Reaction of 11C-benzoyl chlorides with metalloid reagents: 11C-labeling of benzyl alcohols, benzaldehydes, and phenyl ketones from [11C]CO

Article abstract of DOI:10.1002/jlcr.3609

In this article, we describe the carbon-11 (¹¹C, t_1/2?=?20.4?minutes) labeling of benzyl alcohols, benzaldehydes, and ketones using an efficient 2-step synthesis in which ¹¹C-carbon monoxide is used in an initial palladium-mediated reaction to produce ¹¹C-benzoyl chloride as a key intermediate. In the second step, the obtained ¹¹C-benzoyl chloride is further treated with a metalloid reagent to furnish the final ¹¹C-labeled product. Benzyl alcohols were obtained in moderated to high non-isolated radiochemical yields (RCY, 35%–90%) with lithium aluminum hydride or lithium aluminum deuteride as metalloid reagent. Changing the metalloid reagent to either tributyltin hydride or sodium borohydride, allowed for the reliable syntheses of ¹¹C-benzaldehydes in RCYs ranging from 58% to 95%. Finally, sodium tetraphenylborate were utilized to obtain ¹¹C-phenyl ketones in high RCYs (77%–95%). The developed method provides a new and efficient route to 3 different classes of compounds starting from aryl iodides or aryl bromides.

Full text of DOI:10.1002/jlcr.3609

Reaction of 11C-benzoyl chlorides with metalloid reagents: 11C-labeling of
benzyl alcohols, benzaldehydes and phenyl ketones from [11C]CO
Sara Roslin1, Kenneth Dahl2 and Patrik Nordeman1,*
1Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala
University, Box 574, Uppsala 751 23, Sweden
2Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and
Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA 02114,
USA.
Correspondence
Patrik Nordeman, Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry,
Uppsala University, Uppsala 75123, Sweden.
E-mail: patrik.nordeman@akademiska.se
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been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/jlcr.3609
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ABSTRACT
In this article we describe the carbon-11 (11C, t1/2 = 20.4 min) labeling of benzyl alcohols,
benzaldehydes and ketones using an efficient two-step synthesis in which 11C-carbon
11
monoxide is used in an initial palladium-mediated reaction to produce C-benzoyl chloride
as a key intermediate. In the second step, the obtained 11C-benzoyl chloride is further treated
with a metalloid reagent to furnish the final 11C-labeled product. Benzyl alcohols were
obtained in moderated to high non-isolated radiochemical yields (RCY, 35-90%) with lithium
aluminium hydride or lithium aluminium deuteride as metalloid reagent. Changing the
metalloid reagent to either tributyltin hydride or sodium borohydride, allowed for the reliable
syntheses of 11C-benzaldehydes in RCYs ranging from 58-95%. Finally, sodium
11
tetraphenylborate were utilized to obtain C-phenyl ketones in high RCYs (77-95%). The
developed method provides a new and efficient route to three different classes of compounds
starting from aryl iodides or aryl bromides.
GRAPHICAL ABSTRACT
KEYWORDS
carbon-11, carbonylation, carbon monoxide, benzyl alcohols, benzaldehydes, phenyl ketones
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1. INTRODUCTION
Short-lived positron-emitting radionuclides are utilized in different molecular imaging
applications including positron emission tomography (PET). PET is a non-invasive imaging
modality in which physiological and biochemical processes can be studied in vivo following
the intravenous administration of a radiolabeled bioactive compound called radiotracer.1,2
PET is frequently being used in cardiology,3 neurology4 as well as oncology5, and more
recently has proven to be a valuable technique in drug discovery.6,7
The abundance of carbon in organic molecules makes carbon-11 (t1/2 = 20.4 min) an
appealing isotope for PET radiotracer development. Carbon-11 is obtained as either
[11C]carbon dioxide ([11C]CO2) or [11C]methane from the cyclotron, from which a number of
secondary precursors can be obtained by well-established on-line procedures.9 The secondary
precursor [11C]carbon monoxide ([11C]CO), commonly prepared via metal-mediated
reduction of in-target produced [11C]CO2, has been increasingly recognized as an 11C-synthon
11
for PET radiotracer production. Various C-labeled functional groups can be prepared from
11
11
[11C]CO, including, C-amides,12 11C-esters,13 11C-carboxylic acids14 and C-ketones15. We
11
have previously reported the preparation of C-labeled acid chlorides via a novel palladium-
mediated carbonylation of aryl iodides with [11C]CO and tetrabutylammonium chloride.16
The in situ generated 11C-benzoyl chloride derivative was then utilized to produce a series of
11C-labeled amides, esters and aldehydes in high radiochemical yields (Scheme 1, route A).
