First selective lithiation of pyridylpiperazines: Straightforward access to potent pharmacophores

Article abstract of DOI:10.1016/j.tet.2005.03.026

The three isomers of pyridylpiperazines have been lithiated for the first time. The use of a superbase, an aminoalkoxide containing lithiating agent overcomes the chelating influence of the basic piperazine nitrogens, so that selective mono lithiation occurred alpha to pyridine nitrogen. This methodology offers a new access to diverse potent pharmacophores not easily prepared by other routes.

Full text of DOI:10.1016/j.tet.2005.03.026

Tetrahedron 61 (2005) 4761–4768
First selective lithiation of pyridylpiperazines: straightforward
access to potent pharmacophores
*
´ ´
Frederic Louerat, Philippe Gros and Yves Fort
*
¨
` ´ ´
Synthese Organometallique et Reactivite, UMR CNRS 7565, Universite Henri Poincare, Bd des Aiguillettes,
´
`
54506 Vandoeuvre-les-Nancy, France
´
´
Received 25 January 2005; revised 4 March 2005; accepted 7 March 2005
Available online 2 April 2005
Abstract—The three isomers of pyridylpiperazines have been lithiated for the first time. The use of a superbase, an aminoalkoxide
containing lithiating agent overcomes the chelating influence of the basic piperazine nitrogens, so that selective mono lithiation occurred
alpha to pyridine nitrogen. This methodology offers a new access to diverse potent pharmacophores not easily prepared by other routes.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ing progress for treatment of diabetes was also found with
pyrimidylpiperazine D which inhibits sorbitol dehydro-
genase via chelation of the zinc atoms.5 The ability to create
variations of heteroarylpiperazines is an important task: a
recent paper by Stewart and co-workers6 showed that a
variation in the nature and substitution of the (het)aryl ring
on piperazine in A dramatically influenced the intrinsic
activity. At this time, the number of available substituted
pyridylpiperazines remains limited due to a lack of efficient
methodologies for introduction of diversity on the pyridine
ring. The SNAr reactions between piperazine and halogen-
opyridines require vigorous conditions (high temperatures,
prolonged reaction times) sometimes conflicting with
sensitive functionalities.7 In addition, the Pd8 or Ni-
catalyzed9 amination reactions which can be performed
under milder conditions also sometimes hardly tolerate
electrophilic substituents or protic moieties like alcohols.
The selective chemical modification of heterocyclic com-
pounds to attain optimal bioactivity provides a challenge of
modern synthetic chemistry for the discovery of new drug
candidates. Pyridylpiperazines and analogs are key units
found in a wide range of relevant pharmacophores with a
broad spectrum of activity (Fig. 1). For example, ABT-724
(A)1,2 and analogues have been reported as selective
dopaminergic D4 agonists (erectile dysfunction treatment).
Compounds B and C containing a substituted pyridine were
reported, respectively, as candidates with analgesic3 and
HIV-1 reverse transcriptase inhibitory activity.4 A promis-
A relatively unexplored route is the functionalization of the
parent 2-, 3- and 4-pyridylpiperazines which are commer-
cially available or easily prepared by literature procedures.5
Our expertise in the field of selective lithiation of pyridine
derivatives10 and especially of aminosubstituted pyridines11
drawn us to investigate the reaction of tritylated derivatives
1–312 (Fig. 2) with the BuLi-LiDMAE (LiDMAEZMe2-
NCH2CH2OLi) reagent developed in this laboratory.
Figure 1. Pyridylpiperazines with important pharmacological activity.
Keywords: Selective lithiation; Pyridylpiperazines; Chelation.
The BuLi-LiDMAE reagent displays a strong affinity for
pyridine nitrogen via chelation of lithium and promotes
lithiation alpha to this atom. However, the piperazine
nitrogens in 1–3 are also expected to chelate lithium cations
and thus to compete with the target pyridine nitrogen for
complexation of the lithiating agent. This was confirmed
*
Corresponding authors. Tel.: C33 3 83 68 47 81; fax: C33 3 83 68 47 85;
e-mail addresses: philippe.gros@sor.uhp-nancy.fr;
yves.fort@sor.uhp-nancy.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.026

¨
F. Louerat et al. / Tetrahedron 61 (2005) 4761–4768
4762
expected complexation by piperazine nitrogens, 8 equiv of
reagent were necessary to achieve complete metallation.
The ideal metallation temperature was found to be different
for the three isomers. While 3 was efficiently lithiated at
0 8C, 1 was found inert at such temperature and warming to
20 8C was required to realize the reaction. Substrate 2 was
found to be more sensitive since nucleophilic addition of
BuLi was observed above K78 8C. In contrast, nucleophilic
addition never occurred with 1 or 3. Moreover, while
compound 5a was formed as a single product at K78 8C,
formation of isomer 6a was obtained in notable amount at 0
or K40 8C. From this, it appeared that the kinetic product
was likely at C-2 and the thermodynamic product rather at
C-6. Unfortunately we did not succeed in finding conditions
able of forming exclusively compound 6a.
Figure 2. Tritylpiperazines used in metallation studies.
by our first attempts to metallate 1–3 with BuLi or LTMP.
With these reagents, whatever the conditions, no reaction
occurred and starting materials were fully recovered even
when a large excess of base (up to 8 equiv) was used.13 Thus
it was hypothesized that a basic reagent containing a
chelating agent like the BuLi-LiDMAE superbase might
be able to favour complexation by pyridine nitrogen and
promote selective metallation.
We performed charge calculations in the three isomers to
explore the possible reasons behind the different chelating
ability of nitrogens and the relevant protons acidities
(Table 2).
Table 2. Calculated Mulliken chargesa
2. Results and discussion
Metallations with BuLi-LiDMAE are generally performed
in hexane14 but, as compounds 1–3 were sparingly soluble
in this solvent, we turned to the more polar and also non
complexing toluene. The substrates were reacted with BuLi-
LiDMAE under various conditions and the reaction media
were quenched with MeSSMe as electrophile (Table 1).
In contrast with results obtained with BuLi, all substrates
could be selectively lithiated alpha to pyridine nitrogen with
BuLi-LiDMAE clearly demonstrating the role of lithium
aminoalkoxide into the lithiation process. However, due to
Substrate N-1
N-2
N-3
H-2
—
H-6
1
2
K0.1489 0.0102
K0.0652 0.0091
K0.1334 0.0036
K0.0980
K0.0984 0.2154
K0.0981 0.2061
0.2057
0.2132
0.2061
0.2108
3
Pyridine
K0.0987
—
—
0.2108
a Calculations performed using semi-emprical PM3 method.
Table 1. Lithiation of 1–3 with BuLi-LiDMAEa
The first observation was the expected increase of pyridine
nitrogen electronegativity by incorporation of piperazine at
C-2 or C-4 with a larger effect at C-2. On the contrary,
piperazine at C-3 decreased notably the electronegativity
of N-1. For all three compounds, the N-3 nitrogen had a
notable electronegativity, supporting an ability to chelate
lithium ions. The electronic influence of the piperazine
moiety on the pyridine protons acidities was also assessed
by comparison with pyridine itself, where it was revealed
that with the substituted analogs (1–3), the piperazine at C-2
or C-4 decreased the charge on protons alpha to nitrogen
while piperazine at C-3 induced a slight increase. Since
these charge values reflected proton acidities, the following
order of acidity can be established: 1–3!2.
Substrate
Base (equiv) T (8C)
Product, yield (%)b
1
4–8
4
8
0
n.r.
4a, 40
4a, 90
n.r.
20
20
0
2
3
4
From our knowledge, this is the first reported direct
lithiation of the pyridine ring of pyridylpiperazines. We
further demonstrated this methodology for the preparation
of addition derivatives by reaction with a set of electro-
philes. Applying the best conditions found previously
(Table 1), an array of pyridyl halides, alcohols and ketones
was prepared in good to excellent yields (Table 3).
