The use of lithium amides in the palladium-mediated synthesis of [carbonyl-11C]amides

Article abstract of DOI:10.1002/ejoc.200700255

Weakly nucleophilic amines were converted into the corresponding lithium amides and used in either one- or two-pot palladium-mediated reactions with [¹¹C]carbon monoxide and aryl iodides. It was found that palladium acyl complexes may be prepared in a separate step and have sufficient life-time to be used in a subsequent reaction with a nucleophile. This two-pot procedure was used for the labelling synthesis of eleven amides (nine of which are analogues of WAY-100635, a 5-HT_1A radioligand) from weakly nucleophilic amines. The results were compared to a direct one-pot procedure using lithium amides. Both approaches extend the scope of palladium-mediated carbonylation using [¹¹C]carbon monoxide and aryl iodides allowing use of weakly nucleophilic amines. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700255

FULL PAPER
DOI: 10.1002/ejoc.200700255
The Use of Lithium Amides in the Palladium-Mediated Synthesis of
[Carbonyl-11C]Amides
Oleksiy Itsenko,[a] Elisabeth Blom,[a] Bengt Långström,[a,b] and Tor Kihlberg*[b]
Keywords: Carbon monoxide / Carbonylation / Palladium / Lithium / Amides
Weakly nucleophilic amines were converted into the corre-
sponding lithium amides and used in either one- or two-pot
palladium-mediated reactions with [11C]carbon monoxide
and aryl iodides. It was found that palladium acyl complexes
may be prepared in a separate step and have sufficient life-
time to be used in a subsequent reaction with a nucleophile.
This two-pot procedure was used for the labelling synthesis
of eleven amides (nine of which are analogues of WAY-
100635, a 5-HT1A radioligand) from weakly nucleophilic
amines. The results were compared to a direct one-pot pro-
cedure using lithium amides. Both approaches extend the
scope of palladium-mediated carbonylation using [11C]car-
bon monoxide and aryl iodides allowing use of weakly nucle-
ophilic amines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
mans,[4,5] and a more metabolically stable compound with
good PET tracer properties would be of interest. Several
structural analogues of WAY-100635 were studied, most of
Introduction
Among the imaging techniques used for in vivo studies of
neurotransmitter-receptor interactions on a molecular level,
positron emission tomography (PET) has proved to be of
great value.[1] The use of PET at different stages of drug
development seems particularly promising.[2] The need for
new radioactive tracers for PET has stimulated research in
the synthetic chemistry of short-lived positron emitters.
Carbon-11 is an important positron emitting radionuclide
because the isotopic labelling does not change the biochem-
ical properties of the labelled compound. However, em-
ploying typical preparative procedures is not easy in a label-
ling synthesis owing to the short half-life of the radionu-
clide (20.3 min) and practical difficulties in handling sub-
micromolar amounts of labelled compounds.[3]
which retained the aryl–piperazine pharmacophore.[4–6]
A
compelling, but not yet explored, synthetic route to such
analogues is palladium-mediated carbonylation of aryl ha-
lides or triflates using [11C]carbon monoxide.[7]
We intended to use this approach to create a library of
structurally related [carbonyl-11C]amides using amine 1
(Figure 1) and various aryl iodides.[8] However, the pre-
viously described procedure[7] provided only 0–15% decay-
corrected radiochemical yields of the amides. The bottle-
neck was, conceivably, the low reactivity of parent amine 1.
Indeed, difficulties in attaining high radiochemical yield
when carrying out carbonylations with the use of low-reac-
tive nucleophiles have already been noted.[9]
[Carbonyl-11C]WAY-100635 has proved to be a valuable
tracer for imaging 5-HT1A-subtype serotonin receptors.[4]
The tracer, however, undergoes rapid metabolism in hu-
Figure 1. Amine precursor for labelling analogues of WAY-100635.
[a] Department of Biochemistry and Organic Chemistry, Uppsala
University,
Box 576, Husargatan 3, BMC, 751 23 Uppsala, Sweden
Fax: +46-18-4713818
This report describes stepwise and one-pot protocols
used to perform carbonylation reactions with [11C]carbon
monoxide, employing lithium amides to promote the reac-
tions.
[b] Uppsala Imanet, GE Healthcare,
Box 967, 751 09 Uppsala, Sweden
Fax: +46-18-666819
E-mail: Tor.Kihlberg@ge.com
Eur. J. Org. Chem. 2007, 4337–4342
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4337

O. Itsenko, E. Blom, B. Långström, T. Kihlberg
FULL PAPER
monoxide was used in amounts of ca. 20–30 nmol in a mix-
ture with He as the carrier gas. The labelling syntheses were
performed in a two- (method A) and one-step (method B)
manner.
