Regioselective transformation of O-propargylic arylaldoximes to four-membered cyclic nitrones by copper-catalyzed skeletal rearrangement

Article abstract of DOI:10.1021/ol2012583

(E)-O-Propargylic arylaldoximes were regioselectively converted, in the presence of copper catalysts, into their corresponding four-membered cyclic nitrones in good to excellent yields. The reactions proceeded via a tandem [2,3]-rearrangement and 4π-elect

Full text of DOI:10.1021/ol2012583

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3616–3619
Regioselective Transformation of
O-Propargylic Arylaldoximes to Four-
Membered Cyclic Nitrones by Copper-
Catalyzed Skeletal Rearrangement
Itaru Nakamura,*,†,‡ Toshiharu Araki,‡ Dong Zhang,‡ Yu Kudo,‡ Eunsang Kwon,† and
Masahiro Terada†,‡
Research and Analytical Center for Giant Molecules, and Department of Chemistry,
Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
itaru-n@m.tohoku.ac.jp
Received May 12, 2011
ABSTRACT
(E)-O-Propargylic arylaldoximes were regioselectively converted, in the presence of copper catalysts, into their corresponding four-membered
cyclic nitrones in good to excellent yields. The reactions proceeded via a tandem [2,3]-rearrangement and 4π-electrocyclization of the
N-allenylnitrone intermediate and involved cleavage of the carbonꢀoxygen bond.
Metal-catalyzed skeletal rearrangements have been uti-
lized in elegant transformations, often via unique reaction
mechanisms, in the construction of complex molecules.
Since the pioneering works by Trost,1 such skeletal rearran-
gements have mainly focused on 1,n-enynes2 or propargylic
esters3 as substrates. Recently, however, we have demon-
strated that O-propargylic oximes, in the presence of
π-acidic metal catalysts, can act as attractive substrates for
skeletal rearrangements.4 In particular, we reported that the
copper-catalyzed skeletal rearrangement of O-propargylic
arylaldoximes 1afforded the corresponding four-membered
cyclic nitrones 2 in good yields.5 However, there was an
obvious drawback in the regioselectivity, when 1 has
different substituents at the propargylic position and the
oxime moiety (R2 ¼ R3) (eq 1). Herein, we report on the
copper-catalyzed skeletal rearrangement of (E)-1 that
produced 2 with excellent regioselectivities by using
[CuCl(cod)]2 as catalysts under mild reaction conditions
(eq 1).6 Moreover, mechanistic studies revealed that the
present reaction proceeds via a tandem [2,3]-rearrange-
ment and 4π-electrocyclization.
† Research and Analytical Center for Giant Molecules.
‡ Department of Chemistry.
(1) For pioneering works: (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: (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) Anorbe, L.; Domınguez, G.; Perez-Castells, J.
´
Chem.;Eur. 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.; Genet, J.-P. Angew.
Chem., Int. Ed. 2008, 47, 4268. (g) Tobisu, M.; Chatani, N. Chem. Soc.
Rev. 2008, 37, 300.
(3) For selected reviews: (a) Marion, N.; Nolan, S. P. Angew. Chem.,
ꢀ
ꢀ~
Int. Ed. 2007, 46, 2750. (b) Jimenez-Nunez, 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. (d) Wang, S.; Zhang, G.; Zhang, L. Synlett 2009, 692.
(4) (a) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010,
132, 7884. (b) Nakamura, I.; Okamoto, M.; Terada, M. Org. Lett. 2010,
12, 2453. (c) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc.
2011, 133, 6862.
Previously, (E)-1a was transformed in the presence of
copper bromide (10 mol %) in toluene at 100 °C for 42 h to
afford a 68:32 mixture of the corresponding cyclic nitrone
2a and its regioisomer 2a0 in 96% isolated yield (Table 1,
r
10.1021/ol2012583
Published on Web 06/13/2011
2011 American Chemical Society

