Abnormal and direct para-trifluoroacetylation of branched alkyl phenyl ketones by magnesium-promoted reductive aromatic substitution

Article abstract of DOI:10.1055/s-0031-1290325

Magnesium-promoted reduction of branched alkyl phenyl ketones in the presence of ethyl trifluoroacetate and chlorotri-methylsilane in N,N-dimethylformamide (DMF), followed by air oxidation, and the subsequent treatment of tetrabutylammonium fluoride brought about selective and efficient formation of the corresponding aromatic para-substituted diketones possessing a tri-fluoroacetyl group in good yields through abnormal addition toward the para positions of the aromatic ketones in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290325

LETTER
401
Abnormal and Direct para-Trifluoroacetylation of Branched Alkyl Phenyl
Ketones by Magnesium-Promoted Reductive Aromatic Substitution
p
ara-Trifluoroacet
i
ylation
r
of
B
ranc
o
he
d
A
lkyl
P
f
henyl
K
e
u
tones mi Maekawa,* Taro Ozaki, Dayana Zulkeflee, Taro Murakami, Shin Kihara, Ikuzo Nishiguchi
Department of Materials Science and Technology, Nagaoka University of Technology, 1603-1, Kamitomioka-cho, Nagaoka 940-2188,
Japan
Fax +81(258)479300; E-mail: maekawa@vos.nagaokaut.ac.jp
Received 14 November 2011
In this study, we found that the magnesium-promoted re-
Abstract: Magnesium-promoted reduction of branched alkyl phe-
ductive coupling of branched alkyl phenyl ketones with
ethyl trifluoroacetate led to introduction of the acetals of
trifluoroacetyl groups toward para position of the keto
nyl ketones in the presence of ethyl trifluoroacetate and chlorotri-
methylsilane in N,N-dimethylformamide (DMF), followed by air
oxidation, and the subsequent treatment of tetrabutylammonium
fluoride brought about selective and efficient formation of the cor- groups. Through air oxidation followed by desilylation
responding aromatic para-substituted diketones possessing a tri-
fluoroacetyl group in good yields through abnormal addition toward
the para positions of the aromatic ketones in good yields.
with tetrabutylammonium fluoride, the acetals were easily
transformed into the corresponding aromatic 1,4-dike-
tones, which were direct para-trifluoroacetylated com-
Key words: trifluoroacetylation, cross-coupling, electron transfer,
pounds of meta-directing aromatic ketones.
magnesium, reduction
The first trial was the reductive trifluoroacetylation of ac-
etophenone (1a), which gave an acyloin-type compound
like benzophenone as shown in Scheme 2.
Partially fluorinated compounds are used as agrochemi-
cals, pharmaceutical drugs, and organic materials due to
CF3
CF3
OEt
specific characteristics based on the existence of fluorine
atoms. Recently, organic fluorine-containing compounds
have also concentrated much attention in view of econom-
ical separation of partially fluorinated compounds in fluo-
rous chemistry. Therefore, synthesis of such organic
fluorine-containing compounds has been focused for a
long time, typical synthetic routes of which are direct
fluorinating methods,1–4 halogen exchange,5 oxygen–
fluorine substitution,6 and trifluoromethylation.7–9
O
Bu4NF
98%
Mg, TMSCl
O
TMSO
TMSO
CF3CO2Et
NMP
73%
HO
Ph
Ph
3a
Ph
2a
1a
Scheme 2
Application of aromatic ketones having longer alkyl
chains such as ethyl and propyl groups to this reductive
coupling gave a mixture of two compounds 2 and 4. The
former compound 2 is a normal one by attack to the car-
bonyl carbon and the latter 4 is an abnormal one by attack
toward the aromatic ring.
Trifluoroacetylation is also available for the introduction
of fluorine atoms, but is considerably limited except for
Friedel–Crafts-type acylations,10 palladium-catalyzed tri-
fluoroacetylation,11 and coupling of organometallic com-
pounds and trifluoroacetic acid derivatives.12–22
CF3
O
O
We have already reported the magnesium-promoted
cross-coupling reaction of ethyl trifluoroacetate and ben-
zophenone derivatives in N-methyl-2-pyrrolidinone
(NMP) in the presence of chlorotrimethylsilane followed
by treatment of tetrabutylammonium fluoride to give aro-
matic unsymmetrical acyloins containing a trifluorometh-
yl group (Scheme 1).23,24
Mg, TMSCl
TMSO
TMSO
OEt
R
+
R
CF3CO2Et
NMP
R
TMSO
F3C
OEt
1b (R = Et)
1c (R = Pr)
2b (34%)
2c (21%)
4b (26%)
4c (23%)
CF3
O
CF3
CF3
OEt
Ar
Mg, TMSCl
TMSO
TMSO
OEt
Et
O
Bu4NF
Mg, TMSCl
O
TMSO
TMSO
CF3CO2Et
NMP
Et
CF3CO2Et
NMP
HO
Ar
Ar
Ar
Ar
Ar
1d
Scheme 1
2d (53%)
Scheme 3
SYNLETT 2012, 23, 401–404
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2012
DOI: 10.1055/s-0031-1290325; Art ID: U65711ST
© Georg Thieme Verlag Stuttgart · New York