Results and Discussion
Eleven amides were selected as synthetic targets (Fig-
ure 2). Compounds 1a–i were of interest for biological
screening; compounds 2a and 3a were included to allow
some generalization of the data. All reactions were per-
formed in a 270-μL stainless steel batch-type reactor, using
an automated remote-controlled system for the production
and handling of [11C]carbon monoxide.[10] [11C]Carbon
The reactivity of the nucleophile in palladium-mediated
carbonylation is an important factor influencing the radio-
chemical yield in reactions using [11C]carbon monoxide.[7,9]
It was shown that yields with unreactive amines, such as
anilines, may be increased by converting them into the cor-
responding lithium amides before carbonylation with [11C]-
carbon monoxide.[9a] However, the yields were often low,
presumably owing to side reactions. To avoid at least some
of them we designed a stepwise procedure where [11C]-
carbon monoxide first reacts with a palladium/aryl iodide
complex at high pressure, and then the formed reactive acyl
complex is allowed to react with a lithium amide in a sepa-
rate vessel at ambient pressure.
The two-step procedure, method A, proved to be feasible,
as the results summarized in Table 1 show. The yield of 2a
was almost triple relative to that obtained previously by
using the one-pot reaction.[9a] Generally, the conversion of
[11C]carbon monoxide was high, often nearly quantitative.
The selectivity of the reactions was also good, except the
reaction with 1-iodo-2-methoxybenzene, which gave a
number of labelled byproducts, and thus low radiochemical
yield (Table 1, Entries 9 and 10). Prefabricated tetrakis(tri-
phenylphosphane)palladium(0) was normally used as a
coupling catalyst or it was generated in situ from tris(diben-
zylideneacetone)dipalladium(0) and triphenylphosphane
(1:5). In a number of cases changing the catalyst ligand
from triphenylphosphane to triphenylarsane led to im-
proved radiochemical yields (Table 1, cf. Entries 7 and 8, 9
and 10, 11 and 12, 13 and 14). This improvement may be
linked to the higher kinetic lability of AsPh3 ligands.[11] In
regard to the second step, the reaction of the palladium–
acyl complex with lithium amides was complete within 1–
2 min, and longer reactions time did not lead to any
changes as monitored by HPLC.
Figure 2. Amides labelled at carbonyl position with 11C (marked
by *).
Table 1. Decay corrected radiochemical yields of 11C-labelled amides obtained by using method A.
Entry
Product
Catalyst
Conv. of [11C]O [%][a]
LC yield [%][b]
Isolated yield [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Pd(PPh3)4
99
99
81
79
99
54
14
69
8
58
16
96
95
99
97
79
93
64
72
94
30
9
27
2
22
2
43
60
44
49
64
Pd2dba3/PPh3
Pd2dba3/PPh3
Pd2dba3/PPh3
Pd2dba3/PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd2dba3/AsPh3
Pd(PPh3)4
Pd2dba3/AsPh3
Pd(PPh3)4
Pd2dba3/AsPh3
Pd2dba3/PPh3
Pd2dba3/AsPh3
Pd(PPh3)4
1g
1g
1h
1h
1i
9
10
11
12
13
14
15
1i
9
2a
2a
3a
95
91
17
71
72
[a] Decay-corrected, the fraction of radioactivity left in the crude product after purging unreacted [11C]O with nitrogen. [b] Decay-
corrected radiochemical yield based on [11C]O calculated by using analytical HPLC. [c] Isolated decay-corrected radiochemical yield.
4338
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4337–4342

Lithium Amides in Pd-Mediated Synthesis of [Carbonyl-11C]Amides
FULL PAPER
Table 2. Decay-corrected radiochemical yields of 11C-labelled amides obtained by using method B.
Entry
Product
Catalyst
Conv. of [11C]O [%][a]
LC yield [%][b]
Isolated yield [%][c]
1
2
3
4
5
6
7
1a
1d
1f
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
97
97
98
99
97
96
97
90
64
38
78
87
29
16
50
28
27
67
67
18
1g
1h
1i
3a
[a] Decay-corrected, the fraction of radioactivity left in the crude product after purging unreacted [11C]O with nitrogen. [b] Decay-
corrected radiochemical yield based on [11C]O calculated by using analytical HPLC. [c] Isolated decay-corrected radiochemical yield.
The one-step procedure, method B, was used to synthe- [11C]carbon monoxide can be efficiently trapped by some
size amides 1a, 1d, 1f–i and 3a (Figure 2). To our surprise, lithium amides, this reaction probably played a minor role
the yields of some amides were improved. The improvement in the palladium-mediated carbonylation of amine 1 under
was most noticeable with ortho-substituted iodoarenes (cf. the conditions of method B.
