Overcoming challenges in the palladium-catalyzed synthesis of electron deficient ortho-substituted aryl acetonitriles

Article abstract of DOI:10.1039/c0ob00903b

Highly electron deficient monoaryl, di-aryl and bis-diaryl acetonitriles were effectively synthesized using either a nucleophilic aromatic substitution (NAS) or a palladium-mediated coupling pathway. Synthesis of di-aryl acetonitriles most conveniently pr

Full text of DOI:10.1039/c0ob00903b

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Overcoming challenges in the palladium-catalyzed synthesis of electron
deficient ortho-substituted aryl acetonitriles†
Molly C. Brannock, William J. Behof, Gregory Morrison and Christopher B. Gorman*
Received 19th October 2010, Accepted 3rd February 2011
DOI: 10.1039/c0ob00903b
Highly electron deficient monoaryl, di-aryl and bis-diaryl acetonitriles were effectively synthesized
using either a nucleophilic aromatic substitution (NAS) or a palladium-mediated coupling pathway.
Synthesis of di-aryl acetonitriles most conveniently proceeded via NAS – palladium-mediated coupling
was not required. This reaction, however, results in a product that is more acidic than the reactants.
Facile deprotonation of the product prevents efficient formation of the bis-diaryl acetonitrile through a
NAS pathway. Thus, palladium-mediated coupling is required to prepare the bis-diaryl acetonitrile
efficiently. In the palladium-catalyzed coupling, choice of base and solvent (and thus the counter cation
for the benzylic anion nucleophile) is important. Also, choice of the supporting ligand is important,
indicating the sensitivity of the reaction to steric and ligand electronic effects.
As part of an ongoing research program in the synthesis of
cyano-containing polymers, we became interested in synthesizing
oligomers and polymers with the general repeat unit shown in
Scheme 1. We have recently reported the cascading cyclization
of similar aryl and benzyl cyano-containing oligomers to form
isoquinoline-type fused-ring molecules (Scheme 2).1 These conju-
gated materials may have potential for use in organic devices.
The key synthetic step here is the carbon–carbon bond forma-
tion of a benzyl/phenyl linkage to form a diaryl methane subunit.
Scheme 1 shows the two logical bond deconstructions that could
give rise to this linkage. The aryl group could be nucleophilic
and the benzylic position would then be the electrophile (Scheme
1, top). Alternatively, these roles could be reversed (Scheme 1,
bottom).
Using an aryl organometallic as a nucleophilic equivalent has
been useful to prepare aryl–aryl and aryl–alkyl linkages.2–4 The
use of aryl nucleophiles with ortho substituents, however, has
had mixed results.5 In contrast, deprotonation of RCH2CN or
Scheme
1
Two possible methods of coupling to form
a
R2CHCN and subsequent use as a nucleophilic equivalent has
had several successful precedents. You and Verkade6,7 illustrated
coupling of alkyl acetonitrile anions to aryl halides in the presence
of a proazaphosphatrane ligand. Hartwig et al., Satoh et al. and
Verkade et al. employed, with high efficiency, phenyl acetonitrile
for monoarylations and acetonitrile for di-arylations.6–11 Culkin
and Hartwig8,10 showed that the anion of alkyl nitriles could
undergo a palladium-mediated coupling to aryl halides and
studied the mechanism of this transformation in some detail.
Wu and Hartwig11 later showed that an a-silyl nitrile was an
bis(o-cyanophenyl)acetonitrile (M = metal counterion, LG = leaving
group).
efficient palladium-mediated coupling partner to aryl halides in
the presence of zinc fluoride.
Given these precedents, a cyanobenzyl nucleophile was selected
for this coupling. Moreover, o-cyanophenyl acetonitrile is rela-
tively acidic, (19.2 in dimethyl sulfoxide (DMSO))12 and thus
easily deprotonated. The resulting carbanion would then be a
suitable nucleophile in a carbon–carbon coupling reaction. The
pKa determination of similar molecules containing such groups
will be reported below. Furthermore, the arene is relatively electron
deficient which renders it a good electrophile.
