A photoactivated precipiton for reagent sequestration in solution-phase synthesis

Article abstract of DOI:10.1021/ja017577g

Precipitons are molecular phase tags for chemical separations. They can be switched from a high-solubility to a low-solubility state to facilitate product, reagent, or catalyst isolation. This paper presents the first photoactivated precipiton and demonstrates that this precipiton is an efficient amine scavenging agent in solution-phase syntheses of amides, ureas, and imines. This approach to amine scavenging offers advantages over solid-phase scavenging methods. The amine is captured in a homogeneous medium, so the capture is much faster than seen with isocyanate resins, and only a small excess of the scavenger is required. Copyright

Full text of DOI:10.1021/ja017577g

Published on Web 03/27/2002
A Photoactivated Precipiton for Reagent Sequestration in Solution-Phase
Synthesis
Todd Bosanac and Craig S. Wilcox*
Department of Chemistry and The Combinatorial Chemistry Center, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
Received November 20, 2001
High-throughput testing methods have created a demand for rapid
chemical synthesis techniques. To meet this need, solid-phase
organic synthesis (SPOS) has emerged as a means to create
molecules in parallel or in a single flask.1 In SPOS, products can
be separated by filtration from excess reagent and from byproducts
if they are not covalently attached to the resin. Solid-solid
separations or bead sorting2,3 allow large numbers of test substances
to be generated in a small number of reaction vessels.
There has been concomitant growth in the use of parallel
solution-phase methods for the synthesis of pure molecule libraries.
Figure 1. Benzylamine is removed from 4-allylanisole by reaction of the
In solution-phase syntheses, reactions are carried out in homoge-
neous solutions from which products may be isolated by selective
capture. Techniques for selective product capture use phase tags4
and include fluorocarbon-mediated phase transfers and fluorous
chromatography,5 precipitation or size-based sorting of soluble
polymer-supported or dendrimer-tagged products,6,7 Brønsted or
Lewis acid/base enabled isolations,8,9 and precipiton-based meth-
ods.10
amine with precipiton 4 and subsequent photoinduced precipitation.
Scheme 1. Synthesis of the Amine Scavenging Precipiton 4
Scavenging reagents for solution-phase syntheses contain a
functional group attached to a soluble or insoluble phase tag, and
the functional group is chosen to react with one or more of the
components of a reaction mixture.11 Kaldor et al. first demonstrated
this approach with a polystyrene isocyanate resin.12 These resin-
bound reagents are now commercially available and may also be
used to capture a desired product.13
Precipitons are low molecular weight nonpolymeric phase tags.10
The phase transfer event (precipitation) is caused by structural
isomerization of the phase tag. The first precipitons could not be
used for reagent scavenging because they were chemically activated
and the requisite precipiton-activating reagents remained in solution
after the precipitation of product was complete. Here we describe
the first photoactivated precipiton and demonstrate its use as a
selective and fast scavenger for primary and secondary amines.
The synthesis of amine-scavenging precipiton 4 employs a
palladium-catalyzed cross-coupling14 reaction between arylbromide
1 (prepared via a Wittig reaction) and p-hydroxymethylphenylbo-
ronic acid to afford alcohol 2 in 93% yield (Scheme 1). Alcohol 2
was treated with phthalimide under Mitsunobu conditions and
hydrazinolysis of the resulting imide afforded amine 3 in 91% yield.
Amine 3 with 20% phosgene in toluene afforded isocyanate 4 in
96% yield.15
1
formed. After 15 min, H NMR spectroscopy of the suspension
showed <2% of unisomerized cis urea 5Z and no trace of the
insoluble trans urea, 5E.
A model study to test amine scavenging was carried out (Figure
1). A THF solution containing 0.018 M benzylamine and 0.055 M
4-allyl anisole was prepared. We found that only 1.1 equiv of
isocyanate 4 was required to consume primary, secondary, and
aromatic amines within 10 min at room temperature. Irradiation at
350 nm (for 2, λmax ) 314 nm, ꢀ314 ) 1.0 × 105 M-1 cm-1, ꢀ350
)
4.4 × 104 M-1 cm-1) for 30 min and filtration provided solutions
of clean allyl anisole containing no amine or residual precipiton
scavenger. Benzylamine was equally well removed in the presence
of excess benzoic acid. We have used precipitons at up to 0.1 M
initial concentrations. During irradiation at these and higher
concentrations, the solid that forms causes a progressive decrease
in rate of isomerization. After removal of solid by filtration or
centrifugation, the initial isomerization rate is reestablished.
We synthesized ureas, thioureas, amides, and imines by carrying
out reactions between an excess of nonvolatile amine (1.1 to 1.2
equiv) and the corresponding isocyanate, isothiocyanate, acid
chloride, or aldehyde (Table 1). Removal of the excess amine was
accomplished by adding the precipiton isocyanate scavenger 4 (1.1
equiv relative to excess amine) to covalently trap the amine,
irradiating the mixture at 350 nm, and filtering the resulting
suspension. Products were isolated in excellent yields and purities
(>95% by 1H NMR spectroscopy). Process steps were mechanically
The Z isomer of this bis-biphenyl precipiton is soluble in THF,
Et2O:THF (5:1), CH2Cl2, CHCl3, and EtOAc while the E isomer
is very insoluble (<0.001 M) in most organic solvents. To evaluate
photoisomerization conditions, a 0.016 M solution of urea 5Z
(Figure 1) in THF-d8 containing isomenthol (an internal standard)
was prepared. As the solution was irradiated at 350 nm a precipitate
* Corresponding author. E-mail: daylite@pit.edu.
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10.1021/ja017577g CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Outcome of Precipiton-Based Solution-Phase
mixture prematurely and thereby diminish yields and (2) that the
precipiton-bound urea formed from the excess amine and isocyanate
4 would be so insoluble that the amount remaining after filtration
would be negligible. Typical times for going from starting amine
to isolated urea were less than 1 h: 5-10 min for the reaction to
take place between the amine and isocyanate/isothiocyanate, 5-10
min for the scavenger to react with the excess amine, and 30-40
min for the isomerization, filtration, and evaporation to give pure
urea.
Synthesesa
Amides and imines were synthesized by reactions of acid
chlorides and aldehydes, respectively, with excess amine (1.2 equiv)
in the presence of K2CO3 or MgSO4 in THF. The overall times
required for imine synthesis were about 4.5 h: 3.5 h for imine
formation, 10 min for reaction with the scavenging precipiton, and
1 h for the isomerization and filtration. These isomerization times
could be shortened by removing solid K2CO3 or MgSO4 from the
mixture before the irradiation.
We hope that this method will be useful to those engaged in
parallel solution-phase library synthesis. Because all trapping
reactions are performed in solution, experiment times are much
shorter compared to scavenging conducted with solid supported
scavengers and fewer equivalents of isocyanate are required.
Acknowledgment. This work was supported by funds provided
by the Faculty and College of Arts and Sciences, University of
Pittsburgh.
Supporting Information Available: Experimental details, copies
of 1H and 13C NMR spectra, and complete characterization data for all
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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