Synthesis of substituted asymmetrical biphenyl amino esters as alpha helix mimetics

Article abstract of DOI:10.1016/j.tet.2012.04.106

As part of our ongoing project to develop new molecular probes for estrogen receptor-alpha, we are exploring the utility of internally-substituted asymmetric biphenyls as a proteomimetic scaffold. In this study, we describe synthetic methods for preparing

Full text of DOI:10.1016/j.tet.2012.04.106

Tetrahedron 68 (2012) 5406e5414
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted asymmetrical biphenyl amino esters as alpha helix
mimetics
*
Anna B. Williams, Robert N. Hanson
Department of Chemistry and Chemical Biology, 102 Hurtig Hall, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of our ongoing project to develop new molecular probes for estrogen receptor-alpha, we are
exploring the utility of internally-substituted asymmetric biphenyls as a proteomimetic scaffold. In this
study, we describe synthetic methods for preparing the requisite substituted-bromophenol precursors,
their further elaboration, and the subsequent SuzukieMiyaura coupling of these sterically-hindered and
electronically-rich aromatic systems. The results provide an efficient route with which to generate
further libraries of novel asymmetric biphenyl compounds as potential proteomimetics.
Ó 2012 Published by Elsevier Ltd.
Received 17 February 2012
Received in revised form 20 April 2012
Accepted 26 April 2012
Available online 2 May 2012
Keywords:
Biphenyl proteomimetics
Nuclear receptor
Coactivator binding inhibitor
Coupling reactions
1. Introduction
metabolic concerns, have shown promise,7,8 however, the resulting
products have not met appropriate pharmaceutical criteria. Low
Proteineprotein interactions (PPI) constitute a particular chal-
lenge in therapeutic drug development because such interactions
frequently involve multiple low-energy contacts over a relatively
large surface. Unlike receptors and enzymes, which have well de-
fined binding regions and pockets, the absence of a clear molecular
topography has made it difficult to identify and prepare small
molecules that can effectively disrupt these interactions. In spite of
the demanding criteria, a number of such PPI have been identified
as valid targets for drug development, particularly for those, which
involved binding between an alpha-helical component of one
protein and a shallow groove in the surface of the binding
partner.1e3 One such target of therapeutic interest is the interaction
between a nuclear receptor (NR), such as the estrogen receptor (ER)
molecular weight, non-peptidyl a- helix mimetics provide an at-
tractive alternative, as they may disrupt proteineprotein in-
teractions while retaining many of the ‘drug-like’ properties of
traditional therapeutics. Studies using conformationally con-
strained small molecule scaffolds, which project substituents
mimicking key side chain functionalities, demonstrated significant
potential.9,10 With the objective of imparting more peptide-like
character, Hamilton’s group introduced the concept of conforma-
tionally flexible bi- and tri- aryl scaffolds as ‘proteomimetics’.11,12
The intrinsic energetic constraints of biaryl rotation,13 as well as
the ability to control this rotation through rational selection of
substituent identity and disposition, make this an appealing ap-
proach to mimicking
interested (Fig. 1).
a-helical peptides in which we are particularly
or androgen receptor (AR), and specific a-helical regions of relevant
coactivator proteins.4
Our focus on proteomimetics derives from an ongoing interest
in the development of new therapeutic approaches for the treat-
ment of breast and prostate cancer. Rather than targeting the initial
interaction of the hormone with the ligand binding pocket (LBP) of
the receptor, we propose to disrupt and/or block the downstream
recruitment of the coactivator proteins needed to assemble the
requisite transcription apparatus. Because binding of coactivator
proteins to the NR is governed by a short conserved peptide se-
quence, that is, both context and tissue specific, our attention fo-
cused the development of selective coactivator binding inhibitors
(CBIs).14,15 The conserved NR binding domain of the coactivator
As part of our ongoing program involved with the modulation of
steroid hormone function, we focused on the development of small
molecules that would disrupt the nuclear receptor (NR)-cor-
egulatory binding proteins. Early studies that employed alpha-
helical peptide fragments demonstrated the feasibility of this ap-
proach,5 however, such peptides present numerous challenges as
pharmaceuticals in terms of oral absorption, bioavailability, and
target selectivity.6 Strategies for stabilizing peptide fragments,
undertaken with the objective of inducing selectivity and reducing
proteins is an
a-helical pentapeptide (termed the NR box), which
* Corresponding author. Tel.: þ1 617 373 3313; fax: þ1 617 373 8795; e-mail
generally consists of an LxxLL motif, although the larger coactivator
address: r.hanson@neu.edu (R.N. Hanson).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2012.04.106

A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
5407
Fig. 1. Biphenyl as an alpha helix mimic. (a) Biphenyl is conformationally mobile and can rotate easily about its biaryl axis. (b) This rotation can potentially be constrained through
the introduction of substituents in such a way as to mimic the projection of substituents in the i and iþ4 positions of an alpha helix.
Table 1
binding domain (CBD) of AR is known to prefer an FxxLF variant.
Substitution of biphenyl derivatives (1aej, 8aej)
The first and third leucine (L) residues are considered more es-
sential for binding as they penetrate the CBD while the second
leucine generally makes less specific, hydrophobic contacts along
the cleft.16,17 The bound coactivator peptide is further stabilized in
the CBD through hydrogen-bonding interactions described as
a ‘charge clamp,’ between charged residues of the CBD and the
peptide backbone flanking the coactivator’s NR box.4 We previously
reported our design and synthesis of a proteomimetic scaffold
intended as an NR-CBI, which incorporated Hamilton’s biphenyl
strategy to simulate the alpha-helical core of the NR box.18 In this
approach, the biphenyl was substituted with hydrophobic groups
2
3
20
30
to mimic the projection of the leucine side chains. Our approach is
unique in that it adds asymmetric bipolar functionalization at the 4
and 40 positions. Specifically, amino and ester(acid) termini are
appended to the 4 and 40 positions of the biphenyl to orient the
compound within the CBD, thereby mimicking the role played by
the coactivator backbone in the charge clamp interaction.
a
b
c
d
e
f
g
h
i
Me
H
Me
H
Me
Bn
H
Bn
H
H
H
H
Me
H
H
H
H
Bn
H
H
Me
H
Me
Me
H
Bn
H
H
H
Me
H
H
H
H
Bn
H
H
Preparation of the initial series of 3,30-symmetrically di-
substituted derivatives was accomplished using commercially
available ortho-substituted phenols.18 Modest but reproducible
Bn
Bn
j
Bn
binding affinities were reported for the CBDs of both ERa and AR,
with some preference observed for compounds that included larger
hydrophobic substituents and non-ionized bipolar termini19. In
order to expand this series of novel biphenyl derivatives, in which
we sought to both enhance binding affinity and identify specific
binding modes, we required a synthetic route that would provide
more efficient incorporation of diverse substituents and multiple
internal substitution patterns. In this study we describe the de-
velopment of such a method for the preparation of the appropri-
ately substituted-bromophenol building blocks, their subsequent
functionalization, and the ultimate coupling of the aromatic com-
ponents to provide a series of novel proteomimetic target com-
pounds. Our proposed synthetic approach and target compounds
are shown in Scheme 2 and Tables 1and 2 (Fig. 2).
