M. Bassetti et al. / Tetrahedron Letters 55 (2014) 1608–1612
1609
Table 1
Cl
O
FeCl3 (10%)
AcOH
Hydration of phenylacetylene catalyzed by iron salts in acetic acida
+
Me
Ph
Ph
Ph
1
2
3
Iron salt
O
Me
AcOH
95 °C, 24 h
Ph
Ph
Scheme 1. Conversion of phenylacetylene in neat AcOH.
1
3
Entry
Salt (mol %)
Atmos
1b (%)
3b (2)c (%)
atmospheres, in the absence of added water (Scheme 1). The con-
version proceeded slowly and no further changes occurred after
6 days, when the reaction mixture was composed of 1, 2, and 3
in relative GC percentages 53:32:10. An atmosphere of air or the
addition of water inhibited the process.14 When the reaction was
performed at 105 °C for 48 h, the values changed into 22:29:48
(1:2:3), indicating higher conversion and preferred transformation
into acetophenone upon raising the temperature (Scheme 1).
The hydrochloration reaction constituted therefore a major
drawback for the use of FeCl3 in acetic acid. This competitive
process yielding 2 is well documented in the addition of water to
alkynes using stoichiometric or catalytic FeCl3,5,6 whereas halovi-
nyl derivatives were synthesized upon reaction of alkynes with
ironIII halides in the presence of stoichiometric amounts of carbox-
ylic acids.13
In spite of this chemoselectivity limitation, these experiments
indicated that the iron-catalyzed hydration of phenylacetylene is
feasable in AcOH, whereas other protic solvents which were
screened in previous works proved to be unsuitable.5,6,7a Therefore,
we investigated the activities of other iron salts in oxidation states
II and III and different ligand environments, the changes in the nat-
ure of the counteranions being specifically intended to suppress
the competitive hydrochloration process. For direct comparison,
the conversions were determined by GC after 24 h at 95 °C and
the results are shown in Table 1. Traces or low yields of the ketone
3 were observed in the presence of ironII salts (Table 1, entries
1–3), ferrous chloride being appreciably less active than FeCl3
(Table 1, entries 1 and 5), while the catalytic activity varied largely
within the series of ferric ions. Those complexes with bidentate
oxygen donor ligands acetylacetonate (acac) or acetate were inac-
tive (Table 1, entries 6 and 7), whereas the perchlorate or the ni-
trate salts induced extensive transformation of the alkyne,
although with poor or no conversion into the desired ketone or
other identifiable products (Table 1, entries 8 and 9). Remarkably,
phenylacetylene was hydrated to acetophenone in the presence of
ironIII sulfate hydrate, Fe2(SO4)3ꢀnH2O (I), with conversions larger
than 80% and catalyst loadings as low as 4 mol % (8 mol % in iron).
This iron salt exhibited similar activities under air or nitrogen, and
in the presence of added water (Table 1, entries 10–12). Essentially
full conversion is achieved using 8 mol % of I. The reactions pro-
moted by Fe2(SO4)3ꢀnH2O proceeded in a milky gray heterogeneous
mixture, with a progressive color change from neutral to orange.
The use of methanol instead of acetic acid gave no evidence of
the formation of acetophenone, as well as changing iron sulfate
with iron phosphate (entry 14).
1
2
3
4
5
6
7
8
FeCl2ꢀ4H2O (10)
FeS (10)
Air
Air
Air
N2
Air
N2
Air
Air
Air
N2
Air
Air
Air
Air
48
23
72
40
32
100
100
—
25
5
4
7
<1
100
25 (11)
1
3
30 (29)
34 (32)
—
FeSO4ꢀ7H2O (10)
FeCl3 (10)
FeCl3 (10)
Fe(acac)3 (10)
IronIII acetated (5)
Fe(ClO4)3ꢀ9H2O (10)
Fe(NO3)3ꢀ9H2O (10)
Fe2(SO4)3ꢀnH2O (4)
Fe2(SO4)3ꢀnH2O (4)
Fe2(SO4)3ꢀnH2O (4)
Fe2(SO4)3ꢀnH2O (8)
FePO4 (10)
—
10e
e
9
—
10
11
12f
13
14
84
85
90
99
—
a
Reaction conditions:
(4-10 mol %).
