A practical synthesis of α-aryl methyl ketones via a transition-metal-free Meerwein arylation

Article abstract of DOI:10.1021/jo062483g

We report herein a simple, scalable, transition-metal-free approach to the synthesis of α-aryl methyl ketones from diazonium tetrafluoroborate salts under mild conditions. This methodology uses easily accessible and nontoxic starting material and was applied to the multi-kilogram-scale preparation of 1-(3-bromo-4-methylphenyl)propan-2-one.

Full text of DOI:10.1021/jo062483g

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6 7
A Practical Synthesis of r-Aryl Methyl Ketones
of metals (Pd, Ni, Pb, Cu, and Bi ); however, the high cost
and air sensitivity of most transition-metal catalysts and ligands
plus the additional steps required in order to eliminate residual
metals represent major drawbacks for their general application
on kilogram-scale chemistry, especially for the preparation of
final drug substances. Additionally, only a few isolated examples
have been reported for the direct R-arylation of acetone.2
Although very well studied, the copper-catalyzed addition of
via a Transition-Metal-Free Meerwein Arylation
,
†
†
†
Carmela Molinaro,* Jeffrey Mowat, Francis Gosselin,
†
‡
Paul D. O’Shea, Jean-Fran c¸ ois Marcoux,
R e´ my Angelaud, and Ian W. Davies
‡
‡
n,o,7e,i
Department of Process Research, Merck Frosst Centre for
Therapeutic Research, 16711 Autoroute Transcanadienne,
Kirkland, Qu e´ bec, Canada H9H 3L1, and Department of
Process Research, Merck Research Laboratories,
P.O. Box 2000, Rahway, New Jersey 07065
an aryl diazonium chloride to an activated unsaturated compound
Meerwein arylation) has shown limited use for the preparation
8
(
8
e
of R-aryl carbonyls. Thus, Raucher reported the synthesis of
indoles by reacting 2-nitrobenzene diazonium chlorides with
vinyl acetate to give a mixture of R-aryl aldehyde and the
carmela_molinaro@merck.com
8i
corresponding R-chloro acetate. Tanaka reported the synthesis
ReceiVed December 4, 2006
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We report herein a simple, scalable, transition-metal-free
approach to the synthesis of R-aryl methyl ketones from
diazonium tetrafluoroborate salts under mild conditions. This
methodology uses easily accessible and nontoxic starting
material and was applied to the multi-kilogram-scale prepa-
ration of 1-(3-bromo-4-methylphenyl)propan-2-one.
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†
Merck Frosst Centre for Therapeutic Research.
Merck Research Laboratories.
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A.; Vismara, E. Synthesis 1980, 291. (h) Sakakura, T.; Tanaka, M. J. Chem.
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J. Chem. Soc., Chem. Commun. 1985, 1545. (j) Schmidt, A. H.; Schmitt,
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C. T. Org. Lett. 2004, 6, 83. (l) Mastrorilli, P.; Nobile, C. F.; Taccardi, N.
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(
references therein. (b) Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal,
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reagents: (h) Brown, H. C.; Nambu, H.; Rogic, M. M. J. Am. Chem. Soc.
