Cyanation of arylboronic acids in aqueous solutions

Article abstract of DOI:10.1039/c7cc02886e

A copper-mediated ¹¹C-cyanation method employing arylboronic acids and [¹¹C]HCN has been developed. This method was applied to the radiochemical synthesis of a wide range of aromatic ¹¹C-nitriles in aqueous solutions. The use of readily accessible arylboronic acids as precursors makes this method complementary to the well-established ¹¹C-cyanation methods that utilize aryl halide precursors.

Full text of DOI:10.1039/c7cc02886e

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COMMUNICATION
1
1
[
C]Cyanation of arylboronic acids in aqueous
solutions†
ab
Cite this: Chem. Commun., 2017,
3, 6597
5
bcd
bd
ab
Longle Ma,
Michael S. Placzek,
*
Jacob M. Hooker,
Neil Vasdev* and
ab
Received 14th April 2017,
Accepted 30th May 2017
Steven H. Liang
DOI: 10.1039/c7cc02886e
rsc.li/chemcomm
11
A copper-mediated C-cyanation method employing arylboronic acids was a subject that received long-term attention and is generally
1
1
7
and [ C]HCN has been developed. This method was applied to the performed via the Strecker reaction or by the ring-opening of
11
17
11
radiochemical synthesis of a wide range of aromatic C-nitriles in activated aziridines. The resulting C-labeled aliphatic nitriles
1
1
aqueous solutions. The use of readily accessible arylboronic acids as have been used to prepare C-labeled amino acids such as
1
1
18 11
18
11
precursors makes this method complementary to the well-established [ C]phenylalanine,
C-cyanation methods that utilize aryl halide precursors.
[ C]tyrosine,
and [ C]aspartic acid
11
17
(Fig. 1A). On the other hand, the existing methods for introducing
C]CN into aromatic rings are focused on either nucleophilic
11
ꢀ
[
Positron Emission Tomography (PET) is a highly sensitive non- aromatic substitution (S
N
Ar) reactions with Cr(CO)
3
activated
1
9
11
invasive molecular imaging modality, which can be used to monitor arenes
or Pd-catalyzed
C-cross-coupling reactions with
1
11
20–22
23,24
25
biochemical processes in vivo. Carbon-11 ( C; t = 20.4 min) is a ArBr,
ArI
or ArOTf substrates (Fig. 1B). Alternatively,
1/2
widely utilized radionuclide in radiotracer synthesis, particularly for copper catalyzed transformation from aryl halide into aryl
labeling small organic, drug-like molecules. This is due to the nitrile in the Rosenmund–von Braun reaction could be
11
11
11
11
26
breadth of functional groups (e.g., CH
3
,
CN, CQO, etc.) into employed for C-aromatic cyanation (Fig. 1B). This method
which carbon-11 could be incorporated. Furthermore, the relative
short half-life of carbon-11 allows for repeated in vivo PET studies in
animals or humans within short time intervals while maintaining a
2,3
reasonable imaging window. Carbon-11-labeled radiotracers are
predominantly prepared by methylation reactions between –OH,
1
1
4,5
11
6
–
NH, or –SH groups and [ C]CH I or [ C]CH OTf. Driven by the
3 3
1
1
need to expand beyond C-methylation reactions as a mainstay in
PET radiopharmaceutical production, continued efforts towards
11
employing a more diverse library of C-synthons remain a focus
for several research laboratories,
7–12
and this topic has been
13–15
16
reviewed by us
and others. We are particularly interested in
11
the development of new [ C]HCN-labeling methods because nitriles
are not only frequently present in biologically active agents but also
represents a versatile functional group that can be readily
1
1
15
converted into C-labeled amides, carboxylic acids or amines.
Historically, nucleophilic C-cyanation of aliphatic substrates
1
1
a
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General
Hospital, Boston, MA, USA. E-mail: liang.steven@mgh.harvard.edu,
vasdev.neil@mgh.harvard.edu; Fax: +1-617-726-6165; Tel: +1-617-726-6107
b
Harvard Medical School, Boston, MA, USA
c
McLean Hospital, Belmont, USA
d
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General
Hospital and Harvard Medical School, Charlestown, USA
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Cyanation strategies and utility of boronic precursors in radio-
c7cc02886e
chemical transformations.
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takes advantage of the robust nature and environmentally- Table 1 Preliminary screening of aromatic cyanation
benign characteristics of the copper catalyst and obviates the
limitation imposed by air/moisture sensitive ligands which are
required by Pd-catalyzed reactions. With the increased demand for
11
developing rapid and highly efficient syntheses for C-CN-labeled
PET tracers, we herein report a novel copper(I)-mediated
1
1
C-cyanation of arylboronic acids in aqueous solutions.
Copper-mediated Rosenmund–von Braun type transforma-
a
Entry
R
Base
Cu catalyst Solvent
Yield (%)
1
2
3
4
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
nBu
nBu
4
NOH CuI
NOH CuBr
DMF
DMF
DMF
13
12
tions between arylboronic precursors and various coupling part-
ners have been the subject of extensive investigation
translations into radiochemistry have gained increasing attention.
