Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides

Article abstract of DOI:10.1021/acs.joc.7b01003

Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl₂ precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd₂(dba)₃. Twenty-two substituted benzonitriles have been synthesized using this method.

Full text of DOI:10.1021/acs.joc.7b01003

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Note
Improving Robustness: In-Situ Generation of a
Pd(0) Catalyst For the Cyanation of Aryl Bromides
John Ryan Coombs, Kenneth J. Fraunhoffer, Eric M Simmons,
Jason M Stevens, Steven R. Wisniewski, and Miao Yu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2017
Downloaded from http://pubs.acs.org on June 9, 2017
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Improving Robustness: In-Situ Generation of a Pd(0) Catalyst For the Cyanation of Aryl
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Bromides
John R. Coombs, Kenneth J. Fraunhoffer, Eric M. Simmons, Jason M. Stevens, Steven R.
Wisniewski,* Miao Yu
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Chemical & Synthetic Development, BristolꢀMyers Squibb, 1 Squibb Drive, New Brunswick,
New Jersey 08903
steven.wisniewski@bms.com
ABSTRACT: Conditions have been developed for the palladiumꢀcatalyzed cyanation of aryl
bromides utilizing the airꢀstable XantPhosꢀPdCl2 precatalyst. By employing a trialkylamine as a
reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the
airꢀsensitive Pd2(dba)3. Twentyꢀtwo substituted benzonitriles have been synthesized using this
method.
Substituted benzonitriles are an important class of compounds that both serve as starting
materials for a variety of synthetic transformations1 and are present in active pharmaceutical
ingredients.2 Traditional methods to rapidly access benzonitriles, such as the Sandmeyer or
Rosenmundꢀvon Braun reaction, require harsh reaction conditions such as high reaction
temperatures. As a result, the palladiumꢀcatalyzed cyanation3 of aryl halides has become the
preferred method for the installation of an aryl nitrile moiety. Several different cyanide sources
have been reported in the literature for use in palladiumꢀcatalyzed reactions. NaCN and KCN are
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generally avoided on large scale due to the inherent toxicity. K4Fe(CN)6 is a low toxicity
cyanide source, but cyanation reactions employing this reagent typically require long reactions at
temperatures greater than 100 °C, thus increasing the risk of decomposition of the starting
material.5 Zinc cyanide, on the other hand, is approximately ten times less toxic than the sodium
and potassium cyanide salts.6 As a result, zinc cyanide is the most widely used cyanide source in
palladiumꢀcatalyzed cyanations.7
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The majority of palladiumꢀcatalyzed cyanations employ
tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) as the palladium catalyst. However, the use of
this Pd(0) complex is less than ideal. Pd(0) complexes have limited stability outside of a
glovebox as they oxidize to Pd(II) species. Furthermore, commercially available Pd2(dba)3 has
been shown to contain up to 40% palladium nanoparticles, leading to variability in the amount of
active palladium involved in a reaction.5,8 In addition to these concerns, the
dibenzylideneacetone (dba) ligand can compete with another ligand to bind palladium, and after
the reaction, dba removal can be problematic. In terms of practicality on a process scale,9 the use
of a wellꢀdefined, airꢀstable Pd(II) preꢀcatalyst would be greatly preferred over a Pd(0) species.
There have been several examples reported in the literature employing Pd(II) species in
cyanation reactions with Zn(CN)210ꢀ14; these methods are not without their limitations. The main
drawback associated is the manner in which Pd(II) is reduced to the catalytically active Pd(0)
species. One method to reduce palladium required preformation of Pd(0) by the addition of
Zn(Et)2, a pyrophoric dialkylzinc reagent.10 Similarly, up to 20 mol % Zn dust, which may need
to be activated, can be added as a reductant to generate Pd(0).11 The heterogeneous nature of the
reaction, due the addition of the typically insoluble Zn dust and the relatively insoluble Zn(CN)2,
could cause problems with mass transfer in larger scale reactions. Furthermore, additional steps
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would be required to remove the zinc dust at the end of the reaction. Lastly, the addition of 1ꢀ10
wt % of polymethylhydrosiloxane (PMHS) protects palladium from oxidation, allowing the use
of Pd(OAc)2 in a reaction open to the air.12 Although effective in this transformation, a
PMHS/Pd catalytic system is also capable of reducing aromatic nitro groups to amines, and
therefore the method can be limited by reduction of the substrate.13
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Recently, the Buchwald group published an improved procedure14 for the cyanation of
aryl halides under mild reaction conditions by employing 2ꢀ5 mol % tꢀBuXPhosꢀPdꢀG3.