6
0
5a, 10
5a (5)cC5b (60)cC6a (35)c
8
0
8
8
4
K40
K78
0
5a (40)cC5b (30)cC6a (30)c
5a, 90
7a, 45
7a, 70
7a, 91
6
0
8
0
a All reactions performed on 0.5 mmol of 1–3.
b Isolated yields.
c Ratios determined by H NMR.
1
Derivatives 5a and 7b bearing base compatible

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F. Louerat et al. / Tetrahedron 61 (2005) 4761–4768
4763
Table 3. Monofuntionalization of 1–3a
Electrophile
FG
C2Cl6
CBr4
I2
PhCONMe2
t-BuCOCl
t-BuCHO
Cl
Br
I
COPh
COt-Bu
CH(OH)t-Bu
4b, 95%
4c, 95%
4d, 89%
4e, 70%
4f, 65%
4g, 60%
5c, 90%
5d, 90%
5e, 80%
—
5f, 50%
5g, 72%
7b, 89%
7c, 95%
7d, 77%
7e, 62%
7f, 81%
7g, 65%
b
a All reactions performed on 0.5 mmol of 1–3. All yields are given for isolated compounds.
b Reaction not performed.
substituents15 were of particular interest since they could be
Table 4. Regeneration of free pyridylpiperazinesa
lithiated at the other pyridine alpha carbon allowing further
introduction of diversity. These substrates were then treated
with the superbase at 0 8C to produce the 2,6-difunctional
derivatives in excellent yields (Scheme 1). The high
basicity and low nucleophilicity of the BuLi-LiDMAE
superbase was therefore shown to be compatible with
analogs containing synthetically useful C–Cl and C–SMe
bonds.
FG1
FG2
Product, yield (%)b
SMe
Cl
Br
I
COPh
COt-Bu
CH(OH)t-Bu
Cl
Cl
Cl
10a, O99
10b, O99
10c, O99
10d, O99
10e, 90
10f, 85
10g, 85
—
—
—
—
—
11a, 95
12a, O99
—
—
—
—
—
—
Cl
Br
11b, 96
11c, O99
11d, O99
—
11e, 90
11f, 93
—
—
—
—
12b, O99
12c, O99
12d, O99
12e, 80
12f, 80
12g, 70c
12h, O99
12i, O99
12j, O99
12k, 60
—
Scheme 1. Bis-functionalization. Conditions: (i) BuLi-LiDMAE (8 equiv),
toluene, K20 8C, 1 h. (ii) CBr4 or I2 or PhCONMe2 or C2Cl6 or t-BuCHO
(9 equiv), THF, K78 to K20 8C, 1 h.
I
CH(OH)t-Bu
Br
I
COPh
Cl
SMe
SMe
SMe
11g, 97
11h, 91
11i, 75c
—
—
—
—
To liberate the free piperazines, detritylation was effected
by treatment of products with a stoichiometric amount of
TFA in dichloromethane at room temperature (Table 4). In
all cases, the deprotection proceeded quantitatively afford-
ing a library of polyfunctional pyridylpiperazines which the
free piperazine NH was available for introduction of, for
example, benzimidazoles (see Fig. 1).
a All reactions performed on 0.25 mmol of tritylpiperazine.
b All reactions were found complete (TLC) and products obtained in pure
form after basic aqueous work-up. The lack of material with oxygen-
containing compounds was due to a partial solubility in water.
modification of pyridylpiperazines an important class of
biologically active compounds.
3. Conclusion
4. Experimental
4.1. General
For the fist time, the three isomers of pyridylpiperazines
have been selectively mono- and bis-functionalized on the
carbon alpha to the pyridine nitrogen by use of a BuLi-
LiDMAE superbase used in excess. The generality of the
method was demonstrated by the synthesis of a wide
variety of functionalized pyridylpiperazines. We believe
this represents a new efficient methodology for chemical
All solvents were distilled and stored over sodium wire
before use. 2-Dimethylaminoethanol was distilled under
nitrogen and stored on molecular sieves. n-BuLi was used as

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F. Louerat et al. / Tetrahedron 61 (2005) 4761–4768
4764
a 1.6 M solution in hexanes. All other reagents were
commercially available and used as such. 1H and 13C NMR
spectra were obtained in CDCl3 (unless otherwise stated) on
a Bruker AC400 instrument at 200, 50 MHz, respectively.
GC/MS (EI) were obtained on HP5971 spectrometer.
Starting 2- and 4-pyridylpiperazines are commercially
available. 3-Pyridylpiperazine was prepared by catalyzed
amination of 3-bromopyridine according to a literature
procedure.5
4.3.1. ((6-Methylsulfanyl)-2-pyridyl)-4-trityl-1-pipera-
zine (4a). Column chromatography (80/20 hexane/AcOEt)
1
yielded 200 mg (90%) of 4a as an oil. NMR H (CDCl3):
dZ1.91 (s, 3H), 2.39 (m, 4H), 3.59 (m, 4H), 6.14 (d, JZ
8.2 Hz, 1H), 6.44 (d, JZ7.5 Hz, 1H), 7.1–7.3 (m, 10H),
7.49–7.53 (m, 6H). NMR 13C (CDCl3): dZ38.2, 45.4, 47.6,
76.9, 101.3, 110.1, 126.1, 127.5, 129.2, 137.2, 142.1, 157.2,
159.0.
4.3.2. ((2-Methylsulfanyl)-3-pyridyl)-4-trityl-1-pipera-
zine (5a). Column chromatography (80/20 hexane/AcOEt)
4.2. Preparation of tritylpyridylpiperazines 1–3
1
yielded 200 mg (90%) of 5a as an oil. NMR H (CDCl3):
dZ2.25 (s, 3H), 2.32 (m, 4H), 3.00 (t, JZ4.7 Hz, 4H), 6.72–
6.78 (m, 1H), 6.93–7.13 (m, 10H), 7.37–7.41 (m, 6H), 8.01
(d, JZ4.8 Hz, 1H). NMR 13C (CDCl3): dZ12.4, 47.9, 51.8,
76.7, 118.8, 125.2, 126.0, 127.5, 129.2, 142.4, 143.7, 145.9,
148.7.
A mixture of the appropriate pyridylpiperazine (10 g,
61 mmol) triphenylmethyl chloride (20.5 g, 73 mmol) and
triethylamine (7.5 g, 73 mmol) in DMF (50 mL) was stirred
for 6 h at 20 8C for isomers 1 and 2 or at 100 8C for isomer 3.
The mixture was then filtered and the solid was washed with
THF. The filtrate was evaporated under vacuum and the
crude product purified by chromatography on silica gel
using AcOEt/hexane as eluent.
4.3.3. ((2-Methylsulfanyl)-4-pyridyl)-4-trityl-1-pipera-
zine (7a). Column chromatography (40/60 hexane/AcOEt)
yielded 202 mg (91%) of as 7a a light yellow solid. Mp:
1
193 8C. NMR H (CDCl3): dZ2.36 (m, 4H), 2.48 (s, 3H),
4.2.1. (2-Pyridyl)-4-trityl-1-piperazine (1). Column chro-
matography (70/30 hexane/AcOEt) yielded 23.3 g (94%)
of 1 as a light yellow solid. Mp: 200 8C. NMR 1H (CDCl3):
dZ2.42 (s, 4H), 3.64 (s, 4H), 6.58 (m, 2H), 7.12–7.31 (m,
10H), 7.39–7.54 (m, 6H), 8.15 (d, JZ6.5 Hz, 1H). NMR 13C
(CDCl3): dZ45.8, 47.7, 76.9, 106.9, 113.1, 126.1, 127.5,
129.3, 137.3, 142.3, 147.7, 159.7.
