Palladium-mediated 11C-carbonylations using aryl halides and cyanamide

Article abstract of DOI:10.1039/c7ob01064h

A robust and high-yielding radiochemical synthesis of ¹¹C-N-cyanobenzamides using a palladium-mediated aminocarbonylation with ¹¹C-CO, aryl halides and cyanamide is described. The bidentate ligand 1,1′-bis(diphenylphosphino)ferrocene provided ¹¹C-N-cyanobenzamides from aryl-iodides, bromides, triflates and even chlorides in 28-79% radiochemical yield after semi-preparative HPLC. To further highlight the utility of this method, novel ¹¹C-N-cyanobenzamide analogs of flufenamic acid, meflanamic acid, dazoxiben and tamibarotene were synthesized in 34-71% radiochemical yields.

Full text of DOI:10.1039/c7ob01064h

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Takeharu Haino et al.
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Palladium-Mediated 11C-Carbonylations Using Aryl Halides and
Cyanamide
Received 00th January 20xx,
Accepted 00th January 20xx
P. Nordeman,a S. Y. Chow,b A. F. Odell,c G. Antoni,a and L. R. Odellb*
A
robust and high-yielding radiochemical synthesis of 11C-N-cyanobenzamides using
a palladium-mediated
DOI: 10.1039/x0xx00000x
aminocarbonylation with 11C-CO, aryl halides and cyanamide is described. The bidentate ligand 1,1‘-
bis(diphenylphosphino)ferrocene provided 11C-N-cyanobenzamides from aryl- iodides, bromides, triflates and even
chlorides in 28-79% radiochemical yield after semi-preparative HPLC. To futher highlight the utility of this method, novel
11C-N-cyanobenzamide analogs of flufenamic acid, meflanamic acid, dazoxiben and tamibarotene were synthesized in 34-
71% radiochemical yields.
www.rsc.org/
synthetic methods (e.g. methylation) and potential tracers are
invariably designed to conform within the narrow confines of
existing chemistry, rather being naturally guided by target
biology. To overcome these issues, there is an increasing
demand for the development of new radiochemical methods
that are suitable for the labelling of complex biologically active
molecules. The use of 11C, however, poses a number of
additional challenges as the short half-life of 11C demands the
development of fast and efficient reactions.
Bioisosteric replacement has played a vital role in drug
discovery and development since the term was first coined in
the 1950’s by Harris Friedman.14,15 The concept is based upon
the assumption that atoms or functional groups with
comparably shapes and/or physicochemical properties will
interact similarly with a biological target and elicit analogous
biological effects.15 Thus, bioisosteres have been employed to
improve potency and selectivity, alter physical properties,
modulate metabolism, increase permeability and adsorption
and reduce the toxicity of a biologically active compound.16
However, despite the widespread use of bioisosteres to
optimize these properties in drug discovery and development,
this strategy remains largely unexplored in the field of PET
tracer development.
Introduction
Positron emission tomography (PET) is a powerful noninvasive
modality for the visualization of biological functions, in real
time, using a positron emitting nuclide incorporated into a
bioactive molecule (tracer).1,2 PET is an important clinical
diagnostic tool and has found extensive use in the monitoring
of disease progression and treatment response in cancer
patients.2-4 PET has also emerged as an enabling tool to study
the underlying biological processes in many neurological
disorders and in the development of drugs targeting the CNS.5
One of the most important nuclides used in PET is the
cyclotron-produced carbon-11 (11C) with a half-life of 20.4
min.6 This is mainly due to the potential introduction of the
carbon nuclide into various positions in a molecule of interest
without disturbing its biological activity. 11C is typically
produced in the form of 11C-carbon dioxide (11CO2) and can be
readily transformed into a number of key building blocks
including 11C-carbon monoxide (11CO).7,8 The synthetic
versatility of 11CO is well-known and it can be utilized in
various metal-mediated reactions yielding a host of different
carbonyl and carboxylic acid derivatives including amides,
acids, esters and ketones.9-13
The carboxylic acid is an important functional group
capable of interacting with a biological target through both
hydrogen bonding and electrostatic interactions. Carboxylic
acids can also increase aqueous solubility and influence
pharmacokinetics and are found in a wide range of drug and
biologically active molecules. This has led to the development
of several bioisosteres for this moiety.15-20
Despite these advances, there are
a multitude of
biologically important functional groups and scaffolds that
cannot be prepared using existing 11CO technology. This
highlights one of the major limitations of PET, namely the lack
of generally applicable methods for the incorporation of the
radionuclide into a target molecule. This has created a
situation where tracer synthesis is dominated by a handful of
N-Cyanobenzamides (Scheme 1) are an interesting, yet
relatively unexplored, class of carbonyl derivatives.21,22 They
have been employed as intermediates in the synthesis of
diverse heterocyclic scaffolds and they have also found utility
as carboxylic acid bioisosteres in a number of biologically
active molecules.20,23,24 Recently, we reported the
a.Preclinical PET Platform Chemistry, Department of Medicinal Chemistry, Uppsala
University.
b.Division of Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala University, Box 574, 75123, Uppsala, Sweden.
c. School of Medicine, St. James’ University Hospital, University of Leeds, LS9 7TF,
Leeds, UK.