Table 2
Substitution of phenyl derivatives (2aee, 6aee, 7aee)
2
3
a
b
c
d
e
H
Me
H
Bn
H
H
H
Me
H
Bn
2. Results and discussion
We envisioned the synthesis of the target biphenyl scaffold as
arising from the late-stage Suzuki cross-coupling of two fully-
substituted and functionalized aromatic components. This ap-
proach would allow for the efficient synthesis of a wide variety of
aromatic derivatives from 2- and 3-substituted para-bromophe-
nols. However, during initial attempts to couple the functionalized
biphenyls using Suzuki coupling chemistry, we observed that the
presence of compounds containing the tertiary amine functionality
resulted in complex reaction mixtures, which included multiple
byproducts that possessed similar physicochemical properties and
required rigorous chromatographic separations in order to isolate
the desired product. This presence of undesirable byproducts was
not without precedent, as tertiary amines have been previously
demonstrated as suitable organic reductants for facilitating the
palladium-catalyzed homocoupling of aryl halides.20,21 We there-
fore modified our synthetic strategy by coupling the biaryl scaffold
prior to the introduction of the amine terminus.

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A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
N-bromosuccinimide under ambient conditions to yield (5). O-
Demethylation with boron tribromide then gave the desired phenol
(2e). The four-step synthesis provided 3-benzyl-4-bromophenol
(2e) in a 63% overall (unoptimized) yield.
The decision of which aryl component to boronate rather than
brominate was influenced by observations that many
4-hydroxyphenylboronic esters can readily be crystallized from
hexanes. The choice of boronic esters rather than boronic acids was
based onthe reported stabilityofboronic esters at room temperature.
The substituted 4-hydroxyphenylboronic esters (6) were prepared
using bis(pinacolato)diboron in the presence of potassium acetate
and PdCl2dppf (Scheme 2). These boronate intermediates were not
further functionalized at the phenolic position prior to coupling. The
other aryl coupling partner (7) was prepared by introducing the
ethoxycarbonyl methyl (‘carboxy’) terminus to the bromophenols (2)
via Williamson ether synthesis, using sodium hydride to generate the
phenoxide followed by the addition of ethyl bromoacetate.
The Suzuki coupling reaction is known for its wide tolerance of
functional groups, however, much of that tolerance is due to the
range of reactant-specific reaction conditions employed. Inclusion
of electron-donating substituents on both aromatic coupling part-
ners is known to influence reaction kinetics. Consequently, signif-
icant optimization of the reaction conditions, particularly regarding
the choice of ligand, solvent, and base, was necessary. During the
optimization process, in addition to isolating the expected homo-
coupled product from the competing side-reaction, we isolated
significant quantities of an additional byproduct, resulting from
aryl-transfer from the triphenylphosphine ligand (Eq. 2).
Fig. 2. Retrosynthesis of asymmetrical biphenyl amino esters. The substituted bipolar
biphenyl scaffold was envisioned as originating from the etherification and eventual
cross-coupling of simple mono-substituted 4-halogenated phenols. aSee Table 1 for
identification of structures aej. bSee Table 2 for identification of structures aee.
In our initial study we demonstrated that commercially avail-
able 4-brominated-2-substituted phenols were convenient pre-
cursors for the preparation of the 3,30-disubstituted compounds.
When the 4-brominated material was not readily available, bro-
mination of the 2-substituted phenols with tetrabutylammonium
tribromide gave the 4-brominated derivatives (2b, 2d) in nearly
quantitative yield (Eq. 1).
However, for us to determine the optimal substituent identity
and disposition within the biphenyl scaffold, we required a gen-
eral method for preparing the corresponding isomeric 3-
substituted-4-bromophenols. This objective was achieved in four
steps using 3-bromoanisole as the starting material (Scheme 1).
3-Bromoanisole was converted to its Grignard reagent, followed by
addition of an aldehyde or ketone to yield the corresponding
substituted-(3-methoxyphenyl)methanol (3). The secondary alco-
hol underwent reduction by hydrogenation over Pd/C and the re-
sultant substituted anisole (4) was selectively 4-brominated using
Although seldom discussed in comparison to other side products
of palladium catalysis, this product emerges from the transfer of an
aromatic substituent of the phosphine ligand. Mechanistic studies
have demonstrated that reductive elimination of palladium-bound
aryl and phosphine ligands can result in the formation of a tetra-
substituted phosphonium intermediate. This phosphonium spe-
cies can then oxidatively add back to the metal center, effectively
transferring a phenyl ring to the palladium core, which then con-
tinues through the normal catalytic cycle (Eq. 3).22e24

A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
5409
B
Scheme 1. Preparation of 3-substituted-bromophenol.
AR0ꢀPdLn ꢀ PðArÞ3#PdLn þ PðArÞ3ðAR0Þ#AR
ꢀ PdLn ꢀ PðArÞ3ðAR0Þ
compounds were excellent and final compounds could be easily
purified. A particular feature that was noted regarding the (2,20)
-dibenzyl derivatives during their 1H NMR characterization was the
appearance of diastereotopic protons at the benzylic positions,
suggesting particular conformational constraints. Further spectro-
metric assessment of these proton resonances and their confor-
mational significance will be discussed elsewhere. The final series
of biphenyl amino esters (1aej), as well as their phenolic-ester
precursors (8aej), were submitted for evaluation as NR-CBIs in
order to establish the most effective pattern for substitution. Pre-
liminary results from these assays indicated that a number of the
benzylated derivatives exhibit significant activity as competitive
inhibitors of coregulatory peptide binding, and that compound 1j,
a 2,20-dibenzylated biphenyl amino ester, was a particularly
promising compound for further study (Fig. 3). As illustrated in
Fig. 3, increased concentrations of 1j suppressed the estrogenic
response in a dose related fashion. In the second assay (Fig. 3b), the
compounds produced no inherent estrogen receptor response,
suggesting no effect at the ligand binding site, and did produce
a modest reduction of the downstream effect, indicative of the
disruption of coregulatory peptide-mediated events. Therefore, the
data support the concept that the substituted biphenyls can mimic
the helical peptide scaffold and bind to appropriate recognition
sites. Further details on the conditions of these assays are available
in the Supplementary data and a more thorough analysis of the
biological activity of the complete series of compounds will be
described elsewhere.