3.35 (t, JZ4.8 Hz, 4H), 6.32 (dd, JZ6.2 and 2.3 Hz, 1H),
6.45 (d, JZ2.4 Hz, 1H), 7.12–7.27 (m, 9H), 7.45 (d, JZ
7.2 Hz, 6H), 8.04 (d, JZ5.8 Hz, 1H). NMR 13C (CDCl3):
dZ13.6, 46.6, 47.6, 77.1, 104.8, 105.5, 126.4, 127.8, 129.4,
141.9, 149.2, 155.2, 160.1.
4.3.4. ((6-Chloro)-2-pyridyl)-4-trityl-1-piperazine (4b).
Column chromatography (80/20 hexane/AcOEt) yielded
1
4.2.2. (3-Pyridyl)-4-trityl-1-piperazine (2). Column
chromatography (70/30 hexane/AcOEt) yielded 22 g
206 mg (95%) of 4b as an oil. NMR H (CDCl3): dZ2.36
(m, 4H), 3.59 (m, 4H), 6.33 (d, JZ8.2 Hz, 1H), 6.50 (d, JZ
7.5 Hz, 1H), 7.08–7.3 (m, 10H), 7.47–7.51 (m, 6H). NMR
13C (CDCl3): dZ45.5, 47.6, 76.9, 105.1, 111.9, 126.2,
127.6, 129.3, 139.4, 142.3, 149.4, 159.2.
1
(88%) of 2 as a light yellow solid. NMR H (CDCl3): dZ
2.47 (m, 4H), 3.34 (t, JZ4.8 Hz, 4H), 7.11–7.31 (m, 11H),
7.49–7.53 (m, 6H), 8.06 (d, JZ3.1 Hz, 1H), 8.26 (s, 1H).
NMR 13C (CDCl3): dZ47.7, 48.9, 77.0, 121.9, 123.5, 126.3,
127.7, 129.4, 138.1, 140.5, 142.8, 147.0.
4.3.5. ((2-Chloro)-3-pyridyl)-4-trityl-1-piperazine (5b).
Column chromatography (80/20 hexane/AcOEt) yielded
1
4.2.3. (4-Pyridyl)-4-trityl-1-piperazine (3). Column chro-
matography (70/30 hexane/AcOEt) yielded 21 g (84%) of
3 as a light yellow solid. Mp: 204 8C. NMR 1H (CDCl3): dZ
2.43 (m, 4H); 3.42 (t, JZ4.8 Hz, 4H); 6.60 (d, JZ5.8 Hz,
2H); 7.10–7.30 (m, 9H); 7.53 (d, JZ7.2 Hz, 6H); 8.24
(d, JZ5.8 Hz, 1H). NMR 13C (CDCl3): dZ46.6, 47.6, 77.0,
108.2, 126.4, 127.8, 129.4, 142.2, 150.1, 155.2.
195 mg (90%) of 5b as an oil. NMR H (CDCl3): dZ2.24
(m, 4H), 3.07 (t, JZ4.7 Hz, 4H), 6.93–7.49 (m, 18H), 8.06
(d, JZ4.4 Hz, 1H). NMR 13C (CDCl3): dZ46.1, 56.0, 76.0,
123.1, 126.0, 127.5, 128.0, 129.2, 142.1, 142.8, 146.3,
156.2.
4.3.6. ((2-Chloro)-4-pyridyl)-4-trityl-1-piperazine (7b).
Column chromatography (40/60 hexane/AcOEt) yielded
193 mg (89%) of 7b as a light yellow solid. Mp: 191 8C.
4.3. Monofunctionalisation of tritylpyridylpiperazines
1
NMR H (CDCl3): dZ2.32 (m, 4H), 3.25 (t, JZ4.8 Hz,
4H), 6.37 (d, JZ6.2 Hz, 1H), 6.46 (s, 1H), 7.08–7.27 (m,
9H), 7.49 (d, JZ7.2 Hz, 6H), 7.89 (d, JZ6.0 Hz, 1H). NMR
13C (CDCl3): dZ45.9, 47.1, 76.6, 106.7, 106.8, 126.1,
127.5, 128.9, 141.8, 149.0, 152.2, 156.5.
n-Butyllithium (4.92 mL, 7.87 mmol) was added dropwise
to
a solution of 2-dimethylaminoethanol (0.35 g,
3.93 mmol) in toluene (10 mL) at K5 8C. After 15 min of
stirring, the mixture was allowed to warm to 20 8C for
isomer 1, cooled to K5 8C for isomer 3 or cooled to K78 8C
for isomer 2. A solution of 1, 2 or 3 (0.2 g, 0.50 mmol) in
toluene (2 mL) was then added dropwise. The solution was
then stirred for 2.5 h at the same temperature then treated at
K78 8C with a solution of the appropriate electrophile
(9 mmol) in THF (10 mL). The temperature was maintained
at K78 8C for 1 h and at 0 8C for 30 min. Hydrolysis was
then performed at this temperature with water (3 mL). The
reaction medium was then evaporated under vacuum and the
crude product was purified by chromatography on silica gel
using AcOEt/hexane as eluent.
4.3.7. ((6-Bromo)-2-pyridyl)-4-trityl-1-piperazine (4c).
Column chromatography (80/20 hexane/AcOEt) yielded
226 mg (95%) of 4c as a light yellow solid. Mp: 75 8C.
NMR 1H (CDCl3): dZ2.37 (m, 4H), 3.62 (m, 4H), 6.41 (d,
JZ8.5 Hz, 1H), 6.67 (d, JZ7.2 Hz, 1H), 7.21–7.51 (m,
16H). NMR 13C (CDCl3): dZ45.4, 47.5, 76.8, 104.5, 115.7,
126.1, 127.5, 129.2, 135.5, 139.2, 14, 159.2.
4.3.8. ((2-Bromo)-3-pyridyl)-4-trityl-1-piperazine (5c).
Column chromatography (80/20 hexane/AcOEt) yielded

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F. Louerat et al. / Tetrahedron 61 (2005) 4761–4768
4765
1
214 mg (90%) of 5c as an oil. NMR H (CDCl3): dZ2.12
6.66 (d, JZ8.6 Hz, 1H), 7.09–7.31 (m, 11H), 7.45–7.58 (m,
6H). NMR 13C (CDCl3): dZ26.4, 44.9, 45.9, 47.7, 77.0,
109.4, 113.2, 126.2, 127.6, 129.3, 137.9, 141.6, 152.7,
157.8, 207.0.
(m, 4H), 3.22 (m, 4H), 7.13–7.25 (m, 11H), 7.48–7.52 (m,
6H), 7.97 (d, JZ4.4 Hz, 1H). NMR 13C (CDCl3): dZ47.9,
52.0, 76.7, 123.2, 126.1, 127.7, 128.1, 129.2, 139.5, 142.8,
143.4, 147.7.
4.3.16. ((2-(2,2-Dimethyl-propan-1-one))-3-pyridyl)-4-
trityl-1-piperazine (5f). Column chromatography (80/20
hexane/AcOEt) yielded 120 mg (50%) of 5f as an oil. NMR
1H (CDCl3): dZ1.02 (s, 9H), 2.18 (m, 4H), 3.00 (m, 4H),
6.99–7.30 (m, 11H), 7.52–7.64 (m, 6H), 8.57 (d, JZ4.4 Hz,
1H). NMR 13C (CDCl3): dZ27.4, 41.5, 47.5, 55.3, 76.9,
122.4, 126.2, 127.6, 129.4, 131.0, 142.3, 145.1, 146.9,
150.8, 207.4.
4.3.9. ((2-Bromo)-4-pyridyl)-4-trityl-1-piperazine (7c).
