Low-Pressure Radical11C-Aminocarbonylation of Alkyl Iodides through Thermal Initiation

Article abstract of DOI:10.1002/ejoc.201601106

A radical¹¹C-aminocarbonylation protocol characterized by excellent substrate compatibility was developed to transform alkyl iodides into¹¹C-labelled amides, including the 11β-HSD1 inhibitor [carbonyl-¹¹C]adamantan-1-yl(piperidin-1-yl)methanone. This protocol serves as a complementary extension of palladium-mediated¹¹C-aminocarbonylation, which is limited to the preparation of¹¹C-labelled compounds lacking beta-hydrogen atoms. The use of AIBN as a radical initiator and a low-pressure xenon–[¹¹C]CO delivery unit represents a simple and convenient alternative to previous radical¹¹C-carbonylation methodologies burdened with the need for a proprietary high pressure reactor connected to a light source.

Full text of DOI:10.1002/ejoc.201601106

A Journal of
Accepted Article
Title: Low-Pressure Radical 11C-Aminocarbonylation of Alkyl Iodides via Thermal
Initiation
Authors: Shiao Y. Chow; Luke R. Odell; Jonas Eriksson
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601106
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Low-Pressure Radical 11C-Aminocarbonylation of Alkyl Iodides
via Thermal Initiation
Shiao Y. Chow[a], Luke R. Odell*[a] and Jonas Eriksson*[a]
Abstract: A radical 11C-aminocarbonylation protocol was developed
with excellent substrate compatibility to access 11C-labelled amides
from alkyl iodides, including 11β-HSD1 inhibitor [carbonyl-
11C]adamantan-1-yl(piperidin-1-yl)methanone. This protocol serves
In syntheses involving 11C-labelled precursors, small reaction
vessels are optimal to achieve high reagent concentrations and
thereby sustain fast reaction kinetics without requiring large
amounts of reagents that may increase cost and compromise
the purification process. However, the low solubility of [11C]CO in
most solvents19, coupled with degassing action and venting of
the vessel headspace by poorly soluble transfer gas (e.g.
helium) render efficient transfer of [11C]CO to small volume
reaction vessels difficult, thus hampering its use in production of
as
a
complementary extension of palladium-mediated 11C-
aminocarbonylation, which is limited to the preparation of 11C-
labelled compounds lacking beta-hydrogens. Use of AIBN as radical
initiator and a low-pressure xenon [11C]CO-delivery unit represents a
simple and convenient alternative to previous radical 11C-
carbonylation methodologies burdened with the need for
proprietary high pressure reactor connected to a light source.
a
11C-labelled compounds. To counteract this,
a
highly-
pressurized small autoclave was developed, in which efficient
use of [11C]CO in labelling synthesis was achieved.20–22
Subsequently, retention of [11C]CO in reaction mixture has been
accomplished using less technically challenging approaches,
such as chemical fixation of [11C]CO (i.e. copper complexes,23,24
BH3.THF,25 and highly reactive catalytic transition metal
complexes,26,27), ex-situ conversion28,29 of [11C]CO2 to [11C]CO,
and more advanced techniques like microfluidics.30–32 An
efficient method of confining [11C]CO at ambient pressure in
standard disposable reaction vials using xenon as transfer gas
without the need for chemical fixation agents or high reaction
pressure was reported by Eriksson and co-workers.33 The
method employed highly soluble xenon as transfer gas to bubble
[11C]CO into an organic solvent in a septum equipped vial
without significant pressure increase. Importantly, no venting
was required to complete [11C]CO transfer, hence minimizing
losses prior to the chemical transformation. The utility of this
method was exemplified by 11C-labelling of amides, ureas, and
esters at ambient pressure. Recently, two reports were
published using the same [11C]CO transfer protocol.2,34 This
robust method enables efficient use of [11C]CO in radiosynthesis
of PET tracers. Importantly, the use of disposable glass reaction
vials allows convenient reaction mixture preparation and
eliminates carry over issues associated with the high pressure
autoclave system, thus simplifying implementation into a clinical
GMP-setting.
Introduction
Positron Emission Tomography (PET) is a molecular imaging
modality with diverse use in biomedical research and clinical
diagnostics including monitoring of disease progression.1 In
recent years, a growing number of 11C-labelled compounds
derived from [11C]CO have been prepared for preclinical
imaging2–11
based
on
well-established
carbonylative
transformations, and [11C]phenytoin has advanced to clinical
studies as a P-glycoprotein PET tracer.12 In addition to its
synthetic versatility, incorporation of [11C]CO in radiotracers has
a relatively low risk of isotopical dilution due to the low
abundance of CO in air, often resulting in very high specific
activity suitable for study of low density targets (e.g. receptor
systems). Conventionally, [11C]CO is produced readily from
cyclotron supplied [11C]CO2 via metal-mediated heterogeneous
reduction using heated zinc (400 °C)13 or molybdenum
(850 °C).14 Due to the short half-life of the 11C radionuclide (T1/2
= 20.4 min)1, efficient reduction of [11C]CO2 to [11C]CO and
transfer of [11C]CO to the reaction vessel is critical to produce
useful amounts of product in the subsequent carbonylation
reaction.
Amides2,5–9,22,26,35–38 are the most common class of compounds
explored in palladium mediated 11C-carbonylation. (Scheme 1)
Other structures that have been obtained directly from [11C]CO
using palladium are aldehydes,26,39 carboxylic acids,10,26,40
esters,4,26,41,42 hydrazides40, imides43, ketones26,44, thioesters45
and ureas24. There are also a few examples of compounds
obtained from multi-step synthesis starting with 11C-
carbonylation, e.g. 11C-labelled hydroxamic acid46 from esters,
and alkyl iodides11,39 from aldehydes/carboxylic acids via olefin
carbonylation. However, palladium carbonylation is restricted to
organic halides lacking beta-hydrogen, e.g. methyl, aryl, benzyl
and alkenyl iodides.47,48 This limitation could potentially be
overcome by the recent 11C-carbonylative cross-coupling of alkyl
iodides containing beta-hydrogen and amines using air sensitive
Ni(COD)2 with bathophenanthroline as supporting ligand.49 Prior
to this development, Itsenko and co-workers employed a radical
11C-carbonylation of alkyl iodides for the preparation of alkyl
amides35, esters50,51 and carboxylic acids52 via (1) an initial
Captopril15
anti-hypertension
Lidocaine16
analgesic agent
Alkamide17
Insect repellent
Adamantyl amide18
11β-HSD1 inhibitor
Figure 1. Bioactive alkyl amides
[a] Department of Medicinal Chemistry, Division of Organic Pharmaceutical
Chemistry, Uppsala University, SE-75123 Uppsala, Sweden
E-mail: luke.odell@orgfarm.uu.se
E-mail: jonas.eriksson@orgfarm.uu.se
http://www.ilk.uu.se/research/ofk_en/
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European Journal of Organic Chemistry
10.1002/ejoc.201601106
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photochemical radical homolysis of organoiodides to generate
alkyl radicals induced by UV irradiation followed by (2)
subsequent atom transfer carbonylation. The syntheses were
performed using a highly-pressurized (35 MPa) and patent-
protected autoclave. To the best of our knowledge, no further
studies on the preparation of 11C-labelled alkyl carbonyls have
been reported. Ryu and co-workers have disclosed a metal-free
aminocarbonylation of alkyl halides using 2,2’-azobis(2-
methylpropionitrile) (AiBN) as radical initiator to generate
isotopically unmodified alkyl amides in elevated CO atmosphere
(2.0-2.5 MPa).53 In their works, radical reductive dehalogenation
of the alkyl iodides was induced via a radical chain process
using a radical initiator and (TMS)3SiH as a radical mediator.
