Angewandte
Communications
Chemie
of utilizing oxiranes for the [5+2] intermolecular cycloaddi-
tion with alkynes.
We started our studies to explore optimal reaction
conditions for the [5+2] cycloaddition between 4-methyl-N-
(2-(oxiran-2-yl)ethyl)benzenesulfonamide (1a) and phenyl-
acetylene (2a) (Table 1). We were pleased to find that
[
a]
Table 1: Screening of optimal reaction conditions.
[
d]
Entry
Variation from the standard conditions
none
Yield [%]
[
b]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
74
51
60
68
61
69
68
57
67
54
49
71
70
<5
60
without BF ·OEt2
3
without FeCl3
FeCl (5 mol%)
3
FeCl (15 mol%)
3
BF ·OEt (0.8 equiv)
3
2
BF ·OEt (1.2 equiv)
3
2
FeCl instead of FeCl3
2
Scheme 3. Variation of the alkynes (2). [a] Reaction conditions:
Fe(OTf) instead of FeCl3
3
1
(0.2 mmol), 2 (0.4 mmol), FeCl (10 mol%), BF ·OEt (1 equiv;
3 3 2
0
1
2
3
4
5
CuCl instead of FeCl3
2
0
.2 mmol), CH Cl (2 mL), room temperature and 10 min. [b] A side
2 2
InCl or YbCl instead of FeCl
3
3
3
product, 1-(o-tolyl)-2-(1-tosylpyrrolidin-2-yl)ethan-1-one (5ag), was
obtained in 23% yield.
at 08C
CH ClCH Cl instead of CH Cl
2
2
2
2
MeCN instead of CH Cl2
2
[
c]
none
BF ·OEt , several substituents, including Me, Br, Cl, and
3
2
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), FeCl3
MeCO groups, on the aryl ring were well tolerated, and their
nature of electron and position had an obviously effect on the
yields (3ab–ah). While alkyne 2b with an electron-donating
Me group on the phenyl ring delivered 3ab in 69% yield,
alkyne 2e having an electron-withdrawing MeCO group led
a decrease in the yield (46%; 3ae). Alkyne 2b with a high
(
1
10 mol%), BF ·OEt (1 equiv), CH Cl (2 mL), room temperature,
3 2 2 2
0 min. [b] The reaction gave the same yield under air or argon
atmosphere. [c] 1a (1 mmol) and 30 min. A side-product, 2-(phenyl-
ethynyl)-1-tosylpyrrolidine (4aa), was obtained in 15% yield. [d] Yield of
isolated product.
[9]
treatment of oxirane 1a with alkyne 2a, 10 mol% of FeCl3
and 1 equiv of BF ·OEt in CH Cl at room temperature for
1
7
FeCl3 or BF ·OEt2 alone, albeit giving diminishing yields
(
BF ·OEt revealed a combination of 10 mol% of FeCl and
1
active Br group was also converted to 3ab in 62% yield. In
the case of methyl-substituted arylalkynes 2b, 2 f and 2g, the
reactivity decreased from para to meta to ortho substitution in
terms of yields (3ab, 3af and 3ag). Gratifyingly, diMe-
substituted arylalkyne 2i or 3-ethynylthiophene 2j were
viable for producing the corresponding products 3ai and
3aj. The optimal conditions were found to be tolerated the
alkene and the cyclopropyl ring, thus giving products 3ak and
3al in moderate yields. Encouraged by the resulted described
above, a number of internal alkynes were examined (3am-ar).
Alkyl-substituted internal alkynes 2m–o were viable sub-
strates for the reaction, but 1,2-diarylalkynes 2p–r showed
lower reactivity: 1,2-Diphylalkyne 2p had no reactivity, and
other alkynes, 1,2-di-p-tolylethyne 2q and 1,2-bis(4-methox-
yphenyl)ethyne 2r, delivered 3aq and 3ar in lower yields.
We next turned our attention to explore the generality of
2-(2-aminoethyl)oxiranes 1 in the presence of alkyne 2a,
FeCl and BF ·OEt (Scheme 4). The optimal conditions were
3
2
2
2
0 min was preferred to furnish the desired product 3aa in
4% yield (entry 1). The reaction was successful when using
3
entries 2 and 3). A screen of the amount of both FeCl and
3
3
2
3
equiv of BF ·OEt as the best option (entries 1 and 4–7). A
3 2
series of other Lewis acids, such as FeCl , Fe(OTf) , CuCl ,
InCl and YbCl , were subsequently examined: each of which
2
3
2
3
3
exhibited catalytic activity, but was less efficient than FeCl3
entries 1 and 8–11). A lower reaction temperature (08C)
(
slightly affected the reaction in terms of yield (entry 12).
While CH ClCH Cl was proved to be a highly reactive
2
2
medium (entry 13), MeCN had a rather lower reactivity
entry 14). Gratifyingly, the reaction scale up to 1 mmol of
(
oxirane 1a was successfully performed, providing 3aa in
moderate yield (entry 15).
3
3
2
With the optimal reaction conditions in hand, we set out to
investigate the scope of this intermolecular [5+2] cyclo-
addition protocol with respect to alkenes (2) (Scheme 3).
Initial screening revealed that the optimal conditions were
compatible with a wide range of terminal alkynes, namely
arylalkynes (2b–i), heteroarylalkyne (2j), 3-enyne (2k) and
applicable to a wide range of 2-(2-aminoethyl)oxiranes (1)
bearing diverse substituents at the different position (3ba-
ha). 2-Benzyl-substituted 2-(2-aminoethyl)oxirane 1b could
be smoothly converted into the desired product 3ba in 71%
yield. PhCH CH -substituted 2-(2-aminoethyl)oxirane 1c and
2
2
Me-substituted 2-(2-aminoethyl)oxirane 1d were suitable for
the synthesis of 3ca and 3da in moderate yields. Using other
aliphatic alkyne (2l). In the presence of oxirane 1a, FeCl and
3
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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