Although effective, the need to synthesize a palladacycle precatalyst with an expensive,
proprietary ligand limits the ability to perform this reaction on scale. The biphasic system
employed, such that cyanide slowly diffuses into the organic phase, introduces an additional
parameter that could cause issues on scale.
We sought to develop a general procedure for the cyanation of aryl bromides employing
an airꢀstable, ligated Pd(II) precatalyst that could be easily reduced in situ to an active Pd(0)
species without requiring preformation. Initially, we envisioned that a bulky ligand with a large
bite angle would be required to promote reductive elimination of the benzonitrile.15 Preliminary
experiments showed that when XantPhos16 was combined with Pd2(dba)3, full conversion of 4ꢀ
bromoanisole (1) was achieved with a slight excess of Zn(CN)2 in dimethylacetamide (DMAc) at
85 °C. Unsurprisingly, attempted replacement of Pd2(dba)3 with commerciallyꢀavailable
XantPhosꢀPdCl2 resulted in no conversion of the aryl bromide, presumably because the Pd(II)
precursor does not undergo reduction to the active Pd(0) species under these conditions (Eq 1).
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We next tested the ability of various bases to reduce XantPhosꢀPdCl2 to the active Pd(0)
catalyst (Table 1). Because complete conversion was observed with 0.5 mol % of Pd2(dba)3 (1
mol % Pd loading), optimization was conducted with 1 mol % XantPhosꢀPdCl2. Inorganic and
amine bases were initially screened at a 4:1 ratio of base/palladium. CsOAc was not effective at
facilitating the cyanation (entry 1); however, two different potassium salts (KOAc and K2CO3)
provided moderate levels of conversion after 6 h (entries 2ꢀ3). Presumably, the modest
conversion can be attributed to the low solubility of these bases in DMAc. With 4 mol % of N,Nꢀ
diisopropylethylamine (DIPEA) and triethylamine (NEt3), complete conversion to the desired
nitrile was achieved with 0.60 equiv Zn(CN)2 (entries 4ꢀ5). Decreasing the amount of these two
organic bases to 2 mol % still afforded complete conversion to the desired product (entries 6ꢀ8),
and the amount of Zn(CN)2 can be reduced to 0.55 equiv without affecting the efficiency of the
conversion (entry 7). Employing 1 mol % of DIPEA and NEt3 resulted in diminshed levels of
conversion to the desired product, suggesting that a 2:1 base/palladium ratio was necessary for
the desired reaction (entries 9ꢀ10).
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To ensure optimal reaction conditions were determined, XantPhosꢀPdCl2 was tested in
different solvents (Table 1, entries 11ꢀ13). None of these solvents performed superior to DMAc,
presumably because of the increased solubility of the Zn(CN)2. Several other single component
palladium chloride precatalysts were tested under the optimized conditions (Table 1, entries 14ꢀ
16). These precatalysts performed poorly relative to XantPhosꢀPdCl2, where the highest
conversion to product was only 17 AP.