The method circumvented the need for corrosive chlorinating reagents, such as, SOCl2 or
11
phthaloyl dichloride, which previously have been used in the syntheses of C-labeled acid
chlorides via chlorination of the intermediary 11C-labeled carboxylic acid/carboxylate.17–19 In
the present study, the above described reaction is extended to include aryl bromides as
11
substrates for the initial C-acid chloride formation, as well as metalloid reagents for the
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11
subsequent reduction/nucleophilic reaction, thus enable the formation of C-labeled benzyl
alcohols, benzaldehydes and phenyl ketones (Scheme 1, route B).
<SCHEME 1>
2. EXPERIMENTAL
2.1 General information
All the precursors and references were bought from commercial vendors and used as per
received. Analytical radio-HPLC was performed using a VWR LaChrom ELITE system (L-
2450, L-2300, L-2200) with a Merck Chromolith Performance RP-18e column (4.6×100mm)
using MeCN in 0.09% aqueous TFA. A diode-array detector (L-2450) and a Bioscan Flow-
Count PMT radioactivity detector was used. Method 1: 1-20% MeCN for 7 min and then 20-
90% MeCN for 5 min (12 min total) using a flow of 2 mL/min. Method 2: 5-50% MeCN for
7 min then 50-90% MeCN for 5 min (12 min total) using a flow of 2 mL/min. Method 3: 10-
90% MeCN for 10 min, then 90% for two min (12 min total) using a flow of 2 mL/min. For
the preparative run, the crude mixture was diluted with 1 mL of a mixture of MeCN and 0.9%
aqueous TFA (1:1) and then injected on the preparative HPLC (a VWR LaPrep HPLC system
(P110, P311) with an ACE-5 HL column (10×250mm) using MeCN in 0.09% aqueous TFA
(30-90% over 10 min, then 90% for 5 min, 15 min total), UV detector (P311) and Bioscan
Flow-Count PMT radioactivity detector. The radiochemical purity (RCP) and the molar
activity (determined using a calibration curve) for the isolated product were determined by
analytical radio-HPLC.
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2.2 General procedure for the two-step reaction
[11C]CO2 was produced by 17 MeV proton bombardment of nitrogen gas (AGA, Nitrogen
14
6.0) containing 0.05% oxygen (AGA, Oxygen 4.6) through the N(p,α)11C nuclear reaction
using a Scanditronix MC-17 cyclotron and transferred to the hot cell using helium as a carrier
gas. A carbon monoxide apparatus19 was used to trap, concentrate and reduce [11C]CO2 to
[11C]CO and subsequently perform the initial carbonylative reaction. For the second reaction
step, two 0.8 mL pear shaped oven dried vials were used. In the first vial, Pd(dba)2 (2.3 mg, 4
µmol) and P(t-Bu)3HBF4 (4.7 mg, 16 µmol) was added and then capped and flushed with N2
for 1 min. 400 µL DMF was added, the vial was vortexed (10 seconds) and then heated at
120 °C (30 seconds) during which the color went from red to light brown. The Pd/ligand
mixture was added to a second capped and N2-flushed vial containing tetrabutylammonium
chloride (10 mg, 92 µmol) and the corresponding aryl halide (20 µmol). The vial was
vortexed after which the mixture was added to the carbonylation apparatus (340 µL loop) just
prior to [11C]CO2 delivery. When the reaction was finished the crude mixture was released
from the reaction chamber into a capped 2 mL vial containing the metalloid reagent (50 µL
0.2 M LAH or 30 µmol NaBH4/NaBPh4) and then heated in a heating block for 3 to 5 min.
The vial was allowed to cool for 1 min before piercing of the septa to release and determine
any loss of gaseous radioactivity. In all reactions, >99% of the radioactivity was retained in
the reaction vial after completed reaction, concluding that the [11C]CO trapping efficiency
(TE) was greater than 99% in all experiments.20 An aliquot was drawn from the crude
reaction mixture and analyzed with radio-HPLC to determine the non-isolated radiochemical
yield (RCY).
