Resin-bound triaryl bismuthanes and bismuth diacetates: Novel multidirectional linkers and novel resin-bound arylation reagents

Article abstract of DOI:10.1021/jo049183o

A general synthesis of resin-bound triaryl bismuthanes and resin-bound triaryl bismuth diacetates starting from commercially available chloromethyl polystyrene is reported. For the first time resin-bound bismuth has been utilized as part of a multidirectional linker system for solid-phase organic synthesis and as a resin-bound arylation reagent.

Full text of DOI:10.1021/jo049183o

Resin -Bou n d Tr ia r yl Bism u th a n es a n d
Bism u th Dia ceta tes: Novel
Mu ltid ir ection a l Lin k er s a n d Novel
Resin -Bou n d Ar yla tion Rea gen ts
L. Kyhn Rasmussen,† Mikael Begtrup,† and
Thomas Ruhland*
Department of Medicinal Chemistry, H. Lundbeck A/ S,
F IGURE 1. The linker system.
9 Ottiliavej, DK-2500 Valby, Denmark
SCHEME 1. Su zu k i’s Syn th esis of Resin -Bou n d
Bism u th a n es
tr@lundbeck.com
Received May 14, 2004
Abstr a ct: A general synthesis of resin-bound triaryl bis-
muthanes and resin-bound triaryl bismuth diacetates start-
ing from commercially available chloromethyl polystyrene
is reported. For the first time resin-bound bismuth has been
utilized as part of a multidirectional linker system for solid-
phase organic synthesis and as a resin-bound arylation
reagent.
synthesis of similar compounds by, for example, pal-
ladium-catalyzed cross-coupling reactions often requires
tedious optimization of the catalytic systems for each
individual case. We recognized that the combination of
the versatile chemistry of triaryl bismuthanes coupled
with the advantages of solid-phase chemistry would
provide a powerful tool for solid-phase and solution-phase
synthesis. In this paper we demonstrate that resin-bound
bismuth represents a new and flexible alternative to the
existing multidirectional linker methodologies.
Resin-bound triaryl pnictogenes (group 15 elements)
were first reported by Braun in 1962 while studying the
polymerization process of pnictogene-substituted styrene
monomers.19 Almost 40 years later, Suzuki reported an
improved synthesis of the monomers and their homopo-
lymerization.20
Despite their early description and their obvious
synthetic possibilities, resin-bound bismuthanes have, to
the best of our knowledge, been used neither in SPOS
nor as solid-phase reagents. The most likely explanations
are the difficulties in making a diverse range of differ-
ently substituted resin-bound bismuthanes and the lack
of selectivity by the cleavage of aryl groups from the
bismuth.
In the following we describe a strategy that enables
resin-bound bismuth to be used as a multidirectional
linker in SPOS. Our method allows a simple attachment
of bismuthanes without polymerization starting from
commercially available chloromethyl polystyrene. An-
other key issue in our design strategy was to achieve
sufficient discrimination between the two rather similar
Bi-sp2C bonds A and B shown in Figure 1. It is essential
In recent years intensive research efforts have been
directed toward increasing the flexibility in solid-phase
organic synthesis (SPOS) by means of new linker con-
cepts such as traceless linkers and multidirectional linker
systems.1 Multidirectional linker strategies are particular
attractive as they allow the synthesis of different scaf-
folds by the introduction of a wide range of diverse
fragments in the final cleavage step.
The recent discovery of the chemical potential of
triorganyl bismuth reagents in organic synthesis has
significantly expanded the chemical toolbox, especially
in the areas of mild and selective arylation reactions.2-6
In particular, the pioneering work of Barton et al. has
led to efficient methods for performing O-, N-, and
C-arylations with a wide range of substrates under mild
reaction conditions.7-14 In comparison to palladium-
catalyzed reactions, bismuth-assisted arylations have
only played an “exotic” role and their application to the
synthesis of bioactive compounds is scarce.15-18 The
* To whom correspondence should be addressed. Phone: +45 3643
3304. Fax: +45 3643 8237.
† The Danish University of Pharmaceutical Sciences, 2 Univer-
sitetsparken, DK-2100 Copenhagen, Denmark.
(1) Brase, S.; Dahmen, S. Chem. Eur. J . 2000, 6, 1899-1905.
(2) Barton, D. H. R.; Finet, J .-P. Pure Appl. Chem. 1987, 59, 937-
946.
(3) Abramovitch, R. A.; Barton, D. H. R.; Finet, J . P. Tetrahedron
1988, 44, 3039-3071.
(4) Finet, J . P. Chem. Rev. 1989, 7, 1487-1501.
(5) Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 3, 249-267.
(6) Elliott, G. I.; Konopelski, J . P. Tetrahedron 2001, 57, 5683-5705.
(7) Barton, D. H. R.; Ozbalik, N.; Ramesh, M. Tetrahedron 1988,
44, 5661-5668.
(8) Barton, D. H. R.; Finet, J .-P.; Khamsi, J . Tetrahedron Lett. 1987,
28, 887-890.
(9) Barton, D. H. R.; Finet, J .-P.; Khamsi, J . Tetrahedron Lett. 1988,
29, 1115-1118.
(15) Sorenson, R. J . J . Org. Chem. 2000, 65, 7747-7749.
(16) Fan, P. C.; Ablordeppey, S. Y. J . Heterocycl. Chem. 1997, 34,
1789-1794.
(10) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016.
(11) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997, 53,
4137-4144.
(17) Banfi, A.; Bartoletti, M.; Bellora, E.; Bignotti, M.; Turconi, M.
Synthesis 1994, 8, 775-776.
(12) Barton, D. H. R.; Finet, J .-P.; Khamsi, J .; Pichon, C. Tetrahe-
dron Lett. 1986, 27, 3619-3622.
(18) Morel, S.; Chatel, F.; Boyer, G.; Galy, J . P. J . Chem. Res., Synop.
1998, 1, 4-5.
(13) Barton, D. H. R.; Bhatnagar, N. Y.; Finet, J .-P.; Khamsi, J .;
Motherwell, W. B.;.Stanforth S. P. Tetrahedron 1987, 43, 323-332.
(14) Barton, D. H. R.; Finet, J .-P.; Khamsi, J . Tetrahedron Lett.
1986, 27, 3615-3618.
(19) Braun, B.; Diamon, H.; Becker, G. Makromol. Chem. 1963, 62,
183-195.
(20) Matano, Y.; Begum, S. A.; Suzuki, H. Synthesis 2001, 7, 1081-
1085.
10.1021/jo049183o CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/02/2004
6890
J . Org. Chem. 2004, 69, 6890-6893

