Development of Decarboxylative Cyanation Reactions for C-13/C-14 Carboxylic Acid Labeling Using an Electrophilic Cyanating Reagent

Article abstract of DOI:10.1021/acs.joc.7b00033

Degradation-reconstruction approaches for isotope labeling synthesis have been known for their remarkable efficiency, but applications are scarce due to some fundamental limitations of the chemistries developed to date. The decarboxylative cyanation reaction, as a degradation-reconstruction approach, is especially useful in rapid carboxylic acid carbon isotope labeling, however development toward its application as a widespread technique has stalled at the early stages due to numerous limitations which include somewhat narrow applicability. Employing the electrophilic cyanating reagent N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) as the cyano source, efficient decarboxylative cyanation chemistry has been developed for aryl and alkyl carboxylic acids respectively with two rationally designed reaction pathways. The reactions provided good yields of nitrile products from carboxylic acids, with complete retention of isotopic purity from the [¹³CN]-NCTS used. The reaction conditions are relatively mild requiring no oxidant and no excess toxic heavy metal and the reagent [^13/14CN]-NCTS is a stable, easy-to-handle crystalline solid that can be prepared quickly and effectively from the readily available [^13/14C]-KCN. The following work describes this novel and efficient method for alkyl and aryl carboxylic acid isotopic labeling using a single reagent.

Full text of DOI:10.1021/acs.joc.7b00033

Article
pubs.acs.org/joc
Development of Decarboxylative Cyanation Reactions for C‑13/C-14
Carboxylic Acid Labeling Using an Electrophilic Cyanating Reagent
Fengbin Song,* Rhys Salter, and Lu Chen
Janssen Research & Development LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Welsh and McKean Roads, Spring
House, Pennsylvania 19477-0776, United States
S
* Supporting Information
ABSTRACT: Degradation-reconstruction approaches for isotope labeling synthesis
have been known for their remarkable efficiency, but applications are scarce due to
some fundamental limitations of the chemistries developed to date. The
decarboxylative cyanation reaction, as a degradation-reconstruction approach, is
especially useful in rapid carboxylic acid carbon isotope labeling, however
development toward its application as a widespread technique has stalled at the
early stages due to numerous limitations which include somewhat narrow
applicability. Employing the electrophilic cyanating reagent N-cyano-N-phenyl-p-
toluenesulfonamide (NCTS) as the cyano source, efficient decarboxylative cyanation chemistry has been developed for aryl and
alkyl carboxylic acids respectively with two rationally designed reaction pathways. The reactions provided good yields of nitrile
products from carboxylic acids, with complete retention of isotopic purity from the [13CN]-NCTS used. The reaction conditions
are relatively mild requiring no oxidant and no excess toxic heavy metal and the reagent [13/14CN]-NCTS is a stable, easy-to-
handle crystalline solid that can be prepared quickly and effectively from the readily available [13/14C]-KCN. The following work
describes this novel and efficient method for alkyl and aryl carboxylic acid isotopic labeling using a single reagent.
decarboxylative halogenation and subsequent cyanide sub-
stitution. Hunsdiecker’s reaction along with its modifications,
which includes the recent catalytic variant, suffers from either
the requirement for oxidant, use of highly toxic reagents, or a
limited scope of substrates.6 Barton’s decarboxylative halogen-
ation does however work well with a somewhat broader range
of substrates, but requires preparation of the Barton ester.
Furthermore, the subsequent cyanide nucleophilic substitution
is complicated by the competing elimination reaction for
tertiary and secondary halides giving the nitrile product in low
to moderate yields.7 Therefore, a desirable one-step process
namely decarboxylative cyanation has been developed which
converts carboxylic acid directly into nitrile without going
through the halide intermediate (Scheme 1).
In 1991 Barton reported the first practical decarboxylative
cyanation using sulfonyl cyanides as the cyano source under
photolysis conditions with the aim of introducing C-13/C-14
into carboxylic acid natural products bearing sensitive func-
tional groups.8,9 Despite being effective and versatile under
mild reaction conditions, Barton’s decarboxylative cyanation
has to our knowledge never been applied to labeling synthesis.
The reaction requires both preparation of the Barton ester (as
an additional step) as well as a large excesses of the sulfonyl
cyanide reagent (as the cyano source) in order to achieve good
yields. This is especially the case where p-toluenesulfonyl
cyanide is used, making this economically prohibitive for
labeling synthesis. Considering the potential utility of this
INTRODUCTION
■
Compounds labeled with carbon-14 or tritium are frequently
used as tracers during the development of potential new drug
candidates to aid in the understanding of their absorption,
distribution, metabolism, and excretion properties. While
compounds labeled with tritium are used during basic research
studies, compounds labeled with carbon-14 are preferred for
definitive drug metabolism and pharmacokinetics studies
because their positions are inherently more resistant to cleavage
from metabolic biotransformation. However, they are much
more expensive to make, requiring many more synthetic steps
that result in the increased expenditure of time and effort. If the
economics of time and cost were to be significantly lowered (in
line with tritium synthesis), earlier use of carbon-14 tracers
would prevail by virtue of the higher quality information they
afford leading to better candidate selection/deselection at much
earlier stages of development, before greater investments are
made.