969, 91, 6852 and references therein. Tricarbonylcyclohexadienylium iron
salts: (i) Kelly, L. F.; Narula, A. S.; Birch, A. J. Tetrahedron Lett. 1980,
1, 2455. (π-Chlorobenzene)chromium tricarbonyl: (j) Mino, T.; Matsuda,
T.; Maruhashi, K.; Yamashita, M. Organometallics 1997, 16, 3241. Copper
reagents: (k) Rathke, M. W.; Vogiazoglou, D. J. Org. Chem. 1987, 52,
697. (l) Marino, J. P.; Jaen, J. C. J. Am. Chem. Soc. 1982, 104, 3165 and
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Organometallic Chemistry II; McKillop, A., Ed.; Pergamon: Oxford, 1995;
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Chem. 1996, 68, 819 and references therein. (q) Morgan, J.; Pinhey, J. T.;
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1
2
3
9
1
974, 96, 3250. Grignard reagents with R-bromoketones: (s) Newman,
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10.1021/jo062483g CCC: $37.00 © 2007 American Chemical Society
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J. Org. Chem. 2007, 72, 1856-1858
Published on Web 01/31/2007

TABLE 1. Effect of Catalysts and Promoters on the Arylationa
TABLE 2. Effect of Solvents and Rate of Addition on the
Arylation
b
entry
promoter
assay yield (%)
a
entry
solvent
CH3CN
assay yield (%)
1
2
3
4
5
6
7
8
9
none
0
19
29
16
14
25
23
19
27
48
46
44
34
53
53
1
2
3
4
23
10
56
65
CuCl2 (0.15 equiv)
Cu(OTf)2 (0.15 equiv)
CuO (0.15 equiv)
Cu2O (0.15 equiv)
CuSO4 (0.15 equiv)
FeSO4-7H2O (0.15 equiv)
Pd(OAc)2 (0.15 equiv)
KO2 (1.1 equiv)
KO2CCF3 (1.1 equiv)
CsOAc (1.1 equiv)
NaOAc Buffer (pH 4.5) (1.1 equiv)
NaOAc Buffer (pH 3.0) (1.1 equiv)
NaOAc (1.1 equiv)
acetone
b
acetone/H2O (2:1)
acetone/H2O (2:1)c
a
Determined by HPLC analysis vs authentic standard. b KOAc was added
in one portion. c KOAc solution in H2O was added dropwise over 2 h.
TABLE 3. Effect of the Stoichiometry of Isopropenyl Acetate on
the Arylation
10
11
12
13
14
15
KOAc (1.1 equiv)
a
To a stirred solution of the diazonium salt and isopropenyl acetate in
CH3CN at rt was added the promoter and the reaction quenched after 2 h.
Determined by HPLC analysis vs authentic standard.
a
b
entry
equiv
assay yield (%)
1
2
3
4
5
1
5
10
20
50
30
65
75
93
79
of R-aryl aryl ketones from arene diazonium salts and silyl enol
ethers of aryl ketones in pyridine. It is worth noting that these
last methods using diazonium salts do not report the transition-
metal-free synthesis of R-aryl alkyl ketones. A recent synthetic
challenge has prompted us to develop a new, inexpensive, and
scalable methodology for the arylation of an acetone derivative.
We felt that an attractive approach to the synthesis of R-aryl
methyl ketones would be available through a modification of
the Meerwein arylation. Furthermore, anilines are generally cost-
effective starting materials from which aryl diazonium tetrafluo-
a
Determined by HPLC analysis vs authentic standard.
trobenzene diazonium tetrafluoroborate (3) was also investigated
as a substrate in this reaction (Table 2). However, using the
two best solvents from a previous solvent screen (acetonitrile
and acetone), disappointing assay yields were observed (Table
, entries 1 and 2). Since KOAc is only sparingly soluble in
12
2
9
roborate salts are simple to prepare. This paper highlights our
both acetone and acetonitrile we introduced water as a cosolvent
in order to homogenize the reaction mixture and found that an
acetone/water mixture of 2:1 increased our assay yield signifi-
cantly (Table 2, entry 3 vs 2). We found that a slow addition of
an aqueous solution of KOAc over 2 h afforded an improved
assay yield of the desired ketone 2b (Table 2, entry 4 vs 3).
Furthermore, the slow addition allowed for a safe control of
the reaction rate and nitrogen gas evolution as well as a
significant decrease in the amount of byproducts generated.
Finally, examination of the isopropenyl acetate stoichiometry
revealed that an increase in the number of equivalents from 1
to 20 resulted in a dramatic increase in the assay yield (Table
findings on a catalytic and transition-metal free approach for
the synthesis of R-aryl methyl ketones under mild conditions
using diazonium tetrafluoroborate salts and isoproprenyl acetate,
a readily available and nontoxic starting material.
