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S. Thurow et al. / Tetrahedron Letters 54 (2013) 3215–3218
Table 1
Optimization of reaction conditions
H3PO2
glycerol
1) glycerol
90 °C, 30 min., N2
PhSeSePh
+
H3PO2
N2, 90 ºC
r.t.
N
SePh
3a
PhSeSePh
1a
2)
N
SePh
3a
1a
N
2a
Cl
N
2a
Cl
Entry
H3PO2 (mL)
Timea (h)
Yieldb (%)
1
2
3
4
5c
6
1.0
0.1
0.05
0.01
0.1
—
1.5
1.5
24
24
2.0
24
99
99
75
4
99
—
a
This time include preliminary 30 min of diphenyl diselenide cleavage to in situ
formation of benzeneselenol.
b
Determined by CG–MS analysis.
After generating the benzeneselenol the temperature was allowed to decrease
c
to rt. Then, 2-chloropyridine was added and the stirring remained at rt for addi-
tional 1.5 h.
Figure 1. Reuse of system solvent-reducing agent glycerol/H3PO2.
In view of the explained above, here we describe the simple
synthesis of 2-organylselanyl pyridines by reaction of organyl
diselenides with 2-chloropyridines using glycerol as solvent and
hypophosphorous acid (H3PO2) as reducing agent (Scheme 1).
Initially, we chose diphenyl diselenide 1a (0.5 mmol) and 2-
chloropyridine 2a (1.0 mmol) as model substrates to establish
the best conditions for the reaction using glycerol as solvent and
some experiments were preformed to synthesize compound 3a
in satisfactory yield (Table 1). According the literature, diorganyl
diselenides are reduced to the corresponding organyl selenols by
treatment with H3PO2 and this fact encouraged us to use this
reducing agent to obtain in situ the nucleophilic selenium species
of our reaction.16
Thus, a mixture of diphenyl diselenide 1a and 1.0 mL of H3PO2
(50 wt.% in H2O) in glycerol (0.5 mL) was stirred at 90 °C for
30 min under N2 atmosphere to afford in situ the benzeneselenol.
After this time, 2-chloropyridine 2a (1.0 mmol) was added in the
reaction vessel and the reaction remained at 90 °C for additional
1 h. Under these reaction conditions, the product 3a was obtained
quantitatively (Table 1, entry 1). This excellent result prompted us
to perform this reaction decreasing the quantity of H3PO2 in the
reaction. To our satisfaction, the use of 0.1 mL of H3PO2 furnished
the desired product in the same yield after 1.5 h (Table 1, entry
2). When we used 0.05 and 0.01 mL of H3PO2 a great decrease in
the yield of product 3a was observed. Gratefully, when the reaction
was performed using 0.1 mL of H3PO2 at room temperature, the
corresponding product 3a was obtained in excellent yield after
2.0 h (Table 1, entry 5). When the reaction was carried out without
H3PO2 no product 3a was formed demonstrating the involvement
of H3PO2 in the reaction (Table 1, entry 6). Analysis of the results
shown in Table 1 indicated that the best conditions17 were the pre-
vious reaction of diphenyl diselenide 1a (0.5 mmol) with H3PO2
(0.1 mL) in glycerol (0.5 mL) at 90 °C for 30 min under N2 to
in situ formation of benzeneselenol. Following, the reaction mix-
ture was cooled to room temperature and 2-chloropyridine
(1.0 mmol) was added drop wise and the stirring continued until
complete consumption of the starting material. We believe that
the benzeneselenol acts as a nucleophilic species in the direct
nucleophilic aromatic substitution (SNAr), and the glycerol, a polar
protic solvent, possibly exhibits an activation of this reaction. A
similar situation was described by Sreedhar using thiophenols.6f
After reaction optimization, a study regarding the recovering
and reusing of glycerol was performed. Subsequent to the forma-
tion of product 3a, the reaction mixture was diluted and extracted
with a mixture of hexane/ethyl acetate 95:5 (3 Â 5 mL). The upper
phase was dried and the solvent evaporated. The inferior, glycerol
phase, was dried under vacuum and directly reused in a new reac-
tion with diphenyl diselenide 1a at 90 °C without the addition of
more H3PO2. To our satisfaction, after 30 min at this temperature,
benzeneselenol was formed in situ and reacted with 2-chloropyri-
dine 2a at rt, furnishing the corresponding product 3a in 96% yield
after 2 h. After this successful experiment, we speculate the possi-
ble reuse of the system solvent/reducing agent for additional cycles
(Fig. 1). It was observed that a good level of efficiency was main-
tained even after four reactions. These results showed that the 2-
phenylselanyl pyridine 3a was obtained in 99%, 96%, 95%, 90%,
and 80% yields after successive cycles. After 5 runs, the efficiency
of our solvent-reducing agent system decreased and the yield of
compound 3a was only 60% (Fig. 1).
After that, the versatility of our methodology was evaluated, by
reacting other diaryl diselenides 1b–i with 2-chloropyridine 2a
(Table 2). The obtained results reveal that the reaction worked well
with a range of diaryl diselenides tested, affording excellent yields
of the products 3b–i (Table 2, entries 2–9). According to the results,
the reactions are not sensitive to electronic effects in the aromatic
ring on diaryl diselenide. Diaryl diselenides containing both elec-
tron-donating (OMe, Me) or electron-withdrawing groups (Cl, Br,
F, CF3) gave excellent yields of desired arylselanyl pyridines (Table
2, entries 2–9). Extending the scope of this methodology, when the
reaction was performed with dibenzyl diselenide 1j or dibutyl
diselenide 1k, the respective 2-organylselanyl pyridines 3j and
3k were obtained in high yields. However, for these reactions the
temperature of the second step was 90 and 60 °C, respectively (Ta-
ble 2, entries 10 and 11).
In addition, under the optimized reaction conditions, the possi-
bility of performing the reaction with other substituted 2-chloro-
pyridines 2b–d was also investigated. Thus, reactions of diphenyl
diselenide 1a with 3-amino-2-chloropyridine 2b and 2,3-dichloro-
pyridine 2c gave good yields of desired products (Table 2, entries
12–13). However, when 2,6-dichloropyridine 2d (1.0 mmol) and
diphenyl diselenide 1a (0.5 mmol) were reacted at 90 °C, both
products 2,6-bis(phenylselanyl)pyridine 3n and 2-chloro-6-(phe-
nylselanyl)pyridine were formed in a 68:32 ratio. When the
amount of diphenyl diselenide 2a was increased to 1 mmol and
the temperature was maintained at 90 °C for all the reaction times
(steps 1 and 2), only the formation of bis(phenylselanyl)pyridine
3n was observed, however in moderate yield (Table 2, entry 14).