One strategy to reduce time, effort, and cost of carbon-14
labeled compound preparation is to apply a degradation-
reconstruction synthesis approach using the readily available
parent compound as the starting material.1 To this purpose,
decarboxylative halogenations under Hunsdiecker or Barton
conditions followed by cyanation of the resultant halides have
been explored as a degradation-reconstruction approach for
rapid C-13/C-14 labeling2−5 (Scheme 1), taking advantage of
the carboxylic acid functional group, common in drug
candidates or advanced synthetic intermediates. While not a
new concept, examples of its application are scarce due to the
drawbacks associated with the two key steps involved,
Received: January 5, 2017
© XXXX American Chemical Society
A
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Scheme 1. Degradation-Reconstruction Approach for Carboxylic Acid C-13/C-14 Labeling
approach for C-13/C-14 labeling, it is perhaps surprising that
this area remained untouched for more than two decades and
only recently did pioneering research on transition-metal-
catalyzed decarboxylative cyanation of aryl carboxylic acids
appear.10−12 The efficiency of the catalyzed reactions was
demonstrated by a successful carbon-isotope exchange of an
aryl carboxylic acid in only two steps with 54% overall yield,11
however in general the reaction appeared to be limited to a very
narrow range of aryl carboxylic acids while alkyl carboxylic acids
do not work under these conditions. This combined with
somewhat harsh reaction conditions, which require the
presence of oxidants (excess Ag+ or O2) at high reaction
temperature, prompted us to develop a milder decarboxylative
cyanation that would be applicable to a wider range of
carboxylic acids.
Thus far, decarboxylative cyanation has employed nucleo-
philic cyanides and radical acceptor sulfonyl cyanides as the
cyano source.13 Recently, nonmetallic cyano sources, including
electrophilic cyanating reagents, have been developed.14 With
an electrophilic cyanating reagent, we conceived two unique
decarboxylative cyanation reaction pathways for aryl and alkyl
carboxylic acids, respectively. The following work describes our
design rationale and development effort on the two reactions.
Our goal is to provide alternative and efficient tools leading to
much more rapid and cost-effective access to C-14 tracers for
pharmaceutical research and development, with the view of
changing when and how C-14 tracers are utilized in drug
discovery and development.
RESULTS AND DISCUSSION
■
Palladium Catalyzed Decarboxylative Cyanation of
Aryl Carboxylic Acid Using Electrophilic Cyanating
Reagent NCTS. The decarboxylative cyanations of aryl
carboxylic acids reported thus far utilize nucleophilic cyanides
as the cyano source.10−12 They are oxidative processes in which
an oxidant (excess Ag+ or O2) is indispensable by the nature of
the reaction of coupling between two nucleophiles. Addition-
ally, the high affinity of cyanide toward the transition metal
catalyst usually causes deactivation of the catalyst and so results
in a hampered reaction. Inspired by the nonoxidative
decarboxylative coupling reaction pioneered by Gooßen15 and
encouraged by the rhodium-catalyzed cyanation of aryl boronic
acids using electrophilic cyanating reagent N-cyano-N-phenyl-
p-toluenesulfonamide (NCTS),16,17 we envisioned that replace-
ment of the nucleophilic cyanating reagent, in the reported
decarboxylative cyanation reactions, with an electrophilic
cyanating reagent would render the reaction a nonoxidative
process. Consequently, oxidant can be removed from the
reaction system. Herein we report the first nonoxidative
decarboxylative cyanation of aryl carboxylic acids.
Heating a mixture of 2,4-dimethoxybenzoic acid (1a) and
NCTS in the presence of catalyst Pd(O2CCF3)2 in DMF/
DMSO gave the desired product 2,4-dimethoxybenzonitrile
(2a) in 74% yield (Table 1, entry 1). To confirm the
mechanism is independent of oxidant, the reaction was
repeated in the absence of O2 resulting in the same reaction
outcome and yield. To trace the origin of the cyano group in
the benzonitrile product 2a, N-[13C]-cyano-N-phenyl-p-tolue-
nesulfonamide ([13CN]-NCTS)18 was reacted with 2,4-
dimethoxybenzoic acid (1a) under the same conditions and
B
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Similarly to the narrow substrate scope observed for the
oxidative decarboxylative cyanation,10 the nonoxidative decar-
boxylative cyanation proceeded well only with electron-rich aryl
carboxylic acids bearing at least one ortho substituent and
certain heteroaryl carboxylic acids. On the other hand, it is
interesting to note that this nonoxidative condition gave the
product 2d in much higher yield (75%) than the reported
oxidative process did (29% yield).10 Furthermore, the free
phenol functional group is well tolerated under these reaction
conditions and good yields were obtained for products 2g and
2h, while the corresponding oxidative process in the presence
of Ag2CO3 gave much lower yield presumably due to harsher
reaction conditions.
The reaction mechanism was postulated by analogy to the
rhodium-catalyzed cyanation of aryl boronic acids.16 In view of
the reactivity of ortho-substituted aryl−palladium complex
toward cyanamide giving product of the insertion of CN
into aryl-Pd bond,22 a reasonable explanation for the formation
of benzonitrile in this nonoxidative decarboxylative cyanation
can be represented in the catalytic cycle in Scheme 3. First
decarboxylative palladation of aryl carboxylic acid generates
arylpalladium trifluoroacetate I.23 After coordination of NCTS
to Pd, complex II is formed which allows insertion of CN
into aryl-Pd bond to afford intermediate III. Rearrangement of
III produces the benzonitrile product along with the species IV.
