Selenium-linking strategy for traceless solid-phase synthesis: Direct loading, aliphatic C-H bond formation upon cleavage and reaction monitoring by gradient MAS NMR spectroscopy

Article abstract of DOI:10.1021/jo9806310

The development of a novel traceless linking strategy for the solid- phase synthesis of small non- peptide compounds by the use of resin-bound selenium is described. Compounds were attached by direct loading without the requirement of an auxiliary spacer.

Full text of DOI:10.1021/jo9806310

9204
J . Org. Chem. 1998, 63, 9204-9211
Selen iu m -Lin k in g Str a tegy for Tr a celess Solid -P h a se Syn th esis:
Dir ect Loa d in g, Alip h a tic C-H Bon d F or m a tion u p on Clea va ge
a n d Rea ction Mon itor in g by Gr a d ien t MAS NMR Sp ectr oscop y
Thomas Ruhland,* Kim Andersen, and Henrik Pedersen
Medicinal Chemistry Research, H. Lundbeck A/ S, Ottiliavej 9, DK-2500 Valby, Denmark
Received April 6, 1998
The development of a novel traceless linking strategy for the solid-phase synthesis of small non-
peptide compounds by the use of resin-bound selenium is described. Compounds were attached by
direct loading without the requirement of an auxiliary spacer. We demonstrate the synthesis of a
small [2 × 3]-sized library of single alkyl aryl ethers with two points of diversity by the Mitsunobu
reaction. The selenium-alkyl bond that attaches the alkyl aryl ethers to the resin was smoothly
cleaved under radical conditions by homolysis with tributylstannane and catalytic amount of AIBN
to generate an aliphatic C-H bond in the liberated ethers. The selenium atom remains immobilized
during the entire synthesis, and in the cleavage step, tributylstannyl phenyl selenide is scavenged
on the resin. Reaction monitoring was facilitated by the use of gradient high-resolution magic
angle spinning 2D-NMR. This new linking method can be applied to solid-phase synthesis of many
classes of organic compounds under a broad variation of reaction conditions.
In tr od u ction
have been developed. For aliphatic C-H bond formation,
poly(ethylene glycol)-based sulfur-linking9,10,11 strategies
have been reported. In the latter strategies, attachments
were indirectly achieved in a multistep procedure and
with the help of an auxiliary amide-containing spacer
(Figure 1), which is sensitive, for example, to reducing
reagents such as LiAlH4. Target compounds were liber-
ated upon C-S bond cleavage by hydrogenolysis with H2/
Raney-nickel10,11 or by homolysis either with tributyl-
stannane/AIBN at elevated temperature10 or under
irradiation.9 Hydrogenolysis with H2/Raney-nickel pro-
ceeds smoothly, but its application is neither very suit-
able for automated SPS nor compatible with functional
groups sensitive to reduction. Homolysis turned out
either to be very slow with tributylstannane/AIBN or
unselective under irradiation.
The current development of new methods for the solid-
phase synthesis (SPS) of non-peptide combinatorial
libraries can be considered as a renaissance period
following the pioneering work of Merrifield,1 Leznoff,2
Frechet,3 and Rapoport.4 Triggered by publications
of Ellman and DeWitt5 in the early 1990s, a large num-
ber of technologies for SPS have appeared in recent
years.6 Whenever a solid-phase strategy for a combina-
torial library is considered, the key question is the most
suitable choice of linker. The linker has to be stable to
all reaction conditions during the synthesis and, after
assembly is complete, must liberate the target molecules
selectively and without causing degradation or side
products.
Among the versatile linker strategies so far developed,
the traceless linkers are particularly attractive because
the final target compounds are cleaved without leaving
a specific functional group behind and bear therefore only
those functionalities which have been chosen, for ex-
ample, for biological activity.
Our interest was devoted to C-H bond-forming trace-
less linkers. For aromatic C-H bond formation, poly-
styrene-based silicon7,8- and germanium7-linking methods
Due to these limitations, there is a need for a more
generally applicable aliphatic C-H bond-forming, trace-
less linker. It is well documentated that homolysis with
tributylstannane/AIBN of aryl alkyl selenides proceeds
faster than for the corresponding sulfides,12 suggesting
alkanes to be more smoothly released from a resin-bound
selenide than from resin-bound sulfides previously de-
scribed. This prompted us to elaborate a C-H bond-
forming, traceless linker based on selenium. With the
lack of an auxiliary spacer, this strategy offers addition-
* Phone: +45 3630 1311. Fax: +45 3630 1385. E-mail tr@
lundbeck.com.
(7) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1997, 62, 2885-
2893.
(1) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149-2154.
(2) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327-333.
(3) Frechet, J . M. J . Am. Chem. Soc. 1971, 93, 492-496.
(4) Crowley, J . I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-144.
(5) (a) DeWitt, S. H.; Kiely, J . S.; Stankovic, C. J .; Schroeder, M.
C.; Cody, D. M. R., Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A. 1993,
90, 6909-6913. (b) Bunin, B. A.; Ellman, J . A. J . Am. Chem. Soc. 1992,
114, 10997-10998.
(6) (a) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555-
600. (b) Fru¨chtel, J . S.; J ung, G. Angew. Chem. 1996, 108, 19-46. (c)
Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron 1996,
52, 4527-4554. (d) Balkenhohl, F.; von dem Bussche-Hu¨nnefeld, C.;
Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-
2337. (e) Nefzi, A.; Ostresh, J . M.; Houghten, R. A. Chem. Rev. 1997,
97, 449-472. (f) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. C.
Tetrahedron 1997, 53, 5643-5678.
