Synthesis of selenazoles by in situ cycloisomerization of propargyl selenoamides using oxygen-selenium exchange reaction

Article abstract of DOI:10.1021/jo402661b

Herein, we describe an approach toward selenazole preparation based on the cycloisomerization of propargyl selenoamides. The selenoamides were synthesized in situ using the Ishihara reagent with spontaneous cyclization to form the 2,5-disubstituted selenazoles. Heterocylcles 9a-j were prepared using readily available starting materials, and yields ranged from moderate to good (20-80%). Methylselenazole 9a could be transformed into a bromomethyl derivative 13 using NBS. The intermediate 13 would provide a more versatile building block for further derivatizations, e.g., the cyanide 14.

Full text of DOI:10.1021/jo402661b

Note
pubs.acs.org/joc
Synthesis of Selenazoles by in Situ Cycloisomerization of Propargyl
Selenoamides Using Oxygen−Selenium Exchange Reaction
Chiara Pizzo and S. Graciela Mahler*
́ ́ ́
́
Departamento de Química Organica, Catedra de Química Farmaceutica, Universidad de la Republica (UdelaR), Avda. General Flores
2124, CC1157 Montevideo, Uruguay
S
* Supporting Information
ABSTRACT: Herein, we describe an approach toward
selenazole preparation based on the cycloisomerization of
propargyl selenoamides. The selenoamides were synthesized in
situ using the Ishihara reagent with spontaneous cyclization to
form the 2,5-disubstituted selenazoles. Heterocylcles 9a−j
were prepared using readily available starting materials, and
yields ranged from moderate to good (20−80%). Methyl-
selenazole 9a could be transformed into a bromomethyl derivative 13 using NBS. The intermediate 13 would provide a more
versatile building block for further derivatizations, e.g., the cyanide 14.
he interest in organoselenium compounds has been
growing during the last decades due to its importance
Hantzsch procedure used for oxazole and thiazole synthesis.
This methodology is based on the condensation of α-halo
ketone with selenoureas or selenoamides.11 Selenoureas are
inconvenient due to their high cost and low stability to air and
light.
T
as useful intermediates in synthetic chemistry1 and as
precursors of new materials,2 but the most outstanding field
is related to its biological and medicinal significance.3 In
particular, selenazole heterocycles are being currently studied
because of their interesting biological properties; see Figure 1.4
As part of our interest in the preparation and biological
evaluation of organoselenium compounds,12 we are interested
in a general approach toward the preparation of selenazolyl
compounds. We decided to explore the cycloisomerization of
propargyl selenoamides to obtain selenazoles. Cycloaddition is
a powerful methodology used to prepare aromatic heterocycles
like thiazole and oxazole. The cycloisomerization of propargyl
amides or thioamides has been reported using different catalysts
13
such as SiO2, Au(I),14 Ag(I),15 and p-Ts-OH acid,16 among
others. Herein, we report an efficient tandem procedure for the
synthesis of 2,5-disubtituted selenazoles by in situ cyclo-
isomerization of propargyl selenoamides.
First, we optimized the preparation of selenoamide using
different conditions for O−Se exchange, employing propargyl
amide 6a as a model. The strategies involved the use of the
Woollins reagent (WR)17 or the Ishihara reagent (LiAlH-
SeH).18 Attempts to obtain selenoamides using WR failed,
leading to the recovery of the starting material (see entry 1,
Table 1). The second strategy used LiAlHSeH as reagent,
according to the conditions reported by Sureshbabu and co-
workers for the preparation of selenopeptides.19 This method-
ology uses PCl5 (1 equiv) with a catalytic amount of DMF (0.3
equiv) in PhH for the conversion of peptide amides into
iminochloride, followed by the Cl−Se exchange using Ishihara
reagent (1 equiv), freshly prepared from Se0 and LiAlH4.
Propargyl amide 6a in the mentioned conditions led to the
formation of selenazoline 8a (72%), probably via selenoamide
Figure 1. Biologically relevant selenazole derivatives.
