Iron-catalyzed annulations of 2-(2-alkynyl)phenoxy)-1-arylethanones leading to substituted naphthalen-1-ols

Article abstract of DOI:10.1039/b911669a

A novel intramolecular annulation of 1-(2-alkynylphenoxy)propan-2-ones catalyzed by iron, an economical and environmentally-benign transition metal, has been developed; this new atom-economical route includes dual C-H functionalizations to construct the n

Full text of DOI:10.1039/b911669a

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Iron-catalyzed annulations of 2-(2-alkynyl)phenoxy)-1-arylethanones
leading to substituted naphthalen-1-olsw
Zhi-Qiang Wang,a Yun Liang,a Yong Lei,a Ming-Bo Zhoua and Jin-Heng Li*ab
Received (in Cambridge, UK) 16th June 2009, Accepted 22nd July 2009
First published as an Advance Article on the web 10th August 2009
DOI: 10.1039/b911669a
A novel intramolecular annulation of 1-(2-alkynylphenoxy)-
propan-2-ones catalyzed by iron, an economical and environmentally-
benign transition metal, has been developed; this new
atom-economical route includes dual C–H functionalizations to
construct the naphthalen-1-ol or anthracen-1-ol skeletons.
Table 1 Screening conditionsa
The regio- and chemoselective synthesis of polysubstituted
polycyclic aromatic hydrocarbons is of continuing interest
because these compounds play important roles in the chemical
and pharmaceutical industries.1–6 There are two common types
of transformation: one involves the introduction of substituents
onto a pre-existing aromatic ring1 and the other are transition
metal-catalyzed annulation reactions, such as Diels–Alder
reactions, the [2 + 2 + 2]-cyclotrimerization of alkynes and
the [4 + 2]-benzannulations of enynes.1–6 However, these
methods are restricted to relatively harsh reaction conditions,
unaccessible substrates and/or expensive catalysts; moreover,
regio- and chemoselectivity are unsatisfactory in many cases.
To overcome these drawbacks, herein we report a novel intra-
molecular annulation of 1-(2-alkynylphenoxy)propan-2-ones
catalyzed by iron, an economical and environmentally-benign
transition metal,7 to regioselectively synthesize substituted
naphthalen-1-ols in the presence of KOAc (Scheme 1).
Isolated
yield (%)
Entry
Fe catalyst
Base (equiv.)
1
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeBr3
Fe2(SO4)3
FeF3
—
0
2b
3
KOAc (2)
KOAc (4)
NaOAc (4)
K2CO3 (4)
Et3N (4)
KOAc (4)
KOAc (4)
KOAc (4)
KOAc (4)
KOAc (4)
KOAc (4)
73
92
22
Trace
7
9
8
12
35
0
4
5
6
7
8
9
10c
11
12d
FeCl3
—
FeCl3
47
a
Reaction conditions: 1a (0.2 mmol), Fe catalyst (20 mol%), base,
anhydrous 4 A molecular sieve (100 mg) and MeCN (2 mL) at 120 1C
b
c
d
for 24 h. For 60 h. FeCl3 (10 mol%). At 80 1C.
catalysts examined, FeCl3 was superior to the others, such as
FeBr3, Fe2(SO4)3 and FeF3 (Table 1, entries 7–9). The results
demonstrate that decreasing the amount of FeCl3 reduced the
yield, and the target product 2a was not observed without Fe
catalysts (Table 1, entries 10 and 11). Finally, the reaction
temperature was investigated, and it was found that a lower
temperature disfavored the reaction (Table 1, entry 12).
As shown in Table 2, the scope was explored under the
standardised conditions. Initially, a set of substituents at the
terminal alkyne moiety were evaluated in the presence of
FeCl3 and KOAc (Table 2, entries 1–10). The results indicated
that substituted aryl groups were perfectly tolerated (Table 2,
entries 1–7). The treatment of methyl-substituted substrates 1b
or 1c, for instance, with FeCl3 and KOAc afforded the
corresponding products in good yields (Table 2, entries 1
and 2). Meanwhile, a moderate yield was achieved from the
reaction of substrate 1d, having a 4-F–C6H4 group, with
20 mol% FeCl3 (Table 2, entry 3); 80 mol% or 100 mol%
FeCl3 enhanced the yield to over 70% (Table 2, entries 4 and 5).
We found that both 4-CF3–C6H4-substituted substrate 1e and
thiophen-2-ylalkyne 1f required a greater loading of FeCl3 in
order to give satisfactory yields (Table 2, entries 6 and 7).
Gratifyingly, the standard conditions were compatible
with alkynes having alkyl groups: 1g and 1h (Table 2, entries
8 and 9). It was discovered that the annulation of trimethylsilyl-
substituted alkyne 1i afforded the de-trimethylsilylated
The reaction of 2-(2-(2-phenylethynyl)phenoxy)-1-phenyl-
