Copper(II)-Mediated [11C]Cyanation of Arylboronic Acids and Arylstannanes

Article abstract of DOI:10.1021/acs.orglett.8b00242

A copper-mediated method for the transformation of diverse arylboron compounds and arylstannanes to aryl-[¹¹C]-nitriles is reported. This method is operationally simple, uses commercially available reagents, and is compatible with a wide variety of substituted aryl- and heteroaryl substrates. This method is applied to the automated synthesis of high specific activity [¹¹C]perampanel in 10% nondecay-corrected radiochemical yield (RCY).

Full text of DOI:10.1021/acs.orglett.8b00242

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(II)-Mediated [11C]Cyanation of Arylboronic Acids and
Arylstannanes
Katarina J. Makaravage,† Xia Shao,‡ Allen F. Brooks,‡ Lingyun Yang,‡,# Melanie S. Sanford,*,†
and Peter J. H. Scott*,‡
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡Department of Radiology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, Michigan 48109, United States
#Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P.R.
China
S
* Supporting Information
ABSTRACT: A copper-mediated method for the trans-
formation of diverse arylboron compounds and arylstannanes
to aryl-[11C]-nitriles is reported. This method is operationally
simple, uses commercially available reagents, and is compatible
with a wide variety of substituted aryl- and heteroaryl
substrates. This method is applied to the automated synthesis
of high specific activity [11C]perampanel in 10% nondecay-
corrected radiochemical yield (RCY).
arbon-11 is a radioisotope that is commonly used for
positron emission tomography (PET) imaging.1 The
introduction of carbon-11 into PET radiotracers is particularly
challenging due to its very short half-life (t1/2 = 20 min).2 A
number of methods have been developed for [11C]-radio-
labeling, and some of the most attractive involve the late-stage
introduction of a [11C]CN substituent (Scheme 1).3 [11C]-
particularly in the context of automated radiochemical
synthesis.10
C
A second [11C]radiocyanation method involves the reaction
of aryl halides with [11C]CuCN (i.e., the Rosenmund−von
Braun reaction).11−13 This transformation offers the advantages
of operational simplicity (i.e., no phosphine ligands, no
requirement to preform organometallic intermediates, no
need to remove palladium) and the relatively low toxicity of
Cu.9 However, it suffers from low yields, modest scope, and
forcing reaction conditions (often requiring temperatures of
150−250 °C).2 We sought to develop an alternative Cu-
mediated [11C]radiocyanation that would leverage the advan-
tages while addressing the limitations of the existing Cu
method. Our laboratory has recently reported that arylboron
compounds and arylstannanes undergo Cu-mediated [18F]-
radiofluorination with [18F]KF.14−17 We hypothesized that
changing the nucleophile from fluoride to cyanide under similar
reaction conditions might enable a mechanistically analogous
[11C]radiocyanation reaction (Scheme 2).18 We demonstrate
Scheme 1. Diversification of [11C]Nitrile Substrates
Scheme 2. Inspiration from Cu-Mediated [18F]Fluorination
of Arylorganometallics
Cyanide offers an advantage because it can be readily generated
from [11C]CO2.1,2 Additionally, the nitrile functionality is
common in bioactive molecules4 and can also be rapidly
transformed into other important functional groups, including
amides, carboxylic acids, and amines (Scheme 1).