reaction (Table 1). Cyclohexyliodide and isopropylamine were
used as model substrates using a previously reported two-
chamber vial system,56,57 and the conversion was monitored by
1H NMR. Cyclohexyl iodide, isopropylamine, AiBN, (TMS)3SiH
and triethylamine were added in chamber 1 in THF (3 mL) and
Mo(CO)6 was added to chamber 2 as the ex situ solid CO
source. The internal pressure of the reaction was measured at
0.23 MPa. The initial attempts were met with limited success, as
conversion to the desired amide was poor and formation of the
aldehyde side product derived from quenching of acyl radical by
(TMS)3SiH was observed (1H-NMR). A solvent survey (THF,
MeOH, DMF, NMP) was carried out in order to stabilize either
the alkyl radical (stabilized by non-polar solvent) or acyl radical
(solvated by polar solvent), and THF was found to provide the
best reaction selectivity without formation of the aldehyde side
product. AiBN (T1/2 = 1h at 82°C) was replaced with a more
efficient initiator 1,1’-azobis(cyclohexanecarbonitrile) (ACCN)
(T1/2 = 10h at 85°C) with a longer half-life, and a 5-fold
improvement in conversion was obtained. Increasingly the
amount of ACCN (one-step or portion-wise) was beneficial
returning slightly increased yields of 16-19%. However, the yield
was lower compared to the general results presented by Ryu et
al (different compounds), which could be explained by the
significantly lower CO partial pressure applied in the current
work (0.23 MPa vs 2-2.5 MPa).53
Table 1: Optimization of reaction parameters of radical aminocarbonylation of
cyclohexyl iodide using isotopically unmodified CO
Entry
Radical Initiator
AiBN (25 mol-%)
AiBN (25 mol-%)
AiBN (25 mol-%)
AiBN (25 mol-%)
AiBN (25 mol-%)
ACCN (25 mol-%)
ACCN (50 mol-%)
ACCN (25 + 25 mol-%)
Solvent
THF
THF
MeOH
DMF
NMP
THF
NMR yield
2.9%
-
1.3%
1.1%
1.0%
15%
Scheme 1. Aminocarbonylation of organic halides
1
2[a]
3
4
5
The resulting alkyl radicals underwent addition with CO in the
presence of amine nucleophiles to furnish alkyl amides.
Encouraged by these findings, we sought to explore the
6
applicability of
a
thermally-initiated radical reductive
7
THF
THF
16%
19%
dehalogenation approach coupled with a low-pressure [11C]CO
delivery system to prepare 11C-labelled alkyl amides, an
important class of bioactive compounds and reaction
intermediates.54,55
8[b]
Reaction condition: Chamber 1: Cyclohexyl iodide (0.3 mmol), Isopropylamine
(0.3 mmol), TEA (0.6 mmol), (TMS)3SiH (0.06 mmol), radical initiator (25-50
mol-%), solvent (3 mL). Chamber 2: Mo(CO)6 (0.6 mmol), DBU (1.8 mmol),
THF (3 mL). [a]No (TMS)3SiH added. [b]Second portion of ACCN added after 1h.
Herein, we report the development of low-pressure radical 11C-
aminocarbonylation of unactivated alkyl iodides containing beta-
hydrogens, employing an improved xenon-based [11C]CO-
delivery unit.33 The carbonylative transformation proceeds via
radical dehalogenation of alkyl iodides induced by a radical
initiator and mediator to form alkyl radicals followed by a
subsequent 11C-aminocarbonylation through atom transfer of
[11C]CO and subsequent nucleophilic attack by an amine
nucleophile to produce 11C-labelled alkyl amides.
In general, the conversion of alkyl iodide to amide using CO was
moderate. However, as [11C]CO is used at substoichiometric
amount (low nmol amounts) and serves as the limiting reactant
in 11C-carbonylation, we believed that the diminutive amount of
[11C]CO introduced would be rapidly consumed despite the low
conversion observed in initial mapping studies using CO. Thus,
we proceeded to explore an 11CO-aminocarbonylation protocol
using the model substrates. The reaction mixture (500 µL in
THF) was introduced to a 1 mL capped vial and a semi-
automated unit was used to reduce [11C]CO2 and transfer the
[11C]CO formed into the vial in xenon gas. (Figure 2) The unit
was improved and simplified compared to the previously
reported design,20 with a single valve to direct the process gases
without additional gas purification. The [11C]CO2 (1.1 µAh
irradiation) was utilized efficiently and a total of 82% (decay
corrected) of radioactivity was recovered in the reaction vial as
Results and Discussion
We initiated our studies by conducting
a
short
aminocarbonylation condition screening study with CO
(isotopically unmodified) to map out reaction parameters as a
starting point for the corresponding 11C-aminocarbonylation
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European Journal of Organic Chemistry
10.1002/ejoc.201601106
FULL PAPER
[11C]CO (3.5 GBq, non-decay corrected). The loss of activity was
primarily
due
O2
14N(p,α)11
C
11CO2
C
O
2
-
t
r
a
p
PROTON IRRIDATION ON GAS
TARGET: N2 (99.95%) + O2 (0.05%)
HELIUM
20 mL/min
e
t
i
r
CYCLOTRON
PRODUCING
a
c
s
A
17 MeV PROTONS
A
B
WASTE
WASTE
TRANSFER
NEEDLE
XENON
1.5 mL/min
CO-trap
CAPPED REACTION VIAL
WITH STIRRER BAR
HEATINGBLOCK
Figure 2. Schematic view of the process to produce and deliver [11C]CO for the 11C-aminocarbonylation. A single 12-port/2-position injection valve was used to
direct the gases during the collection of [11C]CO2, on-line reduction over zinc, concentration of [11C]CO and transfer to the reaction vial. The CO2-trap and CO-trap
which concentrated [11C]CO2 and [11C]CO contained silica gel and were cooled with liquid nitrogen to trap the radioactive gases and heated to release them. The
valve was toggled between position A and B in the following order: 1) A: [11C]CO2 transfer from the cyclotron to the CO2-trap. 2) B: On-line reduction to [11C]CO,
removal of residual [11C]CO2 on Ascarite and transfer in helium to the CO-trap. 3) A: [11C]CO transfer in xenon from the CO-trap to the reaction vial. After the
process the needle penetrating the septum of the reaction vial was removed.
to absorption of [11C]CO2 onto the zinc reductant. Typically, the
total time required for the collection of [11C]CO2 and delivery of
[11C]CO to the reaction vial was 3 min. Upon introduction of
[11C]CO, the vial was heated at 100 °C with vigorous stirring for
5 min. Unfortunately, the reaction was sluggish with poor
[11C]CO conversion and reaction selectivity, returning only a
trace amount of the 11C-labelled amide (1) (Table 2).
