Application of the catalytic friedel-crafts acylation reaction and regioselectivity correlations

Article abstract of DOI:10.1055/s-2006-939705

A correlation was found between electronic properties and regioselectivity in the Friedel-Crafts reaction of substituted phenylacetic and benzoic acids with anisole, utilising substoichiometric (down to 1 mol%) amounts of catalyst. Relative reactivities of selected catalysts for this reaction were also studied. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939705

LETTER
1063
Application of the Catalytic Friedel–Crafts Acylation Reaction and
Regioselectivity Correlations
A
pplication of the Cata
a
lytic
F
ried
r
k
A
cylation Reactio
C
n
. Wilkinson,* Fabienne Saez, Wei Lee (Emma) Hon
GlaxoSmithKline, Chemical Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Fax +44(1438)764869; E-mail: Mark.C.Wilkinson@GSK.com
Received 6 January 2006
mixed anhydrides of trifluoroacetic acid, which could
potentially be catalysed by substoichiometric levels of
reagent. Table 1 details representative previous examples.
It should be noted that none of the corresponding ortho-
regioisomer was reported in these examples.
Abstract: A correlation was found between electronic properties
and regioselectivity in the Friedel–Crafts reaction of substituted
phenylacetic and benzoic acids with anisole, utilising substoichio-
metric (down to 1 mol%) amounts of catalyst. Relative reactivities
of selected catalysts for this reaction were also studied.
Key words: catalysis, substituent effects, regioselectivity, Friedel–
Crafts reaction, acylations
To investigate the utility of this catalytic Friedel–Crafts
reaction of TFA anhydrides, we screened our desired sub-
strates with a diverse range of Lewis and Brønsted acids.5
Good reaction rates were achieved with metal triflates,
BF3·OEt2, phosphoric and triflic acids (1–2 mol%). How-
ever, whilst all substantially favored the desired para-iso-
mer, the levels of regioselectivity were all broadly similar
with the exception of BF3·OEt2, which was clearly the
most selective catalyst screened. This observation was
applied as shown below to give para-product 3 in up to
90% isolated yield (the remainder being predominantly
ortho-product), with only a 10 minutes reaction time
(Scheme 2). We also took the opportunity to avoid the use
of a chlorinated solvent, and changed to phenetole as both
reagent and solvent (7 volumes relative to 1 input weight,
12 equiv).
Recently we became interested in the Friedel–Crafts reac-
tion between methylsulfonylphenylacetic acid 1 and
phenetole 2. This was achieved via formation of the acid
chloride, but required 1.9 equivalents of AlCl3 as catalyst
to achieve good rates of reaction. The yield was compro-
mised by production of significant amounts (15–20%) of
the regioisomeric ortho-substituted product 4 (Scheme 1).
X
Y
HO
O
i) CH2Cl2,
SOCl2
EtO
O
+
ii) AlCl3
MeO2S
1.3 equiv
66–72%
MeO2S
of 3
1
2
EtO
3 X = OEt, Y = H, para
4 X = H, Y = OEt, ortho
HO
O
i) TFAA
(1.5 equiv)
EtO
O
+
Scheme 1 AlCl3-catalysed acid chloride Friedel–Crafts reaction.
ii) BF3OEt2
(1 mol%)
MeO2S
12 equiv
(solvent)
MeO2S
As our scale of production increased, we were required to
dispose of correspondingly large quantities of aluminium
waste. Seeking to reduce this waste, we became interested
in literature reports of the Friedel–Crafts reaction of
85–90%
1
2
3
Scheme 2 BF3-catalysed mixed anhydride Friedel–Crafts reaction.
Table 1 Representative Literature Results
Entry
Acid
Ar
Conditions
Catalyst
Yield (%)
801
1
2
3
4
5
Phenyl acetic
Phenyl acetic
Benzoic
Anisole
Toluene
Anisole
Anisole
Anisole
TFAAa (4 equiv), r.t., 1 min
TFAA (4 equiv), r.t., 1 min
TFAA (1.5 equiv), 30 °C, 12 h
TFAA (1.5 equiv), r.t., 2.5 h
TFAA (1.5 equiv), r.t., 10 min
H3PO4 (1.2 equiv)
H3PO4 (1.2 equiv)
Bi(OTf)3 (3.3 mol%)
AlPW12O40 (1.5 mol%)
Al2O3 (1000 wt%)
401
982
Benzoic
963
Benzoic
804
a TFAA = trifluoroacetic anhydride.
