2
NO2
NO2
N
N
N
N
N
HN
HN
HN
HN
4g
4d
94%
4e
100%
4f
73%
100%
Scheme 2. Cleavage of the Boc group in 3. Crude reaction yields given as the products were used without further purification.
of 1. The isomeric 2-methylphenylboronic acid pinacol esters were
previously shown to deprotodeborylate in SM reactions and so were
not selected.13 We also found that N-substituted 3- and 4-meth-
ylphenylboronic acid pinacol esters could react with different aryl
bromides in a Suzuki–Miyaura cross-coupling using microwave-as-
sisted organic synthesis (MAOS) to afford the corresponding
biphenyl compounds. 2-, 3- and 4-bromo-nitrobenzenes and
2-bromo-5-nitropyridine 2 were used as aryl halides partly due to
their facile coupling in the SM process, but also because the nitro
groups can be reduced at a later stage to anilines, which can be
functionalised leading to diversity in the final library.
The SM coupling was achieved employing Leadbeater’s
conditions14 with palladium(II) acetate as the precatalyst and 2
as aryl bromides under microwave irradiation (lw) on compounds
1a and 1b. The expected biphenyls were obtained in good yields,
within 10–20 min (Scheme 1).

J. Spencer et al. / Tetrahedron Letters 52 (2011) 3963–3968
3965
PS-NMM
NO2
NO2
CH2Cl2
R1 Cl
N
N
HN
X
N
X
rt
R1
1-16 h
5
4
6
X = CH or N
NO2
O2N
O2N
O2N
O
O
N
N
O
O
S
O
O
O
N
N
N
N
N
N
6a
6b
6c
6d
F
94%
1 h
68%
16 h
48%
2 h
83%
2 h
NO2
NO2
NO2
NO2
O
S
O
O
O
O
S
O
N
N
N
N
N
N
N
N
O
6e
50%
2 h
6f
6g
6h
70%
16 h
65%
16 h
92%
20 h
O2N
NO2
NO2
NO2
O2N
N
N
N
N
N
N
N
N
N
O
O
N
O
S
O
O
O
S
O
6i
6k
6m
6j
6l
69%
16 h
91%
16 h
61%
16 h
74%
16 h
92%
16 h
NO2
NO2
NO2
N
N
N
N
NO2
N
N
N
N
N
O
O
N
O
O
S
O
6o
48%
6 h
6p
6n
6q
84%
16 h
100%
4 h
75%
16 h
Scheme 3. Functionalisation of compounds 4 to afford 6. Reaction yields given after purification by chromatography. Reaction times given in hours (h).
Table 1
Optimisation of the nitro group reduction of 6
H2
Cat.
NH2
NO2
X
X
EtOH/EtOAc
65 ºC
N
N
1 mL.min-1
N
N
R1
R1
X = CH or N
6
7
Entry
6
Conditions
Product
Yield (%)
NO2
NH2
N
N
1
Raney Ni/H2
94
N
N
O
O
7a
6k
(continued on next page)

3966
J. Spencer et al. / Tetrahedron Letters 52 (2011) 3963–3968
Table 1 (continued)
Entry
6
Conditions
Product
Yield (%)
NO2
N
N
N
2
3
SnCl2ꢀ2H2O
7a
67a
N
N
N
O
6k
6n
NO2
NH2
8
8
Pd/C/H2
Pd/C/H2
97
94
O
O
NO2
NH2
4
6o
S
O
a
Microwave irradiation (maximum power 300 W), EtOH, 130 °C, 30 min.
NH2
H2N
H2N
NH2
O
O
N
N
O
O
S
O
O
O
N
N
N
N
N
N
F
7c
7d
99%
7e
7b
88%
35%
92%
H2N
H2N
N
NH2
NH2
O
S
O
N
O
N
N
N
N
N
O
N
O
O
7f
91%
7g
7h
7i
97%
92%
90%
NH2
NH2
NH2
NH2
N
N
N
N
N
N
S
N
N
N
O
N
O
O
S
O
O
7j
80%
7k
7l
100%
7m
100%
100%
Figure 2. Amines 7 synthesised using Raney Nickel/H-Cube conditions. Crude reaction yield given as the products were used without further purification.