Electronic Supplementary Information (ESI) available: [Radiochromatograms and
NMR spectra]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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carbonylative synthesis of this functional group, under detected using this ligand. The lower RCP was due to the
View Article Online
11
DOI: 10.1039/C7OB01064H
palladium(0)catalysis, starting from an aryl halide, cyanamide formation of a highly lipophilic impurity, possibly the CO-Pd-
and carbon monoxide using a bridged two compartment Xantphos intermediate prior to nucleophilic attack by
setup.25,26 Realizing that this provided an excellent starting cyanamide.29 We continued our ligand screening by using the
point for the development of 11CO-carbonylation chemistry we less strained oxydi-2,1-phenylene)bis(diphenylphosphine)
sought to develop the first synthetic procedure for the (DPEphos), however full trapping of 11CO was not achieved in
preparation of 11C-labelled N-cyanobenzamides.6,27 This would the range 90-150 °C and no improvement in RCP was observed
make a valuable addition to the radiochemistry toolbox, (entry 5-7). To our delight, the bidentate ligand 1,1’-
opening up a new area of 11C-chemical space, that can be bis(diphenylphosphino)ferrocene (dppf) gave complete
exploited in the design and synthesis of novel PET tracers. trapping of 11CO (RTE >99%) and the desired product in high
Herein, we describe a rapid, robust and high yielding method RCP (94±2%, entry 8). This may be attributed to the flexible
for the preparation of 11C-N-cyanobenzamides via a palladium ligand backbone, allowing it to stabilize the electronically and
mediated carbonylation using an aryl halide, cyanamide and structurally disparate intermediates (i.e. Pd(0) and Pd(II))
11CO (Scheme 1).
formed during the reaction.32-34 When the temperature was
increased to 150 °C, small amounts of unknown side-products
were detected in the reaction mixture (entry 9). Using lower
temperature gave lower RTE (84%) indicating that higher
temperatures were essential for the effective conversion of
iodobenzene to the corresponding 11C-N-cyanobenzamide 11C-
2a
.
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Pd-mediated synthesis of 11C-N-cyanobenzamides and 11C-benzamides
n
1
2
3
4
5
6
7
8
Ligand
-
PPh3
Xantphos
Xantphos
DPEPhos
DPEPhos
DPEPhos
dppf
dppf
dppf
dppf
dppf
Temp (°C)
120
120
120
150
90
RTE (%)b
85
RCP (%)c
88
95
75
61
72
88
79
86
94±2d
87
86
87
93±3d
90
74
88
Results and discussion
Method development
>99
>99
85
76
82
>99
>99
84
84
96±2
93
We initiated our search for suitable reaction conditions using
iodobenzene and cyanamide as model substrates, with
bis(dibenzylidene-acetone)palladium(0) as the palladium
source. THF has previously been successfully used as a solvent
for 11C-carbonylations,28 however, the more polar DMF readily
dissolved all components and was therefore chosen for further
evaluation. The radiotrapping efficiency (RTE, defined here as
the fraction of immobilized 11CO at the end of synthesis [EOS])
was determined by removal of non-reacted 11CO by flushing
the crude reaction mixture with helium for 1 min.
120
150
120
150
90
120
140
150
170
120
9
10
11e
12e
13e
14f
15g
dppf
dppf
dppf
63
89
aReaction conditions: Ph-I (20 µmol), H2NCN (400 µmol), Pd(dba)2 (8
µmol), Ligand (monodentate 20 µmol, bidentate 10 µmol), DMF (400
µL), temp, 5 min. bThe fraction of immobilized 11CO after purging with
N2. cDetermined by analytical radio-HPLC. dAverage of three
experiments. ePh-Br was used. fPh-Cl was used. gPh-OTf was used.
The ligand-free carbonylation resulted in a RTE of 85% and
gave conversion of trapped 11CO to product (RCP) of 88%
(Table 1, entry 1) as measured by radio-HPLC. We continued by
evaluating the monodentate ligand triphenyphosphine, which
gave the desired product in the same quantity (RTE 95%, RCP
75%, entry 2). Analysis of the crude reaction mixture suggested
the presence of a side-product, which was identified as 11C-
benzoic acid by co-elution using analytical radio-HPLC. The
Encouraged by the promising result obtained with
iodobenzene, the best conditions (entry 8) were used for the
reaction of cyanamide with bromobenzene. This gave a RTE of
84% and RCP of 87%. When the temperature was increased to
140 °C, the product was formed in a high RCP of 89±3% with
almost quantitative RTE (96±2%, Table 1, entry 12). Increasing
the temperature to 150 °C again resulted in an erosion of the
yield due to the formation of unknown side-products (entry
bidentate
ligand
4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (Xantphos) has previously been successfully
in both 11CO and CO carbonylations.9,29-31 In our setup
complete consumption of 11CO (RTE >99%) was achieved with
this ligand at 120 °C and 150 °C but with lower RCP (61% and
72%, entry 3-4). Interestingly, no formation of acid was
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13). Next, we proceeded by evaluating the less reactive
chlorobenzene in the carbonylative reaction. At 170 °C the RTE
was 63% and the RCP 74% (entry 14). The pseudo-halide
phenyl triflate was reacted under similar conditions as
iodobenzene and was found to smoothly undergo
carbonylation at 120 °C with RTE of 89% and RCP of 88% (entry Table 3. Reaction Scope Using Aryl Bromidesa
15).
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DOI: 10.1039/C7OB01064H
n
Ar-X
Temp
Prod.
