An improved synthesis of N-aryl and N-heteroaryl substituted homopiperazines-from conventional thermal conditions to scaling-up using microwave heating

Article abstract of DOI:10.1016/j.tet.2009.07.086

An efficient Pd(0)-catalyzed Buchwald-Hartwig protocol for the facile preparation of N-aryl and N-heteroaryl substituted homopiperazines is described. The syntheses proceeded with aryl- and heteroaryl halides in high yields using X-Phos as best ligand. Th

Full text of DOI:10.1016/j.tet.2009.07.086

Tetrahedron 65 (2009) 8125–8131
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An improved synthesis of N-aryl and N-heteroaryl substituted
homopiperazinesdfrom conventional thermal conditions
to scaling-up using microwave heating
,
a
a
b
b,
*
Uwe Scho¨n a , Josef Messinger , M. Buckendahl , M.S. Prabhu , A. Konda
*
a Solvay Pharmaceuticals Research Laboratories, Hans-Bo¨ckler-Allee 20, 30173 Hannover, Germany
b Research Support International Limited, S.V. Road, Majiwada, Thane West 400 610, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2009
Received in revised form 29 July 2009
Accepted 29 July 2009
Available online 6 August 2009
An efficient Pd(0)-catalyzed Buchwald–Hartwig protocol for the facile preparation of N-aryl and
N-heteroaryl substituted homopiperazines is described. The syntheses proceeded with aryl- and heteroaryl
halides in high yields using X-Phos as best ligand. The C–N coupling products were prepared both under
conventional as well as microwave heating conditions and examples for microwave-assisted upscaling
are included in this study.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Buchwald–Hartwig amination
X-Phos
Palladium
Microwave
Homopiperazines
1. Introduction
investigation on N-arylation of homopiperazines by means of
palladium chemistry is still missing.
The piperazine scaffold has been classified as a privileged
structure and especially N-arylpiperazines are frequently described
in different therapeutic areas, e.g., as dopamine D4 ligands.1 In fact,
pharmaceutical companies have mainly developed N-arylated pi-
perazines during the past few years, but not much attention has
been devoted to the corresponding homopiperazines in the
literature.
2. Results and discussion
Since our research group is dedicated to the synthesis of N-aryl
and N-heteroaryl substituted homopiperazines as building blocks
for potential new pharmacological entities, we planned to broaden
the synthetic scope of this methodology without any limitations
concerning the substituent pattern. We planned to focus our study
on the synthesis of such target entities via conventional as well as
microwave-assisted Buchwald–Hartwig aminations of heteroaryl
and aryl halides.
Additionally, we were interested to develop a protocol that can
be used for parallel synthetic applications using simple experi-
mental conditions, thus avoiding absolute dry and oxygen-free
reaction conditions for which a glove-box would be required.
Nucleophilic substitution reactions are described for the
synthesis of electron-deficient N-aryl and N-heteroaryl
substituted piperazine and homopiperazine derivatives.2 Novel
routes have been devised that rely on palladium or copper ca-
talysis. Whereas, Nielsen et al.3 described the Pd(0)-catalyzed
coupling of N-protected piperazine and homopiperazine with
substituted 3-bromo- and 3-chloropyridines, Beller et al.4 pub-
lished the synthesis of N-aryl- and N-heteroaryl-piperazines
using the Buchwald–Hartwig amination. An Ullmann-type
methodology has been reported by Buchwald et al., describing
a method for the copper-catalyzed coupling of alkylamines and
aryl halides.5 To the best of our knowledge,
a systematic
2.1. Comparison of conventional and microwave heating
Here, we describe the synthesis of N-aryl and N-heteroaryl
substituted homopiperazines by palladium catalyzed Buchwald–
Hartwig amination6 of different aryl and heteroaryl halides
according to the following general scheme (Scheme 1).
* Corresponding authors. Tel.: þ49 511 857 2311; fax: þ49 511 857 2195.
E-mail address: uwe.schoen@solvay.com (U. Scho¨n).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.086

8126
U. Scho¨n et al. / Tetrahedron 65 (2009) 8125–8131
R1
R1
PPh2
PPh2
PPh2
PPh2
O
PPh2
PPh2
Fe
Pd(OAc)2
ligand
Y
Pd(PPh3)4
Y
+
N
HN
NH
NH
X
R2
R2
2
L2 (Xantaphos)
L4
L1 (BINAP)
L3 (DPPF)
H+
R1
PR2
R3
R1
NMe2
R2
H
P
Pd
Cl
Fe
Pd(OAc)2
ligand
O
Pd
Cl
P
Y
+
H N
N
Y
O
N
N
N(CH3)2
X
O
R2
R2
O
R4
1
Scheme 1. Buchwald–Hartwig approach.
L12 (SK-CC02-A)
L5 - L10
L11 (SK-CC01-A)
As the Pd-catalyzed coupling of homopiperazine with aryl halides
would directly result in the desired product (see also Scheme 2), we
initially attempted the coupling of homopiperazine with bromo-
benzene. However, yields ranged only between 45 and 50%. Similar
results were reported by Zhao et al. for piperazines.7 Thus, we pur-
sued an alternative approach by using 4-Boc-homopiperazine and
aryl/heteroaryl halides as coupling partners, yielding in the Boc-
protected amination products. Subsequent removal of the Boc-group
would lead to the target N-aryl/heteroaryl-homopiperazines.
L
R
R2
R3
R4
remarks
L5
L6
L7
L8
L9
C6H11
N(CH3)2
OCH3
H
H
H
H
DavePhos
S-Phos
C6H11
C6H11
OCH3
OCH(CH3)2 OCH(CH3)2
RuPhos
C6H11
C(CH3)3
C6H5
CH(CH3)2
H
CH(CH3)2
H
CH(CH3)2
H
X-Phos
JohnPhos
N(CH3)2
L10
H
H
PhDavePhos
"Pd",
ligand,
base
OtBu
Figure 1. Phosphine ligands and catalysts selected.