3. RESULTS AND DISCUSSION
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3.1 11C-Labeling of benzyl alcohols
The radiosynthesis of carbon-11 benzyl alcohol ([11C]2a) was selected as a test reaction for
the initial condition screening (Table 1), with iodobenzene (1a) as substrate for the initial
carbonylation reaction, as previously described,16 and lithium aluminium hydride (LAH, 0.2
M in THF) for the subsequent reduction. The reduction reaction outcome was studied in
regards to reduction agent amount, reaction time and temperature as shown in Table 1. Using
100 µL of LAH and heating the reaction to 110 °C for 5 min gave the desired compound
[11C]2a in 84% RCY (Table 1, entry 1). Similar RCYs were observed at decreased reaction
time (3 min, Table 1, entry 2), lower temperature (90 °C, Table 1, entry 3), and with a two-
fold lower LAH amount (50 µL, Table 1, entry 4). However, a further reduction of LAH
amount (20 µL) resulted in a reduced RCY (Table 1, entry 5). A slight improvement in RCY
was observed at 100 °C with 50 µL of LAH (90%, Table 1, entry 6). When the aryl halide
was changed to bromobenzene (1b) a RCY of 87% was obtained (Table 1, entry 7). In these
experiments the temperature for the initial carbonylation reaction was increased to 140 °C.
<TABLE 1>
11
The best conditions (Table 1, entry 6) were next used to synthesize a series of C-benzyl
alcohols starting from the corresponding aryl halides. The results from these experiments are
presented in Table 2. Using methyl 4-iodobenzoate (1c) as substrate a RCY of 86% of
[11C]2b was obtained (Table 2, entry 1). The short reaction time might circumvent the
reduction of the methyl ester by LAH. 4-Iodoanisole (1d) produced [11C]2c in 74% RCY
(Table 2, entry 2), while the corresponding brominated starting material 1e furnished the
same product in 80% RCY (Table 2, entry 3). The meta-substituted precursor 3-methoxy-
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iodobenzene (1f) and para-substituted 4-fluoro-iodobenzene (1g), provided their
corresponding benzyl alcohols [11C]2d and [11C]2e in comparable RCYs (76-77%, Table 2,
entries 4-5). However, only a moderated RCY (35%) of [11C]2f was obtained with 3-
bromoiodobenzene (1h) as substrate (Table 2, entry 6). The competing aryl bromide caused
the RCY to be drop as the dehalogenated product (giving the product [11C]2a) was identified
with radio-HPLC (see supporting information). An attempt to circumvent this problem by
lowering the carbonylative reaction temperature to 90 °C, resulted in a decreased RCY (24%,
Table 2, entry 7) due to an incomplete carbonylative reaction.
<TABLE 2>
Next, we utilized lithium aluminum deuteride as the reducing agent to produce dual labeled
benzyl alcohols. The incorporation of deuterium is well explored in pharmaceutical
development and discovery, where it can offer mechanistic insights for example.22 The
labeling with deuterium has also been explored in studies with 11C-labeled radiotracers,
where the incorporation of deuterium changed the pharmacokinetic properties of the
radiotracers.23,24 Three different compounds were labeled with both carbon-11 and deuterium.
The labeling of these three compounds proceeded in a similar manner as for their non-
deuterated counterparts, yielding the corresponding benzyl alcohols [11C]2g-i in high RCYs
(74-86%, Table 2, entries 8-10).