Column chromatography (40/60 hexane/AcOEt) yielded
226 mg (95%) of 7c as a light yellow solid. Mp: 168 8C.
1
NMR H (CDCl3): dZ2.40 (m, 4H), 3.39 (t, JZ4.8 Hz,
4H), 6.50 (d, JZ5.8 Hz, 1H), 6.72 (d, JZ1.2 Hz, 1H), 7.16–
7.31 (m, 9H), 7.49 (d, JZ7.6 Hz, 6H), 7.92 (d, JZ6.2 Hz,
1H). NMR 13C (CDCl3): dZ46.4, 47.5, 77.0, 107.5, 110.9,
126.4, 127.8, 129.3, 142.1, 143.4, 149.7, 156.6.
4.3.17. ((2-(2,2-Dimethyl-propan-1-one))-4-pyridyl)-4-
trityl-1-piperazine (7f). Column chromatography (40/60
hexane/AcOEt) yielded 195 mg (81%) of 7f as a light
yellow solid. Mp: 68 8C. NMR 1H (CDCl3): dZ1.41 (s, 9H),
2.39 (m, 4H), 3.39 (m, 4H), 6.59 (s, 2H), 7.24 (s, 9H), 7.48
(s, 6H), 8.20 (s, 1H). NMR 13C (CDCl3): dZ27.5, 44.1,
46.2, 47.4, 76.8, 107.8, 109.5, 126.3, 127.6, 129.1, 142.0,
147.0, 148.3, 155.5, 207.7.
4.3.10. ((6-Iodo)-2-pyridyl)-4-trityl-1-piperazine (4d).
Column chromatography (80/20 hexane/AcOEt) yielded
233 mg (89%) of 4d as an oil. NMR H (CDCl3): dZ2.36
(m, 4H), 3.56 (m, 4H), 6.37–6.41 (m, 1H), 6.88–6.93 (m,
2H), 7.20–7.27 (m, 9H), 7.47–7.50 (m, 6H). NMR 13C
(CDCl3): dZ45.3, 47.5, 76.8, 104.9, 123.0, 126.1, 127.5,
129.2, 138.3, 141.6, 154.5, 159.1.
1
4.3.11. ((2-Iodo)-3-pyridyl)-4-trityl-1-piperazine (5d).
Column chromatography (80/20 hexane/AcOEt) yielded
209 mg (80%) of 5d as an oil. NMR H (CDCl3): dZ2.03
(m, 4H), 3.18 (m, 4H), 7.13–7.31 (m, 11H), 7.43–7.53 (m,
6H), 8.04 (d, JZ3.9 Hz, 1H). NMR 13C (CDCl3): dZ47.9,
52.8, 76.9, 123.2, 126.2, 127.6, 129.4, 131.0, 142.3, 145.1,
146.9, 150.8.
4.3.18. ((6-(2,2-Dimethylpropyl-1-hydroxy))-2-pyridyl)-
4-trityl-1-piperazine (4g). Column chromatography (80/
20 hexane/AcOEt) yielded 145 mg (60%) of 4g as an oil.
NMR 1H (CDCl3): dZ0.88 (s, 9H), 2.44 (m, 4H), 3.61 (m,
4H), 4.16 (s, 1H), 6.44–6.48 (m, 2H), 7.15–7.27 (m, 9H),
7.50–7.55 (m, 7H). NMR 13C (CDCl3): dZ26.0, 36.2, 45.8,
47.8, 77.0, 79.9, 105.5, 112.3, 126.2, 127.6, 129.4, 137.1,
142.1, 157.5, 158.3.
1
4.3.12. ((2-Iodo)-4-pyridyl)-4-trityl-1-piperazine (7d).
Column chromatography (40/60 hexane/AcOEt) yielded
201 mg (77%) of 7d as a light yellow solid. Mp: 183 8C.
4.3.19. ((2-(2,2-Dimethylpropyl-1-hydroxy))-3-pyridyl)-
4-trityl-1-piperazine (5g). Column chromatography (80/
20 hexane/AcOEt) yielded 174 mg (72%) of 5g as an oil.
NMR 1H (CDCl3): dZ0.75 (s, 9H), 2.13 (m, 4H), 3.22 (m,
4H), 4.09 (s, 1H), 7.06–7.29 (m, 11H), 7.50–7.56 (m, 6H),
8.27 (d, JZ4.4 Hz, 1H). NMR 13C (CDCl3): dZ26.0, 37.1,
45.9, 47.8, 60.2, 76.5, 122.5, 126.0, 127.5, 128.7, 129.2,
142.1, 143.7, 147.0, 157.1.
1
NMR H (CDCl3): dZ2.35 (m, 4H), 3.31 (t, JZ4.8 Hz,
4H), 6.48 (d, JZ6.2 Hz, 1H), 6.93 (d, JZ2.4 Hz, 1H), 7.11–
7.29 (m, 9H), 7.48 (d, JZ7.6 Hz, 6H), 7.87 (d, JZ6.2 Hz,
1H). NMR 13C (CDCl3): dZ46.2, 47.4, 77.2, 107.8, 117.9,
119.5, 126.4, 127.7, 129.2, 142.1, 150.0, 155.6.
4.3.13. ((6-Phenyl-methanone)-2-pyridyl)-4-trityl-1-
piperazine (4e). Column chromatography (80/20 hexane/
AcOEt) yielded 175 mg (70%) of 4e as a light yellow solid.
Mp: 75 8C. NMR 1H (CDCl3): dZ2.40 (m, 4H), 3.64
(m, 4H), 6.79 (d, JZ8.6 Hz, 1H), 7.11–7.31 (m, 14H), 7.51–
7.65 (m, 8H). NMR 13C (CDCl3): dZ45.7, 47.8, 76.6,
109.4, 113.7, 125.5, 128.0, 128.1, 128.5, 129.2, 132.3,
135.0, 141.2, 143.4, 159.2, 168.4, 187.5.
4.3.20. ((2-(2,2-Dimethylpropyl-1-hydroxy))-4-pyridyl)-
4-trityl-1-piperazine (7g). Column chromatography (40/
60 hexane/AcOEt) yielded 157 mg (65%) of 7g as a light
1
yellow solid. Mp: 158 8C. NMR H (CDCl3): dZ0.90 (s,
9H), 2.29 (m, 4H), 3.36 (m, 4H), 4.18 (s, 1H), 4.71 (s, 1H),
6.44 (d, JZ6.2 Hz, 1H), 6.49 (s, 1H), 7.09–7.28 (m, 9H),
7.50 (d, JZ7.6 Hz, 6H), 8.10 (d, JZ6.0 Hz, 1H). NMR 13C
(CDCl3): dZ26.0, 36.0, 46.5, 47.4, 76.9, 80.5, 106.8, 107.1,
126.3, 127.6, 129.1, 142.2, 147.8, 154.0, 160.5.
4.3.14. ((2-Phenyl-methanone)-4-pyridyl)-4-trityl-1-
piperazine (7e). Column chromatography (40/60 hexane/
AcOEt) yielded 155 mg (62%) of 7e as a light yellow solid.
Mp: 139 8C. NMR 1H (CDCl3): dZ2.43 (m, 4H), 3.44
(m, 4H), 6.72 (d, JZ2.4 Hz, 1H), 7.07–7.54 (m, 13H), 7.93–
8.02 (m, 8H). 8.32 (d, JZ6.0 Hz, 1H). NMR 13C (CDCl3):
dZ46.5, 47.6, 77.2, 108.8, 113.0, 125.6, 128.1, 128.3,
128.5, 129.2, 133.0, 135.0, 141.4, 154.5, 155.7, 160.8,
187.5.
4.4. Bis-functionalisation of tritylpyridylpiperazines
The second functionalisation was performed under con-
ditions described in Section 4.3 except that the metallation
step was performed at K20 8C for 2.5 h.