OtBu
N
N
Br
+
HN
N
O
O
1a
Table 1
Ligand effect on palladium catalyzed amination reactions (refer also to Scheme 2)a
Scheme 2. Buchwald–Hartwig amination of Boc-protected homopiperazine with
bromobenzene (refer also to Tables 1 and 2).
Ligand
Yield (%)
Ligand
L1
L2
0
L3
L4
L5
L6
75c
L7
18c
L9
37b,d
L10
45c
76c
L11
58c
22b
L12
73c
At first we had to optimize the reaction conditions for the syn-
thesis of N-aryl and N-heteroaryl substituted homopiperazines by
using different ligands, bases and solvents at different temperatures.
Initially, we had to identify the ideal phosphine ligand for the con-
densation of 4-Boc-homopiperazine with bromobenzene. Buch-
wald8 and co-workers thoroughly described the Pd-catalyzed
amination of a variety of heteroaryl halides by utilizing bulky, elec-
tron-rich biaryl phosphine ligands. Based on this publication we
selected 12 different ligands/catalysts as summarized in Figure 1.
Thus, in a typical experiment bromobenzene was subjected to
the Pd(0)-catalyzed amination in the presence of one of 12 different
phosphine ligands using Cs2CO3 as base in toluene/t-BuOH (5:1) at
120 ꢀC for 18 h in sealed vials (Scheme 2). The results of this ligand
screening are summarized in Table 1.
The highest yield was achieved by using X-Phos (L8). All other
ligands gave moderate to good yields and the bidentate ligand
Xantaphos (L2) and DPPF (L3) were observed to be highly
ineffective.
In the next phase of this study, the use of other bases was in-
vestigated such as Et3N, K2CO3, K3PO4, KO-t-Bu and NaO-t-Bu. With
K2CO3 and K3PO4 as bases the yields are only moderate (50% and
58% isolated yields, respectively) and with KO-t-Bu and Cs2CO3 the
product was obtained in 70% and 77% isolated yield, respectively.
Product formation was not observed with triethylamine whereas
NaO-t-Bu was identified as best base (99% yield and shorter re-
action time).
L8
Yield (%)
61c
95c 77b
49c
a
Reagents and conditions: 4-Boc-homopiperazine (1 equiv), bromobenzene
(1.1 equiv), Pd(OAc)2 (5 mol %), ligand (5 mol %), Cs2CO3 (1 equiv), toluene/t-BuOH
(5:1), 120 ꢀC, 18 h.
b
Isolated yield.
LC/MS yield.
In the absence of Pd(OAc)2.
c
d
Table 2
Solvent effect on palladium catalyzed amination reactions (see also Scheme 2 for
general description)a
Solvent
Temp (ꢀC)
Yieldb (%)
DMF
NMP
120
120
120
120
120
40
63
43
36
99
1,4-Dioxane
DMA
Toluene/t-BuOH (5:1)
a
Reagents and conditions: 4-Boc-homopiperazine (1 equiv), bromobenzene
(1.1 equiv), Pd(OAc)2 (5 mol %), X-Phos (5 mol %), NaO-t-Bu, 10 h.
b
Isolated yield.
As summarized in Table 2, only the combination of toluene/tert-
butyl alcohol (5:1) was found to result in good yields for the given
amination.
Encouraged by these findings, we next started to investigate the
scope of the Pd(0)-catalyzed Buchwald–Hartwig reaction for the
preparation of N-aryl and N-heteroaryl substituted Boc-homo-
piperazines under conventional conditions and under microwave
heating conditions in order to reduce reaction times. It is well
documented that microwave assistance can lead to enormous rate
enhancement compared to conventional heating.11 Besides a better
reproducibility, higher yields and less side reactions have often
Furthermore,wecompareddifferentsolventsystems(seeTable 2).
Toluene and 1,4-dioxane are often employed as solvents for aryl
aminations, while the mixture composed of toluene/t-BuOH has
served for the amination of aryl sulfonates.9 We recently published
the use of DMF as an excellent solvent for the efficient preparation of
3-benzylaminoestrone from oestrone-triflate.10 Therefore, we also
tested our model reaction in DMF.

U. Scho¨n et al. / Tetrahedron 65 (2009) 8125–8131
8127
been observed. Reports on microwave-assisted Pd-catalyzed aryl
aminations have also appeared in the literature.12
After this substantial optimizationwe extended the product range
by first applying the optimized conventional thermal conditions [i.e.,
4-Boc-homopiperazine (1 equiv), aryl halide (1.2 equiv), NaO-t-Bu
(1 equiv), 5 mol % of X-Phos and 5 mol % of Pd(OAc)2 in toluene/
t-BuOH (5:1) at 120 ꢀC] for the synthesis of six different N-heteroaryl
derivatives of 4-Boc-homopiperazines. Bromopyridines, chloropyr-
idines and 3-bromoquinoline gave the corresponding amination
products in moderate to good isolated yields (Table 4). In addition to
the aminations carried out under conventional heating, we in-
vestigated the microwave supported Buchwald–Hartwig reaction of
selected examples for comparison reasons. The electron-deficient
heteroaryl halides required prolonged reaction times between 10 and
20 min. Furthermore, we changed the solvent system to benzotri-
fluoride/t-BuOH (5:1).
So we carried out different reactions with different substituted
aryl halides under microwave conditions13 and compared the re-
sults with the reactions carried out under conventional thermal
conditions (Scheme 3). In case of conventional heating in addition
we compared NaO-t-Bu and Cs2CO3. Results are summarized in
Table 3.
R1
R1
Y
R2
X-Phos, Pd(OAc)2,
base, toluene, t-BuOH
X
+
Y
R2
N
N
OtBu
OtBu
Table 4
1a - 1u
HN
N
Synthesis of heteroaryl substituted 4-Boc-homopiperazines (X¼Hal, Y¼N; refer also
O
to Scheme 3)a
O
Product
Substrate
Product
Thermal heatingb MWd
Scheme 3. Buchwald–Hartwig amination of Boc-protected homopiperazine with aryl-
and heteroaryl halides (X¼Hal, Y¼CH, N; refer also to Tables 3 and 4).