ethanone (1a) was investigated to optimize the reaction condi-
tions (Table 1).8,9 We found that base played an important role
in the reaction (Table 1, entries 1–6). While the reaction of
substrate 1a with FeCl3 did not occur without base (Table 1,
entry 1), two equivalents of KOAc provided the target
3-(2-hydroxyphenyl)-4-phenylnaphthalen-1-ol (2a) in a 73%
yield (Table 1, entry 2). To our delight, the yield of 2a was
enhanced to 92% by using 4 equivalents of KOAc (Table 1,
entry 3). However, other bases, including NaOAc, K2CO3 and
Et3N, were less effective (Table 1, entries 4–6). Among the Fe
Scheme 1 Iron-catalyzed annulations of 2-(2-(2-alkynyl)phenoxy)-1-
arylethanones.
a Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, China. E-mail: jhli@hunnu.edu.cn;
Fax: +86 731 8872 101; Tel: +86 731 8872 576
b College of Chemistry and Materials Science, Wenzhou University,
Wenzhou 325035, China
w Electronic supplementary information (ESI) available: Experimental
procedures, analytical data and spectra. See DOI: 10.1039/b911669a
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Table 2 FeCl3-catalyzed annulationsa
Table 2 (continued)
Time/h Yield (%)b
Substrate 1
Product 2
Entry
Time/h Yield (%)b
Substrate 1
Product 2
Entry
1
15c,e
24
48
56
45
26
24
48
77
89
47
16c,f
2
3
a
Reaction conditions: 1 (0.2 mmol), FeCl3 (20 mol%), KOAc
(4 equiv.), 4 A molecular sieve (100 mg) and MeCN (2 mL) at 120 1C.
Isolated yield. FeCl3 (80 mol%) was added. FeCl3 (100 mol%)
b
c
d
was added. e 7-Br : 5-Br = 1.2 : 1. Anthracen-1-ol : phenanthren-1-ol =
6.1 : 1.
f
product 2i in 56% yield with 80 mol% FeCl3 (Table 2,
entry 10). A substituent at the phenoxy moiety was sub-
sequently examined (Table 2, entries 11 and 12). The treatment
of substrate 1j, having a methyl group, with 20 mol% FeCl3
gave product 2j in 27% yield, and with 80 mol% FeCl3, in
46% yield. It is pleasing to disclose that substrates 1k–1m,
bearing substituents on the aromatic ring of the arylethanone
moiety, were annulated successfully in moderate to good yields
(Table 2, entries 13–15). 1-(Naphthalen-2-yl)ethanone 1n also
smoothly underwent an annulation reaction with FeCl3 and
KOAc to afford anthracen-1-ol 2n in 45% yield (Table 2,
entry 16).
4c
5d
(1d)
(1d)
(2d)
(2d)
24
24
75
72
6c
24
44
75
54
7c
Substrates 1o was also investigated under the standard
conditions (Scheme 2). Interestingly, treatment of 2-(2-(2-
phenylethynyl)phenoxy)-1-phenylpropan-1-one (1o) with
FeCl3 and KOAc afforded the target product 2o in 74% yield
along with a side-product 3o in 11% yield.
8
48
48
24
58
40
56
A possible mechanism involving a Diels–Alder process was
proposed as outlined in Scheme 3.6,7 Complexation of a FeCl3
with an arylethanone moiety yields intermediate A with the aid
of KOAc. Intermediate A undergoes the [4 + 2] Diels–Alder
reaction to afford intermediate B. Sequent deprotonation/C–O
bond decomposation of intermediate B gives the product 2
and regenerates the active FeCl3 species. Study of the true
mechanism is in progress.
9
10c
In summary, we have described the first example of intra-
molecular annulation of an alkyne with a sp3 carbon nucleo-
phile for the synthesis of substituted naphthalen-1-ols and
anthracen-1-ol using economical and environmentally-benign
11
24
22
24
27
46
84
12c
13
(1j)
(2j)
14c
24
55
Scheme 2 Annulation of 2-(2-(2-phenylethynyl)phenoxy)-1-phenyl-
propan-1-one (1o).
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iron catalyst. This new atom-economical route includes dual
C–H functionalizations to construct the naphthalen-1-ol
or anthracen-1-ol skelectons. Importantly, the present
Fe-catalyzed method provides a potential route to designing
the achiral/chiral hydroxy-containing ligands. Work to extend
the reaction and study the detailed mechanism is currently
underway in our laboratory.
This research was supported by the New Century Excellent
Talents in University (No. NCET-06-0711), Scientific
Research Fund of Hunan Provincial Education Department
(No. 08A037), Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20060542007) and National
Natural Science Foundation of China (No. 20872112).
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This journal is The Royal Society of Chemistry 2009
5244 | Chem. Commun., 2009, 5242–5244