Organic Letters
Letter
drofuran-2-yl)pyridine and propargyl alcohol through a
tandem 5-endo-dig cyclization/Meyer−Schuster rearrange-
ment/Friedel−Crafts reaction sequence.
hols. As illustrated in Scheme 1, electron-donating groups of
methoxyl and methyl on different positions of the aromatic
We initiated our study by using propargyl alcohol 1a and 5-
Scheme 1. Substrate Scope of Tertiary Propargylic
a
(
pyridin-3-yl)pent-4-yn-2-ol 2a as the model substrates to
Alcohols
optimize the reaction conditions. After screening a range of
reaction conditions, we isolated the desired polycyclic
dihydrobenzofuran derivative 3a in 76% yield using the
catalysts BrettphosAuCl/Cu(OTf) (10 mol %) in the first
2
step and the oxidant Cu(OTf) (0.8 equiv) in the second step
2
(Table 1, entry 1). When the reaction proceeded in one step
a
Table 1. Optimization of the Reactions Conditions
b
entry
variations from reaction conditions
yield (%)
1
2
3
4
5
6
7
8
9
76
10
27
38
14
58
51
40
46
45
53
36
41
64
32
42
74
only Cu(OTf) used
2
only Sc(OTf) used
3
only AgOTf used
only AuBrettPhosCl used
AuBrettPhosCl/AgOTf (10 mol %) used
AuBrettPhosCl/AgNTf (10 mol %) used
2
AuBrettPhosCl/AgSbF (10 mol %) used
6
Au(PPh) Cl instead of AuBrettphosCl
3
10
11
12
13
14
15
16
17
AuJohnPhosCl instead of AuBrettphosCl
Au(PPh) NTf instead of AuBrettphosCl
3
2
AuXPhosNTf instead of AuBrettphosCl
2
PhCl instead of 1,4-dioxane
PhCH instead of 1,4-dioxane
3
a
Unless otherwise specified, all reactions were performed on a 0.1
100 °C instead of 140 °C
120 °C instead of 140 °C
Ar instead of air
mmol scale under the standard conditions. Isolated yields.
a
3
Reaction conditions: A mixture of alkynol 2a (0.15 mmol, 1.5 equiv)
ring (R ) afforded the desired products (3a−3e) in moderate
and catalyst (10 mol %) was added to 1,4-dioxane (0.1 M) at 140 °C
under an air atmosphere. After 7 h, propargyl alcohol 2a (0.1 mmol,
to high yields ranging from 69 to 81%. The structure of 3b was
with other electron-donating groups (Et, 3, 5-diMe, 1f, 1g)
and electron-withdrawing groups (CF , Ph, COOMe, NO ,
1
.0 equiv) and Cu(OTf) (0.8 equiv) were added, and the reaction
2
mixture was stirred at the reported temperature for another 12 h.
b
Isolated yields.
3
2
halogen, 1h−1o) at the para positions of the benzene ring
were tested, and the cyclization products 3h−3o were obtained
in moderate to good yields. The reaction also proceeded well
with symmetrical propargylic alcohols with different electronic
under Lewis acid Cu(OTf) , Sc(OTf) , AgOTf, and
2
3
BrettphosAuCl catalysts, the desired product was afforded in
low yields (entries 2−5). Afterward, several representative Ag
1
catalysts were employed in this system instead of Cu(OTf) ,
natures (Me, F, Cl, 1p, 1q, 1r,) on the aromatic rings of R and
2
2
and the desired products were obtained in 40−58% yields
R . Unsymmetrical propargylic alcohol substrates (1s−1x)
(
entries 6−8). Following this approach, several gold catalysts
containing either electron-donating (Me, OMe) or -with-
1
2
with different steric characteristics and electronic were also
tested, but they were all inferior to AuBrettphosCl (entries 9−
1
drawing (Ph, F, Cl) groups on the phenyl rings (R , R ) did
not affect the reaction (3s−3x). To our delight, the sensitive
substituent thiophene (1y) was well tolerated in this
transformation in 49% yield.
2). The influence of solvents on the reaction was then
investigated, but other solvents led to no improvement (entries
3 and 14). Moreover, decreasing the temperature resulted in a
1
Subsequently, pyridylhomopropargylic alcohols 2 bearing
electron-donating (Me) or electron-withdrawing groups (F
significant drop in yield (entries 15 and 16). Finally, replacing
air with argon had almost no effect on the yield of the reaction
2
and Cl) on the heterocyclic (R ) generated the expected
(
entry 17), which indicated that Cu(OTf) may play a major
products 3z−3ac in 14−22% yields, as illustrated in Scheme 2.
Compounds 2 bearing parent pyridine (Scheme 1) are much
better than those bearing functionalized pyridine (3z−3ac)
due to the substituents on pyridine (2z−2ac) that reduced the
electrophilicity of the four-position of pyridine and suppressed
2
role in the oxidation process of the reaction.
With the optimized reaction conditions, the applicability of
the tandem cycloaddition reaction was explored by employing
5
-(pyridin-3-yl)pent-4-yn-2-ol with various propargylic alco-
8
33
Org. Lett. 2021, 23, 832−836