GC yield ( 1%), determined by response factor vs 1,2-diphenylethane as internal
standard.
1 (300 lL, 2.73 mmol), AcOH (10 mL), iron salt
b
c
d
e
f
Relative GC area %.
[Fe3O(OAc)3(H2O)3]OAc.
With formation of unidentified species.
In the presence of H2O (0.50 mL, 28 mmol).
Table 2
Hydration of arylalkynes catalyzed by ironIII sulfate hydrate (8 mol %) in acetic acida
R
Fe2(SO4)3 nH2O
R
O
AcOH, 95 °C
4
5
Entry
R Group
Time (h)
Ketone
Yieldb (%)
1
2
3
4
4
5
6c
4-NMe2
4-OMe
2-OMe
3,4,5-(OMe)3
4-CH@CH2
4-Br
6
7
7
24
24
50
168
5a
5b
5c
5d
5e
5f
81
76
76
75
54
70
28
4-CF3
5g
a
Reaction conditions: alkyne: 1-2 mmol (0.3–0.4 M in acetic acid), I (8 mol %), in
air.
Isolated yields, after column chromatography.
The reaction was performed at 120 °C.
b
c
with increasing electron-withdrawing character of the substituent,
p-bromophenylacetylene (4f) requiring 50 h of reaction at 95 °C,
and p-trifluoromethylphenylacetylene (4g, rp ꢁ CF3 = 0.53) seven
days at 120 °C for a poor conversion into methyl ketone 5g. Along
this trend, p-nitrophenylacetylene (rp ꢁ NO2 = 0.81) gave no evi-
dence of transformations when kept for several days at 120 °C.
The steric hindrance provided by adjacent phenyl rings in
cumulated hydrocarbons did not hinder significantly the reactivity
of the triple bond (Table 3). Only a modest reduction of yield
was found in the transformation of the most congested 1-
ethynylanthracene.
The scope of the reaction was investigated for substrates featur-
ing hydroxyl functional groups, which may be sensitive to the ace-
tic acid solvent and also hinder, as Lewis bases, the catalytic
activity of the ironIII center.6 The reaction of the aliphatic alcohol
12 is outlined in Scheme 2.
The activity of the catalytic system based on Fe2(SO4)3ꢀnH2O in
AcOH was then investigated for different arylacetylenes. The
substrates, conditions, products, and reaction yields are shown in
Tables 2–4. The reaction time and yields depended largely on the
nature of the aryl substituent. High conversions into ketone were
observed with electron rich alkynes, such as those featuring dimeth-
ylamino or methoxy groups (Table 2, entries 1–4). In the case of 4-
Me2NAC6H4AC„CH (4a), when kept in acetic acid for 24 h at 95 °C,
the formation of the hydration product was observed even in the ab-
sence of the iron salt (5a, 57% isolated yield). These transformations
can be regarded as a valid alternative to catalysis by gold complexes,
as in the case of (NHC)AuBr3 (10 mol %, NHC = N,N0-bis(2,6-diisopro-
pylphenyl)imidazol-2-ylidene) used in MeOH at reflux.15
The triple bond was hydrated with conversion comparable to
that of the electron rich aromatic alkynes (overall 76% isolated
yields of 13 and 14), while the OH function was abundantly
acetylated, as indicated by the signals of compound 13 at d 2.52
(COMe) and 2.04 (OCOMe) ppm in the 1H NMR spectrum, and
4-Ethynylstyrene (4e) reacted regio-selectively at the triple
bond affording 4-vinylacetophenone (5e). The reactivity decreased