In a final experiment to label benzyl alcohols, [11C]2a was prepared on a semi-preparative
scale in order to establish the molar activity. Starting from 10 GBq of [11C]CO2, 2.2 GBq
(60% RCY) of radiochemically pure (RCP >99%) [11C]2a was obtained 29 min after end-of-
bombardment (EOB) (see supporting information for further details). The molar activity at
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end-of-synthesis (EOS) was 266 GBq/µmol. The higher molar activity obtained with the
method presented herein are in line with other 11C-carbonylations reported in the literature.25-
27
3.2 11C-Labeling of benzaldehydes
The use of aldehydes in drugs is restricted because of their reactivity. However, this
reactivity, has been exploited in development of selective inhibitors of Hepatitis C NS3
protease and serine protease plasmin.28,29 There are also examples of aldehydes as
pathophysiological biomarkers, which are formed by lipid peroxidation when cells in the
body are subjected to oxidative stress.30 Aldehydes could also be used in the preparation of
alkenes in the Wittig reaction.
In our initial report on 11C-acid chlorides, we described the synthesis of an 11C-benzaldehyde
in 49% and 55% RCY using sodium hydride or triethylsilane, respectively.16 However, the
two-step procedure allows the use of any hydride source since it is separated from the initial
carbonylation reaction. Thus, to further broaden the scope of possible hydride sources, and
more importantly, improve the RCY of the 11C-labeled benzaldehydes, tributyltin and sodium
borohydride were evaluated. Initial experiments with tributyltin hydride as the hydride source
provided the desired product [11C]3a in 37% RCY (Table 3, entry 1) with the benzyl alcohol
as the main by-product. When the reaction time was prolonged to 5 min the RCY increased
marginally (43%, Table 3, entry 2). Surprisingly, no product was formed with heating at
either 55 °C or 130 °C (55 °C was too low for the reaction to proceed and at 130 °C there
were several unidentified byproducts formed). However, by carefully adjusting the
temperature to 90 °C, the desired aldehyde [11C]3a was obtained in excellent RCY (86%,
Table 3, entry 3). Furthermore, doubling the amount of hydride source (30 µmol) returned a
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near quantitative RCY (91%, Table 3, entry 4). Bromobenzene (1b) did not perform equally
well under these conditions (RCY = 59%, Table 3, entry 5).
<TABLE 3>
One unfortunate drawback with this approach is, however, the inherent toxicity of the
organotin reagent. Hence, the less toxic hydride source, sodium borohydride, where therefore
evaluated. To our delight, with sodium borohydride as reducing reagent and heating for 3 min
at 90 °C, [11C]3a was again obtained in near quantitative RCY (91%, Table 3, entry 6). In
addition, no change in RCY was observed at longer reaction time (Table 3, entry 7). It is
11
noteworthy that almost no further reduction of the C-labeled aldehyde to the corresponding
11C-labeled benzyl alcohol [11C]2a occurred under these reaction conditions (Figure 1).
Moreover, RCY (90%, Table 3, entry 8) on a similar magnitude was observed with
bromobenzene as substrate.
<FIGUE 1>
To investigate the scope of the reaction, a set of substituted 11C-labeled aldehydes were
synthesized from different aryl iodides and bromides (Table 4). Utilizing sodium borohydride
as the hydride source, the methyl ester [11C]3b was obtained in 58% RCY from 1c (Table 4,
entry 1). High RCYs were obtained (82-84%, Table 4, entries 2-3) for the para-substituted 4-
methoxy benzaldehyde ([11C]3c) with either the corresponding iodo- and bromo-precursor
(1d, 1e), whereas the 3-methoxy substituted benzaldehyde [11C]3d, was obtained in 65%
RCY from 1f (Table 4, entry 4). The electron deficient substrates, 1i and 1j, yielded the
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desired 4-cyano substituted [11C]3e in good RCYs, 77% and 66%, respectively (Table 4,
entries 5-6). Compound [11C]3f was produced in an excellent RCY (95%, Table 1, entry 7)
starting from 4-iodotoluene (1k). In the last experiment of this set, with 4-fluoroiodobenzene
1l as precursor the desired product ([11C]3g) was obtained in 81% RCY (Table 4, entry 8).
