Solid-phase synthesis with resin-bound triarylbismuthanes: Traceless and multidirectional cleavage of unsymmetrical biphenyls

Article abstract of DOI:10.1021/jo051803d

A multistep solid-phase organic synthesis with resin-bound bismuth linker is described. The flexibilities inherent in this system through novel chemoselective cross-coupling reactions, in conjunction with multidirectional and/or traceless cleavage methodologies, are exploited.

Full text of DOI:10.1021/jo051803d

SCHEME 1. Synthesis of Resin-Bound Bismuthane 5a
Solid-Phase Synthesis with Resin-Bound
Triarylbismuthanes: Traceless and
Multidirectional Cleavage of Unsymmetrical
Biphenyls†
L. Kyhn Rasmussen,‡ Mikael Begtrup,‡ and
Thomas Ruhland*
Department of Medicinal Chemistry, H. Lundbeck A/S,
9 OttiliaVej, DK-2500 Valby, Denmark
tr@lundbeck.com
ReceiVed August 26, 2005
a Reagents and conditions: (a) (i) 0.9 equiv of n-BuLi, THF, -78 °C
1.5 h; (ii) 0.3 equiv of BiCl3, -78 °C to rt over 1-3 h, then rt overnight;
(b) 1 equiv of TMSOTf, 2 equiv of HMPA, MeOH/DCM, 0 °C to rt over
1 h; (c) THF, 0 °C, then rt overnight.
not been described previously. The use of resin-bound bismuth
in SPOS requires that chemical transformations can be per-
formed prior to cleavage without debismuthylation. Function-
alization of triarylbismuthanes at the aryl groups has only been
studied sparsely in solution phase.5,6 We now report the first
application of resin-bound arylbismuthanes in SPOS using the
Suzuki cross-coupling reaction.7 We demonstrate that im-
mobilization of bismuthanes enables chemoselective palladium-
catalyzed cross-coupling reactions that would be difficult or
impossible to perform in solution phase. In addition, we show
that degradation of resin-bound triaryl bismuthanes can be
directed to create either a sp2C-halogen bond (multidirectional
cleavage) or a sp2C-H bond (traceless cleavage). This approach
leads to functionalized biphenyl frameworks of pharmaceutical
interest.8 Han et. al. have reported a convenient multidirectional
and traceless SPOS synthesis of biphenyls using resin-bound
silicon.9 However, the bismuth linker offers additional pos-
sibilities for multidirectional cleavage in comparison to the
silicon linker.4 Furthermore, the bismuth linker carries two aryl
groups that are both utilized in product formation.
A multistep solid-phase organic synthesis with resin-bound
bismuth linker is described. The flexibilities inherent in this
system through novel chemoselective cross-coupling reac-
tions, in conjunction with multidirectional and/or traceless
cleavage methodologies, are exploited.
The availability of flexible synthetic methodologies is para-
mount in modern synthetic chemistry. In recent years, intensive
research efforts have been directed toward increasing flexibility
in solid-phase organic synthesis (SPOS) through new linker
concepts. In the field of drug discovery research, traceless- and
multidirectional-linker strategies are particularly attractive for
the design of small biologically active molecules. SPOS with a
traceless linker allows the synthesis of target molecules devoid
of a “memory” of their former attachment point, and SPOS with
a multidirectional linker enables the introduction of different
functionalities by means of varied cleavage methods.1-3
In a previous report we demonstrated the use of resin-bound
bismuth as an arylation reagent and as a multidirectional linker.4
However, multistep synthesis on resin-bound bismuthanes has
The resin-bound bismuthane 5 was prepared as shown in
Scheme 1. Bromine-lithium exchange was carried out on 1,3-
dibromobenzene 1 using n-butyllithium. Subsequent treatment
with trichlorobismuthane furnished tris(3-bromophenyl) bis-
muthane 2 in 74% yield. The bismuthane 2 was quantitatively
converted into the corresponding bis(3-bromophenyl)bismuth
triflate 2*HMPA complex 3 using the procedure developed by
Suzuki et al.10-12 As expected, complex 3 smoothly bismuthy-
* To whom correspondence should be addressed. Ph: +45 3643 3304. Fax:
+45 3643 8237.