Table 1, Entries 10 and 12 with Table 2, Entries 5 and 6),
In general, we consider the two-pot method preferential
which may be explained by a low stability of the acylating because the reactions were cleaner in most cases. For some
species formed from these substrates. The yield of amide 3a substrates the one-pot method may give better yields, but
was modest with either method (Table 1, Entry 15; Table 2, side reactions must be considered. These include the forma-
Entry 7). [11C]Carbon monoxide was almost completely tion of lithium carbamoyls and reactions induced by lith-
consumed in these reactions; however, we observed more ium amide as a base or nucleophile such as elimination,
labelled byproducts using method B than by using method substitution, etc.
A.
To better understand these results we considered the im-
Conclusions
pact of side reactions. Most side reactions are tolerable to
some extent provided that they do not consume the [11C]-
carbon monoxide because the nonradioactive reactant was
used in excess over the amount of [11C]carbon monoxide.
Side reactions involving [11C]O, which is the limiting rea-
gent, are detrimental. A relevant process under the condi-
tions of method B is the insertion of [11C]carbon monoxide
into the lithium–nitrogen bond with the formation of lith-
ium carbamoyl compounds.[12] This reaction has found syn-
thetic utility and was one of the first published examples of
carbonylation using [11C]carbon monoxide.[13] The prod-
ucts, lithium carbamoyls, are unstable species and react
rapidly with electrophiles producing stable carbonyl com-
pounds.[12,13] First, we repeated the reported carbonylation,
but under modified conditions, which were closer to those
used in method B. Lithium 1-phenylpiperazide (4) was re-
acted with [11C]carbon monoxide (Scheme 1) under high
pressure at 30 °C for 5 min, and the resulting mixture was
transferred from the reactor to a vial containing ethanol at
ambient conditions. In this way, formamide 5 was obtained
in an excellent 75% isolated decay-corrected radiochemical
yield; the conversion of [11C]carbon monoxide was almost
quantitative.
Palladium-mediated carbonylation with the use of [11C]-
carbon monoxide can be performed in two steps: first, a
palladium–acyl complex is prepared from [11C]carbon mon-
oxide under pressure, and in the next step it is reacted with
a lithium amide at ambient pressure. This method could be
a valuable tool for synthesizing labelled amides from unre-
active amines. In some cases performing the reaction in
one-pot manner may be a good option. More focused
mechanistic studies of this reaction under the conditions
used in labelling would be valuable.
Experimental Section
[11C]Carbon dioxide was produced at Uppsala Imanet with a Scan-
ditronix MC-17 cyclotron by using the 14N(p,α)11C nuclear reaction
in a gas target containing nitrogen (AGA, Nitrogen 6.0) and 0.1%
oxygen (AGA, Oxygen 4.8), which was bombarded with 17 MeV
protons. [11C]Carbon monoxide was produced as described pre-
viously.[10] The radiolabelling syntheses were performed on an auto-
mated system for production and handling of [11C]carbon mon-
oxide.[10] HPLC analyses of radiolabelled compounds were per-
formed with a Beckman Nouveau HPLC system equipped with a
Beckman 166 variable-wavelength UV detector and a β+-flow de-
tector, using a gradient elution with an ammonium formate solu-
tion of pH 3.5 and 50:7 mixture of acetonitrile and water as mobile
phase and C18 bonded stationary phase columns. Preparative LC
purification was performed with a Beckman Gold HPLC system
using the same mobile phase. The radioactivity was measured in
an ion chamber, Veenstra Instrumenten bv, VDC-202. In the analy-
sis of the 11C-labelled compounds, isotopically unmodified refer-
ence substances were used for identification in all the LC runs. LC–
MS analysis was performed with a Micromass VG Quattro mass
Scheme 1. Carbonylation of a lithium amide.
The lithium amide of 1, on the other hand, gave a low
yield of the corresponding formamide under the same reac-
tion conditions. The conversion of [11C]carbon monoxide
was 2–6% at (37Ϯ3) °C and 26% at 130 °C. Thus, whereas spectrometer with electrospray ionization. THF was distilled under
Eur. J. Org. Chem. 2007, 4337–4342
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4339

O. Itsenko, E. Blom, B. Långström, T. Kihlberg
FULL PAPER
an atmosphere of nitrogen from sodium/benzophenone. Chemicals
were purchased from Sigma–Aldrich. The precursor for labelling,
N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}pyridine-2-amine
(1) was prepared as described previously.[14]
mode. Thin-layer chromatography (TLC) was performed on Merck
silica gel F-254 aluminium plates. Silica gel 60, Merck was used for
column chromatography. 1-mm precoated plates silica gel 60, F254
Merck were used for preparative TLC.
,
Preparation of 11C-Labelled Compounds 1a–i, 2a, 3a: Typical Pro-
cedures
Isotopically Unmodified Compounds 1a–e, 1g–i: The compounds
prepared from the corresponding acyl chlorides and amine 1.