Selenazole 1a is able to induce apoptosis in human ovarian
cancer (SKOV3) and leukemia HL6 cell lines;5 selenazole 1b is
useful for prevention of nitric oxide-mediated inflammatory
damages;6 selenazofurin 2 is a potent known antiviral agent;7
amselamine 3 is a selective histamine H2-agonist;8 2-
piperidinoselenazole 4a and 4-phenyl-2-piperidinoselenazole
4b exhibit superoxide anion-scavenging activity,9 while 2-
piperidino- and 5-(chloroacetyl)-2-morpholinoselenazoles
(5a,b) strongly inhibit LPS-induced nitric oxide release from
microglial cells.10
The selenazole heterocyclic structure is closely related to its
sulfur and oxygen analogue compounds, but their properties
often present marked differences. There are few strategies for
the synthesis of selenazoles, mainly concerning variations of the
Received: December 6, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo402661b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of the Reaction Conditions for
Synthesis of 2-Phenyl-5-methylselenazole
Scheme 1. Synthesis of 2,5-Disubstituted Selenazoles Using a
Tandem Optimized Reaction Sequence
a
product
a
(ratio),
b
entry
conditions a
conditions b
yield (%)
1
2
WR (1.5 equiv), PhMe, reflux 10 h
6a, 70
8a, 72
(i) PCl5 (3 equiv), DMF (0.3 equiv), p-TsOH ac,
PhH, rt; (ii) LiAlHSeH (3 equiv), rt
rt
3
4
(i) PCl5 (3 equiv), DMF (11 equiv),
PhMe, rt; (ii) LiAlHSeH (3 equiv), rt
8a + 9a
(4:6), 10
(i) PCl5 (3 equiv), DMF (0.3 equiv), Et3N (1
PhMe, rt; (ii) LiAlHSeH (3.2 equiv),
rt
8a + 9a
(7:3), 40
a
equiv),
Percent conversion was 100% in all cases; yields are given as isolated
reflux 9 h
products.
5
6
(i) PCl5 (1 equiv), DMF (0.3 equiv), PipAcOH
PhMe, rt; (ii) LiAlHSeH (1.2 equiv),
rt
8a + 9a
(3:7), 31
(1 equiv)
(i) PCl5 (2 equiv), DMF (0.3 equiv), PipAcOH
PhMe, rt; (ii) LiAlHSeH (1.5 equiv),
rt
9a, 74
(1 equiv)
a
b
1
Ratio based on integration of separated H NMR signals. Isolated
yield of the mixture; PipAcOH = piperidinium acetate.
7a formation, followed by a spontaneous 5-exo-dig cyclization
(see entry 2, Table 1). Attempts to isomerize the exo double
bond to obtain selenazole 9a, by using p-TsOH acid and heat,
were unsuccessful (see entry 2, Table 1). An increase in the
amount of DMF (11 equiv) led to selenazoline 8a (4%) and the
selenazole 9a (6%), in low yields (see entry 3, Table 1). In
order to promote the complete isomerization of 8a to 9a, we
used Et3N (1 equiv) or piperidinium acetate (PipAcOH) (1
equiv) as catalyst (see entries 4 and 5, Table 1, respectively).
However, the conversion of 8a to 9a was improved when
PipAcOH was used but in moderate yield (see entry 5, Table
1). Exploring the effect of the amount of PCl5 and LiAlHSeH
(see entries 4 and 5, Table 1, respectively), we found that the
best yields were achieved when PCl5 (2 equiv) and LiAlHSeH
(1.5 equiv) were used (see entry 6, Table 1). Selenazole 9a,
then, was prepared under these optimized conditions in 74%
yield.
Figure 2. Nonterminal propargyl amides 10 and 11.
Figure 3. Mechanistic proposal for selenazole 9 formation.
process. The product distribution in the presence of NBS or I2
as electrophiles was analyzed; see Scheme 2.
Under optimized conditions, a wide range of aromatic and
aliphatic terminal propargyl amides were converted into the
desired heterocycles (see Scheme 1). Aromatic propargyl
amides 6a−f bearing neutral and both electron-rich and
electron-deficient groups gave the cyclized products 9a−f in
high and good yields from 88 to 55% (see Scheme 1). In
contrast, alkyl propargyl amides 6g−j were converted into their
corresponding selenazoles 9g−j in modest yields (20−36%).