RTE
(%)b
96±2
63
90
91±4
94
88±1
88±3
84±1
78
RCY
(%)c
72
34
68
67
51
48
59
With a suitable carbonylative protocol in hand, we
continued by exploring the generality of the method using aryl
iodides with different electronic properties (Table 2). Here the
RTE and RCP for each reaction was determined as well as the
isolated radiochemical yield (RCY) following semi-preparative
HPLC. From iodobenzene and phenyl triflate 11C-N-cyano-
benzamide 11C-2a was isolated in 79% and 72% RCY,
respectively. Substrates bearing electron withdrawing (EWG)
and electron donating (EDG) groups in the 4-position
performed well affording the desired products in moderate to
high isolated radiochemical yield (11C-2b-f, 41-73%). A good
yield was also obtained when the methoxy group was moved
to the 3-position furnishing 64% RCY of 11C-2g. Notably, full
chemoselectivity was achieved in the reaction with 1-chloro-4-
iodidobenzene and 57% of the 4-chloro substituted product
11C-2e was obtained. Finally, the ortho-CF3 containing
11C-
2a
2a
2b
2c
4a
4b
4c
4d
4e
n
1
2
3
4
5
6
7
8
9
Ph
140
170
140
140
140
140
140
140
140
Phd
4-OMe-Ph
4-CN-Ph
2-naphthalene
2-benzofuran
2-thiophene
3-thiophene
3-pyridine
64
55
aReaction conditions: Ar-Br (20 µmol), H2NCN (400 µmol), Pd(dba)2 (8
µmol), dppf (10 µmol), DMF (400 µL), 140 or 170 °C, 5 min. Values with ±
indicate the average of three experiments. bThe fraction of immobilized
11CO after purging with N2. cAfter semi-preparative HPLC. RCP of the
isolated products were >95%. dPh-Cl.
substrates (entry 4) gave corresponding products 11C-2b and
11C-2c in similar RCY wheras 2-bromonaphthalene 3e yielded
labelled 11C-4a in 51% RCY.
substrate (entry 9) gave
a lower RCY (28%) of the
corresponding 11C-N-cyanobenzamide 11C-2h presumably due
to a combination of unfavorable steric and electronic effects.
A
number of electron-rich heterocycles were also
effectively transformed into the corresponding 11C-N-
cyanamide products. 2-Bromobenzofurane afforded 11C-N-
cyanobenzofuran-2-carboxamide (11C-4b) in 48% RCY while 2-
and 3-bromothiophene gave products 11C-4c and 11C-4d in 59%
and 64% isolated RCY, respectively. Notably, 3-bromopyridine
was transformed into 11C-N-cyanonicotinamide (11C-4e) in 55%
RCY.
Table 2. Reaction Scope Using Aryl Iodidesa
n
1
2
3
4
5
6
7
8
9
Ar-X
Ph
Prod. 11C-2n
RTE (%)b
>99
RCY (%)c
79
a
a
b
c
d
e
f
Synthesis of 11C-cyanobenzamide analogs of various bioactive
molecules
Phd
89
72
73
62
68
57
41
64
28
4-OMe-Ph
4-CN-Ph
4-C6H5-Ph
4-Cl-Ph
4-COH-Ph
3-OMe-Ph
2-CF3-Ph
95±3
92±2
94±3
85±3
72
To further exemplify our developed methodology, we
explored the labeling with 11CO of N-cyanobenzamide analogs
of a variety of bioactive molecules (Scheme 2). Firstly, we
prepared the N-cyanobenzamide derivatives of flufenamic acid
g
h
82
64
(11C- ) and mefenamic acid (11C-
6 7), two nonsteroidal anti-
inflammatory and antipyretic drugs (NSAID) used to treat
muscle and menstrual pain, respectively.35-37 This required
access to the ortho-bromoaniline precursors 5a and 5b, which
were synthesized via a palladium-catalyzed amination using
5% tris(dibenzylidene-acetone)dipalladium(0) and 12%
Xantphos as the ligand in 46% and 72% yield, respectively
(Scheme 2A).38 Despite the potentially palladium-coordinating
amino moiety in close vicinity to the bromide, the reactions
aReaction conditions: Ar-I (20 µmol), H2NCN (400 µmol), Pd(dba)2 (8 µmol), dppf
(10 µmol), DMF (400 µL), 120 °C, 5 min. Values with ± indicate the average of
three experiments. bThe fraction of immobilized 11CO after purging with N2. cAfter
semi-preparative HPLC (decay corrected from EOB). RCP of the isolated products
were >95%. dPh-OTf.
To further extend the utility of the reaction, the scope was
expanded to include aryl- and heteroaromatic bromides (Table
3). By using the protocol from entry 12 in Table 1 (i.e.
increasing the temperature to 140 °C), 11C-N-cyanobenzamide
11C-2a was synthesized in 72% RCY. Using chlorobenzene at
170 °C furnished the same product in reduced 34% RCY (entry
2). Both the electron rich (entry 3) and electron deficient
performed well at 140 °C yielding 11C- in 54±2% RCY and 11C-
6 7
in 34±4% RCY. The precursor of the thromboxane synthase
inhibitor dazoxiben was synthesized from 1-bromo-4-(2-
chloroeth-oxy)benzene (8) and imidazole in 78% yield (Scheme
2B). Using the optimized conditions for aryl bromides, the
radiolabelled 11C-10 was isolated using semi-preparative HPLC
in 71±4%.