402
H. Maekawa et al.
LETTER
These results may suggest two possibilities of electro- Isopentyl phenyl ketone (1m) was transformed into the
philic attack by the carbonyl carbon atom of ethyl trifluo- corresponding para-substituted compound 4m as a main
roacetate. Furthermore, similar cross-coupling reaction of product in 42% yield accompanying with 9% yield of the
ethyl p-tolyl ketone (1d) brought about selective forma- normal compound 2m. It is quite interesting that the ab-
tion of normal product 2d (Scheme 3). On the other hand, normal addition to aromatic ring occurs predominantly in
isobutyrophenone, a branched alkyl phenyl ketone, was the case that the branched carbon atom exists at the b-po-
reduced by magnesium metal for usual Grignard reaction sition of the carbonyl group in the substituents ‘COR’ of
in the presence of ethyl trifluoroacetate and chlorotrime- the starting ketones 1.
thylsilane in DMF25 to give selective formation of 4 as a
The acetal group of 4 locates at adjacent position to the tri-
single product.26 The results of a series of branched alkyl
fluoromethyl group and it is known that hydrolysis of
phenyl ketones are summarized in Table 1. Product 4 was
directly obtained probably because at first dihydroben-
zene derivatives might be formed in situ and easily oxi-
dized during usual workup. In fact, a single peak was
detected by gas chromatography after workup in spite of
the existence of two peaks before an acid-catalyzed
quenching.
such acetal requires stronger reaction conditions.30,31 In-
deed, compound 4 also resists against acidic hydrolysis,
and desilylation by tetrabutylammonium fluoride was an
ideal process to get the aromatic 1,4-diketone 5 smoothly.
Desilylation was easily accomplished by catalytic
amounts of tetrabutylammonium fluoride in a short time
to give the desired products 4 in high yields (Table 2). Re-
Isopropyl (1e, 1i, 1j), tert-butyl (1f), cyclohexyl (1g), and sults were independent of the substituent on the benzene
1-ethylpropyl (1h) groups are applicable as substituents R ring and bulk of the aliphatic carbonyl group.
of starting materials 1e–j, and steric effect seemed to be
Table 2 Synthesis of Fluorine-Containing Aromatic 1,4-Diketones
observed for substituted benzenes, especially the 3-meth-
ylphenyl group (Table 1, entries 1–6). The similar treat-
through Desilylation of 4a
O
O
ment of aromatic ketones with a smaller aliphatic ring
resulted in low yield of para-substituted ketone 4. Thus,
in reactions of 1k and 1l (Table 1, entries 7 and 8), attack
to the carbonyl carbon atom proceeded at the same time
and 2k or 2l was obtained in 16% or 18% yield as the
byproduct, respectively. As for 1l, complicated products
were detected by gas chromatography, which might show
the possibility of opening of the cyclopropane ring in this
electron-transfer reaction.27–29
X
X
R
R
Bu4NF
THF
TMSO
F3C
F3C
OEt
O
5
4
Entry
4
X
R
5
Yield (%)
1
2
4b
H
Et
Pr
5b
5c
5e
5f
80
56
62
73
82
80
71
77
77
74
82
Table 1 Cross-Coupling Reaction of Branched Alkyl Phenyl
4c
4e
4f
H
Ketone and Ethyl Trifluoroacetatea
3
H
i-Pr
t-Bu
O
O
X
X
4
H
Mg, TMSCl
R
R
CF3CO2Et
DMF
5
4g
4h
4i
H
cyclohexyl
Et2CH
5g
5h
5i
TMSO
F3C
6
H
OEt
1
4
7
2-Me
3-Me
H
i-Pr
Entry
1
X
R
4
Yield (%)
8
4j
i-Pr
5j
1
2
3
4
5
6
7
8
9
1e
1f
H
i-Pr
t-Bu
4e
4f
63
80
76
70
51
50
36
16
42
9
4k
4l
cyclopentyl
cyclopropyl
i-Bu
5k
5l
H
10
11
H
1g
1h
1i
H
cyclohexyl
4g
4h
4i
4m
H
5m
H
Et2CH
i-Pr
a Reaction conditions: 4 (1.6 mmol), Bu4NF (0.4 mol equiv), THF (10
mL), –15 °C, 0.5 h.