SYNLETT 2006, No. 7, pp 1063–1066
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939705; Art ID: D00506ST
© Georg Thieme Verlag Stuttgart · New York

1064
M. C. Wilkinson et al.
LETTER
MeO
Whilst this result was pleasing and met our short-term
needs by vastly reducing the amount of costly metal waste
that required disposal, the inferior regioselectivity exhib-
ited by this reaction relative to the literature was still
puzzling. A survey of the related previous work revealed
that as in Table 1, most publications did not report the
generation of the ortho-product at all, and there was only
one report where ortho/para-selectivity was inferior to
that we obtained.2
HO
O
i) TFAA
(1.5 equiv)
MeO
O
+
80 °C
ii) catalyst
R
R
5a–k
6
7
Scheme 3 Screen of substituted phenylacetic acids.
required with Bi(OTf)3 to achieve a comparable reaction
rate. There is also a clear trend that selectivity increased
with the electron-donating ability of the substituent. For
example under BF3 catalysis, R = NO2 gave 8:1 para to
ortho ratio (89% para), whereas R = OMe returned a ratio
of 31:1 (97% para).
The major difference between our substrate and the re-
ported literature was the electron-withdrawing property of
the sulfone. To probe this we examined the Friedel–Crafts
reaction of a selection of para-substituted phenylacetic
acids possessing a range of electron-withdrawing and
donating substituents. Two catalysts were examined –
BF3·OEt2 as before, and Bi(OTf)3, to make a direct com-
parison with the previous literature (e.g. Table 1, entry 3).
Anisole was chosen as the nucleophilic partner for these
reactions to again facilitate comparison with the previous
reports.
We next studied substituted benzoic acids, where the elec-
tronic properties of the substituent may be expected to ex-
hibit a greater influence on the reacting carbonyl. These
reactions were attempted under two reaction conditions –
Bi(OTf)3 in solely anisole, to make a direct comparison
with our previous results, and reactions in an anisole–tol-
uene mixture under BF3 catalysis, which from the result in
Table 2, entry 3 may be expected to exhibit increased
selectivity (Scheme 4).
1
The selectivity was determined by H NMR analysis of
samples of crude reaction mixtures, and results were
sorted in order of the Hammett s value for the substituent,
to probe a potential correlation with electronic properties.
The results are reported in Table 2 (Scheme 3).
The trend of selectivity increasing with electron-donating
ability was repeated in this series but in a more pro-
nounced sense, as could be expected with the more direct
mesomeric interactions possible in the benzoic series.
Again BF3 was in general the more selective catalyst.
It can be seen that the results from our previous screening
were borne out, with BF3·OEt2 being in general more
selective than Bi(OTf)3. A higher catalyst loading was
Table 2 Selectivity Correlation for Reactions of Phenylacetic Acids
BF3·OEt2 (1.7 mol%)a
Bi(OTf)3 (3.3 mol%)a
6
Entry
5
R =
sp
para (%)b
Conversion (%)c
(yield, %)d
para (%)b
Conversion (%)c
1
2
a
b
be
c
NO2
SO2Me
SO2Me
CF3
0.78
89
89
92
97
96
95
96
95
95
97
96
97
61 (54)
96 (82)
(71)
84
83
86
–
91
95
–
0.73
0.73
3
4
0.54
80
94
90
98
99
91
96
96
93
26
70
49
70
64
23
49
48
45
5
d
e
OCF3
Cl
0.35
84
6
0.23
58 (55)
49
7
f
Br
0.23
8
g
h
i
F
0.06
84
9
SMe
i-Pr
0.00
45
10
11
12
–0.15
–0.17
–0.27
58
j
Me
88
k
OMe
63
a Reaction performed in anisole (7 volumes relative to 1 input weight, 14 equiv) at 80 °C, except where noted.
b Determined by 1H NMR ratio of ortho/para-products.
c Conversion of 5a–k to ortho- and para-products by HPLC.
d Isolated yield of analytically pure material.
e Reaction performed in 2 volumes anisole, 5 volumes toluene at 80 °C.