(8) (a) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006-
6007. (b) Chenera, B.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem.
Soc. 1995, 117, 11999-12000. (c) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703-2706. (d) Boehm, T. L.; Showalter,
H. D. H. J . Org. Chem. 1996, 61, 6498-6499. (e) Woolard, F. X.;
Paetsch, J .; Ellman, J . A. J . Org. Chem. 1997, 62, 6102-6103.
(9) Sucholeiki, I. Tetrahedron Lett. 1994, 35, 7307-7310.
(10) J ung, K. W.; Zhao, X.-Y.; J anda, K. D. Tetrahedron Lett. 1996,
37, 6491-6494.
(11) J ung, K. W.; Zhao, X.-Y.; J anda, K. D. Tetrahedron 1997, 53,
6645-6652.
(12) (a) Scaiano, J . C.; Schmid, P.; Ingold, K. U. J . Organomet. Chem.
1976, 121, C4-C6. (b) Liotta, D. Organoselenium Chemistry; J ohn
Wiley & Sons: New York, 1987. (c) Davies, A. G. Organotin Chemistry;
VCH Verlagsgesellschaft: Weinheim, 1997.
10.1021/jo9806310 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/17/1998

Selenium-Linked Traceless Solid-Phase Synthesis
J . Org. Chem., Vol. 63, No. 25, 1998 9205
was achieved by modifing the procedure elaborated by
Farrall and Fre´chet17 for the preparation of polystyrene-
bound sulfur from bromopolystyrene 1. Bromopolysty-
rene 1 was obtained through thallium acetate-catalyzed
bromination of commercially available polystyrene (cross-
linked with 1% divinylbenzene).17 The loading of the
resulting resin was determined by elemental analysis for
bromine to be 3.7 mmol/g. After lithium-bromine ex-
change on resin 1 with excess butyllithium (BuLi) in
hexane/toluene (1:1) and subsequent removal of the
solvents by decantation, the lithiated polystyrene 2 was
suspended in THF and treated with selenium powder.
To liberate the resin from excess selenium, the mixture
was treated several times with NaBH4 in MeOH. After
drying in vacuo, an orange resin was obtained which
displayed no visible swelling properties in any solvent.
It is very likely that Se-Se bonds were formed by
oxidation under air exposure during the workup proce-
dure.17 The Se-Se bond formation has probably caused
a high degree of cross-linking, which explains the poor
swelling property.18 In EtOH, however, within 1-2 h
after addition of NaBH4, the resin became distinctly
swollen and almost colorless. Simultaneously, an inten-
sive gas generation occurred.
Recently, Miyashita et al.19 proved that the reaction
between diphenyl diselenide and NaBH4 in EtOH results
in the formation of hydrogen and the sodium phenylse-
leno(triethyl)borate complex, Na[PhSeB(OEt3)], but not
of sodium phenyl selenide as previously proposed. Con-
sequently, we suggest the analogous structure 3 for the
polystyrene-bound selenide anion after reduction with
NaBH4 in EtOH. This also explains our observation of
strong and delayed hydrogen generation during reduction
and the striking swelling property of the resin in EtOH.
F igu r e 1.
ally the advantage of attachments in a single step by
direct loading.
Twenty-two years ago, derivatives of polystyrene-
bound selenium were described by Heitz et al.13,14,15 for
use as resin-bound oxidation reagents. Additionally, the
authors demonstrated the coupling of polystyrene-bound
selenium to the R-position of a carbonyl compound.
Cleavage of the corresponding R,â-unsaturated carbonyl
compound was achieved by oxidation of the resin-bound
selenide to selenoxide and subsequent spontaneous â-e-
limination.15 They thus demonstrated the utility of
polystyrene-bound selenium as a suitable linker for the
attachment and cleavage of compounds. Retrospectively,
their work has therefore been a forerunner of modern
combinatorial SPS.
In the present paper, we describe a new protocol for
the preparation of polystyrene-bound selenium and dem-
onstrate its first application in SPS by the synthesis of a
library of single aryl alkyl ethers using the Mitsunobu
reaction. Each reaction step was monitored by high-
resolution magic angle spinning (HR-MAS) 1H NMR
spectroscopy, which has been established in recent years
for the nondestructive analysis of intermediate resins.16
In addition, we describe the analysis of intermediate
resins by gradient HR-MAS 2D-NMR experiments with
the help of an HR-MAS double resonance probehead
equipped with a one-axis pulsed field gradient coil.
Even though selenium is almost insoluble in THF, the
desired reaction with lithiated polystyrene 2 took place.
A plausible explanation might be that selenium was
solubilized by the formation of soluble lithium butyl
polyselenides. The source for lithium butyl polyselenides
is possibly the reaction of selenium and lithium butyl
selenide formed by reaction of excess BuLi with selenium.
The formation of soluble polyselenides after treatment
of selenium with, for example, alkali diselenides is well
documented and supports the explanation.20
Sch em e 1
To determine the loading of polystyrene-bound sele-
nium, resin 3 was converted into 4 through alkylation
with chloro-N,N-dimethylacetamide using the reaction
conditions decribed below (Scheme 2). Elemental analy-
sis for nitrogen revealed a loading of 1.8 mmol/g. No
bromine was found by elemental analysis, indicating that
the previously performed lithium-bromine exchange has
gone to completion. The difference between the initial
loading of bromopolystyrene 1 (3.7 mmol/g) and polysty-
rene-bound selenium (1.8 mmol/g) reveals either that the
Resu lts a n d Discu ssion
The preparation of polystyrene-bound selenium 3 used
as starting material for the library synthesis is outlined
in Scheme 1. The preparation of the resin-bound sele-
nium, following the procedure described by Heitz et al.,15
was not successful in our hands. Successful preparation
(17) Farrall, M. J .; Fre´chet, J . M. J . J . Org. Chem. 1976, 41, 3877-
3882.