Once the biphenyl unit had been synthesised, the functionalisa-
tion reactions could be initiated. Boc group cleavage was achieved
with trifluoroacetic acid (TFA) in dichloromethane at room temper-
ature within 2 h or overnight, followed by a basic work-up to lib-
erate the free amine (Scheme 2).15
Compounds 4 were functionalised by reaction with acid or sul-
fonyl chlorides 5 in dichloromethane at room temperature in the
presence of a supported base (PS-NMM: polystyrene N-methyl-
morpholine) (Scheme 3).16 The amidation reaction gave the ex-
pected products in good yields (e.g., 6a in 94% yield) while the
sulfonylation process afforded the corresponding products in
moderate yields (e.g., 6c in 48% yield). Most reactions with acid
chlorides worked very well in a few hours (e.g., 6a in 94% yield
in 1 h, 6d in 83% yield in 2 h and 6n in 100% yield in 4 h), whereas
some required an overnight reaction to give the expected products
in moderate yields (e.g., 6i in 69% yield and 6m in 61% yield).
We next intended to reduce the nitro group in compounds 6 in
order to produce amines for further functionalisation reactions.
Nitro group reduction can be performed by thermal, microwave
or flow chemistry (H-Cube)17 routes. We found the latter to be

J. Spencer et al. / Tetrahedron Letters 52 (2011) 3963–3968
3967
R2Cl
NH
R2
X
5
N
CH2Cl2
PS-NMM
rt, 16 h
N
R1
10
NH2
X
N
N
R1
X
N
O
O
O
N
7
9
N
CH3COOH
R1
X = CH or N
11
µw, 115 ºC, 15 min
NC
S
O
O
O
O
O
HN
HN
HN
NH
O
O
O
N
N
O
N
N
O
O
N
N
N
N
10a
87%
10d
10b
10c
58%
77%
100%
O
O
S
O
O
O
HN
HN
O
O
HN
N
S
N
N
NH
O
S
O
N
N
N
N
N
O
O
O
10e
10f
10g
10h
70%
70%
60%
70%
O
O
O
S
NH
HN
O
NH
N
N
N
N
N
N
N
N
O
O
O
S
O
10i
10j
70%
10k
31%
32%
N
N
N
N
O
N
O
N
N
O
N
N
F
O
11b
11c
11a
54%
42%
90%
Scheme 4. Amine functionalisation reactions of compounds 7. Reaction yields given after purification by chromatography.
the most straightforward option since it generally obviated a
purification or work-up step. The attempted reduction of
nitro-biphenyl derivatives was mainly investigated in an H-Cube,
in ethanol/ethyl acetate (1:1), at 65 °C, with a flow rate of
1 mL minꢁ1 and in full hydrogen mode, as outlined in Table 1.
When Raney Nickel was used as the catalyst, the expected prod-
uct 7a was obtained in very good yield (Table 1, entry 1). A micro-
wave-mediated nitro reduction was attempted using tin chloride
dihydrate (entry 2), but gave an inferior yield and a more compli-
cated work-up, compared with the former reduction. However,
unexpected hydrogenolysis of the benzylic-like unit in 6n and 6o
led to the corresponding 4-tolylaniline 8 when Pd/C and H2 were
used (Table 1, entries 3 and 4). This is akin to a standard debenzyla-
tion reaction in organic synthesis.15 Thereafter, the Raney Nickel/

3968
J. Spencer et al. / Tetrahedron Letters 52 (2011) 3963–3968
O
Cl
PS-NMM
NH2
NH
CH2Cl2
rt, 1 h
O
12
8
71%
Scheme 5. Amine functionalisation reaction of compound 8 and the asymmetric unit of the crystal structure of 12. Reaction yield given after purification by chromatography.
