Copper-catalyzed skeletal rearrangement of O-propargylic alkylaldoximes via N-O bond cleavage

Article abstract of DOI:10.1021/ol203001w

O-Propargylic oximes that possess a proton at the α-position of the oxime group were effectively converted to the corresponding oxiranyl N-alkenylimines via a 5-endo-dig cyclization followed by the cleavage of the N-O bond.

Full text of DOI:10.1021/ol203001w

ORGANIC
LETTERS
2012
Vol. 14, No. 1
206–209
Copper-Catalyzed Skeletal
Rearrangement of O-Propargylic
Alkylaldoximes via NꢀO Bond Cleavage
Itaru Nakamura,*,†,‡ Tomoki Iwata,‡ Dong Zhang,‡ and Masahiro Terada†,‡
Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Sendai 980-8578, Japan, and Department of Chemistry,
Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
itaru-n@m.tohoku.ac.jp
Received November 7, 2011
ABSTRACT
O-Propargylic oximes that possess a proton at the R-position of the oxime group were effectively converted to the corresponding oxiranyl
N-alkenylimines via a 5-endo-dig cyclization followed by the cleavage of the NꢀO bond.
Metal-catalyzed skeletal rearrangements have been em-
ployed in numerous elegant transformations in the con-
struction of complex molecules, often via unique reaction
mechanisms.1 Reaction pathways of such catalytic skeletal
rearrangements can be dramatically affected by substitu-
tion effects, as shown by previous investigations involving
enynes and propargylic esters as substrates.2 Recently,
we have demonstrated that O-propargylic oximes can
undergo unique skeletal rearrangements in the presence
of copper catalysts.3 As shown in Scheme 1 (path a), the
key step of these transformations is the catalytic [2,3]-
migration of the propargylic oxime to the N-allenyl nitrone
via cyclic intermediate A involving a CꢀO bond cleavage.
As expected, the CꢀO bond cleavage process is facilitated
by the elimination of a stable nitrone group as the leaving
group. In contrast, the elimination of a proton from the
R-position of the oxime group of cyclic intermediate A, as
shown inScheme1 (pathb), would obstruct the CꢀO bond
† Research and Analytical Center for Giant Molecules.
‡ Department of Chemistry.
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J.-E.; Shin, S. Org. Biomol. Chem. 2009, 7, 4744–4752. (e) Jadhav, A. M.;
Bhunia, S.; Liao, H.-Y.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 1769–
1771. (f) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7226–7236.
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L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394–8395.
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4198–4199. (e) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc.
2010, 132, 3258–3259. (f) Yeom, H.-S.; Lee, Y.; Jeong, J.; So, E.; Hwang,
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r
10.1021/ol203001w
Published on Web 12/14/2011
2011 American Chemical Society