Table 1. Optimization of the Reaction Conditions
entry
catalyst (mol %)
solvent
toluene
temp, °C
time, h
yield, %a
2a:2a0
E:Z of 2a
1
2
CuCl (10)
100
100
100
100
100
100
100
100
70
24
42
48
27
7
94
70:30
68:32
72:28
85:15
73:27
81:19
82:18
87:13
98:2
>99:1
>99:1
>99:1
84:16
90:10
78:22
84:16
80:20
74:26
-
CuBr (10)
toluene
toluene
toluene
toluene
CH2Cl2
1,4-dioxane
CH3CN
CH3CN
CH3CN
96
3
CuI (10)
18
4
CuOAc (10)
[CuCl(cod)]2 (5)
[CuCl(cod)]2 (5)
[CuCl(cod)]2 (5)
[CuCl(cod)]2 (5)
[CuCl(cod)]2 (5)
none
91
5
quant
quant
46
6
4.5
7
7
8
3
(90)
99(92)
0b
9
14
24
10
100
-
a Combined yields of 2a and 2a0. The yield and ratio were determined using 1H NMR with CH2Br2 as an internal standard. Isolated yield in
parentheses. b 98% of (E)-1a was recovered.
entry 2).5 Whereas the reactions were effectively catalyzed
by either copper chloride or bromide, the use of copper
iodide exhibited significantly lower catalytic activity
(entries 1ꢀ3). Among the copper catalysts tested, [CuCl-
(cod)]2 gave the highest activities (entries 5ꢀ9). Regios-
electivity of the present reaction was significantly affected
by the solvent (entries 5ꢀ8). In particular, the use of
acetonitrile gave 2a with high regioselectivity and moder-
ate E/Z stereoselectivity (entry 8). Moreover, excellent
regioselectivity was attained by conducting the reaction
at 70 °C (entry 9). In the absence of the copper catalyst,
however, the reaction did not proceed, even at 100 °C
(entry 10).
products with low regioselectivity (entry 5). Substrates
having an alkyl group at the alkyne terminus [(E)-1f
and -1g] afforded nitrones 2f and 2g, respectively, in ex-
cellent yields and with high regioselectivities (entries 6 and 7,
respectively).
Table 2. Copper-Catalyzed Reactions of 1aꢀ1g a
Subsequently, the optimal conditions (Table 1, entry 9)
were employed for other (E)-1 substrates. Substrates hav-
ing an electron-rich aromatic ring at the alkyne terminus
[(E)-1a, -1b, -1c] afforded products with high regioselec-
tivities (Table 2, entries 1ꢀ3, respectively);in particular,
bulky substituents at R1 resulted in high stereoselectivity
of the (E)-isomer at the olefinic moiety (entries 2 and 3).
In contrast, substrate (E)-1e, which possesses an elec-
tron-deficient p-(trifluoromethyl)phenyl group, resulted in
1
R1
time
16 h
2
yield, % b 2:20 E:Z of 2
1
2
3
4
5
6
7
1a p-MeOC6H4
1b 2-MeOC10H6
2a
92
82
91
86
89
91
95
98:2
95:5
99:1
94:6
91:9
97:3
93:7
74:26
97:3
4 days 2b
1c 2,6-(MeO)2C6H3 4 days 2c
95:5
1d Ph
24 h
48 h
36 h
2d
2e
2f
73:27
74:26
73:27
83:17
1e p-F3CC6H4
1f n-Pr
1g Cy
7 days 2g
a The reactions of (E)-1 (0.4 mmol) were carried out in the presence of
(5) We previously reported the structure of the product as 4-aryli-
dene-β-lactam. However, thorough analysis of X-ray crystallographic
data has indicated that the structure of cyclic nitrone was more valid
than that of β-lactam. Moreover, vibrational analysis by DFT calcula-
tions suggests the cyclic nitrone structure (see Supporting Information).
( 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.
(6) Four-membered cyclic nitrone:(a) Pennings, M. L. M.; Reinhoudt,
D. N.; Harkema, S.; van Hummel, G. J. J. Am. Chem. Soc. 1980, 102,
7570. (b) Pennings, M. L. M.; Reinhoudt, D. N. J. Org. Chem. 1983, 48,
4043. (c) Verboom, W.; van Eijk, P. J. S. S.; Conti, P. G. M.; Reinhoudt,
D. N. Tetrahedron 1989, 45, 3131.
[CuCl(cod)]2 (5 mol %) in acetonitrile (0.8 mL) at 70 °C. b Combined
yields of 2 and 20. The ratio was determined using 1H NMR.
Substrates with an alkyl group at the propargylic posi-
tion (R2) required an elevated reaction temperature
(100 °C) to afford the desired products in good yields
(Table 3, entries 1 and 2). As a note, the reaction of (E)-1k
having a p-anisyl group on its oxime moiety did not afford
the desired product due to the decomposition of the
Org. Lett., Vol. 13, No. 14, 2011
3617