Synlett 2006, No. 7, 1063–1066 © Thieme Stuttgart · New York

LETTER
Application of the Catalytic Friedel–Crafts Acylation Reaction
1065
MeO
HO
O
HO
O
i) TFAA
80 °C
i) TFAA
(1.5 equiv)
O
O
MeO
+
+
ii) catalyst
(3 mol%)
80 °C
MeO2S
14 equiv
(solvent)
ii) catalyst
MeO2S
83%
R
R
(see text)
5b
10
11
8a–k
6
9
Scheme 5 Relative rate screening of catalysts for toluene reaction.
Scheme 4 Screen of substituted benzoic acids.
Next we sought relative rate data from across a range of
available catalysts. This proved challenging with anisole
as the nucleophile. At 80 °C the reactions were complete
in approximately 10 minutes, making accurate profiling
difficult. Reducing the temperature resulted in the product
crystallizing from solution, preventing representative
sampling from a homogeneous solution. Thus for the
relative rate study we chose toluene as the reagent and
solvent. This less electron-rich nucleophile allowed the
reaction to proceed over 1–2 hours, and more reliable data
to be acquired. The results are shown in Figure 1 for the
five catalysts screened – BF3·OEt2, Bi(OTf)3, TMSOTf,
Yb(OTf)3, and TfOH (see also Scheme 5).
Figure 1 Relative rates for Scheme 5 under a range of catalysts.
It appears that for the reaction with toluene, Bi(OTf)3 gave
faster reactions than BF3·OEt2, and was in general the
most active catalyst. However, analysis of the HPLC pro-
files of these reactions revealed a significant difference in
their progression compared to the reaction profile with
anisole. A new species was generated under all conditions
in varying amounts (ca. 2–14 mol%), which disappeared
as the reaction ran towards completion, to leave virtually
exclusively the desired product 11. LCMS analysis of this
intermediate species indicated m/z of 484, which equates
to the mass of 11 plus an additional acyl fragment. This
piece of evidence, together with the fact that this species
appeared to go on to give product with no detectable by-
product lead us to postulate that this transient species may
be the enol acetate 13 (Scheme 6).
Table 3 Selectivity Correlation for Reactions of Benzoic Acids
BF3·OEt2 (1.7 mol%)a
Bi(OTf)3 (3.3 mol%)e
6
Entry
8
R =
sp
para (%)b
Conversion (%)c
(yield, %)d
para (%)b
Conversion (%)c
1
2
a
b
c
d
e
f
NO2
SO2Me
CF3
OCF3
Cl
0.78
83
83
88
94
94
95
95
99
98
97
99
68
83
86
86
90
91
91
92
97
97
96
99
80
72
81
98
82
85
88
86
64
82
85
0.73
0.54
87 (72)
97
3
4
0.35
81
5
0.23
94
6
Br
0.23
85
7
g
h
i
F
0.06
97
8
SMe
i-Pr
Me
0.00
94 (49)
76
9
–0.15
–0.17
–0.27
10
11
j
88
k
OMe
78
a Reaction performed in 2 volumes anisole, 5 volumes toluene at 80 °C.
b Determined by 1H NMR ratio of ortho/para-products.
c Conversion of 8a–k to ortho- and para-products by HPLC.
d Isolated yield of analytically pure material.
e Reactions performed in 7 volumes anisole at 80 °C.
Synlett 2006, No. 7, 1063–1066 © Thieme Stuttgart · New York

1066
M. C. Wilkinson et al.
LETTER
Representative Experimental Procedure
F3C
O
i) TFAA
80 °C
To a slurry of 4-(methylsulfonyl)phenylacetic acid 1 (5 g, 1 wt) in
toluene (35 mL, 7 vol) was added TFAA (6.39 mL, 2 equiv) and the
solution heated to 80 °C. After 60 min, 3 mol% catalyst (TfOH in
this example) were added, and the solution was stirred at 80 °C until
complete by HPLC analysis (100 min). Industrial methylated spirit
(IMS, 35 mL, 7 vol) was added over 20 min, effecting crystallisa-
tion. The slurry was held at reflux for 1 h, cooled to 20–25 °C over
60 min, then chilled to 0–5 °C. The slurry was stirred for 60 min
then filtered. The solids were washed with IMS (2 × 2 vol) and dried
in vacuo at 50–60 °C to give 2-[4-(methylsulfonyl)phenyl]-1-p-
tolylethanone 11 as a cream white crystalline solid (5.60 g, 83%).
