Development of a 9-borabicyclo[3.3.1]nonane-mediated solid-phase Suzuki coupling for the preparation of dihydrostilbene analogs

Article abstract of DOI:10.1016/S0040-4039(03)00415-5

A novel 9-borabicyclo[3.3.1]nonane-mediated solid-phase Suzuki coupling was developed to generate dihydrostilbenes (bibenzyls) and related compounds. Using optimized conditions (20 mol% PdCl₂(dppf), 10 equiv. Et₃N, and 10 equiv. olefin/9-BBN, in 9:1 DMF/H₂O, 50°C, 18 h), high conversions to desired products were generally obtained. A small combinatorial library of derivatives was successfully prepared via radiofrequency tagging and directed sorting techniques.

Full text of DOI:10.1016/S0040-4039(03)00415-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2939–2942
Development of a 9-borabicyclo[3.3.1]nonane-mediated
solid-phase Suzuki coupling for the preparation of
dihydrostilbene analogs
Ron D. Ferguson, Ning Su and Roger A. Smith*
Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA
Received 11 December 2002; revised 10 February 2003; accepted 12 February 2003
Abstract—A novel 9-borabicyclo[3.3.1]nonane-mediated solid-phase Suzuki coupling was developed to generate dihydrostilbenes
(bibenzyls) and related compounds. Using optimized conditions (20 mol% PdCl2(dppf), 10 equiv. Et3N, and 10 equiv.
olefin/9-BBN, in 9:1 DMF/H2O, 50°C, 18 h), high conversions to desired products were generally obtained. A small combinatorial
library of derivatives was successfully prepared via radiofrequency tagging and directed sorting techniques. © 2003 Elsevier
Science Ltd. All rights reserved.
During the last decade, solid-phase organic synthesis
methodologies have been pursued and developed to the
extent that a staggering variety of synthetic transforma-
tions can now be achieved on polymer support.1 These
research efforts have been stimulated in large part by
the successful application of solid-phase synthesis for
the preparation of small arrays of compounds, and
combinatorial libraries, for the discovery and optimiza-
tion of biologically-active substances.2 One chemical
transformation of key importance in organic synthesis
is carbonꢀcarbon bond formation, and it follows that
solid-phase synthesis examples of such chemistry have
received considerable attention.3
clo[3.3.1]nonane),6 which would lead directly to the
desired ethylene linker fragment, was considered as a
viable alternative route to dihydrostilbenes. In their
elegant solid-phase synthesis of prostaglandins, Ellman
and co-workers achieved Suzuki cross-coupling of
alkyl-9-BBN derivatives with vinyl bromides.7 A more
recent article by Jackson and colleagues describes cross-
couplings by hydroboration of a Wang resin-supported
alkyl olefin, followed by transmetallation with diethyl
zinc, and subsequent palladium-catalyzed coupling with
aryl iodides.8 In this article, we describe our develop-
ment and application of a 9-borabicyclo[3.3.1]nonane-
mediated solid-phase Suzuki coupling to generate
dihydrostilbenes and related compounds.
As part of one of our medicinal chemistry research
programs, we had interest in compounds based on a
dihydrostilbene template structure. Indeed, the dihy-
drostilbene (bibenzyl) fragment has been recognized as
an important or ‘privileged’ substructure in known
drugs and protein ligands.4 Traditional solution-phase
methodologies that have been used for the preparation
of such derivatives involved palladium-catalyzed cou-
pling of an aryl acetylene to an aryl bromide (Sono-
gashira coupling), followed by reduction to give the
ethylene linker. Although solid-phase examples of this
type of coupling step are known,3,5 reduction of the
alkene on solid-phase was not precedented and was
considered to be a substantial challenge. The Suzuki
coupling reaction mediated by 9-BBN (9-borabicy-
In our exploratory methodology studies, N-Fmoc-
phenylalanine was coupled to Wang resin, N-depro-
tected by treatment with piperidine, and then coupled
with p-bromophenyl carbonyl or sulfonyl chloride. The
two bromide substrates were then treated with the
adduct obtained from 9-BBN and styrene, using a wide
variety of reaction conditions for the Suzuki cross-cou-
pling. Reactions were carried out on 10 mmol scale,
using 20 mol% Pd(PPh3)4 or dichloro bis(diphenylphos-
phino)ferrocenyl palladium [PdCl2(dppf)] as catalyst;
NaOH, NaOMe, K2CO3, K3PO4, CsCO3, or Et3N as
base (5–10 equiv.); and THF, aq. THF, DMF, or aq.