Finally, aryl carboxylate displacement followed by decarbox-
ylation affords the arylpalladium trifluoroacetate I to complete
the catalytic cycle.
Table 1. Decarboxylative Cyanation of Aryl Carboxylic Acid
entry
cyanide source
catalyst
yield (%)
a
1
2
3
4
5
6
NCTS
Pd(O2CCF3)2
Pd(O2CCF3)2
No catalyst
74%
[13C]-NCTS
75%([13C]-2a)
b
NCTS
N.D.
b
NCTS
Cu(O2CCF3)2
Pd(O2CCF3)2
Pd(O2CCF3)2
N.D
KCN
trace (<5% by LCMS)
c
b
BtCN
N.D
a
b
NCTS = N-cyano-N-phenyl-p-toluenesulfonamide. N.D. = not
c
detected by LCMS. Bt-CN = 1H-benzotriazole-1-carbonitrile.
the product 2,4-dimethoxybenzo-[13C]-nitrile ([13C]-2a) was
indeed isolated in 75% yield (Table 1, entry 2). LCMS
confirmed the isotopic purity of the reagent [13CN]-NCTS was
retained in the nitrile product [13C]-2a, which is critical for
labeling synthesis. The Pd catalyst is essential to the reaction, as
removal of Pd catalyst from the reaction system or replacing Pd
with Cu prevents formation of the nitrile product (Table 1,
entries 3 and 4). When nucleophilic KCN was used in place of
NCTS, the reaction resulted in only a trace amount of 2a. This
is likely the result of initial reaction with cyanide before Pd(II)
is exhausted (Table 1, entry 5). An alternative electrophilic
cyanating reagent 1-H-benzotriazole-1-carbonitrile
(BtCN)19−21 was also explored, however, test reactions
revealed that no product was formed (Table 1, entry 6). It
should be noted that the advantage of NCTS is that it is a
benchtop stable, easy-to-handle crystalline solid which makes it
convenient for storage and use by radiochemists as a labeling
reagent.
In summary, employing electrophilic NCTS, the palladium
catalyzed nonoxidative decarboxylative cyanation converts aryl
carboxylic acids directly to aryl nitrile products in good yield
under mild conditions with no oxidant. Expansion of the
narrow substrate scope is under further investigation.
Decarboxylative Cyanation of Alkyl Carboxylic Acid
Using Electrophilic Cyanating Reagents. In 1979, Parnes
reported the one-step synthesis of 6,11-dihyro[b,e]thiepin-11-
To probe the scope and limitations of this reaction, we
carried out a series of nonoxidative decarboxylative cyanation
reactions. Our preliminary results are shown in Scheme 2.
Scheme 2. Synthesis of Aryl Nitriles 2 (Isolated Yields) through Nonoxidative Decarboxylative Cyanation for Aryl Carboxylic
Acids 1
a
b
Yield under oxidative deacrboxylative cyanation in the presence of Ag2CO3. N.D. = not detected by LCMS.
C
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cyanation, is a benchtop stable and easy-to-handle crystalline
solid. We hereto decided to explore NCTS as a reasonable
substitute for BtCN.
Scheme 3. Proposed Mechanism for Pd(II) Catalyzed
Nonoxidative Decarboxylative Cyanation of Aryl Carboxylic
Acids
Under identical reaction conditions to those used with
BtCN, NCTS indeed gave the desired nitrile product 2i in
much higher yield (84%). To test this reagent on a
pharmaceutical drug with a substituent at α-position of the
carboxylic acid, we examined Ibuprofen (1j). After 18 h, the
nonsteroidal anti-inflammatory drug was converted to the
nitrile 2j in 28% yield in one step. We reasoned the low yield of
2j might be due to the incomplete decarboxylation of the
intermediate α-cyanocarboxylic acid and thus a CuO catalyzed
decarboxylation29 of the crude mixture after cyanation reaction
indeed improved the yield of the nitrile product to 71%.
Cyanation of 2,4-dimethoxyphenyl acetic acid (1k) followed by
CuO catalyzed decarboxylation gave high yield (90%) of 2,4-
dimethoxyphenyl acetonitrile (2k). Compound 3-(3-
methoxyphenyl)propanoic acid (1l), a “real” alkyl carboxylic
acid with a nonbenzylic reaction site, was subjected to the same
cyanation and subsequent thermal decarboxylation and the
reaction provided 3-(3-methoxyphenyl)propanenitrile (2l) in
64% yield. Lastly, Naproxen (1m) was converted to the [13C]-
nitrile compound 2m in 71% yield by the decarboxylative
cyanation sequence. LCMS confirmed the isotopic purity of the
reagent [13CN]-NCTS was retained in the [13C]-nitrile product
2m.