(3)
This competing reaction was confirmed by replacing the tri-
phenylphosphine ligand with its perdeuterated analog (PPh-d153
)
and observing the incorporation of deuterated d5-phenyl sub-
stituent into the side product. This undesired side-reaction was
effectively suppressed through optimization of several reaction
variables, the most notable being the replacement of triphenyl-
phosphine ligand by the more hindered tri(o-tolyl)phosphine. Our
final Suzuki conditions employed this ligand in addition to the re-
lated PdCl2(P(o-tol)3)2 catalyst at elevated temperatures in a 3:2
mixture of dichloromethane and water to give the biphenyl phe-
nolic esters (8) in good overall yields (47e96%).
The tertiary amine (N-terminus) was incorporated following the
biaryl coupling, using (dimethylamino)ethyl chloride hydrochlo-
ride under Williamson ether conditions. These compounds un-
derwent usually rapid transesterification in the presence of
methanol to give the corresponding methyl ester. Because of the
ease with which this process occurred, all amino-ethyl esters were
subsequently allowed to fully transesterify to their corresponding
amino-methyl esters (1).
Having established the general synthetic methodology, we ap-
plied it to the preparation of a series of internally (2/3, 20/30)
substituted mono- and di- methylated (1aee) and mono- and di-
benzylated biphenyl derivatives (1fej). Overall yields of the target

5410
A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
Scheme 2. Synthesis of biphenyl amino esters.aSee Table 2 for identification of structures aee.bSee Table 1 for identification of structures aej.
The successful development of an efficient method for preparing
now readily introduce substituents at the 2- or 3- positions, such
libraries would include variations in side chains, substitution pat-
terns, as well as diverse polar termini. The development of such
libraries will allow us to explore the therapeutic potential of this
class of compounds.
novel biphenyl proteomimetics provides us with the capacity to
rapidly generate diverse libraries of novel ligands for the coac-
tivator binding domain of nuclear receptors, as well as for other
alpha helix mediated proteineprotein interactions. Because we can
Fig. 3. Compound 1j is an effective inhibitor of interactions between ER
a luciferase reporter gene to evaluate the effectiveness of compounds 8aej and 1aej at inhibiting the interactions between an activated ER
peptide. As observed by the decline in observed luminescence, compound 1j was demonstrated as an inhibitor of ER -coactivator interactions. (b) Compounds were subjected to
a competitive binding assay again estradiol (E2) to assess whether observed inhibition results from undesired effects at the ligand binding domain, rather than the targeted co-
activator binding domain. Compound 1j demonstrated no affinity for the ligand binding domain of ER
a
and LxxLL-containing coactivator proteins. (a) A two-hybrid assay was performed in SK-BR-3 cells using
a
and an LxxLL-containing coactivator
a
a.

A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
5411
3. Experimental
3.1. General
stirred at room temperature in daylight for 1 h. The crude reaction
was concentrated, re-dissolved in hexanes, and filtered to remove
the succinimide bi-products (white solid). The filtrate was con-
centrated and further purified by flash chromatography (silica gel,
100% hexanes) to yield 0.867 g, 2-benzyl-1-bromo-4-
methoxybenzene (94%) as a colorless oil; 1H NMR (400 MHz,
Unless otherwise stated, all reactions were performed under
argon atmosphere, in oven-dried glassware, using solvents, which
were either distilled or purchased as anhydrous and, which were
transferred by syringe. 1H (400 or 500 MHz) and 13C NMR (100 or
125 MHz) spectra were recorded in CDCl3, acetone-d6, or methanol-
CDCl3):
d
7.46 (d, J¼8.0 Hz, 1H), 7.30 (t, J¼8.0 Hz, 2H), 7.22 (t,
J¼7.6 Hz, 1H), 7.20 (d, J¼7.2 Hz, 2H), 6.69 (d, J¼3.6 Hz, 1H), 6.66 (dd,
J¼8.8, 3.6 Hz,1H), 4.08 (s, 2H), 3.73 (s, 3H) ppm; 13C NMR (100 MHz,
d4. Chemical shifts are reported in parts per million (
d
units)
CDCl3): d 159.2, 141.6, 139.6, 133.6, 129.2, 128.7, 126.5, 117.2, 117.2,
downfield from TMS ( 0.00 ppm). Analytical thin-layer chroma-
d
115.6, 113.6, 55.6, 55.6, 42.1 ppm. Elemental analysis calcd (%) for
C14H13BrO (276.0150): C 60.67, H 4.73; found: C 60.64, H 4.78.
tography (TLC) was performed by using polymer-backed silica gel
plates coated with a 0.25 mm thickness of silica gel, and visuali-
zation was achieved by UV light, phosphomolybdic acid staining or
exposure in an iodine chamber. Flash column chromatography was
3.1.4. Synthesis of 3-benzyl-4-bromophenol (2e). To a solution of
compound 5 (0.739 g, 2.67 mmol) in dichloromethane (30 mL) was
added a 1 M solution of boron tribromide in dichloromethane
(8.0 mL, 8.00 mmol). The reaction was stirred at room temperature
overnight. The reaction was quenched with water (40 mL) and
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried with magnesium sulfate, and concen-
trated. Purification was accomplished on silica gel (5% ethyl acetate/
hexanes) to yield 0.665 g 3-benzyl-4-bromophenol (95%) as a yel-
performed on silica gel of 40e63 mm particle size. High resolution
mass spectrometry data was obtained on a Waters QTof (hybrid
quadrupolar/time-of-flight) API US system by electrospray (ESI) in
the [positive or negative] mode. Mass correction was done by an
external reference using a Waters Lockspray accessory. Mobile
phases were water and acetonitrile with 0.1% formic acid. The MS
settings were: capillary voltage¼3 kV, cone voltage¼35, source
temperature¼120 ꢁC and dissolvation temperature¼350 ꢁC [cone
voltage¼10 and dissolvation temperature¼120 ꢁC if experiment
was carried out in low T and low V]. Elemental analyses were
performed on a Model CE 440 CHN Analyzer.
low oil; 1H NMR (400 MHz, CDCl3):
d
7.39 (d, J¼8.4 Hz, 1H), 7.301 (t,
J¼7.6 Hz, 2H), 7.23 (t, J¼8.8 Hz, 1H), 7.19 (d, J¼8.8 Hz, 2H), 6.57 (dd,
J¼8.4, 2.8 Hz, 1H), 6.56 (d, J¼2.4 Hz, 1H), 4.03 (s, 2H), ppm; 13C NMR
(100 MHz, CDCl3):
d 155.1, 142.0, 139.4, 133.8, 129.4, 128.8, 126.7,
118.2, 118.1, 115.6, 115.4, 42.0 ppm. Elemental analysis calcd (%) for
C13H11BrO (261.9993): C 59.34, H 4.21; found: C 59.42, H 4.20.