Time
(h)
Yieldc
(%)
Yieldc
(%)
Br
Table 3
Synthesis of aryl substituted 4-Boc-homopiperazines (X¼Br, Y¼CH; refer also to
1p
1q
16
16
85
53
Scheme 3)12,a
boc
boc
N
N
N
N
N
N
N
.HCl
R1
R2
Baseb
Time (h)
Yieldc (%)
MW 10 min, 160 ꢀ
C
LC/MSd
Yieldc (%)
N
59
68
48
1a
1b
1c
H
H
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Cs
Na
Na
Na
18
8
77
99
86
88
68
98
59
93
66
92
78
93
74
87
75
95
43
68
25
26
N
Br
Br
99
95
95
83
74
4-F
H
18
10
18
10
18
10
18
10
18
10
18
10
18
10
18
10
18
10
4-OCH3
3-OCH3
4-CH3
4-CN
4-CF3
4-Cl
H
N
1r
1s
1t
16
18
18
16
70
92
58
74
100
boc
Cl
N
1de
1e
1f
H
N
H
Cl
Cl
100
91
99
64
81
90
N
N
boc
H
N
1g
1h
1ie
1j
H
N
94
3-CF3
H
Cl
Br
N
N
boc
96
3-Cl
N
N
2-Cl
H
99
100
99
48
75
95
1k
1l
3-Cl
4-Cl
H
boc
N
1u
N
73
10
18
10
18
10
18
10
70
80
96
80
85
72
87
N
3-CH3
4-CHO
N
1me
H
a
Reagents and conditions: 4-Boc-homopiperazine (1 equiv), heteroaryl halide
(1.1 equiv), Pd(OAc)2 (5 mol %), ligand (5 mol %), NaO-t-Bu (1 equiv), toluene/
t-BuOH (5:1), 120 ꢀC, 10–18 h/microwave heating: benzotrifluoride/t-BuOH (5:1),
160 ꢀC for 20 min.
1ne
1oe
3,4-OCH2CH2O–
2-Naphthyl–
b
All reactions were performed in parallel using a carousel from Radley Ltd.
a
Reagents and conditions: 4-Boc-homopiperazine (1 equiv), aryl bromide
(1.2 equiv), Pd(OAc)2 (5 mol %), X-Phos (5 mol %), NaO-t-Bu (1 equiv), toluene/
t-BuOH (5:1), 120 ꢀC, 10–18 h/microwave heating 160 ꢀC for 10 min (reaction car-
ried out in Emrys optimizer microwave device).
c
Isolated yield.
d
Reaction carried out in Emrys optimizer microwave device.
Summarizing these first results using X-Phos as best ligand, we
have developed convenient protocols for the efficient preparation
of N-aryl and N-heteroaryl substituted N-Boc-homopiperazines
starting from N-Boc-homopiperazines and aryl halides or hetero-
aryl halides. The C–N coupling products were prepared in good to
excellent yields both under conventional as well as microwave
heating conditions.
b
Cs¼Cs2CO3; Na¼NaO-t-Bu.
c
Isolated yield.
d
Percentages are based on the product peak area by LC/MS (UV).
Reactions of these substrates were carried out under conventional heating
e
conditions only.
These data clearly demonstrate that it is possible to prepare the
target N-aryl substituted 4-Boc-homopiperazines within 10 min
under microwave conditions with comparable yields and purity,
whereas conventional heating depending on the base used requires
10 to 18 h. All conventional reactions with NaO-t-Bu as base pro-
ceeded in shorter reaction time and resulted in higher yields.
2.2. Upscaling Buchwald–Hartwig amination
Finally, scale-up of the palladium-catalyzed aminations was
envisaged using conventional as well as microwave heating. With

8128
U. Scho¨n et al. / Tetrahedron 65 (2009) 8125–8131
respect to conventional heating recently Federsel et al. published
pilot plant data about optimization and scale-up of Pd-catalyzed
Buchwald–Hartwig chemistry as key step in the synthesis of a 5-HT
receptor antagonist.14
Singel mode plot
350
300
250
200
150
100
50
Power
We first applied the optimized conditions for conventional
heating [4-Boc-homopiperazine (1 equiv), aryl or heteroaryl ha-
lide (1.1 equiv), NaO-t-Bu (1 equiv), X-Phos (5 mol %), Pd(OAc)2
(5 mol %) in toluene/t-BuOH (5:1) at 120 ꢀC; 10–18 h in a sealed
vial] for the synthesis of eight different 1-aryl/heteroaryl-4-Boc-
homopiperazines. These substituted 4-Boc-homopiperazine de-
rivatives were prepared in 10–20 g scale. Subsequently, removal of
the Boc-protection was accomplished in CH2Cl2/HCl or MeOH/HCl
at 0 ꢀC within 3–4 h to afford the corresponding aryl/heteroaryl
substituted homopiperazines in good yields (Table 5).
Temperature
Pressure
0
0
200
400
600
800
1000
1200
1400
time (s)
Table 5
Scale-up synthesis of aryl/heteroaryl substituted homopiperazines
Figure 2. Microwave heating profile for single-mode irradiation (x axis¼time [s] and y
axis¼temperature [ꢀC], pressure [bar], power [W]); 5 ml sample volume.13
Y
Y
N
Y
R1
R2
R2
CH2Cl2, HCl, 0°C
R1
R1
R2
X-Phos, Pd(OAc)2,
NaOt-Bu, toluene,
t-BuOH, 120°C
the pressure in any individual vessel within acceptable limits, our
approach is based on the use of multiple small vessels in parallel
(Anton Paar Synthos 3000, 15 rotor 16MF100, 50 ml each). This
parallel batch processing technique not only circumvents the issue
of penetration depth but also allows carrying out different
Br
+
N
N
N
H
OtBu
HN
N
O
2
OtBu
chemical reactions simultaneously in
experiment.
a
single irradiation
O
1
As heating rates are reduced when processing larger volumes
compared to small volumes, in our case of a Pd-catalyzed Buch-
wald–Hartwig chemistry the reaction time needed to be increased
to 40 min. Furthermore, to increase the absorption rate of micro-
wave energy we had to change the solvent system from toluene/
t-BuOH (5:1) to benzotrifluoride/t-BuOH (5:1).