The reaction selectivity was improved when the solvent was
changed to NMP, however the overall [11C]CO conversion
remained unsatisfactory. We postulated that low [11C]CO
concentration in the solvent phase, due to poor solvent solubility,
may have contributed to the inadequate conversion to the 11C-
amide. This contradicts typical Pd- or Rh-mediated reactions
which performed efficiently using similar concentrations of
[11C]CO in low-pressure systems.33 The higher efficiency of
metal-mediated systems may be explained by either the
increase of [11C]CO concentration in solvent phase via reversible
coordination of [11C]CO to the metal centers, or simply by
significantly higher concentration of CO-activating organo-metal
complexes compared to the concentration of alkyl radicals
formed under the current reaction conditions. Previously
reported successful radical 11C-aminocarbonylation initiated by
UV-light irradiation did not use transition metals. However, high
pressure (35-40 MPa) was employed to transfer reagent solution
into the specialized autoclave containing [11C]CO in helium gas
(0.4 MPa) resulting in a depleted gas phase.35 This observation
led us to investigate if the ratio of gas phase versus solvent
phase could have an effect on the radiochemical yield. To this
end, we proceeded with manipulating the ratio of solvent and
gas phase in the reaction vial. The gas phase was reduced or
nearly eliminated, while the reagent concentrations was kept
unchanged (Table 2, entry 2-4; Figure 3a-b). A correlation
between increased solvent phase fraction and increased
radiochemical yields (RCY) was observed and both conversion
of [11C]CO and reaction selectivity were improved. Equations
were derived from (i) and (ii) to calculate the fraction [11C]CO
residing in the solvent phase (iii) and the relative concentrations
(iv) at the different solvent and gas phase ratios. (Figure 3a,
Table 2: Optimization of reaction parameters of radical 11C-
aminocarbonylation of cyclohexyliodide
Iodide
mM
50
50
50
AiBN
mol-%
25
25
25
25
25
25
100
25
Entry
Solvent
Vs
Conv.[a] RS[b]
RCY[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
THF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
500
500
750
950
750
750
750
750
750
350
350
350
350
6%
3.4%
3.5%
9%
10%
28%
88%
90%
69%
90%
88%
79%
92%
47%
71%
94%
98%
0.6%
1.0%
3.1%
7.5%
4.5%
17%
21%
23%
28%
4%
50
50
6.5%
19%
24%
29%
30%
9%
100
100
150
200
100
200
300
400
25
25
25
25
16%
18%
24%
11%
17%
24%
25
Reaction condition: Upon xenon-delivery of [11C]CO, the reaction was heated
at 100 °C and stirred vigorously for 5 min. [a]Percentage of [11C]CO converted
to non-volatile compounds. [b]Reaction selectivity determined from percentage
of desired amide product in the crude reaction mixture assessed by analytical
rp-HPLC. [c]Decay-corrected radiochemical yield for non-isolated product
calculated from the [11C]CO conversion and the reaction selectivity.
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European Journal of Organic Chemistry
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FULL PAPER
Table 3). The Ostwald solubility constant (L) is defined as the
and in the gas phase at equilibrium.
ratio between the concentration of gas molecules in the solvent
Figure 3. Influence of solvent phase fraction and reactant concentrations on the radiochemical yield and reaction selectivity
(a) (b) (c)
(a) The radiochemical yield improved with increased solvent phase fraction. Concentrations of non-volatile reagents were kept unchanged. The solid line
represents the theoretically calculated fraction [11C]CO residing in the solvent phase, equation (iii). (b) The radiochemical yield increased with increased
concentrations of the alkyl iodide and amine (1:1). A solvent volume of 750 µL (80.4% solvent phase) gave higher yield than 350 µL (37.5% solvent phase). (c)
The reaction selectivity increased with increased reactant concentrations at low solvent volume (350 µL).
reactants was increased (50, 100, 150, and 200 mM, entry 4, 6,
(i)
8-9) in a bid to promote [11C]CO-consumption by the alkyl
(
)
radicals.
Interestingly,
a
direct
correlation
between
( )
(ii)
radiochemical yield and the amount of reactants used was
observed (Figure 3b). The need for a higher concentration of
reactants suggests radical generation may be the rate-limiting
step, resulting in the low [11C]CO conversion in the subsequent
11C-aminocarbonylation step. Increasing the amount of AiBN (up
to 1 equiv.) however did not improve the RCY significantly due
to possible early termination of the radical chain reaction. (Entry
7) To further investigate the effect of using higher concentration
of reactants, the same amount of reactants was maintained
albeit in smaller reaction volume (350 µL) to avoid excessive use
of reactants (Entry 10-13). Similarly, the radiochemical yield
improved with higher reactant concentrations and interestingly,
increasing the reactant concentrations had a more pronounced
effect on reaction selectivity using smaller reaction volume
(Figure 3b-c).
Combining (i) and (ii) gave
Fraction [11C]CO residing in solvent phase
(iii)
(iv)
Concentration [11C]CO in solvent phase
L = Ostwald solubility constant, Cs = [11C]CO concentration in solvent phase,
Cg = [11C]CO concentration in gas phase, Vs = volume of solvent phase, Vg
=
volume of gas phase, ns = amount of [11C]CO in the solvent, n = total amount
of [11C]CO
It was concluded that the increase in radiochemical yield with
reduction of gas phase, potentially, could be explained by the
exponentially increased fraction [11C]CO residing in the solvent
phase (Figure 3a) or the corresponding increase in solvent
phase [11C]CO concentration (Table 3), calculated using
equation (iii) and (iv), respectively.
Table 3: Calculated solvent phase [11C]CO concentration, solvent phase
Table 4: Screening of reaction parameters
fraction and radiochemical yield
Reaction
Condition
300 s
Stirring
100 °C
[
11C]CO
Parameter
RS[b]
RCY[c]
conv.[a]
Entry
VS
Vg
[a]
CS
RCY
(µL)
(µL)
Standard
(Entry 12)
24%
98%
24%
-
-
2
3
4
50
883
683
433
183
23
5.4%
1.0x
1.3x
3.2x
6.3x
9.7x
ND
ND
1.0%
3.1%
7.5%
250
500
750
910
26.8%
53.6%
80.4%
97.5%
Reaction
Time
180 s
420 s
28%
32%
87%
87%
24%
28%
[a]The amount of [11C]CO was not known hence concentration of [11C]CO in the solvent (CS)
is presented as multiples calculated using equation (iv) and LCO in NMP = 0.075.58 ND = Not
Determined.
Agitation
Method
Shaking
None
27%
11%
95%
86%
26%
9%
80 °C
120 °C
24%
26%
92%
74%
22%
19%
Temperature
For practical reasons, the total solvent volume of 750 µL was
used for further optimizations focused on the influence of radical
initiator and the amine and alkyl iodide concentrations. The more
efficient ACCN was used in lieu of AiBN however no significant
improvement in the radiochemical yield was observed. Due to
the much shorter reaction time (5 min) compared to the
aminocarbonylation with isotopically unmodified CO (20 h), the
advantage of ACCN having a longer half-life was less important
and not beneficial in this case. Next, the concentration of
Reaction conditions: Cyclohexyl iodide (400 mM), isopropylamine (1 equiv),
TEA (2 equiv), AiBN (25 mol-%), (TMS)3SiH (20 mol-%), NMP (375 µL).
[a]Percentage of [11C]CO converted to non-volatile compounds. [b]Reaction
selectivity determined from percentage of desired amide product in the crude
reaction mixture assessed by analytical rp-HPLC. [c]Decay-corrected
radiochemical yield for non-isolated product calculated from the [11C]CO
conversion and the reaction selectivity.
The same reaction conditions as in Entry 13 were chosen to
probe the optimal reaction time, agitation method and reaction
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European Journal of Organic Chemistry
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temperature (Table 4). No significant difference in yields was
observed using 3, 5 or 7 min reaction times. Higher reaction
temperature was employed to increase reaction rate and
improve the solubility of [11C]CO in the solvent, however this
resulted only in decreased yield and purity due to side product
formation. Vigorous agitation of the reaction mixture was found
to be crucial, in which similar radiochemical yield was
maintained using mechanical shaker, while a drastic decrease in
yield was observed in the absence of agitation. For economical,
practical and ease of handling reasons, entry 13 remained the
optimal reaction condition.
