Thermally-induced skeletal rearrangement of (Z)-O-propargylic α,β-unsaturated aldoximes to multisubstituted pyridine oxides

Article abstract of DOI:10.1016/j.tetlet.2011.09.107

(Z)-Propargylic oxime ethers derived from α,β-unsaturated aldehydes were converted to the corresponding 2,3,6-trisubstituted pyridine oxides in moderate to acceptable yields with high regioselectivity. The reaction proceeds via a tandem thermal [2,3] rear

Full text of DOI:10.1016/j.tetlet.2011.09.107

Tetrahedron Letters 52 (2011) 6470–6472
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Tetrahedron Letters
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Thermally-induced skeletal rearrangement of (Z)-O-propargylic a,b-unsaturated
aldoximes to multisubstituted pyridine oxides
Itaru Nakamura a,b, , Dong Zhang b, Masahiro Terada a,b
⇑
a Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
(Z)-Propargylic oxime ethers derived from a,b-unsaturated aldehydes were converted to the correspond-
ing 2,3,6-trisubstituted pyridine oxides in moderate to acceptable yields with high regioselectivity. The
Received 23 August 2011
Revised 20 September 2011
Accepted 22 September 2011
Available online 29 September 2011
reaction proceeds via a tandem thermal [2,3] rearrangement, 4 electrocyclization, and ring expansion.
p
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Oxime
Skeletal rearrangement
Alkyne
Electrocyclization
Multisubstituted pyridines are found in numerous natural and
synthetic pharmaceutical agents.1 Pyridine scaffolds are also of
great interest in material science.2 Therefore, there is still a need
to develop efficient methodologies to synthesize pyridine deriva-
tives, of which the substituents are introduced in a regioselective
manner.3 We recently reported that the copper-catalyzed skeletal
cyclization of the corresponding Z isomers of O-propargylic oxime
(Z)-1 produced 2,3,6-trisubstituted pyridine oxides 3 that have a
different substitution pattern from 2, at an elevated temperature
in the absence of a copper catalyst (Eq. 2).
In our previous study, we reported that (Z)-1a was converted
into four-membered cyclic nitrone 4a in the presence of copper
in fairly high yield (Table 1, entry 1).4a In this reaction, a trace
amount of 2,3,6-trisubstituted pyridine oxide 3a was detected by
a thorough analysis of the crude mixture. The structure of 3a
was determined by NMR, IR, and X-ray crystallographic analyses.
The reaction of (Z)-1a proceeded even in the absence of the copper
catalyst (entries 2, 4–14). Among the solvents tested, the use of po-
lar DMF improved the mass balance, although a long reaction time
was needed (entries 5–10). An apparent temperature effect was
also observed; the yield of 3a was increased when the reaction
temperature was elevated (entries 4, 5, 11–14). In particular, the
reaction at 180 °C was completed within 15 min, affording 3a in
a good isolated yield (entry 14). Although the copper complex
exhibited catalytic activity for the formation of 4a in DMF at
100 °C (entry 3 vs entry 5) attempts to improve the chemical yield
by optimizing the copper catalyst failed.
rearrangement of (E)-O-propargylic
a,b-unsaturated aldoximes
(E)-1 afforded 2,3,4,(5)-multisubstituted pyridine oxides 2 in good
4–6
to high yields (Eq. 1).
Herein, we report that the thermal
Thus, thermally-induced skeletal rearrangement at 180 °C was
carried out using various substrates (Z)-1, as summarized in
Table 2.7 The reaction of substrate 1b having an electron-donating
p-anisyl group at the b position of the oxime group (R4) afforded
the desired product 3b in a higher yield than that of 1c that had
an electron-withdrawing p-nitrophenyl group (entries 2 and 3).
The reaction of 1e, whose R3 is a hydrogen atom, afforded 3e in a
⇑
Corresponding author.
E-mail address: itaru-n@m.tohoku.ac.jp (I. Nakamura).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.107