It should be noted that this method is limited to primary and
secondary carboxylic acids since sequential decarboxylative
cyanation requires abstraction of an α-proton and some strong-
base sensitive functional groups, such as −OH, −NH2, −NHR,
may also require protection prior to use of LDA to generate the
dianion. These results have shown that the sequential
decarboxylative cyanation of alkyl carboxylic acid to alkyl
nitrile can be achieved in good yield under mild conditions in
the absence of oxidant or excess toxic heavy metal and provides
an alternative to Hunsdiecker or Barton reactions for rapid alkyl
carboxylic acid C-13/C-14 labeling synthesis.
one-3-yl acetic [14C]-acid by trapping the dianion of the
unlabeled acid with 14CO2 followed by spontaneous decarbox-
ylation of the resulting malonic acid.24 The synthesis was
exceptionally short, but it only produced the labeled acid in low
specific activity because the decarboxylation of the malonic acid
intermediate was not selective between C12 and C14
carboxylate and half of the 14CO2 radioactivity ended up as
waste. Nonetheless, encouraged by Parnes’ initial work, our
search for alternative pathways to fulfill decarboxylative
cyanation of alkyl carboxylic acids led us to investigate the
decomposable α-cyanocarboxylic acid as a key intermediate for
the reaction. This gives the desired nitrile product via
decarboxylation (Scheme 4). Retrosynthetically, the α-
cyanocarboxylic acid intermediate could be accessed through
α-cyanation of the alkyl carboxylic acid with an electrophilic
cyanating reagent +CN source. Through the sequential process,
the alkyl carboxylic acid is degraded to CO2 and replaced by
cyanide, thus providing a pathway to decarboxylative cyanation
of alkyl carboxylic acids.
Consequently, 1-H-benzotriazole-1-carbonitrile (BtCN) was
selected as the electrophilic cyanating reagent because it has
been used for α-cyanation of alkyl nitrile and alkyl carboxylate
esters providing malononitrile and cyanoacetate in good
yields.19,20,25−27 Treatment of the dianion of 3,4-dichlorophe-
nylacetic acid (1i, 2eq ) with Bt13CN28 (1 equiv) at 0 °C to
room temperature followed by acidic workup gave 3,4-
dichlorophenylaceto-[13C]-nitrile ([13C]-2i) in 71% yield
(Scheme 5). Of particular interest is that the [13C]-nitrile of
Bt13CN was transferred to the product without loss of the C-13
isotopic purity; essential for labeling synthesis. During our
preparation of Bt13CN, it was found that Bt13CN decomposed
gradually on silica gel, complicating its purification by flash
chromatography on silica gel and reducing the yield. In contrast
NCTS, used successfully for aryl carboxylic acid decarboxylative
Synthesis of N-[13/14C]-Cyano-N-phenyl-p-toluenesul-
fonamide ([13/14CN]-NCTS). In order for the above
decarboxylative cyanation chemistry to be practical to radio-
chemists and therefore reduced to practice, generation of the
labeling reagent [13/14CN]-NCTS should be simple and cost-
effective from readily available 13/14C-feed stocks. We therefore
developed an efficient two-step synthesis of [13/14CN]-NCTS
from readily available [13/14C]-KCN (Scheme 6). Treatment of
the readily available [13C]-KCN with Br2 at 0 °C rapidly
afforded the intermediate [13C]-BrCN, which was reacted
directly with N-phenyl-p-toluenesulfonamide at 0 °C to give
[13CN]-NCTS in 83% yield after isolation. Following the same
procedure starting from low specific activity [14C]-KCN (2.9
mCi/mmol or 107.3 MBq/mmol), [14CN]-NCTS was
prepared conveniently in 68% radiochemical yield. The
radiochemical purity of the prepared reagent [14CN]-NCTS
was found to be stable on storage as solid at room temperature
for three months.
Scheme 4. Strategy for Decarboxylative Cyanation of Alkyl Carboxylic Acids
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Scheme 5. Decarboxylative Cyanation of Alkyl Carboxylic Acids
Scheme 6. Synthesis of [13/14CN]-NCTS
Bruker AC-400 (400 MHz) spectrometer using tetramethylsilane as an
internal standard. Electrospray mass spectra (MS-ES) were recorded
on a Hewlett-Packard 59987A spectrometer. HRMS was performed on
TOF LC-MS in ESI mode.
CONCLUSIONS
■
The aforementioned results demonstrate both the utility of this
method and the application of the isotopically labeled
electrophilic cyanating reagent [13/14CN]-NCTS in providing
efficient access to labeled nitrile products in good yield from
both aryl and alkyl carboxylic acids under mild, nonoxidative
conditions in the absence of excess toxic metals. The reagent
itself is a benchtop stable and easy-to-handle crystalline solid
that can be prepared quickly and effectively from the readily
available [13/14C]-KCN.
2,4-Dimethoxybenzonitrile (2a).30 General Procedure A. A
solution of N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) (87.1
mg, 0.32 mmol), 2,4-dimethoxybenzoic acid (116.6 mg, 0.64 mmol),
and palladium(II) trifluoroacetate (21.3 mg, 0.06 mmol) in DMF/
DMSO (19/1 v/v, 3 mL) was heated at 120 °C with stirring for 3 h.
After it was cooled to room temperature, the reaction mixture was
filtered and the solid was washed with EtOAc (2 mL X 3). The filtrate
solution was concentrated and the residue was purified by
chromatography on silica gel (heptane to 15% EtOAc in heptane)
1
EXPERIMENTAL SECTION
to give product 2a (39.6 mg, 76%) as white solid: H NMR (CDCl3,
■
400 MHz) δ 7.48 (d, J = 8.6 Hz, 1H), 6.52 (dd, J = 2.5, 8.6 Hz, 1H),
6.46 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H); MS (ES, m/z) 164
(M+H+).