10
28
-
1
Reaction conditions: Iodide (400 mM), nucleophile (1 equiv), TEA (2 equiv),
AiBN (25 mol-%), (TMS)3SiH (20 mol-%), and NMP (375 µL). Radiochemical
purity was >99% for all entries. [a]Percentage of [11C]CO converted to non-
volatile compounds. [b]Decay-corrected radiochemical yield for product
purified by semi preparative rp-HPLC, based on [11C]CO transferred to the
reaction vial.
Primary amines and secondary alkyl amines performed well as
substrates returning the 11C-labelled amides (1-3) in good yields,
while a slightly lower yield was observed for aniline product (4)
due to decreased nucleophilicity. The specific activity of (4) was
101±13 GBq/µmol (n=2) at end of synthesis (after purification),
the compound was obtained with 1.32±0.04 GBq and >99%
radiochemical purity. The total synthesis time was 25 min from
end of radionuclide production to isolated product.
With the optimized reaction conditions in hand, the full scope of
the radical 11C-aminocarbonylation reactions was explored with
cyclohexyl iodide and amines, including primary, secondary and
aryl amines.
Table 5. Reaction scope of radical 11C-carbonylation of alkyl iodides
The reaction scope was further explored with selected iodides.
Isopropyl iodide underwent a smooth reaction with piperidine to
afford the 11C-amide product (6). A lower yield was observed for
(5) due to the slow and challenging reductive dehalogenation of
n-butyl iodide forming instable alkyl radicals typical for primary
alkyl iodides. Interestingly, only trace amount of [11C]CO
conversion was observed in sterically hindered tert-butyl iodide
(7) while the more strained adamantyl iodide reacted efficiently
to give the desired amide (8) in 18% yield. In the former case, it
is likely that the combination of high radical stability coupled with
a slow carbonylation reaction rate59 led to poor [11C]CO-
conversion. Notably, (8) was reported as a highly potent and
selective 11β-HSD1 inhibitor18, highlighting the potential utility of
our method developed herein to produce biologically-active PET
tracers. Lastly, isopropanol and water were exploited as
nucleophiles to produce the corresponding alkyl ester (9) and
carboxylic acid (10) derivatives. The use of isopropanol returned
moderate yield and only trace amounts of product were
observed in the use of water, possibly due to lower
nucleophilicity than the corresponding amines.
Conv.[a]
(%)
Isolated
RCY[b] (%)
Entry
1
Product
n
32
25±1.4
24±1.4
2
2
32
2
3
4
36
30
24±1.4
20±0.4
2
4
5
18
9±0
2
6
7
24
2
18±0.7
2
2
-
Scheme 2: Possible mechanism of 11C-aminocarbonylation of alkyl iodides
A possible mechanism for the radical 11C-aminocarbonylation of
alkyl iodides is depicted in Scheme 2. We believe that the
radical 11C-carbonylative transformation developed herein
involves an initial radical dehalogenation of alkyl halides to form
alkyl radicals followed by aminocarbonylation in the presence of
[11C]CO and amine nucleophiles to furnish the desired alkyl
amides. In the initial radical chain reactions, the radical initiator
AiBN undergoes thermally-induced decomposition and
subsequent H-abstraction60 a of (TMS)3SiH gives (TMS)3Si·,
8
9
37
27
18±2.8
11±0.8
2
2
11β-HSD1 inhibitor
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10.1002/ejoc.201601106
FULL PAPER
(1 equiv) was added dropwise and the reaction was allowed to return to
room temperature and left stirring overnight. The reaction mixture was
filtered, washed with chilled DCM, and the solvent was removed in vacuo.
which in turn, mediates the reductive dehalogenation of the alkyl
iodide substrate. The formed alkyl radical undergoes addition to
[11C]CO to form an acyl radical,61 which could be either
quenched by the starting alkyl iodide to form an acyl iodide, or
further oxidized to furnish an acylium ion.62 In the final ionic step,
the acyl iodide or acylium ion is trapped by the amine
nucleophile to afford the desired 11C-labeled alkyl amide.
N-isopropylcyclohexanecarboxamide35 (1) (CAS 6335-52-0) Prepared
using method A. Spectral data were in agreement with literature values.
White solid (39 mg, 78%) 1H NMR (400 MHz, CDCl3): δ 5.19 (s, 1H), 4.07
(dt, J = 8.0, 6.6 Hz, 1H), 2.00 (tt, J = 11.7, 3.5 Hz, 1H), 1.89–1.72 (m, 4H),
1.74–1.52 (m, 1H), 1.48–1.35 (m, 2H), 1.31–1.18 (m, 3H), 1.13 (d, J =
6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 175.4, 45.8, 41.1, 29.9,
25.9, 23.0. EI-MS: m/z 169.2.
Conclusions
N-butylcyclohexanecarboxamide63 (2) (CAS 128037-34-3) Prepared
using method A. Spectral data were in agreement with literature values.
White solid (39 mg, 71%), Rf = 0.12 (10% EtOAc in n-pentane). 1H NMR
(400 MHz, CDCl3): δ 5.38 (s, 1H), 3.45–3.12 (m, 2H), 2.04 (tt, J = 11.8,
3.5 Hz, 1H), 1.90–1.75 (m, 4H), 1.70 – 1.62 (m, 1H), 1.52–1.15 (m, 10H),
0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.3, 45.7,
39.3, 31.9, 29.9, 25.9, 20.2, 13.9. EI-MS: m/z 183.2.
In conclusion, we have developed a low-pressure and versatile
radical 11C-aminocarbonylation protocol for the synthesis of 11C-
labeled alkyl amides. We showed herein that our 11C-
carbonylative
transformation
provides
good
substrate
accessibility and represents a simple and convenient method to
afford productive amounts of 11C-labelled amides. Furthermore,
the use of an alcohol nucleophile led to formation of the
corresponding radiolabeled ester.
N-cyclohexylcyclohexanecarboxamide64
(3)
(CAS
7474-36-4)
Prepared using method A. Spectral data were in agreement with
1
literature values. White solid (57 mg, 90%) H NMR (400 MHz, CDCl3): δ
5.25 (s, 1H), 3.87–3.34 (m, 1H), 2.01 (dd, J = 11.4, 3.1 Hz, 1H), 1.95–
1.52 (m, 12H), 1.48–1.03 (m, 8H). 13C{1H} NMR (100 MHz, CDCl3): δ
175.6, 48.2, 45.7, 33.3, 29.8, 25.9, 25.7, 25.0. EI-MS: m/z 209.1.
Experimental Section
CHEMISTRY
N-phenylcyclohexanecarboxamide65 (4) (CAS 2719-26-8) Prepared
using method A. Spectral data were in agreement with literature values.
White solid (36 mg, 59%) 1H NMR (400 MHz, CDCl3): δ 7.58–7.45 (m,
2H), 7.36–7.28 (m, 2H), 7.15–7.04 (m, 2H), 2.22 (ddt, J = 11.7, 7.1, 3.5
Hz, 1H), 1.96 (dd, J = 13.0, 3.6 Hz, 2H), 1.89–1.78 (m, 2H), 1.76–1.66 (m,
1H), 1.62–1.47 (m, 2H), 1.39–1.22 (m, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 174.2, 138.0, 128.9, 124.0, 119.6, 46.5, 29.6, 25.6. EI-MS: m/z
203.1.
General Information
All reagents were purchased at high commercial quality and used without
further purification. Yields refer to isolated, homogenous and
spectroscopically pure material, unless otherwise stated. Reaction
outcome was determined using EI-MS. Crude reaction mixtures were
purified by silica gel chromatography (E. Merck silica gel, particle size
0.043–0.063 mm). Thin layer chromatography was carried out using E.
