Precipiton reagents: Precipiton phosphines for solution-phase reductions

Article abstract of DOI:10.1021/ol049369+

(Equation Presented) Several Precipiton phosphines were prepared and employed in the Staudinger reaction and in the reduction of secondary ozonides. Both amines and aldehdyes were obtained in good to excellent yields and purities. After use of the phosphine, isomerization and precipitation of the spent phosphorus reagent were induced by exposure to visible light in the presence of erythrosin B, a triplet sensitizer. Products were isolated by simple filtration. The use of the triplet sensitizer has the added advantage of eliminating [2 + 2] cycloaddition reactions between trans-Precipitons.

Full text of DOI:10.1021/ol049369+

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2321-2324
Precipiton Reagents: Precipiton
Phosphines for Solution-Phase
Reductions
Todd Bosanac and Craig S. Wilcox*
Department of Chemistry and The Combinatorial Chemistry Center,
UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
daylite@pitt.edu
Received April 7, 2004
ABSTRACT
Several Precipiton phosphines were prepared and employed in the Staudinger reaction and in the reduction of secondary ozonides. Both
amines and aldehdyes were obtained in good to excellent yields and purities. After use of the phosphine, isomerization and precipitation of
the spent phosphorus reagent were induced by exposure to visible light in the presence of erythrosin B, a triplet sensitizer. Products were
isolated by simple filtration. The use of the triplet sensitizer has the added advantage of eliminating [2 + 2] cycloaddition reactions between
trans-Precipitons.
The rate at which useful new molecules are prepared has
dramatically increased over the past decade due to advances
in high-throughput screening and parallel synthesis. Often,
the rate-limiting step in a reaction sequence is separation of
desired product(s) from excess reagent(s), byproduct(s), and/
or catalyst(s). Polymers derived from polystyrene have been
used as supports for reagents so that expended reagents can
be conveniently separated from a reaction mixture by
filtration.1 Although the insoluble nature of the resin is
required at the filtration stage, it is a disadvantage during
the reaction stage; it causes delayed reaction times and
difficulties in monitoring reaction progress. To circumvent
these disadvantages, chemists have developed alternative
phase tags,2 also called solubility control auxiliaries,3 that
alter the affinity of an attached compound for one phase over
another. Reagents, catalysts, and scavenger reagents have
been attached to phase tags, both polymeric4 and nonpoly-
meric, which include fluorous tags,5 polyaromatic tags,6
Brønsted or Lewis acid/base tags,7 and norbornenyl tags.8
Reagents bearing such tags can be removed from solution
by a phase transfer event.9
Many of the phase tags currently employed are structurally
“static”. By this we mean that the phase tag is not actively
modified (chemically or structurally) during the separation
process. (Exceptions include the traditional ionizable group
(4) (a) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002,
102, 3325. (b) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345. (c) Barrett,
A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem. ReV. 2002, 102, 3301.
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P.; Curran, D. P. Science 1997, 275, 823. (b) Luo, Z.; Zhang, Q.;
Oderaotoshi, Y.; Curran, D. P. Science 2000, 291, 1766.
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(7) (a) Ley, S. V.; Massi, A.; Rodr´ıguez, F.; Harwell, D. C.; Lewthwaite,
R. A.; Pritchard, M. C.; Reid, A. M. Angew. Chem., Int. Ed. 2001, 40,
1053. (b) Perrier, H.; Labelle, M. J. Org. Chem. 1999, 64, 2110. (c) Yoshida,
J.; Itami, K.; Mitsudo, K.; Suga, S. Tetrahedron Lett. 1999, 40, 3403.
(8) Barrett, A. G. M.; Roberts, R. S.; Schro¨der, J. Org. Lett. 2000, 2,
2999.
(1) (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.;
Gordon, E. M. J. Med. Chem. 1994, 37, 1233. (b) Gallop, M. A.; Barrett,
R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994,
37, 1385. (c) Wendeborn, S.; De Mesmaeker, A.; Brill, W. K.-D.; Berteina,
S. Acc. Chem. Res. 2000, 33, 215. (d) Lazo, J. S.; Wipf, P. J. Pharm. Exp.
Ther. 2000, 293, 705.
(2) (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174. (b) Flynn,
D. L.; Deraj, R. V.; Naing, W.; Parlow, J. J.; Weidner, J. J.; Yang, S. Med.
Chem. Res. 1998, 8, 219-243.
(9) (a) Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel,
A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964. (b) Yoshida, J.; Itami,
K. Chem. ReV. 2002, 102, 3693. (c) Also see: Chem. ReV. 2002, 102 (10)
(thematic issue: Heterocycles).
(3) Link, A. Angew. Chem., Int. Ed. 2000, 39, 4039.
10.1021/ol049369+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/10/2004