In order to explore the scope of the cyclization process we
tried to cyclize nonterminal propargyl amides like 10 and 11,
but in all cases the starting material was recovered; see Figure 2.
The proposed mechanism for selenazole formation is similar
to those presented for the oxazole synthesis, and it is depicted
in Figure 3.14a Once the selenoamide 7 is formed, the Se atom
promotes a 5-exo-dig cyclization, favored according to Baldwin’s
rules. The electrons of the triple bond take a proton from the
media to form selenazoline 8. The exo-double bond isomerizes
with PipAcOH toward the aromatic selenazole 9.
Scheme 2. Synthesis of 5-(Halomethyl)selenazoline 12 Using
Different Electrophiles
The cycloisomerization of propargyl amide 6a using NBS did
not lead to the desired 5-(bromomethyl)selenazole (12a); a
mixture of compound 8a and 9a in a 3:7 ratio and low yield was
isolated. When I2 was used as electrophile, a mixture of the
desired vinyl iodide 12b was obtained, together with
compounds 8a and 9a. The first attempt using the optimized
conditions for selenazoline preparation followed by the
Based on this mechanism, we decided to study the effect of
using different electron acceptors to see how electrophiles can
compete with the proton uptake within the cyclization reaction
B
dx.doi.org/10.1021/jo402661b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 2. Conditions Assayed for the Synthesis of 5-(Iodomethyl)selenazoles
a
b
entry
conditions
product (ratio), yield,
%
1
2
3
(i) PCl5 (2 equiv), DMF (0.3 equiv), PhMe, rt; (ii) LiAlHSeH (1.5 equiv), 0 °C; (iii) I2 (1.5 equiv), 0 °C
(i) PCl5 (2 equiv), CH2Cl2, −10 °C; (ii) LiAlHSeH (1.5 equiv), −10 °C; (iii) I2 (1.5 equiv), −10 °C
(i) PCl5 (1.5 equiv), CH2Cl2, 0 °C; (ii) I2 (2 equiv), 0 °C; (iii) LiAlHSeH (1.5 equiv), 0 °C
9a + 12b (7:3), 19
9a + 12b (7:3), 39
9a + 12b (7:3), 33
a
b
1
Ratio based on integration of separated H NMR signals. Isolated yield of the mixture.
Table 3. Optimization of the Bromination Reaction To Obtain 5-(Bromomethyl)selenazole 13
a
b
entry
NBS (eq)
radical initiator (eq)
hν time (h)
heating time (h)
conversion (%)
compd 13 yield (%)
1
2
3
4
5
6
1.1
1.8
1.1
0.9
1.5
1.1
1
8
rt, overnight
rt, overnight
reflux, 4 h
45
100
75
20
11
21
44
10
68
[PhC(O)O−]2 (0.02)
[PhC(O)O−]2 (0.02)
[PhC(O)O−]2 (0.02)
1
1
reflux, 2 h
78
reflux, 6 h
30
AIBN (0.1)
rt, overnight
100
a
b
1
% based on integration of separated H NMR signals. Isolated yield.
mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred
for 30 min at 0 °C. The reagent lithium hydrogen selenide
(LiAlHSeH) was formed in situ as a gray solution that was directly
used in our present studies.
addition of I2 at 0 °C led to a mixture of 9a and 12b in a 7:3
ratio (see entry 1, Table 2). We also explored the effect of the
solvent influence by replacing with CH2Cl2, but no change in
the product ratio was observed. Furthermore, the order and
temperature of I2 addition did not seem to affect the product
distribution (see entries 2 and 3, Table 2). Attempts to
isomerize the vinyl iodoselenazoline 12b toward the corre-
sponding 5-(iodomethyl)selenazole using PipAcOH led to
decomposition of the starting material.
We then decided to investigate further transformations of the
methyl selenazole 9a and performed a selective bromination of
the methyl group present at the 5-position; see Table 3. N-
Bromosuccinimide (NBS) was used as brominating reagent
under different conditions; in all cases, the bromo derivative 13
was selectively obtained (see Table 3). The best conditions
were obtained when NBS (1.1 equiv), AIBN (0.1 equiv), hν (1
h) in CCl4 at room temperature were used (see entry 6, Table
3).