Box 8204, Department of Chemistry, North Carolina State University,
Raleigh, NC, 27695-8204, USA. E-mail: cbgorman@ncsu.edu; Fax: +1-
919-515-8920; Tel: +1-919-515-4252
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0ob00903b
The examples given above suggest several challenges and raise
several questions regarding the carbon–carbon bond forming
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Scheme 4 NAS reactions run to compare with previously reported,
Pd-mediated couplings. Conditions: (CH3)2CHCN, sodium hexamethyl-
disilazide (NaHMDS), toluene (i) 1a, 100 ◦C, 1 h (ii) 1b, 90 ◦C, 2 h.
palladium/ligand under the same conditions and obtained 42%
(X = Br) and 72% (X = Cl) yield, respectively. Thus, palladium-
mediated coupling does result in a higher yield. However, in this
case, the results provide evidence for competition between NAS
and the palladium-mediated pathway.
We then turned to the NAS of 2,6-dichlorobenzonitrile (3a) with
o-cyanophenyl acetonitrile (4). When two equivalents of 4 were
reacted with 3a in the presence of sodium tert-butoxide (NaOtBu)
(Scheme 5), only the mono-coupled product 5a was obtained in
91% yield. When 5a was isolated and reacted with 4 for a longer
period of time (72 h) and in excess (3.2 equivalents) base, only a
small amount (13%) of bis-coupled product 6a was isolated. This
reaction was clearly inefficient for the formation of 6.
Scheme 2 Example of the conversion of a multiple-cyano containing
oligomer to the fully cyclized, aromatic product.
reaction under study here. First, since our proposed arene is so
electron deficient, can simple nucleophilic aromatic substitution
compete with palladium-mediated coupling? This question may
also be relevant in some of the examples shown above. Second,
in the work above, limitations were observed when ortho cyano
groups were present on the arene electrophile.13 The presence of
o-cyano groups in our target might thus be an issue. Third, since
the methine proton in the product (e.g. Ph2(CN)CH) should be
more acidic than the proton that must be removed in the starting
material (e.g. Ph(CN)CH2), can the reaction be driven forward in
a reaction solution in which a less acidic proton must be removed
in the presence of a more acidic proton? This issue is illustrated in
Scheme 3.
Scheme 5 Attempted formation of 6a via NAS.
Our strategy then shifted toward a palladium-mediated cou-
pling given the poor results when attempting to prepare 6 via NAS.
Culkin and Hartwig8 showed that Pd(OAc)2/BINAP is an efficient
palladium/ligand combination to couple phenyl acetonitrile an-
ions with p-tBu-bromobenzene. These conditions were used as the
starting point to optimize the reaction for the formation of 6.
Because it is the second coupling that is challenging, the reaction
of 5 with 4 was explored. Since palladium-mediated couplings
typically are more efficient on aryl bromides than chlorides, 3a
was replaced with 3b, and 5b was synthesized in 93% yield using
NAS in dimethyl formamide (DMF) (Scheme 6).
Scheme 3 Equilibrium between benzylic anions.
In this paper, nucleophilic aromatic substitution and palladium-
mediated coupling reactions will be explored to determine how
efficiently the reaction illustrated in the bottom half of Scheme
1 can occur. The relative efficacy of these two pathways will
be compared. Choice of base, solvent, and catalyst/ligand will
be shown to be key parameters in optimizing the palladium-
catalyzed coupling. Finally, an optimal, high yielding route will
be illustrated.
In the work of Hartwig et al.8,10,11 and You and Verkade6,7
discussed above, both electron rich and electron deficient aryl
halide substrates were explored. In the coupling of interest here,
the aryl halide is electron deficient, begging the question as to
whether, in this case, a nucleophilic aromatic substitution (NAS)
reaction would be applicable. We tested this in three ways. First, a
reaction from the literature was repeated under NAS conditions.
Then from this, two new coupling reactions were explored.
Initially, the NAS pathway was investigated in the case of an
electron deficient arene. Culkin and Hartwig reported formation
of 2 from p-bromobenzonitrile (1a) in 99% yield in the presence of
palladium acetate (Pd(OAc)2) and 2,2¢-bis(diphenylphosphino)-
1,1¢-binaphthyl (BINAP),8 and You and Verkade reported a
similar reaction using p-chlorobenzonitrile (1b) to achieve 2 in
92% yield in the presence of Pd(OAc)2 and a proazaphosphatrane
ligand (Scheme 4).6 We repeated these reactions in the absence of
Scheme 6 Preparation of 5b.