(5) Matano, Y.; Aratani, Y.; Miyamatsu, T.; Kurata, H.; Miyaji, K.;
Sasako, S.; Suzuki, H. J. Chem. Soc., Perkin Trans. 1 1998, 16, 2511-
2517.
(6) Supniewski, J. V.; Adams, R. J. Am. Chem. Soc. 1926, 48, 507-
517.
(7) Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177-9180.
(8) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven,
T. R. J. Org. Chem. 1994, 59, 8151-8156.
(9) Han, Y.; Walker, S. D.; Young, R. N. Tetrahedron Lett. 1996, 37,
2703-2706.
† Dedicated to Prof. Dr. P. Knochel on the occasion of his 50th birthday.
‡ The Danish University of Pharmaceutical Sciences, 2 Universitetsparken,
DK-2100 Copenhagen, Denmark.
(1) Gil, C.; Bra¨se, S. Curr. Opin. Chem. Biol. 2004, 8, 230-237.
(2) Brase, S.; Dahmen, S. Chem. Eur. J. 2000, 6, 1899-1905.
(3) Backes, B. J.; Ellman, J. A. Curr. Opin. Chem. Biol. 1997, 1, 86-
93.
(4) Rasmussen, L. K.; Begtrup, M.; Ruhland, T. J. Org. Chem. 2004,
69, 6890-6893.
10.1021/jo051803d CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/07/2006
1230
J. Org. Chem. 2006, 71, 1230-1232

TABLE 1. Cleavage of Biphenyls from Resin 7a-da
SCHEME 2. Suzuki Cross-Coupling of Resin-Bound
Bromophenylbismuthane 5 and Aryl Boronic Acidsa
a Reagents and conditions: (a) TFA/CH2Cl2 (1:1), rt, 1 h; (b) 2 equiv of
Br2, CH2Cl2, 60 °C,12 h; (c) 2 equiv of I2, THF, 60 °C, 12 h. b Isolated
yields of analytically pure biphenyls after purification by column chroma-
tography.
a Conversion of resin-bound bis(bromophenyl) bismuthane 5 to biphenyls
after 12 h was determined by standardized GC-MS after cleavage from
the resin by treatment with TFA/CH2Cl2 (1:1) at rt for 1 h. “Conversion”
represents the relative amounts of bromobenzene and biphenyls after
cleavage.
were obtained in isolated yields from 48% to 83% over two
steps (calculated from starting resin 5). Halo-debismuthylation
takes place through three repetitive cycles of oxidation of BiIII
by halogen to BiV and subsequent reductive elimination.16-19
lated resin-bound aryl Grignard reagent 4, affording the resin-
bound bismuthane 5 with a loading of 1.9 mmol/g (based on
Br).4
Traceless cleavage was performed using TFA/CH2Cl2 (1:1)
at room temperature and afforded the biphenyls in yields from
58% to 68% over two steps (Table 1, entries 1-4). The
mechanism of proto-debismuthylation is not known in detail
but is probably similar to that of proto-desilylation.20 In
comparison to resin-bound silicon, traceless cleavage from resin-
bound bismuth seems to give significantly higher yields.9 As
mentioned earlier, both aryl groups of the bismuth linker can
be utilized in product formation, resulting in a high resin
loading.21,22
Both, triarylbismuthanes and boronic acids, act as donors in
palladium-catalyzed cross-coupling reactions with arylbro-
mides.13,14 Therefore, a chemoselective cross-coupling reaction
with arylbromides in the presence of both, a triarylbismuthane
and a boronic acid, would be difficult or even impossible in
solution phase. However, immobilization of the bromophenyl
bismuthane on solid phase prevents the bismuthane from
coupling with the resin-bound aryl bromide.
Mild reaction conditions were required for the Suzuki
coupling reaction in order to suppress side reactions of the
immobilized bismuthane. Therefore, different solvents, pal-
ladium sources, ligands, and promoters were screened. With
tetrahydrofuran as solvent, with the combination of Pd2dba3 and
tri-tert-butylphosphane as catalyst, and with potassium fluoride
as promoter, satisfactory conversion was obtained at 40 °C
within 12 h (Scheme 2). It was found that the solid-phase
approach required larger amounts of palladium catalyst and
promoter than similar cross-coupling reactions in solution.15 We
also compared the performance of different boronic acid
derivatives. Phenyl boronic acid performed better (87% conver-
sion) than its 1,3-propanolate derivative (51% conversion),
whereas with potassium phenyl trifluoroborate no conversion
was observed.