cleavage and, in turn, cause the cleavage of the NꢀO bond,
which would be driven by the donation of electrons from
the copper atom via intermediate B.4ꢀ6 The resulting
copper carbenoid intermediate C would undergo further
transformations due to the highly substituted reactant.
Herein, we report the copper-catalyzed skeletal rearrange-
ments of O-propargylic alkylaldoximes 1 to afford the
corresponding N-alkenyl oxiranylketimines 2 in good to
excellent yields via NꢀO bond cleavage (eq 1).7
presence of a bulky base such as Cy2NMe was effective for
driving the reaction to completion within 30 min to afford
2a in a good yield (entry 3). Similarly, but to a lesser extent,
the use of a less bulky base such as iPr2NEt afforded 2a in
an acceptable yield (entry 4). Unsurprisingly, the use of a
small organic base (Et3N, entry 5) or an inorganic base
(K2CO3, entry 6) did not improve the reaction. The catalytic
activitiesof copperbromideand copperiodide weresimilar
to that of copper chloride, whereas the activities of copper
acetate and cupric chloride were diminished (entries 7ꢀ10,
respectively).
Scheme 1. Bond Cleavage in Cu-Catalyzed Skeletal Rearran-
gement of O-Propargylic Oximes
Table 1. Optimization of the Reaction Conditions
time/
h
yield/
a
entry
catalyst
base
none
solvent
%
1
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
24
7
39b
51
79
66
48
44
76
74
11
0
none
3
Cy2NMe
iPr2NEt
Et3N
0.5
4
4
5
4
6
K2CO3
48
0.5
1
7
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
8
9
CuOAc
CuCl2
1
10
1
a The yields were determined using 1H NMR, with CH2Br2 as an
internal standard. 2a was converted to the corresponding oxiranylke-
tone by treatment with 1 N HCl. b Trace amounts of four-membered
cyclic nitrones were observed.
Initially, to determine the optimal conditions, the reac-
tions were carried out using (E)-1a that was derived from
phenylacetaldehyde. As shown in Table 1 (entry 1), using
toluene at 100 °C, and in the presence of catalytic amounts
of copper chloride, the reaction afforded the correspond-
ing product 2a in 39% yield (as determined by 1H NMR),
along with small amounts of the four-membered cyclic
nitrones.3c The use of acetonitrile as the solvent resulted in
a faster reaction, thus suppressing the formation of the
undesirable byproducts (entry 2). For our reactions, the
Using the optimized reaction conditions (Table 1, entry 3),
the substitution effects at the oxime moiety were investi-
gated using various substrates, as listed in Table 2. The
substrate possessing an electron-deficient aromatic ring at
R3 [(E)-1b, entry 1] exhibited a significantly faster reaction
than that having an electron-rich p-anisyl group [(E)-1d,
entry 3]. For the benzyl-substituted substrates, both E- and
Z-isomers exhibited similar reactivities (entries 2 and 4,
respectively). In contrast, for the alkyl-substituted sub-
strates (and witha bulky tert-butyl groupasthesubstituent
at the alkyne terminus), the Z-isomer [(Z)-1e, entry 6] pro-
ceeded to afford 2e in a good yield, whereas the E-isomer
[(E)-1e, entry 5] was unreactive. Accordingly, the reaction
of (E)-1f, which has a less bulky phenyl group at R1,
afforded the 2f in a 76% yield (entry 7).
(7) Concerning the stereochemistries of the products, the obtained
products possessed only the (E)-configuration at the alkenyl moiety
and the trans-isomers at the epoxy moiety. In contrast, the E/Z-
isomers at the imine moiety were inseparable; in the cases where the
substituent at the alkyne terminus was less bulky, both stereoisomers
were observable using 1H NMR spectroscopy. See footnote a of Table 1,
footnote d of Table 2, and Supporting Information.
Next, the substitution effects of the O-propargylic group
were examinedusing various substrates, aslistedin Table 3.
In all cases, the substrates possessed a tert-butyl moiety
at either the alkyne terminus (R1) or at the propargyl
position (R2) to ensure the stability of the product; none-
theless, the reactions were tolerant toward a wide variety of
Org. Lett., Vol. 14, No. 1, 2012
207

Table 2. Copper-Catalyzed Reactions of 1bꢀfa
Table 3. Copper-Catalyzed Reaction of (E)-1gꢀna
time/
yield/
b,c
entry
1
R3
h
2
%
time/
yield/
d
entry
1
R1
R2
h
2 (3)b,c
%
1
2
3
4
5
6
7
(E)-1b
(E)-1c
(E)-1d
(Z)-1c
(E)-1e
(Z)-1e
(E)-1f
p-F3C-C6H4
0.75
1
2b
2c
2d
2c
2e
2e
2f
84
Ph
87
1
2
3
4
5
6
7
8
1g
1h
1i
p-MeOC6H4
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Pr
Cy
0.5
2g
93
89
87
85e
59
76
80
57
p-MeO-C6H4
2
83
0.75
1.5
2h
Ph
Et
Et
Et
1
87
p-F3CC6H4
Cy
2i
48
7
trace
71d
76d
1j
0.75
0.5
2j
1k
1l
n-Pr
(3k)
(3l)
2m
(3n)
3
t-Bu
0.75
0.75
0.75
1m
1n
t-Bu
a The reaction of 1 (0.3 mmol) was carried out in the presence of CuCl
(10 mol %) and Cy2NMe (50 mol %) in acetonitrile (0.6 mL) at 100 °C.
b Isolated yield. c E/Z ratio of the imine moiety of 2cꢀe was 1:99. d NMR
yield. 2e and 2f were unstable under the purification conditions. Thus,
2e and 2f were converted to the corresponding oxiranylketones by
treatment with 1 N HCl.
t-Bu
Ph
a The reaction of (E)-1 (0.3 mmol) was carried out in the presence
of CuCl (10 mol %) and Cy2NMe (50 mol %) in acetonitrile (0.6 mL) at
100 °C. b N-Vinylimine 2 was converted to the corresponding ketone 4 by
treatment with 1 M HCl in Et2O at rt for 1 h. c The E/Z ratios of the imine
moiety of 2g (59:41), 2h (69:31), 2i (57:43), 2j (26:74), and 2m (1:99) were
determined by 1H NMR spectroscopy using CDCl3 as the solvent.
d Isolated yield. e 2j:3j = 93:7.
Scheme 2. Plausible Mechanism
substituents at either position. Relative to a phenyl-type
substrate (entry 2), an electron-rich aromatic ring at the
alkyne terminus resulted in a faster reaction (entry 1),
whereas an electron-poor p-trifluoromethylphenyl group
caused a slow reaction (entry 3). Although substrates that
possess a bulky alkyl substituent such as cyclohexyl (entry 4)
or tert-butyl group (Table 1) at the alkyne terminus (R1)
afforded high yields, the substrate that has a relatively
small normal propylsubstituent[(E)-1k] resultedinalower
yield, presumably due to the instability of N-vinylimine 2k
under the reaction conditions (entry 5). It should be noted
that the crude products of the copper-catalyzed reactions
of 1a, 1e, 1f, 1k, 1l, and 1n included significant amounts of
byproducts and, therefore, were treated with 1 N HCl after
the reaction to obtain the corresponding oxiranylketones 3
in the analytically pure form.7
A plausible mechanism of the copper-catalyzed rearran-
gement reaction is illustrated in Scheme 2. First, the
π-acidic copper catalyst is coordinated to the alkynyl moiety
of 1 to form adducts 4 and 40. Next, a 5-endo-dig cyclization
occurs via nucleophilic attack of the oxime nitrogen atom
onto the electrophilically activated triple bond to afford
vinylcopper intermediates 5 or 50. The proton at the
R-position of the oxime group is abstracted by the base
to form the common enamine intermediate 6, which rear-
ranges to metal-carbenoid 7 via cleavage of the NꢀO bond,
assisted by the donation of electrons from the copper atom.
The oxirane ring is then formed via nucleophilic attack of
(8) Hirata, Y.; Nakamura, S.; Watanabe, N.; Kataoka, O.; Kurosaki,
T.; Anada, M.; Kitagaki, S.; Shiro, M.; Hashimoto, S. Chem.;Eur. J.
2006, 12, 8898–8925.
(9) Cuadrado, P.; Gonzalez-Nogal, A. M.; Sanchez, A.; Sarmentero,
M. A. Tetrahedron 2003, 59, 5855–5859.
(10) Baldwin, J. E.; Pudussery, R. G.; Qureshi, A. K.; Sklarz, B.
J. Am. Chem. Soc. 1968, 90, 5325–5326.
208
Org. Lett., Vol. 14, No. 1, 2012

the oxygen anion onto the carbenoid carbon to afford product
2 following the subsequent protodemetalation step.8ꢀ10 In the
case of R3 = phenyl, the oxime (E)-1 isomerizes to its (Z)-
isomer [(Z)-1] prior to cyclization, presumably due to the
higher acidity of the R-proton (Table 2, entries 2 and 4). In
contrast, in the cases of R3 = alkyl, the reaction of an alkyl
(E)-oxime such as (E)-1e was sluggish due to (1) steric re-
pulsion between the substituents on the oxime group and the
alkyne terminus within the cyclized intermediate 50 and (2)
lower acidity of the R proton (Table 2, entry 5). The experi-
mental result for the reaction of (E)-1f clearly indicates that
decreased steric interactions allow for the successful reaction
of the (E)-isomer(Table2).ItislikelythatCy2NMe serves not
only as an electron-donating ligand to facilitate the donation
of electrons from the copper atom during the conversion from
6 to 7, but also as a Brønsted base to facilitate the proton
transfer processes as well as to scavenge any acid components
thus stabilizing the acid-sensitive product 2.
In conclusion, we have developed an new approach in
the efficient synthesis of oxiranyl imine derivatives from
readily accessible starting materials. It is noteworthy that
the present reaction proceeds via an intramolecular addi-
tion of an NꢀO bond onto an alkyne triple bond. Further
investigations on its reaction mechanisms are currently
underway in our laboratories.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward
Synthesis” from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available. Experimental pro-
cedures and characterization of the products 2 and 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
209