Int. Pharmacodyn. Ther. 1978, 233, 107; (e) Lydiard, R. B.; Gelenberg, A. J.
Pharmacotherapy 1981, 1, 163; (f) Jue, S. G.; Dawson, G. W.; Brogden, R. N. Drugs
1982, 24, 1.
H-cube conditions were used to reduce the other (piperazin-1-
ylmethyl)nitrobiphenyl derivatives (Fig. 2). Many of the products 7
were obtained in very good yields without any further purification.
The amine group could next be functionalised by amidation and
sulfonylation reactions with the corresponding acid or sulfonyl
chlorides 5 in the presence of a supported base (PS-NMM). Pyrrole
derivatives were synthesised by reaction of 7 with 2,5-dimethoxy-
tetrahydrofuran (9) in acetic acid (Scheme 4)18
The elaborated biaryl products were obtained in moderate to
good yields after purification by chromatography on silica gel. An
amide coupling of 8 led to an interesting biphenyl derivative 12
in good yield (Scheme 5). Very small crystals of 12 were grown
and analysed by a synchrotron X-ray diffraction crystal structure
determination which shows a very interesting structure with a Z0
value of 3 (Supplementary data, S19).
In summary, a (piperazin-1-ylmethyl)biaryl library has been
synthesised over a few steps using, inter alia, the MAOS-mediated
Suzuki-Miyaura coupling reaction. This library is composed of a
number of very interesting drug-like molecules. The crystal struc-
ture of 12 has stimulated our interest into examining analogues in
the solid state and results will be disclosed in due course.
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Acknowledgements
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12. (a) Spencer, J.; Baltus, C. B.; Patel, H.; Press, N. J.; Callear, S. K.; Male, L.;
Coles, S. J. ACS Comb. Sci. 2011, 13, 24. and references cited therein; For
recent related articles on the use of boronic acid pinacol esters see: (b)
White, J. R.; Price, G. J.; Schiffers, S.; Raithby, P. R.; Plucinski, P. K.; Frost, C.
G. Tetrahedron Lett. 2010, 51, 3913; (c) Huang, J.; Macdonald, S. J. F.; Cooper,
A. W. J.; Fisher, G.; Harrity, J. P. A. Tetrahedron Lett. 2009, 50, 5539; (d)
Auvinet, A.-L.; Harrity, J. P. A.; Hilt, G. J. Org. Chem. 2010, 75, 3893; (e)
Harrisson, P.; Morris, J.; Marder, T. B.; Steel, P. G. Org. Lett. 2009, 11, 3586;
(f) Primas, N.; Bouillon, A.; Rault, S. Tetrahedron 2010, 66, 8121; (g) Schultz,
M. J.; Coats, S. J.; Hlasta, D. J. Org. Lett. 2004, 6, 3265.
13. (a) Spencer, J.; Burd, A. P.; Adatia, T.; Goodwin, C. A.; Merette, S. A. M.; Scully,
M. F.; Deadman, J. J. Tetrahedron 2002, 58, 1551; (b) We have since found that
2-(N- and S-substituted methyl)phenylboronates can undergo SM reactions
under optimized conditions. Baltus, C. B.; Spencer, J.; Press, N. J. unpublished
results.
Novartis is thanked for funding this work (PhD award to C.B.). BP
is acknowledged for providing funding for a CEM Explorer micro-
wave reactor. The EPSRC Mass Spectrometry Unit (University of
Swansea) is thanked for HR-MS measurements. EPSRC is also
thanked for funding the National Crystallography Service, and
Diamond Light Source for providing access to synchrotron facilities
(Newcastle University). The University of Greenwich and the School
of Science are thanked for financial support.
Supplementary data
Supplementary data (general procedures, analytical data for
compounds and crystallography data (CCDC 810173)) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.05.025.
14. Leadbeater, N.; Marco, M. J. Org. Chem. 2003, 68, 888.
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