3.1.1. Synthesis of (3-methoxyphenyl)(phenyl)methanol (3).25 Atwo-
neck flask equipped with a reflux condenser was loaded with
magnesium turnings (1.895 g, 78.0 mmol) and oven-dried over-
night. The flask was subsequently flame-dried under Argon prior to
the addition of tetrahydrofuran (50 mL) and iodine (1 chip). The
temperature was cooled to 0 ꢁC and 3-bromoanisole (7.634 mL,
11.3 g, 60.0 mmol) was slowly added via syringe. The solution was
stirred for 2 h while gradually warming to room temperature be-
fore heating at 60 ꢁC for 4 h. The solution was then returned to
room temperature and benzaldehyde (1.218 mL, 1.27 g, 12.0 mmol)
was added by syringe and the reaction was stirred at room tem-
perature overnight. A saturated solution of aqueous ammonium
chloride (150 mL) was added to quench the magnesium and the
solution was stirred at room temperature for 2 h. The aqueous
phase was extracted with ethyl acetate and the combined organic
layers were washed with brine, dried with magnesium sulfate, and
concentrated. Flash chromatography on silica gel (5% ethyl acetate/
hexanes) yielded 1.02 g of (3-methoxyphenyl)(phenyl)methanol
3.1.5. General procedure for the preparation of 2-substituted-4-
bromophenol (2b, 2d). Tetrabutylammonium tribromide (4.527 g,
9.39 mmol) was added to a solution of ortho-cresol (0.820 g,
7.82 mmol) in chloroform (55 mL) and the solution was stirred at
room temperature for 3 h. The solvent was removed by rotary
evaporation and the crude product was partitioned between ether
(100 mL) and 1 N hydrochloric acid (aq, 70 mL). The organic layer
was washed sequentially with 1 N HCl and brine, dried over mag-
nesium sulfate, and concentrated. The crude product was purified
by chromatography on silica gel (10% ethyl acetate in hexanes) to
yield product 2b27 (1.27 g, 87% yield) as a white solid (mp
58e61 ꢁC); 1H NMR (500 MHz, CDCl3):
d
7.24 (d, J¼2.0 Hz, 1H), 7.17
(dd, J¼8.5, 2.5 Hz, 1H), 6.65 (d, J¼8.0 Hz, 1H), 4.66 (s, 1H), 2.21 (s,
3H) ppm.
3.1.5.1. Synthesis of 2-benzyl-4-bromophenol (2d).28 Pale yellow
(75%) as a yellow oil; 1H NMR (400 MHz, CDCl3):
d
7.36 (m, 4H), 7.26
oil; 1H NMR (400 MHz, CDCl3):
6.67 (dd, J¼7.2, 1.2 Hz, 1H), 4.77 (s, 1H), 3.95 (s, 2H) ppm.
d
7.31 (t, J¼7.2 Hz, 2H), 7.23 (m, 5H),
(m, 2H), 6.96 (s, 1H), 6.95 (d, J¼6.8 Hz, 1H), 6.81 (dd, J¼7.2, 2.0 Hz,
1H), 5.82 (s, 1H), 3.79 (s, 3H), 2.24 (s, 1H) ppm.
3.1.6. General procedure for the preparation of the aryl boronic esters
(6aee). Compound 2b (1.50 g, 8.02 mmol), bis(pinacolato)diboron
(2.24 g, 8.82 mmol), potassium acetate (2.36 g, 24.1 mmol), and
PdCl2dppf (0.328 g, 0.40 mmol) were dissolved in dioxane and
heated to reflux (80 ꢁC) overnight. After cooling to room temper-
ature, activated carbon was added and the resultant mixture was
filtered through Celite (prepared with ethyl acetate). The filtrate
was concentrated and the concentrate was re-dissolved ethyl ace-
tate and washed with brine. The combined organic layers were
dried with magnesium sulfate, concentrated and purified by flash
chromatography (silica gel, 5% ethyl acetate/hexanes) to yield the
desired product, 6b (1.25 g, 67% yield) as a white solid (mp
100e103 ꢁC).
3.1.2. Synthesis of 1-benzyl-3-methoxybenzene (4).26 A 500 mL
round-bottom flask was loaded with compound 3 (0.783 g,
3.65 mmol) and 10% palladium on carbon and flushed with argon. A
5:1 solution of ethanol (150 mL) and ethyl acetate (30 mL) was
added. The reaction vessel was then flushed with hydrogen for
10 min at room temperature. A hydrogen balloon was attached and
the reaction progressed at room temperature for 5 h. The crude
reaction mixture was then filtered through Celite (prepared with
ethyl acetate) and concentrated. Flash chromatography (silica gel,
5% ethyl acetate/hexanes) yielded 0.669
methoxybenzene (92%) as a colorless oil; 1H NMR (400 MHz,
CDCl3):
g of 1-benzyl-3-
d
7.27 (t, J¼7.2 Hz, 2H), 7.19 (t, J¼8.0 Hz, 4H), 6.78 (d, J¼8.4 Hz,
1H), 6.74 (d, J¼6 Hz, 1H), 6.73 (s, 1H), 3.95 (s, 2H), 3.75 (s, 3H) ppm.
3.1.6.1. Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
3.1.3. Synthesis of 2-benzyl-1-bromo-4-methoxybenzene
(5). Compound 4 (9.150 mmol, 1.814 g) and N-Bromosuccinimide
(0.660 g, 3.33 mmol) were dissolved in acetonitrile (20 mL) and
yl)phenol (6a).29 Solid; mp 114e116 ꢁC; 1H NMR (300 MHz,
CDCl3):
1H), 1.33 (s, 12H) ppm.
d
7.72 (d, J¼8.4 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 4.93 (br s,

5412
A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
3.1.6.2. Synthesis of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenol (6b). Solid; mp 100e103 ꢁC; 1H NMR
(300 MHz, CDCl3):
J¼8.1 Hz, 1H), 4.81 (s, 1H), 2.24 (s, 3H), 1.32 (s, 12H) ppm.