Reaction of 4 and 5 under palladium-mediated conditions was
then explored. The results are shown in Table 1. A maximum yield
of 62% was obtained. Comparison of entries 1 and 2 in Table 1
indicates that use of the aryl bromide indeed does result in a higher
yield. Comparison of entries 2 and 3 indicates that NAS is less
efficient compared to palladium-mediated coupling. Comparison
of entries 3 and 4 in Table 1 indicates that microwave heating was
more efficient than thermal heating and gave a much higher yield
of product. Moreover, extending the reaction time under thermal
heating showed no further increase in yield when the reaction
time was increased from 4 h to 6 h. For these reasons, microwave
heating was used in all subsequent reactions. Also, poor yields
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Table 1 Results of coupling 5 and 4 under Pd-mediated coupling
conditions
Table 2 Variation of base
Yield% ofa
Entry
Eq. KOtBu
Heat Source
T/◦C
Time
% 6ba
Entry
Base
Recovered 5b
6b
1
2
3
4a
4b
4c
5
3.2
3.2
3.2
3.2
3.2
3.2
2.1
1.1
Microwave
Microwave
Microwave
Thermal
Thermal
Thermal
130
130
130
80
80
80
5 min
5 min
5 min
2 h
4 h
6 h
0b
33c
62
17
37
36
29
5
1
2
3
4
5
6
7
8
CsF
NEt3
Pyridine
Ph2NH
Cs2CO3
NaOMe
NaOiPr
LiOtBu
NaOtBu
KOtBu
93
100
97
98
87
47
53
100
74
15
3
4
ndb
nd
1
8
22
1
nd
26
62
37
Microwave
Microwave
130
130
5 min
5 min
6
Conditions: 0.3 M THF, 1.2 eq. 4, 0.1 eq. Pd(OAc)2, 0.2 eq. BINAP.a Values
obtained from HPLC with an estimated error of 5%. b Molecule 5a was
used instead of molecule 5b. c No Pd catalyst or BINAP was added.
9
10
11
KOtBu/0.1 eq.
18-crown-6
Conditions: 0.3 M in THF, 1.2 eq. 4, 3.2 eq. base, 0.1 eq. Pd(OAc)2, 0.2
eq. BINAP, 130 ◦C, mW, 100 W, 5 min. a Values obtained from HPLC with
an estimated error of 5%. b Not detected by HPLC.
were obtained when fewer than 3 equiv. of base were added. This
point is treated below.
Palladium-catalyzed coupling can be greatly influenced by the
base employed. Furthermore, the data above indicate that excess
base is required. This requirement likely results because (1) both 5
and 6 are deprotonated preferentially to 4 and (2) any equilibrium
between 5- or 6- and 4 favors 5- or 6-. At first, we speculated
that the opposite might be true. You and Verkade showed that
the reaction between bromobenzene and benzyl cyanide to form
diphenyl acetonitrile could be accomplished in 93% yield using
1.4 equivalents of sodium hexamethyl disilazide.6 The pKa values
of benzyl cyanide and diphenyl acetonitrile are 21.9 and 17.5,
respectively.14 Thus, we speculate that there likely was some
equilibrium between the anion of the product and that of the
starting material in this case. However, in our case, the o-cyano
groups likely have an important influence on the pKa (and more
importantly, the relative pKa) values of our starting materials and
product.
To determine the relative acidity of the protons on 4, 5 and 6,
pKa measurements in DMSO were performed using the procedure
developed by Bordwell et al.15 The pKa of 4 was measured to be
19.2, consistent with that reported in the literature.12 Molecule
5b had a pKa of 13.6 and molecule 6b had pKa1 and pKa2 values
of 13.2. The similarity of the two pKa values for 6b is consistent
with the findings of Streitwieser where unfused diprotic structures
were determined to have indistinguishable pKa values.16 Thus, if
the anion of 4 is produced, it is likely in equilibrium with the anion
of 5 (cf. Scheme 3) and the (di)anion of 6. Given the values, this
equilibrium is likely to be unfavorable, resulting in the need to use
more than one, or even two, equivalents of base. This need is in
contrast to the results reported by You and Verkade above.