Our investigations of the reaction started with the studies of
the effect of several Cu, Fe, and Pd catalysts on the arylation
of isopropenyl acetate with 4-nitrobenzenediazonium tetrafluo-
roborate (1) in acetonitrile at rt to give 4-nitrophenylacetone
(2a) (Table 1, entries 2-8). Although the reaction does proceed
in each case, the yields were relatively low (14-29%), and
several side reactions were observed. We next turned our
attention to transition-metal-free promoters (Table 1, entries
1
3
3
, entries 1-4). A further increase to 50 equiv resulted in a
9
-15). We were delighted to find that nucleophilic promoters
decrease in assay yield, presumably due to solubility issues
were efficient mediators of the arylation, obviating the need
for transition metals. Thus, acetate and trifluoroacetate salts were
observed to be efficient promoters for the arylation reaction
(Table 3, entry 5).
We next applied these conditions to a variety of diazonium
9
tetrafluoroborate salts (Table 4). The reaction is tolerant of
several functional groups. A series of 2-arylnitrodiazonium
species can be arylated to provide 2-nitrophenylacetones,
precursors for indole synthesis (Table 4, entries 1-5). A series
of R-aryl methyl ketones containing other functional groups such
as cyano, ester, Cl, and CF3 can also be synthesized (Table 4,
entries 6-12).
(
Table 1, entries 10-15). A marginal pH dependence was
10
observed for this reaction as demonstrated when the reactions
were carried out in buffered acetate solutions (Table 1, entries
1
2 and 13). From this screen, NaOAc and KOAc emerged as
the most efficient promoters of the reaction affording 2-nitro-
1
1
phenylacetone in 53% yield (Table 1, entries 14 and 15).
In order to demonstrate this chemistry on a wider range of
substrates such as synthetically useful indole precursors, 2-ni-
(12) Other solvents tested on the arylation of isopropenyl acetate with
2
-nitro-4-(trifluoromethoxy)aniline include: THF, DCE, toluene, chlo-
(9) Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572.
(10) Rondestvedt, C. S., Jr.; Vogl, O. J. Am. Chem. Soc. 1955, 77, 2313.
(11) No residual metals were detected in KOAc when tested by ICPMS.
robenzene, benzonitrile, t-BuOH, t-BuCN, CF3CH2OH. Yields varied
between 0-35.%.
(13) Isopropenyl acetate is available at $40/kg from several suppliers.
J. Org. Chem, Vol. 72, No. 5, 2007 1857

TABLE 4. Synthesis of Various r-Aryl Methyl Ketones
kilogram amounts in the preparation of 1-(3-bromo-4-meth-
ylphenyl)propan-2-one.
Experimental Section
2
-Nitrophenylacetone16 (2b). To a stirred solution of isopropenyl
acetate (4.4 mL, 40 mmol) in acetone (13 mL) and water (7 mL)
was added 0.1 mL of a solution of KOAc (200 mg, 2 mmol) in
water (1 mL) followed by 2-nitrobenzenediazonium tetrafluorobo-
rate (474 mg, 2 mmol). Then, the rest of the aqueous KOAc solution
was added dropwise over 2 h and stirred overnight. The reaction
mixture was diluted with MTBE and water, and the layers were
separated. The aqueous layer was back-extracted with MTBE. The
combined organic extracts were washed with aqueous saturated
R1
R2
a
entry
yield (%)
product
1
2
3
4
5
6
7
8
9
H
NO2
NO2
NO2
NO2
NO2
H
76
65
60
34
13
58
70
71
72
58
62
39
2b
2c
2d
2e
2f
2a
2g
2h
2i
CF3
CH3
OCF3
OCH3
NO2
Cl
CF3
H
H
H
H
3 4
NaHCO and brine and dried over MgSO . The solvent was
removed under reduced pressure and the crude mixture purified
by column chromatography on silica gel with hexane/EtOAc (3:1)
CN
CO2Me
Cl
10
11
12
2j
2k
2l
to provide 244 mg (76%) of 2b: 1H NMR (400 MHz, CDCl
3
) δ
CF3
CH3
8
.14 (1 H, d, J ) 8.0 Hz), 7.61 (1 H, t, J ) 7.0 Hz), 7.48 (1 H, t,
H
J ) 7.3 Hz), 7.30 (1 H, d, J ) 7.6 Hz), 4.14 (2 H, s), 2.34
a
Isolated yield after column chromatography.
(3 H, s).