Synthesis of 5-Methylene-2-phenyl-4,5-dihydro-1,3-selenazole
(8a). To a stirred solution of N-(prop-2-ynyl)benzamide 6a (0.70
mmol) in dry PhMe (3.5 mL) were added PCl5 (291 mg, 1.4 mmol)
and DMF (0.016 mL, 0.03 mmol) at room temperature and the
solution allowed to sit for 30 min. A freshly prepared THF solution of
LiAlHSeH (1.0 mmol, 10 mL, 0.1 M) was added at room temperature.
The reaction mixture was stirred overnight at room temperature. Then
the solvent was removed at reduced pressure until dryness. The
residue was poured into water (50 mL), NaHCO3 was added until pH
7, and the mixture was extracted with ethyl acetate (5 × 30 mL). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified by chromatography on SiO2
1
(n-hexane/EtOAc 5:1) to give 8a (108 mg, 70%) as a yellow oil: H
NMR δ 5.18 (t, J = 2.7 Hz, 1H), 5.32 (dd, J = 2.8, 4.6 Hz, 1H), 5.60
(dd, J = 2.4, 4.3 Hz, 1H), 7.40 − 7.49 (m, 2H), 7.69 (d, J = 6.8 Hz,
1H); 13C NMR δ 75.8, 108.0, 128.7, 128.8, 131.4, 135.5, 149.2, 166.4;
HRMS calcd for C10H10NSe [M + H]+ 223.9900, found 223.9930.
Optimized Procedure for the Synthesis of Selenazoles. 5-
Methyl-2-phenylselenazole (9a). To a stirred solution of N-(prop-2-
ynyl)benzamide 6a (0.70 mmol) in dry PhMe (3.5 mL) were added at
room temperature PCl5 (291 mg, 1.4 mmol) and DMF (0.016 mL,
0.03 mmol) and the solution allowed to sit for 30 min. A freshly
prepared of LiAlHSeH solution in THF (1 mmol, 10 mL, 0.1 M) was
added at room temperature. The reaction mixture was stirred at the
same temperature for 1 h. Then piperidinium acetate (102 mg, 0.7
mmol) was added, and the reaction was refluxed for 2 h and stirred
overnight at room temperature. Then the solvent was removed at
reduced pressure until dryness. The residue was poured into water (50
mL), NaHCO3 was added until pH 7, and the mixture was extracted
with ethyl acetate (5 × 30 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. The residue was purified
by chromatography on SiO2 (n-hexane/EtOAc 5:1) to give 9a (89 mg,
74%) as a yellow oil: 1H NMR δ 2.58 (d, J = 1.4 Hz, 3H), 7.39 − 7.42
(m, 3H), 7.48 (dd, J = 1.4, 2.5 Hz, 1H), 7.83 − 7.85 (m, 2H); 13C
NMR δ 14.8, 126.8, 129.0, 129.9, 136.6, 141.3, 142.3, 173.9; HRMS
calcd for C10H10NSe [M + H]+ 223.9900, found 223.9910.
Compound 13 would provide an easy access to different
building blocks for the construction of chemical libraries; e.g., it
was readily converted into the cyanide 14 (see Scheme 3).
Scheme 3. Synthesis of 5-(Cyanomethyl)selenazole 14
In conclusion, we have developed a catalyst-free pathway for
the preparation of 2,5-disubstituted selenazoles directly from
terminal propargyl amides. This reaction involves readily
available starting materials and tolerates a wide range of aryl
and alkyl substituents. Bromination using NBS, under free-
radical conditions, was also a useful strategy, providing further
transformations into the selenazole moiety.