4
27–29
and their
nBu NOH Cu O
Not observed
Not observed
4
4
4
2
nBu
nBu
NOH Cu(OTf)
NOH CuI
2
DMF
DMF
b
3
0
31
5
11
For example, Riss et al. and our laboratory developed
6
7
8
9
None
NaOH
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMF
DMF
DMF
DMF
Trace
1
1
C-carboxylation reactions with arylboronic esters using
13
3
2
Et
3
N
Not observed
Not observed
copper(I) catalysts (Fig. 1C). Mossine et al. and Preshlock
et al. reported aromatic F-fluorinations using boronic acid/
ester precursors, respectively (Fig. 1C). Moreover, Zhang et al.
and Wilson et al. disclosed aromatic I/ I-iodination reactions
3
3
18
K
2
CO
CO
3
10
Cs
2
3
DMF
18
34
11
Cs CO3
2
1,4-Dioxane
MeCN
DMA
DMSO
2
DMF : H O = 1 : 1 18
Not observedc
35
131 123
12
13
14
Cs
2
Cs
2
Cs
2
CO
CO
CO
3
3
3
Not observed
9
4
involving copper catalysts and boronic acids/esters (Fig. 1C).
Inspired by their pioneering work, we envisioned that 15
2
Cs CO3
1
1
C-aromatic cyanation could be achieved using widely available
3
6
11
16
OMe nBu
OMe Cs
OMe Cs CO3
4
NOH CuI
DMF
DMF
36
33
and easily-handled arylboronic acid precursors, C-cyanide
and copper catalysts.
17
2
CO
3
CuI
CuI
18
2
2
DMF : H O = 1 : 1 36
To evaluate several reaction parameters including copper
catalysts, bases, and solvents, we initiated our preliminary
a
The reactions were carried out at 60 1C and stopped at 1 h; isolated
b
c
yields are reported. The reaction was carried out at 90 1C. The
studies by selecting phenylboronic acids and KCN under non- desired cyanated product was not observed, but the homocoupling
product of the boronic acid was isolated instead.
radioactive conditions. After a survey of copper catalysts, we
found that CuI and CuBr outperformed Cu O and Cu(OTf) in
2
2
cyanation reactions (Table 1, entries 1–4). When 0.55 equiv. of 150 1C, the RCC of 2a was increased to 22% (Table 2, entry 4). The
the CuI catalyst was added to the reaction mixture, 13% and amount of the boronic acid substrate was also found to influence
3
6% cyanated products were obtained for para-Br- and para- the reaction outcome (Table 2, entry 5) and a 37% RCC was
OMe-phenylboronic acids, respectively (Table 1, entries 1 and achieved when the substrate loading was doubled. Further
6). Further increasing the temperature did not improve the increasing the quantity of the boronic acid substrate was expected
yield within the 1 hour reaction window (Table 1, entry 5). to lead to insoluble materials given the limited amount of the
The presence of bases such as nBu NOH was essential to this solvent (200 mL) under the present conditions; therefore, we varied
transformation (Table 1, entry 6); therefore, we evaluated a alternative parameters to further improve the yield. For example,
variety of inorganic and organic bases. We found that K CO when the amount of Cs CO was doubled from 4 mg to 8 mg, a
1
4
2
3
2
3
and Et N were both ineffective for CuI catalyzed reactions. significant increase of RCC from 37% to 61% was achieved
3
However, NaOH and Cs
1
7
2
CO
3% and 18% desired aryl nitrile, respectively (Table 1, entries sufficient for a satisfactory RCC (Table 2, entries 7 and 8). Lastly, a
–10). We next screened different solvents and found DMF to variety of copper ligands were tested and DMEDA was shown to
3
promoted the reaction and yielded (Table 2, entry 6). Shorter reaction times were apparently not
be the optimal solvent for this model reaction (Table 1, entries benefit the radiochemical transformation by further improving
1–14). It is noteworthy that when a DMF/water mixture was the RCC to 65% (Table 2, entries 9–13). In addition, we found that
used, a nearly identical yield of the cyanated product was an additional amount of Cs CO increased the RCC to 70%
1
2
3
observed (Table 1, entry 15). The use of the DMF/water mixture (Table 2, entry 14). This experimentation led us to determine
as the solvent was beneficial to the development of our the optimal molar ratio for the reactants as follows: 1 : 5 : 4.5 : 4
1
1
C-cyanation reaction, because with increased Cs
CO
2 3
2 3
solubility for CuI/boronic acid/Cs CO /DMEDA.
in aqueous solution, we were able to carry out the trapping of
Arylboronic acids with different functional groups were
reacted with [ C]HCN/[ C]CsCN under the optimized condi-
1
1
11
11
[
C]HCN gas in a basic solution of Cs
2
CO
Aromatic C-cyanation was optimized using 1a as the model tions established in Table 2 to explore the substrate scope of
substrate. A 1 : 2 ratio (mass ratio) of a CuI : 1a mixture was this transformation. Substrates bearing electron-donating
3
directly.
