Convenient laboratory method for the synthesis of symmetrical 1,3-diphenylacetone derivatives

Article abstract of DOI:10.1055/s-0030-1260160

A practical one-pot, two-step procedure for the synthesis of symmetrical 1,3-diphenylacetone derivatives from the corresponding phenylacetate has been developed. This procedure has been demonstrated by the synthesis of 1,3-diphenylacetone at the >50-gram scale in >99% purity. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260160

PRACTICAL SYNTHETIC PROCEDURES
2721
Convenient Laboratory Method for the Synthesis of Symmetrical
1
,3-Diphenylacetone Derivatives
1
D
,3-Diphenylaceto
u
ne
D
erivative
a
s
ne R. Romer
The Dow Chemical Company, Core R&D, 1776 Building, Midland, MI 48674, USA
E-mail: drromer2@dow.com
PSP
Received 27 May 2011; revised 8 July 2011
No206
Abstract: A practical one-pot, two-step procedure for the synthesis of symmetrical 1,3-diphenylacetone derivatives from the corresponding
phenylacetate has been developed. This procedure has been demonstrated by the synthesis of 1,3-diphenylacetone at the >50-gram scale in
>99% purity.
Key words: condensation, ketones, esters, addition, aldol reaction
CO2Et
Ph
AcOH
NaH
OEt
Ph
Ph
Ph
Ph
HCl, H2O
reflux
toluene
O
O
O
1
2
3 86%
Scheme 1 Two-step, one-pot synthesis of 1,3-diphenylacetone (3)
1
,3-Diphenylacetone (1,3-diphenylpropan-2-one or DPA, Directed Claisen condensations of nitriles with esters are
3
) is a well-known and highly useful compound. First re- a well-known method for the synthesis of b-ketonitriles.
1
ported by Young in 1891, 1,3-diphenylacetone has been These nitriles can in turn be hydrolyzed and decarboxylat-
used in a wide variety of applications as diverse as cos- ed to the ketone. Such an approach has been used by sev-7
2
3
metics and hair-care products, polymers, coatings appli- eral authors for the synthesis of 1,3-diphenylacetone.
4
cations, and more recently in organic light-emitting However, this method suffers as the hydrolysis/decarbox-
devices.
5
ylation step requires strong acid (60% H SO ), high tem-
2 4
peratures (160 °C), and extended reaction periods,
followed by extractive isolation.
We recently required a supply of high purity 1,3-diphenyl-
acetone (3) as well as 1,3-bis(4-bromophenyl)acetone
(
4,4¢-dibromodiphenylacetone, 7) for an internal develop- Claisen condensations of esters, giving a b-keto ester, are
8
ment project (Scheme 1). Although 1,3-diphenylacetone also known. In these cases, a stronger base is required
3) itself is available from several vendors and it is very due to the decreased acidity of the ester relative to the ni-
(
inexpensive, we found that the quality of the material was trile. Several different non-nucleophilic bases for this con-
poor and extensive purification was required prior to use. version have been reported, including isopropyl Grignard,
Symmetrical halogenated derivatives such as 1,3-bis(4- diethylaminomagnesium bromide, and lithium dibutyl-
bromophenyl)acetone (7) are much less readily available, amide. These reports generally show very high yields of
expensive, and require significant lead time. With this in the desired b-keto ester, which can subsequently be hy-
mind, we set out to develop a method for the synthesis of drolyzed and decarboxylated under mild conditions to
symmetrical 1,3-diphenylacetone derivatives that would give 1,3-diphenylacetone. Using these previous works as
provide high purity products in a convenient manner.
a basis, we have developed a convenient two-step, one-pot
procedure for the synthesis of symmetrical 1,3-diphenyl-
acetone derivatives via Claisen condensation of phenyl-
acetates followed by hydrolysis and decarboxylation.