SCHEME 2. Syn th esis of Resin -Bou n d Bism u th a n esa
a
Key: (a) (i) NaOH, DMSO, 90 °C, 1.5 h, (ii) chloromethyl polystyrene, rt overnight and 90 °C 3 h; (b) 5 equiv of i-PrMgBr, THF, -30
°C, 3 h; (c) 1 equiv of TMSOTf, 2 equiv of HMPA, MeOH/DCM, 0 °C to rt over 1 h, quantitative; (d) THF, 0 °C to rt over 1 h, then rt
overnight; (e) PhI(OAc)2, DCM, rt, 24 h.
to cleave bond B selectively because cleavage of bond A
would lead to lower yield and contamination of the
products.
From literature it is known that in unsymmetrically
substituted triaryl bismuthanes the most electron-
deficient aryl group is selectively transferred in aryla-
tions reactions. To improve the required discrimination
in the cleavage step between the two different types of
Bi-sp2C bonds we have chosen a phenoxy group as spacer
for the bismuth atom.21
The synthesis of the resin-bound triarylbismuthanes
is shown in Scheme 2. Resin 2 was prepared by reaction
of 4-iodophenol 1 with commercially available chlorom-
ethyl polystyrene (loading 2.38 mmol/g, cross-linked with
1-2% divinylbenzene, mesh 200).22 The resin-bound aryl
Grignard compound 3 was prepared from resin 2 by iodo-
magnesium exchange using isopropylmagnesium bro-
mide.
F IGURE 2. Prepared resin-bound triaryl bismuthanes 6a -c
and triaryl bismuth(V) diacetates 7a -c.
To obtain resin-bound bismuthanes, a suitable bismuth
electrophile was needed to be coupled to resin 3. The
choice of the electrophilic bismuth reagent is crucial, and
BiCl3, Ar2BiCl, and Ar2BiOTf were considered. The
reaction with BiCl3 would give an intermediate resin-
bound dichloroarylbismuth, which in theory could react
solvents. The diaryl bismuth triflate HMPA complexes
5a -c were prepared in quantitative yield from the
bismuthanes 4a -c as shown in Scheme 2. The bismuth-
anes 4a -c were obtained by reaction of the aryl Grignard
in a second step with 2 equiv of aryl Grignard reagent.
or lithium species with bismuth(III) chloride.24,26
However, as known from literature, scrambling of the
Three different resin-bound triaryl bismuthanes 6a -c
were prepared from resin 3 with loadings from 0.9-1.1
aryl groups via ligand-ligand exchange may take place
with the consequence that bismuth would be lost from
mmol/g (Figure 2). The conversion of the attachment is
the solid phase.23 Ar2BiCl has the disadvantage of
in the range of 77-89%, the apparent reduction in resin
undergoing dismutation reactions in solution.24 Recently,
loading being due to high mass of the attached bismuth
Suzuki et al. used Ar2BiOTf ‚2HMPA complexes for the
construct. Resins 6a -c were subsequently oxidized quan-
synthesis of unsymmetrically substituted triaryl bis-
titatively with diacetoxy iodobenzene to the resin-bound
muthanes, avoiding the disadvantages of BiCl3 and
triaryl bismuth(V) diacetates 7a -c (Figure 2).27
Ar2BiCl.25 In addition, the complexes are readily acces-
Complete oxidation was verified by high-resolution
sible, air-stable, and soluble in most common organic
magic angle spinning (HR MAS) 1H NMR. The recorded
1
HR MAS H NMR spectra of resin 6c and 7c are shown
(21) Barton, D. H. R.; Bhatnagar, N. Y.; Finet, J .-P.; Motherwell,
in Figure 3. The change in chemical shifts of the aromatic
protons (∆δ (HA) ) 0.34 ppm, ∆δ (HB) ) 0.13 ppm) can
be seen when comparing the two spectra; this is in
W. B. Tetrahedron 1986, 42, 3111-3122.
(22) Kobayashi, S.; Aoki, Y. Tetrahedron Lett. 1998, 39, 7345-7348.
(23) Challenger, F.; Allpress. J . Chem. Soc., Perkin Trans. 1 1921,
119, 913-926.
(24) Henry Gilman; H. L. Yablunky. J . Am. Chem. Soc. 1941, 63,
207-211.
(26) Henry Gilman; H. L.Yablunky; A. C. Svigoon. J . Am. Chem.
Soc. 1939, 61, 1170-1172.
(27) Combes, S.; Finet, J . P. Tetrahedron 1998, 54, 4313-4318.
(25) Matano, Y.; Miyamatsu, T.; Suzuki, H. Organometallics 1996,
15, 1951-1953.
J . Org. Chem, Vol. 69, No. 20, 2004 6891