<TABLE 4>
3.3 11C-Labeling of ketones
Ketones are a common structural element found in a wide range of bioactive natural products
as well as pharmaceuticals. Using the conditions developed for the labeling of aldehydes with
sodium borohydride, we envisioned that phenyl ketones could be labeled using a similar
strategy with the commensally available metalloid reagent, sodium tetraphenylborate. To test
this hypothesis, precursor 1a was subjected to the carbonylative reaction and subsequent
addition of sodium tetraphenylborate (30 µmol), which resulted in a RCY of 90% of [11C]4a
(Table 5, entry 1). Comparable RCY (86%, Table 5, entry 2) was also obtained when the
substrate was changed to the corresponding aryl bromide (1b) using 140 °C reaction
temperature in the carbonylative reaction.
Next, we proceeded to evaluate the 11C-labeling of different phenyl ketones with sodium
tetraphenylborate as metalloid reagent. Using the present conditions, [11C]4b was labeled in
88% RCY from 4-iodoanisole 1d (Table 5, entry 3). When the precursor was changed to the
corresponding bromine 1e, a RCY of 93% (Table 5, entry 4) was achieved. A similar RCY
was obtained when 4-fluoroiodobenzene (1g) was used substrate (95%, Table 5, entry 5). The
4-chloroiodobenzene 1l provided the labeled phenyl ketone [11C]4d in 77% RCY (Table 5,
entry 6).
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<TABLE 5>
4. CONCLUSIONS
11
In conclusion, we have described the C-radiolabeling of benzyl alcohols, benzaldehydes
and phenyl ketones using a two-step synthesis procedure. The methodology uses [11C]CO in a
11
palladium-mediated reaction to produce a C-benzoyl chloride as a key intermediate, which
11
in turn is treated with different metalloid reagents in a second step to yield the final C-
labeled product. Using lithium aluminiumhydride, sodium borohydride or sodium
tetraphenylborate, 11C-labeled benzyl alcohols, aldehydes or phenyl ketones could be
obtained, respectively. The method could be used with either aryl iodides (120 °C
carbonylative reaction temperature) or aryl bromides (140 °C carbonylative reaction
temperature) with comparable results. The two-step reaction procedure is essential for the
labeling method since these metalloid reagents obstruct the initial carbonylative process.
Using the developed method it was possible to obtain a diverse set of carbon-11 labeled
benzyl alcohols, benzaldehydes and phenyl ketones in RCYs ranging between 35-95%.
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SCHEME 1 Palladium-mediated 11C-carbonylations using organic nucleophiles (A, literature
method) and metalloid reagents (B, the work presented herein)
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11
TABLE 1 Optimization of the reaction conditions for the synthesis of C-labeled benzyl
alcohol [11C]2a
LAHa amount (µL)
RCY (%)b
Entry
PhI/Br
Temp/time (°C/min)
110 / 5
1a (X=I)
100
100
100
50
84
85
83
86
46
90
87
1
2
110 / 3
1a
90 / 3
3
1a
90 / 3
4
1a
1a
20
90 / 3
5
50
100 / 3
6
1a
7c
1b (X=Br)
50
100 / 3
b
aLithium aluminium hydride. Average of two reactions. RCY: Non-isolated radiochemical
yield determined by radio-HPLC from an aliquot of the reaction mixture. The trapping of
c
[11C]CO in the carbonylation reaction was >99% for all experiments. 140 °C carbonylation
temperature. Pd=Pd(dba)2, L=P(t-Bu)3HBF4.