Table 1. Optimization of the Cyanation with XantPhos-PdCl2
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Ph
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P
Ph
1 mol % XantPhos-PdCl2
DMAc (1 M)
O
P
Br
CN
PdCl2
Ph
Ph
MeO
MeO
85 °C, 6 h
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2
XantPhos-Pd-Cl2
Producta
entry
base (mol %)
equiv. Zn(CN)2
SMa
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(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
CsOAc (4%)
KOAc (4%)
K2CO3 (4%)
NEt3 (4%)
DIPEA (4%)
NEt3 (2%)
DIPEA (2%)
DIPEA (2%)
NEt3 (1%)
0.60
0.60
0.60
0.60
0.60
0.55
0.55
0.60
0.60
0.60
0.55
0.55
0.55
0.55
0.55
0.55
97.3
66.4
69.2
00.3
00.1
00.5
00.3
00.6
12.4
89.7
61.3
88.0
66.3
100
02.7
33.6
30.8
99.7
99.9
99.5
99.7
99.4
87.6
10.3
38.7
12.0
33.7
0.00
16.3
17.4
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DIPEA (1%)
Dioxane as solvent
Toluene as solvent
MeTHF as solvent
(PPh3)2PdCl2
DPEPhos-PdCl2
DPPF-PdCl2
83.7
82.6
Reaction conditions: 4-Bromoanisole (1.0 mmol), Zn(CN)2 (0.55-0.60 equiv),
XantPhos-PdCl2 (0.01 equiv), base (0.01-0.04 equiv), DMAc. DIPEA is N,N-
diisopropylethylamine. NEt3 is triethylamine. (a) Conversion determined by ratio
of the HPLC areas of 4-bromoanisole and 4-methoxybenzonitrile
While NEt3 and DIPEA were equally as effective at facilitating the desired
transformation, DIPEA was chosen to investigate the substrate scope. A representative set of aryl
bromides were subjected to the general conditions to afford the corresponding benzonitriles
(Table 2), with all of the reactions conducted at greater than 1 g scale. Electronꢀwithdrawing
(entries 1ꢀ7), electronꢀdonating (entries 8ꢀ12), and electronꢀneutral (entries 13ꢀ15) aryl bromides
provided the desired products in yields of up to 96%. The mild reaction conditions are
demonstrated by the tolerance of nitrile, ester, ketone, nitro, and amine functional groups on the
aromatic ring. The electrophilic compatibility of the cyanation was tested by subjecting an array
of aryl (pseudo)halides to the reaction conditions (entry 15). Phenyl triflate and iodobenzene
afforded the benzonitrile product in high yield, whereas phenyl tosylate and chlorobenzene were
unreactive under the reaction conditions. Electronꢀpoor aryl chlorides show some reactivity
under the reaction conditions as demonstrated by the formation of 6% of the dinitrile product in
the cyanation of 3g (entry 7). Although 91% conversion was observed for the styrenyl bromide
3i, polymerization of the product was observed, attributing to the low isolated yield (entry 10).
Table 2. Scope of the Cyanation with Aryl Bromides
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A variety of heteroaryl bromides were also subjected to the optimized reaction conditions
(Table 3). Seven different heterocyclic bromides afforded the desired cyanation products in
yields of up to 93%. Nitrogenꢀcontaining heterocycles such as quinoline (entry 1), isoquinoline
(entry 2), pyridine (entries 3ꢀ4), and indole (entry 5) were successful coupling partners in the
cyanation. Fiveꢀmembered heterocyclic bromides, furan and thiophene (entries 6 and 7),
provided the corresponding products in yields of 63% and 79%, respectively.
Table 3. Scope of the Cyanation with Heteroaryl Bromides
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Attempts to elucidate the mechanism for the reduction of XantPhosꢀPdCl2 to the active
Pd(0) catalyst by 31P NMR were unsuccessful, presumably because of the instability of the Pd(0)
species. However, the kinetics of the Pd2(dba)3/XantPhos and XantPhosꢀPdCl2/DIPEA systems
were measured for three different substrates: an electronꢀwithdrawing (4ꢀbromobenzonitrile), an
electronꢀneutral (bromobenzene), and an electronꢀdonating aryl bromide (4ꢀbromoanisole).
Linear kinetics were observed for the consumption of the aryl bromide starting material for all
reactions, and there was not a significant difference in the initial reaction rates between the three
different substrates. A general trend was observed across the two catalytic systems (see
Supporting Information for graph of kinetics) in which the cyanation with Pd2(dba)3/XantPhos
was slightly faster in each case than the XantPhosꢀPdCl2/DIPEA system. The difference in
reaction rates between these two catalysts systems may be due to incomplete reduction of the
Pd(II) preꢀcatalyst in the XantPhosꢀPdCl2/DIPEA system.