1
F IGURE 3. HR MAS H NMR of (a) resin 6c and (b) 7c. The sample spinning speed was 5000 Hz, and 128 scans were acquired.
A Carr-Purcell-Meiboom-Gill sequence consisting of 50 echoes were applied for backbone suppression. For 6c the total echo
time was 150 ms, whereas for 7c the total echo time was 100 ms. (* DCM, **H2O)
TABLE 1. N-Ar yla tion s by Use of Resin s 6a -c
SCHEME 3. Clea va ge fr om Resin s 6a -c
accordance with studies of similar compounds in solution-
phase chemistry.11 Similar changes are observed when
comparing the spectra from 6a /b with 7a /b.
Cleavage from resin-bound bismuthanes 6a-c (Scheme
3) was achieved using an imide, a carbamate, or an amide
in the presence of a stoichiometric amount (1.5 equiv) of
copper(II) acetate and a base in dichloromethane at 40
°C (Table 1). To avoid undesired protonation and thereby
cleavage of the bismuth from the resin, a base (either
pyridine or triethylamine) was used as cosolvent.10 Nine
different N-arylated products were obtained in yields
from 57% to 83% after purification by column chromato-
a
Conditions: 2 equiv of substrate, 1.5 equiv of Cu(OAc)2,
b
CH2Cl2/base, 40 °C, 24 h. Yield of product after flash chroma-
tography, purities >95% by 1H NMR. c Pyridine as base. Tri-
d
ethylamine as base.
graphy with NMR purities of >95%. The yields were
approximately 30% lower than those reported for similar
reactions in solution phase,10 problably as a result of the
6892 J . Org. Chem., Vol. 69, No. 20, 2004