Functionalized biphenyls of potential pharmaceutical interest
have been synthesized using a chemo-selective Suzuki cross-
coupling reaction followed by multidirectional or traceless
cleavage with bromine, iodine, or trifluoroacetic acid from resin-
bound bismuthanes. Substituted biphenyls were obtained in
moderate to good overall yields over two steps. To the best of
our knowledge this report is the first use of resin-bound bismuth
in SPOS and the first example of a solid-phase strategy for the
achievement of chemo-selective cross-coupling reactions. In
addition, halo- and proto-debismuthylation reactions have been
used for the first time as synthetically useful tools.23 We would
also like to emphasize that dimetalated arenes, such as the resin-
bound bismuth-palladium arene intermediate, have rarely been
reported in the literature.24
The biphenyls were cleaved by halo-debismuthylation from
the resin-bound bismuthanes by treatment with a solution of
iodine or bromine in tetrahydrofuran or dichloroethane, respec-
tively (Table 1, entries 5-12). The halogen-substituted biphenyls
(16) Challenger, F.; Allpress, C. F. J. Chem. Soc. 1915, 107, 16-25.
(17) Challenger, F.; Wilkinson, J. F. J. Chem. Soc. 1922, 121, 91-104.
(18) Beveridge, A. D.; Harris, G. S.; Inglis, F. J. Chem. Soc. A 1966, 5,
520-528.
(19) Challenger, F. J. Chem. Soc. 1914, 105, 2210-2218.
(20) Chan, T. H.; Fleming, I. Synthesis 1979, 79, 761-786.
(21) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60, 6006-6007.
(22) Chenera, B.; Finkelstein, J. A.; Veber, D. F. J. Am. Chem. Soc.
1995, 117, 11999-12000.
(23) In an earlier report, Kauffmann and Steinseifer investigated the halo-
debismuthylation of alkyldiarylbismuthanes (in solution) as a synthetic tool.
In this case the approach failed because of unselective halo-debismuthylation
reactions. Kauffmann, T.; Steinseifer, F. Chem. Ber. 1985, 118, 1031-
1038.
(10) Matano, Y.; Miyamatsu, T.; Suzuki, H. Organometallics 1996, 15,
1951-1953.
(11) Matano, Y.; Begum, S. A.; Miyamatsu, T.; Suzuki, H. Organome-
tallics 1999, 18, 5668-5681.
(12) Ikegami, T.; Suzuki, H. Organometallics 1998, 17, 1013-1017.
(13) Rao, M. L. N.; Yamazaki, O.; Shimada, S.; Tanaka, T.; Suzuki, Y.;
Tanaka, M. Org. Lett. 2001, 3, 4103-4105.
(14) Barton, D. H. R.; Ozbalik, N.; Ramesh, M. Tetrahedron 1988, 44,
5661-5668.
(15) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
(24) Shimada, S.; Yamazaki, O.; Tanaka, T.; Rao, M. L. N.; Suzuki, Y.;
Tanaka, M. Angew. Chem., Int. Ed. 2003, 42, 1845-1848.
J. Org. Chem, Vol. 71, No. 3, 2006 1231

(2 × 20 mL). The combined organic phases were washed with brine
(20 mL) and dried over MgSO4. The crude product was concen-
trated in vacuo and purified by column chromatography (heptane)
Experimential Section
General Procedure for Suzuki Cross-Coupling of Resin 5.
Synthesis of 7a. To a suspension of resin 5 (2.0 g, 3.7 mmol) in
THF (20 mL) were added phenylboronic acid (1.1 g, 9.3 mmol),
potassium fluoride (3.2 g, 56 mmol), tris(dibenzylideneacetone)-
dipalladium (0.17 g, 0.19 mmol), and tri-tert-butylphosphane (0.11
g, 0.56 mmol). The reaction was heated to 40 °C for 12 h. The
resulting resin was filtered through a sintered glass filter (G3) and
washed with THF (3 × 10 mL), H2O (3 × 10 mL), MeOH-H2O
1:1 (3 × 10 mL), THF-H2O 1:1 (3 × 10 mL), THF (3 × 10 mL),
and CH2Cl2 (3 × 10 mL) and dried overnight at 40 °C in vacuo to
give 7a as a black resin. Calculated from gain in weight resin 7a
had a loading of 1.6 mmol/g. Resins 7b-d were prepared
analogously.