As illustration, temperature and power profiles for a typical
Buchwald–Hartwig reaction in the microwave field (in sealed ves-
sel) are depicted below (Fig. 2: monomode; Fig. 3: multimode).
Whereas in case of single-mode irradiation it takes about 200 s to
reach the reaction temperature of 160 ꢀC, in case of the multimode
system this time is prolonged to about 600 s.
Entry
Y
R1
R2
1 Yield (%)
2 Yield (%)
1
2
3
4
5
6
7
8
C
C
C
C
C
C
C
4-N
H
4-F
H
H
H
H
H
3-CF3
H
H
1a: 99
1b: 88
1e: 92
1f: 93
1g: 87
1h: 95
1l: 96
1p: 85
2a: 100
2b: 90
2e: 93
2f: 100
2g: 100
2h: 85
2l: 100
2p: 100
4-CH3
4-CN
4-CF3
4-Cl
3-CH3
H
For the scale-up of microwave reactions, different microwave
reactors are available and several studies have compared their
performance.15 These studies confirmed that microwave sup-
ported reactions can be scaled up starting from monomode re-
actors with small vials to large-scale multimode reactors with
larger vials. In order to achieve a larger volume, whilst keeping
The rotor 16MF100 offers simultaneous processing of up to 16
different reactions. In our case we selected eight examples from
Tables 3 and 4 for scale-up. Each derivative was produced two
times. For the scale-up the individual reactions were performed
Multiwave Plot
300
1400
Pressure
Temperature
T Vessel 1
T Vessel 2
T Vessel 3
T Vessel 4
T Vessel 5
T Vessel 6
T Vessel 7
T Vessel 8
T Vessel 9
T Vessel 10
T Vessel 11
T Vessel 12
T Vessel 13
T Vessel 14
T Vessel 15
T Vessel 16
Power
250
200
150
100
50
1200
1000
800
600
400
200
0
0
0
500 1000 1500 2000 2500 3000 3500 4000 4500 5000
Time [s]
Figure 3. Microwave heating profile for multimode irradiation (x axis¼time [s] and y axis¼temperature [ꢀC], pressure [bar], power [W]); rotor 16MF50; 16ꢁ50 ml sample volume.16

U. Scho¨n et al. / Tetrahedron 65 (2009) 8125–8131
8129
with 5 g of Boc-homopiperazine each. The results are summarized
in Table 6.
size: 1.7 mm) using electrospray ionization (ESI) mode. The solvents
and all commercially available reagents were used as received. Re-
actions were monitored by TLC on silica gel 60 F254 (E. Merck,
Darmstadt) and spots were detected by UV-absorption (254 nm).
Some new compounds were isolated by preparative HPLC.
For most of the described compounds the corresponding ana-
lytical data are already known. Applying the copper-catalyzed
coupling methodology5 these N-aryl and N-heteroaryl substituted
homopiperazines have been described in EP 1764367.18
Table 6
Microwave-assisted scale-up (refer also to Scheme 3; benzotrifluoride was used
instead of toluene, X¼Br, Y¼CH)a
Compound 1 R1, R2
Isolated amountb Yieldc Synthos Yieldc Biotage
(g)
3000 (%)
(%)
1a
1b
1c
1e
1g
1h
1l
H
4-F
12.6
11.6
9.3
10.4
16.2
16.6
10.6
91
79
61
72
94
88
73
94
95
83
74
99
81
90
95
73
4-OCH3
4-CH3
4-CF3
4-Cl, 3-CF3
3-CH3
4.2. Synthesis of Boc-protected derivatives (1)
4.2.1. Thermal conditions
1u
3-Quinoline 15.4
4.2.1.1. General procedure for conventional heating. In an oven
dried reaction tube, Pd(OAc)2 (5 mol %), ligand X-Phos (5 mol %)
and Cs2CO3 or NaO-t-Bu (0.5 mmol) were taken up in toluene/
t-BuOH (20 ml, 5:1). The reaction mixture was purged with ni-
trogen and was capped with a rubber septum. After stirring for
1 min, 4-Boc-homopiperazine (0.1 g, 0.5 mmol), aryl or hetero-
aryl bromide (0.6 mmol) in toluene/t-BuOH (10 ml, 5:1) were
added via a syringe. Then, the septum was replaced with a Teflon
screw cap and the resulting mixture with stirring was heated at
120 ꢀC in an oil bath for about 10–18 h. The reaction mixture was
cooled to rt and filtered over CeliteÔ and rinsed well with ethyl
acetate. The filtrate was subsequently evaporated under reduced
pressure and the residue was purified by flash column chroma-
tography on silica gel.
a
Reagents and conditions per vessel: 4-Boc-homopiperazine (5 g, 25 mmol), aryl
or heteroaryl bromide (1.1 equiv), Pd(OAc)2 (5 mol %), X-Phos (5 mol %), NaO-t-Bu
(1.1 equiv), 50 ml of benzotrifluoride/t-BuOH (5:1), 160 ꢀC for 40 min.
b
Total isolated amount from two reactions of 5g.
Isolated yield.
c
Comparing the yields these data clearly demonstrate that mi-
crowave supported reactions can be scaled up starting from mono-
mode reactors with small vials to large-scale multimode reactors
with larger vials. Within one run eight different homopiperazine
derivatives were synthesized separately in 10 g scale each.
Finally, we used the same conditions to synthesize compound 1h
16 times in parallel [in total 80 g of 4-Boc-homopiperazine, 114 g of
4-bromo-1-chloro-2-trifluoromethyl-benzene, 800 ml of benzotri-
fluoride/t-BuOH (5:1), 40 min at 160 ꢀC]. Each vessel was analyzed
separately giving a very reproducible picture: ELSD (n¼16) in all
cases indicated a conversion rate of 100%, whereas UV detector
analysis (n¼16) showed a conversion rate between 91 and 100%.
After work-up and purification, 147 g of 1h was isolated (97% yield).
Thus, within 1 day by principally repeating the set of experiments
seven times, about 1 kg of these BOC-protected N-aryl or heteroaryl
substituted homopiperazines become rapidly accessible.
4.2.1.2. 4-Phenyl-1,4-diazepane-1-carboxylic acid tert-butyl ester
(1a)18. Yield (using NaO-t-Bu): 99%, 137 mg (0.49 mmol) of yellow
thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v).
1H NMR (501 MHz, DMSO-d6)
d ppm 1.20 and 1.33 (s, 9H), 1.73–
1.89 (m, 2H), 3.11–3.25 (m, 2H), 3.42–3.60 (m, 6H), 6.53–6.59 (m,1H),
6.67–6.74 (m, 2H), 7.09–7.16 (m, 2H); 13C NMR (126 MHz, DMSO-d6)
d
ppm 24.4, 24.8, 27.7, 27.9, 44.7, 44.8, 45.3, 45.4, 47.4, 48.2, 48.6, 49.1,
78.2, 78.3, 111.4, 111.5, 115.4, 129.0, 129.1, 146.9, 154.0, 154.3. HRMS
calcd for C16H25N2O2 [MþH]þ: 277.1916; found: 277.1911.
3. Conclusions
In summary, we have developed a convenient protocol for the
efficient preparation of N-aryl and N-heteroaryl substituted
homopiperazines starting from Boc-homopiperazines and aryl ha-
lides or heteroaryl halides followed by routine deprotection under
acidic conditions. In order to speed up the synthesis we switched
from conventional heating to microwave irradiation using a mon-
omode system for the preparation of small amounts as well as
a multimode system for large-scale synthesis. Based on these re-
sults, one will be able to synthesize these Boc-protected N-aryl- or
N-heteroaryl-substituted homopiperazines up to 1 kg within 1 day.
In order to compare different classes of ligands further in-
vestigations will include the use of well-defined NHC-containing
palladium(II) precatalysts.17
4.2.1.3. 4-(4-Fluorophenyl)-1,4-diazepane-1-carboxylic acid tert-butyl
ester (1b)18. Yield (using NaO-t-Bu): 88%, 130 mg (0.44 mmol) of
yellow thick mass; Rf¼0.4 (EtOAc/Hexane, 3:7, v/v).
1H NMR (501 MHz, DMSO-d6)
d ppm 1.20 and 1.32 (s, 9H), 1.70–
1.88 (m, 2H), 3.12–3.26 (m, 2H), 3.40–3.61 (m, 6H), 6.64–6.74 (m,
2H), 6.96 (t, J¼8.7 Hz, 2H); 13C NMR (126 MHz, DMSO-d6)
d ppm
24.3, 24.7, 27.7, 27.9, 44.4, 44.7, 45.0, 45.4, 48.0, 48.7, 48.8, 49.3, 78.2,
78.3, 112.4, 115.3 (d, J¼22.0 Hz), 115.4 (d, J¼22.0 Hz), 143.7, 154.0 (d,
J¼232.0 Hz), 154.0, 154.3. HRMS calcd for C16H24N2O2F [MþH]þ:
295.1822; found: 295.1817.
4.2.2. Microwave heating (EmrysÔ Optimizer)
4.2.2.1. General procedure for the microwave palladium catalyzed
amination of aryl bromides. In a pressure vial (10 ml) Pd(OAc)2
(5 mol %), ligand (5 mol %) and NaO-t-Bu (53 mg, 0.55 mmol) were
taken up in 1 ml of toluene/t-BuOH (5:1), flushed with nitrogen,
stirred for a minute and capped with a rubber septum. Then,
through a syringe 4-Boc-homopiperazine (0.1 g, 0.5 mmol) and
aryl/heteroaryl halide (0.55 mmol) were added in 4 ml of toluene/
t-BuOH (5:1). The septum was replaced with a sealed cap and the
reaction tube was heated to 160 ꢀC under microwave irradiating
conditions. The total heating time of all reactions was between 8
and 10 min. After the reaction vials were cooled to rt, the mixture
was filtered over CeliteÔ and rinsed well with ethyl acetate. The
filtrate was subsequently evaporated under reduced pressure and
the residue purified by flash chromatography on silica gel.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded with a Bruker
Avance 500 spectrometer at 501 MHz (1H NMR) and at 126 MHz (13
C
NMR) in CDCl3 using tetramethylsilane as the internal standard.
Multiplicities are described using the following abbreviations:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet. Coupling
constants (J) are quoted in hertz. High-resolution mass spectra were
obtained with Waters Micromass Q-TOF Premier (ESI, positive ions,
mass resolution >12,000). LC/MS spectra were obtained using Wa-
ters Micromass ZQ equipped with a C-18 column (50ꢁ2.1 mm; grain

8130
U. Scho¨n et al. / Tetrahedron 65 (2009) 8125–8131
4.2.2.2. 4-(4-Methoxyphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1c)18. Yield: 74%, 113 mg (0.25 mmol) of yellow col-
oured thick mass; Rf¼0.3 (EtOAc/Hexane, 3:7, v/v). 1H NMR
6.94–7.02 (m, 2H), 7.33–7.41 (m,1H); 13C NMR (126 MHz, DMSO-d6)
ppm 23.5, 23.9, 27.4, 27.7, 43.4, 44.1, 44.6, 45.5, 48.3, 48.4, 48.6,
49.0, 78.2, 78.3, 109.8, 115.4,116.3, 116.5,123.1 (q, J¼272.0 Hz),126.9
(q, J¼33.0 Hz), 127.0 (q, J¼32.0 Hz), 131.9, 146.0, 153.9, 154.1. HRMS
calcd for C17H23N2O2F3Cl [MþH]þ: 379.1400; found: 379.1404.
d
(501 MHz, DMSO-d6) d ppm 1.22 and 1.34 (s, 9H), 1.70–1.90 (m, 2H),
3.08–3.25 (m, 2H), 3.38–3.54 (m, 6H), 3.64 (s, 3H), 6.60–6.69 (m,
2H), 6.71–6.81 (m, 2H); 13C NMR (126 MHz, DMSO-d6)
d
ppm 24.6,
25.1, 27.7, 27.9, 44.8, 44.9, 45.4, 47.9, 48.6, 49.1, 49.6, 55.2, 55.3, 78.2,
78.3, 112.7, 112.7, 114.8, 141.4, 150.3, 154.0, 154.3. HRMS calcd for
C17H25N2O3 [MþH]þ: 307.2022; found: 307.2018.