All reagents were purchased from commercial sources and used
without further purification unless otherwise noted. N-Cyano-N-
phenyl-p-toluenesulfonamide (NCTS) was purchased from Combi-
Blocks Inc. and purified by chromatography on silica gel (heptane to
50% EtOAc in heptane). K14CN with specific activity 56 mCi/mmol
or 2072 MBq/mmol was purchased from ViTrax Co., 660 S. Jefferson
St., Placentia, CA 92870. 1H and 13C NMR spectra were recorded on a
2,4-Dimethoxybenzo-[13C]-nitrile ([13C]-2a).11 The general
procedure A was followed with [13CN]-NCTS (136.7 mg, 0.50
mmol), 2,6-dimethoxybenzoic acid (182.2 mg, 1.00 mmol), Pd-
(O2CCF3)2 (33.2 mg, 0.10 mmol), and DMF/DMSO (19/1 v/v, 5
E
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mL). After the reaction was over, purification by chromatography on
silica gel (heptane to 20% EtOAc in heptane) gave product [13C]-2a
(61.7 mg, 75%) as white solid: H NMR (CDCl3, 400 MHz) δ 7.48
1H NMR (CD3OD, 400 MHz) δ 7.39 (d, J = 8.0 Hz, 1H), 6.51 (d, J =
4.0 Hz, 1H), 6.45 (dd, J = 4.0, 8.0 Hz, 1H), 3.87 (s, 3H): MS (ES, m/
z) 150 (M+H+); 13C NMR (CD3OD, 100 MHz) δ 165.2, 164.8, 136.0,
118.2, 109.5, 100.2, 92.6, 56.5.
1
(dd, J = 5.9, 8.6 Hz, 1H), 6.52 (dd, J = 2.0, 8.6 Hz, 1H), 6.46 (t, J = 2.0
Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H); MS (ES, m/z) 165 (M+H+); 13
C
2-(3,4-Dichlorophenyl)acetonitrile-1-13C ([13C]-2i). To a sol-
ution of diisopropylamine (0.84 mL, d= 0.722 g/mL, 6.06 mmol) in
THF (2.8 mL) at −78 °C was added n-BuLi (2.40 mL, 2.5 M in
hexanes, 6.0 mmol) dropwise. It was stirred at −78 °C for 30 min to
give LDA at ∼1.0 M concentration.
NMR (CDCl3, 100 MHz) δ 164.7, 162.9, 134.9, 116.9, 105.8 (d, J =
5.1 Hz), 98.6 (d, J = 3.6 Hz), 94.1 (d, J = 86.3 Hz), 56.0, 55.7; HRMS
(ESI-TOF) m/z: [M+H]+calcd for C813CH10NO2 165.0740, found
165.0745.
2,6-Dimethoxybenzonitrile (2b).31 The general procedure A
was followed with NCTS (87.1 mg, 0.32 mmol), 2,6-dimethox-
ybenzoic acid (116.6 mg, 0.64 mmol), Pd(O2CCF3)2 (21.3 mg, 0.06
mmol), and DMF/DMSO (19/1 v/v, 3 mL). After the reaction was
over, purification by chromatography on silica gel (heptane to 15%
EtOAc in heptane) gave product 2b (42.0 mg, 80%) as white solid: 1H
NMR (CDCl3, 400 MHz) δ 7.44 (t, J = 8.3 Hz, 1H), 6.55 (d, J = 8.6
Hz, 2H), 3.91 (s, 6H); MS (ES, m/z) 164 (M+H+).
To a solution of 2-(3,4-dichlorophenyl)acetic acid (451.1 mg, 2.20
mmol) in THF (4 mL) at 0 °C under N2 was added the above LDA
solution (4.20 mL, ∼ 1.0 M, 4.2 mmol) dropwise. The mixture became
a yellow suspension. After the mixture was stirred at 0 °C for 15 min, a
solution of 1H-benzo[d][1,2,3]triazole-1-carbonitrile-13C (145.1 mg,
1.00 mmol) in THF (2 mL) was added. The resulted dark red solution
was stirred for 18 h while the temperature slowly rose to room
temperature. Water (2 mL) was added to the dark red solution and it
was stirred at room temperature for 1 h. HCl aqueous solution (1N, 10
mL) was added to acidify the mixture. EtOAc (10 mL) was added to
the acidified mixture and the mixture was stirred at room temperature
for 10 min. Yellow precipitate was observed in the organic phase. The
mixture was filtered. The organic phase was separated. The aqueous
phase was extracted with EtOAc (10 mL × 3). The combined organic
phase was dried over Na2SO4. Filtration and concentration of the
filtrate gave the crude product as brown oil. Chromatography on silica-
gel (heptane to 20% EtOAc in heptane) gave the product [13C]-2i
(133.8 mg, 71% yield) as colorless oil: 1H NMR (CDCl3, 400 MHz) δ
7.47 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 4.0 Hz, 1H), 7.19 (dd, J = 4.0, 8.0
Hz, 1H), 3.73 (d, J = 12.0 Hz, 3H); MS (ES, m/z) 187 (M+H+), 189
(M+H+); 13C NMR (CDCl3, 100 MHz) δ 133.3, 132.5, 131.1, 129.9
(d, J = 3.6 Hz), 127.3 (d, J = 3.1 Hz), 116.9, 22.9 (d, J = 58.6 Hz);
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C713CH6Cl2N 186.9905,
found 186.9906.