(18) Hodge, P. Chem. Soc. Rev. 1997, 26, 417-424.
(19) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetra-
hedron 1997, 53, 12469-12486.
(20) (a) Weller, F.; Adel, J .; Dehnicke, K. Z. Anorg. Allg. Chem. 1987,
548, 125-132. (b) Sheldrick, W. S.; Braunbeck, H. G. Z. Naturforsch.
1989, 44b, 1397-1401. (c) Fenske, D.; Kra¨uter, G.; Dehnicke, K. Angew.
Chem., Int. Ed. Engl. 1990, 4, 390-391. (d) Mu¨ller, V.; Grebe, C.;
Mu¨ller, U.; Denicke, K. Z. Anorg. Allg. Chem. 1993, 619, 416-420. (e)
Mu¨ller, V.; Ahle, A.; Frenzen, G.; Neumu¨ller, B.; Dehnicke, K. Z. Anorg.
Allg. Chem. 1993, 619, 1247-1256.
(13) Kato, M. German Patent Application DE 2649163, 1976.
(14) Kato, M.; Michels, R.; Heitz, W. J . Polym. Sci., Polym. Lett. Ed.
1976, 14, 413-415.
(15) Michels, R.; Kato, M.; Heitz, W. Makromol. Chem. 1976, 177,
2311-2320.
(16) (a) Fitch, W. L.; Detre, G.; Holmes, C. P. J . Org. Chem. 1994,
59, 7955-7956. (b) Keifer, P. A.; Baltusis, L.; Rice, D. M.; Tymiak, A.
A.; Shoolery, J . N. J . Magn. Reson. 1996, 119, 65-75. (c) Garigipati,
R. S.; Adams, B.; Adams, J . L.; Sarkar, S. K. J . Org. Chem. 1996, 61,
2911-2914. (d) Wehler, T.; Westman, J . Tetrahedron Lett. 1996, 37,
4771-4774.

9206 J . Org. Chem., Vol. 63, No. 25, 1998
Ruhland et al.
Sch em e 2
Sch em e 3
F igu r e 2. Aryl alkyl ether derivatives released from the
resins 7 a -c and 8 a -c. The yields are reported for isolated
material after purification by solid-phase extraction and are
based on the initial loading of resin-bound selenium. The
purities measured by GC are given in brackets.
polymer-bound alkyl aryl ethers 7a -c and 8a -c. No
1
resin-bound alcohol was detected by HR-MAS H NMR,
indicating that the coupling went to completion (Figure
4a). Cleavage of the products was achieved with tribu-
tylstannane and a catalytic amount of AIBN in toluene
1
at 90 °C for 12 h. HR-MAS H NMR analyses of the resin
after cleavage showed only very pure resin-bound tribu-
tylstannyl selenide 11 (Figure 4b) and no traces of the
intermediate resin-bound aryl alkyl ethers, revealing that
the cleavage was quantitative (see below).
Due to the high selectivity for the cleavage of the bond
between selenium and an aliphatic carbon compared with
that between selenium and an aromatic carbon,12 it is
expected that selenium remains immobilized on the resin
after the cleavage reaction. Accordingly, no contamina-
tion with organoselenium impurities was observed in the
NMR spectra of the isolated products.
The purification of products from the reduction of alkyl
phenyl selenides with tributylstannane in solution is
described to be hampered by the presence of the gener-
ated tributylstannyl phenyl selenide22 but not by the
presence of excess tributylstannane.23 Whereas tribu-
tylstannane is easily removable, tributylstannyl phenyl
selenide causes a problem due to its tendency to hydro-
lyze on silica gel. In the present cleavage reaction, this
interfering byproduct is immobilized on the resin as
resin-bound tributylstannyl selenide 11, and excess of
tributylstannane is removed by solid-phase extraction.
reaction between lithiated polystyrene and selenium was
incomplete or that the selenium linker is only partially
available for reactions.
The solid-phase synthesis of a [2 × 3]-sized alkyl aryl
ether library is outlined in Scheme 3. The first point of
diversity was introduced by alkylation of polystyrene-
bound selenium with 2-[2-(2-chloroethoxy)ethoxy]ethanol
and 6-bromohexanol, respectively, yielding resin-bound
alcohols 5 and 6. Prior to alkylation, the resin was
treated with NaBH4 in EtOH to ensure that cross-linking
diselenides were reduced. The second point of diversity
was introduced by ether formation with phenols by
means of the Mitsunobu reaction. The reaction was
carried out with triphenylphosphine and diisopropylaza-
dicarboxylate (DIPAD) as reagents in N-methyl-morpho-
line (NMM) as solvent as previously reported.21 Coupling
of each of the resin-bound alcohols 5 and 6 with 4-phen-
yl-, 2-fluoro-, and 3-methoxy-phenol furnished the six
1
The generation of 11 is documented by HR-MAS H NMR
of the resin after cleavage (see below).
The alkyl aryl ethers (9a -c and 10a -c) were obtained
as single, discrete compounds in 57-83% yield and 78-
88% purity (GC) after purification by solid-phase extrac-
tion (Figure 2). The automation of solid-phase extraction
makes it possible to purify even large libraries prepared
by this method. As documented by GC, tributylstannane
is undetectable in the isolated products. According to GC
and 1H NMR, other residual Sn impurities are either
undetectable or at most very low. The linking strategy
(22) (a) Pfenninger, J .; Heuberger, C.; Graf, W. Helv. Chim. Acta
1980, 63, 2328-2337. (b) Schlatter, H.-R.; Lu¨thy, C.; Graf, W. Helv.