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Scheme 2A. Precursor synthesis and radiolabeling of 11C-6 and 11C-7, analogs of flufenamic acid and mefanamic acid, respectively; 2B. Synthesis of 11C-N-cyanobenzamide analog of
dazoxiben 11C-10. 2C. Radiosynthesis of 11C-N-cyanobenzamide 11C-12 and 11C-tamibarotene (11C-13)
Finally, we synthesized compound 11 a precursor for the
labelling of tamibarotene, a synthetic retinoic acid receptor
agonist.39,40 Tamibarotene is approved in Japan for use against
Conclusions
In conclusion,
a
palladium mediated 11C-carbonylative
all-trans-retinoic acid refractive acute promyelocytic
leukemia41 and is currently being investigated for the
treatment of insulin resistence,42 vasculitis43 intracerebral
hemorrhage44 and Alzhiemer’s disease.45,46 11C-Tamibarotene
(11C-13) was prepared from the iodo-precursor 11 via an
alkoxycarbonylation using the conditions from Table 3 at 150
°C using methanol as the nucleophile (Scheme 2C). Subsequent
hydrolysis of the methyl ester intermediate using sodium
hydroxide the afforded 11C-13 in 16% RCY and a specific
activity of 205 GBq/µmol. Notably, our method gave a similar
yield with a 5-fold improvement in specific activity compared
to the oxidative alkoxylation procedure reported by Suzuki and
co-workers (44 GBq/µmol and RCY 26±13%).47 Importantly, the
methodology yielding 11C-N-cyanobenzamides from aryl
halides has been described. The substrate scope was found to
be excellent and electron rich as well as electron deficient aryl
iodides and bromides all performed well. The method was also
extended to include the carbonylation of challenging
heteroaryl bromides, phenyl triflate and even chlorobenzene.
Notably, good to high isolated radiochemical yields were
obtained ranging from 28-79% after semi-preparative HPLC.
Moreover, the developed method was exemplified by
synthesizing novel 11C-N-cyanobenzamide analogs of the
NSAID‘s flufenamic acid and mefenamic acid as well as
dazoxiben and tamibarotene in 34-71% decay corrected RCY.
This method allows rapid and robust access to new 11C-
chemical space and exploration of cyanobenzamide
bioisosteres of the ubiquitous carboxylic acid group.
corresponding
11C-N-cyanobenzamide
analogue
was
synthesized using the optimized conditions for aryl iodides
yielding 11C-12 in 55±8% RCY and a specific activity of 291
GBq/µmol after semi-preparative-HPLC. The radiochemical
purity in both syntheses was in excess of 99%. Thus, both the
11C-labelled parent molecule and its corresponding 11C-
cyanobenzamide bioisostere were efficiently prepared from a
common precursor, using similar reaction conditions, further
highlighting the utility of the method developed herein.
Experimental
General Chemical Information
Chemicals were purchased from commercial suppliers and
were used without further purification. NMR spectra were
recorded on a Varian Mercury plus spectrometer (1H at 400
MHz and 13C at 101 MHz) at ambient temperature. Chemical
shifts (δ) are reported in ppm referenced to methanol,
chloroform or DMSO. Thin-layer chromatography (TLC) was
conducted on aluminum sheets precoated with silica gel 60
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F254 (0.2 mm, Merck) and visualized by UV-light (254 nm). = 7.3 Hz, 6H), 1.30 (t, J = 7.3 Hz, 9H). 13C NMVRiew(1A0rti0cleMOnHlinze,
Flash column chromatography (FCC) was performed using MeOD) δ 179.1, 138.6 (d, J = 2.3 Hz), 1D3O1I.:610(.q10, 3J9C/-FC7=O1B0.110H64zH),
silica gel 60 (40–63 µm, Merck). Analytical UHPLC-MS was 128.8, 128.2, 126.5 (q, JC-F = 31.8 Hz), 125.8 (q, J = 5.1 Hz),
performed with an ion-trap mass spectrometer and UV-DAD 124.0 (q, J = 272.9 Hz), 119.4, 46.5, 7.8. HRMS calcd for
detection using a C18 (50×3 mm) column using a gradient of C9H5F3N2O [M+H]+ m/z 215.0432, found m/z 215.0429.
10-90 (1.5 mL/min, 2 min) and MeCN (0.05% HCOOH) in H2O
(0.05% HCOOH) as the eluent.
N-Cyanobenzofuran-2-carboxamide (4b). 1H NMR (400
MHz, MeOD) δ 7.66 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.4, 0.8 Hz,
11CO2 was created through the 14N(p,n)11C nuclear reaction 1H), 7.43-7.36 (m, 2H), 7.29-7.24 (m, 1H), 3.20 (q, J = 7.3 Hz,
at the Uppsala University Hospital by a Scandtronix MX17 6H), 1.29 (t, J = 7.3 Hz, 9H).13C NMR δ 170.8, 156.6, 153.1,
cyclotron and transferred to the hotlab where it was reduced 129.1, 127.6, 124.5, 123.4, 121.3, 112.7, 111.2, 47.9, 9.2.
over a bead of zinc (400 °C) and then used in the carbonylation HRMS calcd for C10H6N2O2 [M+H]+ m/z 187.0508, found m/z
reaction which was remotely controlled.48 Semi-preparative 187.0509.
radio-HPLC was performed using a VWR LaPrep HPLC system
N-Cyanothiophene-2-carboxamide (4c). 1H NMR (400
(P110, P311) with a Beckman CoutlerTM UltrapshereTM ODS MHz, MeOD) δ 7.64-7.61 (m, 1H), 7.53-7.50 (m, 1H), 7.15-6.91
column (10×250mm) with a gradient of 10-90 % (6 mL/min, 10 (m, 1H), 3.20 (q, J = 7.3 Hz, 6H), 1.30 (t, J = 7.3 Hz, 9H). 13C NMR
min) of MeCN in H2O. Analytical radio-HPLC was performed (100 MHz, MeOD) δ 173.9, 142.9, 131.4, 131.3, 128.5, 121.8,
using a VWR LaChrom ELITE system (L-2130, L-2200, L-2400) 47.9, 9.2. HRMS calcd for C6H4N2OS [M+H]+ m/z 153.0123,
with
a
Merck Chromolith Performance RP-18e column found m/z 153.0129.