Figure 2. Cyclobutanes.
cyclobutanes were obtained as a 1:1 ratio of regioisomers
(Figure 2). On long irradiation, this undesired cycloaddition
product was the major product. Cyclobutane formation,
which was not observed with other less-soluble derivatives
related to 1E, was facilitated by the higher accessible
concentrations of this derivative.
Figure 1. Irradiation of TBS ether 1Z.
and metal chelating tags, which are modified by introduction
of new components to the tag solution, and the norbornene
tags.) In other cases, precipitation or phase transfer is caused
by a change in environment (a solvent change or a change
in temperature).
Precipiton phase tags undergo activation and structural
modification prior to the separation event. Precipitons exist
in two isomeric forms, one form (Z) is soluble in common
organic solvents (up to 0.3 M), whereas the other form (E)
is insoluble.10 The solubility change is caused by a structural
isomerization of the phase tag. Precipitons have been used
for product isolation,10a-c reagent sequestration,10d and
removal of metals10e from polymerization solutions. Herein
we describe the preparation and some uses of phosphine
Precipiton reagents.
Such cycloadditions are known to occur via the singlet
excited state, while isomerization occurs through both the
singlet and triplet states.13 Thus, a general solution to this
problem is to use a triplet sensitization of the isomerization.
We found erythrosin B (5 mol %) to be effective. Erythrosin
B can be easily removed from reaction solution by filtration
through SiO2 or by sequestration using MP-carbonate,14
polymeric basic resin.
a
Phosphine 7 was prepared from bromide 6 by conversion
to the boronic acid, which was subsequently subjected to a
Suzuki cross-coupling reaction with 4-bromo phenyldiphe-
nylphosphine (Scheme 1). Phosphines 8 and 9 were prepared
Phosphines are employed for a wide variety of transforma-
tions in organic synthesis, and the difficulty associated with
separating phosphine oxide from products is well recognized.
To address this, we chose to prepare several Precipiton
phosphines and examine their use for reductions of azides
(the Staudinger reaction11) and secondary ozonides.
We examined the effects that appended solubilizing groups
might have on both the physical and photochemical proper-
ties of the phase tag. tert-Butyldimethylsilyl ether 1Z (Figure
1) was prepared by standard procedures. Ether 1E (the (E)-
isomer of TBS-ether 1Z) was partially soluble in THF (4.2
mg/mL, 8.8 mM). (The saturated solution was prepared by
irradiation of a THF solution containing 0.024 M TBS-ether
1Z with 350 nm light.) As expected, the (E)-isomer
underwent an irreversible (at 350 nm) [2 + 2] cycloaddition
reaction12 leading to a 8.7:1 ratio of very soluble syn- and
anti-cyclobutanes 2-5, respectively (up to 1.0 M in hexanes,
THF, ether, CH2Cl2, CHCl3, EtOAc). The syn- and anti-
Scheme 1a
a Reagents and conditions: (a) t-BuLi, -78 °C, THF; (b)
(MeO)3B, -78 to 23 °C, 69%; (c) 4-bromophenyldiphenylphos-
phine, Pd(PPh3)4, THF/aq Na2CO3, 34%; (d) KOH, 18-crown-6,
4-bromobenzyltriphenylphosphonium bromide, CH2Cl2, -78 °C,
77% (8), 67% (9); (e) n-BuLi, -78 °C, THF; (f) ClPPh2, -78 to
23 °C, 74% (8), 51% (9).
(10) (a) Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem., Int. Ed.
2001, 40, 1875. (b) Bosanac, T.; Wilcox, C. S. Tetrahedron Lett. 2001, 42,
4309. (c) Bosanac, T.; Wilcox, C. S. Chem. Commun. 2001, 1618. (d)
Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, (e) Pallack, M.
E.; Brittain, W. J.; Bosanac, T.; Wilcox, C. S. Macromolecules 2002.
(11) Vaultier, M.; Knouzi, N.; Carrie´, R. Tetrahedron Lett. 1983, 24,
763.
(12) (a) Green, B. S.; Heller, L. J. Org. Chem. 1974, 39, 196. (b) Ito,
Y.; Kajita, T.; Kunimoto, K.; Matsuura, T. J. Org. Chem. 1989, 54, 587.
(c) Leigh, W. J.; Lewis, T. J.; Lin, V.; Postigo, J. A. Can. J. Chem. 1996,
74, 263.
via Wittig olefination reactions.15 Treatment of terephthal-
dehyde with 18-crown-6, 4-bromophenyltriphenylphospho-
2322
Org. Lett., Vol. 6, No. 14, 2004