4.2.3.8. 4-(3-Methylphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1l)18. Yield: 96%, 20.8 g (72 mmol) of yellow coloured
thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v). 1H NMR (501 MHz,
DMSO-d6) d ppm 1.21 and 1.26 (s, 9H), 1.71–1.88 (m, 2H), 2.21 (s, 3H),
4.2.2.3. 4-(4-Methylphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1e)18. Yield: 99%, 143 mg (0.49 mmol) of yellow col-
oured thick mass; Rf¼0.4 (EtOAc/Hexane, 3:7, v/v). 1H NMR
3.11–3.24 (m, 2H), 3.41–3.59 (m, 6H), 6.37–6.41 (m, 1H), 6.47–6.55 (m,
2H), 6.97–7.04 (m,1H); 13C NMR (126 MHz, DMSO-d6)
d
ppm 21.5, 24.4,
24.9, 27.7, 27.9, 44.8, 45.4, 45.5, 47.4, 48.2, 48.6, 49.2, 78.2, 78.3, 108.7,
112.0, 112.1, 116.3, 116.4, 128.9, 129.0, 137.9, 138.1, 147.0, 154.0, 154.3.
HRMS calcd for C17H27N2O2 [MþH]þ: 291.2073; found: 291.2074.
(501 MHz, DMSO-d6) d ppm 1.22 and 1.34 (s, 9H),1.70–1.90 (m, 2H),
2.15 (s, 3H), 3.07–3.24 (m, 2H), 3.39–3.57 (m, 6H), 6.57–6.65 (m,
2H), 6.91–6.98 (m, 2H); 13C NMR (126 MHz, DMSO-d6)
d
ppm 19.8,
24.4, 24.9, 27.7, 27.9, 44.8, 44.9, 45.4, 47.5, 48.2, 48.8, 49.3, 78.2,
78.3,111.5,111.6,123.7,123.8,129.5,129.6,144.7,144.8,154.0,154.3.
HRMS calcd for C17H27N2O2 [MþH]þ: 291.2073; found: 291.2072.
4.2.3.9. 4-(4-Pyridyllphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1p)18. Yield: 85%, 17.5 g (63.75 mmol) of light brown
solid, mp 78–80 ꢀC; Rf¼0.4 (DCM/MeOH/NH3, 90:10:01, v/v).
4.2.3. Upscaling using conventional heating
4.2.4. Upscaling using microwave heating (Synthos 3000)
4.2.3.1. General procedure. In a steel bomb, 4-Boc-homopiperazine
(15 g, 75 mmol), Pd(OAc)2 (5 mol %), ligand X-Phos (5 mol %) and
NaO-t-Bu (7.2 g, 75 mmol) were taken up in toluene/t-BuOH
(250 ml, 5:1). The reaction mixture was purged with nitrogen and
after stirring for 5 min, aryl bromide (0.15 mol) in toluene/t-BuOH
(50 ml, 5:1) was added. Then, the resulting mixture was purged
with nitrogen, sealed and heated at 120 ꢀC with stirring in an oil
bath for about 10–18 h. The reaction mixture was cooled to rt and
filtered over CeliteÔ and rinsed well with ethyl acetate. The filtrate
was subsequently evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica gel.
4.2.4.1. General procedure for the palladium catalyzed amina-
tion. Each liner (100 ml) containing 50 ml of benzotriflouride/
t-BuOH (5:1) was filled with 5 g of 4-Boc-homopiperazine (25 mmol)
and 27.5 mmol of the aryl halide (1.1 equiv), Pd(OAc)2 (5 mol %),
X-Phos (5 mol %) and NaO-t-Bu (2.64 g, 27.5 mmol). The stirred re-
action mixture was heated in total for 50 min at 160 ꢀC (10 min for
heating up to 160 ꢀC, further 40 min at constant temperature of
160 ꢀC). After the reaction vials were cooled to rt, the mixture was
filtered over CeliteÔ. Theorganicphasewasdriedwithsodiumsulfate
and concentrated under reduced pressure. The outcome of the re-
action was monitored by LC/MS-analysis and the residue purified by
flash chromatography on silica gel (ethyl acetate/cyclohexane (1:9)).
4.2.3.2. 4-Phenyl-1,4-diazepane-1-carboxylic acid tert-butyl ester
(1a)18. Yield: 99%, 20.5 g (74 mmol) of yellow coloured sticky mass;
Rf¼0.4 (EtOAc/Hexane, 2:8, v/v).
4.2.4.2. 4-(4-Trifluoromethylphenyl)-1,4-diazepane-1-carboxylic acid
tert-butyl ester (1g)18. Yield: 94%, 8.1 g (23.5 mmol) of yellow col-
oured thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v).
4.2.3.3. 4-(4-Fluorophenyl)-1,4-diazepane-1-carboxylic acid tert-butyl
ester (1b)18. Yield: 88%, 19.4 g (66 mmol) of buff coloured solid, mp
95–98 ꢀC; Rf¼0.4 (EtOAc/Hexane, 3:7, v/v).
4.2.4.3. 4-(3-Trifluoromethyl-4-chlorophenyl)-1,4-diazepane-1-carb-
oxylic acid tert-butyl ester (1h). Yield: 88%, 8.3 g (22 mmol) of
yellow coloured thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v).