1
-(3-Bromo-4-methylphenyl)propan-2-one (5). A visually clean
60 L cylindrical reactor equipped with a mechanical stirrer, a
dropping funnel, and a N inlet and outlet was charged with
isopropenyl acetate (57.4 L, 526 mol), 3-bromo-4-methylbenzene-
diazonium tetrafluoroborate salt (4) (7.5 kg, 26.3 mol), acetonitrile
1
Finally, we required multi-kilogram quantities of 1-(3-bromo-
-methylphenyl)propan-2-one (5) as part of an ongoing drug
2
4
discovery program in our laboratories. This newly developed
methodology is a viable process for multi-kilogram quantities
synthesis of R-aryl methyl ketone 5. Thus, large quantities of
the starting materials and solvents required are common easily
accessible chemicals and the 3-bromo-4-methyldiazonium tet-
(37.5 L), and water (3.75 L). The light yellow slurry was cooled to
an internal temperature of 0-4 °C, and a solution of KOAc (2.85
kg, 29.0 mol, 110 mol %) in water (3.75 L) was added over 3 h.
Caution: Gas eVolution, proper Venting required!! The internal
temperature rose to 15-18 °C. The batch was allowed stir 30 min
1
4,15
rafluoroborate salt (4) is a bench stable solid at rt.
transition-metal free synthesis of 4.8 kg of R-aryl methyl ketone
was completed in a safe and inexpensive manner using the
The
2
and N evolution ceased. Water (37.5 L) was added, and the layers
were cut. The upper organic layer was washed with brine (18.75
L) and then concentrated under vacuum. HPLC analysis: 4.8 kg,
80% assay yield. An analytical sample was obtained by distillation
under vacuum (clear oil, bp 113 °C, 0.4 mmHg): 1H NMR (500
5
developed methodology (eq 1).
MHz, CDCl
J ) 8 Hz), 3.65 (2H, s), 2.38 (3H, s), 2.11 (3H, s); C NMR (125
MHz, CDCl ) δ 205.7, 136.5, 133.3, 133.0, 130.9, 128.2, 124.9,
9.7, 29.3, 22.4; HRMS ESI (m/z) [M + H] calcd for C10
BrO 227.0065, found 227.0066.
-(3-Bromo-4-methylphenyl)propan-2-one (5) on a Prepara-
3
) δ 7.39 (1H, s), 7.20 (1H, d, J ) 8 Hz), 7.05 (1H, d,
13
3
+
81
12
-
4
H
1
tive Scale. 3-Bromo-4-methylbenzenediazonium tetrafluoroborate
salt (4) (75 g, 263 mmol) was suspended in acetonitrile (375 mL)
and water (37.5 mL). The slurry was cooled to 0-5 °C, and
isopropenyl acetate (574 mL, 5.26 mol) was added. A solution of
KOAc (28.4 g, 289.3 mmol) in water (37.5 mL) was added over 2
h. Caution: Gas eVolution, proper Venting required!! The solution
In conclusion we have described a new transition-metal free
approach to the synthesis of R-aryl methyl ketones from
diazonium tetrafluoroborate salts and isopropenyl acetate under
mild conditions. This methodology is simple, scalable, envi-
ronmentally friendly and was demonstrated safely on multi-
was allowed stir for 30 min, and N
added, and the layers were separated. The organic layer was washed
with brine, dried with MgSO , and concentrated under reduced
2
evolution ceased, water was
(14) Diazonium ions are known to exhibit unstable characteristics that
4
can cause some salts to be explosive. The reactivity of each individual
diazonium compound should be investigated to determine their explosive
potential before running large scale experiments.
pressure to afforded ketone 5 as a red oil (78-80% HPLC assay
yield).
Supporting Information Available: Experimental procedures
and spectroscopic data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) The dried diazonium salt intermediate has an exotherm of 35.8 cal/g
initiating at 100 °C and a smaller exotherm of 3.5cal/g initiating at 175 °C
as measured by DSC. Therefore, it is considered a stable intermediate at rt.
(16) Strazzolini, P.; Giumanini, A. G.; Runcio, A.; Scuccato, M. J. Org.
Chem. 1998, 63, 952.
JO062483G
1
858 J. Org. Chem., Vol. 72, No. 5, 2007