4.4.1. ((2-Bromo-6-methylsulfanyl)-3-pyridyl)-4-trityl-1
piperazine (8a). Column chromatography (90/10 hexane/
4.3.15. ((6-(2,2-Dimethyl-propan-1-one))-2-pyridyl)-4-
trityl-1-piperazine (4f). Column chromatography (80/20
hexane/AcOEt) yielded 156 mg (65%) of 4f as an oil. NMR
1H (CDCl3): dZ1.18 (s, 9H), 2.43 (m, 4H), 3.63 (m, 4H),
1
AcOEt) yielded 169 mg (72%) of 8a as an oil. NMR H
(CDCl3): dZ2.20 (s, 3H), 2.38 (m, 4H), 3.12 (m, 4H), 7.10–
7.30 (m, 11H), 7.49–7.52 (m, 6H). NMR 13C (CDCl3): dZ

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4766
13.1, 47.9, 51.7, 76.8, 122.6, 126.1, 127.6, 128.8, 129.4,
134.5, 142.6, 145.1, 157.0.
a pH O7. The solution was then extracted thrice with
CH2Cl2. Evaporation of solvent under vacuum gave the free
pyridylpiperazine in pure form.
4.4.2. ((2-Iodo-6-methylsulfanyl)-3-pyridyl)-4-trityl-1-
piperazine (8b). Column chromatography (90/10 hexane/
4.5.1. ((6-Methylsulfanyl)-2-pyridyl)-1-piperazine (10a).
Yielded 52 mg (O99%) of 10a as an oil. NMR 1H (CDCl3):
dZ2.49 (s, 3H), 3.22 (t, JZ4.9 Hz, 4H), 3.78 (t, JZ4.9 Hz,
4H), 6.36 (d, JZ8.2 Hz, 1H), 6.60 (d, JZ7.5 Hz, 1H), 7.36
(t, JZ8.0 Hz, 1H). NMR 13C (CDCl3): dZ22.2, 42.7, 45.2,
101.9, 111.1, 137.6, 157.7, 176.8. MS (EI) m/z (rel. int.):
209 (59, MC), 167 (92), 153 (100), 141 (72), 124 (14), 109
(14), 79 (12), 78 (12), 56 (25).
1
AcOEt) yielded 189 mg (74%) of 8b as an oil. NMR H
(CDCl3): dZ2.32 (s, 3H), 2.38 (m, 4H), 3.09 (m, 4H), 6.83
(d, JZ8.2 Hz, 1H), 7.08–7.31 (m, 10H), 7.42–7.59 (m, 6H).
NMR 13C (CDCl3): dZ13.1, 47.8, 51.5, 76.7, 108.9, 122.6,
126.1, 127.6, 128.3, 129.3, 142.4, 145.6, 157.3.
4.4.3. ((2-Methylsulfanyl-6-phenyl-methanone)-3-pyri-
dyl)-4-trityl-1-piperazine (8c). Column chromatography
(90/10 hexane/AcOEt) yielded 214 mg (87%) of 8c as an
4.5.2. ((2-Methylsulfanyl)-3-pyridyl)-1-piperazine (11a).
Yielded 49 mg (95%) of 11a as an oil. NMR H (CDCl3):
1
1
oil. NMR H (CDCl3): dZ2.22 (s, 3H), 2.36 (m, 4H), 3.12
(m, 4H), 7.10–7.30 (m, 16H), 7.49–7.52 (m, 6H). NMR 13C
(CDCl3): dZ14.1, 47.8, 51.8, 76.5, 118.4, 122.6, 125.5,
127.6, 128.1, 128.4, 129.5, 132.2, 135.4, 141.4, 145.5,
150.3, 156.1, 187.6.
dZ2.10 (s, 1H), 2.51 (s, 3H), 2.90–2.98 (m, 4H), 3.01–3.08
(m, 4H), 6.97 (t, JZ4.8 Hz, 1H), 7.19 (d, JZ7.8 Hz, 1H),
8.19 (d, JZ4.8 Hz, 1H). NMR 13C (CDCl3): dZ12.5, 46.1,
52.3, 118.9, 125.2, 138.0, 143.8, 146.0. MS (EI) m/z (rel.
int.): 209 (56, MC), 167 (78), 162 (100), 152 (55), 119 (18),
92 (11), 78 (21), 56 (22).
4.4.4. ((2,6-Dichloro)-4-pyridyl)-4-trityl-1-piperazine
(9a). Column chromatography (20/80 hexane/AcOEt)
yielded 168 mg (78%) of 9a as a light yellow solid. Mp:
4.5.3. ((2-Methylsulfanyl)-4-pyridyl)-1-piperazine (12a).
Yielded 52 mg (O99%) of 12a as an oil. NMR 1H (CDCl3):
dZ2.53 (s, 3H), 3.06 (t, JZ4.8 Hz, 4H), 3.37 (t, JZ4.8 Hz,
4H), 6.45 (dd, JZ6.2 Hz, 1H), 6.56 (d, JZ2.4 Hz, 1H), 8.13
(d, JZ5.8 Hz, 1H). NMR 13C (CDCl3): dZ13.6, 44.2, 45.8,
105.1, 105.8, 149.5, 154.9, 160.5. MS (EI) m/z (rel. int.):
209 (51, MC), 167 (100), 151 (17), 106 (18), 79 (21), 56
(37).
1
202 8C. NMR H (CDCl3): dZ2.40 (m, 4H), 3.42 (t, JZ
4.8 Hz, 4H), 6.51 (s, 2H), 7.17–7.32 (m, 9H), 7.49 (d, JZ
7.2 Hz, 6H). NMR 13C (CDCl3): dZ46.6, 47.4, 77.2, 106.1,
126.5, 127.8, 129.3, 141.9, 151.1, 158.0.
4.4.5. ((2-Bromo-6-chloro)-4-pyridyl)-4-trityl-1-pipera-
zine (9b). Column chromatography (40/60 hexane/AcOEt)
yielded 125 mg (53%) of 9b as a light yellow solid. Mp:
1
112 8C. NMR H (CDCl3): dZ2.39 (m, 4H), 3.40 (t, JZ
4.5.4. ((6-Chloro)-2-pyridyl)-1-piperazine (10b). Yielded
49 mg (O99%) of 10b as an oil. NMR 1H (CDCl3): dZ2.00
(s, 1H), 3.24 (t, JZ5.6 Hz, 4H), 3.79 (t, JZ5.1 Hz, 4H),
6.72 (m, 2H), 7.55 (t, JZ6.5 Hz, 1H). NMR 13C (CDCl3):
dZ42.5, 45.0, 107.3, 114.3, 142.5, 147.6, 158.1. MS (EI)
m/z (rel. int.): 197 (30, MC), 155 (100), 141 (39), 129 (38),
113 (25), 78 (15), 56 (14).
4.8 Hz, 4H), 6.52 (d, JZ1.8 Hz, 1H), 6.67 (d, JZ1.8 Hz,
1H), 7.14–7.31 (m, 9H), 7.48 (d, JZ7.2 Hz, 6H). NMR 13C
(CDCl3): dZ46.8, 47.5, 77.0. 106.7, 110.2, 126.4, 127.6,
129.6, 142.0, 151.4, 158.0, 163.4.
4.4.6. ((2-Chloro-6-iodo)-4-pyridyl)-4-trityl-1-piperazine
(9c). Column chromatography (40/60 hexane/AcOEt)
yielded 177 mg (69%) of 9c as a light yellow solid. Mp:
4.5.5. ((2-Chloro)-3-pyridyl)-1-piperazine (11b). Yielded
1
1
156 8C. NMR H (CDCl3): dZ2.40 m, 4H), 3.39 (t, JZ
47 mg (96%) of 11b as an oil. NMR H (CDCl3): dZ2.24
5.2 Hz, 4H), 6.54 (d, JZ2.0 Hz, 1H), 6.93 (s, 1H), 7.14–
7.31 (m, 9H), 7.49 (d, JZ7.2 Hz, 6H). NMR 13C (CDCl3):
dZ46.5, 47.5, 77.2, 106.8, 116.2, 117.4, 126.5, 127.9,
129.3, 150.8, 156.9, 163.4.