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In summary, we report the use of DIPEA as a mild, homogeneous reducing agent to
facilitate the reduction of XantPhosꢀPdCl2 to an active Pd(0) catalyst, which has enabled a wide
array of (hetero)aryl nitriles to be prepared in high yield. The developed methodology allows for
the use of a wellꢀdefined and airꢀstable Pd(II) precursor for the cyanation of aryl bromides.
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EXPERIMENTAL SECTION
General Considerations. All reagents were purchased from commercial sources. Standard
benchtop techniques were employed for handling airꢀsensitive reagents. Melting points (°C) are
uncorrected. NMR spectra were recorded on a 400 or 500 MHz spectrometer. Data are presented
as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
br = broad), coupling constant J (Hz) and integration. Analytical thinꢀlayer chromatography
(TLC) was performed on TLC silica gel plates (0.25 mm) precoated with a fluorescent indicator.
Visualization of the TLC plates was effected with ultraviolet light. Standard flash
chromatography procedures were followed using 100ꢀ200 mesh silica gel. HRMS samples were
run on the Thermo LTQꢀOrbitrap with Acquity Classic inlet
General procedure for the cyanation. To a 20 mL scintillation vial with stir bar was added
XantPhosꢀPdCl2 (53 mg, 0.07 mmol, 0.01 equiv), (hetero)arylbromide (7 mmol), and zinc
cyanide (461 mg, 3.85 mmol, 0.55 equiv). The vial was capped with a pressure relief septa, and
evacuated and purged with N2 five times. Degassed N,NꢀDimethylacetamide (7 mL) (degassed
by sparging N2) was added along with degassed N,NꢀDiisopropylethylamine (24 ꢁL, 0.138
mmol, 0.02 equiv), all under N2. The reaction mixture was heated to 85 °C until complete
conversion was observed, as judged by HPLC. The reaction mixture was cooled to rt, and 20 mL
of an 10:2:88 (NaCl, K2CO3, H2O, wt %) solution was added followed by EtOAc (20 mL). The
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layers were separated, and the aqueous layer was extracted with EtOAc (2x20 mL). The
combined organics were washed with H2O (20 mL) and dried (Na2SO4). After concentrating in
vacuo, the crude product was purified by flash column chromatography to yield the desired
product.
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4-Methoxybenzonitrile (2). The title compound was obtained as a white solid in 96% yield (894
mg). mp 57ꢀ60 °C. 1H NMR (500 MHz, CDCl3): δ 7.60ꢀ7.57 (m, 2H), 6.97ꢀ6.92 (m, 2H), 3.86 (s,
13
3H); C NMR (125.8 MHz, CDCl3): δ 162.8, 133.9, 119.2, 114.7, 103.9, 55.5; Physical and
spectral data were in accordance with literature data.22
4-(Trifluoromethyl)benzonitrile (3a). The title compound was obtained as an offꢀwhite solid in
90% yield (1080 mg). mp 36ꢀ38 °C. 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J=10.0 Hz, 2 H),
7.79 (d, J=10.0 Hz, 2 H); 13C NMR (125.8 MHz, CDCl3): δ 134.5 (q, J=41.8 Hz), 132.2, 126.2
(q, J=5.0 Hz), 123.1 (q, J=338.8 Hz), 117.5, 116.1. 19F NMR (470 MHz, CDCl3): δ ꢀ63.5.
Physical and spectral data were in accordance with literature data.17
4-Fluorobenzonitrile (3b). The title compound was obtained as a white solid in 82% yield (696
mg). mp 34ꢀ36 °C. 1H NMR (500 MHz, CDCl3): δ 7.71 (dd, J=12.5, 7.5 Hz, 2 H), 7.21 (dd,
J=12.5, 12.5 Hz, 2 H); 13C NMR (125.8 MHz, CDCl3): δ 165.1 (d, J=320 Hz), 134.7 (d, J=10.0
Hz), 118.1, 116.9 (d, J=28.8 Hz), 108.6 (d, J=5.0 Hz). 19F NMR (470 MHz, CDCl3): δ ꢀ102.4.