Amine 1 and triethylamine were dissolved in dry dichloromethane
(10 mL). After cooling to 0 °C, a solution of the respective substi-
tuted acyl chloride was added dropwise. The reaction mixture was
stirred at room temp. under an atmosphere of nitrogen overnight
and thereafter extracted with a 10% water solution of NaCO3 and
dichloromethane. The organic phase was dried with MgSO4 and
concentrated under reduced pressure. The crude product was puri-
fied by column or preparative thin-layer chromatography.
Method A: A palladium reagent (2.5 μmol) was dissolved in THF
(200 μL) in a capped 1-mL vial. The vial was flushed with nitrogen
and shaken to dissolve the reagent. A 1-mL vial was charged with
an aryl halide (7 μmol) and THF (150 μL) the same way, and the
resulting solution was then added to the vial with the palladium
reagent. The combined solution was injected into the reactor filled
with [11C]carbon monoxide in helium by using a pressure of
35 MPa. An amine (13 μmol) was placed in a 2-mL flat-bottom LC
vial, dissolved in THF (200 μL), and then the solvent was evapo-
rated with a flow of nitrogen. The residue was redissolved in THF
(200 μL) and nBuLi (5 μL of 1.6 m in THF) was added to the solu-
tion. This vial was attached to the outlet of the reactor. The reactor
was immersed in a heating bath (75 °C) for 5 min and then dis-
charged into the vial containing the lithium amide, and the reaction
mixture was heated at 70 °C for 5 min. After the measurement of
the radioactivity the vial was purged with nitrogen to remove unre-
acted [11C]O and the radioactivity was measured again. The solvent
was then removed using a nitrogen flow. The crude product was
redissolved in acetonitrile (0.4 mL) and water (0.8 mL) and injected
into the preparative HPLC.
N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-N-pyridin-2-ylbenz-
amide[6c] (1a): A colourless oil was obtained after purification by
preparative TLC (dichloromethane/methanol, 10:1), yield: 0.108 g
(65%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.41 (ddd, J = 0.8,
2.0, 4.8 Hz, 1 H), 7.36–7.32 (m, 2 H), 7.30–7.25 (m, 2 H), 7.23–
7.17 (m, 2 H), 7.02–6.95 (m, 2 H), 6.91–6.87 (m, 2 H), 6.86–6.82
(m, 1 H), 6.76 (dm, J = 8.0 Hz, 1 H), 4.33 (t, J = 6.8 Hz, 2 H),
3.84 (s, 3 H), 2.97 (m, 4 H), 2.80 (t, J = 6.8 Hz, 2 H), 2.69 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.5, 156.3,
152.1, 148.4, 141.2, 136.9, 136.0, 130.0, 129.6, 128.6, 127.8, 122.7,
120.8, 120.7, 118.0, 111.1, 56.1, 55.2, 53.1, 50.4, 45.2 ppm. ESI-
MS: m/z = 417 [M + H]+.
Method B: A palladium reagent (2.5 μmol) was dissolved in THF
(200 μL) in a capped 1 mL LC vial. Another 1 mL vial was charged
with an aryl halide (5.0 μmol) and THF (200 μL) and the resulting
solution was then added to the vial with the palladium reagent. An
amine (10.0 μmol) was dissolved in THF (200 μL) in a 2 mL LC
vial and the THF was evaporated with a flow of nitrogen. The
residue was redissolved in THF (200 μL) and a solution of nBuLi
(4 μL of 1.6 m in THF) added to it. The resulting solution of the
lithium amide was transferred with a syringe to the vial containing
the aryl halide-palladium complex. The combined solution was in-
jected into the reactor filled with [11C]carbon monoxide in helium
using a pressure of 35 MPa. The reactor was immersed in a heating
bath (130 °C) for 5 min and then discharged into an empty vial.
After the radioactivity measurement, the vial was purged with ni-
trogen to remove unreacted [11C]O, and the radioactivity was mea-
sured again. The solvent was removed with a nitrogen flow. The
crude product was redissolved in acetonitrile (0.4 mL) and water
(0.8 mL), and then injected into the preparative HPLC.
Synthesis of 4-Phenylpiperazine-1-[carbonyl-11C]carbaldehyde (5): 1-
Phenylpiperazine (10 μL) was dissolved in THF (500 μL) in a
capped 1-mL LC vial. After flushing the vial with nitrogen, tBuLi
(36 μL of 1.7 m in THF) was added. The resulting mixture was
transferred to the reactor filled with [11C]carbon monoxide in he-
lium using the pressure of 35 MPa. The reactor was kept at 30 °C
for 5 min and then discharged into a 2-mL LC vial containing etha-
nol (200 μL). After the measurement of the radioactivity, the vial
was purged with nitrogen and the radioactivity was measured
again. The crude product was diluted with acetonitrile (0.6 mL)
and water (0.8 mL) and injected into the preparative HPLC.