2-(4-Bromophenyl)-5-methylselenazole (9b). Prepared in an
analogous route as described for 9a starting from 4-bromo-N-(prop-
2-yn-1-yl)benzamide 6b. The residue was purified by chromatography
on SiO2 (n-hexane/EtOAc 5:1) to give 9b (148 mg, 70%) as a yellow
solid: mp 82.3−84.1 °C; 1H NMR δ 2.59 (d, J = 1.3 Hz, 3H), 7.46 (d,
EXPERIMENTAL SECTION
LiAlHSeH 0.1 M Preparation. To a stirred suspension of
selenium powder (0.08 g, 1.0 mmol) in dry THF (9 mL) was
added lithium aluminum hydride solution (1 M) in THF (1 mL, 1.0
■
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dx.doi.org/10.1021/jo402661b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
J = 1.3 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H); 13
C
Synthesis of (E)-5-(iodomethylene)-2-phenyl-4,5-dihydroselena-
zole (12b). To a stirred solution of N-(prop-2-ynyl)benzamide 6a
(0.70 mmol) in dry CH2Cl2 (3.5 mL) was added crystalline PCl5 (291
mg, 1.4 mmol) at −10 °C. Stirring was continued for 30 min. A freshly
prepared THF solution of LiAlHSeH (1.0 mmol) was added, and the
reaction mixture was stirred at the same temperature for another 1 h.
Then I2 (267 mg, 1.0 mmol) was added, and the reaction was stirred
overnight at −10 °C. The solvent was removed at reduced pressure
until dryness. The residue was poured into water (50 mL), NaHCO3
was added until pH 7, and the mixture was extracted with ethyl acetate
(5 × 30 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The residue was purified by chromatog-
raphy on SiO2 (n-hexane/EtOAc 5:1) to give 12b (29 mg, 12%) as
NMR δ 14.9, 124.1, 128.2, 132.2, 135.7, 142.0, 142.6, 172.5; HRMS
calcd for C10H9BrNSe [M + H]+ 301.9005, found 301.9030.
5-Methyl-2-(4-(trifluoromethyl)phenyl)selenazole (9c). Prepared
in an analogous route as described for 9a starting from N-(prop-2-yn-
1-yl)-4-(trifluoromethyl)benzamide 6c. The residue was purified by
chromatography on SiO2 (n-hexane/EtOAc 5:1) to give 9c (111 mg,
1
55%) as a yellow solid: mp 109.0−111.6 °C; H NMR δ 2.62 (d, J =
1.3 Hz, 3H), 7.53 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.94
(d, J = 8.1 Hz, 2H); 13C NMR δ 14.9, 124.1 (q, JCF3 = 271 Hz), 126.1
(q, J = 4 Hz), 127.0, 131.5 (q, J = 32 Hz), 139.8, 142.9, 143.0, 171.9;
HRMS calcd for C11H9F3NSe [M + H]+ 291.9774, found 291.9744.
2-(3-Chlorophenyl)-5-methylselenazole (9d). Prepared in an
analogous route as described for 9a starting from 3-chloro-N-(prop-
2-yn-1-yl)benzamide 6d. The residue was purified by chromatography
on SiO2 (n-hexane/EtOAc 8:1) to give 9d (75 mg, 42%) as a yellow
oil: 1H NMR δ 2.61 (d, J = 1.3 Hz, 3H), 7.31 − 7.38 (m, 2H), 7.49 (d,
J = 1.3 Hz, 1H), 7.69 (dt, J = 7.3, 1.6 Hz, 1H), 7.85 (t, J = 1.6 Hz, 1H);
13C NMR δ 14.9, 125.0, 126.6, 129.8, 130.3, 135.1, 138.4, 142.4, 142.7,
172.0; HRMS calcd for C10H9ClNSe [M + H]+ 257.9510, found
257.9540.
