1
564
G. Chelucci / Tetrahedron Letters 51 (2010) 1562–1565
Table 1 (continued)
Entry Halo-heterocycle
Product
Methoda
Temp (°C)
Time (h)
Conversionb (%)
Yieldc (%)
Cl
N
1
4
D
25
2
100
95
N
2
n
1
n
a
Method: A = heterocycle (0.66 mmol), Pd(OAc)
2
(5.0 mol %), PPh
3
(20.0 mol %), NaBH
4
(1.7 equiv), TMEDA (1.7 equiv), THF (13.2 mL). B = heterocycle (0.66 mmol),
(dppf) (5.0 mol %), NaBH (1.7 equiv),
(3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL).
Pd(OAc) (10.0 mol %), PPh (40.0 mol %), NaBH (3.4 equiv), TMEDA (3.4 equiv), THF (13.2 mL). C = heterocycle (0.66 mmol), PdCl
2
3
4
2
4
TMEDA (1.7 equiv), THF (13.2 mL). D = heterocycle (0.66 mmol), PdCl
2
(dppf) (5.0 mol %), NaBH
4
b
Determined by 1H NMR.
Isolated yields after flash chromatography.
c
Cl
OH
N
a or b
+
+
Cl
N
N
Cl
N
Cl
4
5
3
6
a: Pd(PPh ) Cl (1.0 mol%), Et SiH (1.4 equiv), MeCN, 70 ºC, 18 h, 92% conversion, 4 (85%), 5 (5%), 6 (8%).
3
2
2
3
b: PdCl (dppf) (5.0 mol%), NaBH (3.4 equiv), TMEDA (3.4 equiv), THF, 25 ºC, 6 h, 100% conversion, 4 (95%).
2
2
4
Scheme 2. Reagents and conditions: (a) Pd(PPh
NaBH
3
)
2
Cl
2
3 2 2
(1.0 mol %), Et SiH (1.4 equiv), MeCN, 70 °C, 18 h, 92% conversion, 4 (85%), 5 (5%), 6 (8%); (b) PdCl (dppf) (5.0 mol %),
4
(3.4 equiv), TMEDA (3.4 equiv), THF, 25 °C, 6 h, 100% conversion, 4 (95%).
of other substrates and in particular of haloheterocycles has ap-
peared in the literature.
Thus, we decided to examine the scope and limitations of this
methodology for the hydrodehalogenation of heteroaromatic ha-
lides, reporting in this occasion the reductive removal of halo-
group from halogenated pyridines and quinolines by means of cou-
chloropyridines resulted less reactive than the related bromohet-
erocycles. Thus, for instance, chloropyridine 1i was unreactive un-
der the conditions in which the related bromoropyridine 1c was
smoothly reduced (entry 9 vs 3). Fortunately, also in this case,
the use of PdCl (dppf) was beneficial, allowing the tetrahydro-
2
quinoline 2i to be obtained in excellent yield (95%) after 6 h. In
4
ple NaBH –TMEDA under palladium catalysis (Scheme 1).
this circumstance, to speed up the reaction, 3.4 equiv of the cou-
Starting our investigation to optimize the reaction conditions,
the reductions were carried out with 2-bromo-6-phenylpyridine
ple NaBH
4
–TMEDA (Method D) was employed. The use of
PdCl (dppf) resulted also essential for the rapid and high yielding
2
1
a. After a careful examination of various reaction conditions, we
concluded that the best results for the intended hydrodehalogen-
ation were achieved using 5 mol % Pd(OAc) with 20 mol % PPh
as the catalyst, 1.7 equiv of NaBH and TMEDA as the reducing sys-
reduction of a variety of chloro-pyridines and -quinolines (entries
10–14).
2
3
Very recently, Zacuto and Hirner have demonstrated the versa-
tility of 7-chloroquinoline as a synthetic intermediate for the syn-
thesis of more complex 7-mono- and 2,7-di-substituted
4
11
tem and THF as the solvent (Method A). Under these conditions
the substitution of the bromine with hydrogen in 1a was complete
at room temperature in less than 30 min giving the dehalogenated
pyridine 2a in almost quantitative yield (Table 1, entry 1). Similar
results were obtained with the (6-bromopyridin-2-yl)phenylmeth-
anol 1b and 2-bromobenzo[h]quinoline 1d (entries 2 and 4). The
more sterically hindered bromide in pyridines 1c and 1e (entries
1
2
quinolines. For this purpose they have developed a practical syn-
thesis of 7-chloroquinoline 4 via a chemoselective reduction of 4,7-
dichloroquinoline 3 (Scheme 2). Under their best reaction condi-
tions that resulted in an optimal balance between conversion
3 2 2 3
(92%) and chemoselectivity [Pd(PPh ) Cl (1.0 mol %), Et SiH
(1.4 equiv), MeCN, 70 °C, 18 h], reduced compound 4 was obtained
in 85% yield with the over reduction byproduct quinoline 5 (5%)
and 7-chloro-4-hydroxyquinoline 6 (8%), which appeared to result
from a reaction between 3 and water in the reaction solution or in
the quench.
3
and 5) was also removed quantitatively at room temperature, al-
beit after a somewhat extended reaction time (6 and 1.5 h, respec-
tively). These reaction conditions failed to reduce 2-bromo-3-
cyano-6-methylpyridine 1f (entry 6), and even increasing the num-
ber of equivalents (from 1.7 to 3.4) of the couple NaBH
4
–TMEDA
On this basis, we decided to examine the chemoselective reduc-
tion of 4,7-dichloroquinoline 3 using our protocol. We were de-
lighted to find that under method D, dichloro compound 3 was
completely converted after 6 h at room temperature, giving the
7-chloroquinoline as the sole product in 95% isolated yield
(Scheme 2).
(
Method B) was unproductive. Whereas partial conversion of the
starting material was obtained when the reaction was carried out
at 60 °C for 72 h. Impressively, this transformation could take place
0
when [1,1 -bis(diphenylphosphino)ferrocene] dichloropalladium(II)
[
2
PdCl (dppf)] was used as the catalyst. Thus, 5 mol % of PdCl
2
(dppf),
NaBH
4
(1.7 equiv) and TMEDA (1.7 equiv) (Method C) converted 1f
As pointed out by Hor and co-workers10, the effect of TMEDA is
suggested to be threefold: (a) weak coordination to the electroni-
in the related hydroalogenated pyridine 2f in excellent yield (95%)
after 6 h at room temperature. For the hydrodehalogenation of
meta-bromopyridines 1g and 1h (entries 7 and 8), method A was
successful only when the reaction was carried out at 60 °C, giving
the reduced products in good yield. However, the results were also
cally unsaturated intermediate and hence stabilization of the cata-
ꢀ
lyst; (b) capturing of BH
3
from BH4 , thus providing an extra drive
for the hydride transfer to the Pd centre and (c) facilitating an
alternative debromination pathway through the elimination of
HBr.
2
in this case improved using PdCl (dppf) (Method C). As expected,