Physical and spectral data were in accordance with literature data.18
Terephthalonitrile (3c). The title compound was obtained as a white solid in 83% yield (1202
1
13
mg). mp 222ꢀ224 °C. H NMR (500 MHz, DMSOꢀd6): δ 8.08 (s, 4H); C NMR (125.8 MHz,
DMSOꢀd6): δ 133.2, 117.5, 115.7; Physical and spectral data were in accordance with literature
data.19
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Methyl-3-cyanobenzoate (3d). The title compound was obtained as a white solid in 80% yield
(902 mg). mp 59ꢀ61 °C. 1H NMR (400 MHz, CDCl3): δ 8.34 (dt, 1H, J = 1.7, 0.8 Hz), 8.28 (dt,
1H, J = 7.9, 1.5 Hz), 7.85 (dt, 1H, J = 7.8, 1.4 Hz), 7.60 (t, 1H, J = 7.8 Hz), 3.97 (s, 3H); 13C
NMR (100.6 MHz, CDCl3): δ 165.0, 135.9, 133.6, 133.2, 131.3, 129.4, 117.8, 112.9, 52.6.
Physical and spectral data were in accordance with literature data.
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4-Benzoylbenzonitrile (3e). The title compound was obtained as a white solid in 83% yield
1
(1202 mg). mp 111ꢀ113 °C. H NMR (500 MHz, CDCl3): δ 7.91−7.86 (m, 2H), 7.79 (m, 4H),
13
7.69−7.61 (m, 1H), 7.54−7.50 (m, 2H); C NMR (125.8 MHz, CDCl3): δ 195.0, 141.2, 136.3,
133.3, 132.2, 130.2, 130.0, 128.6, 118.0, 115.6; Physical and spectral data were in accordance
with literature data.20
3-Nitrobenzonitrile (3f). The title compound was obtained as a white solid in 86% yield (889
mg). mp 112ꢀ114 °C. 1H NMR (400 MHz, CDCl3): δ 8.55 (t, 1H J = 1.8 Hz), 8.49 (ddd, 1H, J =
8.3, 2.3, 1.0 Hz), 8.01 (dt, 1H, J = 7.8, 1.3 Hz), 7.75 (t, 1H, J = 8.3 Hz); 13C NMR (100.6 MHz,
CDCl3): δ 148.2, 137.6, 130.6, 127.5, 127.2, 116.5, 114.1. Physical and spectral data were in
accordance with literature data.21
4-Chlorobenzonitrile (3g). The title compound was obtained as a white solid in 84% yield (813
mg). mp 90ꢀ93 °C. 1H NMR (400 MHz, CDCl3): δ 7.63ꢀ7.60 (m, 2H), 7.49ꢀ7.46 (m, 2H); 13C
NMR (100.6 MHz, CDCl3): δ 139.5, 133.3, 129.6, 117.9, 110.7. Physical and spectral data were
in accordance with literature data.22
3,5-Dimethoxybenzonitrile (3h). The title compound was obtained as a white solid in 90% yield
(1027 mg). mp 84ꢀ86 °C. 1H NMR (500 MHz, CDCl3): δ 6.76 (d, J = 2.3 H, 2H), 6.65 (t, J = 2.3
Hz, 1H), 3.81 (s, 6H); 13C NMR (125.8 MHz, CDCl3): δ 160.9, 118.7, 113.4, 109.8, 105.6, 55.6;
Physical and spectral data were in accordance with literature data.14
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3-Vinylbenzonitrile (3i). The title compound was obtained as a colorless oil in 39% yield (280
mg). 1H NMR (500 MHz, CDCl3): δ 7.59ꢀ7.57 (m, 2 H), 7.52 (d, J=10.0 Hz, 1 H), 7.42 (t,
J=10.0 Hz, 1 H), 6.68 (ds, J=17.5, 12.5 Hz, 1 H), 5.81 (d, J=17.5 Hz, 1 H), 5.38 (d, J=12.5 Hz, 1
H); 13C NMR (125.8 MHz, CDCl3): δ 138.7, 134.8, 131.1, 130.4, 129.8, 129.4, 118.8, 116.6,
112.8. Physical and spectral data were in accordance with literature data.23
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2-Methylbenzonitrile (3j). The title compound was obtained as a colorless oil in 60% yield (488