starting compound under the reaction conditions (entry 4).
The reaction of ketimine 1l afforded the product in a
moderate yield (eq 2).
Scheme 1. Isomerization of (Z)-2 through Zwitterionic Inter-
mediate 3
Table 3. Copper-Catalyzed Reactions of 1hꢀ1k a
1
R2
R3
time
2
yield, %b 2:20 E:Z of 2
1c 1h n-Pr p-F3CC6H4 24 h 2h
2c 1i i-Pr p-F3CC6H4 25 h 2i
77
71
88
nd
98:2
95:5
97:3
-
73:27
74:26
74:26
-
Moreover, previous 13C-labeling experiments (eq 4)
are in agreement with the isomerization mechanism
involving zwitterionic intermediate 3 (Scheme 1).5a
That is to say, the reaction of (E)-1m-c (R2 = R3 =
Ph), in which the alkyne sp-carbons were enriched with
13C (15% and 85%, see eq 4), with a catalytic amount of
copper bromide in toluene at 100 °C afforded (E)-2m-c,
which possessed 13C content of 15% at the nitrone
carbon and 85% at the sp2-carbon within the four-
membered ring bound to the benzylidene group. This
result indicates that the carbonꢀcarbon bond of the
alkyne triple bond does not cleave during the reaction.
Apparently, the present reaction proceeds via cleavage
of the carbonꢀoxygen bond.
3
4
1j Ph
1k Ph
2-naphthyl 18 h 2j
p-anisyl 16 h
-
a The reaction of (E)-1 (0.4 mmol) was conducted in the presence of 5
mol % of [CuCl(cod)]2 in acetonitrile (0.8 mL) at 70 °C. b Combined
yield of 2 and 20. The ratio was determined using 1H NMR. c At 100 °C.
Next, isomerization experiments werecarried out togain
insight into the mechanism of the reactions. Product (Z)-
2a, albeit a minor product, was successfully converted to
isomers (E)-2a and (E)-2a0, in the absence of copper
catalysts, at 100 °C. However, the conversion did not occur
at a lower reaction temperature of 70 °C (eq 3). In contrast,
(E)-2a remained unchanged, even at 100 °C.7 These results
strongly suggest that only the (Z)-isomer can undergo
isomerization. This also explains the higher regioselectivity
and lower E/Z selectivity of substrate (E)-1a under the
reaction temperature of 70 °C rather than that at 100 °C
(Table 1, entries 4 and 5). We believe that the isomerization
of (Z)-2a to isomers (E)-2 and (E)-20 proceeds through
cleavage and reformation of the sp3 carbonꢀnitrogen
bond via zwitterionic intermediate 3, which possesses an
allylic cation moiety (Scheme 1). Presumably, the relaxa-
tion of the 1,3-allylic strain between R1 and R2 within (Z)-2
drives the ring-opening step. Accordingly, the low regios-
electivity for substrate (E)-1e can be explained by the
stabilization of the anionic moiety of intermediate 3 due
to the electron-withdrawing p-(trifluoromethyl)phenyl
group at R1 that facilitates the isomerization to the minor
regioisomer 2e0, even at 70 °C (Table 2, entry 4).
Scheme 2. Plausible Mechanism
3618
Org. Lett., Vol. 13, No. 14, 2011

A plausible mechanism for the reaction of (E)-1 is
illustrated in Scheme 2. First, the π-acidic copper catalyst
coordinates with the alkyne moiety of (E)-1. Next, nucleo-
philic attack by the oxime nitrogen atom onto the electro-
philically activated triple bond leads to the five-membered
cyclic intermediate 5. Then, N-allenylnitrone intermediate
7 forms either via stepwise process through cleavage of the
carbonꢀoxygen bond and subsequent elimination of the
copper catalyst (5 f 6 f 7) or via direct process via
fragmentation of 5 through a concerted pathway.8 The
key intermediate7 rotates into its rotational conformer (70)
and then undergoes a 4π-electrocyclization to afford prod-
uct 2.9 Further mechanistic studies are underway in our
laboratory.
In conclusion, we have developed a novel and efficient
synthetic method for the construction of highly strained
four-membered cyclic nitrones from readily available
O-propargylic arylaldoximes. Further transformation
of the present products is now being studied 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).
(7) The reaction of (E)-2a at 100 °C for 12 h afforded a >97:3 mixture
of (E)-2a and (E)-2a0.
(8) Pd(II)-catalyzed [2,3] rearrangement of O-allyl oximes: Grigg, R.;
Markandu, J. Tetrahedron Lett. 1991, 32, 279.
(9) 4π-Azabutadiene electrocyclization: (a) Bongini, A.; Panunzio,
M.; Tamanini, E.; Martelli, G.; Vicennati, P.; Monari, M. Tetrahedron:
Asymmetry 2003, 14, 993. (b) Liang, Y.; Jiao, L.; Zhang, S.; Xu, J. J. Org.
Chem. 2005, 70, 334.
Supporting Information Available. Experimental pro-
cedures and characterization of 1 and 2. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 14, 2011
3619