The pKa values may be only partially relevant, however. There
are reports that suggest weak bases such as potassium carbonate
(K2CO3)17 and dimethylamino pyridine (DMAP)18 are able to
deprotonate 4. However, in THF the relative acidities of 4–6 might
be quite different. Based on computations, Ding et al. suggest that
neutral acids are typically eleven orders less acidic in THF than in
DMSO.19 Furthermore, even if the anions of 5 and 6 are produced,
they may be innocent or unreactive. Their reactivity particularly
depends on the solvent and counter-cation present.20 Thus, some
variation of base, solvent and counter-cation was explored.
To explore variation of base in an efficient manner, reactions
were conducted under otherwise identical conditions and analyzed
by HPLC. Both the percentage of unreacted 5 and the percentage
of 6 are given in Table 2. Weak bases (entries 1–5) clearly
were ineffective. Potassium tert-butoxide yielded the greatest
conversion. Addition of 18-crown-6, however, resulted in little
recovered starting material or product. Thus, use of the larger
potassium counterion favors product formation, but complexation
of the potassium tends to produce side products (e.g. loss of
starting material without formation of product).
As this reaction generates anions that must transmetallate to
palladium, and as metalated nitriles form both complex aggregates
with counterions21 and also complex to palladium,7 the choice of
counterion and solvent is likely to have a large influence on the
efficiency of this reaction. Thus, several solvents were explored for
further optimization of the coupling. The results are presented in
Table 3. The best conditions found above are reproduced as Entry
1. Inoh et al. used Cs2CO3/DMF to deprotonate p-nitro toluenes
(pKa of 20.4 in DMSO),22 yet entries 2 and 3 in Table 3 indicate
poor conversion and loss of starting material when DMF was
used. When 6b was heated in DMF briefly, decomposition was
observed indicating that DMF is not a suitable solvent for this
reaction. N-Methylpyrrolidone (NMP) was tried as an alternative
polar, aprotic solvent (Table 3, entry 4). The desired product
was obtained in 20% yield with no starting material recovered.
However, when mixed NMP/THF was used (Table 3, entries 5–
9), excellent results were obtained. In 90/10 THF/NMP, in the
presence of 0.1 eq. 18-crown-6, an 83% yield of product was
obtained. Note that in the presence of NMP, 18-crown-6 increased
the reaction yield. This behavior was not the case in pure THF.
To test the efficiency of a milder base in this solvent system,
(Table 3, entries 10–13) several other, weaker bases than KOtBu
were explored. The moderate conversion to 6b using potassium
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Table 3 Variation of solvent and then further variation of base
Table 4 Variation of ligand
Yield% ofa
Yield% ofa
Entry Solvent
Ratio
Base
Recovered 5b
6b
Entry
Ligand
Recovered 5b
6b
1c
2
3
4
5
6
7
8
9
THF
—
—
—
—
KOtBu
KOtBu
Cs2CO3
KOtBu
15
14
28
ndb
5
24
ndb
ndb
62
31
26
20
71
65
71
49
83
1
2
3
4
5
6
7
8
BINAP
dppf
dppf
dppb
dppe
P(tBu)3
P(Cy)3
P(Ph)3
0
1
2
1
50
18
7
83b,c
75c
87
89
53
36
90
64
DMF
DMF
NMP
THF/NMP 90/10 KOtBu
THF/NMP 85/15 KOtBu
THF/NMP 80/20 KOtBu
THF/NMP 50/50 KOtBu
33
THF/NMP 90/10 KOtBu + 0.1 eq. ndb
Conditions: 0.3 M THF/NMP 90/10 solvent, 1.2 eq. 4, 3.2 eq. KOtBu, 0.1
eq. Pd(OAc)2, 0.2 eq. ligand, 130 ◦C, mW, 100 W, 5 min. a Values obtained
from HPLC with an estimated error of 5%. b Data from entry 9 of Table
3 repeated for ease of comparison. c 0.1 eq. 18-crown-6.