4.2.3.4. 4-(4-Methylphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1e)18. Yield: 92%, 19.5 g (69 mmol) of yellow coloured
thick mass; Rf¼0.4 (EtOAc/Hexane, 3:7, v/v).
4.2.4.4. 4-(3-Methylphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1l)18. Yield: 73%, 5.3 g (18 mmol) of yellow coloured
thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v).
4.2.3.5. 4-(4-Cyanophenyl)-1,4-diazepane-1-carboxylic acid tert-butyl
ester (1f)18. Yield: 93%, 21 g (70 mmol) of pale yellow solid; Rf¼0.3
(EtOAc/Hexane, 3:7, v/v).
4.2.4.5. 4-(3-Quinolylphenyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester (1u). Yield: 94%, 7.7 g (23.5 mmol) of yellow coloured
thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v). 1H NMR (501 MHz,
4.2.3.6. 4-(4-Trifluoromethylphenyl)-1,4-diazepane-1-carboxylic acid
tert-butyl ester (1g)18. Yield: 87%, 22.4 g (65 mmol) of yellow col-
oured thick mass; Rf¼0.4 (EtOAc/Hexane, 2:8, v/v). 1H NMR
DMSO-d6) d ppm 1.02 and 1.24 (s, 9H), 1.80–1.94 (m, 2H), 3.20–3.32
(m, 2H), 3.54–3.64 (m, 2H), 3.64–3.69 (m, 2H), 3.71–3.81 (m, 2H),
7.32–7.37 (m, 2H), 7.38–7.43 (m,1H), 7.67–7.71 (m,1H), 7.76–7.82 (m,
(501 MHz, DMSO-d6)
d
ppm 1.15 and 1.29 (s, 9H), 1.70–1.87 (m, 2H),
1H), 8.66–8.74 (m, 1H); 13C NMR (126 MHz, DMSO-d6)
d ppm 24.0,
3.15–3.29 (m, 2H), 3.46–3.59 (m, 4H), 3.60–3.70 (m, 2H), 6.79–6.89
24.6, 27.4, 27.8, 44.2, 44.7, 45.4, 48.0, 48.4, 48.6, 48.8, 78.2, 78.3,111.0,
111.1,124.2,125.9,126.4,128.2,129.2,140.3,140.5,140.6,153.9,154.2.
HRMS calcd for C19H26N3O2 [MþH]þ: 328.2025; found: 328.2020.
(m, 2H), 7.36–7.48 (m, 2H); 13C NMR (126 MHz, DMSO-d6)
d
ppm
23.8, 24.2, 27.5, 27.8, 43.9, 44.7, 45.5, 47.9, 48.5, 48.7, 48.9, 78.3, 78.4,
111.1, 111.2, 115.2 (q, J¼32.0 Hz), 125.2 (q, J¼272.0 Hz), 126.2, 149.7,
153.9, 154.2. HRMS calcd for C17H24N2O2F3 [MþH]þ: 345.1790;
found: 345.1788.
4.3. Synthesis of N-aryl and N-heteroaryl substituted
homopiperazines (2)
4.2.3.7. 1-(3-Trifluoromethyl-4-chlorophenyl)-1,4-diazepane-1-carb-
oxylic acid tert-butyl ester (1h). Yield: 95%, 26.9 g (71 mmol) of pale
light solid, mp 108–110 ꢀC; Rf¼0.3 (EtOAc/Hexane, 2:8, v/v). 1H
4.3.1. General procedure for removal of the Boc-group
Aryl substituted 4-Boc-homopiperazine (60 mmol) was dis-
solved in methanol, cooled to 5–10 ꢀC and HCl gas was passed until
saturation for 3–4 h. The methanol solution was concentrated un-
der reduced pressure to collect the deprotected N-aryl/heteroaryl
NMR (501 MHz, DMSO-d6)
d ppm 1.14 and 1.29 (s, 9H), 1.69–1.82
(m, 2H), 3.19–3.30 (m, 2H), 3.47–3.58 (m, 4H), 3.60–3.72 (m, 2H),

U. Scho¨n et al. / Tetrahedron 65 (2009) 8125–8131
8131
substituted homopiperazine hydrochloride salt, which was further
References and notes
purified by crystallization.
1. Stewart, A. O.; Cowart, M. D.; Moreland, R. B.; Latshaw, S. P.; Matulenko, M. A.;
Bhatia, P. A.; Wang, X.; Daanen, J. F.; Nelson, S. L.; Terranova, M. A.; Namovic, M. T.;
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K. S.; Andersen, K. J. Org. Chem. 2002, 67, 5257–5268.
4.3.1.1. 1-Phenyl-1,4-diazepane (2a)18$1HCl. Yield: 100%, 12.7 g
(60 mmol) of brown coloured thick mass; Rf¼0.4 (DCM/MeOH/NH3,
85:15:01, v/v).
3. Nielsen, S. F.; Nielsen, E. O.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem.
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(c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264–1267; (d) Louie,
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For reviews, see: (f) Hartwig, J. F. In Handbook of Organopalladium Chemistry
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Chem. Soc. 2003, 125, 6653–6654.
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Konda, A. Tetrahedron Lett. 2005, 46, 7111–7115.
11. For reviews, see: (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (b)
Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6, 314–320; (c) Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002.
12. (a) Scho¨n, U.; Messinger, J.; Buckendahl, M.; Prabhu, M. K. S.; Konda, A. Tetrahedron
Lett. 2007, 48, 2519–2525; (b) Maes, B. U. W.; Loones, K. T. J.; Lemiere, G. L. F.;
Hamann, L. G. Synlett 2003, 1822–1825; (c) Wan, Y.; Altermann, M.; Hallberg, A.
Synthesis 2002, 1597–1600.
13. EmrysÔ Optimizer from Biotage (formely Personal Chemistry): a fully auto-
mated single-mode (300 W) microwave reactor that incorporates a gripper for
robotic vessel transfer. The system is used for the efficient optimization of re-
action conditions and for the unattended generation of libraries (sealed vessels,
processing volume 0.5–5 ml, max pressure 20 bar, IR temperature sensor).
