J. Li et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 3
Table 2 (continued)
Entry Arenediazonium tetrafluoroborate
Br
a
Optimization of reaction conditions with aryl iodide
Product
Yielda (%)
OCH
3
OCH
3
Br
catalyst/additive
temp, solvent, time
CH
3
CH
3
+
NCTS
1
1
1
1
1
1
2
3
4
5
6
7
53
I
CN
3
l
N2+BF -
4
CN
2a
3a
Br
Br
Entry Catalyst
Additive
(equiv)
Time Temp Solvent
Yieldb
(%)
(
equiv)
(h)
(°C)
36
42
52
59
62
1
2
3
4
5
6
7
PdCl
Pd(PPh
Pd(OAc)
PdCl
PdCl
PdCl
PdCl
2
(0.15)
Cl
(0.15)
Ag
2
2
2
2
2
2
2
O (0.5)
O (0.5)
24
24
70
70
EtOH
EtOH
EtOH
toluene
dioxane
66b
n.r.c
62
H
3
C
CH
3
H
3
C
CH
3
+BF -
3m
3
)
2
2
(0.15) Ag
N
2
4
CN
2
Ag
Ag
Ag
Ag
Ag
CO
3
(0.5) 24
70
NO2
NO2
d
2
2
2
2
(0.15)
(0.15)
(0.15)
(0.15)
O (0.5)
O (0.5)
O (0.5)
O (0.5)
24
24
24
24
100
100
80
n.r.
tracee
n-propanol 15
isopropanol trace
58
3n
N
2
+BF -
COOC H5
4
CN
a
Reaction conditions: reactions were carried out with 4-iodoanisole 2a
(0.5 mmol), NCTS (1.0 mmol, 2.0 equiv) in solvent (5.0 mL), under air.
COOC H5
2
2
b
Isolated yield.
No reaction.
c
d,e
Carried out in sealed tube.
3o
N
2
+BF -
COCH
4
CN
COCH
3
3
3
Furthermore, p-CH O-arenediazonium tetrafluoroborates with
ortho- or meta-substitution showed no evidence of steric hindrance
and were readily converted to the corresponding nitriles (3d–3f vs.
3p
N
2
+BF -
Ph
4
CN
Ph
3
a). However, 2,6-dimethyl-4-bromo-arenediazonium tetrafluo-
roborate afforded the corresponding nitrile (3m) in a relatively
low 36% yield. Also, cyanation did not occur with N-heterocyclic
substrates (3r, 3s), perhaps due to the more ready formation of
Pd–N complexes rather than Pd–Ar species in the palladium-
mediated catalytic process.
To broaden the scope of our NCTS Pd/Ag-catalyzed system, we
studied its possible use in the cyanation of aryl halides. We applied
the protocol to 4-iodoanisole as a model substrate, because aryl
iodides have been used extensively in TMC cyanations involving
3q
N
N
2
+BF -
4
CN
CN
1
8
9
0
0
N
N
3
r
+BF -
2
4
N
N
C–CN cleavage with acetone cyanohydrin, acetonitrile, and ethyl
1
4b–d
3s
cyanoacetate as a cyanide source.
combination of PdCl /Ag
(entry 2) and equivalent to Pd(OAc)
entry 3). When solvents were compared, EtOH was the best
As shown in Table 3, a
N
2
+BF -
4
CN
2
2
O
(entry 1) was preferable to Pd
/Ag CO
3
(
(
PPh)
3
Cl
2
/Ag
2
O
2
2
a
Reaction conditions: arenediazonium tetrafluoroborate (0.5 mmol), NCTS
1.0 mmol, 2.0 equiv), Pd(OAc) (0.15 equiv) and Ag CO (0.5 equiv) in EtOH
3.0 mL), under air, at 55–60 °C for 15 h, isolated yield.
(
(
2
2
3
option resulting in a 66% yield, which was much better than the
yields with toluene, dioxane, n-propanol, and isopropanol (entry
1
vs. 4–7). Because an aryl iodide is generally more stable than
an arenediazonium salt, a reaction temperature of 70 °C was
and 13). When the reaction time was changed, 15, 30, and 10 h
produced yields of 74%, 72%, and 52%, respectively (entries 11,
used successfully. In summary, with 4-iodoanisole as substrate,
the most effective reaction conditions were 0.15 equiv PdCl
0.5 equiv Ag O, EtOH, 24 h, 70 °C (entry 1).
We then briefly explored the substrate scope of the NCTS cyana-
tion using the optimized PdCl /Ag O system in EtOH (Table 4). Our
method was effective for aryl iodide and aryl bromide substrates
2
,
1
4, and 15). Based on the above results, our selected optimal reac-
tions for the NCTS protocol were 0.15 equiv Pd(OAc) , 0.5 equiv
Ag CO , EtOH, 15 h, 55–60 °C (entry 11).
Using the selected optimized reaction conditions, we examined
2
2
2
3
2
2
the substrate scope of this protocol. The structures and yields of
the various aromatic nitriles obtained are listed in Table 2. Firstly,
we explored the cyanation of arenediazonium tetrafluoroborates
bearing electron-donating groups, such as alkyl, alkyloxy, and
N-alkyl. The corresponding nitriles were obtained in moderate to
good isolated yields (3a–3h). Substrates with electron-withdraw-
containing both electron-donating groups, such as OCH
CH , and electron-withdrawing groups, such as Br, I, CO Et, COCH
NO
diiodobenzene provided only the mononitrile product (3k).
Despite the presence of a strongly electron-donating p-OCH
group, the NCTS protocol gave only a trace yield of nitrile with
the substrate 1-chloro-4-methoxybenzene (entry 3); however, aryl
chlorides are generally less reactive than aryl iodides and bro-
mides. Similarly to the arenediazonium salt substrates, diverse
functional groups were readily tolerated on the aryl iodides or
bromides under the applied reaction conditions.
3
, OC
2
H
5
,
3
2
3
,
2
, Ph (3a–3p). Yields ranged from 32% to 69%. Interestingly, 1, 4-
3
2
ing functional groups, such as halide, ester, ketone, and NO , fur-
nished products in moderate isolated yields (3i–3p). Moreover,
with para-phenyl arenediazonium tetrafluoroborate, the cyanation
proceeded smoothly in a reasonable 62% isolated yield (3q). Thus,
diverse functional groups on the phenyl ring of the arenediazo-
nium tetrafluoroborate substrate were readily tolerated. In partic-
ular, halide substituents, such as iodide and bromine, were not
converted to cyano groups under the reaction conditions (3j–3m).
Thus, NCTS could be applied successfully in cyanation reactions
of both arenediazonium salts and aryl halides with an appropriate
Pd/Ag catalysis system. A polar solvent can play an important role