Merck silica plates (60F-254) with UV light (254 nm) and/or iodine vapour
as the visualization agent. Blue light-emitting diodes (12 V, 2 W, λ = 465
nm) were used for irradiation of reaction mixtures. 1H NMR spectra of
reference compounds were recorded at 400 MHz and 13C{1H} NMR
spectra at 100 MHz. The chemical shifts for 1H NMR and 13C{1H} NMR
spectra were referenced to tetramethylsilane via residual solvent signals
(1H, CDCl3 at 7.26 ppm; 13C, CDCl3 at 77.16 ppm). Low resolution
GC/MS analyses were performed with a CP-SIL 8 CB low bleed (30 m ×
0.25 mm) capillary column using a 70−300 °C temperature gradient and
electron impact ionization at 70 eV. Accurate mass values were
determined on a mass spectrometer equipped with an electron-impact
ion source and TOF detector.
1-(piperidin-1-yl)pentan-1-one66 (5) (CAS 18494-52-5) Prepared using
method B. Spectral data were in agreement with literature values. 1H
NMR (400 MHz, CDCl3) δ 3.46 (s, 4H), 2.36 – 2.27 (m, 2H), 1.67 – 1.49
(m, 4H), 1.40 – 1.29 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 171.4, 45.7, 42.8, 32.9, 27.5, 27.4, 25.9, 24.4, 22.4, 13.7.
2-methyl-1-(piperidin-1-yl)propan-1-one67 (6) (CAS 17201-04-6)
Prepared using method B. Spectral data were in agreement with
literature values1H NMR (400 MHz, CDCl3) δ 3.49 (t, J = 5.5 Hz, 4H),
2.84 – 2.74 (m, 1H), 1.68 – 1.57 (m, 2H), 1.59 – 1.48 (m, 4H), 1.13 –
1.08 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 175.7, 45.1, 30.5, 26.7,
25.1, 19.9. EI-MS: m/z 155.3
Synthesis of Reference Compounds
Method A57: To the CO releasing chamber (Cco) of a H-tube was added
2,2-dimethyl-1-(piperidin-1-yl)propan-1-one68 (7) (CAS 55581-65-2)
Prepared using method A. Spectral data were in agreement with
literature values. White solid (9 mg, 17%). 1H NMR (400 MHz, CDCl3): δ
3.74–3.41 (m, 4H), 1.69–1.59 (m, 2H), 1.58–1.50 (m, 4H), 1.27 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ 176.1, 46.2, 38.7, 28.4, 26.1, 24.7. EI-
MS: m/z 169.1.
Mo(CO)6 (0.6 mmol) and MeCN (3.0 mL). The reaction chamber (Crxn
)
was charged with alkyl iodide (0.3 mmol), amine (0.6 mmol), fac-Ir(ppy)3
(2 mol-%), Hantzsch ester (0.15 mmol), tributylamine (0.6 mmol) and
MeCN (3.0 mL). The chambers were capped and subjected to a 5 minute
N2 flush, after which DBU (1.8 mmol) was added to Cco. The assembly
was placed in a Dry-Syn heating block with Cco on a heating plate at 70
ºC and Crxn outside of the heating block (Tmeasured = 25 °C). Crxn was then
subjected to visible light radiation using blue LED strips for 20 h. The
crude reaction mixture was then dry loaded with silica gel directly and
Adamantan-1-yl(piperidin-1-yl)methanone67 (8) (CAS 22508-49-2)
Prepared using method A. Spectral data were in agreement with
literature values. White solid (56 mg, 72%). 1H NMR (400 MHz, CDCl3): δ
3.81–3.41 (m, 4H), 2.04–2.01 (m, 2H), 2.01–1.97 (m, 6H), 1.75–1.68 (m,
6H), 1.66–1.59 (m, 3H), 1.57–1.46 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3): δ 175.5, 46.4, 41.7, 39.1, 36.7, 28.6, 26.3, 24.8. EI-MS: m/z
247.2.
purified
using
standard
column
chromatography
(2.5:2.5:95
EtOAc:HCOOH:Hexane).
Method B: Amine or alcohol (8.0 mmol) was dissolved in DCM (5 mL) in
the presence of triethylamine (1 equiv) and cooled to 0 °C. Acid chloride
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European Journal of Organic Chemistry
10.1002/ejoc.201601106
FULL PAPER
Isopropyl cyclohexanecarboxylate (9) (CAS 6553-80-6) Prepared
using method B. Spectral data were in agreement with literature values.
1H NMR (400 MHz, CDCl3): δ 4.98 (pd, J = 6.2, 1.0 Hz, 1H), 2.29 – 2.16
(m, 1H), 1.96 – 1.55 (m, 5H), 1.48 – 1.35 (m, 2H), 1.32 – 1.23 (m, 3H),
1.21 (s, 3H), 1.20 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 175.87,
67.16, 43.52, 29.12, 25.92, 25.58, 21.94. EI-MS: m/z 170.2
the solvent used in the reaction. The resulting solution was purged to
remove unreacted [11C]CO and potential labelled volatiles. A radioactivity
measurement (Aconverted) was carried out on the transfer vial to measure
the amount of [11C]CO converted to non-volatile products in the radical
carbonylation reaction. Purification was performed by semi-preparative
high performance liquid chromatography. Column effluent was monitored
using both UV detector (214 nm) and radiodetector. The radioactivity of
the collected fraction containing the product (AP) was then measured.
The isolated radiochemical yields were calculated based on [11C]CO
transferred to the reaction vial (A0), activity in the collected fraction (AP)
and RCP. A0 and AP were decay corrected to the same time point before
calculation:
Cyclohexanoic acid (10) (CAS 98-89-5) Commercially purchased. 1H
NMR (400 MHz, CDCl3): δ 2.33 (tt, J = 11.2, 3.6 Hz, 1H), 1.98 – 1.88 (m,
2H), 1.81 – 1.58 (m, 3H), 1.52 – 1.38 (m, 2H), 1.36 – 1.14 (m, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 182.8, 43.3, 29.2, 26.1, 25.8. EI-MS:
m/z 128.2
RADIOCHEMISTRY
The radiochemical purity (RCP), concentration and identities of the
labelled products were assessed by analytical HPLC. The identity of the
radioactive compound was determined via co-injection with an
isotopically unmodified reference compound. The concentration was
assessed by calibration curve based on reference compound solutions
with known concentrations. Specific activity (GBq/µmol) was calculated
from the activity (AP) at end of synthesis (after purification), concentration
and volume of the collected fraction.
General Information
All reagents were purchased at high commercial quality and used without
further purification. Transfer gas helium 6.0 and target gas
nitrogen/0.05% oxygen mixture for 11C-radionuclide production were
purchased from AGA (Sweden). Xenon 99.995% was purchased from
Fluka (USA). Disposable reaction vials (crimp neck, conical 0.9 mL were
purchased from VWR (Sweden) and capping septum (1.5 mm, 11 mm
aluminium crimp cap, silicone/PTFE seal) was purchased from Scantec
Nordic (Sweden). All presented radiochemical yields are decay corrected.
