Precipiton strategies applied to the isolation of α-substituted β-ketoesters

Article abstract of DOI:10.1016/S0040-4039(01)00726-2

Diaryl alkene 1Z is a 'precipiton', a protecting group that allows reaction products to be isolated by simple filtration. Here we illustrate the use of this protecting group for the preparation and isolation, without distillation or chromatography, of pure α-substituted β-ketoesters. The precipiton 1Z was prepared in 43% overall yield. It is anticipated that development of precipiton-based syntheses will provide a new alternative for automated reaction product isolation that may be useful for bench-scale and process-scale chemical preparations.

Full text of DOI:10.1016/S0040-4039(01)00726-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4309–4312
Precipiton strategies applied to the isolation of a-substituted
b-ketoesters†
Todd Bosanac and Craig S. Wilcox*
Department of Chemistry and The Combinatorial Chemistry Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 23 March 2001; revised 27 April 2001; accepted 1 May 2001
Abstract—Diaryl alkene 1Z is a ‘precipiton’, a protecting group that allows reaction products to be isolated by simple filtration.
Here we illustrate the use of this protecting group for the preparation and isolation, without distillation or chromatography, of
pure a-substituted b-ketoesters. The precipiton 1Z was prepared in 43% overall yield. It is anticipated that development of
precipiton-based syntheses will provide a new alternative for automated reaction product isolation that may be useful for
bench-scale and process-scale chemical preparations. © 2001 Elsevier Science Ltd. All rights reserved.
excess reagents, catalysts, and solvent to be removed
from the resin-bound products. However, there are
OH
disadvantages associated with SPOS: the supports can
be expensive; typical loading capacities range from 0.1
1Z
Soluble
1E
Insoluble
to 1.0 mmol/g—resulting in effective molecular weights
of 1,000–10,000 and making large scale or even multi-
gram SPOS impractical; reaction conditions developed
for homogeneous processes often must be re-optimized
for SPOS; and reaction progress is difficult to monitor.
Alternatives to SPOS (i.e. fluorous synthesis,2 soluble
polymer-supported organic synthesis or SPSOS,3 and
dendrimer-supported organic synthesis4) attach a reac-
tant molecule to a ‘phase-tag’ which facilitates product
isolation by a phase-transfer event (solvent-induced
precipitation or liquid–liquid partition).
OH
Advances in high through-put screening and parallel
synthesis have stimulated interest in new approaches to
product separation.1 Often the most costly stage in a
synthetic transformation is purification of the product.
Solid-supported organic synthesis, also called solid-
phase organic synthesis (SPOS), is the dominant
method for automated syntheses because it allows
1) CBr4, PPh3
CHO
2) HSnBu3, Pd(PPh3)4
Br
CH2Cl2, 60%
3Z
1) t-BuLi, -78 οC to 0 οC, then
ZnCl2, THF, 0 οC to 23 οC
OTBS
Br
2) 3Z, Pd(PPh3)4, reflux
1Z
OH
3) TBAF
71%
Scheme 1.
* Corresponding author.
† This paper is dedicated to Professor Ronald Breslow on the occasion of his 70th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00726-2