Experimental details: 5 ml sample volume, magnetic stirring, fibre-optic tem-
perature measurement, sealed 10 ml reaction vessel (glass); rapid cooling with
compressed air.
4.3.1.2. 1-(4-Fluorophenyl)-1,4-diazepane (2b)18$1HCl. Yield: 90%,
12.7 g (54 mmol) of buff coloured solid, mp: 212–215 ꢀC; Rf¼0.3
(DCM/MeOH/NH3, 90:10:01, v/v).
4.3.1.3. 1-(4-Methylphenyl)-1,4-diazepane (2e)18$1 HCl. Yield: 93%,
12.6 g (55.8 mmol) of buff coloured solid, mp 212–215 ꢀC; Rf¼0.4
(DCM/MeOH/NH3, 90:10:01, v/v). 1H NMR (501 MHz, DMSO-d6)
d
ppm 2.12–2.19 (m, 2H), 2.21 (s, 3H), 3.06–3.17 (m, 2H), 3.22–3.35
(m, 2H), 3.48–3.60 (m, 2H), 3.71–3.82 (m, 2H), 6.82–6.99 (m, 2H),
7.03–7.13 (m, 2H), 9.47 (br s, 2H); 13C NMR (126 MHz, DMSO-d6)
d
ppm 19.9, 23.7, 44.2, 44.3, 47.0, 48.7, 113.9, 130.5, 129.8, 144.8.
HRMS calcd for C12H19N2 [MþH]þ: 191.1548; found: 191.1544.
4.3.1.4. 1-(4-Cyanophenyl)-1,4-diazepane (2f)18$1HCl. Yield: 100%,
14.25 g (60 mmol) of coloured mass; Rf¼0.3 (DCM/MeOH/NH3,
90:10:01, v/v). 1H NMR (501 MHz, DMSO-d6)
d ppm 2.08–2.14 (m,
2H), 3.06–3.11 (m, 2H), 3.17–3.22 (m, 2H), 3.57–3.61 (m, 2H), 3.80–
3.83 (m, 2H), 6.87–6.91 (m, 2H), 7.55–7.59 (m, 2H), 9.47 (br s, 2H);
13C NMR (126 MHz, DMSO-d6)
d ppm 24.0, 44.5, 44.6, 44.9, 46.5,
96.7, 111.8, 120.1, 133.4, 150.9. HRMS calcd for C12H16N3 [MþH]þ:
202.1344; found: 202.1340.
4.3.1.5. 1-(4-Trifluoromethylphenyl)-1,4-diazepane (2g)18. Yield: 100%,
16.8 g (60 mmol) of brown coloured thick mass; Rf¼0.4 (DCM/MeOH/
NH3, 85:15:01, v/v).
14. (a) Federsel, H.-J.; Hedberg, M.; Qvarnstro¨m, F. R.; Sjo¨gren, M. P. T.; Tian, W. Acc.
Chem. Res. 2007, 40,1377–1384; (b) Federsel, H.-J.; Hedberg, M.; Qvarnstro¨m, F. R.;
Tian, W. Org. Process Res. Dev. 2008, 12, 512–521.
15. (a) Review: Kremsner, J. M.; Stadler, A.; Kappe, C. O. Top. Curr. Chem. 2006, 266,
223–278; (b) Leadbeater, N. E.; Schmink, J. R. Tetrahedron 2007, 63, 6764–6773;
(c) Moseley, J. D.; Lenden, P.; Lockwood, M,; Ruda, K.; Sherlock, J.-P.; Thomson,
A. D.; Gilday, J. P. Org. Process Res. Dev. 2008, 12, 30–40; (d) Bowman, M. D.;
Holcomb, J. L.; Kormos, L. K.; Leadbeater, N. E.; Williams, V. A. Org. Process Res.
Dev. 2008, 12, 41–57.
16. Anton Paar Synthos 3000: a multimode microwave instrument with two
magnetrons (1400 W continuously delivered output power) dedicated for
batch scale-up that allows processing of volumes of up to 1 l in a variety
of different rotor systems (8, 16, 48, 64). Experimental details for rotor
16MF100: 16ꢁ50 ml sample volume, magnetic stirring; temperature
measurement in one reference vessel via an internal gas balloon ther-
mometer, surface temperature monitoring of 16 individual vessels by IR
thermography, sealed 50 ml PFA liner; cooling by venting air through
cooling gaps.
4.3.1.6. 1-(3-Trifluoromethyl-4-chlorophenyl)-1,4-diazepane (2h)$
1HCl. Yield: 85%, 16 g (51 mmol) of buff coloured solid, mp 212–
215 ꢀC; Rf¼0.3 (DCM/MeOH/NH3, 90:10:01, v/v).
4.3.1.7. 1-(3-Methylphenyl)-1,4-diazepane (2l)18$1HCl. Yield: 100%,
13.59 g (60 mmol) of reddish brown coloured thick mass;
Rf¼0.4(DCM/MeOH/NH3, 85:15:01, v/v).
4.3.1.8. 1-(4-Pyridyl)-1,4-diazepane (2p)18$1HCl. Yield: 100%, 12.81 g
(60 mmol) of reddish coloured thick mass; Rf¼0.4 (DCM/MeOH/NH3,
90:10:01, v/v).
Acknowledgements
17. (a) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440–1449; (b) Kant-
chev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46,
2768–2813; (c) Diez-Gonzales, S.; Nolan, S. P. Top. Organomet. Chem. 2007,
21, 47–82.
18. Oizumi, K.; Naito, S.; Nakao, A.; Shinozuka. T.; Matsiu, S.; Shimada, K. EP Patent
1764367, 2007.
We thank Dr. Anneke Mu¨hlebach, Joachim Adam und Norbert
Reinecke for analytical support, as well as Ute Kluge, Uwe Rein-
ecker, Thomas Wartmann, Ju¨rgen Fasterding and Theresa Wind-
orfer for technical support.