A survey of the literature showed that there were relative-
ly few practical laboratory methods for the synthesis of
1
,3-diphenylacetone. Many early preparations of 1,3-
diphenylacetone relied on pyrolysis of phenylacetic acid Initial experiments focused on the work of Hammel and
6
8c
or its salts. Although simple and high-yielding, pyrolysis Levine, however we have found it more convenient to
generally requires specialized equipment and is not con- use sodium diethylamide generated from sodium hydride
venient for routine laboratory preparations.
and diethylamine (Scheme 2). The Claisen condensation
was readily performed by generation of the amide base in
tetrahydrofuran, followed by dropwise addition of ethyl
phenylacetate (1), and refluxing overnight. GC analysis of
a quenched aliquot of the reaction mixture showed only
1,3-diphenylacetone (3). Evidently, the intermediate b-
SYNTHESIS 2011, No. 17, pp 2721–2723
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.08.2011
DOI: 10.1055/s-0030-1260160; Art ID: M54911SS
Georg Thieme Verlag Stuttgart · New York
©

2
722
D. R. Romer
PRACTICAL SYNTHETIC PROCEDURES
keto ester 2 hydrolyzed and decarboxylated in the injec- sation step without any need for removal of the mineral oil
tion port of the GC.
as is normally done for organic preparations. The oil is
conveniently retained in the heptanes mother liquor dur-
ing the subsequent crystallization step.
CO2Et
Ph
NaH
OEt
Ph
Ph
Hydrolysis/decarboxylation of b-keto ester is classically
performed by alkaline hydrolysis of the ester followed by
acidification and decarboxylation. However, as noted
above, any attempt to hydrolyze 2 under basic conditions
resulted in a near a quantitative retro-Claisen reaction to
give phenylacetic acid (5).
Et2NH, THF
O
O
1
2
Scheme 2 Claisen condensation of ethyl phenylacetate (1)
Reasoning that diethylamine could be used catalytically in
the reaction, and changing the solvent to toluene (due to For the hydrolysis/decarboxylation step, we utilized the
internal safety considerations for further scale-up), we previously reported acidic conditions of a 1:1 mixture of
9
were pleased to note that after complete addition of 1 and acetic acid–20% aqueous hydrochloric acid at reflux. Un-
refluxing overnight, 3 was again observed as the sole der these conditions, 2 was rapidly converted into 3,
product in the reaction mixture by GC analysis. However, which could be isolated and crystallized from heptanes to
upon cooling to 60 °C and careful quenching of the reac- give high purity 1,3-diphenylacetone (3) in excellent
tion mixture with 10% aqueous hydrochloric acid, a sub- overall yield.
stantial amount of a new product was observed in the GC,
Likewise, starting from commercially available ethyl 4-
which was subsequently identified as phenylacetic acid
bromophenylacetate, we have utilized this two-step meth-
(
5) (Scheme 3). Evidently, under the initial aqueous alka-
od for the preparation of 1,3-bis(4-bromophenyl)acetone
7), via the b-keto ester 6 (Scheme 4).
line conditions at the beginning of the quench at a relative-
ly high quench temperature (60 °C) the b-keto ester 2 is
hydrolyzed to the b-keto acid 4, which undergoes a retro-
Claisen reaction rather than decarboxylation to generate
two equivalents of phenylacetic acid (5).
(
CO2Et
OEt
NaH
O
toluene
O
Br
Br
Br
CO2H
6
CO2Et
Ph
aq HCl (10%)
OH
Ph
Ph
Ph
aq HCl (20%), AcOH
Ph
O
O
O
O
Br
Br
5
7
87%
2
4
Scheme 3 Hydrolysis, retro-Claisen of 2
Scheme 4 Synthesis of 1,3-bis(4-bromophenyl)acetone (7)
Fortunately, this retro-Claisen can be circumvented by ei- With the successful identification of a viable laboratory
ther conducting the quench procedure at low (<30 °C) route for the synthesis of symmetrical 1,3-diphenylace-
temperature, or by adding the contents of the first reactor tone derivatives, we investigated the possibility of utiliz-
to a second reactor containing 10% aqueous hydrochloric ing a two-step, one-pot process without isolation of the
acid. In either case, 2 can be isolated by aqueous workup intermediate b-keto ester. For this work, we focused on
followed by recrystallization of 2 from heptanes.
the parent, unsubstituted 1,3-diphenylacetone (3)
Scheme 1).