18-crown-6
10
11
12
13
THF/NMP 90/10 KOH
THF/NMP 90/10 Cs2CO3
THF/NMP 90/10 K2CO3
THF/NMP 90/10 K2CO3 + 0.1 eq. 94
18-crown-6
84
64
93
18
9
1
10
14
15
16
17
18
THF/NMP 90/10 KOCH3
THF/NMP 90/10 KOiPr
THF/HOtBu 75/25 KOtBu
THF/HOtBu 50/50 KOtBu
THF/HOtBu 25/75 KOtBu
4
76
6
18
21
47
16
75
63
61
solvent and supporting ligand. In the absence of palladium,
NAS could form the products, but not as efficiently as under
palladium-mediated coupling conditions. Microwave heating also
contributed substantially to the increased yield when compared to
thermal heating. KOtBu was found to be the best base in a 90/10
ratio of THF/NMP with P(Cy)3 as the supporting ligand.
Conditions: 1.2 eq. 4, 3.2 eq. base, 0.1 eq. Pd(OAc)2, 0.2 eq. BINAP,
130 ◦C, mW, 100 W, 5 min. a Obtained from HPLC with an estimated error
of 5%. b Not detected by HPLC. c Entry 10 of Table 2 repeated for ease
of comparison.
Experimental section
Instrumental analysis
hydroxide (KOH) (Table 3, entry 10) indicates that KOH was
strong enough for deprotonation, but this base was not efficient.
It was suspected that the formation of water upon the protonation
of hydroxide anion might be hindering the further formation of
product by inactivating the palladium. To test the effect of water
on the yield, reactions containing 0.22, 0.44, and 1.1 equivalents
of water were run. Yields were found to change minimally from
71% to 76% when 0.22 eq. were added, 70% when 0.44 equivalents
were added, but decreased dramatically from 71% to 39% when 1.1
eq. were added. Carbonate bases were also explored but gave poor
yields. The slightly less basic potassium methoxide and potassium
iso-propoxide gave little advantage in yield. Furthermore, addition
of tert-butyl alcohol (as a buffer) systematically decreased the yield
of the desired product. Thus the relatively strong potassium tert-
butoxide base was employed.
Next, additional monodentate and bidentate phosphine ligands
were tested for coupling efficiency (Table 4). The bidentate bis-
diphenylphosphinoferrocene (dppf) was used both in the presence
and absence of 18-crown-6 (entries 2 and 3 respectively). A
slight increase in yield was observed in the absence of 18-crown-
6, so subsequent reactions were run without this additive. Use
of the bidentate bis-diphenylphosphinobutane (dppb) and bis-
diphenylphosphinoethane (dppe) resulted in good yields (entries 4
and 5). Three monodentate ligands were then explored (entries 6, 7,
and 8). Of those tested, tri-cyclohexylphosphine (P(Cy)3) provided
the best results. The comparably poor yield obtained with P(tBu)3
indicates a large sensitivity to the steric bulk of the supporting
ligand.
HPLC was performed on a Grace Nucleosil C18 (5 micron, 4.6 mm
ID, 250 mm length) column. The mobile phase was a 70 : 30
acetonitrile/H2O solvent system at a flow rate of 1.0 mL min-1.
Solvents were filtered HPLC-grade, and the H2O was adjusted
to a pH of 2.88 using glacial acetic acid. 3,5-Dimethylanisole
served as the internal standard. UV-vis spectra were recorded on
a JASCO V-550 spectrophotometer. LCMS data were collected
from an Agilent Technologies 6210 LC-TOF mass spectrometer
equipped with an Agilent SB-C18 1.8 mm 2.1 ¥ 50 mm column.
Samples were diluted in methanol and analyzed via a 1 mL injection
at 400 mL min-1 in a water–methanol gradient with 0.1% formic
acid. The mass spectrometer was operated in positive-ion mode
with a capillary voltage of 4 kV, nebulizer◦pressure of 30 psig, and
a drying gas flow rate of 12 L min-1 at 350 C. The fragmentor and
skimmer voltages were 210 and 65 V, respectively.
pKa measurements
The procedure of Bordwell15 was followed for the pKa determi-
nation of mono-protic acids 4 and 5. DMSO was distilled under
reduced pressure from sodium amide and a few milligrams of
triphenylmethane without first being dried over molecular sieves.
All solvents and stock solutions were made and stored in the
nitrogen drybox until removed for spectral analysis in a quartz
cuvette capped with a rubber septum and parafilm to minimize
exposure to air and moisture. Unknown acids were first added
(via syringe) to the potassium dimsyl solutions and then titrated
with indicator acids. All indicators were purified as described in
the literature.23 Toluene and tetrahydrofuran were distilled from
sodium and benzophenone and were stored in a nitrogen filled dry
box. The pKa value for the diprotic acid 6 was obtained in the same
way, assuming that only the dianionic species was formed (e.g. no
Conclusions
In palladium-mediated coupling to form diaryl acetonitriles,
the reaction yield varied substantially with the choice of base,
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spectral signature for the intermediate, mono-anionic species was
observed during the titration).