Chim. Acta 1974, 63, 1044-1052.
(21) Richter, L. S.; Gadek, T. R. Tetrahedron Lett. 1994, 35, 4705-
4706.
(23) Crich, D.; Sun, S. J . Org. Chem. 1996, 61, 7200-7201.

Selenium-Linked Traceless Solid-Phase Synthesis
J . Org. Chem., Vol. 63, No. 25, 1998 9207
described is consequently useful for the synthesis of
combinatorial libraries with potential use within a
number of research areas including material sciences and
biological sciences.
Even small traces of organostannyl compounds in the
isolated products might cause problems for biological
evaluation in screening assays using living cells due to
the potent toxicity properties of these substances. In
contrast to receptor binding and enzyme assays, this type
of assay is, however, seldom used for evaluation of
combinatorial libraries. Because the use of proper solid-
phase extraction procedures eliminates this problem, the
linking strategy has potentially a broad application in
the solid-phase synthesis of combinatorial libraries.
Alternatively, the removal of the tin reagent could
possibly be simplified by, for example, the use of catalytic
strategies or by the use of stannanes substituted with
fluorinated alkyl groups. These and their byproducts are
subsequently removed by extraction into a fluorinated
solvent.24
1
The HR-MAS H NMR spectra of resins 7a and 11 are
shown in Figures 4-7, and the letter coding used in the
interpretation of the spectra is shown in Figure 3. HR-
1
MAS H NMR spectroscopy was carried out at a spinning
rate of 4 kHz with 4-5 mg of swollen resin in CD2Cl2.
Interfering backbone signals were sufficiently suppressed
by the Carr-Percell-Meibom-Gill spin-echo sequence;
however, due to decreases of T2 relaxation times, the
signal intensity of protons very close to the backbone
were also reduced. Because J couplings remained un-
1
F igu r e 4. MAS H NMR spectra of 7a (a) and 11 (b). In each
case, 16 scans were acquired. In the case of 7, a Carr-Percell-
Meibom-Gill sequence with 50 cycles and a refocusing delay
of 0.0015 s was applied for backbone suppression. The assign-
ment letters refer to Figure 3.
1
resolved, full interpretation of the obtained HR-MAS H
NMR spectra is difficult (Figure 4).
superior for routine analysis of samples with poorly
resolved 1D-1H NMR spectra.
From the COSY45 spectrum in Figure 5a, it is possible
to identify and assign all protons of polymer-bound aryl
alkyl ether 7a as indicated in Figure 4a. Figure 8 shows
the solution-phase 1D-1H NMR of the corresponding
liberated aryl alkyl ether 9a , which correlates well with
1
the 1D-HR-MAS H NMR for the resin-bound aryl alkyl
ether 7a . As demonstrated in Figure 5a, it would have
been very difficult to identify the signal of the methylene
group adjacent to selenium without the COSY45 experi-
ment. It appears as a small and broad signal at 3.1 ppm.
The assignment of this signal was confirmed by its strong
correlation to a superimposed signal at 3.8 ppm and
additionally by its weak intensity and broad line shape
that correlates to the proximity of this methylene group
to the resin backbone.
13C chemical shifts of resin-bound intermediates were
not available by HR-MAS 13C NMR spectra due to low
signal-to-noise ratios. However, as shown in Figures 6
and 7, valuable information about 13C chemical shifts
were obtained indirectly by 2D-HSQC and 2D-HMBC
NMR experiments for proton-bearing carbons and qua-
ternary carbon atoms, respectively.
F igu r e 3.
Information about coupling constants in poorly re-
solved spectra may be obtained from f2 projections of 2D-
J RES spectra25 or from a 2D-E.COSY variant.26 How-
ever, by use of an HR-MAS probehead equipped with a
magic angle pulsed field gradient coil, it was found that
for these relatively high loaded resin samples sufficient
structural information was achieved with fast 2D-
COSY45 and optionally 2D-HSQC and 2D-HMBC experi-
ments using gradient coherence selection. The total
acquisition time for each of the presented 2D spectra in
Figures 5-7 was less than 6 min by use of standard one-
axis solution gradient pulse programs. The high quality
and short acquisition times obtained make these methods
In all spectra, we found a weak signal pattern of a
1
common impurity. On the basis of the HR-MAS H NMR
spectra of 7a , the structure of this byproduct was
determined to be polymer-bound butyl phenyl selenide,
with a broad signal at 2.9 ppm for the selenium-bound
methylene group (Figure 4a).27 This byproduct may have
(24) Curran, D. P.; Hadida, S. J . Am. Chem. Soc. 1996, 118, 2531-
2532.
(25) Shapiro, M. J .; Chin, J .; Marti, R. E.; J arosinski, M. A.
Tetrahedron Lett. 1997, 38, 1333-1336.
(26) Meissner, A.; Bloch, P.; Humpfer, E.; Spraul, M.; Sørensen, O.
W. J . Am. Chem. Soc. 1997, 119, 1787-1788.
(27) The chemical shifts for the aliphatic protons of an authentic
sample of butyl phenyl selenide measured by solution-phase 1H NMR
(CD2Cl2) are in the range of 0.1 ppm, the same as that for the observed
resin-bound impurity.

9208 J . Org. Chem., Vol. 63, No. 25, 1998
Ruhland et al.