DMF as solvent.9 The reaction mixtures were heated at
50°C for 18 h, and then, following cleavage from the
resin, the conversion to desired product was assessed by
LC–MS analysis.9
* Corresponding author. Tel.: +1-203-812-2154; fax: +1-203-812-6182;
e-mail: roger.smith.b@bayer.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00415-5

2940
R. D. Ferguson et al. / Tetrahedron Letters 44 (2003) 2939–2942
Overall, this set of trial reactions demonstrated that the
dihydrostilbene product could be obtained in good
yield, and that the preferred catalyst was PdCl2(dppf),
with NaOH, K2CO3, and Et3N identified as the pre-
ferred bases.
Fmoc-phenylalanyl Wang resin was prepared and
deprotected,11 and then coupled with m- and p-bromo-
phenyl carbonyl and sulfonyl chlorides (four reactions,
9 MicroKans per reaction).12 After directed sorting
guided by radiofrequency-tag scanning, the intermedi-
ates were subjected to the 9-borabicyclo[3.3.1]nonane-
mediated Suzuki coupling conditions, using nine olefin
substrates (9 reactions, 4 MicroKans per reaction).13
Reaction products were cleaved from the resin, and
analyzed by LC–MS/UV/ELSD. The results are sum-
marized in Table 1. In several cases, the products were
purified by preparative reverse phase HPLC, and then
characterized by NMR and MS.14 Yields of these
purified products were generally in the range 20–45%,
based on the substitution level for the Fmoc-pheny-
lalanyl Wang resin 2, and the mass of product 1
obtained after HPLC purification.14 In general, these
isolated yields correlated with the percent conversion
values determined by HPLC (Table 1).
In a second trial, the preferred reaction conditions were
assessed for four additional 9-BBN/aryl olefin adducts.
From these experiments, it was concluded that the most
consistent and best results were obtained by using 20
mol% PdCl2(dppf), 10 equiv. Et3N, and 10 equiv.
olefin/9-BBN, in 9:1 DMF/H2O, 50°C, 18 h. High
conversion to the desired product was observed in most
cases. Unfortunately, in the case of 2,4,6-trimethyl-
styrene, no detectable amount of product was formed,
presumably due to suppressed formation of the 9-BBN
adduct intermediate resulting from steric hindrance by
the two ortho methyl groups.
The optimized methodology was then applied to a
prototype combinatorial synthesis, on 40 mmol scale
and using IRORI MicroKans (microreactors).10 Thus,
Several trends are evident from the product analyses
listed in Table 1. First, similar results are obtained for
Table 1. Dihydrostilbene (R1=aryl) and related analogs 1 prepared by solid-phase synthesis according to Scheme 1
Cpd
X
Isomer
R1
R2
Conversiona (%)
1a
1b
1c
1d
1e
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
CO
CO
SO2
SO2
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
\99 (92)
97 (83)
\99 (80)
\99 (69)
\99 (89)
93 (72)
95 (74)
90 (74)
B1
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
2-MeO-Ph
2-MeO-Ph
2-MeO-Ph
2-MeO-Ph
3-NO2-Ph
3-NO2-Ph
3-NO2-Ph
3-NO2-Ph
4-AcO-Ph
4-AcO-Ph
4-AcO-Ph
4-AcO-Ph
Ph
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
B1
B1
B1
47 (35)
55 (50)
66 (71)
72 (82)
97 (85)
87 (71)
\99 (86)
\99 (81)
\99 (88)
98 (81)
\99 (91)
\99 (72)
B1
1s
1t
1u
1v
1w
1x
1y
1z
1aa
1bb
1cc
1dd
1ee
1ff
1gg
1hh
1ii
1jj
Ph
Ph
Ph
4-Pyridinyl
4-Pyridinyl
4-Pyridinyl
4-Pyridinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
B1
B1
B1
22 (28)
18 (34)
74 (56)
20 (42)
\99 (\99)
\99 (92)
\99 (77)
\99 (63)
a Percent conversion based on purity of crude product; analyses by LC–MS/ELSD (and LC–MS/UV at 254 nm). (ELSD: evaporative
light-scattering detection.)