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T. Bosanac, C. S. Wilcox / Tetrahedron Letters 42 (2001) 4309–4312
We have recently described an approach to product
separation based on a change in solubility caused by
structural isomerization of an ancillary portion of the
desired product.5 This auxiliary we term a ‘precipiton’,
a group of atoms (molecular fragment) that is purpose-
fully attached to a reactant molecule and that can be
isomerized after the reaction in order to cause precipita-
tion of the attached product. Our first-generation pre-
cipiton was benzyl alcohol 1Z, which is freely soluble in
most organic solvents in the Z form and nearly insolu-
ble in the E form.5 In our earlier work, isomerization
(with a concomitant change in solubility) was achieved
by heating the cis-olefin with diphenyldisulfide. In this
communication, we describe a more efficient synthesis
of precipiton 1Z, new isomerization conditions, and the
use of our method for the synthesis and isolation of
pure a-substituted b-ketoesters.
yield of 3Z.9 The bromide 3Z was then coupled to
TBS-protected p-bromobenzyl alcohol.6b Deprotection
of the product by tetra n-butyl ammonium fluoride
(TBAF) provided 1Z in 71% yield for two steps. This
two-pot synthesis yields 1Z in 43% overall yield.
To demonstrate the usefulness and to extend the scope
of our method we prepared a family of a-substituted
b-ketoesters. These products serve as useful intermedi-
ates in the preparation of heterocyclic compounds10 and
can also be chemoselectively and diasteroselectively
reduced to form aldol-type products.11 Both solid-
phase12 and soluble polymer-supported13 protocols for
the synthesis of a-substituted b-ketoesters have been
reported.
Acetoacetate ester 4Z was prepared by treatment of 1Z
with diketene and a catalytic amount of N,N-dimethyl-
amino pyridine (Scheme 2). An advantage of our
approach to product isolation is that it allows an excess
of alkylating reagent to be used. This excess, which can
increase reaction rates and product yields, may be
removed without the use of chromatography or
distillation.
Our first synthesis of precipiton 1Z employed a Wittig
olefination that gave a 1.2:1.0 mixture of E and Z
isomers. A better synthesis was realized by applying a
variant of Negishi’s process6a,b to form the stilbene
system (Scheme 1). Commercially available 4-biphenyl-
carboxaldehyde was converted to the dibromoalkene
under standard Corey–Fuchs conditions.7 The resulting
dibromide was then selectively reduced with tributyltin
hydride in the presence of a catalytic amount of tetra-
kis(triphenylphosphine)palladium(0).8 These two steps
could be carried out in ‘one pot’ to give a 60% isolated
The b-ketoester 4Z was deprotonated with sodium
hydride to generate the enolate, which was then treated
with an excess of an alkylating agent.14 Upon comple-
tion of the alkylation event (generally in 3 h at 23°C)
O
O
, DMAP
O
O
THF
98%
1Z
4Z
OH
O
CH3
Scheme 2.
Table 1. Alkylations of b-ketoester 4Z
1) NaH, THF, RX
2) I2, BzOOBz
O
O
O
CH3
O
R
O
4Z
7E-11E
O
CH3
Entry
RX
Product
Yield (%)
1
2
3
4
5
6
7
EtO2CCH2Br
CH3I
PhCH2Br
PhCOCH2Br
CH3CH2CH2I
CH3(CH2)10CH2I
5E
6E
7E
8E
9E
10E
11E
91
84
70
89
64
41a
72
p-OMePhCH2
a This flocculent, waxy solid was difficult to filter.