2-(3,4-Dichlorophenyl)acetonitrile (2i). General Procedure B.
To a solution of 2-(3,4-dichlorophenyl)acetic acid (451.1 mg, 2.20
mmol) in THF (3 mL) at 0 °C under N2 was added the prepared LDA
solution (4.20 mL, ∼ 1.0 M, 4.2 mmol) dropwise. The mixture became
a yellow solution. After the mixture was stirred at 0 °C for 15 min, a
solution of NCTS (272.3 mg, 1.00 mmol) in THF (3 mL) was added.
The reaction mixture turned into a yellow suspension after addition of
NCTS solution. The reaction mixture was stirred for 18 h while the
temperature slowly rose to room temperature. Water (2 mL) was
added to the creamy suspension and the suspension turned into a clear
biphase mixture. HCl aqueous solution (1N, 10 mL) was added to
acidify the mixture. EtOAc (10 mL) was added to the acidified mixture
and the mixture was stirred at room temperature for 10 min. The
organic phase was separated and the aqueous phase was extracted with
EtOAc (10 mL X 3). The combined organic phase was dried over
Na2SO4. Filtration and concentration of the filtrate gave the crude
product as yellowish oil. Chromatography on silica-gel (heptane to
20% EtOAc in heptane) gave the product 2i (155.6 mg, 84% yield) as
colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.47 (d, J = 8.0 Hz, 1H),
7.45 (d, J = 4.0 Hz, 1H), 7.19 (dd, J = 4.0, 8.0 Hz, 1H), 3.73 (s, 3H);
MS (ES, m/z) 186 (M+H+), 188 (M+H+); 13C NMR (CDCl3, 100
MHz) δ 133.3, 132.5, 131.1, 129.9, 127.3, 116.9, 22.9.
2,4,5-Trimethoxybenzonitrile (2c).32 The general procedure A
was followed with NCTS (109.0 mg, 0.40 mmol), 2,4,5-trimethox-
ybenzoic acid (169.9 mg, 0.80 mmol), Pd(O2CCF3)2 (26.6 mg, 0.08
mmol), and DMF/DMSO (19/1 v/v, 3 mL). After the reaction was
over, purification by chromatography on silica gel (heptane to 15%
EtOAc in heptane) gave product 2c (66.0 mg, 85%) as white solid: 1H
NMR (CDCl3, 400 MHz) δ: 6.97 (s, 1H), 6.50 (s, 1H), 3.95 (s, 3H),
3.92 (s, 3H), 3.84 (s, 3H); MS (ES, m/z) 194 (M+H+).
5-Bromo-2,4-dimethoxybenzonitrile (2d).10 The general pro-
cedure A was followed with NCTS (87.1 mg, 0.32 mmol), 5-bromo-
2,4-dimethoxybenzoic acid (167.1 mg, 0.64 mmol), Pd(O2CCF3)2
(21.3 mg, 0.06 mmol), and DMF/DMSO (19/1 v/v, 3 mL). After the
reaction was over, purification by chromatography on silica gel
(heptane to 25% EtOAc in heptane) gave product 2d (58.2 mg, 75%)
1
as white solid: H NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.46 (s,
1H), 3.97 (s, 3H), 3.95 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
162.6, 160.6, 136.9, 115.5, 102.3, 95.9, 94.9, 56.5, 56.4; MS (ES, m/z)
242 (M+H+), 244 (M+H+); 13C NMR (CDCl3, 100 MHz) δ 162.6,
160.6, 136.9, 115.5, 102.3, 95.9, 94.9, 56.5, 56.4.
2,6-Dimethoxynicotinonitrile (2e).33 The general procedure A
was followed with NCTS (109.0 mg, 0.40 mmol), 2,6-dimethox-
ynicotinic acid (146.6 mg, 0.80 mmol), Pd(O2CCF3)2 (42.0 mg, 0.13
mmol), and DMF/DMSO (19/1 v/v, 3 mL). After the reaction was
over, purification by chromatography on silica gel (heptane to 15%
EtOAc in heptane) gave product 2e (46.0 mg, 70%) as white solid: 1H
NMR (CDCl3, 400 MHz) δ 7.70 (d, J = 8.6 Hz, 1H), 6.36 (d, J = 8.1
Hz, 1H), 4.04 (s, 3H), 3.98 (s, 3H): MS (ES, m/z) 165 (M+H+).
Anthracene-9-carbonitrile (2f).34 The general procedure A was
followed with NCTS (109.0 mg, 0.40 mmol), anthracene-9-carboxylic
acid (177.9 mg, 0.80 mmol), Pd(O2CCF3)2 (42.0 mg, 0.13 mmol),
and DMF/DMSO (19/1 v/v, 3 mL). After the reaction was over,
purification by chromatography on silica gel (heptane to 15% EtOAc
1
in heptane) gave product 2f (62.0 mg, 76%) as white solid: H NMR
(CDCl3, 400 MHz) δ 8.70 (s, 1H), 8.41−8.47 (m, 2H), 8.09 (d, J =
8.1 Hz, 2H), 7.69−7.76 (m, 2H), 7.56−7.63 (m, 2H): MS (ES, m/z)
204 (M+H+).
