Angewandte
Chemie
incomplete conversions of about 45–50% (entries 4,5). Elec-
tron-rich gold catalysts facilitate protodeauration, thus
increasing the reaction efficiency. AgNTf2 alone was an
ineffective catalyst even at 10 mol% loading. The product
yields of compound 3a varied with solvents, with a yield of
a trisubstituted alkene (entries 7,8), their corresponding
reactions delivered the desired bicyclic compounds 3h and
3i in moderate yields (50–57%), whereas cycloisomerization
product 1i’ was produced in 5% yield (entry 8). For
1
compound 3h, the N-phenyl protons have a H NOE on the
7
1
1% in dichloroethane (DCE), 78% in toluene, and 70% in
,4-dioxane (entries 8–10). In entries 1–10, only one diaste-
single methyl but no effect on the two gem-methyl groups. In
Table 2, high product yields (> 70%) could be easily obtained
if 1,6-enynes did not bear electron-rich trisubstituted alkenes.
We examined the scope of N-hydroxyamines to under-
stand their effects on reaction chemistry (Table 3). In
reomeric form of 3a was formed with the two methine
protons trans to each other, according to the H NOE effect.
This stereochemistry is in accordance with starting trans-
configured 1,6-enyne 1a. The molecular framework of com-
pound 3a was confirmed by X-ray diffraction of its NTs-
1
Table 3: Scope of N-hydroxyamines.
[7]
bridged analogue 3c (Table 2, entry 2).
Table 2 assesses the scope of the annulation reactions with
various acyclic O- and N-linked 1,6-enynes 1b–1e bearing
[
a]
Table 2: Scope of 1,6-enynes with N-hydroxyanilines.
[c]
Entry
N-hydroxyamines
t (h)
Yields [%]
[
d]
1
2
3
4
5
6
R=4-Me-C H (2b)
16
4
5
4.5
6
24
6b (61)
6c (81)
6d (80)
6e (82)
6 f (70)
6
4
R=4-F-C H (2c)
6
4
R=4-Cl-C H (2d)
6
4
R=4-Br-C H (2e)
6
4
[b]
R=4-CO
R=Isopropyl (2g)
Et-C H (2 f)
2 6 4
Entry
Substrates
t (h)/8C
Yields (%)
[
d]
6g (39), 1a (30)
[
[
a] 1a (0.19m, 1 equiv), 2a (1.1 equiv). [b] L=P(tBu)2(o-biphenyl).
c] Product yields are given after purification from a silica column. [d] 2b
and 2g (2.2 equiv).
[
c]
1
2
3
4
Z=NTs, R=H (1b)
12/25
6/25
2.5/25
2.5/25
3b (72), 1b-H (13)
3c (74), 4c (17)
3d (92)
Z=NTs, R=Ph (1c)
Z=O, R=2-furyl (1d)
Z=O, R=3-thienyl (1e)
entries 1 and 6, less efficient amines 2b and 2g were used
with two-fold proportions whereas other amines were used
with 1.1 equivalents. The reaction duration and product yields
reveal superior reactivity for less basic N-hydroxyanilines 2c–
3e (88)
2
f to afford desired annulation products 6c–6 f in satisfactory
yields (70–81%) at brief periods (4–6 h). In contrast, highly
nucleophilic amines 2b and 2g gave desired products 6b and
6g in relatively low yields, 61% and 39%, over protracted
periods (16–24 h). These data indicate that less basic N-
hydroxyamines 2c–2 f enable satisfactory products yields
(> 70%), presumably because of their highly efficient proto-
deauration reactions (see Scheme 1).
1
2
5
6
7
8
Z=O, R =H, R =Ph
12/55
12/25
12/25
36/25
3f (79)
3
R =Ph (1f)
1
2
Z=O, R =R =Me
3g (61)
3
[c]
R =Ph (1g)
1
2
Z=O, R =R =Me
3h (50)
3
R =H (1h)
Z=NTs, R =R =Me
R =H (1i)
1
2
3i (57); 1i’ (5)
3
[d]
Alkene- and benzene-bridged 1,6-enynes 7 were also
investigated, with a goal of constructing useful carbocyclic
frameworks (Table 4). In entries 1,2, 1,6-enynes 7a and 7b
[
[
(
a] 1a (0.19m, 1 equiv), 2a (1.1 equiv), L=P(tBu) (o-biphenyl),
b] Product yields are given after purification from a silica column. [c] 2a
2.0 equiv) and [d] 2a (3.0 equiv).
2
2
3
bearing a trans-1,2-disubstituted alkene (R = H, R = Ph,
CN) gave expected products 8a and 8b in good yields (78–
9
2%), whereas an electron-rich alkene, such as 1,6-enyne 7c
1
2
various mono- and 1,2-disubstituted alkenes, yielding bicyclic
products 3b–3e in 72–92% yields (entries 1–4), together with
hydration product 1b-H and indole species 4c in a minor
proportion (13–17%). X-ray diffraction of the 3c cycloadduct
confirmed the molecular structure with the nitrogen linked to
(R = R = Me), delivered compound 8c in only 55% yield
(entry 3). Alkoxy-derived 1,6-enynes 7d and 7e yielded 8d
and 8e, 8e’ (entries 4,5). The enhanced yields (78–85%) of
resulting 8d and 8e relative to that of their unsubstituted
[
7]
[8]
analogue 8a reflected the Ingold-Thorpe effect. X-ray
diffraction of annulations were applicable to cycloalkene-
bridged 1,6-enynes 7 f and 7g, yielding the expected products
8 f and 8g in 54% and 89% yields, respectively. The data from
Tables 2 and 4 clearly indicate that 1,6-enynes 1h, 1i, 7c, and
7 f bearing electron-rich alkenes are less efficient substrates;
this reaction trend matches well with the well-known cyclo-
[7]
the CMe carbon and the oxygen linked to the CPh carbon.
We prepared C(3)-phenyl substituted 1,6-enynes 1 f and 1g to
test the stereocontrol of the reaction. Gratifyingly, their
resulting products 3 f and 3g were obtained with single
diastereomers (d.r. > 30:1) in 79% and 61% yields, respec-
1
tively. H NOE of compound 3 f was performed to elucidate
[1]
its stereochemistry. For 1,6-enynes 1h and 1i bearing
additions between nitrones and alkenes.
Angew. Chem. Int. Ed. 2015, 54, 14924 –14928
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim