Polymer-assisted Horner-Emmons olefination using PASSflow reactors: pure products without purification.

Article abstract of DOI:10.1016/S0960-894X(02)00265-2

A PASSflow protocol for the Horner-Emmons olefination of aldehydes using polymer-bound hydroxide ions in flowthrough reactors is presented which allows preparation of alkenes in very high yield with minimal purification.

Full text of DOI:10.1016/S0960-894X(02)00265-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1833–1835
Polymer-Assisted Horner–Emmons Olefination Using PASSflow
Reactors: Pure Products Without Purification
a
b
c
a,
Wladimir Solodenko, Ulrich Kunz, Gerhard Jas and Andreas Kirschning *
aInstitut fu¨r Organische Chemie der Universita¨t Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
b
Institut fu¨r Chemische Verfahrenstechnik, TU Clausthal, Leibnizstr. 17, 38678 Clausthal-Zellerfeld, Germany
c
CHELONA GmbH, Hermannswerder, Haus 17, 14473-Potsdam, Germany
Received 11 December 2001; accepted 1 February 2002
Abstract—A PASSflow protocol for the Horner–Emmons olefination of aldehydes using polymer-bound hydroxide ions in flow-
through reactors is presented which allows preparation of alkenes in very high yield with minimal purification. # 2002 Elsevier
Science Ltd. All rights reserved.
Polymer-supported reagents have seen a dramatic
1
microchannel pore system of the support. This compo-
site material was embedded in a solvent-resistant tube
which was followed by encapsulation with a pressure-
resistant fiber-reinforced epoxy resin casing with two
standard HPLC-fittings (Fig. 2). The polymer particles
inside the pore volume can swell and shrink only in the
pore volume, whereas the outer dimensions of the rod
stay stable. Technical problems like bypassing or high
pressure drop as observed in pure polymer packings are
renaissance lately, because this hybrid solid/solution-
phase technique allows simple purification and the pos-
sibility to use reagents in excess to drive reactions in
solution to completion. The opportunity to employ this
technique in conjunction with continuous flow processes
is particularly appealing as this application would create
an ideal almost workup-free technique for automated
2
solution-phase synthesis.
Recently, we reported on a new reactor system for
polymer-assisted, solution-phase synthesis in the flow-
through mode, which we termed the PASSflow tech-
3
nique. A monolithic flowthrough microreactor, which is
loaded with polymer-bound reagents or catalysts allowed
to perform organic transformations in solution associated
with low to moderate pressure drop. The monolithic block
contains a novel, chemically functionalized highly porous
polymer/glass composite. Polyvinylchlorobenzene (cross-
linked with 2–20% of divinylbenzene) was prepared by
precipitation polymerization in the pore volume of
highly porous glass rods to yield a polymeric matrix
4
inside the rod (Fig. 1).
The polymeric structures obtained are small beads (1–
mm diameter), and are crosslinked with polymeric
5
bridges. This results in a monolithic polymeric phase
with a high surface area which is wedged inside the
Figure 1. Scanning electron microscopic presentation of polystyrene/
glass-composite. The scales are depicted close to the lower frame of the
photograph.
*Corresponding author. Fax: +49-511-762-3011; e-mail: andreas.
kirschning@oci.uni-hannover.de
0
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00265-2