4-Fluoro-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-pyridin-
2-ylbenzamide (1b):[15] A colourless oil was obtained after purifica-
tion by preparative TLC (dichloromethane/methanol, 10:1), yield:
0.069 g (42%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.42 (ddd,
J = 0.8, 1.9, 4.9 Hz, 1 H), 7.43–7.38 (m, 1 H), 7.36–7.30 (m, 2 H),
7.04–7.00 (m, 1 H), 6.99–6.94 (m, 1 H), 6.91–6.81 (m, 5 H), 6.75
(dm, J = 8.0 Hz, 1 H), 4.28 (t, J = 6.7 Hz, 2 H), 3.83 (s, 3 H), 2.92
(m, 4 H), 2.76 (t, J = 6.7 Hz, 2 H), 2.64 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 169.5, 164.7, 162.2, 156.4, 152.1,
148.6, 141.2, 137.1, 132.2, 132.1, 131.0, 130.9, 122.8, 122.7, 120.9,
120.8, 118.0, 115.1, 114.9, 111.2, 56.3, 55.3, 53.3, 50.5, 45.5 ppm.
ESI-MS: m/z = 435 [M + H]+.
4-Bromo-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-pyridin-
2-ylbenzamide (1c): A colourless oil was obtained after purification
by preparative TLC (dichloromethane/methanol, 10:1), yield:
0.120 g (71%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.40 (ddd,
J = 0.8, 2.0, 4.8 Hz, 1 H), 7.44–7.39 (m, 1 H), 7.34–7.30 (m, 2 H),
7.21–7.17 (m, 2 H), 7.05–7.00 (m, 1 H), 6.99–6.94 (m, 1 H), 6.91–
6.80 (m, 3 H), 6.76 (dm, J = 8.0 Hz, 1 H), 4.26 (t, J = 6.8 Hz, 2
H), 3.82 (s, 3 H), 2.92 (m, 4 H), 2.74 (t, J = 6.8 Hz, 2 H), 2.64 (m,
4 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.4, 156.2,
152.1, 148.6, 141.2, 137.1, 135.0, 131.1, 130.2, 124.5, 122.7, 122.6,
121.0, 120.8, 117.9, 111.1, 56.2, 55.3, 53.2, 50.5, 45.5 ppm. ESI-
MS: m/z (%) = 495 (50.5), 497 (49.5) [M + H]+.
4-Iodo-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-pyridin-2-
ylbenzamide (1d):[16] A colourless oil was obtained after purification
by preparative TLC (dichloromethane/methanol, 10:1), yield:
0.160 g (51%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.41 (ddd,
J = 0.9, 1.9, 4.9 Hz, 1 H), 7.55–7.52 (m, 2 H), 7.44–7.39 (m, 1 H),
7.07–7.01 (m, 3 H), 6.99–6.94 (m, 1 H), 6.91–6.81 (m, 3 H), 6.77
(dm, J = 8.1 Hz, 1 H), 4.27 (t, J = 6.8 Hz, 2 H), 3.83 (s, 3 H), 2.93
(m, 4 H), 2.74 (t, J = 6.8 Hz, 2 H), 2.64 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 169.5, 156.1, 152.1, 148.6, 141.2,
137.1, 137.0, 135.5, 130.2, 122.6, 122.6, 120.9, 120.8, 117.9, 111.1,
96.7, 56.2, 55.2, 53.2, 50.5, 45.5 ppm. ESI–MS: m/z = 543
[M + H]+.
Preparation of Reference Compounds: Melting points were deter-
mined with a Bibby Sterlin, Stuart Scientific Melting point appara-
tus SMP3. NMR spectra of isotopically unmodified reference com-
pounds were recorded with a Varian Unity spectrometer at
1
400 MHz for H and at 100 MHz for 13C, at 25 °C in CDCl3 (sol-
vent peak used as reference). LC–MS analyses were performed with
a Gilson HPLC and Finnigan AQA mass spectrometer, in ESI-
4340
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4337–4342

Lithium Amides in Pd-Mediated Synthesis of [Carbonyl-11C]Amides
FULL PAPER
4-Methoxy-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N- 120.8, 118.0, 111.1, 56.3, 55.3, 53.2, 50.5, 44.3, 20.0, 16.5 ppm.
pyridin-2-ylbenzamide (1e): A colourless oil was obtained after puri-
fication by preparative TLC (dichloromethane/methanol, 10:1),
yield: 0.154 g (82%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.41
(ddd, J = 0.8, 2.0, 4.9 Hz, 1 H), 7.38–7.34 (m, 1 H), 7.30–7.26 (m,
2 H), 7.00–6.92 (m, 2 H), 6.90–6.80 (m, 3 H), 6.73–6.67 (m, 3 H),
4.28 (t, J = 6.8 Hz, 2 H), 3.81 (s, 3 H), 3.72 (s, 3 H), 2.92 (m, 4 H),
2.75 (t, J = 6.8 Hz, 2 H), 2.63 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 170.0, 160.8, 156.8, 152.0, 148.3, 141.2, 136.7,
130.6, 128.1, 122.7, 122.5, 120.7, 120.3, 117.9, 113.0, 111.0, 56.3,
55.1, 55.0, 53.1, 50.4, 45.4 ppm. ESI–MS: m/z = 447 [M + H]+.
