Regioselective synthesis of polysubstituted pyridines via hetero-Diels-Alder reaction of isotellurazoles with acetylenic dienophiles

Article abstract of DOI:10.1016/j.tetlet.2009.09.060

Treatment of substituted isotellurazoles or their Te-oxides with acetylenic dienophiles efficiently afforded polysubstituted pyridine derivatives through a pathway involving hetero-Diels-Alder reaction of isotellurazoles and the subsequent tellurium extru

Full text of DOI:10.1016/j.tetlet.2009.09.060

Tetrahedron Letters 50 (2009) 6651–6653
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of polysubstituted pyridines via hetero-Diels–Alder
reaction of isotellurazoles with acetylenic dienophiles
*
Kazuaki Shimada , Yukichi Takata, Yu Osaki, Akiko Moro-oka, Hisashi Kogawa, Maiko Sakuraba,
Shigenobu Aoyagi, Yuji Takikawa, Satoshi Ogawa
Department of Chemical Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate 020-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2009
Revised 7 September 2009
Accepted 11 September 2009
Available online 15 September 2009
Treatment of substituted isotellurazoles or their Te-oxides with acetylenic dienophiles efficiently affor-
ded polysubstituted pyridine derivatives through a pathway involving hetero-Diels–Alder reaction of iso-
tellurazoles and the subsequent tellurium extrusion from the intermediary cycloadducts.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Isotellurazole
Hetero-Diels–Alder reaction
Acetylenic dienophiles
Polysubstituted pyridine
Azafluorenone
relatively low heteroaromaticity of tellurium-containing five-
R2
R3
R2
R2
membered heteroaromatics6 and the subsequent feasible extru-
X
N
R3
R3
Δ
sion of elemental tellurium from the intermediary cycloadduct B
+
X
or B0 under mild reaction conditions. However, only limited pre-
R1
R1
[ 4 + 2 ]
- X
N
R4
R1
N
R4
R4
parative methods for tellurazoles and isotellurazoles had been re-
ported within these decades in spite of their potentiality as
reactive heterodienes.7,8 In the course of our studies on syntheses
and reactions of higher-row chalcogen-containing heterocycles,
we reported a convenient preparation of isotellurazoles 2 by the
way of reaction of Te-alkenyl tellurocarbamates9 with hydroxyl-
amine O-sulfonic acid involving intramolecular SN2 replacement
on the oxime nitrogen atom followed by deoxygenation of Te-oxi-
des 20.10 These successful results envisaged us to the attempts for
the synthesis of pyridine ring systems using hetero-Diels–Alder
reaction of 2 or 20. Here, we describe a new and efficient conversion
of 2 or 20 into polysubstituted pyridines 4 in a high regioselective
manner via hetero-Diels–Alder reaction with acetylenic dieno-
philes under mild reaction conditions. Short-step construction of
biologically intriguing 2-aza- and 4-azafluorenone alkaloid skele-
tons from the resulting pyridines 4 is also described in this Letter.
Isotellurazoles 2 and their Te-oxides 20 were prepared easily
from phenylacetylene or 1-hexyne by using our reported method.9
However, all attempts for deoxygenation of isotellurazole Te-oxi-
des 20 bearing two alkyl groups at the C-2 and C-4 positions were
unsuccessful in spite of applying various reducing agents.
1 (X = Se)
2 (X = Te)
2' (X = TeO)
3
A (X = Se)
B (X = Te)
B' (X = TeO)
4
Polysubstituted and fused pyridine cores have been found in a
wide variety of naturally occurring polycyclic alkaloid skeletons
having biological, pharmaceutical, and agrochemical activities,
and studies on efficient synthesis of pyridine ring systems preserve
a considerable importance in current organic synthesis in spite of
the long history of pyridine chemistry. Among the modern meth-
odologies for the syntheses of pyridine rings, thermal reactions of
chalcogen- and nitrogen-containing five-membered heterocycles
with dienophiles have been extensively studied. However, syn-
thetic application of such compounds has been limited within
the area of oxygen- or nitrogen-bridged five- or six-membered het-
eroaromatics due to the easiness in preparation and their treatabil-
ity.1–5 Among the five-membered heterocycles bearing a chalcogen
atom, tellurazoles and isotellurazoles have been presumed to be-
have as heavy chalcogen-bridged reactive azadienes based on the
Isotellurazoles 2 and Te-oxides 20 were thermally stable enough
up to 150 °C when heated in the absence of any electrophilic re-
* Corresponding author. Tel./fax: +81 19 621 6324.
E-mail address: shimada@iwate-u.ac.jp (K. Shimada).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.060

