L. K. Soares et al. / Tetrahedron Letters 55 (2014) 992–995
993
Table 1
O
Optimization of reaction conditionsa
N
N
N
N
N
N
N
N
N
N
conditions
H
N
C6H5
SeC6H5
+
SeC6H5
N
H
2
C6H5
O
N
3a
1a
N
Cl
Liarozole
Alcaftadine
Yield of 3ab (%)
Zolpidem
Entry
2 (equiv)
Solvent
Temp. (°C)
Time (h)
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
1.5
3.0
2.0
2.0
2.0
2.0
DMF
DMF
DMF
DMF
90
120
120
48
48
48
48
72
72
72
47
58
73
48
Figure 1. Drugs containing imidazolyl moiety in their structures.
120
145
145
145
145
145
reflux
reflux
DMF
71
mixture of the Markovnikov and anti-Markovnikov adducts was
obtained.
PEG-400
DMSO
THF
n.r.
n.r.
n.r.
n.r.
The biological activity23 and usefulness of selenium-containing
compounds in organic synthesis24 are well documented, including
a number of books25 and reviews.26 Of special interest are the
nitrogen-functionalized organoselenium compounds, which pres-
ent interesting pharmaceutical properties, including antimicro-
bial,27 antioxidant,28 and antidepressant-like.29 Besides, catalytic
amounts of optically active amino diselenides were used in the
synthesis of valuable chiral building blocks in organic synthesis.30
Thus, the search for general and selective methods to prepare
highly functionalized nitrogen-containing organoselenium com-
pounds has attracted the attention of organic synthetic chemists
in the last years.
DCM
a
Reactions performed using 1a (0.5 mmol), imidazole 2 and solvent (5.0 mL).
Yields are given for isolated product 3a.
b
the same reaction conditions described in Table 1, entry 3. Unfor-
tunately, when the reactions were performed using 0.75 mmol (1.5
equiv) of imidazole 2, product 3a was obtained only in 48% yield
(Table 1, entry 4). When 1.5 mmol (3 equiv) of imidazole 2 was
used, no increasing in yield was observed compared to the use of
2 equiv (Table 1, entries 5 vs 3). These results suggest that the
use of an excess of imidazole is preferable to afford good yields
of 3a. The unreacted 1-phenylselanyl-2-phenylethyne 1a was eas-
ily recovered to be used in further reactions. When the reactions
were carried out using other solvents, such as PEG-400, DMSO,
THF, and DCM, no product was observed after 72 h and compound
1a was recovered (Table 1, entries 6–9).
Thus, in an optimized reaction, 1-phenylselanyl-2-phen-
ylethyne 1a was reacted with imidazole 2 (2 equiv) in DMF at
145 °C during 48 hours under air atmosphere, yielding (Z)-1-(1-
phenyl-(2-phenylselanyl)vinyl)-1H-imidazole 3a in 73%. In
contrast to the previously described methods to prepare N-alke-
nyl-imidazoles,10–22 to our satisfaction the reaction described here
was 100% stereo- and regioselective, giving exclusively the
(Z)-alkene 3a.
Recently, we have described the use of selanylalkynes as starting
material in the hydrochalcogenation of alkynes to prepare vinyl
chalcogenides.31,32 The nucleophilic chalcogenolate anions were
generated in situ by using the system (RY)2/NaBH4/PEG-400 (Y = S,
Se, Te)31 or KF/Al2O3.32 In this context, we report herein the selective
preparation of N-alkenyl-b-arylselanyl imidazoles by the additive-
free nucleophilic addition of imidazole to arylselanylalkynes
(Scheme 1).33
Initially, we chose 1-phenylselanyl-2-phenylethyne 1a
(0.5 mmol) and imidazole 2 (1.0 mmol) as the standard starting
materials to establish the best reaction conditions for the synthesis
of N-alkenyl-b-arylselanyl imidazole 3a (Table 1). We examined
the influence of temperature, solvent, as well as the amount of
imidazole 2. When the reaction was performed at 90 °C in DMF
(5 mL) under air atmosphere, it proceeded slowly to give 3a in
47% yield after stirring for 5 days and a large amount (49%) of start-
ing 1-phenylselanyl-2-phenylethyne 1a was recovered (Table 1,
entry 1). The temperature was then increased to 120 °C and only
58% yield of 3a was formed after a long reaction time (Table 1,
entry 2). Fortunately, when the reaction was performed at
145 °C, the desired product (Z)-3a was obtained in 73% yield after
stirring for 48 h (Table 1, entry 3). In this reaction, a small amount
(13%) of starting 1-phenylselanyl-2-phenylethyne 1a was isolated
during the step of purification of the product. The yield of 3a, how-
ever, remained almost the same even after stirring for more time at
145 °C.
To evaluate the efficiency and generality of our protocol and to
examine the reactivity of imidazole 2 against different aryl-
selanylalkynes, the method was extended to different aromatic,
propargylic (alcohol derivatives) and aliphatic alkynes and also a
sort of arylselenides (Table 2).
Firstly, different phenylselanylalkynes 1a–f were reacted with
imidazole 2 under our optimal conditions (Table 2, entries 1–6).
As it can be seen in Table 2, the reactivity of alkynol derivatives
is influenced by steric effects. Thus, the unsubstituted phenylsela-
nyl alkynol 1b and the dimethylated derivative 2b afforded,
respectively 3b and 3c in 61 and 70% yields after 48 h (entries 2
and 3). When phenylselanyl alkynols containing sterically hin-
dered substituents (1d and 1e) were used, only reasonable yields
of the respective alkenes 3d and 3e were isolated, even after 96 h
of reaction (Table 2, entries 4 and 5). To our satisfaction, the reac-
tion of 2 with hex-1-ynyl(phenyl)selanyl 1f gave 3f in 70% yield
after 96 h (Table 2, entry 6). Despite a small amount of the E-iso-
mer was observed here, Z:E ratio = 97:3, this is a very interesting
result, once the selective preparation of vinyl selenides from low
reactive aliphatic alkynes is not trivial.26a
Aiming to increase the yield of 3a as well as the consumption of
1a, we examined the influence of the amount of substrate 2 under
N
N
N
DMF
+
R
SeR1
SeR1
145 °C
N
H
R
single isomer
The NOESY spectrum of 3c (see in Support information) in
CDCl3 shows NOE cross peak of the vinylic hydrogen at 6.97 ppm
(H-4, Fig. 2) to the methyl ones of the carbinol moiety at
1.31 ppm (H-1, Fig. 2). These observations corroborate for a
1a-j
2
3a-j
Scheme 1. General scheme of the reaction.
Soares, Liane K.