Scheme 2
Table 1. Comparison of Precipiton Phosphines
phosphine
irradiation time (h)
% yield (% purity)a
7
8
9
3.5
2
1
77 (93)
83 (>95)
88 (>95)
time of isomerization. Phosphine 7 required irradiation for
3.5 h and therefore was no longer used for additional
experiments since we saw no advantage compared to the
other phosphines.
a Yields refer to the isolated product. Purities were determined by 1H
NMR and GC-MS.
Other azido substrates were reduced employing both
phosphines 8 and 9 to afford the corresponding amines in
good yields and purities. The reaction works equally well
with secondary azides (Table 2, entry 1) and is compatible
with functionalized azides (Table 2, entry 2). However, other
azides were either reluctant to undergo reduction or not
tolerant of the isomerization conditions (see below). Ada-
mantyl azide, after 24 h, afforded only starting material.
An unexpected product was obtained with benzylic azides.
We observed that upon reduction of 4-methylbenzyl azide
followed by isomerization, a mixture of expected 4-meth-
ylbenzylamine and symmetrical imine was obtained (Scheme
2). The imine product is formed via a photooxidation of the
expected amine product. The oxidation is catalyzed by
erythrosin B.16 By carrying out the isomerization reaction
in acetonitrile and irradiating for 5 h, one may obtain solely
the imine product from the azide in good yields and excellent
purities (Table 3). Upon completion of isomerization, the
nium bromide, and powdered potassium hydroxide afforded
a 1.3:1.0 separable mixture of Z,Z and Z,E isomeric bromides.
This mixture was treated with n-butyllithium followed by
chlorodiphenylphosphine to afford phosphine 8 as a 1.3:1.0
mixture of separable (Z,Z)- and (Z,E)-isomers. (Z)-4,4′-
Formylstilbene was treated with 18-crown-6, 4-bromophe-
nyltriphenylphosphonium bromide, and powdered potassium
hydroxide to generate a 1.3:1.0 separable mixture of Z,Z,Z
and Z,Z,Z isomeric bromides that were subsequently treated
with n-butyllithium followed by chlorodiphenylphosphine to
yield phosphine 9 as a 1.3:1.0 mixture of separable (Z,Z,Z)-
and (Z,Z,E)-isomers.
The Staudinger reduction of 3-(p-tert-butylphenoxy)propyl
azide was studied to compare the effectiveness of isomeric
phosphines 7-9 (Table 1). The reactions were conducted
by heating a solution of phosphine (1.1 equiv of 7, and 0.55
equiv of 8 and 9) and azide in THF until azide was consumed
(2 h). The resulting phosphorimine was hydrolyzed by the
addition of water, and heating was continued until hydrolysis
was complete (∼12 h). The phosphine oxide was precipitated
from solution by irradiation at >400 nm in the presence of
erythrosin B, which was subsequently removed by the
addition of MP-carbonate. All phosphines afforded product
in good yields and purities; the only difference was in the
Table 3. Synthesis of Imines from Azides
Table 2. Reduction of Azides to Amines
a Yields are for the isolated products. Purities were determined to be
1
>95% in all cases by H NMR and GC-MS.
sensitizer was removed by filtration through a plug of SiO2.
Reduction of secondary ozonides is often accomplished
with triphenylphosphine. The workup of a reaction that
employs triphenylphosphine often requires column chroma-
tography to separate the product from excess phosphine and
phosphine oxide. Use of Precipiton phosphines affords
(13) Hammond, G. S.; Saltiel, J.; Lamola, A. A.; Turro, N. J.; Bradshaw,
J. S.; Cowan, D. O.; Counsell, R. C.; Vogt, V.; Dalton, C. J. Am. Chem.
Soc. 1964, 86, 3197.
(14) Argonaut Technologies (Foster City, CA).
(15) ) Bellucci, G.; Chiappe, C.; Lo Moro, G. Tetrahedron Lett. 1996,
37, 4225.
1
a Yields refer to the isolated products. Purities were determined by H
NMR and GC-MS.
(16) (a) Pandey, G. Synlett 1992, 546.
Org. Lett., Vol. 6, No. 14, 2004
2323

secondary ozonide was reduced with Precipiton phosphine
(0.55 equiv of 8 or 9). Photoisomerization with visible light
in the presence of erythrosin B followed by filtration through
a plug of SiO2 with ether afforded the aldehydes in excellent
yields and purities (Table 4). The tert-butyldimethylsilyl
protecting group did not tolerate ozonolysis as well as the
tert-butyldiphenylsilyl protecting group (Table 1, entries 2
and 3).
Table 4. Reduction of Secondary Ozonides
We conclude from these experiments that reductions with
Precipiton phosphines can afford amines and aldehydes in
good to excellent yields, free of phosphine oxide, without
resorting to extractions or chromatography. A triplet sensi-
tizer, erythrosin B, was shown to be an effective catalyst
for the photoisomerization and to eliminate [2 + 2] cycload-
dition byproducts that can form upon long irradiation at 350
nm. The sensitizer allows use of light of wavelengths >400
nm. The sensitizer was easily removed from solution by
addition of MP-carbonate or filtration through SiO2. Benzylic
amines are not compatible with the erythrosin B-catalyzed
photoisomerization conditions. However, conditions were
developed to take advantage of this side reaction and provide
a useful method for preparing symmetrical imines from the
corresponding azides.
1
a Purity determined by H NMR and GCMS.
Acknowledgment. This work was supported by a grant
phosphorus containing byproducts that, after isomerization,
can be easily removed by filtration. Ozonolysis products can
then be isolated without need for chromatography.
Each of several alkenes was treated in a solution of
dichloromethane with a stream of ozone at -78 °C until a
blue color persisted. Excess ozone was removed by passing
a stream of nitrogen through the solution, and the resulting
from the National Institute of General Medical Sciences.
Supporting Information Available: Experimental de-
1
tails, copies of H and 13C NMR spectra, and complete
characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049369+
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Org. Lett., Vol. 6, No. 14, 2004