Purification was performed by semi-preparative high performance liquid
chromatography (VWR LaPrep) equipped with pump (LP-1200), UV
detector (Detector 40D), radiodetector (Flow-Count PMT, Bioscan), auto-
sampler (TPS, built in-house) and a column (Phenomenex Kinetex 5µm
C18 100 Å 150x10.0 mm). Eluents: A = water 0.1% TFA; B = acetonitrile;
isocratic elution; 5.0 mL/min. Product elution was monitored using both
UV detector (214 nm) and radiodetector. The radiochemical purity and
identities of the labelled products were assessed by analytical HPLC
(VWR LaChrom Elite) equipped with an auto-sampler (L-2200), pump (L-
2130), diode array detector (L-2450), radiodetector (Flow-Count PMT,
Bioscan) and a column (Chromolith Performance RP-18e, 100x4.6 mm).
Eluents: A = water; B = acetonitrile; 0-10 min 5-95% B; 4 mL/min.
Design and Function of [11C]CO Dispensing Unit
A unit for converting [11C]CO2 to [11C]CO and confining it in a reaction vial
with reagent solution was built in-house. (Figure 2) Helium (20 mL/min)
and xenon (1.5 mL/min) were used as carrier gases and the gas flow was
regulated by mass flow controllers to maintain constant flow rate. A
single 2-position/12 port injection valve (Valco 25.EDC12UWE, Vici) was
used to direct the stream of 11C-labeled gas.
1.
The valve was switched to connect the gas stream from the
cyclotron to the CO2-trap. Incoming [11C]CO2 was concentrated at
the silica gel trap (100-120 mesh, 50 mg, Alltech) submerged in
liquid nitrogen (–196 °C) in a Dewar flask maneuvered using a
pneumatic cylinder (Festo).
2.
The valve was switched to connect the helium gas stream to the
CO- and CO2-traps and the reductor column,
a quartz tube
containing zinc granules (14–50 mesh, Merck) heated at 400 °C.
The CO-trap was submerged into liquid nitrogen (–196 °C). (Note:
Cooling the CO-trap when still connected to the xenon stream was
not possible as xenon froze and clogged the CO-trap.) The release
of [11C]CO2 was induced via removal of the Dewar flask and
subsequent heating using cable heater (100 W, 062BC020AX,
Watlow). The released [11C]CO2 passed through the reductor zinc
column to form reduced [11C]CO, and subsequent passage through
a Ascarite II column (~20-30 mesh, 0.2 g, Aldrich) removed any
incidental trace of [11C]CO2. [11C]CO was concentrated at the
cooled CO-trap (–196 °C) containing anhydrous silica gel (100-120
mesh, 1 mg, Alltech).
The valve was switched to connect the CO-trap to the xenon gas
stream and the transfer needle. The transfer needle, controlled by a
pneumatic cylinder (SMC), was lowered to pierce the septum of the
reaction vial and rest in the reaction solution. A magnet was
positioned externally to avoid the needle from hitting the stirrer bar.
The release of [11C]CO was induced via removal of cooling and
application of heating using cable heater (88 W, 062BC016AX,
Watlow). The released [11C]CO was delivered to the reaction vial in
the xenon gas stream bubbled through the reaction solvent. Once
the quantitative transfer of [11C]CO was completed, the transfer
needle was removed. The high solubility of the xenon transfer gas
in organic solvents circumvented significant pressure increase and
the transferred [11C]CO remained in the vial since no vent needle
was used.
Standard Radical 11C-Aminocarbonylation Protocol
Amine (400 mM), TEA (800 mM equiv), AiBN (25 mol-%), (TMS)3SiH (20
mol-%) were added into an oven-dried 1 mL capped disposable glass vial
equipped with a magnetic stirrer bar. The mixture was dissolved in NMP
(375 µL) and purged with nitrogen for 2 min. Alkyl iodide (400 mM) was
added to the mixture 5 min prior to the introduction of [11C]CO. [11C]CO2
was obtained by the 14N(p,α)11C nuclear reaction using 17 MeV protons
(MC-17 cyclotron, Scanditronix). Typically 1 µAh irradiations were made.
[
11C]CO2 was transferred in a stream of helium to the 11CO-delivery unit
and concentrated at the CO2-trap. The [11C]CO2 was released and
transferred in helium gas (20 mL/min) through a column containing
3.
heated zinc and reduced to
[ [
11C]CO. Unreacted 11C]CO2 was
subsequently removed by a column containing Ascarite while the [11C]CO
was transferred to and concentrated at the CO-trap. The carrier gas was
changed to xenon (1.5 mL/min), and
[
11C]CO was released and
transferred to the capped reaction vial. A radioactivity measurement (A0)
was carried out to determine total amount of [11C]CO introduced (3.1 +/-
0.8 GBq). The reaction mixture was stirred vigorously in a heating block
at 100 °C with an adjacent magnetic stirrer for 5 min. A radioactivity
measurement (A1) was taken to confirm that no [11C]CO leaked from the
vial during the reaction. The crude reaction mixture was transferred by
cannula to a 1.5 mL transfer vial followed by a 2:3 acetonitrile:water
mixture (1 mL) to rinse the reaction vial. The water component was
added to improve chromatography by reducing the elution strength from
The xenon flow (1.5 ml/min) was turned on (Valco valve, Vici) when
incoming [11C]CO2 was collected at the CO2-trap, and was turned off after
[
11C]CO was delivered to the reaction vial. The transfer process took 3
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European Journal of Organic Chemistry
10.1002/ejoc.201601106
FULL PAPER
min and only minute amounts of xenon gas was consumed. The
configuration of the 12-port valve allows helium to pass through the zinc
reductor column, and xenon to pass through the needle at all times
regardless of the position of the valve. This prevents incidental oxidation
of the zinc reductant by atmospheric oxygen and the needle was purged
free from air. By design all flow paths were open at all times reducing
pressure build-up and the risk of leakages. In addition, the dispensing
unit, operated using solely carrier and transfer gas, eliminates the need
for cleaning in between use as well as clogging issues seen commonly in
the transfer of reagent solutions using small diameter tubing. The tubing
to the CO2-trap (1/16” o.d., 0.75 mm i.d.) and all other tubing (1/16” o.d.,
0.5 mm i.d.) were stainless steel except the PEEK tubing connected to
the moving transfer needle. Monitoring of radioactive gas transfer at each
step was carried out using activity detectors (pin diods) positioned at
CO2-trap, CO-trap and the reaction vial.
The authors would like to thank Carl Tryggers Foundation
(CTS13:333/14:356) and Uppsala University for their financial
support.
Keywords: Radical carbonylation • 11C • Carbon monoxide •
Xenon • Radical initiator • Reductive dehalogenation
(1)
(2)
Schubiger, P. A.; Lehmann, L.; Friebe, M.; Yang, D. J. J. Nucl. Med.
2007, 48 (10), 1750.
van der Wildt, B.; Wilhelmus, M. M. M.; Bijkerk, J.; Haveman, L. Y. F.;
Kooijman, E. J. M.; Schuit, R. C.; Bol, J. G. J. M.; Jongenelen, C. A. M.;
Lammertsma, A. A.; Drukarch, B.; Windhorst, A. D. Nucl. Med. Biol.
2016, 43 (4), 232.
(3)
Verbeek, J.; Eriksson, J.; Syvanen, S.; Labots, M.; de Lange, E. C. M.;
Voskuyl, R. A.; Mooijer, M. P. J.; Rongen, M.; Lammertsma, A. A.;
Windhorst, A. D. EJNMMI Res. 2012, 2 (1), 36.
[carbonyl-11C]N-isopropylcyclohexanecarboxamide (1)
(4)
(5)
Lu, S.; Hong, J.; Itoh, T.; Fujita, M.; Inoue, O.; Innis, R. B.; Pike, V. W. J.
Label. Compd. Radiopharm. 2010, 53 (8), 548.