ESI–MS: m/z = 445 [M + H]+.
5-Benzoyl-5H-dibenzo[b,f]azepine (2a):[17] A solution of benzoyl
chloride in dichloromethane was added dropwise to an ice-bath
cooled solution of amine 2 and triethylamine in dichloromethane.
The reaction mixture was warmed up to room temp. and stirred
for 1 h. After the addition of water, the mixture was extracted with
dichloromethane three times. The combined organic solvent was
removed under reduced pressure and the product was purified on
silica by column chromatography (100% ethyl acetate ) to yield
0.150 g (74%) of yellow crystals. M.p. 130–131 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.39–7.32 (m, 3 H), 7.28–7.20 (m, 6
H), 7.17–7.12 (m, 4 H), 7.08–7.06 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 169.9, 135.3, 133.3, 130.0, 129.5,
129.0, 128.9, 128.4, 128.3, 128.1, 127.6, 127.2 ppm. ESI–MS: m/z
= 298 [M + H]+.
4-Acetyl-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-pyridin-
2-ylbenzamide (1f): Thionyl chloride (0.22 mL, 3.02 mmol) was
added dropwise to the solution of 4-acetylbenzoic acid (0.164 g,
1.00 mmol) in ethyl acetate (3 mL). The reaction mixture was
stirred at 77 °C under an atmosphere of nitrogen for 4 h, and the
solvent was then removed under reduced pressure to yield 4-ace-
tylbenzoyl chloride, which was used directly in the next step, follow-
ing the above procedure. A yellow oil was obtained after purifica-
tion by column chromatography (dichloromethane/methanol,
N-(4-Nitrophenyl)-N-phenylbenzamide (3a):[18] A solution of so-
dium hydride (0.006 g, 0.25 mmol) in dry DMF was added to a
solution of amine 3 (0.050 g, 0.23 mmol) in dry DMF. The reaction
mixture was stirred 15 min at room temp. under an atmosphere of
nitrogen and thereafter benzoyl chloride (0.04 mL, 0.35 mmol) was
added dropwise. The mixture was stirred at room temp. under an
atmosphere of nitrogen overnight. Workup and purification was
performed as described previously. A colourless oil was obtained
after purification by preparative TLC (100% dichloromethane),
yield: 0.024 g (33%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.19–
8.15 (m, 2 H), 7.48–7.45 (m, 2 H), 7.37–7.23 (m, 8 H), 7.13–7.09
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.7,
149.5, 144.8, 142.8, 135.1, 130.9, 129.7, 129.2, 128.1, 128.1, 127.4,
126.6, 124.4 ppm. ESI–MS: m/z = 319 [M + H]+.
1
10:1), yield: 0.037 g (50%). H NMR (400 MHz, CDCl3, 25 °C): δ
= 8.40 (ddd, J = 0.9, 2.0, 4.9 Hz, 1 H), 7.79–7.76 (m, 2 H), 7.44–
7.34 (m, 3 H), 7.05–7.01 (m, 1 H), 6.99–6.94 (m, 1 H), 6.92–6.77
(m, 4 H), 4.28 (t, J = 6.6 Hz, 2 H), 3.83 (s, 3 H), 2.93 (m, 4 H),
2.75 (t, J = 6.6 Hz, 2 H), 2.64 (m, 4 H), 2.54 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 197.3, 169.5, 155.9, 152.1,
148.7, 141.3, 140.5, 137.7, 137.2, 128.7, 127.9, 122.8, 122.6, 121.2,
120.9, 118.0, 111.2, 56.2, 55.3, 53.3, 50.6, 45.5, 26.6 ppm. ESI–MS:
m/z = 459 [M + H]+.