1
yellow oil: H NMR δ 5.08 (d, J = 3.1 Hz, 1H), 6.16 (t, J = 3.1 Hz,
1H), 7.41 − 7.49 (m, 3H), 7.65 − 7.68 (m, 2H); 13C NMR δ 62.9,
79.7, 128.5, 128.9, 131.7, 135.4, 146.7, 166.0; HRMS calcd for
C10H8INSe 348.8866, [M]+ found 348.8869
Synthesis of 5-(Bromomethyl)-2-phenylselenazole (13). To a
stirred solution of 9a (600 mg, 2.7 mmol) in CCl4 (45 mL) were
added NBS (529 mg, 3.0 mmol) and AIBN (49 mg, 0.3 mmol). Then
the solution was irradiated with hν for 1 h (200 W, tungsten lamp)
using an ice bath to avoid overheating and stirred overnight at room
temperature, protected from light. The formed succinimide was
filtered off, and the filtrate was concentrated under vacuum. The
residue was purified by chromatography on SiO2 (n-hexane/EtOAc
3:1) to give 13 (554 mg, 68%) as a white solid: mp 80.6−82.0 °C; 1H
NMR δ 4.82 (d, J = 0.8 Hz, 2H), 7.40 − 7.45 (m, 3H), 7.76 (t, J = 0.8
Hz, 1H), 7.86 (dd, J = 1.6, 7.9 Hz, 2H); 13C NMR δ 26.6, 127.0, 129.3,
130.8, 136.3, 143.1, 144.2, 177.4; HRMS calcd for C10H9NSe [M − Br
+ H]+ 222.9005, found 222.9028.
2-(4-Isopropylphenyl)-5-methylselenazole (9e). Prepared in an
analogous route as described for 9a starting from 4-isopropyl-N-(prop-
2-yn-1-yl)benzamide 6e. The residue was purified by chromatography
on SiO2 (n-hexane/EtOAc 4:1) to give 9e (112 mg, 61%) as a yellow
oil: 1H NMR δ 1.27 (d, J = 7.0 Hz, 6H), 2.58 (d, J = 1.3 Hz, 3H) 2.93
(hept, J = 6.9,Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 1.3, 2.5
Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H); 13C NMR δ 14.8, 23.9, 34.1, 126.8,
127.1, 134.5, 140.6, 142.2, 151.0, 174.0; HRMS calcd for C13H16NSe
[M + H]+ 266.0369, found 266.0399.
Synthesis of 5-(Cyanomethyl)-2-phenylselenazole (14). To a
stirred solution of 9a (150 mg, 0.5 mmol) in DMF (10 mL) was added
KCN (39 mg, 0.60 mmol) at 0 °C. The reaction mixture was stirred at
room temperature for 2 h, poured into water, and extracted with Et2O.
The combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified by chromatography on SiO2
(n-hexane/EtOAc 4:1) to give 14 (38 mg, 36%) as a yellow solid: mp
2-(4-Methoxyphenyl)-5-methylselenazole (9f). Prepared in an
analogous route as described for 9a starting from 4-methoxy-N-
(prop-2-yn-1-yl)benzamide 6f. The residue was purified by chroma-
tography on SiO2 (n-hexane/EtOAc 6:1) to give 9f (115 mg, 88%) as
a white solid: mp 65.2−66.0 °C; 1H NMR δ 2.57 (d, J = 1.3 Hz, 3H),
3.85 (s, 3H), 6.92 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 1.3 Hz, 1H), 7.77
(d, J = 8.9 Hz, 2H); 13C NMR δ 14.9, 55.5, 114.4, 128.2, 129.8, 140.2,
142.1, 161.1, 173.7; HRMS calcd for C11H12NOSe [M + H]+
254.0006, found 254.0036.
1
76.8−78.0 °C; H NMR δ 4.02 (d, J = 1.3 Hz, 2H), 7.41 − 7.47 (m,
3H), 7.72 (t, J = 1.3 Hz, 1H), 7.85 (dd, J = 1.7, 7.8 Hz, 2H); 13C NMR
δ 18.7, 116.7, 127.1, 129.3, 130.9, 132.4, 135.9, 144.2, 176.8; HRMS
calcd for C10H10NSe [M − CN + H]+ 223.9900, found 223.9926.
2-Ethyl-5-methylselenazole (9g). Prepared in an analogous route
as described for 9a starting from N-(prop-2-yn-1-yl)propionamide 6g.
The residue was purified by chromatography on SiO2 (n-hexane/
1
ASSOCIATED CONTENT
EtOAc 6:1) to give 9g (31 mg, 25%) as a yellow oil: H NMR δ 1.35
■
(t, J = 7.6 Hz, 3H), 2.51 (d, J = 1.3 Hz, 3H), 2.96 (q, J = 7.6 Hz, 2H),
7.22 (d, J = 1.3 Hz, 1H); 13C NMR δ 14.8, 30.7, 140.1, 140.3, 179.5;
HRMS calcd for C6H10NSe [M + H]+ 175.9900, found 175.9902.