(s, 1H), 3.03–3.15 (m, 8H), 7.17–7.35 (m, 2H), 8.05 (d, JZ
4.3 Hz, 1H). NMR 13C (CDCl3): dZ46.1, 52.0, 123.1,
127.3, 128.1, 142.8, 146.3. MS (EI) m/z (rel. int.): 197 (15,
MC), 162 (71), 155 (100), 140 (16), 78 (27), 76 (12), 56
(38).
4.4.7. ((2-Chloro-6-(2,2-dimethylpropyl-1-hydroxy))-4-
pyridyl)-4-trityl-1-piperazines (7b). Column chroma-
tography (40/60 hexane/AcOEt) yielded 145 mg (61%) of
4.5.6. ((2-Chloro)-4-pyridyl)-1-piperazine (12b). Yielded
49 mg (O99%) of 12b as an oil. NMR 1H (CDCl3): dZ3.05
(t, JZ4.9 Hz, 4H), 3.35 (t, JZ4.8 Hz, 4H), 6.40 (d, JZ
6.2 Hz, 1H), 6.48 (s, 1H), 7.89 (d, JZ5.9 Hz, 1H). NMR 13C
(CDCl3): dZ45.9, 47.1, 106.7, 106.8, 149.0, 152.2, 156.5.
MS (EI) m/z (rel. int.): 197 (27, MC), 155 (100), 139 (13),
112 (7), 56 (13).
1
7b as a light yellow solid. Mp: 181 8C. NMR H (CDCl3):
dZ0.88 (s, 9H), 2.41 (m, 4H), 3.40 (t, JZ4.8 Hz, 4H), 4.12
(s, 1H), 6.41 (s, 1H), 6.49 (s, 1H), 7.17–7.31 (m, 9H), 7.50
(m, 6H). NMR 13C (CDCl3): dZ26.1, 36.1, 46.7, 47.5, 77.2,
80.8, 105.9, 106.1, 126.4, 127.8, 129.2, 142.1, 151.0, 156.8,
160.9.
4.5.7. ((6-Bromo)-2-pyridyl)-1-piperazine (10c). Yielded
60 mg (O99%) of 10c as an oil. NMR 1H (CDCl3): dZ2.48
(s, 1H), 2.95 (t, JZ5.1 Hz, 4H), 3.51 (t, JZ4.8 Hz, 4H),
6.50 (d, JZ8.2 Hz, 1H), 6.73 (d, JZ7.2 Hz, 1H), 7.28
(t, JZ7.5 Hz, 1H). NMR 13C (CDCl3): dZ42.7, 45.3, 104.8,
116.0, 139.5, 142.8, 159.4. MS (EI) m/z (rel. int.): 243 (31,
MC), 241 (33), 199 (100), 158 (26), 157 (25), 105 (17), 78
(26), 56 (25).
4.5. Regeneration of free pyridylpiperazines
A solution of TFA (1 mL of a 25% solution in CH2Cl2,
1.2 equiv) was added to a solution of the tritylpyridyl-
piperazine (0.25 mmol) in dichloromethane (5 mL) at rt for
0.5 h. The solution was then extracted thrice with water and
treated with a solution of satured Na2CO3 in order to obtain

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4767
4.5.8. ((2-Bromo)-3-pyridyl)-1-piperazine (11c). Yielded
60 mg (O99%) of 11c as an oil. NMR H (CDCl3): dZ
3.09–3.17 (m, 8H), 4.22 (s, 1H), 7.25–7.36 (m, 2H), 8.08
(d, JZ4.4 Hz, 1H). NMR 13C (CDCl3): dZ45.5, 51.5,
123.1, 128.8, 139.9, 144.0, 147.8. MS (EI) m/z (rel. int.):
243 (7, MC), 241 (8), 201 (35), 199 (36), 162 (100), 105
(9), 78 (34), 56 (20).
4.2 Hz, 4H), 3.51 (t, JZ4.1 Hz, 4H), 6.75 (d, JZ8.2 Hz,
1H), 7.22 (d, JZ8.2 Hz, 1H), 7.56 (t, JZ8.2 Hz, 1H). NMR
13C (CDCl3): dZ27.5, 43.2, 45.8, 46.5, 105.1, 109.6, 113.1,
137.9, 157.9, 207.0. MS (EI) m/z (rel. int.): 247 (14, MC),
205 (36), 191 (35), 179 (100), 162 (16), 148 (12), 108 (16),
78 (11), 56 (28).
1
4.5.16. ((2-(2,2-Dimethyl-propan-1-one))-3-pyridyl)-1-
piperazine (11e). Yielded 55 mg (90%) of 11e as an oil.
NMR 1H (CDCl3): dZ1.13 (s, 9H), 1.85 (s, 1H), 2.82 (t, JZ
4.8 Hz, 4H), 2.98 (t, JZ4.1 Hz, 4H), 7.14–7.21 (m, 1H),
7.56 (d, JZ7.2 Hz, 1H), 8.61 (d, JZ4.8 Hz, 1H). NMR 13C
(CDCl3): dZ27.6, 41.9, 47.1, 55.9, 122.6, 128.9, 146.8,
157.2, 164.0, 208.8. MS (EI) m/z (rel. int.): 247 (14, MC),
205 (41), 163 (70), 157 (74), 135 (85), 121 (100), 115 (74),
73 (61), 59 (88).
4.5.9. ((2-Bromo)-4-pyridyl)-1-piperazine (12c). Yielded
60 mg (O99%) of 12c as an oil. NMR 1H (CDCl3): dZ3.04
(t, JZ4.8 Hz, 4H), 3.35 (t, JZ4.8 Hz, 4H), 6.62 (dd, JZ
6.0 Hz, 1H), 6.82 (d, JZ6.2 Hz, 1H), 7.99 (d, JZ6.2 Hz,
1H). NMR 13C (CDCl3): dZ44.7, 46.3, 107.8, 111.2, 143.4,
149.8, 156.5. MS (EI) m/z (rel. int.): 243 (22, MC), 241
(23), 201 (99), 199 (100), 105 (33), 56 (40).
4.5.10. ((6-Iodo)-2-pyridyl)-1-piperazine (10d). Yielded
72 mg (O99%) of 10d as an oil. NMR 1H (CDCl3): dZ1.98
(s, 1H), 2.95 (t, JZ4.1 Hz, 4H), 3.50 (t, JZ4.1 Hz, 4H),
6.52 (d, JZ7.5 Hz, 1H), 7.55 (m, 2H). NMR 13C (CDCl3):
dZ42.8, 45.9, 105.2, 113.3, 123.3, 138.7, 168.0. MS (EI)
m/z (rel. int.): 289 (23, MC), 247 (51), 233 (33), 221 (100),
120 (20), 105 (27), 78 (25), 56 (40).
4.5.17. ((2-(2,2-Dimethyl-propan-1-one))-4-pyridyl)-1-
piperazine (12f). Yielded 49 mg (80%) of 12f as oil.
NMR 1H (CDCl3): dZ1.42 (s, 9H), 2.98 (t, JZ4.1 Hz, 4H),
3.32 (t, JZ4.8 Hz, 4H), 4.84 (s, 1H), 6.69–6.73 (m, 1H),
7.25 (d, JZ2.7 Hz, 1H), 8.26 (d, JZ5.9 Hz, 1H). NMR 13C
(CDCl3): dZ27.5, 44.2, 45.6, 46.9, 108.1, 109.8, 113.3,
148.6, 155.7, 208.2. MS (EI) m/z (rel. int.): 247 (9, MC);
232 (5); 205 (5); 163 (100); 120 (5); 105 (5); 79 (4); 56 (6).