I. Nakamura et al. / Tetrahedron Letters 52 (2011) 6470–6472
6471
Table 1
Optimization of the reaction conditions
Ph
O
N
Ph
O
N
conditions
N
O
Ph
Ph
+
Ph
Ph
Ph
Ph
Ph
4a
3a
(Z)-1a
a
Entry
Solvent
Copper catalyst
Temp. (°C)
Time (h)
Yield 3ab (%)
Yield 4ab (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
DMF
DMF
DMF
DMSO
DCE
1,4-Dioxane
Toluene
THF
+
100
100
100
80
7
7
3
7
4
6
6
12
9
10
5
5
6
12
39
62
84
71
ꢀ
+
86
c
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
67
23
23
23
23
23
23
3
84
100
100
100
100
100
100
120
140
160
180
82
48
27
55
58
74
83
40
0
9
10
11
12
13
14
DMF
DMF
DMF
DMF
3
3
0.25
60 (58)
0
a
b
c
Copper catalyst, +: with 10 mol % CuBr(PPh3)3, ꢀ: without copper catalyst.
The yield was determined by 1H NMR using CH2Br2 as the internal standard. Isolated yield in parentheses.
5% of (Z)-1a was recovered.
Table 2
The reaction of 1a–ha
O
N
Ph
O
N
Ph
Ph
Ph
ð3Þ
DMF
H
Ph
Ph
180° C, 15 min
R4
H
O
N
4a
R4
H
R1
3a, 60%
180 °C
DMF
N
R2
O
A plausible mechanism for the present reaction is shown in
Scheme 1. First, the thermal [2,3]-rearrangement of (Z)-1 leads to
N-allenylnitrone species 5. Its rotamer 50 undergoes 4
-electrocyc-
R2
H
R1
p
3
lization to form four-membered cyclic nitrone 6.8 The sp3-carbon–
nitrogen bond is cleaved to form zwitterionic intermediate 7. At a
low reaction temperature, the re-formation of the C–N bond takes
place via zwitterionic intermediate 8, yielding another four-mem-
bered cyclic nitrone 4 having a longer conjugated chain than 6, as
the thermodynamic product at 100 °C. At a high reaction tempera-
ture, the re-formation of the sp3-carbon–nitrogen bond occurs via
(Z)-1
Entry
1
R1
R2
R4
Time (h)
3 (4)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1h
Ph
Ph
Ph
Ph
Ph
n-Pr
Cy
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Pr
n-Pr
Ph
0.25
0.25
0.25
0.5
3a
3b
3c
3d
3e
3f
3g
3h
(4h)
58
51
37
38
12
56
53
18
56d
p-MeOC6H4
p-O2NC6H4
Me
H
Ph
Ph
Ph
Ph
R4
N
R4
N
0.5
R4
H
0.25
0.25
3
R4
R2
O
N
O
O
N
N
O
H
H
c
9
7 days
R2
R1
R1
R1
•
•
a
b
c
R1
The reaction of 1 was carried out in DMF at 180 °C.
6
R2
R2
Isolated yield.
At 100 °C.
(Z)-1
5'
5
d
11% of 3h was obtained.
R4
R2
R2
O
O
N
O
N
low yield (entry 5). Substrates 1f and 1g bearing an alkyl group at
the alkyne terminus (R1) were effectively converted into products
3f and 3g in moderate yields (entries 6 and 7). In contrast, the reac-
tion of 1h with an alkyl substituent at the propargylic position (R2)
gave the desired product in a low yield due to the decomposition of
1h and 4h at 180 °C (entry 8), although the reaction of 1h at 100 °C
afforded cyclic nitrone 4h in an acceptable yield (entry 9).
As expected from the results of Table 1, when isolated 4a was
heated at 180 °C for 15 min, 3a was obtained in 60% isolated yield,
suggesting that four-membered cyclic nitrone 4 is a key intermedi-
ate to produce pyridine oxide 3 in the present reaction (Eq. 3).
R1
R1
R4
R4
R2
R1
7
8
4
R4
O
O
N
R4
R1
R2
N
O
N
R4
R1
R1
R2
R2
9
10
3
Scheme 1. Plausible mechanism.