2-Me
3-Me
H
1j
i-Pr
4j
To clarify the reaction mechanism of this abnormal addi-
tion, the reduction potential of aromatic ketone, ethyl tri-
fluoroacetate, and chlorotrimethylsilane was measured by
cyclic voltammetry with Ag/AgCl as a reference electrode
as shown in Table 3.
1k
1l
cyclopentyl
cyclopropyl
i-Bu
4k
4l
H
1m
H
4m
a Reaction conditions: 1 (5 mmol), Mg (3 mol equiv), TMSCl (4 mol
equiv), CF3CO2Et (10 mol equiv), DMF (30 mL), 27 °C, 6 h.
Measurement of reduction potential showed that isobuty-
rophenone has more positive reduction potential than eth-
Synlett 2012, 23, 401–404
© Thieme Stuttgart · New York

LETTER
para-Trifluoroacetylation of Branched Alkyl Phenyl Ketones
403
path B
Table 3 Reduction Potential of Aromatic Ketone, Ethyl Trifluoro-
acetate, and Chlorotrimethylsilanea
Substrate
Reduction
potential
Substrate
Reduction
potential
Mg(+e)
TMSCl
Mg(+e)
path A
V vs. Ag/AgCl
V vs. Ag/AgCl
O
R
O
R
TMSO
R
O
CF3CO2Et
TMSCl
–2.47
path A
–2.26
no wave
TMSCl
CF3CO2Et
TMSO
–O
R
TMSO
TMSO
R
1e
OEt
CF3
OEt
a Working electrode: Pt; counter electrode: Pt; reference electrode:
Ag/AgCl; substrate: 7 mmol/L; solvent: DMF; supporting electrolyte:
Bu4NClO4; scan rate: 200 mV/s.
CF3
2
path B
CF3
OEt
CF3
OEt
–O
TMSO
yl trifluoroacetate, and chlorotrimethylsilane showed no
significant reduction wave in the range between –3.0 V
and 0 V, as shown in Table 3, clearly indicating that this
reaction might be initiated by single-electron transfer
from magnesium to aromatic ketone.
CF3CO2Et
TMSCl
TMSO
R
TMSO
R
CF3
OEt
TMSO
A plausible reaction mechanism may be proposed below.
Initial electron transfer to the carbonyl group of aromatic
ketone was followed by attack of chlorotrimethylsilane,
and the second electron transfer afforded benzyl anion,
which was stabilized by resonance effect. In case of
ketones with a small alkyl group or a plane substituent
(R), attack of ethyl trifluoroacetate occurs at the carbonyl
carbon atom to give normal acetal of trifluoroacetylated
compound 2 after final trimethylsilylation to the oxygen
atom (path A).
H+
air oxidation
O
R
4
Scheme 4
Acknowledgment
This work was supported in part by Grant-in-Aid for Scientific Re-
search(C), No. 22605003 from Japan Society for the Promotion of
Science (JSPS).
On the other hand, for bulky ketones possessing a second-
ary or a tertiary alkyl group, the carbonyl carbon atom is
hindered, and an attack of the ethyl trifluoroacetate occurs
at the aromatic carbon atom in the para position to afford
adducts after trimethylsilylation (path B). After acid hy-
drolysis and air oxidation, the product 4 will be obtained
(Scheme 4).
References and Notes
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1747.
Aromatic ketone with a medium-sized alkyl group can
choose both path A and path B to form a mixture of 2 and
4.
As a summary, magnesium-promoted reduction of a phe-
nyl ketone possessing a bulky alkyl group in the presence
of ethyl trifluoroacetate and chlorotrimethylsilane afford-
ed abnormal acetals of trifluoroacetylated compound at
the para position of the carbonyl group in high yield, and
these results are dependent on the bulkiness of alkyl
group. The obtained acetals can be easily converted into
the corresponding aromatic 1,4-diketones by desilylation
through tetrabutylammonium fluoride. This procedure en-
abled us to introduce the trifluoroacetyl group toward para
position of meta-directing aromatic ketones in just two
steps.32
(5) Yoneda, N.; Fukuhara, T.; Yamagishi, K.; Suzuki, A. Chem.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
© Thieme Stuttgart · New York
Synlett 2012, 23, 401–404

404
H. Maekawa et al.
LETTER
(15) Ruiz, J.; Astruc, D.; Gilbert, L. Tetrahedron Lett. 1996, 37,
4511.