Synthesis of 2,6-bis-[cyano-(2-cyano-phenyl)-methyl]-benzonitrile
(6a)
To 5a (80 mg, 0.29 mmol), 4 (50 mg, 0.35 mmol), and NaOtBu
(104 mg, 0.93 mmol) was added THF (1.5 mL) in the drybox. The
solution was allowed to react at reflux for 72 h. The reaction was
quenched using dilute HCl, extracted with EtOAc, and purified
by column chromatography on silica gel (1 : 1 EtOAc/hexanes) to
give the desired product (14.4 mg, 13%) as a white solid: Mp. >
240◦ (dec.); UV-vis (THF) lmax (log e): 225 (4.7), 278 (3.7) nm; 1H
NMR (CD2Cl2): d = 5.88 and 5.89 (s, 2H, diastereotopic), 7.51–
7.59 (m, 4H), 7.66–7.87 (m, 7H); 13C NMR (CD2Cl2): d = 40.3, 40.3
(diastereotopic), 113.2, 113.3, 113.5, 113.8, 114.4, 116.4, 116.5,
116.7, 116.8, 130.1, 130.5, 130.5, 130.7, 130.7, 134.4, 134.5, 134.8,
135.0, 136.5, 136.5, 139.2; IR (KBr): 3076, 2924, 2227, 1595, 1450,
1266, 763 cm-1; ESI-MS (210 V, MeOH–0.1% formic acid) m/z
(%): 406 ([MH+Na]+, 100), 384 (49), 385 (12), 407 (26). HRMS
(ESI) for C25H13N5 [M+H]+ calcd 383.1171, found 383.1167.
Synthesis of 4-(cyano-dimethyl-methyl)-benzonitrile (2)
NaHMDS (256 mg, 1.4 mmol) and toluene (2 mL) were added to a
Schlenk flask containing 4-chlorobenzonitrile (137 mg, 1 mmol).
Under nitrogen, isobutyronitrile (83 mg, 1.2 mmol) was added
dropwise and allowed to react at 90 ◦C for 2 h. The reaction was
quenched using dilute HCl, extracted with EtOAc, and purified
by column chromatography on silica gel (1 : 4 EtOAc/hexanes) to
give the desired product (123 mg, 72%) as a pale yellow solid. All
spectral data matched reported values.6,8 Mp: 86–88 ◦C; 1H NMR
(CD2Cl2): d = 1.75 (s, 6H), 7.63 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6
Hz, 2H); 13C NMR (CD2Cl2): d = 29.0, 37.7, 112.2, 118.4, 123.5,
126.3, 133.0, 146.7; IR (KBr): 3040, 2985, 2920, 2225, 1608, 1505,
1475, 1468, 1454, 1404, 1390, 1368, 1288, 1237, 1198, 1181, 1102,
1021, 930, 766, 734, 631, 569, 551, 541 cm-1.
Synthesis of 2,6-bis-[cyano-(2-cyano-phenyl)-methyl]-4-
methyl-benzonitrile (6b)
To a microwave vial was added 5b (84 mg, 0.25 mmol), 4 (43
mg, 0.3 mmol), KOtBu (90 mg, 0.8 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol), P(Cy)3 (16.8 mg, 0.050 mmol), THF (450 mL), NMP
(50 mL), and 3,5-dimethylanisole as an internal standard (350 mL).