F igu r e 5. Magnitude gradient COSY45 spectra of 7a (a) and 11 (b). The relaxation delay was 1.5 s. 2048 × 128 point matrixes
with one scan per increment were aquired. The total acquisition times were 4 min. In F1, linear prediction to 256 points was
performed followed by zero filling to 512 points. A sine bell window function was applied in both dimensions. For 11, only the
high-field aliphatic area is shown.
F igu r e 6. Phase-sensitive gradient HSQC spectra of 7a (a) and 11 (b) with echo-antiecho coherence selection. The relaxation
delay was 1.1 s, and the evolution delay for J CH couplings was 0.00185 s. 2048 × 128 point matrixes with two scans per increment
were acquired. The total acquisition times were 5 min 35 s. In F1, linear prediction to 256 points was performed followed by zero
filling to 512 points. A squared cosine window function was applied in both dimensions. Only positive levels are plotted.
been formed in the synthesis of resin-bound selenium by
alkylation of polystyrene-bound lithiumselenide with
butylbromide, the latter generated by lithium-bromine
exchange between butyllithium and bromopolystyrene.

Selenium-Linked Traceless Solid-Phase Synthesis
J . Org. Chem., Vol. 63, No. 25, 1998 9209
Con clu sion
In the present investigation, we demonstrate the use
of polystyrene-bound selenium as a novel C-H bond-
forming traceless linker in the SPS of an aryl alkyl ether
library. Without the requirement of an auxiliary spacer,
the first building block was attached in a single step to
the polymer, and the final compounds were cleaved
selectively under mild conditions. Even though toxic
substances are used in the presented linking strategy,
the contamination of the isolated products is reduced to
a minimum by solid-phase extraction facilitated by the
immobilization of selenium and interfering organostannyl
compounds onto the resin. Fast purification of the
cleaved products can be achieved by automated solid-
phase extraction. The broad stability of alkyl phenyl
selenides toward various reaction conditions and the high
loading of 1.8 mmol/g make this resin very suitable in
SPS of non-peptide compounds. Extensions of our basic
strategy to the preparation of the homologous polystyrene-
bound tellurium, oxidative cleavage strategies, and the
SPS of heterocycles are under active investigation in our
laboratory. Additionally, we have shown that very short
acquisition times for gradient HR-MAS 2D-NMR experi-
ments on resin-bound intermediate resin can be achieved,
thus demonstrating the full benefit of gradient coherence
selection.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under
positive pressure of nitrogen. Unless otherwise noted, starting
materials were obtained from commercial suppliers and used
without further purification. Tetrahydrofuran (THF) was
distilled under N2 from sodium/benzophenone immediately
prior to use. Flash column chromatography was carried out
according to the procedure described by Still.28 For flash
column chromatography and for solid-phase extraction, Schar-
lau 60 230-400 mesh silica gel (sorbil) was used. Thin-layer
chromatography (TLC) was performed on Merck 60 F254 0.25
µm silica gel plates. Unless otherwise stated, TLC Rf values
given were determined with the solvent used for column
F igu r e 7. Magnitude gradient HMBC spectrum of 7a . The
relaxation delay was 1.0 s, and the evolution delay for long-
range J CH couplings was 0.05 s. 2048 × 128 point matrixes
with two scans per increment were acquired. The total
acquisition times were 5 min 54 s. In F1, linear prediction to
256 points was performed followed by zero filling to 1024
points. A squared cosine window function was applied in both
dimensions. Only the aromatic area is shown.
Assignment of the proton chemical shift for resin-bound
tributylstannyl selenide 11, obtained after cleavage of the
ethers 9, could be done unambiguously by either analyz-
ing the COSY45 spectrum (Figure 5b) or the line width
in the 1D-1H NMR spectrum (Figure 4b) taking advan-
tage of the decreasing T2 relaxation time with the
1
chromatography. 1H NMR and H-decoupled 13C NMR spectra
were recorded at 500.13 and 125.67 MHz, respectively, on a
Bruker Avance DRX 500 instrument. NMR spectra of polymer-
bound substances were recorded with a 4 mm 1H/13C double
resonance high-resolution MAS probehead optimized for proton
resonance and equipped with a one-axis pulsed field gradient
coil. Unless otherwise noted, compounds were measured in
deuterated chloroform (99.8%). Chemical shifts for 1H NMR
are reported in ppm with TMS as internal reference. Chemical
shifts for 13C NMR and high-resolution MAS NMR are reported
in ppm relative to chemical shifts of deuterated solvents.
Coupling constants (J values) are in hertz. For GC, samples
were dissolved in methylene chloride (c ) approximately 1 mg/
mL). GC was performed on a Varian Star 3400 CX instrument
using an injector temperature of 200 °C, detector temperature
of 325 °C, gas flow of 4.9 mL/min at 65 °C, a split flow of 150
mL/min, and a Restek Rtx-5 column with a length of 15 m,
inner diameter of 0.32 mm, and a cross-bonded phase of 0.50
mm. A temperature gradient of 15 deg/min from 65 °C to 275
°C was used. Retention times (Rt values) are in minutes.
High-resolution mass spectra (HRMS) were performed at the
University of Odense, Department of Chemistry (Odense,
Denmark) with the peak-matching method using a Varian
MAT 311A mass spectrometer. Elemental analyses were
performed at the University of Vienna, Department of Physical
Chemistry (Vienna, Austria) with a Perkin-Elmer 2.400 CHN
elemental analyzer. Polystyrene for the preparation of bro-
1
distance to the backbone. The aliphatic part of the H
spectrum of 11 is similar to that of the published solution-
phase spectrum of tributylstannyl phenyl selenide.22
F igu r e 8. Solution 1H NMR spectrum in CDCl3 of 9a after
cleavage from the resin and purification by solid-phase extrac-
tion. The assigment letters refer to Figure 3 for compound 7a .