4.5.11. ((2-Iodo)-3-pyridyl)-1-piperazine (11d). Yielded
72 mg (O99%) of 11d as an oil. NMR 1H (CDCl3): dZ2.00
(s, 1H), 2.99 (t, JZ3.1 Hz, 4H), 3.10 (t, JZ5.1 Hz, 4H),
7.20–7.30 (m, 2H), 8.08 (t, JZ3.1 Hz, 1H). NMR 13C
(CDCl3): dZ46.2, 53.4, 123.4, 127.9, 145.3, 146.3, 150.9.
MS (EI) m/z (rel. int.): 289 (15, MC), 247 (33), 162 (100),
219 (14), 105 (15), 78 (35), 56 (25).
4.5.18. ((6-(2,2-Dimethylpropyl-1-hydroxy))-2-pyridyl)-
1-piperazine (10g). Yielded 52 mg (85%) of 10g as oil.
NMR 1H (CDCl3): dZ0.91 (s, 9H), 2.96 (t, JZ4.5 Hz, 4H),
3.47 (t, JZ2.7 Hz, 4H), 4.20 (s, 1H), 6.49 (d, JZ3.8 Hz,
1H), 6.53 (d, JZ4.8 Hz, 1H), 7.42 (t, JZ7.2 Hz, 1H). NMR
13C (CDCl3): dZ26.0, 36.1, 45.7, 46.2, 80.0, 105.4, 112.2,
127.9, 137.1, 157.2. MS (EI) m/z (rel. int.): 249 (22, MC);
192 (49); 181 (90); 163 (71); 149 (100); 135 (35); 121 (27);
107 (22); 78 (46); 56 (40).
4.5.12. ((2-Iodo)-4-pyridyl)-1-piperazine (12d). Yielded
72 mg (O99%) of 12d as an oil. NMR 1H (CDCl3): dZ3.00
(t, JZ4.8 Hz, 4H), 3.31 (t, JZ4.8 Hz, 4H), 4.23 (s, 1H),
6.62 (dd, JZ6.2 Hz, 1H), 7.05 (d, JZ2.4 Hz, 1H), 7.93 (d,
JZ6.2 Hz, 1H). NMR 13C (CDCl3): dZ44.8, 46.2, 108.0,
118.1, 119.3, 150.0, 155.5. MS (EI) m/z (rel. int.): 288 (13,
MC), 258 (55), 105 (50), 78 (33), 69 (68), 56 (100).
4.5.19. ((2-(2,2-Dimethylpropyl-1-hydroxy))-3-pyridyl)-
1-piperazine (11f). Yielded 57 mg (93%) of 11f as an oil.
NMR 1H (CDCl3): dZ0.92 (s, 9H), 2.92–3.12 (m, 8H), 4.85
(s, 1H), 7.14–7.22 (m, 1H), 7.46 (d, JZ8.2 Hz, 1H), 8.33 (d,
JZ4.8 Hz, 1H). NMR 13C (CDCl3): dZ27.1, 31.6, 46.3,
47.1, 76.1, 122.7, 128.7, 143.8, 147.6, 157.1. MS (EI) m/z
(rel. int.): 249 (26, MC), 192 (100), 174 (53), 145 (46), 107
(30), 79 (43), 56 (29).
4.5.13. ((6-Phenyl-methanone)-2-pyridyl)-1-piperazine
(10e). Yielded 60 mg (90%) of 10e as an oil. NMR
1H (CDCl3): dZ2.28 (s, 1H), 2.93 (t, JZ4.1 Hz, 4H),
3.49 (t, JZ3.1 Hz, 4H), 6.62 (d, JZ8.9 Hz, 1H), 6.79 (d,
JZ8.5 Hz, 1H), 7.27–7.71 (m, 4H), 8.09 (d, JZ7.2 Hz, 2H).
NMR 13C (CDCl3): dZ45.6, 46.3, 109.5, 113.7, 127.6,
130.9, 132.3, 138.0, 147.7, 152.8, 158.1, 194.0. MS (EI) m/z
(rel. int.): 267 (21, MC), 225 (40), 221 (43), 199 (100), 105
(94), 77 (59).
4.5.20. ((2-(2,2-Dimethylpropyl-1-hydroxy))-4-pyridyl)-
1-piperazine (12g). Yielded 43 mg (70%) of 12g as an
oil. NMR 1H (CDCl3): dZ0.92 (s, 9H), 3.00 (t, JZ7.7 Hz,
4H), 3.29 (t, JZ7.8 Hz, 4H), 4.21 (s, 1H), 6.54–6.60 (m,
2H), 8.20 (d, JZ4.8 Hz, 1H). NMR 13C (CDCl3): dZ26.1,
36.2, 45.5, 47.1, 80.7, 107.5, 109.8, 148.6, 155.2, 160.4. MS
(EI) m/z (rel. int.): 249 (2, MC); 234 (3); 192 (100); 163 (4);
149 (6); 135 (14); 121 (2); 107 (4); 79 (2); 57 (3).
4.5.14. ((2-Phenyl-methanone)-4-pyridyl)-1-piperazine
(12e). Yielded 53 mg (80%) of 12e as an oil. NMR H
1
(CDCl3): dZ1.97 (s, 1H), 3.16 (t, JZ5.5 Hz, 4H), 3.53
(t, JZ5.1 Hz, 4H), 6.83 (dd, JZ2.7 Hz, 1H), 7.37–7.57 (m,
4H), 7.98 (d, JZ6.8 Hz, 2H). 8.36 (d, JZ5.9 Hz, 1H). NMR
13C (CDCl3): dZ43.7, 45.0, 109.1, 110.4, 128.1, 130.9,
133.0, 136.3, 149.3, 155.4, 173.9, 194.9. MS (EI) m/z (rel.
int.): 267 (48, MC), 225 (100), 197 (12), 182 (7), 154 (7),
119 (12), 105 (29), 77 (36), 56 (10).
4.5.21. ((2,6-Dichloro)-4-pyridyl)-1-piperazine (12h).
Yielded 57 mg (O99%) of 12h as an oil. NMR 1H
(CDCl3): dZ2.41 (s, 1H), 2.99 (t, JZ4.8 Hz, 4H), 3.33 (t,
JZ4.8 Hz, 4H), 6.58 (s, 2H). NMR 13C (CDCl3): dZ45.3,
47.0, 106.3, 151.2, 158.1. MS (EI) m/z (rel. int.): 231 (21,
MC); 189 (100); 176 (7); 146 (3); 112 (3); 76 (4); 56 (13).
4.5.15. ((6-(2,2-Dimethyl-propan-1-one))-2-pyridyl)-1-
piperazine (10f). Yielded 52 mg (85%) of 10f as an oil.
NMR 1H (CDCl3): dZ1.43 (s, 9H), 1.75 (s, 1H), 2.99 (t, JZ
4.5.22. ((2-Bromo-6-chloro)-4-pyridyl)-1-piperazine
(12i). Yielded 69 mg (O99%) of 12i as an oil. NMR H
1

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F. Louerat et al. / Tetrahedron 61 (2005) 4761–4768
4768
(CDCl3): dZ1.54 (s, 1H), 2.97 (t, JZ4.8 Hz, 4H), 3.31 (t,
JZ4.8 Hz, 4H), 6.60 (s, 1H), 6.75 (s, 1H). NMR 13C
(CDCl3): dZ46.3, 50.7, 106.8, 110.3, 113.6, 141.5, 157.6.