R. D. Ferguson et al. / Tetrahedron Letters 44 (2003) 2939–2942
2941
Scheme 1. Solid-phase synthesis of dihydrostilbenes (R1=aryl) and related analogs 1.
polymer-supported aryl bromides 4 substituted at either
the 3- or 4-position, with either sulfonyl or carbonyl
amide groups. Regarding the styrene reagents 6, both
electron-donating and -withdrawing substituents on the
phenyl ring are well-tolerated, and high conversions to
products 1 are obtained. However, reactions with
ortho-methoxy styrene failed to provide significant
amounts of the desired products (Table 1, 1i–1l). In
Mol. Diversity 1999, 4, 131; (c) Lebl, M. Curr. Opin. Drug
Discovery Dev. 1999, 2, 385; (d) Booth, S.; Hermkens, P.
H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron
1998, 54, 15385.
2. (a) Dolle, R. E. J. Comb. Chem. 2002, 4, 369; (b) Dolle,
R. E. J. Comb. Chem. 2001, 3, 477; (c) Dolle, R. E. J.
Comb. Chem. 2000, 2, 383.
3. (a) Franzen, R. Can. J. Chem. 2000, 78, 957; (b) Kings-
bury, C. L.; Mehrman, S. J.; Takacs, J. M. Curr. Org.
Chem. 1999, 3, 497; (c) Lorsbach, B. A.; Kurth, M. J.
Chem. Rev. 1999, 99, 1549.
4. (a) Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W.
J. Med. Chem. 2000, 43, 3443; (b) Bemis, G. W.; Murcko,
M. A. J. Med. Chem. 1996, 39, 2887.
5. Berteina, S.; Wendeborn, S.; Brill, W. K.-D.; De Mes-
maeker, A. Synlett 1998, 676.
6. (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314;
(b) Collier, P. N.; Campbell, A. D.; Patel, I.; Taylor, R.
J. K. Tetrahedron Lett. 2000, 41, 7115.
7. Thompson, L. A.; Moore, F. L.; Moon, Y.-C.; Ellman, J.
A. J. Org. Chem. 1998, 63, 2066.
contrast,
a disubstituted olefin, namely 2-phenyl-
propene (6, R1=Ph, R2=CH3), gave high conversions
to products (Table 1, 1u–1x). Heteroaryl olefins 6 were
also investigated; however, results were only fair, with
4-vinylpyridine giving no significant amounts of
product, and 2-vinylquinoline giving modest yields
(Table 1, 1y–1ff). Finally, the methodology was success-
fully extended to an alkyl olefin, namely vinylcyclohex-
ane (6, R1=cyclohexyl, R2=H) (Table 1, 1gg–1jj).
In summary, we have developed optimal conditions for
a solid-phase 9-BBN-mediated Suzuki coupling, to per-
mit the preparation of a variety of dihydrostilbenes and
related derivatives. The application of this methodology
was successfully demonstrated by the preparation of a
small combinatorial library, using radiofrequency tag-
ging and directed sorting techniques.
8. Jackson, R. F. W.; Oates, L. J.; Block, M. H. Chem.
Commun. 2000, 1401.
9. Trial reactions were conducted in 2-mL 96-well
polypropylene microtiter plates on 10 mmol scale. The
reaction mixtures were sonicated (30 min, rt), and then
heated at 50°C for 18 h without mixing. Conversion to
the desired product was assessed by LC–MS analysis,
following cleavage from resin (1:1:0.1 TFA/CH2Cl2/
water, 30 min, rt).