TABLE 2. N-, C-, a n d O-Ar yla tion s by Use of Resin s
7a -c
SCHEME 4. Clea va ge fr om Resin s 7a -c
12a -c, 13a -c, 14a -c, and 15a -c were carried out using
10% copper(II) acetate for 11-14 and pivaloate for 15.
The use of a catalytic amount of copper(II) salts has the
advantage of easier work up compared to cleavages from
resin-bound triaryl bismuthanes using stoichiometric
amounts of copper(II) acetate. Ortho-arylations of phenols
takes place in the absence of copper additives. The
cleavage with â-naphthol was performed using 2-tert-
butyl-1,1,3,3-tetramethylguanidine (TMG) as the base
and furnished 16a -c in moderate to good yields. In total,
18 N-, O-, and C-arylated derivatives 11-16 were
obtained in moderate to excellent yields (39-99%) after
purification by column chromatography, with NMR puri-
ties better than 95%.
We have reported a general, convenient, and efficient
synthesis of resin-bound triaryl bismuthanes and resin-
bound triaryl bismuth diacetates that overcomes the
disadvantages of previously reported methods. For the
first time, resin-bound bismuth was used in SPOS as a
multidirectional linker system and as a resin-bound
arylation reagent. The utility was proven by O-, N- and
C-arylations leading to products of high diversity. Thus
N-arylimides, N-arylcarbamates, N-arylamides, N-arylpip-
erazines, N-arylimidazoles, N-arylamines, N,N-diaryl-
amines, diaryl ethers, and biphenyls were obtained in
moderate to good yields. Discrimination between the two
different types of aryl groups was improved by the use
of an electron-rich spacer between the linking bismuth
atom and the polymer backbone. The oxidations of resins
6a -c to the corresponding resin-bound triaryl bismuth
a
Yield of product after flash chromatography, purity >95% by
1H NMR. b 2 equiv of substrate, 10% Cu(AcO)2, THF/triethylamine
(25% v/v), rt 24 h. c 2 equiv of substrate, 10% Cu(AcO)2, THF, 50
°C 24 h. 1.5 equiv of substrate, 10% Cu(AcO)2, THF, rt 24 h.e 1.5
d
equiv of substrate, 10% Cu(PivO)2, DCM, rt 24 h. f 1.5 equiv of
g
substrate, 10% Cu(PivO)2, THF, rt 24 h. 1.5 equiv of substrate,
1.2 equiv of TMG, THF, rt 24 h.
poor solubility of copper(II) acetate in the solvent used,
with the consequence that the copper(II) acetate is not
able to diffuse completely into the resins. Despite the
better solubility, the use of Cu(II) triflate or Cu(II)
pivaloate gave even lower yields, in accordance with
similar studies from solution-phase chemistry. Another
plausible explanation can be deducted from the fact that
the resin-bound bismuthanes are unsymmetrical (i.e., two
identical aryl groups available per Bi), whereas the
reactions reported in solution phase have been carried
out with symmetrical triaryl bismuthanes (i.e., three
identical aryl groups available per Bi).
The resin-bound triaryl bismuth diacetates 7a -c were
treated with nucleophiles, resulting in formation of C-N,
C-O, and C-C bonds under conditions similar to those
reported for solution-phase synthesis (Table 2). Yields
obtained from resins 7a -c (Scheme 4) are comparable
to analogous reactions in solution phase.11,12,28-30 The O-
and N-arylation reactions leading to products 11a -c,
1
diacetates 7a -c were verified by HR MAS H NMR. The
resin-bound triaryl bismuth diacetates were superior as
multidirectional linkers compared to resin-bound triaryl
bismuthanes. Cleavage from resin-bound triaryl bismuth
diacetates allows arylation of a wide range of substrates
under mild conditions requiring only catalytic quantities
of copper(II) salts and gives yields similar to those
reported for analogous solution phase chemistry.
Ack n ow led gm en t. We thank J ens Christian Mad-
sen for his expertise carrying out the HR MAS NMR
experiments and Robert Dancer and Ejner K. Moltzen
for proofreading the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(28) Fedorov, A.; Combes, S.; Finet, J . P. Tetrahedron 1999, 55,
1341-1352.
(29) Combes, S.; Finet, J . P. Tetrahedron 1999, 55, 3377-3386.
(30) Fedorov, A. Y.; Finet, J . P. Tetrahedron Lett. 1999, 40, 2747-
2748.
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