Prepared following the general procedure. Run 1: Starting from 2.97 GBq,
0.34 GBq isolated 21 min post-EOB (decay-corrected RCY 24%). Run 2:
Starting from 3.44 GBq, 0.42 GBq isolated 23 min post-EOB (decay-
corrected RCY 26%). Rt = 3.13 min (Reference: 3.08 min). RCP >99%.
Hong, J.; Lu, S.; Xu, R.; Liow, J.-S.; Woock, A. E.; Jenko, K. J.;
Gladding, R. L.; Zoghbi, S. S.; Innis, R. B.; Pike, V. W. Nucl. Med. Biol.
42 (12), 967.
[carbonyl-11C]N-butylcyclohexanecarboxamide (2)
(6)
(7)
Rahman, O.; Takano, A.; Amini, N.; Dahl, K.; Kanegawa, N.; Långström,
B.; Farde, L.; Halldin, C. Nucl. Med. Biol. 2015, 42 (11), 893.
Bergman, S.; Estrada, S.; Hall, H.; Rahman, R.; Blomgren, A.; Larhed,
M.; Svedberg, M.; Thibblin, A.; Wångsell, F.; Antoni, G. J. Label.
Compd. Radiopharm. 2014, 57 (8), 525.
Prepared following the general procedure. Run 1: Starting from 3.33 GBq,
0.39 GBq isolated 21 min post-EOB (decay-corrected RCY 25%). Run 2:
Starting from 4.0 GBq, 0.53GBq isolated 18 min post-EOB (decay-
corrected RCY 25%). Rt = 3.99 min (Reference: 3.91 min). RCP >99%.
[carbonyl-11C]N-cyclohexylcyclohexanecarboxamide (3)
(8)
(9)
Nordeman, P.; Estrada, S.; Odell, L. R.; Larhed, M.; Antoni, G. Nucl.
Med. Biol. 2014, 41 (6), 536.
Prepared following the general procedure. Run 1: Starting from 2.59 GBq,
0.34 GBq isolated 18 min post-EOB (decay-corrected RCY 25%). Run 2:
Starting from 0.87 GBq, 0.11 GBq isolated 18 min post-EOB (decay-
corrected RCY 23%). Rt = 4.48 min (Reference: 4.37 min). RCP >99%.
Åberg, O.; Stevens, M.; Lindh, J.; Wallinder, C.; Hall, H.; Monazzam,
A.; Larhed, M.; Långström, B. J. Label. Compd. Radiopharm. 2010, 53
(10), 616.
[carbonyl-11C]N-phenylcyclohexanecarboxamide (4)
(10) Åberg, O.; Lindhe, Ö.; Hall, H.; Hellman, P.; Kihlberg, T.; Långström, B.
J. Label. Compd. Radiopharm. 2009, 52 (8), 295.
Prepared following the general procedure. Run 1: Starting from 4.62 GBq,
0.44 GBq isolated 22 min post-EOB (decay-corrected RCY 20%). Run 2:
Starting from 2.81 GBq, 0.28 GBq isolated 20 min post-EOB (decay-
corrected RCY 20%). Rt = 4.56 min (Reference: 4.52 min). Run 3 and 4
specific activity assessment: 101±13 GBq/µmol at end of synthesis and
1.32±0.04 GBq product. RCP >99%.
(11) Syvänen, S.; Eriksson, J.; Genchel, T.; Lindhe, Ö.; Antoni, G.;
Långström, B. BMC Med. Imaging 2007, 7:6.
(12) Mansor, S.; Boellaard, R.; Froklage, F. E.; Bakker, E. D. M.; Yaqub, M.;
Voskuyl, R. A.; Schwarte, L. A.; Verbeek, J.; Windhorst, A. D.;
Lammertsma, A. J. Nucl. Med. 2015, 56 (9), 1372.
[carbonyl-11C]1-(piperidin-1-yl)pentan-1-one (5)
(13) Welch, M. J.; Ter-Pogossian, M. M. Radiat. Res. 1968, 36 (3), 580.
(14) Zeisler, S. K.; Nader, M.; Theobald, A.; Oberdorfer, F. Appl. Radiat. Isot.
1997, 48 (8), 1091.
Prepared following the general procedure. Run 1: Starting from 2.73 GBq,
0.12 GBq isolated 18 min post-EOB (decay-corrected RCY 9%). Run 2:
Starting from 0.72 GBq, 0.034 GBq isolated 17 min post-EOB (decay-
corrected RCY 9%). Rt = 3.68 min (Reference: 3.59 min). RCP >99%.
(15) Smith, C.; Vane, J. FASEB J. 2003, 17 (8), 788.
(16) Holmdahl, M. Acta Anaesthesiol Sc Suppl 1998, 13, 8.
(17) Gaudin, J.-M.; Lander, T.; Nikolaenko, O. Chem. Biodivers. 2008, 5 (4),
617.
[carbonyl-11C]2-methyl-1-(piperidin-1-yl)-propan-1-one (6)
Prepared following the general procedure. Run 1: Starting from 2.31 GBq,
0.24 GBq isolated 17 min post-EOB (decay-corrected RCY 18%). Run 2:
Starting from 3.33 GBq, 0.30 GBq isolated 19 min post-EOB (decay-
corrected RCY 17%). Rt = 2.87 min (Reference: 2.81 min). RCP >99%.
(18) Webster, S. P.; Ward, P.; Binnie, M.; Craigie, E.; McConnell, K. M. M.;
Sooy, K.; Vinter, A.; Seckl, J. R.; Walker, B. R. Bioorg. Med. Chem. Lett.
2007, 17 (10), 2838.
[carbonyl-11C]Adamantan-1-yl(piperidin-1-yl)methanone (8)
(19) Purwanto; Deshpande, R. M.; Chaudhari, R. V.; Delmas, H. J. Chem.
Eng. Data 1996, 41 (6), 1414.
Prepared following the general procedure. Run 1: Starting from 2.38 GBq,
0.30 GBq isolated 23 min post-EOB (decay-corrected RCY 18%). Run 2:
Starting from 4.52 GBq, 0.23 GBq isolated 34 min post-EOB (decay-
corrected RCY 24%). Rt = 6.04 min (Reference: 5.96 min). RCP >99%.
(20) Kihlberg, T.; Langstrom, B.; Ferm, T.; Eriksson, J. Methods and
apparatus for production and use of [11c] carbon monoxide in labeling
synthesis; ; WO2006008603.
(21) Hostetler, E. D.; Burns, H. D. Nucl. Med. Biol. 2002, 29 (8), 845.
(22) Kihlberg, T.; Långström, B. J. Org. Chem. 1999, 64 (25), 9201.
(23) Kealey, S.; Miller, P. W.; Long, N. J.; Plisson, C.; Martarello, L.; Gee, A.
D. Chem. Commun. 2009, 25, 3696.
[carbonyl-11C]Isopropyl cyclohexanecarboxylate (9)
Prepared following the general procedure. Run 1: Starting from 4.02 GBq,
0.15 GBq isolated 25 min post-EOB (decay-corrected RCY 11%). Run 2:
Starting from 2.94 GBq, 0.17 GBq isolated 25 min post-EOB (decay-
corrected RCY 14%). Rt = 4.23 min (Reference: 4.17 min). RCP >99%.
(24) Kealey, S.; Husbands, S. M.; Bennacef, I.; Gee, A. D.; Passchier, J. J.
Label. Compd. Radiopharm. 2014, 57 (4), 202.
(25) Audrain, H.; Martarello, L.; Gee, A.; Bender, D. Chem. Commun. 2004,
5, 558.