There are currently two major methods for the [11C]-
cyanation of aromatic and heteroaromatic substrates. The first
uses aryl halide precursors in combination with a Pd catalyst to
engage [11C]cyanide in aryl−CN cross coupling.5−8 These
reactions often provide high yields, exhibit broad scope, and
proceed under mild conditions. However, Pd is relatively toxic;9
furthermore, the Pd-aryl intermediates and phosphine ligands
required for these reactions can be challenging to handle,
Received: January 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00242
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
here that the combination of Cu(OTf)2, pyridine, and
[11C]KCN effectively promotes the [11C]radiocyanation of
diverse aryl boronic acids, aryl boronate esters, aryl
trifluoroborates, and arylstannanes under relatively mild
conditions. We show that this transformation is compatible
with a wide variety of functional groups and of aryl/heteroaryl
substrates. Furthermore, it is readily translated to the
automated synthesis of the radiotracer [11C]perampanel.19
Notably, while this work was underway, the team of Hooker,
Vasdev, and Liang published a related method for the Cu-
mediated [11C]cyanation of arylboronic acids.20
Our initial studies focused on establishing the feasibility of
the Cu-mediated cyanation of aryl organometallic reagents
under conditions analogous to those for our [18F]-
radiofluorination reactions.15 Using Cu(OTf)2 and pyridine in
DMA at 100 °C, the reaction of 4-methoxyphenyl tributyl-
stannane (1-SnBu3) with KCN afforded 4-methoxybenzonitrile
(1) in 28% yield in 1 h, as determined by 1H NMR
spectroscopy (Table 1, entry 1). Comparable results were
41% RCC was obtained upon the addition of exogenous water
(0.2 mL, 17% v/v) to the anhydrously prepared [11C]KCN
reaction mixture. Furthermore, an even higher yield (66%
RCC, entry 8) was observed when the [11C]KCN was prepared
and used directly as an aqueous solution. This modification
decreased the overall synthesis time by 4 min (approximately
20% of the 11C half-life). The improved RCC under these
conditions is likely due to increased solubility of [11C]KCN.
Using this aqueous [11C]KCN preparation, we next
evaluated the [11C]radiocyanation of other aryl organometallic
substrates. As summarized in Table 1, entries 8−11, various
arylboron compounds afforded comparable and/or improved
RCCs relative to their stannane counterpart, with the
trifluoroborate (1-BF3K) giving the best result (93% RCC).
Notably, KF was not required for the [11C]radiocyanation of
arylboronate ester (1-Bpin), likely due to the decreased
amount of KCN available in the reactions.
The scope of this transformation was further evaluated using
a variety of organoboron and organostannane substrates
(denoted by the footnotes in Figure 1). These studies showed
that electron-donating ([11C]1−4), -neutral ([11C]5), and
-withdrawing ([11C]6−7) substituents on the aromatic ring are
all well-tolerated. Ortho-substituted substrates underwent
[11C]radiocyanation in comparable yields to their unsubstituted
counterparts ([11C]8−10).20 In addition, carbonyl groups
([11C]11−14) were compatible with the reaction conditions.19
Significantly, precursors containing unprotected benzoic acid
([11C]12) and phenol ([11C]4) substituents also afforded
modest to excellent yields. Aryl bromides were tolerated at
various sites around the phenyl ring ([11C]16−18), and could
serve as handles for further elaboration of the products.
Pyridine derivatives and related nitrogen heterocycles also
underwent [11C]radiocyanation in moderate to high yields
([11C]19−25).
Overall, the scope of this transformation is broader, and
many of the RCCs are higher than those of previously reported
methods for the [11C]radiocyanation of aromatic substrates.8,20
As an example, our method affords quinoline product [11C]20
in 71% RCC from 20-B(OH)2. For comparison, recently
reported Cu-mediated [11C]radiocyanation conditions provide
18% RCC for the same substrate,20 while a Pd-mediated
method affords 46% RCC from the analogous aryl bromide.8
Notably, subjecting 20-B(OH)2 to our related Cu-mediated
fluorination affords only trace amounts of product (<10% 19F
NMR yield),21 demonstrating that this cyanation reaction also
has improved scope relative to fluorination. Finally, it is
noteworthy that a number of the products in Figure 1 have not
been labeled with [11C]nitrile before, including [11C]3−4, 6,
8−9, 12, 14−15, 17−19, 22, 25, and 27.
Table 1. Initial Results with KCN and Optimization with
a
[11C]KCN
entry
[M]
changes from standard product (yield or RCC, %)
b
Results with KCN
1
2
3
4
5
1-SnBu3
1-B(OH)2
1-BF3K
1-Bpin
none
none
none
none
1 (28)
1 (32)
1 (26)
1 (6)
1-Bpin
Results with [11C]KCN
KF (1.2 equiv)
c
1 (21)
6
1-SnBu3
1-SnBu3
1-SnBu3
1-B(OH)2
1-BF3K
[11C]KCN in DMA
[11C]1 (42)
[11C]1 (41)
[11C]1 (66)
[11C]1 (79)
[11C]1 (93)
[11C]1 (76)
d
7
DMA prep, H2O
8
none
none
none
none
9
10
11
1-Bpin
a
Standard conditions: substrate (10 μmol, 1 equiv), Cu(OTf)2 (2
b
equiv), pyridine (15 equiv), DMA (1 mL, 10 mM). KCN (2 equiv),
1
100 °C, 1 h. Yield determined by H NMR spectroscopy with 1,3,5-
c
trifluorobenzene as an internal standard. [11C]KCN in H2O, 100 °C,
5 min. Reported values indicate radiochemical conversion (RCC) of
d
determined by radio-TLC (n ≥ 2). H2O (0.2 mL, 17% v/v).