T. Bosanac, C. S. Wilcox / Tetrahedron Letters 42 (2001) 4309–4312
4311
the reaction mixture was partitioned between EtOAc
and aqueous NH4Cl. The organic layer was evaporated
and the residue was dissolved in Et2O or CCl4 contain-
ing I2 and benzoyl peroxide. The isomerization process
(monitored by NMR) was complete in 4–24 h. An
aqueous work-up with bisulfite, followed by evapora-
tion of the organic layer, gave crude product, that was
then purified simply by trituration with ether, hexanes,
and/or methanol. All contaminants not bound to the
precipiton were removed by this trituration. This proto-
col afforded precipiton-bound products in good yields
and with purities over 95%15 (Table 1).
The precipiton-bound products are quite insoluble in
ether, hexanes, and methanol, but slightly soluble in
THF. They can be cleaved from the precipiton by
methanolysis (MeOH/TEA in THF, reflux, 1–2 h)15
(Table 2). After the reaction mixture was evaporated to
dryness, the desired methyl esters were separated from
the ether-insoluble benzyl alcohol precipiton 1E by
trituration with ether or MeOH. Evaporation of the
volatile components from the filtrates furnished the
methyl b-ketoesters 12 through 16 in good yields and
with purities over 95%. Complete deacylation of com-
pound 8E and partial deacylation of 11E were observed
Table 2. Methanolytic removal of product from precipiton
O
O
O
MeOH:TEA
THF, reflux
+
+
H3CO
H3CO
CH3
1E
R
R
O
O
R
7E-11E
12-16
17,18
CH3
O
Entry
Starting material
RX
Product
Yield (%)
1
2
3
4
5
6
7
7E
8E
8E
9E
10E
11E
11E
PhCH2Br
PhCOCH2Br
PhCOCH2Br
CH3CH2CH2I
CH3(CH2)10CH2I
p-OMePhCH2Cl
p-OMePhCH2Cl
12
78
91
63
85
85
71
65:29
15a
17b
13
14
16c
16:18d
a Reflux 1.5 h.
b Reflux 22 h.
c Reflux 0.75 h.
d Reflux 4 h.
Table 3. Hydrogenation of b-ketoesters 5E and 6E
5% Rh/C, H2
THF:MeOH
(2:1)
O
O
R
O
R
5E,6E
19,20
CH3
O
CH3
O
O
Entry
RX
Compound
Product
Yield (%)
917
2
EtO2CC
CH3I
H2Br
6E
5E
20
19
91

4312
T. Bosanac, C. S. Wilcox / Tetrahedron Letters 42 (2001) 4309–4312
with longer methanolysis reaction times. In those cases
the methyl esters 17 and 18 were isolated. (Table 2,
entries 3 and 7) Shorter reaction times for methanolysis
of 8E and 11E afforded only the b-ketoester products
(Table 2, entries 2 and 6). The methyl esters arising
from the cleavage of compounds 5E and 6E were too
volatile to conveniently isolate.
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Proc. Natl. Acad. Sci. USA 1995, 92, 6419–6423; (b)
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In cases involving volatile cleavage products it is useful
to retain the larger protecting group during subsequent
transformations. By design, however, the trans-ester is
not easily dissolved in solvents used for organic reac-
tions. We expected that reduction of the olefin would
yield a product soluble in standard organic solvents.
Hydrogenation over 5% Rh/C in THF:MeOH (2:1)
reduced the alkene of b-ketoesters 5E and 6E in high
yield (Table 3). The products were soluble in both Et2O
and toluene at concentrations greater then 0.5 M.
5. Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem., Int.
Ed. 2001, in press.
6. (a) Negishi, E. J. Org. Chem. 1977, 42, 1821; (b) Negishi,
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These experiments demonstrate a new application of
the precipiton approach to product isolation. The
method does not require distillation or chromatography
steps to provide a-substituted b-ketoesters in high
purity and in yields equal to other methods. The load-
ing capacity of the precipiton reported here is over 3
mmol/g and, even without precipiton recycling, the
costs are competitive with SPOS. The process can be
automated and may be especially useful in large-scale
preparations.
8. Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem.
1996, 61, 5716.
9. Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.
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Acknowledgements
The authors thank Dr. Jaemoon Yang for his contribu-
tions to this work and Professor Dennis Curran for
helpful discussions.
12. Tietze, L. F.; Steinmetz, A.; Balkenhohl, F. Bioorg. Med.
Chem. Lett. 1997, 7, 1303.
13. Zhao, X.; Janda, K. D. Tetrahedron Lett. 1997, 38, 5437.
14. Side products arising from incomplete reaction and/or
dialkylation could be eliminated by washing the 60%
sodium hydride mineral oil dispersion with pentane and
drying the residue in vacuo prior to use.
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15. All products were fully characterized. Reactions were
monitored by TLC or 1H NMR. Purities were determined
1
by H NMR and were greater then 95% for all isolated
compounds. Experimental procedures may be obtained
from the corresponding author.
.