(28) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

9210 J . Org. Chem., Vol. 63, No. 25, 1998
Ruhland et al.
mopolystyrene according to the procedure described by Ferrall
and Fre´chet17 was purchased from Rapp Polymere GmbH
(Tu¨bingen, Germany) (H 1000, 100-200 mesh, cross-linked
with 1% divinylbenzene).
H, 6.46; N, 2.22; Br, < 0.1. According to the elemental analysis
for N, a loading of 1.59 mmol/g was calculated for resin 4,
which corresponds to a loading of 1.84 mmol/g for the initial
loading of polystyrene-bound selenium, assuming that the
alkylation went to completion.
P r ep a r a tion of Resin -Bou n d Selen iu m . Bromopolysty-
rene17 (24.0 g, 2.94 mmol/g)29 was preswollen in dry toluene
(200 mL) for 15 min, and BuLi (100 mL, 160 mmol, 1.6 M in
hexane) was added. The mixture was stirred for 2 h at room
temperature, and the resin was allowed to settle. After the
solvents were carefully removed by decantation, BuLi (200 mL,
320 mmol, 1.6 M in hexane) and dry toluene (200 mL) were
added. The suspension was heated at 60 °C for 3 h. After
the mixture cooled to room temperature, the solvent was
removed by decantation without further washing. After the
temperature was reduced to 0 °C, dry THF (250 mL) was
added. Immediately afterwards, selenium powder (25.1 g, 318
mmol, 100 mesh) was carefully added in small portions (1-2
g) under intensive stirring (CAUTION: generation of heat).
The addition of selenium was complete within approximately
5 min. After the black suspension was heated at 50 °C for 12
h, the mixture was cooled to room temperature and filtered.
The black residue was washed with THF (1 × 250 mL),
methanol (1 × 250 mL), 2 N aqueous HCl/THF (1:2, 1 × 250
mL), and water (3 × 250 mL). For safety reasons, the excess
selenium was removed from the residue bit by bit. Small
portions of the residue (2-3 g) were suspended in methanol
(250 mL) in a 3-L Erlenmeyer flask and treated carefully in
small portions with excess of fine granulated sodium borohy-
dride (5 g, 132 mmol) (CAUTION: generation of heat, hydro-
gen, and toxic sodium selenides). Immediately after the gas
evolution ended, the resin was filtered and washed with
methanol (1 × 250 mL). The procedure was repeated for each
resin fraction until the excess selenium was removed. The
combined fractions were suspended in methanol (500 mL) and
treated with sodium borohydride (5 g, 132 mmol) as described
above for each single portion. The procedure was repeated
about 20 times until the filtrate did not contain any more
selenium. After every fourth treatment with sodium borohy-
dride, the resin was additionally washed with 2 N aqueous
NaOH/THF (1:2, 1 × 250 mL), water (1 × 250 mL), 2 N
aqueous HCl/THF (1:2, 1 × 250 mL), water (1 × 250 mL), THF
(1 × 250 mL), and methanol (1 × 250 mL) (washing with
methylene chloride should be omitted because the solvent
could couple to the resin). Finally, the pale yellow resin and
sodium borohydride (5 g, 132 mmol) were refluxed in ethanol/
methanol (20:1, 500 mL) for 2 h. The resin was filtered and
washed as described above with the exception that THF (2 ×
250 mL) was used in the last washing step. After drying in
vacuo at room temperature, an orange resin (24.3 g) was
obtained.
The resins 5 and 6 were prepared according to the procedure
described above by alkylation with 2-[2-(2-chloroethoxy)ethoxy]-
ethanol and 6-bromohexanol, respectively.
Alk yl Ar yl Eth er Syn th esis by th e Mitsu n obu Rea c-
t ion . 2-[2-[2-(3-Met h oxy-p h en oxy)et h oxy]et h oxy]et h -
ylsela n yl P olystyr en e (7c). The procedure for a typical
experiment follows. Resin-bound alkyl alcohol 5 (500 mg, 0.74
mmol) was preswollen in 4-methylmorpholin (5 mL) for 5 min.
Neat 3-methoxyphenol (571 mg, 4.60 mmol) and triphenylphos-
phine (1.21 g, 4.61 mmol) were added at room temperature.
After complete dissolution, neat diisopropyl azodicarboxylate
(930 mg, 4.60 mmol) was added in small portions over a period
of 15 min at room temperature. After the suspension was
stirred for 12 h at room temperature, the resin was filtered
and subsequently washed with THF (3 × 10 mL), DMSO (2 ×
10 mL), THF (2 × 10 mL), water (2 × 10 mL), methanol (2 ×
10 mL), and methylene chloride (3 × 10 mL) and dried in vacuo
at room temperature for 12 h. Resin 7c was calculated to have
a loading of 1.28 mmol/g, assuming the Mitsunobu reaction
went to completion.
The resins 7a , 7b, 8a , 8b, and 8c were prepared according
to the procedure described above.