Acknowledgements
(26) Dahl, K.; Schou, M.; Amini, N.; Halldin, C. Eur. J. Org. Chem. 2013, 7,
1228.
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European Journal of Organic Chemistry
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(27) Dahl, K.; Schou, M.; Rahman, O.; Halldin, C. Eur. J. Org. Chem. 2014,
2, 307.
(59) Litwinienko, G.; Beckwith, L.; Ingold, K. Chem. Soc. Rev. 2011, 40 (5),
2157.
(28) Nordeman, P.; Friis, S. D.; Andersen, T. L.; Audrain, H.; Larhed, M.;
Skrydstrup, T.; Antoni, G. Chem. Eur. J. 2015, 21 (49), 17601.
(29) Taddei, C.; Bongarzone, S.; Haji Dheere, A. K.; Gee, A. D. Chem.
Commun. 2015, 51 (59), 11795.
(60) Chatgilialoglu, C.; Timokhin, V. I. In Encyclopedia of Radicals in
Chemistry, Biology and Materials; John Wiley & Sons, Ltd, 2012.
(61) Sumino, S; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014,
47 (5), 1563.
(30) Miller, P. W.; Long, N. J.; de Mello, A. J.; Vilar, R.; Audrain, H.; Bender,
D.; Passchier, J.; Gee, A. Angew. Chem. Int. Ed. 2007, 46 (16), 2875.
(31) Kealey, S.; Plisson, C.; Collier, T. L.; Long, N. J.; Husbands, S. M.;
Martarello, L.; Gee, A. D. Org. Biomol. Chem. 2011, 9 (9), 3313.
(32) Dahl, K.; Schou, M.; Ulin, J.; Sjoberg, C.-O.; Farde, L.; Halldin, C. RSC
Adv 2015, 5 (108), 88886.
(62) Amos, R. I. J.; Gourlay, B. S.; Yates, B. F.; Schiesser, C. H.; Lewis, T.
W.; Smith, J. A. Org. Biomol. Chem. 2013, 11, 170.
(63) Whittaker, A. M.; Dong, V. M. Angew. Chem. Int. Ed. Engl. 2015, 54 (4),
1312.
(64) Do, H.; Bachman, S.; Bissember, A.; Peters, J.; Fu, G. J. Am. Chem.
Soc. 2014, 136 (5), 2162.
(33) Eriksson, J.; van den Hoek, J.; Windhorst, A. D. J. Label. Compd.
Radiopharm. 2012, 55 (6), 223.
(65) McCallum, T.; Barriault, L. J. Org. Chem. 2015, 80 (5), 2874.
(66) Li, W.; Wu, X. Chem. Eur. J. 2015, 21 (20), 7374.
(67) Akhrem, I. S.; Avetisyan, D. V; Afanas’eva, L.; Vitt, S. V; Petrovskii, P.
V; Orlinkov, A. Tetrahedron Lett. 2008, 49 (8), 1399.
(68) Xie, W.; Zhao, M.; Cui, C. Organometallics 2013, 32 (24), 7440.
(34) Stevens, M. Y.; Chow, S. Y.; Estrada, S.; Eriksson, J.; Apslund, J.;
Orlova, A.; Mitran, M.; Antoni, G.; Larhed, M.; Åberg, O.; Odell, L. R.
ChemOPEN. DOI: 10.1002/open.201600091.
(35) Itsenko, O.; Kihlberg, T.; Långström, B. J. Org. Chem. 2004, 69 (13),
4356.
(36) Eriksson, J.; Åberg, O.; Långström, B. Eur. J. Org. Chem. 2007, 3, 455.
(37) Åberg, O.; Långström, B. J. Label. Compd. Radiopharm. 2012, 55 (14),
477.
(38) Donohue, S. R.; Halldin, C.; Schou, M.; Hong, J.; Phebus, L.; Chernet,
E.; Hitchcock, S. A.; Gardinier, K. M.; Ruley, K. M.; Krushinski, J. H.;
Schaus, J.; Pike, V. W. J. Label. Compd. Radiopharm. 2008, 51 (3),
146.
(39) Eriksson, J.; Antoni, G.; Långström, B. J. Label. Compd. Radiopharm.
2006, 49 (12), 1105.
(40) Karimi, F.; Långstrom, B. J. Chem. Soc. Perkin Trans. 1 2002, 2111-
2115.
(41) Takashima-Hirano, M.; Ishii, H.; Suzuki, M. ACS Med. Chem. Lett. 2012,
3 (10), 804.
(42) Ishii, H.; Minegishi, K.; Nagatsu, K.; Zhang, M.-R. Tetrahedron 2015, 71
(10), 1588.
(43) Karimi, F.; Kihlberg, T.; Långstrom, B. J. Chem. Soc. Perkin Trans 1
2001, 13, 1528.
(44) Karimi, F.; Barletta, J.; Långstrom, B. Eur. J. Org. Chem. 2005, 11,
2374.
(45) Dahl, K.; Itsenko, O.; Rahman, O.; Ulin, J.; Sjoberg, C.-O.; Sandblom,
P.; Larsson, L.; Schou, M.; Halldin, C. J. Label. Compd. Radiopharm.
2015, 58 (5), 220.
(46) Lu, S.; Zhang, Y.; Kalin, J. H.; Cai, L.; Kozikowski, A. P.; Pike, V. W. J.
Label. Compd. Radiopharm. 2016, 59 (1), 9.
(47) Wu, L.; Fang, X.; Liu, Q.; Jackstell, R.; Beller, M.; Wu, X. F. ACS Catal.
2014, 4, 2977.
(48) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2015, 137, 4924.
(49) Rahman, O.; Långström, B.; Halldin, C. ChemistrySelect 2016, 1 (10),
2498.
(50) Itsenko, O.; Långström, B. Org. Lett. 2005, 7 (21), 4661.
(51) Itsenko, O.; Kihlberg, T.; Långström, B. Eur. J. Org. Chem. 2005, 17,
3830.
(52) Itsenko, O.; Kihlberg, T.; Långstrom, B. Nat Protoc. 2006, 1 (2), 798.
(53) Ryu, I.; Nagahara, K.; Kambe, N.; Sonoda, N.; Kreimerman, S.;
Komatsu, M. Chem. Commun. 1998, 18, 1953.
(54) Montalbetti, C.; Facque, V. Tetrahedron 61, 10827.
(55) Greenberg, A.; Breneman, C.; Liebman, J. The Amide Linkage:
Structural Significance in Chemistry, Biochemistry, and Material
Science; Wiley-interscience, 2003.
(56) Chow, S. Y.; Stevens, M. Y.; Odell, L. R. J. Org. Chem. 2016, 81 (7),
2681.
(57) Chow, S. Y.; Stevens, M. Y.; Åkerbladh, L.; Bergman, S.; Odell, L. R.
Chem. Eur. J. 2016, 22 (27), 9155.
(58) Burr, B.; Lyddon, L. 87th Annu. Conv. Gas Process. Assoc. 2008, 1,
100.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601106
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Radical Carbonylation
Shiao Y. Chow, Luke R. Odell*, Jonas
Eriksson*
Page 1 – Page 10
11
Low-pressure, radical 11C-aminocarbonylation, alkyl amides
Low-Pressure Radical C-
Aminocarbonylation of Alkyl
Iodides via Thermal Initiation
TOC text
A practical and efficient protocol for the preparation of 11C-labelled alkyl amides using a low-pressure
xenon system is presented. This methodology, based on thermally initiated radical carbonylation,
provides a valuable complement to the transition metal mediated reaction manifold as it allows the use
of non-activated β-hydride containing substrates.
This article is protected by copyright. All rights reserved