2-Isopropyl-5-methylselenazole (9h). Prepared in an analogous
route as described for 9a starting from N-(prop-2-ynyl)isobutyramide
6h. The residue was purified by chromatography on SiO2 (n hexane/
EtOAc 6:1) to give 9h (31 mg, 23%) as a yellow oil: 1H NMR δ 1.35
(d, J = 6.9 Hz, 6H), 2.51 (d, J = 1.4 Hz, 3H), 3.21 (hept, J = 6.9 Hz,
1H), 7.24 (d, J = 1.4 Hz, 1H); 13C NMR δ 14.7, 23.7, 36.6, 139.6,
140.1, 185.2; HRMS calcd for C7H12NSe [M + H]+ 190.0057, found
190.0035.
S
* Supporting Information
1H and 13C spectra for compounds 9a−j, 12b, 13, and 14. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gmahler@fq.edu.uy.
Notes
2-(tert-Butyl)-5-methylselenazole (9i). Prepared in an analogous
route as described for 9a starting from N-(prop-2-yn-1-yl)pivalamide
6i. The residue was purified by chromatography on SiO2 (n-hexane/
EtOAc 10:1) to give 9i (29 mg, 20%) as a yellow oil: 1H NMR δ 1.40
(s, 9H), 2.51 (d, J = 1.3 Hz, 3H), 7.24 (d, J = 1.3 Hz, 1H); 13C NMR δ
14.7, 31.3, 40.5, 139.7, 140.3, 188.4.; HRMS calcd for C8H13NSe [M]+
203.0213, found 203.0237.
2-(4-Methoxybenzyl)-5-methylselenazole (9j). Prepared in an
analogous route as described for 9a starting from 2-(4-methox-
yphenyl)-N-(prop-2-yn-1-yl)acetamide 6j. The residue was purified by
chromatography on SiO2 (n-hexane/EtOAc 5:1) to give 9j (67 mg,
36%) as a yellow oil: 1H NMR δ 2.47 (d, J = 1.4 Hz, 3H), 3.80 (s, 3H),
4.16 (s, 2H), 6.87 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.27
(dd, J = 1.4, 2.6 Hz, 1H); 13C NMR δ 14.7, 42.6, 55.4, 114.3, 130.3,
130.8, 140.7, 141.4, 158.8, 178.1; HRMS calcd for C12H14NOSe [M +
H]+ 268.0162, found 268.0175.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CSIC-UdelaR supported this work. C.P. is grateful to the
Agencia Nacional de Investigacion
́
e Innovacion
́
(ANII) for a
fellowship from (BE_POS_2010_1_2362). We thank Dr. A.
́
Rodriguez-Haralambides for HRMS.
REFERENCES
■
(1) (a) Liotta, D.; Monahan, R. Science 1986, 231, 356−361.
(b) Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 3740−3749. (c) Rhoden,
C. R. B.; Zeni, G. Org. Biomol. Chem. 2011, 9, 1301−1313.
(d) Levason, W.; Reid, G.; Zhang, W. Dalton Trans. 2011, 40,
8491−8506.
D
dx.doi.org/10.1021/jo402661b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(2) (a) Beri, R. B.; Pawan, K.; Khanna, P. K. Cryst. Eng. Commun.
2010, 12, 2762−2768. (b) Sudesh, T.; Manjare, S. T.; Kim, S.; Heo,
W. D.; Churchill, D. G. Org. Lett. 2014, 16, 410−412. (c) Kumar, A.;
Rao, G. K.; Kumar, S.; Singh, A. K. Organometallics 2014,
DOI: 10.1021/om4007196.
(3) (a) Mugesh, G.; du Mont, W. W.; Sies, H. Chem. Rev. 2001, 101,
2125−2179. (b) Nogueira, C. W.; Zeni, G.; Rocha, T. B. T. Chem. Rev.
2004, 104, 6255−6285. (c) Ninomiya, M.; Garud, D R.; Koketsu, M.