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Tetrahedron Lett. 2000, 41, 9957.
A mixture of TMSCl (20 mmol), ethyl trifluoroacetate (50
mmol), magnesium turnings (15 mmol) for the Grignard
reagent with no pretreatment, and anhyd DMF (10 mL) was
placed in a 100 mL four-necked flask and after activation of
magnesium for 30 min, a solution of isobutyrophenone (5
mmol) in anhyd DMF (20 mL) was added dropwise at r.t.
The reaction mixture was stirred for 6 h. Then, 1 M HCl (50
mL) was added to the flask, and the mixture was stirred for
30 min. The reaction mixture was extracted with EtOAc.
Usual workup, subsequent silica gel column
(19) Ohtaka, J.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett.
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chromatography gave 1-[4-(1-ethoxy-2,2,2-trifluoro-1-
trimethylsiloxyethyl)phenyl]-2-methylpropan-1-one (4e) in
63% yield.
1H NMR (400 MHz, CDCl3): d = 0.26 (9 H, s), 1.23 (6 H, d,
J = 8.0 Hz), 1.24 (3 H, t, J = 8.0 Hz), 3.35 (1 H, sept, J = 8.0
Hz), 3.49–3.59 (2 H, m), 7.70 (2 H, d, J = 8.3 Hz), 7.97 (2 H,
d, J = 8.3 Hz) ppm. 13C NMR (100 MHz, CDCl3): d = 1.08,
14.72, 19.03, 35.54, 58.56, 97.65 (q, 2JCF = 31.3 Hz), 122.38
(q, 1JCF = 287.5 Hz), 127.91, 128.46, 136.97, 140.83, 204.05
ppm. 19F NMR (376 MHz, CDCl3): d = –81.63 ppm. IR
(neat): 3063, 2978, 1687, 1384, 847 cm–1. LRMS (EI): m/z =
362 [M+]. HRMS (EI): m/z calcd for C17H25O3F3Si:
362.1525; found: 362.1573.
(24) Maekawa, H.; Ozaki, T.; Nishiguchi, I. Tetrahedron Lett.
2010, 51, 796.
(25) Aprotic polar solvent is required for this coupling reaction.
Use of DMF as a solvent gave better yield of coupling
compounds than that of NMP.
(26) Only para-substituted compounds were isolated while
ortho-substituted ones can not be detected by gas
chromatography. The reason is not clear, but it may be
attributed to steric effects between the acyl group on the
benzene ring and the acetal of trifluoroacetyl group.
(27) Mandell, L.; Johnston, J. C.; Day, R. A. Jr. J. Org. Chem.
1978, 43, 1616.
2-Methyl-1-(4-trifluoroacetylphenyl)propan-1-one (5e);
Typical Procedure for the Desilylation of Acetal 4e
To a solution of 4e (2.5 mmol) in anhyd THF (10 mL) is
added dropwise 1 M TBAF (1 mL) at –15 °C, and the
reaction mixture was stirred for 30 min. Then the reaction
mixture was added to 100 mL of H2O and ice, and stirring
was continued for 30 min. The product was extracted with
EtOAc. Usual workup and subsequent silica gel column
chromatography gave 2-methyl-1-(4-trifluoroacetylphenyl)-
propan-1-one (5e) in 62% yield. 1H NMR (400 MHz,
CDCl3): d = 1.24 (6 H, d, J = 6.6 Hz), 3.56 (1 H, sept, J = 6.6
Hz), 8.08 (2 H, d, J = 8.4 Hz), 8.16 (2 H, d, J = 8.4 Hz) ppm.
13C NMR (100 MHz, CDCl3): d = 18.77, 36.05, 116.42 (q,
1JCF = 291.0 Hz), 128.68, 130.35 (q, 3JCF = 1.8 Hz), 132.60,
141.29, 180.56 (q, 2JCF = 36.0 Hz), 203.47 ppm. 19F NMR
(376 MHz, CDCl3): d = –72.05 ppm. IR (neat): 3023, 2977,
1726, 1689, 1214, 857, 759 cm–1. LRMS (EI): m/z = 244
[M+]. HRMS (EI): m/z calcd for C12H11O2F3: 244.0711;
found: m/z = 244.0696.
(28) Brieger, G.; Nestrick, T. J.; Fu, T. H. J. Org. Chem. 1979, 44,
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phenyl]-2-methylpropan-1-one (4e); Typical Procedure
for the Coupling Reaction of Isobutyrophenone and
Ethyl Trifluoroacetate
Synlett 2012, 23, 401–404
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