3.1.8. General procedure for the preparation of the biphenyl phenolic
esters (8aej). To a screw-cap reaction vial was added compound 7g
(0.050 g, 0.19 mmol), sodium carbonate (0.041 g, 0.386 mmol),
PdCl2(P(o-tol)3)2 (0.0076 g, 0.0097 mmol), and tri(o-tolyl)phosphine
(0.0029 g, 0.0097 mmol). After flushing the vial with argon, a 3:2
mixture of dichloromethane (1.0 mL) and water (0.67 mL) was added
and the vial was capped and heated to 115 ꢁC for 1 h. The reaction
mixture was cooled to room temperature and 3-benzyl-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.1197 g, 0.386 mmol)
was added as a solution in an additional 1.0 mL dichloromethane and
0.67 mL water. The vial was again capped and returned to 115 ꢁC
overnight. The crude reaction mixture was taken up in ethyl acetate
and washed with brine. The combined organic layers were dried
with magnesium sulfate, concentrated, and purified by flash chro-
matography on silica gel (10% ethyl acetate/hexanes) to yield product
8g (0.067 g, 96% yield) as a solid (mp 70e72 ꢁC).
d
7.59 (s, 1H), 7.55 (d, J¼7.5 Hz, 1H), (6.76,
3.1.6.3. Synthesis of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenol (6c). Solid, mp 90e93 ꢁC; 1H NMR
(500 MHz, CDCl3):
2 Hz, 1H), 2.26 (s, 3H), 1.32 (s, 12H) ppm.
d
7.66 (d, J¼8.0 Hz,1H), 6.62 (s,1H), 6.62 (dd, J¼9,
3.1.6.4. Synthesis of 2-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenol (6d).18 Solid, mp 112e115 ꢁC; 1H NMR
(400 MHz, CDCl3):
J¼8.0 Hz, 1H), 5.43 (s, 1H), 1.34 (s, 12H) ppm.
d
7.67 (s, 1H), 7.61 (dd J¼7.2, 1.6 Hz, 1H), 6.78 (d,
3.1.6.5. Synthesis of 3-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenol (6e). Yellow oil; 1H NMR (400 MHz,
CDCl3):
d
7.73 (d, J¼8.8 Hz, 1H), 7.23 (d, J¼7.2 Hz, 2H), 7.17 (t,
3.1.8.1. Synthesis of ethyl 2-((40-hydroxy-2-methyl-[1,10-bi-
J¼6.8 Hz, 2H), 7.15 (t, J¼7.2 Hz, 1H), 6.66 (dd, J¼8.4, 2.4 Hz, 1H), 6.57
phenyl]-4-yl)oxy)acetate (8a). Solid, mp 100e102 ꢁC; 1H NMR
(d, 2.8 Hz, 1H), 4.83 (s, 1H), 4.28 (s, 2H), 1.27 (s, 12H) ppm. 13C NMR
(500 MHz, CDCl3):
d
7.12 (d, J¼8.0 Hz, 2H), 7.11 (d, J¼8.5 Hz, 1H),
(100 MHz, CDCl3):
d
158.6, 150.4, 142.4, 139.5, 129.3, 128.4, 125.9,
6.84 (d, J¼9.0 Hz, 2H), 6.82 (d, J¼3.0 Hz, 1H), 6.75 (dd, J¼8.5, 3.0 Hz,
1H), 5.36 (s, 1H), 4.65 (s, 2H), 4.30 (q, J¼7.0 Hz, 2H), 2.22 (s, 3H), 1.32
117.3, 117.3, 112.9, 83.7, 61.1, 41.1, 25.0, 21.4, 14.4 ppm. HRMS calcd
for C19H23BO3 [MþNa] 332.1674, found 332.1685.
(t, J¼7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 169.7, 156.9,
154.7, 137.3, 135.6, 134.0, 131.2, 130.7, 116.8, 115.2, 111.8, 65.6, 61.8,
21.0, 14.4 ppm. HRMS calcd for C17H18O4 [MþNa] 309.1103, found
309.1097.
3.1.7. General procedure for the preparation of the ethyl (phenoxy)
acetates (7aee). To a solution of 4-bromo-3-methylphenol (1.00 g,
5.35 mmol) in anhydrous tetrahydrofuran (40 mL) was added so-
dium hydride (60% w/w) (0.321 g, 8.02 mmol). The reaction was
stirred for 30 min prior to the slow addition of ethyl bromoacetate
(0.890 mL, 1.34 g, 8.02 mmol). The reaction (milky-white suspen-
sion) was stirred overnight at room temperature. Ethanol was added
to quench the remaining sodium hydride (color change to trans-
lucent yellow), and the solvent was evaporated. The crude product
was partitioned in ethyl acetate and water and the organic layer was
washed with brine, dried with magnesium sulfate, and concen-
trated. The product, 7c (1.42 g, 97% yield) was isolated as a solid (mp
36e38 ꢁC) and taken forward without further purification.
3.1.8.2. Synthesis of ethyl 2-((40-hydroxy-20-methyl-[1,10-bi-
phenyl]-4-yl)oxy)acetate (8b). Solid, mp 94e97 ꢁC; 1H NMR
(500 MHz, CDCl3):
d
7.20 (d, J¼8.5 Hz, 2H), 7.04 (d, J¼8.5 Hz, 1H),
6.93 (d, J¼9.0 Hz, 2H), 6.74 (d, J¼3.0 Hz, 1H), 6.69 (dd, J¼8.0, 2.5 Hz,
1H), 5.40 (s, 1H), 4.66 (s, 2H), 4.30 (q, J¼7.5 Hz, 2H), 2.20 (s, 3H), 1.32
(t, J¼7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 169.6, 156.7,
154.9, 137.3, 135.4, 134.2, 131.3, 130.8, 117.2, 114.5, 112.9, 65.8, 61.8,
20.8, 14.4 ppm. HRMS calcd for C17H18O4 [MþNa] 309.1103, found
309.1114.
3.1.8.3. Synthesis of ethyl 2-((40-hydroxy-2,30-dimethyl-[1,10-bi-
3.1.7.1. Synthesis ofethyl 2-(4-bromophenoxy)acetate(7a).30 Solid,
phenyl]-4-yl)oxy)acetate (8c). Solid, mp 89e91 ꢁC; 1H NMR
mp 55e57 ꢁC; 1H NMR (300 MHz, CDCl3):
d
7.39 (d, J¼9.0 Hz, 2H),
(400 MHz, CDCl3): d 7.11 (d, 8.8 Hz, 1H), 7.04 (s, 1H), 6.99 (d,
6.80 (d, J¼9.0 Hz, 2H), 4.59 (s, 2H), 4.27 (q, J¼7.2 Hz, 2H), 1.30 (t,
J¼8.0 Hz, 1H), 6.82 (d, J¼2.0 Hz, 1H), 6.79 (d, J¼8.0 Hz, 1H), 6.75 (dd,
J¼8.0, 2.0 Hz, 1H), 4.86 (s, 1H), 4.64 (s, 2H), 4.30 (q, J¼6.4 Hz, 2H),
2.28 (s, 3H), 2.24 (s, 3H), 1.32 (t, J¼7.2 Hz, 3H) ppm; 13C NMR
J¼7.2 Hz, 3H) ppm.
3.1.7.2. Synthesis of ethyl 2-(4-bromo-2-methylphenoxy)acetate
(100 MHz, CDCl3): d 169.2, 156.7, 152.6, 137.0, 135.4, 134.0, 132.0,
(7b). Yellow oil; 1H NMR (300 MHz, CDCl3):
d
7.27 (s, 1H), 7.21 (dd,
130.9, 128.0, 123.3, 116.5, 114.5, 111.6, 65.5, 61.4, 20.8, 15.8, 14.2 ppm.