Cleavage by Hom olysis. 1-[2-(2-Eth oxyeth oxy)eth oxy]-
3-m eth oxyben zen e (9c). The procedure for a typical experi-
ment follows. Resin 7c (1.00 g, 1.28 mmol) was preswollen in
toluene (10 mL) for 5 min. Neat tributylstannane (1.62 g, 5.6
mmol) and AIBN (20 mg, 0.12 mmol) were added, and the
mixture was heated in a sealed tube to 90 °C for 12 h. After
cooling to room temperature, the resin was filtered and washed
with THF (2 × 2 mL), acetone (1 × 2 mL), and methylene
chloride (2 × 2 mL). The filtrates were combined, and the
solvents were evaporated in vacuo. The residue was purified
by solid-phase extraction using silica gel (approximately 50
g). Nonpolar tin impurities were removed by washing the
column with pure heptane. Subsequently, elution with hep-
tane/ethyl acetate (15:1) gave 213 mg (70%) of the desired
product 9c as a clear oil (78% purity by GC, Rt ) 9.3). An
analytical sample was obtained by flash chromatography
(heptane/ethyl acetate, 5:1) and subsequent microdistillation
(0.1 mmHg, 90-95 °C): TLC (heptane/ethyl acetate, 2:1) Rf
1
) 0.41; H NMR δ 1.21 (t, 3H, J ) 7.0), 3.52 (q, 2H, J ) 7.0),
3.60 (t, 2H, J ) 4.8), 3.70 (t, 2H, J ) 4.8), 3.76 (s, 3H), 3.84 (t,
2H, J ) 4.9), 4.12 (t, 2H, J ) 4.9), 6.50 (m, 3H), 7.15 (t, 1H, J
) 8.1); 13C NMR δ 15.5, 55.6, 67.0, 67.8, 70.1, 70.2, 71.3, 101.6,
106.9, 107.1, 130.2, 160.5, 161.2; HRMS calcd for C13H20O4,
240.1362; found, 240.135. Anal. Calcd for C13H20O4: C, 64.98;
H, 8.39. Found: C, 64.90; H, 8.65.
The loading of the resin was calculated to be 1.84 mmol/g
determined by elemental analysis for nitrogen after alkylation
with chloro-N,N-dimethylacetamide as described below.
The aryl alkyl ethers 9a , 9b, 10a , 10b and 10c were
prepared according to the procedure described above.
1-Hexyloxy-3-m eth oxyben zen e (10c). This compound
was cleaved from resin 8c (924 mg, 1.23 mmol). Solid-phase
extraction (heptane and then heptane/ethyl acetate, 15:1) gave
146 mg (57%) of the desired product as a clear oil (87% purity
by GC, Rt ) 8.0). An analytical sample was obtained by flash
chromatography (heptane/ethyl acetate 30:1) and subsequent
Alk yla tion of Resin -Bou n d Selen iu m . N,N-Dim eth yl-
for m ylm eth ylsela n yl P olystyr en e (4). The procedure for
a typical experiment follows. Polymer-bound selenium (50 mg)
was suspended in ethanol/methanol (40:1, 0.5 mL) and treated
with sodium borohydride (40 mg, 1 mmol) at room tempera-
ture. After approximately 1 h, gas and heat generation
occurred and the resin became swollen and almost colorless.
The mixture was stirred for approximately 3 h until the gas
evolution stopped. The resin was allowed to settle, and the
above solution was removed by a pipette. After being washed
with ethanol under an N2 atmosphere (1 × 20 mL), the resin
was treated with chloro-N,N-dimethylacetamide (207 mg, 1.7
mmol) in ethanol (0.5 mL), and the mixture was stirred for 12
h at room temperature. The almost colorless resin was
filtered, washed with ethanol (2 × 25 mL), water (2 × 25 mL),
THF (1 × 25 mL), ethanol (1 × 25 mL), water (1 × 25 mL),
acetone (1 × 25 mL), and methylene chloride (3 × 25 mL) and
dried in vacuo at room temperature. Anal. Found: C, 67.97;
1
microdistillation (0.1 mmHg, 50-55 °C): TLC Rf ) 0.32; H
NMR δ 0.90 (t, 3H, J ) 6.6), 1.33 (m, 4H), 1.44 (m, 2H), 1.76
(p, 2H, J ) 7.1), 3.76 (s, 3H), 3.91 (t, 2H, J ) 6.6), 6.46 (m,
1H), 6.48 (m, 2H), 7.15 (t, 1H, J ) 8.1); 13C NMR δ 14.5, 23.1,
26.2, 29.7, 32.0, 55.6, 68.4, 101.4, 106.5, 107.1, 130.2, 160.9,
161.3; HRMS calcd for C13H20O2, 208.1463; found, 208.145.
Anal. Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C, 74.69;
H, 9.93.
2-[2-(2-E t h oxyet h oxy)et h oxy]-1-flu or ob en zen e (9b ).
This compound was cleaved from resin 7b (950 mg, 1.24 mmol).
Solid-phase extraction (heptane and then heptane/ethyl ac-
etate, 5:1) gave 200 mg (72%) of the desired product as a clear
oil (88% purity by GC, Rt ) 7.4). An analytical sample was
obtained by flash chromatography (heptane/ethyl acetate, 4:1)
and subsequent microdistillation (0.1 mmHg, 70-75 °C): TLC
(29) The loading of bromopolystyrene was determined by elemental
analysis for bromine: Anal. found: C, 63.72; H, 5.03; Br, 29.32.