Acknowledgements
We wish to thank Anthony Paiva and Lee Huang for
LC–MS analyses, and Wendy Lee and William Scott
for helpful discussions.
10. (a) Nicolaou, K. C.; Xiao, X.-Y.; Parandoosh, Z.; Senyei,
A.; Nova, M. P. Angew. Chem., Int. Ed. Engl. 1995, 34,
2289; (b) Xiao, X.-Y.; Parandoosh, Z.; Nova, M. P. J.
Org. Chem. 1997, 62, 6029; (c) IRORI, 9640 Towne
Centre Drive, San Diego, CA 92121, USA.
References
1. (a) Wendeborn, S.; De Masmaeker, A.; Brill, W. K.-D.;
Berteina, S. Acc. Chem. Res. 2000, 33, 215; (b) Hall, S. E.

2942
R. D. Ferguson et al. / Tetrahedron Letters 44 (2003) 2939–2942
11. IRORI MicroKans were each loaded with 30 mg Wang-
polystyrene resin (Novabiochem, 100–200 mesh, 1.30
mmol/g declared substitution), and then N-Fmoc-phenyl-
alanine was loaded onto the resin by using Sieber’s
2,6-dichlorobenzoyl chloride coupling method.15 Resin
loading by UV–vis spectroscopy (analysis of released
Fmoc-piperidine adduct at u=302 nm, m=8200 M−1
2H), 7.65 (m, 2H), 7.10–7.30 (m, 12H), 4.60 (m, 1H),
2.85–3.20 (m, 6H); LC–MS m/z 374.1 (MH+), tR 3.24
min. Calcd exact mass for C24H23NO3=373.2.
Compound 1g, N-({4-[2-(4-methoxyphenyl)ethyl]phenyl}
sulfonyl)phenylalanine (0.9 mg, 5%): 1H NMR l 12.80
(bs, 1H), 7.45 (d, 2H), 7.25 (d, 2H), 7.10–7.20 (m, 8H),
6.80 (d, 2H), 3.70 (s, 3H), 3.65 (m, 1H), 2.70–2.90 (m,
6H); LC–MS m/z 440.1 (MH+), tR 3.26 min. Calcd exact
mass for C24H25NO5S=439.2.
cm−1 16
was found to be 1.37 mmol/g or 105% of theoret-
)
ical substitution. Just prior to the reaction with sulfonyl
or carbonyl chloride, the resin was N-Fmoc-deprotected
by treatment with 30% piperidine in DMF (30 min, rt),
washed with DMF (5×), MeOH (3×), DCM (3×), and
MeOH (3×), and dried in vacuo.
Compound 1p, N-({3-[2-(3-nitrophenyl)ethyl]phenyl}
1
sulfonyl)phenylalanine (3.9 mg, 21%): H NMR l 12.75
(bs, 1H), 8.20 (d, 1H), 8.10 (t, 1H), 8.00 (m, 1H), 7.65 (m,
1H), 7.55 (m, 1H), 7.45 (m, 1H), 7.30–7.40 (m, 3H),
7.05–7.20 (m, 5H), 3.80 (m, 1H), 2.80–3.00 (m, 5H), 2.65
(m, 1H); LC–MS m/z 455.0 (MH+), tR 3.17 min. Calcd
exact mass for C23H22N2O6S=454.1.
12. Conversion of 3 to 4 was achieved by treatment with 3
molar equiv. of the appropriate carbonyl or sulfonyl
chloride, plus diisopropylethylamine (3 equiv.), in
dichloromethane with mixing at rt overnight.
Compound
1s,
N-[(4-{2-[4-(acetyloxy)phenyl]ethyl}
13. Each olefin 6 (10 equiv.) was separately treated at 0°C
with 9-BBN (11 equiv.) in THF under argon, and then
the mixtures were allowed to warm to rt, and were mixed
by shaking at rt for 5 h. MicroKans containing 4 were
treated with a solution of triethylamine (10 equiv.) and
PdCl2(dppf) (0.2 equiv.) in degassed DMF/water (9:1).