J¼8.7, 2.4 Hz, 1H), 6.56 (d, J¼8.7 Hz, 1H), 4.60 (s, 2H), 4.25 (q,
HRMS calcd for C18H20O4 [MþNa] 323.1259, found 323.1260.
J¼7.2 Hz, 2H), 2.26 (s, 3H), 1.29 (t, J¼6.6 Hz, 3H) ppm.
3.1.8.4. Synthesis of ethyl 2-((40-hydroxy-20,3-dimethyl-[1,10-bi-
3.1.7.3. Synthesis of ethyl 2-(4-bromo-3-methylphenoxy)acetate
phenyl]-4-yl)oxy)acetate (8d). Solid, mp 107e109 ꢁC; 1H NMR
(7c). Solid, mp 36e38 ꢁC; 1H NMR (500 MHz, CDCl3):
d
7.40 (d,
(500 MHz, CDCl3):
d
7.08 (s, 1H), 7.05 (d, J¼8.5 Hz, 1H), 7.03 (dd,
J¼8.5 Hz, 1H), 6.81 (d, J¼2.5 Hz, 1H), 6.61 (dd, J¼9, 3.5 Hz, 1H), 4.58
J¼7.5, 2.0 Hz, 2H), 6.72 (s, 1H), 6.72 (d, J¼8.0 Hz, 1H), 6.67 (dd, J¼8.0,
2.5 Hz, 1H), 5.06 (br s, 1H), 4.68 (s, 2H), 4.29 (q, J¼7.0 Hz, 2H), 2.32
(s, 3H), 2.21 (s, 3H), 1.31 (t, 7.0 Hz) ppm; 13C NMR (100 MHz, CDCl3):
(s, 2H), 4.27 (q, J¼7.5 Hz, 2H), 2.36 (s, 3H),1.30 (t, J¼7.0 Hz, 3H) ppm.
3.1.7.4. Synthesis of ethyl 2-(2-benzyl-4-bromophenoxy)acetate
d 169.7,155.1,154.7,137.3,135.0,134.5,132.4,131.3,127.7,127.0,117.1,
112.8, 111.0, 66.0, 61.6, 20.9, 16.5, 14.4 ppm. HRMS calcd for
(7d).18 Solid, mp 69e71 ꢁC; 1H NMR (400 MHz, CDCl3):
d
7.25 (m,
7H), 6.62 (d, J¼11.0 Hz, 1H), 4.59 (s, 2H), 4.27 (q, J¼7.2 Hz, 2H), 1.30
C18H20O4 [MþH] 301.1440, found 301.1449.
(t, J¼8.5 Hz, 3H) ppm.
3.1.8.5. Synthesis of ethyl 2-((40-hydroxy-2,20-dimethyl-[1,10-bi-
3.1.7.5. Synthesis of ethyl 2-(3-benzyl-4-bromophenoxy)acetate
phenyl]-4-yl)oxy)acetate (8e). Oil; 1H NMR (500 MHz, CDCl3):
d 6.99
(7e). Solid, mp 40e43 ꢁC; 1H NMR (400 MHz, CDCl3):
d
7.46 (d,
(d, J¼8.0 Hz, 1H), 6.92 (d, J¼7.5 Hz, 1H), 6.81 (d, J¼2.5 Hz, 1H), 6.73
(dd, J¼7.0, 4.0 Hz, 1H), 6.72 (d, J¼3.0 Hz, 1H), 6.67 (dd, J¼8.0, 3.0 Hz,
1H), 4.84 (s, 1H), 4.64 (s, 2H), 4.29 (q, J¼7.0 Hz, 2H), 2.01 (s, 3H), 1.98
(s, 3H), 1.31 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
J¼8.8 Hz, 1H), 7.30 (t, J¼7.6 Hz, 2H), 7.25 (m, 2H), 7.18 (d, J¼6.4 Hz,
2H), 6.69 (d, J¼2.8 Hz, 1H), 6.65 (dd, J¼8.8, 2.8 Hz, 1H), 4.55 (s, 2H),
4.23 (q, J¼6.4 Hz, 2H), 4.06 (s, 2H), 1.27 (t, J¼7.2 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3):
d
168.8, 157.4, 141.9, 139.3, 133.7, 129.3,
d 169.5, 157.0, 154.8, 138.1, 138.1, 135.0, 133.8, 131.1, 131.0, 116.7,
128.8, 126.6, 117.9,116.7, 114.2, 65.7, 61.7, 42.1,14.4 ppm. HRMS calcd
116.3, 112.6, 111.6, 65.7, 61.6, 20.4, 20.2, 14.4 ppm. HRMS calcd for
for C17H17BrO3 [MþNa] 371.0259, found 371.0259.
C18H20O4 [MþNa] 323.1259, found 323.1258.

A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
5413
3.1.8.6. Synthesis of ethyl 2-((2-benzyl-40-hydroxy-[1,10-bi-
was then washed with brine, dried with magnesium sulfate, and
concentrated. Flash chromatography on silica gel (75% ethyl ace-
tate/hexanes) yielded the ethyl ester product (0.021 g, 74% yield),
which, for stability reasons, was allowed to auto-transesterify at
room temperature in methanol (10 mL) over a period of a few days
to yield the corresponding methyl ester, 1h as an oil.
phenyl]-4-yl)oxy)acetate (8f). Solid, mp 109e113 ꢁC; 1H NMR
(400 MHz, CDCl3):
d
7.21 (t, J¼6.4 Hz, 2H), 7.14 (t, J¼8.0 Hz, 2H), 7.07
(d, J¼8.0 Hz, 2H), 6.98 (d, J¼7.2 Hz, 2H), 6.80 (d, J¼8.8 Hz, 2H), 6.78
(dd, J¼6.4, 3.0 Hz, 1H), 6.73 (d, J¼2.5 Hz, 1H), 5.12 (s, 1H), 4.59 (d,
2H), 4.24 (q, 6.4 Hz, 2H), 3.90 (s, 2H), 1.28 (t, 7.2 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3):
d 169.6, 157.1, 155.4, 141.3, 140.2, 135.9,
133.6, 131.6, 130.9, 129.1, 128.5, 126.1, 116.6, 115.2, 112.4, 65.6, 61.8,
39.5, 25.0, 14.4 ppm. HRMS calcd for C23H22O4 [MþNa] 385.1416,
found 385.1429.