N-Cyanonicotinamide (4e). 1H NMR (400 MHz, MeOD) δ
(4.6×100mm) and a gradient of 10-90 (method 1: 4 mL/min, 10
min. Method 2: 4 mL/min, 5 min. Method 3: 4 mL/min, 7 min) 9.14-9.07 (m, 1H), 8.62 (dd, J = 5.1, 1.7 Hz, 1H), 8.41 (ddd, J =
MeCN in H2O. Both HPLC-systems were buffered with 0.09% 8.0, 2.2, 1.7 Hz, 1H), 7.51 (ddd, J = 8.0, 5.1, 0.9 Hz, 1H), 3.22 (q,
6
TFA (for purification of 11C- , 0.1% HCOOH was used), used J = 7.3 Hz, 6H), 1.32 (t, J = 7.3 Hz, 9H). 13C NMR (100 MHz,
254 nm UV-detection and were equipped with a Bioscan Flow- MeOD) δ 176.5, 151.4, 149.9, 138.6, 134.5, 124.9, 122.1, 47.9,
Count PMT radioactivity detector. See supporting information 9.2. HRMS calcd for C7H5N3O [M+H]+ m/z 148.0511, found m/z
for further information.
Synthesis and characterization of precursors and references
148.0514.
2-Bromo-N-(3-(trifluoromethyl)phenyl)aniline (5a). 3-
(trifluoromethyl)aniline (80 mg, 0.5 mmol), 1-bromo-2-
iodobenzene (141 mg, 0.5 mmol), tris(dibenzylidene-
Compounds 2a
according to reference 24. Compounds 2f
-
e
,
4a and 4e are known and were synthesized
2g 4b 4d 10,
,
,
,
,
6
,
7
,
acetone)dipalladium(0) (23 mg,
5
mol%), 4,5-bis(di-
12 were synthesized in a peptide coupling reaction from the
corresponding carboxylic acid. The carboxylic acid (0.5 mmol),
PyBOP (260 mg, 0.5 mmol), Et3N (436 µL, 2.5 mmol),
cyanamide (32 mg, 0.75 mmol) were dissolved in 1,4-dioxane
(2 mL) and the reaction was stirred for 12 hours at ambient
temperature. The crude mixture was concentrated and
purified by FCC (Acetone/MeOH [99:1] containing 2% Et3N).
Compounds 2h and 4c were synthesized from the
corresponding acid chloride. The acid chloride (0.5 mmol),
cyanamide (32 mg, 0.75 mmol), Et3N (174 µL, 1 mmol) were
dissolved in 1,4-dioxane (2 mL) and stirred at 50 °C for 12
hours. The mixture was concentrated and purified by FCC
(Acetone/MeOH [99:1] containing 2% Et3N). This yielded 40-
70% of the corresponding N-acyl cyanamides as the Et3N-salt.
N-Cyano-4-formylbenzamide (2f). 1H NMR (400 MHz,
MeOD) δ 10.04 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.3
Hz, 2H), 3.22 (q, J = 7.3 Hz, 6H), 1.31 (t, J = 7.3 Hz, 9H). 13C NMR
(100 MHz, MeOD) δ 193.8, 178.2, 143.6, 139.6, 130.2, 130.1,
122.6, 47.9, 9.2. HRMS calcd for C9H6N2O2 [M+H]+ m/z
175.0508, found m/z 175.0509.
phenylphosphino)-9,9-dimethylxanthene (35 mg, 12 mol%),
cesium carbonate (488 mg, 1.5 mmol) was added to DMF (5
mL), capped and stirred at 60 °C for 12 hours. After cooling,
the mixture was filtered, concentrated and purified by FCC
(pentane:EtOAc [7:1] yielding 73 mg (46%) of 5
. 1H NMR δ 7.61
(ddd, J = 8.0, 1.3, 0.5 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32-7.24
(m, 2H), 7.24-7.18 (m, 2H), 7.14-7.10 (m, 1H), 6.93 (ddd, J =
8.0, 6.4, 2.5 Hz, 1H).13C NMR δ 146.0, 142.0, 134.6, 132.6 (q, JC-
= 31.8 Hz), 131.0 , 129.4, 125.7 (d, JC-F = 271.4 Hz), 124.9,
F
122.1, 121.4, 117.6 (q, JC-F = 4.0 Hz), 117.1, 114.5(q, JC-F = 4.0
Hz). HRMS calcd for C13H9NBrF3 [M+H]+ m/z 315.9949, found
m/z 315.9944.
N-(2-bromophenyl)-2,3-dimethylaniline (5b). Synthesized
as per 5a from 2,3-dimethylaniline. 1H NMR (400 MHz, CDCl3) δ
7.65 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (s, 1H), 7.28-7.21 (m, 3H),
7.17-7.15 (m, 1H), 6.87 (dd, J = 8.4, 1.5 Hz, 1H), 6.81 (ddd, J =
8.0, 7.2, 1.5 Hz, 1H), 2.49 (s, 3H), 2.32 (s, 3H). 13C NMR (101
MHz, Chloroform-d) δ 143.04, 139.38, 138.24, 132.68, 131.25,
128.15, 126.39, 126.12, 121.72, 119.56, 110.82, 20.67, 13.89.