6652
K. Shimada et al. / Tetrahedron Letters 50 (2009) 6651–6653
agents. However, when a CH2Cl2 solution of 2a (R1 = CH3, R2 =
C6H5), 2b (R1 = R2 = C6H5), or their corresponding Te-oxides, 2a0 or
2b0, was treated with dimethyl acetylenedicarboxylate (DMAD),
all substrates underwent facile conversion into the corresponding
pyridine derivative 4a or 4b, respectively, even at room tempera-
ture along with the gradual extrusion of elemental tellurium. Sim-
ilar reactions of isotellurazoles 2 or isotellurazole Te-oxides 20 with
various acetylenic dienophiles also gave pyridine derivatives 4 in
high to moderate yields, and sole regioisomers of 4 were obtained
in all cases using unsymmetrical acetylenic dienophiles bearing
an electron-withdrawing group (EWG). Especially, pyridine 4c,
synthesized from 2a and methyl propynoate, were identical in all
respects with those of the reported product.11 These results
indicated that both 2 and 20 underwent hetero-Diels–Alder-type
regioselective manner to afford 4 bearing the electron-withdrawing
group at the C-3 position. In contrast, a similar conversion of the
corresponding isoselenazole 1a (R1 = CH3, R2 = C6H5) into the same
pyridine 4a using DMAD required much higher temperature with a
prolonged reaction time, and reaction of 1a with methyl propiolate
only gave the recovery even after long-time refluxing in toluene.
Interestingly, the reactivity of N,N-dimethylpropynamide toward
2a was much lower than that of methyl propiolate, and electron-
rich acetylenes, such as phenylacetylene and diphenylacetylene,
were inactive toward the reaction with 2a. These results strongly
suggested that inverse-electron-demand Diels–Alder pathway
was negligible for the reaction mechanism. However, treatment of
SnCl4 (1.0 mol amt.) with 2a or with the reaction mixture of 2a-
methyl phenylpropynoate at room temperature formed insoluble
materials in the solvent, and in both cases 2a was completely
cycloaddition with unsymmetrical dienophiles
3 in a highly
Table 1
Regioselective synthesis of polysubstituted pyridines 4 from isoselenazole 1, isotellurazoles 2, or isotellurazole Te-oxides 20 and acetylenic dienophiles 3
R2
EWG
R2
Δ
EWG
R3
+
X
- X
N
R1
R3
R1
N
1 (X=Se)
2 (X=Te)
2' (X=TeO)
4
3
Isochalcogenazole (1, 2, 20)
Dienophile (3)
Solvent
Temp (°C)
Time (h)
Yield of 4 (%)
R1
R2
X
EWG
R3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C4H9
n-C4H9
Se
Se
Te
Te
Te
Te
Te
Te
Te
Te
Te
Te
Te
Te
Te
Te
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COCH3
COOCH3
H
COOCH3
H
C6H5
n-C4H9
C6H5
TMS
COC6H5
C6H5
C6H5
H
C6H5
COOCH3
H
n-C4H9
COOCH3
H
COOCH3
COOCH3
COOCH3
C6H5
Toluene
Toluene
CH2Cl2
Reflux
Reflux
rt
12
24
12
24
24
36
12
72
12
24
24
24
24
12
48
24
24
6
91 (4a)
0a
91 (4a)
79 (4c)11
96 (4g)
90
93
71
88
Quant.
83
CH2Cl2
rt
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
140b
150b
130b
150b
rt
COCH3
COC6H5
COC6H5
CHO
150b
Reflux
100
70
rt
rt
150
rt
70
rt
rt
CONMe2
p-TolSO2
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
90
59
69
H
H
25c,12
95 (4e)
50 (4b)
24 (4d)
77 (4a)
22 (4b)c
48
C6H5
C6H5
CH3
C6H5
CH3
CH3
Te
Te
TeO
TeO
TeO
TeO
Benzene
CH2Cl2
CH2Cl2
Toluene
Toluene
24
48
12
24
rt
150b
42 (4f)
a
b
c
Substrate 2 was recovered in quantitative yield.
Reaction was carried out in a sealed tube.
A mixture of uncharacterized polymeric products was mainly obtained besides pyridine 4.
X R2
EWG
EWG
Path A
[4+2]
N
R1
R3
R2
R2
Te
3
B, B'
R3
EWG
R3
R1
R1
N
N
- Te
R2
Te
R2
Te
EWG
R3
Path B
EWG
4
2
R3
R1
R1
N
N
C
D
Scheme 1. Plausible pathways for the formation of polysubstituted pyridines 4 involving a concerted and/or stepwise cyclization of isotellurazole 2 with acetylenic
dienophiles 3.

K. Shimada et al. / Tetrahedron Letters 50 (2009) 6651–6653
6653
recovered after neutralization even after the reaction mixture was
Supplementary data
heated at higher temperature for prolonged time. These phenom-
ena suggested that 2 were deactivated by the Lewis acid due to their
basicity. All the results of reactions of 1, 2, or 20 with symmetrical
and unsymmetrical acetylenic dienophiles are presented in Table 1.
Further conversion of pyridines 4c–f bearing an ester group and
a phenyl group at the C-3 and C-4 positions, respectively, into the
corresponding 2-azafluorenones 5c–f was successfully achieved by
Friedel–Crafts cyclization using PPA.11 Treatment of 4g bearing a
phenyl group at the C-2 position with PPA in a similar manner gave
the corresponding 4-azafluorenone 6, that is, an alkyl analogue of
naturally occurring onychine possessing antimicrobial activity,13
in 74% yield. Therefore, a simple, short-step, and efficient entry
to the synthesis of derivatives and analogues of 2-aza- and 4-aza-
fluorenone alkaloids having biological and pharmacological activi-
ties would be delivered through a hetero-Diels–Alder methodology
starting from 2 or 20.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.060.
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nals assignable to possible bicyclic cycloadduct
B or ionic
intermediates C and/or D were not detected at all throughout
the NMR monitoring.
In conclusion, we found an efficient and versatile synthesis of
polysubstituted pyridines 4 starting from isotellurazoles 2 or
isotellurazole Te-oxides 20 via hetero-Diels–Alder pathway
as well as a facile and convenient conversion of 4 bearing an ester
group at the C-3 position into 2-aza- and 4-azafluoreonone alka-
loid skeletons. Further applications of the new synthetic protocol
to various polycyclic alkaloid ring systems having substituted
and fused pyridine cores are now in progress in our laboratory.
14. Theoretical calculation was carried out using the B3LYP/6-311G (d, p) for C, N,
H and 3-21G (d) for Te level of theory.