mg). 1H NMR (500 MHz, CDCl3): δ 7.61 (dd, J=10.0, 1.0 Hz, 1 H) 7.50 (td, J=10.0, 1.0 Hz, 1
H), 7.34ꢀ7.27 (m, 2 H), 2.57 (s, 3 H); 13C NMR (125.8 MHz, CDCl3): δ 141.9, 132.7, 132.5,
130.2, 126.2, 118.2, 112.8, 20.5. Physical and spectral data were in accordance with literature
data.17
4-(N, N-Dimethylamino)benzonitrile (3k). The title compound was obtained as a white solid in
51% yield (523 mg). mp 73ꢀ75 °C. 1H NMR (400 MHz, CDCl3): δ 7.46 (d, 2H, J = 8.8 Hz), 6.64
(d, 2H, J = 9.1 Hz), 3.04 (s, 6H); 13C NMR (100.6 MHz, CDCl3): δ 152.4, 133.3, 120.7, 111.4,
97.3, 39.9. Physical and spectral data were in accordance with literature data.25
2-Cyanonaphthalene (3l) The title compound was obtained as a white solid in 91% yield (975
1
mg). mp 62ꢀ64 °C. H NMR (CDCl3, 400MHz): δ = 8.21 (s, 1H), 7.94ꢀ7.86 (m, 3H), 7.68ꢀ7.57
(m, 3H); 13C NMR (CDCl3, 100 MHz): δ = 134.5, 134.0, 132.1, 129.1, 128.9, 128.3, 128.0,
127.6, 126.2, 119.2, 109.2. Physical and spectral data were in accordance with literature data.24
1-Cyanonaphthalene (3m). The title compound was obtained as a white solid in 91% yield (978
mg). mp 34ꢀ36 °C. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, 1H, J = 8.3 Hz), 8.10 (d, 1H, J = 8.3
Hz), 7.96ꢀ7.93 (m, 2H), 7.72 (ddd, 1H, J = 8.3, 7.1, 1.3 Hz), 7.66ꢀ7.62 (m, 1H), 7.55 (dd, 1H, J =
8.3, 7.1 Hz); 13C NMR (100.6 MHz, CDCl3): δ 133.0, 132.6, 132.3, 132.0, 128.4, 128.3, 127.3,
124.7, 124.6, 117.6, 109.8. Physical and spectral data were in accordance with literature data.25
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Benzonitrile (3n). The title compound was obtained as a white solid in 94% yield (678 mg) from
bromobenzene. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, 1H, J = 8.3 Hz), 8.10 (d, 1H, J = 8.3 Hz),
7.96ꢀ7.93 (m, 2H), 7.72 (ddd, 1H, J = 8.3, 7.1, 1.3 Hz), 7.66ꢀ7.62 (m, 1H), 7.55 (dd, 1H, J = 8.3,
7.1 Hz); 13C NMR (100.6 MHz, CDCl3): δ 133.0, 132.6, 132.3, 132.0, 128.4, 128.3, 127.3,
124.7, 124.6, 117.6, 109.8. Physical and spectral data were in accordance with literature data.19
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4-Cyanoquinoline (4a) The title compound was obtained as a white solid in 93% yield (1003
mg). mp 103ꢀ106 °C. 1 H NMR (CDCl3, 400MHz): δ = 9.00 (d, 1H, J = 4.3 Hz), 8.18ꢀ8.13 (m,
2H), 7.83 (ddd, 1H, J =8.4, 7.0, 1.5 Hz), 7.70 – 7.74 (m, 2H); 13C NMR (100 MHz, CDCl3).
= 149.4, 147.9, 131.3, 130.3, 129.3, 125.7, 124.9, 124.9, 118.7, 115.5. Physical and spectral data
were in accordance with literature data.26
6-Cyanoisoquinoline (4b). The title compound was obtained as a white solid in 83% yield (1202
mg). mp 137ꢀ140 °C. 1H NMR (500 MHz, CDCl3): δ 9.32 (d, J = 1 Hz, 1H), 8.69 (d, J = 5.8 Hz,
1H), 8.2 ppm (m, 1H), 8.08 (dd, J = 7.2 Hz, 1.1 Hz, 1H), 7.95 (m, 1H), 7.66 (dd, J = 8.3 Hz, 7.3
13
Hz, 1H); C NMR (125.8 MHz, CDCl3): δ 152.9, 145.4, 136.4, 135.0, 132.7, 127.7, 126.5,
117.4, 116.3, 109.4; IR (neat) 3092, 3064, 2224, 1615, 1494, 1373, 1029, 824, 765 cmꢀ1; HRMS
(ESI) m/z: calcd for C10H7N2 [M+H]+ 155.06037, found 155.06013.
