C O M M U N I C A T I O N S
Table 3. Cu-Catalyzed Cyclization of 1g-q a
Scheme 1. Plausible Mechanism
Time/
h
Yield/
b
%
Entry
1
R1
R2
2
1
2
3
4
5
6
7
8
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
p-anisyl
p-F3C-C6H4
H
n-Pr
(CH2)3OTIPS
Cy
t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
2.5
2.5
6
5
9
24
3
1
11
16
2g
2h
2i
2j
2k
2l
-
2n
-
2p
2q
75
52
80
87
87
81
0c
p-anisyl
p-F3C-C6H4
n-Pr
86
9
Ph
Ph
Ph
0c
10d
11d
47
44
6. Ionic cleavage of the C-O bond and subsequent elimination of
the Cu catalyst leads to N-allenyl nitrone intermediate 8. Its rotamer
(8′) undergoes a 6π-3-azatriene electrocyclization to afford dihy-
dropyridine 4, which isomerizes to 2 under the reaction conditions.
The significant effects of the substituent at the R-position of the
oxime group can be attributed to the steric repulsion between R1
and R3 within cyclized intermediate 6. In the case of (Z)-1a, the
reaction did not result in the formation of pyridine N-oxide 2a but
instead afforded product 3a presumably due to the alkylidene group
transfer (eq 4).12 This surprising result indicates that the geometry
of the oxime moiety is crucial for the electrocyclization process.
Cy
a The reaction of 1 (0.4 mmol) in the presence of CuBr(PPh3)3 (10
mol %) and PPh3 (10 mol %) in DMSO (0.8 mL) at 120 °C. b Isolated
yield. c Decomposition of the starting material was observed. d CuBr (10
mol %) and PPh3 (20 mol %) were used.
and 3, respectively), whereas the substrate with an alkyl substituent
at the R-position (1e) required a longer reaction time (entry 4).
Finally, the oxime of cyclohex-1-enecarbaldehyde (1f) afforded the
tetrahydroisoquinoline derivative 2f in good yield (entry 5).
As shown in Table 3, we shifted our attention to investigate the
substitution effects on the propargyl moiety. Although an electron-
donating p-anisyl group at R1 did not significantly affect the reaction
(entry 1), the presence of an electron-withdrawing p-(trifluorom-
ethyl)phenyl group (substrate 1h) resulted in a moderate yield of
2h (entry 2) due to a partial decomposition of 1h. Substrate 1i,
with a terminal alkyne group, was efficiently converted to the
3-monosubstituted pyridine N-oxide 2i in good yield (entry 3).
Substrates that possess a small alkyl group (R1) at the alkyne
terminus (1j, 1k, and 1l) afforded the corresponding 2-alkylpyridine
N-oxides (2j, 2k, and 2l, respectively) in high yields (entries 4-6);
a bulky tert-butyl group, however, at the alkyne terminus caused
the interruption of the cyclization reaction (entry 7). Next, the
electronic property of the substituent (R2) adjacent to the propargyl
carbon was investigated. Although an electron-donating p-anisyl
group (entry 8) was beneficial, an electron-withdrawing p-(trifluo-
romethyl)phenyl group (entry 9) interfered with the desired
transformation; a mixture of unidentified products was obtained.
Substrates 1p and 1q, which bear an alkyl group at R2, were not
very reactive (entries 10 and 11, respectively), even though the
loading amount of PPh3 was reduced to 20 mol %.
In conclusion, we have successfully developed an entirely new
approach to multisubstituted pyridine derivatives in a catalytic,
efficient, and regioselective manner. Since pyridine N-oxides have
recently received much attention in catalytic C-H functionaliza-
tion,14 the present methodology is useful to synthesize these
substrates. Further investigations into the reaction mechanism,
including the previously reported five-σ bond-cleavage rearrange-
ment, are currently underway in our laboratory.
Acknowledgment. This work was financially supported by a
Grant-in-Aid for Scientific Research from Japan Society for
Promotion in Science (JSPS).
Note Added after ASAP Publication. Table 1, footnotes e and f,
were corrected May 19, 2010.
The reaction of (E)-1a in the presence of CuCl (10 mol %) at
60 °C afforded the 3-benzylidene-3,4-dihydropyridine N-oxide 4a,
which readily isomerized to 2a at 120 °C (eq 3).13 This transforma-
tion strongly suggests that dihydropyridine 4 serves as a reactive
intermediate in the reaction pathway toward 2.
Supporting Information Available: Experimental procedures and
characterization of 1, 2, 3a, and 4a. This material is available free of
References
(1) For pioneering studies, see:(a) Trost, B. M.; Tanoury, G. J. J. Am. Chem.
Soc. 1988, 110, 1636. (b) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc.
1991, 113, 1850.
(2) For selected reviews, see:(a) Aubert, C.; Buisine, O.; Malacria, M. Chem.
ReV. 2002, 102, 813. (b) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004,
104, 1317. (c) An˜orbe, L.; Dom´ınguez, G.; Pe´rez-Castells, J. Chem.sEur.
J. 2004, 10, 4938. (d) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328.
(e) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348, 2271.
(f) Michelet, V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008,
47, 4268. (g) Tobisu, M.; Chatani, N. Chem. Soc. ReV. 2008, 37, 300.
(3) For selected reviews, see:(a) Marion, N.; Nolan, S. P. Angew. Chem., Int.
Ed. 2007, 46, 2750. (b) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV.
2008, 108, 3326. (c) Correa, A.; Marion, N.; Fensterbank, L.; Malacria,
M.; Nolan, S. P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718.
(4) For selected examples, see:(a) Chatani, N.; Kataoka, K.; Murai, S.;
Furukawa, N.; Seki, Y. J. Am. Chem. Soc. 1998, 120, 9104. (b) Kusama,
As illustrated in Scheme 1, a plausible mechanism of the present
reaction can be described as follows: first, a π-acidic Cu catalyst
becomes coordinated to the alkyne moiety of 1. Next, a nucleophilic
attack by the oxime nitrogen atom onto the electrophilically
activated carbon-carbon triple bond gives cyclized intermediate
9
J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010 7885