HRMS: m/z = 276.0395 [M + H]+, calculated for C14H15NBr:
276.0388
N-Cyano-3-methoxybenzamide (2g). 1H NMR (400 MHz,
MeOD) δ 7.55-7.52 (m, 2H), 7.30-7.26 (m, 1H), 7.04-7.01 (m,
N-Cyano-2-((3-(trifluoromethyl)phenyl)amino)benzamide
(6). 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 7.9 Hz, 1H),
7.48-7.37 (m, 3H), 7.29 (d, J = 3.1 Hz, 2H), 7.19 (d, J = 7.7 Hz,
1H), 6.86-6.77 (m, 1H), 3.18 (q, J = 7.3 Hz, 6H), 1.28 (t, J = 7.3
Hz, 9H). 13C NMR (101 MHz, DMSO-d6) δ 180.6, 145.6, 144.6,
1H), 3.81 (s, 3H), 3.20 (q, J = 7.3 Hz, 6H), 1.30 (t, J = 7.3, 9H). 13
C
NMR (100 MHz, MeOD) δ 178.8, 160.9, 139.0, 130.0, 121.9,
118.4, 114.4, 55.7, 47.9, 9.2. HRMS calcd for C10H6N2O2 [M+H]+
m/z 177.0664, found m/z 177.0660.
N-Cyano-2-(trifluoromethyl)benzamide (2h). 1H NMR (400
MHz, MeOD) δ 7.71-7.68 (m, 1H), 7.64-7.52 (m, 3H), 3.21 (q, J
2
1
132.9, 132.7, 132.6 (q, JCF = 32.0 Hz), 131.2, 125.6 (q, JCF
=
271.4 Hz), 123.5 (q, 4JCF = 1.5 Hz), 123.0, 122.4, 119.8, 118.6 (q,
This journal is © The Royal Society of Chemistry 20xx
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3
3JCF = 4.0 Hz), 116.24 (d, JCF = 4.0 Hz), 116.18, 47.9, 9.2. HRMS bis(dibenzylideneacetone)-palladium(0) (2.3 mg, V8iewµAmrtioclle)Oanlninde
calcd for C15H10F3N3O [M+H]+ m/z 306.0854, found m/z 1,1‘-bis(diphenyl-phosphino)ferrocene (4.8 mg, 10 µmol)
DOI: 10.1039/C7OB01064H
306.0859.
which was then capped and flushed with argon for 2 min
N-Cyano-2-((2,3-dimethylphenyl)amino)benzamide (7). 1H before dry DMF (400 µL) was added. After a second flush with
NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 7.8, 1.6 Hz, 1H), 7.49 argon (2 min) the DMF/Pd(dba)2/dppf solution was heated at
– 7.35 (m, 3H), 7.28 – 7.18 (m, 2H), 6.26 (dd, J = 8.4, 0.9 Hz, 90 °C for 1 min, creating a homogenous solution. The mixture
1H), 2.36 (s, 3H), 1.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ was added to the first vial and subsequently added to the
167.2, 155.2, 141.4, 139.6, 135.3, 133.8, 133.0, 131.6, 127.9, injection loop (200 µL capacity) of the 11C-carbon monoxide
126.9, 126.6, 123.3, 117.9, 114.6, 20.0, 13.3. HRMS calcd for system.47 After the reaction was finished, the radioactivity was
C16H16N3O [M + H]+, 266.1293, found 266.1301.
measured. After flushing with nitrogen for 1 min, the activity
1-(2-(4-Bromophenoxy)ethyl)-1H-imidazole (9). 1H NMR was measured again yielding the RTE. An aliquot was taken for
(400 MHz, MeOD) δ 7.71 (t, J = 1.1 Hz, 1H), 7.41–7.33 (m, 2H), the determination of RCP. The crude mixture was diluted with
7.21 (t, J = 1.3 Hz, 1H), 6.97 (t, J = 1.2 Hz, 1H), 6.86–6.81 (m, 50% aqueous MeCN (total volume 500 µL) and purified by
2H), 4.40 (dd, J = 5.5, 4.5 Hz, 2H), 4.23 (dd, J = 5.5, 4.5 Hz, 2H). semi-preparative radio-HPLC. After collecting the product, RCP
13C NMR (101 MHz, MeOD) δ 159.0, 138.9, 133.4, 129.0, 121.0, was determined for the pure product. The identity was
117.6, 114.3, 68.8, 47.5. ESI-HRMS calcd for C11H12BrN2O determined by co-elution of the corresponding non-
[M+H]+ m/z 267.0133, found m/z 267.0133.
isotopically labeled N-cyanobenzamide. For the molar activity
of 11C-12 and 11C-13, a calibration curve with five points using
4-(2-(1H-Imidazol-1-yl)ethoxy)-N-cyanobenzamide (10). 1
H
NMR (400 MHz, MeOD) δ 7.91 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), the corresponding reference. The total mass and the
7.25 (s, 1H), 6.99 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.47 – 4.39 concentration of the purified product was then determined.
(m, 2H), 4.34 – 4.27 (m, 2H), 3.20 (q, J = 7.3 Hz, 6H), 1.30 (t, J = The amount of activity was calculated back to the end of
7.3 Hz, 12H). 13C NMR (101 MHz, MeOD) δ 179.4, 162.3, 138.8, synthesis to get comparable data, expressed in GBq/µmol. The
131.6, 131.1, 128.7, 123.3, 121.2, 114.7, 68.5, 47.9, 29.9, 9.3. molar activity was determined to be 291 GBq/µmol for 11C-12
ESI-HRMS calcd for C13H13N4O2 [M+H]+ m/z 257.1039, found and 205 GBq/µmol for 11C-13
.
m/z 257.1037.