N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]-ethyl}-N-pyridin-2-yl-4-
(trifluoromethyl)benzamide (1g): A colourless oil was obtained after
purification by preparative TLC (dichloromethane/methanol, 10:1),
yield: 0.100 g (61%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.40
(ddd, J = 0.8, 2.0, 4.9 Hz, 1 H), 7.47–7.40 (m, 5 H), 7.03 (ddd, J
= 1.0, 4.9, 7.4 Hz, 1 H), 6.99–6.94 (m, 1 H), 6.91–6.78 (m, 4 H),
4.29 (t, J = 7.2 Hz, 2 H), 3.82 (s, 3 H), 2.94 (m, 4 H), 7.76 (t, J =
7.2 Hz, 2 H), 2.66 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 169.1, 155.9, 152.1, 148.7, 141.2, 139.7, 139.7, 137.3,
4-Phenylpiperazine-1-carbaldehyde[19] (5): A mixture of 1-phenyl-
piperazine (0.662 g, 4.1 mmol) and formamide (5 mL, 126 mmol)
was stirred at 80 °C under reduced pressure overnight. Then the
mixture was poured into water (200 mL) and extracted with dichlo-
romethane (3ϫ40 mL). The combined organic fractions were dried
with MgSO4, and the product was concentrated under reduced
pressure. Chromatographic purification (dichloromethane/meth-
anol, 10:1) yielded 5 as white crystals (0.686 g, 88%). M.p. 84–
85 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.10 (s, 1 H), 7.32–
7.27 (m, 2 H), 6.96–6.91 (m, 3 H), 3.71 (t, J = 5.3 Hz, 2 H), 3.52
(t, J = 5.3 Hz, 2 H), 3.20–3.12 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 160.6, 150.8, 129.1, 120.7, 116.9, 50.4, 49.2,
45.4, 39.8 ppm. ESI–MS: m/z = 191 [M + H]+.
2
3
131.6 (q, JC,F = 32.6 Hz), 128.8, 124.9 (q, JC,F = 3.8 Hz), 122.7,
122.6, 121.3, 120.8, 118.0, 111.1, 56.2, 55.3, 53.3, 50.5, 45.5 ppm.
ESI–MS: m/z = 485 [M + H]+.
2-Methoxy-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-
pyridin-2-ylbenzamide (1h): A colourless oil was obtained after pu-
rification by preparative TLC (dichloromethane/methanol, 10:1),
yield: 0.069 g (42%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.40
(ddd, J = 0.8, 1.9, 4.8 Hz, 1 H), 7.41–7.34 (m, 1 H), 7.28–7.24 (m,
2 H), 7.01–6.94 (m, 3 H), 6.92–6.84 (m, 4 H), 6.73 (dm, J = 8.4 Hz,
1 H), 4.29 (m, 2 H), 3.85 (s, 3 H), 3.64 (s, 3 H), 2.97 (m, 4 H), 2.75
(m, 2 H), 2.65 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 168.7, 155.5, 152.1, 147.9, 141.2, 136.4, 130.7, 129.0, 126.3,
122.7, 121.3, 121.0, 120.8, 120.6, 120.4, 118.0, 111.1, 110.7, 56.3,
55.3, 55.2, 53.2, 50.5, 44.5 ppm. ESI–MS: m/z = 447 [M + H]+.
Acknowledgments
Financial support from The Swedish Science Research Council and
the Uppsala University Amersham Fund is gratefully acknowl-
edged. This work was conducted in collaboration with Imanet, GE
Healthcare.
[1] a) K. Herholz, P. Herscovitch, W.-D. Heiss, NeuroPET: PET in
Neuroscience and Clinical Neurology, 1st ed., Springer, Berlin,
Heidelberg, 2004; b) A. D. Gee, Br. Med. Bull. 2003, 65, 169–
177.
[2] a) M. Bergström, A. Grahnén, B. Långström, Eur. J. Pharma-
col. 2003, 59, 357–366; b) C. M. Lee, L. Farde, Trends Pharma-
col. Sci. 2006, 27, 310–316.
[3] a) B. Långström, G. Bergson, Radiochem. Radioanal. Lett.
1980, 43, 47–54; b) B. Långström, U. Obenius, S. Sjöberg, G.
Bergson, J. Radioanal. Chem. 1981, 64, 279–286; c) B.
Långström, T. Kihlberg, M. Bergström, G. Antoni, M.
N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-2,3-dimethyl-N-
pyridin-2-ylbenzamide (1i): A colourless oil was obtained after puri-
fication by column chromatography (dichloromethane/methanol,
1
10:1), yield: 0.069 g (42%). H NMR (400 MHz, CDCl3, 25 °C): δ
= 8.38 (ddd, J = 0.8, 2.0, 4.8 Hz, 1 H), 7.42–7.33 (m, 1 H), 7.04–
6.81 (m, 9 H), 4.26 (m, 2 H), 3.82 (s, 3 H), 2.95 (m, 4 H), 2.68 (m,
2 H), 2.60 (m, 4 H), 2.26 (s, 3 H), 2.20 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 171.3, 152.1, 148.2, 141.3, 137.2,
136.9, 136.7, 134.7, 130.2, 128.6, 125.3, 125.1, 124.8, 122.7, 122.4,
Eur. J. Org. Chem. 2007, 4337–4342
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4341

O. Itsenko, E. Blom, B. Långström, T. Kihlberg
FULL PAPER
Björkman, B. H. Forngren, T. Forngren, P. Hartvig, K. Mark-
ides, U. Yngve, M. Ögren, Acta Chem. Scand. 1999, 53, 651–
669.