The olefin/9-BBN reaction mixtures (7) were then added
under argon, the reaction mixtures were capped, and the
mixtures were mixed by orbital shaking at 50°C for 18 h.
The mixtures were then cooled to rt, filtered, washed with
DMF (7×), MeOH (5×), DCM (3×), MeOH (3×), and
DCM (2×), and dried in vacuo. MicroKans were sorted,
and then individually treated with 1:1:0.1 TFA/DCM/
water at rt for 2 h, to release the products 1.
1
phenyl)sulfonyl]phenylalanine (6.0 mg, 32%): H NMR l
12.75 (bs, 1H), 8.20 (d, 1H), 7.45 (m, 2H), 6.95–7.15 (m,
11H), 3.80 (m, 1H), 2.90 (m, 5H), 2.70 (m, 1H), 2.15 (s,
3H); LC–MS m/z 468.1 (MH+), tR 3.16 min. Calcd exact
mass for C25H25NO6S=467.1.
Compound 1u, N-[4-(2-phenylpropyl)benzoyl]phenylala-
1
nine (6.8 mg, 44%): H NMR l 12.70 (bs, 1H), 8.55 (d,
1H), 7.60 (m, 2H), 7.10–7.30 (m, 12H), 4.55 (m, 1H),
2.80–3.20 (m, 5H), 1.15 (d, 3H); LC–MS m/z 388.1
(MH+), tR 3.34 min. Calcd exact mass for C25H25NO3=
387.2.
Compound 1ee, N-({4-[2-(2-quinolinyl)ethyl]phenyl}
1
sulfonyl)phenylalanine (3.9 mg, 21%): H NMR l 12.80
(bs, 1H), 8.40 (d, 1H), 8.20 (d, 1H), 8.00 (m, 2H), 7.80 (t,
1H), 7.60 (t, 1H), 7.55 (d, 1H), 7.40 (m, 2H), 7.30 (m,
2H), 7.00–7.20 (m, 5H), 3.80 (m, 1H), 3.15–3.30 (m, 4H),
2.90 (m, 1H), 2.70 (m, 1H); LC–MS m/z 461.3 (MH+), tR
2.22 min. Calcd exact mass for C26H24N2O4S=460.2.
Compound 1ii, N-{[4-(2-cyclohexylethyl)phenyl]sulfonyl}
14. Proton (1H) nuclear magnetic resonance (NMR) spectra
were measured in DMSO-d6 solution with a General
Electric GN-Omega 400 (400 MHz) spectrometer, using
residual protonated solvent (DMSO l 2.49) as reference
standard. HPLC-electrospray mass spectra (LC–MS)
were obtained using a Finnigan LCQ ion-trap mass spec-
trometer with electrospray ionization, and a YMC Pro
C18 2.0×23 mm column. Gradient elution from 90% A to
95% B over 6 min was used on the HPLC, in which
buffer A was 98% water, 2% acetonitrile and 0.02% TFA,
and buffer B was 98% acetonitrile, 2% water and 0.02%
TFA. Representative examples of isolated products are as
follows:
1
phenylalanine (5.6 mg, 34%): H NMR l 12.75 (bs, 1H),
8.20 (d, 1H), 7.40 (d, 2H), 7.05–7.20 (m, 7H), 3.80 (m,
1H), 2.90 (m, 1H), 2.65 (m, 3H), 1.70 (m, 5H), 1.45 (m,
2H), 1.20 (m, 4H), 0.90 (m, 2H); LC–MS m/z 416.1
(MH+), tR 3.72 min. Calcd exact mass for C23H29NO4S=
415.2.
15. Sieber, P. Tetrahedron Lett. 1987, 28, 6147.
16. Bunin, B. A. The Combinatorial Index; Academic Press:
New York, 1998; p. 219.
Compound 1a, N-[4-(2-phenylethyl)benzoyl]phenylalan-
ine (3.5 mg, 23%): 1H NMR l 12.80 (bs, 1H), 8.60 (d,