Coord. Chem. Rev. 2011, 255, 2968−2990.
(4) Koketsu, M.; Ishihara, H. 1,3-Selenazoles. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E.
F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 4, pp 791−
821. (b) Koketsu, M.; Ishihara, H. Curr. Org. Chem. 2003, 7, 175.
(c) Mlochowski, J.; Kloc, K.; Lisiak, R.; Potaczek, P.; Wojtowicz, H.
ARKIVOC 2007, 6, 14−46.
(5) Hak, J. A.; Koketsu, M.; Eun, M. Y. E.; Yong, M. K.; Ishihara, H.;
Hyun, O. Y. J. Cell. Biochem. 2006, 99, 807−815.
(6) Choi, S. Y.; Jo, Y. O.; Koketsu, M.; Ishihara, H.; Kim, S. H.; Kim,
S. Y. J. Korean Soc. App. Biol. Chem. 2009, 52, 371−374.
(7) Wray, S. K.; Smith, R. H. A.; Gilbert, B. E.; Knight, V. Antimicrob.
Agents Chemother. 1986, 29, 67−72.
(8) (a) Traiffort, E.; Ruat, M.; Arrang, J. M.; Leurs, R.; Piomelli, D.;
Schwartz, J. C. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 2649−2653.
(b) van der Goot, H.; Eriks, J. C.; Leurs, R.; Timmerman, H. Bioorg.
Med. Chem. Lett. 1994, 4, 1913−1916.
(9) Sekiguchi, A.; Nishina, A.; Kimura, H.; Fukumoto, R. H.; Kanoh,
K.; Ishihara, H.; Koketsu, M. Chem. Pharm. Bull. 2005, 53, 1439−1442.
(10) Nam, K. N.; Koketsu, M.; Lee, E. H. Eur. J. Pharmacol. 2008,
589, 53−57.
(11) (a) Narender, M.; Reddy, M. S.; Kumar, V. P.; Prakash Reddy,
V. P.; Nageswar, Y. V. D.; Rao, R. K. J. Org. Chem. 2007, 72, 1849−
1851. (b) Madhav, B.; Narayana, S.; Murthy, B. S. P.; Kumar, A.;
Ramesh, K.; Nageswar, Y. V. D. Tetrahedron Lett. 2012, 53, 3835−
3838. (c) Ninomiya, M.; Garud, D. R.; Koketsu, M. Heterocycles 2010,
81, 2027−2055.
́
(12) Pizzo, C.; Faral-Tello, P.; Salinas, G.; Flo, M.; Robello, C.; Wipf,
P.; Mahler, S. G. Med. Chem. Commun. 2012, 3, 362−367.
(13) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593−
3595.
(14) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org.
Lett. 2004, 6, 4391−4394. (b) Kang, J.-E.; Kim, H.-B.; Lee, J.-W.; Shin,
S. Org. Lett. 2006, 8, 3537−3540. (c) Doherty, S.; Knight, J. G.;
Hashmi, A. S. K.; Smyth, C. H.; Ward, N. A. B.; Robson, K. J.;
Tweedley, S.; Harrington, S. T.R. W.; Clegg, W. Organometallics 2010,
29, 4139−4147. (d) Hashmi, A. S. K.; Blanco Jaimes, M. C.; Schuster,
A. M.; Rominger, F. J. Org. Chem. 2012, 77, 6394−6408.
(15) Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379−4382.
(16) Pan, Y.; Zheng, F.; Lin, H.; Zhan, Z. J. Org. Chem. 2009, 74,
3148−3151.
(17) Hua, G.; Woollins, J. D. Angew. Chem., Int. Ed. 2009, 48, 1368−
1377.
(18) Ishihara, H.; Koketsu, M.; Fukuta, Y.; Nada, F. J. Am. Chem. Soc.
2001, 123, 8408−8409.
(19) Vishwanatha, T. M.; Narendra, N.; Chattopadhyay, B.;
Mukherjee, M.; Sureshbabu, V. V. J. Org. Chem. 2012, 77, 2689−2702.
E
dx.doi.org/10.1021/jo402661b | J. Org. Chem. XXXX, XXX, XXX−XXX