IR: 3023, 3002, 2924, 1934, 1683, 1294, 1144 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.43 (3 H, s), 3.05 (3 H, s), 4.38 (2 H, s), 7.30 (2
H, d, J = 8 Hz), 7.47 (2 H, d, J = 8 Hz), 7.90 (2 H, d, J = 2 Hz), 7.92
(2 H, d, J = 2 Hz). 13C NMR (100 MHz, CDCl3): d = 21.74, 44.61,
44.97, 127.68, 128.63, 129.57, 130.72, 133.72, 139.07, 141.15,
O
O
O
5b
+
ii) catalyst,
toluene
MeO2S
MeO2S
12
11
O
O
MeO2S
SO2Me
13
Scheme 6 Formation and reaction of postulated enol acetate.
Spectroscopic evidence (1H NMR) was used to further
support this hypothesis. Analysis of the reaction mixture 144.72, 195.92. LCMS (ES+): m/z (%) = 289 (100) [M + H]+.
HRMS: m/z calcd for C16H17O3S: 289.0898 (DM = 5.0 ppm); found:
at the mid point of the reaction showed olefinic signals at
ca. d = 6.6 ppm which were entirely absent when the reac-
tion had run to completion. Similar enol acetates have
been reported as impurities in previous work.1
289.0913 [M + H]+.
Acknowledgment
It is interesting that the analogous enol acetate is not
formed to the same degree during reactions with anisole.
Alcide Perboni is acknowledged as the source of inspiration for this
work, as well as for initial results. Richard Ward, Roger Barrett,
Presumably, the degree of enol acetate formation reflects Hugh Clark, and Kathy Harwood are thanked for important contri-
butions. Catherine Duckett is thanked for analytical assistance.
the difference in the kinetics of mixed anhydride reacting
with either solvent or initially formed product, with the
difference being accounted for by the reduction in nucleo-
philicity moving from anisole to toluene. Thus, reaction of
mixed anhydride with the initially formed product is fa-
vored in toluene over reaction with solvent.
References and Notes
(1) Veeramaneni, V. R.; Pal, M.; Yeleswarapu, K. R.
Tetrahedron 2003, 59, 3283.
(2) Matsushita, Y.-I.; Sugamoto, K.; Matsui, T. Tetrahedron
Upon complete consumption of the starting material 5b
and intermediate 13, the reaction catalysed by triflic acid
was crystallized with IMS to give an 83% isolated yield.
The reaction catalysed by Yb(OTf)3 was isolated in an
analogous fashion to give an 81% yield.
Lett. 2004, 45, 4723.
(3) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, N. Tetrahedron
Lett. 2003, 44, 5343.
(4) Ranu, B. C.; Ghosh, G.; Jana, U. J. Org. Chem. 1996, 61,
9546.
(5) Lewis acids: TMSOTf, Hf(OTf)4, Yb(OTf)3, Cu(OTf)2,
In(OTf)3, Zn(OTf)2, CuI, TMSI, AlCl3, ZnCl2, TiCl4, BiCl3,
FeCl3, Fe3O4, ZnO, Al2O3, Ti(Oi-Pr)2Cl2, Ti(Oi-Pr)4,
BF3·OEt2, Zn(OAc)2, CeSO4·8H2O, H3(PW12O40), graphite.
Brønsted acids: oxalic acid, trichloroacetic acid, TFA, HCl,
HBr, H2SO4, HNO3, TfOH, H3PO4.
In conclusion we have demonstrated a correlation be-
tween electronic properties of the acid component and
regioselectivity in the substoichiometrically catalysed
Friedel–Crafts acylation. We have applied this reaction to
an improved preparation of a pharmaceutical intermediate
with considerable reduction in resultant waste.
(6) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
Synlett 2006, No. 7, 1063–1066 © Thieme Stuttgart · New York