(
Surprisingly, the Claisen condensation works equally well
in the absence of diethylamine. Simply adding ethyl phe- Neat ethyl phenylacetate (1) was added to a slurry of 60
nylacetate (1) to a slurry of sodium hydride in toluene, fol- wt% sodium hydride (1.1 equiv) in mineral oil in toluene
lowed by quenching and isolation gives a high yield of 2. at ambient temperature. Working at a 100-gram scale, this
The reaction can also be performed equally well in hep- required 2.5 hours in order to control the vigorous exo-
tanes as solvent, although in this case efficient mixing therm. After completion of addition, the reaction mixture
during the quench phase is required as 2 will crystallize was heated to 75 °C and complete conversion to the inter-
out of the mixture, forming a thick slurry.
mediate b-keto ester 2 was observed by HPLC analysis.
The reaction mixture was cooled to 0 °C, and concentrated
aqueous hydrochloric acid (1.5 equiv relative to NaH) was
slowly added to the vigorously stirred solution so as to
keep the temperature of the reaction mixture below 20 °C.
After quenching, the reaction mixture was heated and tol-
uene was distilled off until the temperature of the distillate
reached 100 °C (alternatively, a Rotovap can be used to
remove the toluene). Acetic acid and 20% aqueous hydro-
chloric acid were then added and the reaction mixture was
heated to reflux overnight. Upon cooling to 65 °C, hep-
tanes and water were added, and after through mixing,
Two comments regarding the use of sodium hydride alone
as the base are warranted. First, it was noted that there was
an induction period for the reaction of ethyl phenylacetate
(
1) with sodium hydride. The temperature of the mixture
remained stable until approximately 30% of 1 had been
added, followed by a very rapid increase in temperature.
Thus, care should be taken to monitor the temperature of
the reaction mixture during the course of the addition.
Second, we have found that commercial 60 wt% sodium
hydride in mineral oil can be used directly in the conden-
Synthesis 2011, No. 17, 2721–2723 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1,3-Diphenylacetone Derivatives
2723
while at 60 °C, the phases were separated. The heptanes was isolated by filtration and washed with cold heptanes, giving
1
,3-diphenylacetone (3) (55.1 g, 86%) as a white solid; 99.2% puri-
phase is then slowly cooled during which a separate phase
was observed. Upon further cooling to <10 °C, the prod-
uct crystallized and was isolated by filtration followed by
washing with cold heptanes, in 86% yield. This product
assayed by HPLC at 99.2% purity.
ty (HPLC).
1
H NMR (500 MHz, CDCl ): d = 7.28 (t, J = 7.2 Hz, 4 H), 7.32 (t,
3
J = 7.3 Hz, 2 H), 7.22 (dd, J = 7.7, 0.9 Hz, 4 H), 3.78 (s, 4 H).
13C NMR (126 MHz, CDCl
26.91, 48.96.
): d = 205.38, 133.91, 129.38, 128.57,
3
1
This procedure demonstrates a practical and convenient,
two-step, one-pot method for the synthesis of highly pure,
symmetrical 1,3-diphenylacetone derivatives using com-
mon laboratory apparatus at a relatively large (100-g)
scale. We anticipate it will prove to be generally useful to
GC-MS [CI (CH )]: m/z = 211 (M + 1, 100%).
4
1
,3-Bis(4-bromophenyl)acetone (7)
A similar procedure was used for the synthesis of 1,3-bis(4-bro-
mophenyl)acetone starting from 4-bromoethyl phenylacetate; yield:
other symmetrical 1,3-diphenylacetone derivatives with 87%; 99.4% purity.
substituents compatible with the reaction conditions.
1
H NMR (500 MHz, CDCl ): d = 7.43 (d, J = 8.3 Hz, 4 H), 7.00 (d,
3
J = 8.3 Hz, 4 H), 3.66 (s, 4 H).
1
3
Ethyl phenylacetate and NaH (60 wt% dispersion in mineral oil)
were purchased from Sigma Aldrich and used as received. Solvents
and other reagents (toluene, heptanes, AcOH, and aq HCl) were
purchased from ThemoFisher Scientific. Large-scale reactions were
performed in a 2-L jacketed, 3-necked, bottom-drain round-bottom
flask equipped with a thermowell, reflux condenser, addition fun-
C NMR (126 MHz, CDCl ): d = 204.10, 132.58, 131.79, 131.12,
3
121.20, 48.40.
GC-MS [CI (CH )]: m/z = 369 (M + 1, 100%).
4
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2
(
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1
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ther cooling to 0 °C resulted in crystallization of the product. This
1
(
Synthesis 2011, No. 17, 2721–2723 © Thieme Stuttgart · New York