The◦mixture was allowed to react in the microwave reactor at
130 C, 100 W, for a run time of 3 min, hold time of 5 min, and
pressure limit of 150 psi. An aliquot was removed and diluted in
a 70 : 30 acetonitrile/acidified H2O (pH = 2.88) solution, filtered,
and analyzed by HPLC to yield converted product and recovered
starting material. Mp. > 240 ◦C (dec.); UV-vis (THF) lmax (log e):
225 (4.8), 250 (4.1), 278 (3.8) nm; 1H NMR (CDCl3): d = 2.51–2.56
(s, 3H, diastereotopic), 5.81–5.82 (s, 2H, diastereotopic), 7.49–7.61
(m, 6H), 7.68–7.79 (m, 4H); 13C NMR (CDCl3): d = 22.4, 22.5
(diastereotopic), 39.8, 39.9 (diastereotopic), 110.0, 110.5, 112.9,
113.1, 114.1, 114.1, 116.0, 116.1, 116.3, 116.3, 129.7, 129.7, 130.0,
130.1, 131.0, 134.0, 134.0, 134.4, 136.1, 136.2, 138.5, 146.3, 146.4;
IR (KBr): 3061, 2920, 2225, 1604, 1447, 1265, 1199, 1114, 873, 760,
736, 700 cm-1; ESI-MS (210 V, MeOH–0.1% formic acid) m/z (%):
420 ([MH+Na]+, 100), 398 (43), 399 (11), 421 (27). HRMS (ESI)
for C26H15N5 [M+H]+ calcd 397.1327, found 397.1320.
Synthesis of 2-chloro-6-[cyano-(2-cyano-phenyl)-methyl]-
benzonitrile (5a)
To a stirring solution of KOtBu (246 mg, 2.2 mmol) in THF (4 mL)
was added 4 (340 mg, 2.4 mmol) dropwise. Upon anion formation,
the solution was added dropwise to a Schlenk flask containing a
stirring solution of 2,6-dichlorobenzonitrile (172 mg, 1.0 mmol) in
THF (1 mL). The combined solution was allowed to react at 80 ◦C
for 16 h. The reaction was quenched using dilute HCl, extracted
with EtOAc, and purified by column chromatography on silica gel
(1 : 2 EtOAc/hexanes) to give th◦e desired product (253 mg, 91%)
1
as a yellow solid: Mp: 138–142 C; H NMR (CDCl3): d = 5.87
(s, 1H), 7.51–7.76 (m, 7H); 13C NMR (CDCl3): d = 39.9, 112.8,
113.6, 113.7, 116.1, 116.4, 127.9, 129.8, 130.2, 130.8, 134.2, 134.4,
134.6, 135.9, 138.9, 139.0; IR (KBr): 2917, 2229, 1589, 1483, 1446,
1204, 1172, 1138, 889, 768, 632 cm-1; Anal. Calcd for C16H18ClN3
(277.04): C, 69.20; H, 2.90; N, 15.13. Found: C, 69.35; H, 2.87; N,
15.03.
Synthesis of 2-bromo-6-[cyano-(2-cyano-phenyl)-methyl]-4-
methyl-benzonitrile (5b)
Acknowledgements
To a stirring solution of KOtBu (1.38 g, 12.3 mmol) in DMF
(15.5 mL) was added 4 (1.91 g, 13.4 mmol). The solution was
stirred for 30 min then added dropwise to a stirring solution of
3b (1.55 g, 5.6 mmol) in DMF (7.8 mL) in a Schlenk flask. The
solution was heated to 85 ◦C and allowed to react under nitrogen
for 12 h. The reaction was quenched using 2 M HCl, extracted with
EtOAc, rinsed with brine, and purified by column chromatography
on silica gel (1 : 2 EtOAc/hexanes) to give the desired product (1.75
g, 93%) as a white solid: Mp: 141–144 ◦C; 1H NMR (CDCl3): d =
2.43 (s, 1H), 5.83 (s, 1H), 7.36–7.75 (m, 7H); 13C NMR (CDCl3): d
= 21.8, 39.7, 112.6, 112.7, 114.9, 116.0, 116.2, 127.1, 129.1, 129.5,
129.9, 133.9, 134.2, 134.3, 135.8, 138.4, 146.2; IR (KBr): 3072,
2921, 2229, 1598, 1551, 1485, 1451, 1290, 1255, 1213, 1099, 911,
863, 766, 732, 652 cm-1; Anal. Calcd for C17H10BrN3 (335.01): C,
60.73; H, 3.00; N, 12.50. Found: C, 60.68; H, 2.98; N, 12.33.
This work was supported by the Department of Energy (Grant
DE-FG02-05ER46238). Mass spectra were obtained at the NCSU
Department of Chemistry Mass Spectrometry Facility. Funding
was obtained from the North Carolina Biotechnology Center and
the NCSU Department of Chemistry.
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