1834
W. Solodenko et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1833–1835
Table 1. Horner–Emmons olefination in the PASSflow mode
Aldehyde
Z
Alkene
% Yielda
E/Z-ratio)b
(
CN
CO Et
99 (1.4:1)c
93 (9:1)
2
Figure 2. Cross sectional view through the PASSflow reactor
PTFE=polytetrafluoroethylene).
(
CN
CO Et
97 (2.6:1)d
97 (only E-)
2
CN
CO Et
99 (1.6:1)c
96 (4:1)
2
CN
CO Et
99 (3:1)d
97 (only E-)
Scheme 1.
2
avoided. The benzylic chlorine was aminated using tri-
methyl amine in toluene to yield the corresponding
polymer-anchored quarternary ammonium ion.
CN
87 (2.3:1)
94 (2:1)
Combinatorial chemistry and automation of multistep
syntheses require new strategies with minimal workup
or ideally without purification protocols. In this context,
CN
CN
5
polymer-assisted Wittig-type olefinations including
6
e
99 (2:1)
e
Horner–Emmons variants are particularly appealing.
CO
2
Et
93 (only E-)
Recently, an interesting protocol of the polymer-assisted
Horner–Emmons olefination was reported by Barrett
and co-workers. They performed a ring opening
metathesis (ROMP) with 2-norbornenemethanol phos-
phonates; the polymerization afforded an immobilized
phosphonate which in the presence of base and a carbonyl
compound exclusively afforded (E)-configured a,b-
CN
CO Et
92 (2:1)
99 (only E-)
2
a
1
7
Yields of isolated products (purity >95% according to H NMR and
1
unsaturated esters.
GC). All compounds were characterized by H NMR, IR, MS, and
correlation with the reported data.
In this communication, we demonstrate that PASSflow
reactors can ideally be employed for the efficient pre-
paration of alkenes by applying of the Horner–Emmons
olefination. Basically, workup like extraction, filtration
and chromatographic purification is fully avoided.
b
1
10
Ratio determined by H NMR spectroscopy.
Pure E- and Z-isomers were separated by flash column chromato-
c
graphy (silica gel; pentane/ether=95:5.
d
Pure E-isomer was obtained after crystallization from ethanol.
Mixture of exo/endo-isomer.
e
We found that the reactor (hydroxide loaded) can suc-
cessfully be employed for the Horner–Emmons olefina-
tion under the following conditions (Scheme 1 and
Table 1). An equimolar mixture of diethyl phosphono-
acetonitrile and aldehyde in acetonitrile circulates at
byproduct was trapped on the positively charged poly-
mer. To overcome this complication the protocol was
modified by drying the reactor in vacuo after it had been
loaded with hydroxide ions. Instead of acetonitrile,
anhydrous THF served as the solvent of choice. Under
these conditions, the Horner–Emmons olefination was
found to proceed smoothly, thus exclusively furnishing
the pure a,b-unsaturated esters. Remarkably the olefi-
nations proceeded rather rapidly and were completed
within 30–120 min. Advantageously, the polymer does
not need to be loaded with the phosphonate ion prior to
8
room temperature through the reactor. The reactor
itself acts as a base thereby forming the intermediate
phosphonate ion. This polymer-bound species reacts
with the aldehyde to yield the alkene. Diethyl phosphate
is a problematic byproduct of this reaction which in this
case remains bound in the reactor. The desired alkene is
formed in very high yield and in excellent purity after
removal of the solvent.
6
olefination but the anion is generated in situ. Indeed, we
were unable to quantitatively load the reactor with these
anions owing to solubility problems, which led to blocking
of the PASSflow reactor. Finally, it needs to be pointed
out that a single reactor was used for more than ten
When the less reactive triethyl phosphonoacetate was
employed under the conditions described above forma-
9
11
tion of the a,b-unsaturated esters was also observed.
examples of Horner–Emmons olefination reactions.
However, in this case the target a,b-unsaturated esters
were partly hydrolyzed (up to 40%) also yielding the
corresponding a,b-unsaturated carboxylic acids. This
In essence, the polymer-assisted Horner–Emmons olefi-
nation method described in this communication has the