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TABLE 2 Scope of 11C-labeled benzyl alcohols
RCY (%)a
Entry
PhI/Br
4-MeCOO-Ph-I (1c)
4-OMe-Ph-I (1d)
4-OMe-Ph-Br (1e)
3-OMe-Ph-I (1f)
4-F-Ph-I (1g)
3-Br-Ph-I (1h)
1h
Product
[11C]2b
[11C]2c
[11C]2c
[11C]2d
[11C]2e
[11C]2f
[11C]2f
[11C]2g
[11C]2h
[11C]2i
86
74
80
76
77
35
24
81
86
74
1
2
3b
4
5
6
7c
8
1a
9
1d
10
1g
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aAverage of two reactions. RCY: Non-isolated radiochemical yield determined by radio-
HPLC from an aliquot of the reaction mixture. The trapping of [11C]CO in the carbonylation
b
c
reaction was >99% for all experiments. 140 °C carbonylation temp. 90 °C carbonylation
temp. Pd=Pd(dba)2, L=P(t-Bu)3HBF4.
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FIGURE 1 Aliquot of reaction mixture of 1a and NaBH4 (from Table 3, entry 9). A: Radio-
chromatogram of [11C]3a (4.18 min, 90.9%) and byproduct [11C]2a (2.21 min, 1.6%) B:
Spectrum max chromatogram of reference 3a (4.13 min) with added 2a (2.16 min). See
supporting information for more information.
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TABLE 3 Optimization of the reaction conditions in the synthesis of 11C-labeled
benzaldehyde [11C]3a
RCY (%)a
Entry
PhI/Br
1a
Reagent / µmol Time / temp (°C / min)
Product
[11C]3a
[11C]3a
[11C]3a
[11C]3a
[11C]3a
[11C]3a
[11C]3a
[11C]3a
Bu3SnH / 15
Bu3SnH / 15
Bu3SnH / 15
Bu3SnH / 30
Bu3SnH / 30
NaBH4 / 30
NaBH4 / 30
NaBH4 / 30
110 / 3
110 / 5
90 / 5
90 / 5
90 / 5
90 / 3
90 / 5
90 / 3
37
43
86
91
59
91
90
90
1
2
1a
3
1a
4
1a
5b
6
1b
1a
7
1a
8b
1b
aAverage of two reactions. RCY: Non-isolated radiochemical yield determined by radio-
HPLC from an aliquot of the reaction mixture. The trapping of [11C]CO in the carbonylation
b
reaction was >99% for all experiments. 140 °C carbonylation temp. Pd=Pd(dba)2, L=P(t-
Bu)3HBF4.
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TABLE 4 Scope of 11C-labeled benzaldehydes from sodium borohydride
RCY (%)a
Entry
PhI/Br
Reagent (30 µmol)
NaBH4
Product
[11C]3b
[11C]3c
[11C]3c
[11C]3d
[11C]3e
[11C]3e
[11C]3f
[11C]3g
58
82
84
65
77
66
95
81
1
2
1c
1d
NaBH4
3b
4
NaBH4
1e
NaBH4
1f
4-CN-Ph-I (1i)
4-CN-Ph-Br (1j)
4-Me-Ph-I (1k)
4-F-Ph-I (1l)
NaBH4
5
6b
7
NaBH4
NaBH4
NaBH4
8
aAverage of two reactions. RCY: Non-isolated radiochemical yield determined by radio-
HPLC from an aliquot of the reaction mixture. The trapping of [11C]CO in the carbonylation
b
reaction was >99% for all experiments. 140 °C carbonylation temp. Pd=Pd(dba)2, L=P(t-
Bu)3HBF4.
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TABLE 5 Scope of 11C-labeled phenyl ketones from sodium tetraphenylborate
Entry
PhI/Br
Reagent (30 µmol)
NaBPh4
Product
[11C]4a
[11C]4a
[11C]4b
[11C]4b
[11C]4c
[11C]4d
RCY (%)a
90
86
88
93
95
77
1
2b
3
1a
NaBPh4
1b
NaBPh4
1d
4b
5
NaBPh4
1e
1g
NaBPh4
4-Cl-Ph-I (1l)
NaBPh4
6
aAverage of two reactions. RCY: Non-isolated radiochemical yield determined by radio-
HPLC from an aliquot of the reaction mixture. The trapping of [11C]CO in the carbonylation
b
reaction was >99% for all experiments. 140 °C carbonylation temp. Pd=Pd(dba)2, L=P(t-
Bu)3HBF4.
This article is protected by copyright. All rights reserved.