Selenium-Linked Traceless Solid-Phase Synthesis
J . Org. Chem., Vol. 63, No. 25, 1998 9211
1
Rf ) 0.15; H NMR δ 1.20 (t, 3H, J ) 7.0), 3.52 (q, 2H, J )
262 mg (80%) of the desired product as a solid (87% purity by
GC, Rt ) 11.7). An analytical sample was obtained by flash
chromatography (heptane/ethyl acetate, 30:1). Recrystalliza-
tion from heptane gave white crystalls: mp 61-62 °C (lit.30
63.0-63.5 °C); TLC Rf ) 0.42; 1H NMR δ 0.91 (t, 3H, J ) 6.2),
1.34 (m, 4H), 1.46 (m, 2H), 1.78 (p, 2H, J ) 7.1), 3.97 (t, 2H,
J ) 6.6), 6.94 (d, 2H, J ) 8.5), 7.27 (t, 1H, J ) 7.4), 7.38 (t,
2H, J ) 7.6), 7.49 (d, 2H, J ) 8.5), 7.53 (d, 2H, J ) 7.8); 13C
NMR δ 14.5, 23.1, 26.2, 29.7, 32.1, 68.5, 115.3, 127.0, 127.1,
128.5, 129.1, 134.0, 141.4, 159.2; HRMS calcd for C18H22O,
254.1670; found, 254.166. Anal. Calcd for C18H22O: C, 84.99;
H, 8.72. Found: C, 84.73; H, 8.97.
7.0), 3.60 (t, 2H, J ) 4.8), 3.72 (t, 2H, J ) 4.8), 3.87 (t, 2H, J
) 5.0), 4.19 (t, 2H, J ) 5.0), 6.89 (m, 1H), 7.02 (m, 3H); 13C
NMR δ 15.9, 67.4, 69.9, 70.5, 70.7, 71.8, 116.4, 117.0 (d, J C,F
) 18.3), 122.2 (d, J C,F ) 6.8), 125.0 (d, J C,F ) 3.5), 147.8 (d,
J C,F ) 10.6), 153.7 (d, J C,F ) 245.6); HRMS calcd for C12H17
FO3, 228.1162; found, 228.118. Anal. Calcd for C12H17FO3:
C, 63.14; H, 7.51. Found: C, 63.36; H, 7.35.
-
1-F lu or o-2-h exyloxyben zen e (10b). This compound was
cleaved from resin 8b (985 mg, 1.33 mmol). Solid-phase
extraction (heptane) gave 174 mg (67%) of the desired product
as a clear oil (80% purity by GC, Rt ) 5.9). An analytical
sample was obtained by flash chromatography (heptane) and
subsequent microdistillation (15 mmHg, 95-105 °C): TLC Rf
) 0.31; 1H NMR δ 0.90 (t, 3H, J ) 6.9), 1.34 (m, 4H), 1.47 (m,
2H), 1.81 (p, 2H, J ) 7.1), 4.02 (t, 2H, J ) 6.6), 6.86 (m, 1H),
6.95 (t, 1H, J ) 7.8), 7.05 (m, 2H); 13C NMR δ 14.6, 23.2, 26.3,
Note Ad d ed in P r oof. After the submission of the
present manuscript, an account of polymer-supported
selenium reagents and their use in organic synthesis has
been published by Nicolaou et. al. (Nicolaou, K. C.;
Pastor, J .; Barluenga, S.; Wissinger, N. Chem. Commun.
1998, 1947-1948).
29.9, 32.2, 70.1, 115.7, 116.8 (d, J C,F ) 18.4), 121.5 (d, J C,F
)
6.8), 124.8 (d, J C,F ) 3.4), 147.9 (d, J C,F ) 10.6), 153.6 (d, J C,F
) 245.4); HRMS calcd for C12H17FO, 196.1263; found, 196.126.
1-[2-(2-E t h oxyet h oxy)et h oxy]-4-p h en ylb en zen e (9a ).
This compound was cleaved from resin 7a (997 mg, 1.21 mmol).
Solid-phase extraction (heptane and then heptane/ethyl ac-
etate, 5:1) gave 285 mg (83%) of the desired product as a solid
(84% purity by GC, Rt ) 12.7). An analytical sample was
obtained by flash chromatography (heptane/ethyl acetate, 4:1).
Recrystallization from heptane gave white crystals: mp 62-
63 °C; TLC Rf ) 0.17; 1H NMR δ 1.22 (t, 3H, J ) 7.0), 3.54 (q,
2H, J ) 7.0), 3.62 (t, 2H, J ) 4.8), 3.73 (t, 2H, J ) 4.8), 3.88
(t, 2H, J ) 4.9), 4.17 (t, 2H, J ) 4.9), 6.98 (d, 2H, J ) 8.6),
7.28 (t, 1H, J ) 7.3), 7.40 (t, 2H, J ) 7.6), 7.51 (d, 2H, J )
8.6), 7.54 (d, 2H, J ) 7.6); 13C NMR δ 15.6, 67.1, 67.9, 70.2,
70.3, 71.4, 115.3, 127.1, 127.2, 128.5, 129.1, 134.3, 141.2, 158.8;
HRMS calcd for C18H22O3, 286.1569; found, 286.157. Anal.
Calcd for C18H22O3: C, 75.50; H, 7.74. Found: C, 75.27; H,
8.00.
Ack n ow led gm en t. The very skillful technical as-
sistance by Mr. J ens Schiøtt and Mr. J ohnny Angelsø
is gratefully acknowledged. The preparation of the
manuscript by Ms. V. Nielsen is highly appreciated.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
and GC chromatograms of isolated products and GC chro-
matogram of tributylstannane after heating to 90 °C according
to the cleavage procedure to document the efficient removal
of this substance by the workup procedure used (20 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9806310
1-Hexyloxy-4-p h en ylben zen e (10a ).30 This compound
was cleaved from resin 8a (1.02 g, 1.29 mmol). Solid-phase
extraction (heptane and then heptane/ethyl acetate, 15:1) gave
(30) (a) Suzumura, H. Bull. Chem. Soc. J pn. 1962, 35, 108-111.
(b) Coates, D., Gray, G. W. Mol. Cryst. Liq. Cryst. 1975, 31, 275-283.