3.1.9.1. Synthesis of methyl 2-((40-(2-(dimethylamino)ethoxy)-2-
methyl-[1,10-biphenyl]-4-yl)oxy)acetate
(1a). Oil;
1H
NMR
(400 MHz, acetone-d6):
d
7.22 (d, J¼9.2 Hz, 2H), 7.10 (d, J¼8.0 Hz,
1H), 6.98 (d, J¼8.8 Hz, 2H), 6.86 (d, J¼2.4 Hz, 1H), 6.79 (dd, J¼8.8,
2.8 Hz, 1H), 4.75 (s, 2H), 4.13 (t, 5.6 Hz, 2H), 3.75 (s, 3H), 2.72 (t,
5.6 Hz, 2H), 2.30 (s, 6H), 2.22 (s, 3H) ppm; 13C NMR (100 MHz,
3.1.8.7. Synthesis of ethyl 2-((20-benzyl-40-hydroxy-[1,10-bi-
phenyl]-4-yl)oxy)acetate (8g). Solid, mp 70e72 ꢁC; 1H NMR
(400 MHz, CDCl3):
d
7.22 (t, J¼8.0 Hz, 2H), 7.16 (t, J¼4.4 Hz, 2H), 7.14
acetone-d6): d 169.3, 158.1, 157.4, 136.8, 135.2, 134.0, 130.9, 130.5,
116.6, 114.3, 111.9, 66.5, 64.9, 58.3, 51.5, 45.5, 20.3 ppm. HRMS calcd
for C20H25NO4 [MþH] 344.1862, found 344.1863.
(d, J¼8.8 Hz, 1H), 7.99 (d, J¼9.0 Hz, 2H), 6.88 (d, J¼6.4 Hz, 2H), 6.72
(dd, J¼8.0, 2.8 Hz, 1H), 6.63 (d, J¼2.4 Hz, 1H), 4.98 (s, 1H), 4.64 (s,
2H), 4.29 (q, 7.2 Hz, 2H), 3.88 (s, 2H), 1.31 (t, 6.4 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3):
d
169.4, 156.9, 155.1, 141.4, 140.2, 135.1,
3.1.9.2. Synthesis of methyl 2-((40-(2-(dimethylamino)ethoxy)-20-
134.5, 131.7, 130.9, 129.1, 128.5, 126.1, 117.0, 114.5, 113.4, 65.8, 61.7,
39.3, 14.4 ppm. HRMS calcd for C23H22O4 [MþNa] 385.1416, found
385.1399.
methyl-[1,10-biphenyl]-4-yl)oxy)acetate
(1b). Oil;
1H
NMR
(400 MHz, acetone-d6):
d
7.23 (d, J¼8.8 Hz, 2H), 7.09 (d, J¼9.2 Hz,
1H), 6.98 (d, J¼8.8 Hz, 2H), 6.85 (d, J¼2.8 Hz, 1H), 6.80 (dd, J¼8.8,
2.8 Hz, 1H), 4.78 (s, 2H), 4.10 (t, J¼5.6 Hz, 2H), 3.76 (s, 3H), 2.68 (t,
5.6 Hz, 2H), 2.27 (s, 6H), 2.22 (s, 3H) ppm. 13C NMR (100 MHz, ac-
3.1.8.8. Synthesis of ethyl 2-((2,30-dibenzyl-40-hydroxy-[1,10-bi-
phenyl]-4-yl)oxy)acetate (8h). Solid, mp 104e105 ꢁC; 1H NMR
etone-d6): d 170.1, 159.1, 158.0, 137.4, 135.8, 134.8, 131.7, 131.3, 117.2,
(500 MHz, CDCl3):
d
7.26 (t, 7.5 Hz, 2H), 7.19 (t, J¼7.5 Hz, 4H), 7.15 (t,
115.3, 112.7, 67.2, 65.8, 59.2, 52.3, 46.3, 21.0 ppm. HRMS calcd for
C20H25NO4 [MþH] 344.1862, found 344.1864.
J¼7.5 Hz, 2H), 6.97 (dd, J¼8.0, 2.0 Hz, 1H), 6.95 (d, J¼6.5 Hz, 2H),
6.77 (dd, J¼8.0, 2.5 Hz, 1H), 6.75 (d, J¼8.0 Hz, 1H), 6.73 (d. J¼2.5 Hz,
1H), 4.86 (s,1H), 4.58 (s, 2H), 4.24 (q, J¼7.0 Hz, 2H), 3.94 (s, 2H), 3.89
3.1.9.3. Synthesis of methyl 2-((40-(2-(dimethylamino)ethoxy)-
(s, 2H), 1.27 (t, 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
169.4,
2,30-dimethyl-[1,10-biphenyl]-4-yl)oxy)acetate (1c). Oil; 1H NMR
157.1, 153.0, 141.4, 140.2, 140.1, 135.9, 133.9, 132.3, 131.6, 129.1, 129.0,
128.5, 126.9, 126.6, 126.1, 116.8, 115.6, 112.3, 65.6, 61.7, 39.6, 36.6,
14.4 ppm. HRMS calcd for C30H28O4 [MþNa] 475.1885, found
475.1892.
(400 MHz, methanol-d4):
d
7.06 (d, J¼8.4 Hz, 1H), 7.02 (m, 2H), 6.91
(d, 1H), 6.81 (d, J¼2.8 Hz), 6.74 (dd, J¼8.8, 2.8 Hz, 1H), 4.70 (s, 2H),
4.15 (t, J¼6.0 Hz, 2H), 3.79 (s, 3H), 2.84 (t, J¼5.4 Hz, 2H), 2.39 (s, 6H),
2.24 (s, 3H), 2.20 (s, 3H) ppm; 13C NMR (100 MHz, methanol-d4):
d
170.4, 157.1, 155.9, 136.8, 135.6, 134.0, 131.5, 130.6, 127.6, 126.1,
3.1.8.9. Synthesis of ethyl 2-((20,3-dibenzyl-40-hydroxy-[1,10-bi-
116.1, 111.5, 110.4, 66.0, 64.8, 58.1, 44.9, 19.8, 15.4 ppm. HRMS calcd
for C21H27NO4 [MþH] 358.2018, found 358.2017.
phenyl]-4-yl)oxy)acetate (8i). Solid, mp 140e143 ꢁC; 1H NMR
(500 MHz, acetone-d6):
d
¼7.23 (m, 9H), 7.94 (d, J¼8.5 Hz, 1H), 7.05
(dd, J¼8.0, 2.0 Hz), 7.03 (d, J¼2.0 Hz, 1H), 6.99 (d, J¼8.0 Hz, 2H), 6.75
(d, J¼8.5 Hz, 1H), 6.71 (dd, J¼8.5, 3.0 Hz, 1H), 6.65 (d, J¼2.5 Hz, 1H),
5.22 (br s, 1H), 4.66 (s, 2H), 4.32 (q, J¼7.0 Hz, 2H), 4.05 (s, 2H), 3.88
(s, 2H), 1.33 (t, J¼6.5 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
3.1.9.4. Synthesis of methyl 2-((40-(2-(dimethylamino)ethoxy)-
20,3-dimethyl-[1,10-biphenyl]-4-yl)oxy)acetate (1d). Oil; 1H NMR
(400 MHz, acetone-d6):
d
7.07 (m, 3H), 6.87 (d, J¼8.8 Hz, 1H), 6.84
(d, J¼2.4 Hz, 1H), 6.79 (dd, J¼8.0, 2.8 Hz, 1H), 4.80 (s, 2H), 4.09 (t,
d
169.5, 155.0, 154.8, 141.4, 141.0, 140.1, 134.9, 134.7, 132.3, 131.7,
J¼6.0 Hz, 2H), 3.76 (s, 3H), 2.67 (t, J¼6.0 Hz, 2H), 2.28 (s, 3H), 2.27 (s,
130.2, 129.3, 129.1, 128.5, 128.5, 126.1, 126.1, 117.0, 113.4, 111.4, 66.1,
61.6, 39.3, 36.2, 14.4 ppm. HRMS calcd for C30H28O4 [MþNa]
475.1885, found 475.1884.