obtained with the corresponding boronic acid (1-B(OH)2) and
trifluoroborate (1-BF3K) substrates (32% and 26% yields,
respectively), while the boronate ester afforded a lower yield
(6%). However, the yield with the boronate ester could be
increased to 21% by the addition of 1.2 equiv of KF. This
additive likely promotes transmetalation via the formation of a
borate intermediate. Notably, no fluorinated product was
observed upon the addition of KF.
As a final demonstration of this method, we pursued the
automated, clinical-scale synthesis of [11C]perampanel. Per-
ampanel, an FDA-approved drug for epilepsy, has been
[11C]radiolabeled once before using a Pd-mediated method
with an aryl bromide precursor to afford [11C]26 in 40% RCC
(manual, radio-TLC) and 9.7% RCY (isolated, nondecay
corrected).8 Our manual method provided 90 2% RCC of
[11C]26 from the arylboronate ester using approximately 1 mCi
of [11C]KCN per reaction. The synthesis was scaled to 450
mCi of [11C]KCN, and the [11C]radiocyanation and sub-
sequent HPLC purification of [11C]26 were conducted using
an automated radiosynthesis module. Without further opti-
We next translated this method to [11C]radiocyanation using
anhydrous [11C]KCN. Gratifyingly, the product ([11C]1) was
formed in 42% RCC, as determined by radio-TLC with identity
confirmed by radio-HPLC (entry 6). Subsequent studies
revealed that anhydrous conditions (which were essential for
the analogous [18F]radiofluorination with [18F]KF) are not
required for [11C]radiocyanation. For example, a comparable
mization, this procedure afforded [11C]26 in 10.4
0.4%
nondecay corrected radiochemical yield (RCY; Scheme 3). The
B
DOI: 10.1021/acs.orglett.8b00242
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Substrate scope. Reported values indicate radiochemical conversion (RCC) of determined by radio-TLC (n ≥ 2). General conditions:
substrate (0.01 mmol, 1 equiv), Cu(OTf)2 (2 equiv), pyridine (15 equiv), [11C]KCN in H2O (0.1 mL), DMA (10 mM), 100 °C, 5 min. [M] = (a)
SnBu3, (b) B(OH)2, (c) BF3K, (d) Bpin.
fully automated synthesis lasted approximately 32 min from the
end of bombardment.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00242.
a
Scheme 3. Automation of [11C]Perampanel
Optimization details, experimental procedures, radio-
HPLC/TLC traces, and complete characterization for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: mssanfor@umich.edu.
*E-mail: pjhscott@umich.edu.
a
General conditions: 26-Bpin (0.01 mmol, 1 equiv), Cu(OTf)2 (2
equiv), pyridine (15 equiv), [11C]KCN, DMA, 100 °C, 5 min.
Radiochemical yield (RCY) determined by isolated material after
preparative-HPLC (n = 2). QC was performed to confirm the correct
product was formed and purify was >95%. NDC = nondecay
corrected. DC = decay corrected. SA = specific activity.
ORCID
Allen F. Brooks: 0000-0003-3773-3024
Melanie S. Sanford: 0000-0001-9342-9436
Peter J. H. Scott: 0000-0002-6505-0450
Notes
In conclusion, this paper describes a Cu-mediated [11C]-
radiocyanation of diverse aryl organometallic reagents. This
method is compatible with a wide range of substrates, including
those containing carboxylic acids, phenols, aldehydes, and
heterocycles. This method is also amenable to automation on a
clinically relevant scale, as demonstrated in the synthesis of
[11C]perampanel.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge NIH R01EB021155 (M.S.S. and P.J.H.S.) and
China Scholarship Council No. 201607060008 (L.Y. and
P.J.H.S.) for financial support.
C
DOI: 10.1021/acs.orglett.8b00242
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b00242
Org. Lett. XXXX, XXX, XXX−XXX