2-Hydroxy-6-methoxybenzonitrile (2g).35 The general proce-
dure A was followed with NCTS (68.1 mg, 0.25 mmol), 2-hydroxy-6-
methoxybenzoic acid (84.1 mg, 0.50 mmol), Pd(O2CCF3)2 (16.6 mg,
0.05 mmol), and DMF/DMSO (19/1 v/v, 2.5 mL). After the reaction
was over, purification by chromatography on silica gel (heptane to 50%
EtOAc in heptane) gave the product 2g (30.1 mg, 81%) as white solid:
1H NMR (CD3OD, 400 MHz) δ 7.36 (dd, J = 8.0, 8.0 Hz, 1H), 6.55
(d, J = 8.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H): MS (ES,
m/z) 150 (M+H+); 13C NMR (CD3OD, 100 MHz) δ 164.0, 163.1,
136.1, 115.4, 109.0, 102.9, 90.6, 56.7; HRMS (ESI-TOF) m/z: [M
2-(4-Isobutylphenyl)propanenitrile (2j).36 The general proce-
dure B was followed with Ibuprofen (247.5 mg, 1.20 mmol) in THF (3
mL), LDA solution (1.15 mL, 2.0 M in THF, 2.3 mmol), and NCTS
(272.3 mg, 1.00 mmol) in THF (3 mL). After the α-cyanation reaction
and workup, the yellowish oil crude product was dissolved in CH3CN
(5 mL) and treated CuO (36.0 mg, 0.45 mmol). The mixture was
stirred at 85 °C for 30 min. Filtration and concentration of the filtrate
gave the crude product. Chromatography on silica-gel (heptane to
30% EtOAc in heptane) gave the product 2j (133.0 mg, 71% yield) as
white solid: 1H NMR (CDCl3, 400 MHz) δ 7.25 (d, J = 8.0 Hz, 2H),
7.15 (d, J = 8.0 Hz, 2H), 3.87 (q, J = 7.6 Hz, 1H), 2.47 (d, J = 7.1 Hz,
2H), 1.77−1.92 (m, 1H), 1.63 (d, J = 7.6 Hz, 3H), 0.90 (d, J = 8.0 Hz,
6H); MS (ES, m/z) 188 (M+H+); 13C NMR (CDCl3, 100 MHz) δ
141.6, 134.3, 129.8, 126.4, 121.9, 44.9, 30.9, 30.2, 22.3, 21.5; HRMS
+
+H]+ calcd for C8H8NO2 150.0550, found 150.0554.
4-Hydroxy-2-methoxybenzonitrile (2h). The general procedure
A was followed with NCTS (43.6 mg, 0.16 mmol), 4-hydroxy-2-
methoxybenzoic acid (53.8 mg, 0.32 mmol), Pd(O2CCF3)2 (10.6 mg,
0.03 mmol), and DMF/DMSO (19/1 v/v, 1.5 mL). After the reaction
was over, purification by chromatography on silica gel (heptane to 50%
EtOAc in heptane) gave the product 2h (18.9 mg, 79%) as white solid:
F
DOI: 10.1021/acs.joc.7b00033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ESI-TOF) m/z: [M+H]+ calcd for C13H18N 188.1434, found
188.1437.
N-[14C]-Cyano-N-phenyl-p-toluenesulfonamide ([14CN]-
NCTS). To a vigorously stirred solution of Br2 (186.0 mg, 1.17
mmol) in 3 mL CH2Cl2 at 0 °C was added the mixture of KCN (66.0
mg, 1.01 mmol) and K14CN (3.8 mg, 3.17 mCi or 117.29 MBq,
specific activity 56 mCi/mmol or 2072 MBq/mmol) in H2O (1.2 mL)
dropwise. The reaction mixture was allowed to stir for additional 10
min at 0 °C.
p-Toluenesulfonaniline (382.0 mg, 1.55 mmol) and Et3N (0.30 mL,
2.16 mmol) in CH2Cl2 (1.5 mL) were cooled in an ice−water bath. To
it was added the above crude Br14CN solution (only the organic layer
was added). After stirring for 10 min, the mixture was concentrated to
dryness. Chromatography on silica gel (heptane to 20% EtOAc in
heptane) gave [14CN]-NCTS (198.0 mg, 2.15 mCi or 79.55 MBq,
68% radiochemical yield).
2-(2,4-Dimethoxyphenyl)acetonitrile (2k). The general proce-
dure B was followed with 2,4-dimethoxyphenylacetic acid (431.6 mg,
2.20 mmol) in THF (3 mL), LDA solution (4.20 mL, ∼ 1.0 M, 4.2
mmol), and NCTS (272.3 mg, 1.00 mml) in THF (3 mL). After the α-
cyanation reaction and workup, the yellowish oil crude product was
dissolved in CH3CN (5 mL) and treated CuO (36.0 mg, 0.45 mmol).