4-Cyano-2,6-lutidine (4c). The title compound was obtained as a white solid in 73% yield (675
mg). mp 81ꢀ84 °C. 1H NMR (400 MHz, CDCl3): δ 7.19 (s, 2H), 2.58 (s, 6H); 13C NMR (100.6
MHz, CDCl3): δ 159.3, 121.7, 120.7, 116.9, 24.4. Physical and spectral data were in accordance
with literature data.21
tert-Butyl 5-cyanopyridin-2-ylcarbamate (4d). The title compound was obtained as a white
solid in 75% yield (1145 mg). mp 190ꢀ192 °C. 1H NMR (500 MHz, CDCl3): δ 9.10 (s, br, 1 H),
8.63 (s, 1 H), 8.18 (d, J=8.0 Hz 1 H), 7.93 (dd, J=8.0, 4.0 Hz 1 H), 1.59 (s, 9H); 13C NMR (125.8
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MHz, CDCl3): δ 155.1, 151.7, 141.4, 116.9, 112.2, 103.4, 82.5, 28.2; IR (neat) 3181, 3067, 2980,
2230, 1723, 1524, 1256, 1150, 770 cmꢀ1; HRMS (ESI) m/z: calcd for C11H14N3O2 [M+H]+
220.10805, found 220.10782.
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tert-Butyl 5-cyano-1H-indole-1-carboxylate (4e). The title compound was obtained as a white
1
solid in 85% yield (1441 mg). mp 125ꢀ127 °C. H NMR (500 MHz, CDCl3): δ 8.26 (d, J = 8.6
Hz, 1 H), 7.9 (dd, J = 1.5 Hz, 0.8 Hz, 1 H), 7.71 (d, J = 3.8 Hz, 1H), 7.56 (dd, J = 8.7 Hz, 1.4 Hz,
13
1H), 6.63 (dd, J = 3.8 Hz, 0.8 Hz, 1H), 1.69 (s, 9H); C NMR (125.8 MHz, CDCl3): δ 148.9,
137.0, 130.4, 128.0, 127.2, 125.7, 119.7, 115.9, 106.8, 106.0, 84.8, 28.0; Physical and spectral
data were in accordance with literature data.27
Furan-3-carbonitrile (4f). The title compound was obtained as a brown solid in 63% yield (408
mg). mp 26ꢀ28 °C. 1H NMR (500 MHz, CDCl3): δ 7.98 (t, J=1.5 Hz, 1 H), 7.53 (t, J=2.0 Hz, 1
H), 6.66 (t, J=2.0 Hz, 1 H); 13C NMR (125.8 MHz, CDCl3): δ 149.7, 144.1, 113.1, 111.1, 97.9.
Physical and spectral data were in accordance with literature data.28
Thiophene-3-carbonitrile (4g). The title compound was obtained as a yellow oil in 79% yield
(604 mg). 1H NMR (500 MHz, CDCl3): δ 7.97 (dd, J=5.0, 1.5 Hz, 1 H), 7.46 (dd, J=10.0, 3.0 Hz,
1 H), 7.33 (dd, J=10.0, 1.5 Hz, 1 H); 13C NMR (125.8 MHz, CDCl3): δ 135.5, 128.7, 127.4,
115.2, 110.7. Physical and spectral data were in accordance with literature data.18
ASSOCIATED CONTENT
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13
Kinetic Data, copies of H and C NMR spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
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The Chemical and Synthetic Development senior leadership team is acknowledged for their
support during the preparation of this manuscript. Jonathan Marshall (BMS) is acknowledged for
obtaining HRMS data. Robert Wethman (BMS) is acknowledged for helping to obtain IR
spectra. Thomas Razler and Michael Schmidt (BMS) are acknowledged for reviewing the
manuscript.
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