1
1
1
1
11
reacted with [ C]HCN/[ C]CsCN trapped in a solution of groups such as methoxy and phenyl groups on the para-
Cs CO in a 3 : 1 DMF/water (v/v) mixture at 120 1C for 5 min. position gave rise to the desired products in good RCCs
2
3
A 13% radiochemical conversion (RCC) of 2a was determined (Fig. 2, 2a and 2b), making this method complementary to
by radioTLC (Table 2, entry 1). Increasing the loading of the CuI existing S Ar methods where electron-withdrawing groups are
N
catalyst (Table 2, entries 2 and 3) did not affect the RCC of 2a. necessary to activate the aromatic ring. However, 2,4,6-
However, by elevating the reaction temperature from 120 1C to trimethlyphenyl boronic acid is less reactive and afforded an
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Table 2 Optimization of aromatic C-cyanation of boronic acids
Communication
11
a
Entry
CuI (mg)
pMeOPhB(OH)
2
(mg)
Cs
2
CO
3
(mg)
Additive
T (1C)
Time (min)
RCC (%)
1
2
3
4
5
6
7
3
9
1
1
1
1
1
1
2
4
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
8
8
8
8
8
8
8
8
None
None
None
None
None
None
None
None
120
120
120
150
150
150
150
150
150
150
150
150
150
150
5
5
5
5
5
5
1
3
5
5
5
5
5
5
13
13
10
22
37
61
13
23
24
64
37
45
65
70
Pyridine (2 mL)
1,10-Phenanthroline (2 mg)
Bis-pyridine (2 mL)
TMEDA (2 mL)
DMEDA (2 mL)
0
1
2
3
4
b
c
d
16
DMEDA (2 lL)
a
b
0
0
Radiochemical conversion and product identity were determined by radioTLC and radioHPLC, respectively. TMEDA = N,N,N ,N -
c
0
d
tetramethylethylenediamine. DMEDA = N,N -dimethylethylenediamine. Molar ratio for the optimal reaction conditions: CuI (5.25 mmol) :
boronic acid (26 mmol) : Cs CO (24 mmol) : DMEDA (19 mmol) = 1 : 5 : 4.5 : 4.
2
3
8% RCC (Fig. 2, 2c). This is possibly due to steric hindrance
exerted by the ortho-substituents. Parent phenylboronic acid
and substrates bearing electron-withdrawing groups on the
para-position were less favored and showed moderate RCCs
ranging from 34 to 50% (Fig. 2, 2d–2g). We were pleased to see
halogen-substituted arylboronic acid afforded a good RCC of
the corresponding nitrile (Fig. 2, 2e), a significant advantage
over the Pd-catalyzed methods (i.e., a multi-halogen bearing
precursor utilized with the Pd-catalyzed method would raise
regioselectivity concerns). Furthermore, meta-substituents on
the phenyl ring are well tolerated with the radiochemical
conditions established herein. Substrates bearing meta-amino
and meta-CF groups both proceed smoothly to afford the
3
11
C-cyanated product (Fig. 2, 2h and 2i). Under our reaction
conditions, the unprotected benzamide and aniline (Fig. 2, 2g and
h) did not interfere with the copper-mediated transformation. This
observation holds true for heteroaromatic boronic acid substrates as
2
11
well. Pyridine-3-boronic acid produced [ C]3-pyridine nitrile with
good conversion (Fig. 2, 2j; 450% RCC). Both quinoline and furan
11
based boronic acids are radiolabeled with C-cyanide, albeit in
lower RCCs (Fig. 2, 2k and 2i). As proof-of-concept, we selected 1a as
the substrate and carried out the radiosynthesis and isolation
of 2a. A slightly modified procedure using the reaction mixture
11
(
DMF/water) as the [ C]HCN trapping solution was adopted in
order to improve the operational-simplicity (see the ESI†). We
isolated 0.455 GBq (12.3 mCi) of 2a, after semi-preparative HPLC
purification which resulted in an RCY of 4.2% (n = 2, non-decay
11
Fig. 2 Substrate scope of the C-aromatic cyanation reactions.
11
corrected, relative to starting [ C]HCN) and the specific activity was
ꢀ
1
ꢀ1
determined to be 16 GBq mmol (433 mCi mmol ) with a total into Cu(III) intermediate 4 under aerobic oxidative conditions.
synthesis time of 26 min. Intermediate 4 participated in a transmetallation reaction
1
1
The mechanism of the [ C]cyanation of arylboronic acids with the borate complex to give rise to intermediate 5. After
is proposed as follows: CuI underwent ligand exchange with reductive elimination, cyanated product 2d was formed and
1
1
C-cyanide in the presence of the ligand to afford Cu(I) Cu(I) species were regenerated to complete the catalytic cycle
intermediate 3. Intermediate 3 was subsequently converted (Scheme 1).
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1
1
1
1
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9
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1
1
1395–1400.
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2
1
1
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11
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2
2
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