4-Iodo-N-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2-yl)benzamide (11). The compound
Acknowledgements
was synthesized according to reference 49 using 4-iodobenzoic
acid. 1H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 7.91 (d, J = 8.2
Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 1.8 Hz, 2H), 7.55 (d,
J = 8.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 1.64 (s, 4H), 1.23 (d, J =
4.7 Hz, 12H). 13C NMR (101 MHz, DMSO) δ 164.5, 144.5, 140.0,
137.2, 136.4, 134.4, 129.5, 126.4, 118.3, 118.1, 99.1, 34.6,
34.6, 34.0, 33.6, 31.6, 31.6. ESI-HRMS calcd for C21H25INO
[M+H]+ m/z 434.0981, found m/z 434.0982.
N1-Cyano-N4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)terephthalamide (12). 1H NMR (400 MHz,
DMSO) δ 10.27 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6
Hz, 2H), 7.73 – 7.64 (m, 1H), 7.64 – 7.53 (m, 1H), 7.29 (d, J = 8.6
Hz, 1H), 1.65 (s, 6H), 1.24 (d, J = 5.2 Hz, 12H). 13C NMR (101
MHz, DMSO) δ 167.0, 164.2, 144.6, 140.2, 139.2, 136.3, 134.1,
128.3, 128.0, 126.5, 118.3, 118.1, 109.6, 34.6, 34.6, 34.0, 33.6,
31.7, 31.6. ESI-HRMS calcd for C23H26N3O2 [M+H]+ m/z
376.2025, found m/z 376.2037.
4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)carbamoyl)benzoic acid (13). 1H NMR (400 MHz, DMSO) δ
10.24 (s, 1H), 8.13 – 7.93 (m, 4H), 7.67 (s, 1H), 7.58 (d, J = 10.9
Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 1.64 (s, 4H), 1.24 (d, J = 5.0 Hz,
12H). 13C NMR (101 MHz, DMSO) δ 167.2, 165.0, 145.0, 140.5,
139.2, 136.8, 133.8, 129.7, 128.2, 126.9, 118.8, 118.6, 35.0,
34.4, 34.0, 32.1, 32.1. ESI-HRMS calcd for C22H26NO3 [M+H]+
m/z 352.1913, found m/z 352.1913.
The authors acknowledge support from Uppsala University and
the Carl Tryggers Stiftelse för Vetenskap Forskning (CTS13:333
and CTS14:356).
Notes and references
1
2
3
4
S. M. Ametamey, M. Honer, P. A. Schubiger, Chem. Rev.
2008, 108, 1501-1516.
M. Bergström, A. Grahnen, B. Långström, Eur. J. Clin.
Pharmacol. 2003, 59, 357-366.
J. M. Miller, D. Kumar, J. J. Mann, R. V. Parsey, Curr.
Radiopharm. 2008, 1, 12-16.
P. M. Matthews, E. A. Rabiner, J. Passchier, R. N. Gunn, Brit.
J. Clin. Pharmaco. 2012, 73, 175-186.
5
6
C. M. Lee, L. Farde, Trends Pharmacol. Sci. 2006, 27, 310-316.
B. Långström, O. Itsenko, O. Rahman, J. Labelled Compd.
Radiopharm. 2007, 50, 794-810.
7
8
P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem., Int.
Ed. 2008, 47, 8998-9033.
B. H. Rotstein, S. H. Liang, M. S. Placzek, J. M. Hooker,A. D.
Gee, F Dollé,A. A. Wilson, N. Vasdev. Chem. Soc. Rev., 2016
45, 4708-4726.
,
9
F. Karimi, B. Långström, Eur. J. Org. Chem. 2003, 11, 2132-
2137.
10 K. Dahl, M. Schou, N. Amini, C. Halldin, Eur. J. Org. Chem.
2013, 7, 1228-1231.
11 O. Rahman, J. Labelled Compd. Radiopharm. 2015, 58, 86-98.
12 T. L. Andersen, S. D. Friis, H. Audrain, P. Nordeman, G.
Antoni, T. Skrydstrup, J. Am. Chem. Soc. 2015, 137, 1548-
1555.
Radiochemistry
13 S. Kealey, A. D. Gee, P. W. Miller, J. Labelled Compd.
Radiopharm. 2014, 57, 195-201.
14 H. L. Friedman, NASNRS 1951, 206, 295-358.
15 N. Meanwell, J. Med. Chem. 2011, 54, 2529-2591.
The aryl halide (20 µmol) and cyanamide (16.8 mg, 400 µmol)
were added to an oven dried 2 mL vial, capped and flushed for
2 min with argon. To a second oven dried 2 mL vial was added
6 | J. Name., 2012, 00, 1-3
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ARTICLE
16 C. Ballatore, D. M. Huryn, A. B. Smith III, ChemMedChem 45 D. Holthoewer, K. Endres, F. Schuck, C. Hiemke, VUie.wSAcrhticmleiOttn,linFe.
2013, 8, 385-95. Fahrenholz, Neurodegener. Dis. 2011, D1O0,I:2120.41-023298/C.7OB01064H
17 T. S. Elliott, A. Slowey, Y. Ye, S. J. Conway, MedChemComm 46 H. Fukasawa, M. Nakagomi, N. Yamagata, H. Katsuki, K.
2012, 3, 735-751.
Kawahara, K. Kitaoka, T. Miki, K. Shudo, Biol. Pharm. Bull.
2012, 35, 206-1212.
18 P. Lassalas, B. Gay, C. Lasfargeas, M. J. James, V. Tran, K. G.
Vijayendran, K. G. Brunden, M. C. Kozlowski, C. J. Thomas, A. 47 M. Takashima-Hirano, H. Ishii, M. Suzuki, ACS Med. Chem.