The mixture was stirred at 85 °C refluxed for 30 min, and over
weekend at room temperature. Filtration and concentration of the
filtrate gave brown-yellowish oil. Chromatography on silica-gel
(heptane to 30% EtOAc) gave the 2k (159.0 mg, 90% yield) as
white solid: 1H NMR (CDCl3, 400 MHz) δ 7.24 (d, J = 8.1 Hz, 1H),
6.45−6.50 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.61 (s, 2H); MS (ES,
m/z) 178.1 (M+H+); 13C NMR (CDCl3, 100 MHz) δ 161.0, 157.8,
129.7, 118.4, 111.0, 104.0, 98.7, 55.51, 55.47, 18.3; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C10H12NO2 178.0863, found 178.0840.
3-(3-Methoxyphenyl)propanenitrile (2l). The general proce-
dure B was followed with 3-(3-methoxyphenyl)propanoic acid (396.4
mg, 2.20 mmol) in THF (3 mL), LDA solution (4.20 mL, ∼ 1.0 M, 4.2
mmol), and NCTS (272.3 mg, 1.00 mml) in THF (3 mL). After the α-
cyanation reaction and workup, the crude product was dissolved in
DMF (2 mL)/HOAc (0.2 mL) and the solution was heated at 120 °C
for 3 h. Saturated NaHCO3 aqueous solution was added to basify the
cooled reaction mixture and it was extracted with Et2O (10 mL × 3).
The combined extracts were washed with brine, dried over Na2SO4.
Filtration and concentration of the filtrate gave the crude product.
Chromatography on silica gel (heptane to 30% EtOAc in heptane)
gave the product 2l (102.8 mg, 64% yield) as slightly yellowish oil: 1H
NMR (CDCl3, 400 MHz) δ 7.26 (t, J = 8.0 Hz, 1H), 6.76−6.84 (m,
3H), 2.94 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 8.0 Hz, 2H); MS (ES, m/z)
162.1 (M+H+); 13C NMR (CDCl3, 100 MHz) δ 159.9, 139.6, 129.9,
120.5, 119.2, 114.1, 112.5, 55.2, 31.6, 19.3; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C10H12NO 162.0913, found 162.0902.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00033.
■
S
Characterization (1H and 13C NMR spectra) of the
products and the reagent [13CN]-NCTS (PDF)
AUTHOR INFORMATION
Corresponding Author
*fsong@its.jnj.com
■
ORCID
Fengbin Song: 0000-0003-2381-283X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2-(6-Methoxynaphthalen-2-yl)propanenitrile-1-13C (2m).
The general procedure B was followed with 2-(6-methoxynaphtha-
len-2-yl)propanoic acid (138.2 mg, 0.60 mmol) in THF (1 mL), LDA
solution (0.58 mL, 2 M in THF, 1.16 mmol), and NCTS (136.7 mg,
0.50 mmol) in THF (2 mL). After the α-cyanation reaction and
workup, the yellowish oil crude product was dissolved in CH3CN (3
mL) and treated CuO (40.0 mg, 0.49 mmol). The mixture was stirred
at 85 °C for 1 h. Filtration and concentration of the filtrate gave the
crude product as brown-yellowish oil. Chromatography on silica gel
(heptane to 30% EtOAc in heptane) gave the product 2m (75.1 mg,
We sincerely thank Dr. Ronghui Lin, Dr.Yong Gong, Dr.Scott
Ballentine, and Dr.Wei Zhang for helpful discussions. Thanks
Dr. Scott Ballentine for the help with HRMS.
REFERENCES
■
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71% yield) as white solid: H NMR (CDCl3, 400 MHz) δ: 7.72−7.79
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N-[13C]-Cyano-N-phenyl-p-toluenesulfonamide ([13CN]-
NCTS). To a vigorously stirred solution of Br2 (186.0 mg, 1.17
mmol) in CH2Cl2 (3 mL) at 0 °C was added K13CN (70.0 mg, 1.06
mmol) in H2O (1.2 mL) dropwise. The reaction mixture was allowed
to stir for additional 5 min at 0 °C.
p-Toluenesulfonaniline (327.0 mg, 1.25 mmol) and Et3N (0.30 mL,
2.16 mol) in CH2Cl2 (1.5 mL) were cooled in an ice−water bath. To it
was added the above crude Br13CN solution (the aqueous layer was
separated out and only the organic layer was added). After stirring for
10 min, the mixture was concentrated to dryness. Chromatography on
silica gel (heptane to 20% EtOAc in heptane) gave [13CN]-NCTS
1
(242.0 mg, 83%) as white solid: H NMR (CDCl3, 400 MHz) δ 7.64
(d, J = 8.1 Hz, 2H), 7.36−7.44 (m, 3H), 7.34 (d, J = 8.1 Hz, 2H), 7.20
(d, J = 1.0 Hz, 2H), 2.47 (s, 3H); MS (ES, m/z) 274 (M+H+); 13C
NMR (CDCl3, 100 MHz) δ 146.7, 134.6, 132.3, 130.2, 130.0, 129.9,
128.4, 126.5 (d, J = 1.5 Hz), 108.7, 21.8; HRMS (ESI-TOF) m/z: [M
+H]+ calcd for C1313CH13N2O2S 274.0726, found 274.0734.
G
DOI: 10.1021/acs.joc.7b00033
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Article
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DOI: 10.1021/acs.joc.7b00033
J. Org. Chem. XXXX, XXX, XXX−XXX