General Procedure for Traceless Cleavage with TFA. Syn-
thesis of Biphenyl 8a. To a suspension of resin 7a (0.30 g, 0.48
mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL).
The suspension was stirred for 12 h at room temperature. The resin
was filtered and extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were washed with H2O (20 mL) and brine (20 mL)
and dried over MgSO4. The crude product was concentrated in
vacuo and purified by column chromatography (heptane) to yield
49 mg (68%) of 8a as a solid, mp 66.5-67.7 °C. 1H NMR (CDCl3)
δ: 7.4 (2H, t, J ) 7.1 Hz), 7.4 (4H, t, J ) 7.5 Hz), 7.6 (4H, d, J
) 7.5 Hz). 13C NMR (CDCl3) δ: 126.1, 126.2, 127.7, 140.2.
Biphenyls 8b-d were prepared analogously.
1
to yield 113 mg (62%) of 9a as an oil. H NMR (CDCl3) δ: 7.3
(1H, t, J ) 7.5 Hz), 7.4 (1H, t, J ) 7.0 Hz), 7.42-7.48 (3H, m),
7.5 (1H, d, J ) 7.5 Hz), 7.6 (2H, t, J ) 7.5 Hz), 7.7 (1H, t, J ) 1.9
Hz). 13C NMR (CDCl3) δ: 123.3, 126.2, 127.5, 128.27, 129.29,
130.58, 130.63, 130.7, 140.1, 143.7. Biphenyls 9b-d were prepared
analogously.
General Procedure for Cleavage with Iodine. Synthesis of
3-Iodobiphenyl 10a. To a suspension of resin 7a (0.50 g, 0.80
mmol) in THF (10 mL) was added iodine (0.39 g, 1.6 mmol). After
stirring at 60 °C for 12 h, the reaction was filtered, and the resin
was extracted with THF (3 × 5 mL). To the combined organic
phases was added aqueous Na2S2O3 (1 M, 5 mL), and the organic
solvent was concentrated in vacuo. To the residue were added H2O
(20 mL) and EtOAc (20 mL). The phases were separated, and the
aqueous phase extracted with EtOAc (2 × 20 mL). The combined
organic phases were washed with brine (20 mL) and dried over
MgSO4. The crude product was purified by column chromatography
1
(heptane) to yield 131 mg (60%) of 10a as viscous oil. H NMR
(CDCl3) δ: 7.2 (1H, t, J ) 8.0 Hz), 7.36 (1H, t, J ) 7.5 Hz), 7.43
(2H, t, J ) 7.1 Hz), 7.51-7.55 (3H, m), 7.7 (1H, d, J ) 8.0 Hz),
7.9 (1H, t, J ) 1.4 Hz). 13C NMR (CDCl3) δ: 95.2, 126.8, 127.5,
128.3, 129.3, 130.8, 136.56, 136.60, 140.0, 143.8. Biphenyls 10b-d
were prepared analogously.
General Procedure for Cleavage with Bromine. Synthesis of
3-Bromobiphenyl 9a. To a suspension of resin 7a (0.50 g, 0.80
mmol) in dichloroethane (10 mL) was added bromine (0.50 g, 3.2
mmol). After stirring at 60 °C for 12 h, the reaction was filtered.
The resin was extracted with CH2Cl2 (2 × 5 mL) and THF (2 × 5
mL). To the combined organic phases was added aqueous Na2S2O3
(1 M, 5 mL), the organic solvents were removed in vacuo, and to
the residue were added H2O (20 mL) and EtOAc (20 mL). The
phases were separated, and the aqueous phase extracted with EtOAc
Acknowledgment. We thank Dr. Robert Dancer and Ejner
K. Moltzen for proofreading the manuscript. The secretarial
assistance of Ms. Vibeke Larsen is highly appreciated.
Supporting Information Available: Experimental procedures
and NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051803D
1232 J. Org. Chem., Vol. 71, No. 3, 2006