W. Solodenko et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1833–1835
1835
following profound advantages12 over alternate poly-
The microreactor (chloride loaded, 0.4 mequiv capacity) was
flushed with 1 M sodium hydroxide solution (60mL; until no
5
,6
mer-assisted Wittig-type olefinations:
(a) the flow-
chloride was detected using AgNO
(
3
), followed by water
through reactors can repeatedly be regenerated and
used; (b) various phosphonates can be used without the
necessity of modifying the polymer; (c) none of the two
reactants needs to be employed in excess; (d) the reac-
tion times of these polymer-assisted olefinations are
short (30–120 min versus 4–48 h of alternate polymer-
150mL), methanol (30mL), acetonitrile (30mL), and finally
dry acetonitrile (30mL). Then, a solution of diethylphosphono
acetonitrile (38.8 mg, 0.219 mmol) and 4-chlorobenzaldehyde
(
31.1 mg, 0.221 mmol) in anhydrous acetonitrile (3 mL) was
pumped through the reactor (2.5 mL/min) at room tempera-
ture in a cyclic mode. After 1 h the reactor system was rinsed
with acetonitrile (15 mL). The combined organic reaction
mixtures were concentrated in vacuo to yield the target p-
chlorocinnamonitrile (E/Z*=72:28; 35 mg, 0.213 mmol; 97%).
7
assisted Wittig-type olefinations ); and (e) workup is
extremely simple.
ꢀ
1
ꢀ1
1
IR: ꢀCN 2216 cm , ꢀC=C 1665 cm
CDCl ) d 5.34* (d, J=12.1 Hz,=CH), 5.85 (d, J=16.6 Hz,=
CH), 6.95* (d, J=12.1 Hz,=CH), 7.35 (d, J=16.6 Hz,=CH),
. H NMR (200MHz,
Acknowledgements
3
+
35
+
37
7.05–7.70 (m, H ). MS: 163 (M , Cl ), 165 (M , Cl ). Crys-
ar
tallization from ethanol gave the pure (E)-isomer, mp 78–
0 C (mp 78 C; Texier-Boullet, F.; Foucaud, A. Synthesis
979, 884).
. Typical procedure for the Horner–Emmons olefination in the
Financial support by the Fonds der Chemischen Industrie
is gratefully acknowledged.
ꢁ
ꢁ
8
1
9
References and Notes
2
flowthrough mode using triethyl phosphonoacetate (Z=CO Et):
The reactor was loaded with hydroxide ions as described in ref
8 followed by successive washing with methanol (30mL), and
diethyl ether (30mL). Finally the reactor was dried in vacuo at
1
. Recent reviews: (a) Kirschning, A.; Monenschein, H.; Wit-
tenberg, R. Angew. Chem. 2001, 113, 670; Angew. Chem. Int.
Ed. 2001, 40, 650. (b) Kirschning, A.; Monenschein, H.; Wit-
tenberg, R. Chem. Eur. J. 2001, 6, 4445. (c) Ley, S. V.; Bax-
endale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Tay-
lor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815. (d)
Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res. Rev. 1999, 19,
2 5
room temperature over P O for 2–4 h. The reactor prepared
in this way was washed with anhydrous THF (15 mL). After
this procedure, a solution of 4-chlorobenzaldehyde (27.3 mg,
0.194 mmol) and triethyl phosphonoacetate (41.4 mg,
0.185 mmol) in anhydrous THF (3 mL) was allowed to circu-
late through the reactor (2.5 mL/min) at room temperature.
After 2 h the reactor system was rinsed with anhydrous THF
(15 mL). The combined reaction mixtures were concentrated in
vacuo to yield target ethyl p-chlorocinnamate (only E-isomer;
9
2
7.
. Taylor, R. T. In Polymer Reagents and Catalysts; Ford, W.
T., Ed.; ACS Symposium Series 308; Washington, DC, 1986; p
ꢀ
1
1
3
32.
. Kirschning, A.; Altwicker, C.; Dra
38 mg, 0.18 mmol; 97%). IR:
ꢀ
ꢀ
C¼O 1708 cm
,
n
C=C
1 1
¨
ger, G.; Harders, J.;
nfeld, H.; Solodenko, W.;
1638 cm . H NMR (200 MHz, CDCl ) d 1.32 (t, J=7.14 Hz,
3
Hoffmann, N.; Hoffmann, U.; Scho
¨
Kunz, U. Angew. Chem. Int. Ed. 2001, 40, 3995.
3H, CH
J=16.05 Hz, 1H,=C
J=16.05 Hz, 1H,=C
3
), 4.25 (q, J=7.14 Hz, 2H, CH
2
), 6.39 (d,
a
H), 7.31–7.42 (m, 4H, Har), 7.62 (d,
+
+
35
4
1
. (a) Sundmacher, K.; Kunne, H.; Kunz, U. Chem. Ing. Tech.
998, 70, 267. (b) Altwicker, C. PhD thesis 2001, Technical
¨
b
H). MS: 210(M , Cl ), 212 (M ,
3
7
Cl ).
1
University of Clausthal.
. Cainelli, G.; Contento, M. F.; Manescalchi, F.; Regnoli, R.
J. Chem. Soc., Perkin Trans. 1 1980, 2516.
10. The J-values in the H NMR spectra served as analytical
data for determining the configuration of the olefinic double
bonds (trans-isomers: 16.7–15.4 Hz and cis-isomer 12.2–
10.7 Hz).
5
6
1
. (a) Bernhard, M.; Ford, W. T.; Nelson, E. C. J. Org. Chem.
983, 48, 3164. (b) Clarke, S. D.; Harrison, C. R.; Hodge, P.
11. The by-product formed in course of the olefination can
simply be removed from the reactor by washing with 1 M HCl.
The reactor was regenerated by successively washing with
methanol (10mL), water (10mL), 1 N NaOH (10mL), water
(10mL), 2 M HCI (10mL) and water (30mL).
Tetrahedron Lett. 1980, 21, 1375. (c) Castells, J.; Font, J.;
Virgili, A. J. Chem. Soc. 1979, 1.
7
. Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F.
J. Org. Lett. 1999, 1, 579.
. Typical procedure for the Horner–Emmons olefination in the
flowthrough mode using diethyl phosphonoacetonitrile (Z=CN):
8
12. For automation common HPLC-equipment can be used
(e.g., pumps, detectors, valves, dosing facilities).