6472
I. Nakamura et al. / Tetrahedron Letters 52 (2011) 6470–6472
R4
H
R4
O
N
Δ
R1
R2
R4
O
(or cat. Cu)
4π
6π
O
N
(Z)-1
(E)-1
N
H
R2
R1
R1
•
H
3
R2
6
5'
H
O
N
O
N
R3
O
R1
cat. Cu
H
R1
H
N
R2
R2
R4
R1
R3
•
R3
R4
2
R4
12
R2
11
Scheme 2. Electrocyclization steps in the reaction of (Z)-1 and (E)-1.
R4
In conclusion, we have developed a new approach to the
multisubstituted pyridine oxides. It should be noted that three dif-
ferent substituents can be substituted at the 2, 3, and 6 positions of
the pyridine ring in a regiospecific manner. Further investigations
of the reaction mechanism are underway in our laboratory.
R4
H
R4
O
Δ
N
O
O
H
N
H
N
R2
R1
H
•
R2
R1
R1
R4
R2
13
5
(Z)-1
Acknowledgments
H
O
H
N
This work was financially supported by a Grant-in-Aid for Sci-
entific Research from Japan Society for Promotion in Science (JSPS).
O
N
N
Cu
R4
O
R1 R4
R2
R1
•
R2
R2
R1
Cu
14
Supplementary data
11
(E)-1
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.107.
Scheme 3. [2,3]-Rearrangement process in the reaction of (Z)-1 and (E)-1.
intermediate 9. Resulting dihydropyridine oxide 10 readily isomer-
izes to 2,3,6-trisubstituted pyridine oxide 3. The reaction of 1h at
180 °C afforded only small amounts of 3h although corresponding
cyclic nitrone 4h was obtained in a good yield at 100 °C (Table 2,
entries 8 and 9). These results suggest that the low stabilizing abil-
ity of the alkyl group at R2 toward the carbocation of intermediate
8 resulted in the suppression of the cleavage of the sp3-carbon–
nitrogen bond of the cyclic nitrone 4h.
References and notes
1. (a) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752; (b) Hill, M. D. Chem. Eur. J.
2010, 16, 12052.
2. For representative examples, (a) Li, N.; Wang, P.; Lai, S.-L.; Liu, W.; Lee, C.-S.;
Lee, S.-T.; Liu, Z. Adv. Mater. 2010, 22, 527; (b) Yan, S.; Chen, W.; Yang, X.; Chen,
C.; Huang, M.; Xu, Z.; Yeung, K. W. K.; Yi, C. Polym. Bull. 2011, 66, 1191.
3. (a) Henry, G. D. Tetrahedron 2004, 60, 6043; (b) Bagley, M. C.; Glover, C.;
Merritt, E. A. Synlett 2007, 2459.
4. (a) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010, 132, 7884; (b)
Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2011, 133, 6862.
5. (a) Nakamura, I.; Araki, T.; Terada, M. J. Am. Chem. Soc. 2009, 131, 2804
(withdrawn); (b) Nakamura, I.; Araki, T.; Terada, M. J. Am. Chem. Soc. 2011, 133,
6861; (c) Nakamura, I.; Araki, T.; Zhang, D.; Kudo, Y.; Kwon, E.; Terada, M. Org.
Lett. 2011, 13, 3616.
The reaction of Z isomer (Z)-1 afforded 2,3,6-trisubstituted pyr-
idine oxide, whereas that of E isomer (E)-1 produced 2,3,4,5-tetra-
4
substituted pyridine oxides 2 (Scheme 2, Eq. 2 versus Eq. 1). The
key to changing the substitution pattern is the geometry of the nit-
rone moiety in the electrocyclization step of the N-allenylnitrone
intermediates 50 and 11 (Scheme 2); that is, in the latter case, the
carbon–carbon double bond can be located close to the allene moi-
6. Nakamura, I.; Okamoto, M.; Terada, M. Org. Lett. 2010, 12, 2453.
7. Representative procedure for the reaction of 1. To a 3 mL pressure vial were
added
1 (0.4 mmol) and DMF (0.8 mL) under argon atmosphere and the
reaction mixture was stirred at 180 °C for 15–30 min. After removing the
solvents in vacuo, the crude product was purified by silica gel column
chromatography using hexane/ethyl acetate (1:1) as eluent to obtain 3 in an
analytically pure form.
ety, enabling participation in the 6
the former case, the olefinic moiety is at the opposite side, result-
ing in exclusive 4 -electrocyclization. Moreover, it is noteworthy
p-electrocyclization, whereas in
p
8. Pennings, M. L. M.; Reinhoudt, D. N. J. Org. Chem. 1982, 47, 1816.
that the cyclization of the Z isomer proceeds without the aid of
any catalysts, whereas the E isomer requires a copper catalyst.9
In the [2,3]-rearrangement of (E)-1, the substituent R1 derived
from the alkyne terminus and the substituent at the oxime moiety
(R4–CH@CH–) approach each other (Scheme 3). To overcome the
steric repulsion, the catalyst possibly generates the cyclic vinylcop-
per intermediate 14, which allows the rearrangement to proceed
quickly. In contrast, because the substituent at the oxime moiety
is located at the opposite side of R1 in the rearrangement of (Z)-1
to 5, as indicated in 13 as the transition state, the reaction of
(Z)-1 proceeds in a concerted manner even in the absence of the
catalyst.10 However, it should be noted that the copper catalyst
exhibited catalytic activity in DMF at 100 °C (Table 1, entry 3 vs
5), suggesting that the cyclization process in the reaction of the Z
isomer was also accelerated by the copper catalyst.
9. Results of the reaction of (E)-1a;4a
Ph
O
N
conditions
Ph
N
O
Ph
DMSO, 120 °C
Ph
Ph
Ph
(E)-1a
2a
75% NMR yield
10 % NMR yield [80% recovery of (E)-1a]
w/ 10 mol% CuBr(PPh3), 10mol% PPh3, 2h,
w/o Cu catalyst, 2h
ð4Þ
10. Mageswaran, S.; Ollis, W. D.; Southam, D. A.; Sutherland, I. O.; Thebtaranonth,
Y. J. Chem. Soc., Perkin Trans. 1 1981, 1969.