MS (EI) m/z (rel. int.): 277 (21, MC), 235 (100), 139 (12),
119 (8), 76 (12), 56 (19).
References and notes
1. Cowart, M.; Latshaw, S. P.; Bhatia, P.; Daanen, J. F.; Rohde,
J.; Nelson, S. L.; Patel, M.; Kolasa, T.; Nakane, M.; Uchic,
M. E.; Miller, L. N.; Terranova, M. A.; Chang, R.; Donnelly-
Roberts, D. L.; Namovic, M. T.; Hollingsworth, P. R.;
Martino, B. R.; Lynch, J. J., III; Sullivan, J. P.; Hsieh, G. C.;
Moreland, R. B.; Brioni, J. D.; Stewart, A. O. J. Med. Chem.
2004, 47, 2864–3853.
4.5.23. ((2-Chloro-6-iodo)-4-pyridyl)-1-piperazines (12j).
Yielded 80 mg (O99%) of 12j as an oil. NMR 1H (CDCl3):
dZ1.65 (s, 1H), 2.61 (t, JZ5.2 Hz, 4H), 3.32 (t, JZ5.2 Hz,
4H), 6.61 (s, 1H), 6.99 (s, 1H). NMR 13C (CDCl3): dZ46.2,
51.0, 93.4, 104.5, 107.4, 117.8, 156.8. MS (EI) m/z (rel.
int.): 323 (33, MC), 281 (100), 268 (10), 154 (9), 119 (9),
76 (9), 56 (14).
¨
2. (a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem.
¨
¨
¨
Lett. 1999, 9, 97–102. (b) Lober, S.; Aboul-Fadl, T.; Hubner,
H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2002, 12, 633–636.
3. Shao, B.; Huang, J.; Sun, Q.; Valenzano, K. J.; Schmid, L.;
Nolan, S. Bioorg. Med. Chem. Lett. 2005, 15, 719–723.
4. Genin, M. J.; Poel, T. J.; Yagi, Y.; Biles, C.; Althaus, I.;
Keiser, B. J.; Kopta, L. A.; Friis, J. M.; Reusser, F.; Adams,
j.W.J.; Olmsted, R. A.; Voorman, R. L.; Thomas, R. C.;
Romero, D. L. J. Med. Chem. 1996, 39, 5267–5275.
5. Mylari, B. M.; Oates, P. J.; Beebe, D. A.; Brackett, N. S.;
Coutcher, J. B.; Dina, M. S.; Zembrowski, W. J. J. Med. Chem.
2001, 44, 2695–2700.
4.5.24. ((2-Chloro-6-(2,2-dimethylpropyl-1-hydroxy))-4-
pyridyl)-1-piperazine (12k). Yielded 42 mg (60%) of 12k
1
as an oil. NMR H (CDCl3): dZ0.92 (s, 9H), 2.97 (t, JZ
4.8 Hz, 4H), 3.29 (t, JZ4.8 Hz, 4H), 4.18 (s, 1H), 6.47 (s,
1H), 6.55 (s, 1H). NMR 13C (CDCl3): dZ25.9, 36.1, 45.6,
47.5, 81.0, 106.4, 113.7, 130.5, 143.2, 161.2. MS (EI) m/z
(rel. int.): 283 (2, MC), 268 (3), 227 (76), 226 (100), 183
(8), 171 (11), 170 (13), 169 (20), 57 (8).
6. 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.;
Donnelly-Roberts, D. L.; Miller, L. N.; Nakane, M.; Sullivan,
J. P.; Brioni, J. D. J. Med. Chem. 2004, 47, 2348–2355.
7. (a) Neuville, L.; Zhu, J. Tetrahedron Lett. 1997, 38,
4091–4094. (b) Hepperle, M.; Eckert, J.; Gala, D. Tetrahedron
Lett. 1999, 40, 5655–5659.
4.5.25. ((2-Bromo-6-methylsulfanyl-3-pyridyl)-1-pipera-
zine (11g). Yielded 70 mg (97%) of 11g as an oil. NMR 1H
(CDCl3): dZ2.50 (s, 3H), 2.95–2.99 (m, 4H), 3.06–3.11 (m,
4H), 7.03–7.15 (m, 2H), 7.29 (d, JZ3.1 Hz, 1H). NMR 13C
(CDCl3): dZ13.1, 46.0, 51.9, 119.1, 122.7, 128.0, 134.9,
145.2. MS (EI) m/z (rel. int.): 289 (21, MC), 287 (21), 245
(26), 242 (49), 240 (45), 183 (42), 105 (100), 77 (69), 57
(58).
8. (a) Zhao, S.-H.; Miller, A. K.; Berger, J.; Flippin, L. A.
Tetrahedron Lett. 1996, 37, 4463–4466. (b) Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617–620.
(c) Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, A.;
Goodman, A. Tetrahedron Lett. 2002, 43, 3359–3363.
9. Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 2002, 58,
6913–6924.
4.5.26. ((2-Iodo-6-methylsulfanyl)-3-pyridyl)-1-pipera-
zine (11h). Yielded 76 mg (91%) of 11h as an oil. NMR
1H (CDCl3): dZ2.20 (s, 1H), 2.47 (s, 3H), 2.92–2.94 (m,
4H), 2.99–3.04 (m, 4H), 6.83 (d, JZ7.9 Hz, 1H), 7.29–7.36
(m, 1H). NMR 13C (CDCl3): dZ13.2, 46.1, 52.2, 119.1,
127.3, 129.6, 144.0, 146.0. MS (EI) m/z (rel. int.): 335 (45,
MC), 288 (100), 277 (13), 96 (16), 84 (15), 78 (13), 56 (68).
10. For a review see Gros, Ph.; Fort, Y. Eur. J. Org. Chem. 2002,
20, 3375–3383.
11. (a) Cuperly, D.; Gros, Ph.; Fort, Y. J. Org. Chem. 2002, 67,
¨
238–241. (b) Gros, Ph.; Louerat, F.; Fort, Y. Org. Lett. 2002, 4,
1759–1761. (c) Martineau, D.; Gros, Ph.; Fort, Y. J. Org.
Chem. 2004, 69, 7914–7918.
12. All our first attempts at metallation of free amines resulted in
sluggish reactions and degradation. To address this, the
piperazine NH group was tritylated to avoid its deprotonation
and consumption of basic reagents.
4.5.27. ((2-Methylsulfanyl-6-(2-phenyl-methanone))-3-
pyridyl)-1-piperazine (11i). Yielded 58 mg (75%) of 11i
as an oil. NMR 1H (CDCl3): dZ2.50 (s, 3H), 2.89–2.99 (m,
4H), 3.03–3.09 (m, 4H), 6.97 (d, JZ3.3 Hz, 1H), 7.19 (d,
JZ5.1 Hz, 1H), 7.36–7.56 (m, 5H). NMR 13C (CDCl3): dZ
12.5, 46.2, 52.5, 118.9, 125.2, 128.2, 129.6, 132.3, 135.3,
138.0, 143.8, 156.1, 186.3.
13. Metallation attempts were performed using 2–8 equiv of
n-BuLi or LTMP in THF at K78 or 0 8C for 2–6 h.
14. Hexane is generally the best solvent for metallations with
BuLi-LiDMAE since this non chelating solvent favours
aggregates formation.
15. The C–Cl and C–SMe moieties were found stable under BuLi-
LiDMAE lithiation conditions. See for example Refs. 7a–c and
(a) Gros, Ph.; Viney, C.; Fort, Y. Synlett 2002, 4, 628–630.
(b) Kaminski, T.; Gros, P. h.; Fort, Y. Eur. J. Org. Chem. 2003,
3855–3860.
Acknowledgements
The authors would like to thank A. Anen for his helpful
experiments during the initiation of this work.