B. Smith III, D. M. Huryn, C. Ballatore, J. Med. Chem. 2016
59, 3183-3203.
,
Lett. 2012, 3, 804-807.
48 T. Kihlberg, B. Långström, Method and Apparatus for
19 F. Allen, C. Groom, J. Liebeschuetz, D. Bardwell, T. Olsson, P.
Production and use of [11C]carbon monoxide in Labelling
Wood, J. Chem. Inf. Model. 2012, 52, 857-866.
Synthesis., PCT/SE02/01222, 2002.
20 R. Rönn, T. Gossas, Y. A. Sabnis, H. Daoud, E. Åkerblom, U. H. 49 S. D. Friis, T. L. Andersen, T. Skrydstrup, Org. Lett., 2013, 15,
Danielson, A. Sandström, Bioorg. Med. Chem. 2007, 15,
4057-4068.
1378-1381.
21 J. C. J. Howard, Org. Chem. 1964, 29, 761-762.
22 W. Mock, X. Xu, Bioorg. Chem. 1994, 22, 373-386.
23 S. Kleeb, L. Pang, K. Mayer, D. Eris, A. Sigl, R. C. Preston, P.
Zihlmann, T. Sharpe, R. P. Jakob, D. Abgottspon, A. S. Hutter,
M. Scharenberg, X. Jiang, G. Navarra, S. Rabbani, M. Smiesko,
N. Lüdin, J. Bezençon, O. Schwardt, T. Maier, B. Ernst, J. Med.
Chem. 2015, 8, 2221-2239.
24 T. Tomoo, T. Nakatsuka, T. Katayama, Y. Hayashi, Y. Fujieda,
M. Terakawa, K. Nagahira, J. Med. Chem. 2014, 57, 7244-
7262.
25 R. S. Mane, P. Nordeman, L. R. Odell, M. Larhed, Tetrahedron
Lett. 2013, 54, 6912-6915.
26 P. Nordeman, L. R. Odell, M. Larhed, J. Org. Chem. 2012, 77,
11393-11398.
27 K. Serdons, A. Verbruggen, G. M. Bormans, Methods 2009
48, 104-111.
,
28 O. Åberg, M. Stevens, J. Lindh, C. Wallinder, H. Hall, A.
Monazzam, M. Larhed, B. Långström, J. Labelled Compd.
Radiopharm. 2010, 53, 616-624.
29 J. Martinelli, D. Watson, D. Freckmann, T. Barder, S.
Buchwald, J. Org. Chem. 2008, 73, 7102-7107.
30 A. Wiꢀckowska, R. Fransson, L. R. Odell, M. Larhed, J. Org.
Chem. 2011, 76, 978-981.
31 P. W. Miller, L. E. Jennings, A. J. deMello, A. D. Gee, N. J.
Long, R. Vilar, Adv. Synth. Catal. 2009, 351, 3260-3268.
32 Y. Wan, M. Alterman, M. Larhed, A. Hallberg, J. Org. Chem.
2002, 67, 6232-6235.
33 B. Roberts, D. Liptrot, L. Alcaraz, Org. Lett. 2010, 12, 1264-
1267.
34 D. Young, S. Chien, T. Hor, Dalton Trans. 2012, 41, 12655-
12665.
35 R. Guinamard, C. Simard, C. Del Negro, Pharmacol. Ther.
2013, 138, 272-284.
36 J. J. Prusakiewicz, K. C. Duggan, C. A. Rouzer, L. J. Marnett,
Biochemistry 2009, 48, 7353-7355.
37 Y. Chi, K. Li, Q. Yan, S. Koizumi, L. Shi, S. Takahashi, Y. Zhu, H.
Matsue, M. Takeda, M. Mitamura, Pharmacol. Exp. Ther.
2011, 339, 257-266.
38 Y. Guari, D. S. van Es, J. N. H. Reek, P. C. J. Kamer, P. W. N. M.
van Leeuwen, Tetrahedron Lett. 1999, 40, 3789-3790.
39 H. Kagechika, E. Kawachi, Y. Hashimoto, K. Shudo, T. Himi, J.
Med. Chem. 1988, 31, 2182-2192.
40 C. Yuan, Y. S. Zhang, Y. N. Cheng, X. Xue, W. F. Xu, X. J. Qu,
Leuk. Lymphoma 2012, 53, 295-304.
41 T. Tobita, A. Takeshita, K. Kitamura, K. Ohnishi, M. Yanagi, A.
Hiraoka, T. Karasuno, M. Takeuchi, S. Miyawaki, R. Reda,
Blood 1997, 90, 967-973.
42 O. Yoshikawa, Y. Ebata, H. Tsuchiya, A. Kawahara, C. Kojima,
Y. Ikeda, S. Hama, K. Kogure, K. Shudo, G. Shiota, Obesity
2013, 21, E22-E25.
43 C. Miyabe, Y. Miyabe, N. N. Miura, K. Takahashi, Y.
Terashima, E. Toda, F. Honda, T. Morio, N. Yamagata, N.
Ohno, Arthritis Rheum. 2013, 65, 503-512.
44 H. Matsushita, M. Hijioka, A. Hisatsune, Y. Isohama, K.
Shudo, H. Katsuki, Blood F. Metab. 2011, 31, 222-234.
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DOI: 10.1039/C7OB01064H
A rapid, efficient and high-yielding synthesis of 11C-cyanobenzamides, including novel analogs of
various drug molecules, is described.