[9] a) F. Karimi, B. Långström, Org. Biomol. Chem. 2003, 3, 541–
546; b) O. Rahman, T. Kihlberg, B. Långström, J. Org. Chem.
2003, 68, 3558–3562.
[4] J. Passchier, A. Van Waarde, Eur. J. Nucl. Med. 2001, 28, 113–
[10] T. Kihlberg, B. Långström, T. Ferm, J. Eriksson, Methods and
Apparatus for Production and Use of [11C]Carbon Monoxide
in Labelling Synthesis, International patent application,
WO2006008603, 2006.
129.
[5] I. A. Cliffe, Nucl. Med. Biol. 2000, 27, 441–447.
[6] a) L. Lang, E. Jagoda, B. Schmall, B.-K. Vuong, H. R. Adams,
D. L. Nelson, R. E. Carson, W. C. Eckelman, J. Med. Chem.
1999, 42, 1576–1586; b) A. A. Wilson, A. Garcia, J. Li, J. N.
DaSilva, S. Houle, J. Labelled Compd. Radiopharm. 1999, 42,
611–620; c) Z.-P. Zhuang, M. P. Kung, H. F. Kung, J. Med.
Chem. 1994, 37, 4572–4575; d) S. Houle, J. N. DaSilva, A. A.
Wilson, Nucl. Med. Biol. 2000, 27, 463–466; e) A. A. Wilson,
T. Inaba, N. Fischer, L. M. Dixon, J. Nobrega, J. N. DaSilva,
S. Houle, Nucl. Med. Biol. 1998, 25, 769–776; f) L. Lang, E.
[11] V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585–
9595.
[12] a) V. Rautenstrauch, M. Joyeux, Angew. Chem. 1979, 91, 72–
73; b) V. Rautenstrauch, M. Joyeux, Angew. Chem. 1979, 91,
73–74; c) J. J. P. Furlong, E. S. Lewkowicz, N. S. Nudelman, J.
Chem. Soc. Perkin Trans. 2 1990, 8, 1461–1465; d) N. S. Nudel-
man, E. S. Lewkowicz, D. G. Perez, Synthesis 1990, 10, 917–
920.
Jagoda, Y. Ma, M. B. Sassaman, W. C. Eckelman, Bioorg. Med. [13] M. R. Kilbourn, P. A. Jerabek, M. J. Welch, J. Chem. Soc.
Chem. 2006, 14, 3737–3748; g) D. K. Maiti, P. K. Chakraborty,
D. C. Chugani, O. Muzik, T. J. Mangner, H. T. Chugani, Appl.
Radiat. Isot. 2005, 62, 721–727; h) M. Karramkam, F. Hinnen,
M. Berrehouma, C. Hlavacek, F. Vaufrey, C. Halldin, J. A.
McCarron, V. W. Pike, F. Dolle, Bioorg. Med. Chem. 2003, 11,
2769–2782; i) S. Marchais-Oberwinkler, B. Nowicki, V. W. Pike,
C. Halldin, J. Sandell, Y.-H. Chou, B. Gulyas, L. T. Brennum,
L. Farde, H. V. Wikstroem, Bioorg. Med. Chem. 2005, 13, 883–
893; j) N. Saigal, R. Pichika, B. Easwaramoorthy, D. Collins,
B. T. Christian, B. Shi, T. K. Narayanan, S. G. Potkin, J. Mu-
kherjee, J. Nucl. Med. 2006, 47, 1697–1706.
Chem. Commun. 1983, 16, 861–862.
[14] Z.-P. Zhuang, M. P. Kung, H. F. Kung, J. Med. Chem. 1994,
37, 1406–1407.
[15] L. Lang, E. Jagoda, B. Schmall, B.-K. Vuong, H. R. Adams,
D. L. Nelson, R. E. Carson, W. C. Eckelman, J. Med. Chem.
1999, 42, 1576–1586.
[16] Z.-P. Zhuang, M. P. Kung, H. F. Kung, J. Med. Chem. 1998,
41, 157–166.
[17] F. Karimi, B. Långström, Org. Biomol. Chem. 2003, 3, 541–
546.
[18] P. J. Sajan, D. N. Dhar, Tetrahedron 1986, 42, 5979–5983.
[19] N. Sinha, S. Jain, N. Anand, Tetrahedron Lett. 2005, 46, 153–
156.
[7] T. Kihlberg, B. Långström, J. Org. Chem. 1999, 64, 9201–9205.
[8] The library of WAY-100635 analogues was further screened to
identify metabolic stability of the individual compounds (M.
Lavén, O. Itsenko, K. Markides, B. Långström, J. Pharm. Bio-
med. Anal. 2006, 25, 40, 943–951) and their effectiveness as
tracers for imaging 5-HT1A receptor system. The results of
these studies will be published elsewhere.
Received: March 22, 2007
Published Online: July 3, 2007
4342
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4337–4342