6H), 2.22 (s, 3H) ppm; 13C NMR (100 MHz, acetone-d6):
d 169.4,
158.2, 155.3, 136.6, 134.8, 134.3, 131.9, 130.9,127.7, 126.4, 116.4,111.9,
111.01, 66.5, 65.2, 58.4, 45.6, 20.3, 15.8 ppm. HRMS calcd for
C21H27NO4 [MþH] 358.2018, found 358.2024.
3.1.8.10. Synthesis of ethyl 2-((2,20-dibenzyl-40-hydroxy-[1,10-bi-
phenyl]-4-yl)oxy)acetate (8j). Oil; 1H NMR (500 MHz, CDCl3):
d
7.20
3.1.9.5. Synthesis of methyl 2-((40-(2-(dimethylamino)ethoxy)-
(m, 4H), 7.15 (m, 2H), 6.99 (dd, J¼7.0, 1.5 Hz, 1H), 6.93 (d, J¼8.5 Hz),
6.88 (d, J¼7.0 Hz, 4H), 6.73 (dd, J¼8.0, 3.0 Hz, 1H), 6.72 (s, 1H), 6.67
(dd, J¼7.5, 2.0 Hz, 1H), 6.59 (d, J¼2.5 Hz, 1H), 4.73 (s, 1H), 4.58 (s,
2H), 4.25 (q, J¼7.5 Hz, 2H), 3.59 (d, J¼15 Hz, 1H), 3.56 (d, J¼15 Hz,
1H), 3.52 (d, J¼15 Hz, 1H), 3.46 (d, J¼15.5 Hz, 1H), 1.28 (t, J¼7.0 Hz,
2,20-dimethyl-[1,10-biphenyl]-4-yl)oxy)acetate (1e). Oil; 1H NMR
(400 MHz, acetone-d6):
d 6.96 (m, 2H), 6.86 (m, 2H), 6.79 (m, 2H),
4.75 (s, 2H), 4.10 (t, J¼5.6 Hz, 2H), 3.76 (s, 3H), 2.68 (t, J¼6.8 Hz, 2H),
2.27 (s, 6H), 2.00 (s, 3H), 2.00 (s, 3H) ppm; 13C NMR (100 MHz,
acetone-d6):
d 169.4, 158.4, 157.4, 137.7, 137.4, 134.7, 133.6, 130.8,
3H) ppm; 13C NMR (100 MHz, CDCl3):
d
169.0, 157.0, 154.8, 141.2,
130.7, 116.1, 115.9, 111.7, 111.6, 66.4, 64.9, 58.4, 45.6, 19.6 ppm. HRMS
140.4,140.4, 134.1,133.0, 131.5, 131.5, 129.1,129.0, 128.2, 125.9, 116.3,
116.2, 112.8, 111.7, 65.4, 61.4, 39.4, 39.3, 14.1 ppm. HRMS calcd for
C30H28O4 [MþNa] 475.1885, found 475.1884.
calcd for C21H27NO4 [MþH] 358.2018, found 358.2018.
3.1.9.6. Synthesis of methyl 2-((2-benzyl-40-(2-(dimethylamino)
ethoxy)-[1,10-biphenyl]-4-yl)oxy)acetate
(1f). Oil;
1H
NMR
3.1.9. General procedure for the preparation of the biphenyl amino-
methyl esters (1aej). Compound 8h (0.0203 g, 0.056 mmol) was
combined with cesium carbonate (0.091 g, 0.280 mmol), dissolved
in acetone (2 mL), and heated to 80 ꢁC for 1e2 h. After cooling to
room temperature, 2-(dimethylamino)ethyl chloride hydrochloride
(0.090 g, 0.277 mmol) was added and the reaction was returned to
80 ꢁC overnight. The reaction was again cooled to room tempera-
ture, concentrated, and taken up in ethyl acetate. The organic layer
(400 MHz, acetone-d6):
d
7.22 (t, J¼7.2 Hz, 2H), 7.16 (m, 4H), 7.01 (d,
J¼7.2 Hz, 2H), 6.95 (d, J¼8.8 Hz, 2H), 6.84 (dd, J¼8.0, 2.8 Hz, 1H),
6.78 (d, J¼2.8 Hz,1H), 4.71 (s, 2H), 4.12 (t, J¼5.6 Hz, 2H), 3.94 (s, 2H),
3.71 (s, 3H), 2.71 (t, J¼6.0 Hz, 2H), 2.29 (s, 6H) ppm; 13C NMR
(100 MHz, acetone-d6):
d 169.2, 158.3, 157.5, 141.5, 140.1, 135.4,
133.7, 131.4, 130.7, 129.0, 128.4, 126.0, 116.6, 114.3, 112.2, 66.5, 64.9,
58.3, 51.5, 45.5, 39.0 ppm. HRMS calcd for C26H29NO4 [MþH]
420.2175, found 420.2162.

5414
A.B. Williams, R.N. Hanson / Tetrahedron 68 (2012) 5406e5414
3.1.9.7. Synthesis of methyl 2-((20-benzyl-40-(2-(dimethylamino)
ethoxy)-[1,10-biphenyl]-4-yl)oxy)acetate 1H
(1g). Oil; NMR
(500 MHz, acetone-d6):
Center for providing HRMS data and the Microanalysis Center at the
University of Illinois at Urbana-Champaign for providing elemental
analysis. A.B.W. was supported by a training award from the De-
partment of Energy, DE-SC0001781.
d
7.163 (m, 6H), 7.00 (d, J¼6.8 Hz, 2H), 6.95
(d, J¼8.8 Hz, 2H), 6.85 (dd, J¼8.4, 2.0 Hz, 1H), 6.79 (d, J¼2.8 Hz, 1H),
4.77 (s, 2H), 4.069 (t, J¼6.0 Hz, 2H), 3.94 (s, 2H), 3.75 (s, 3H), 2.67 (t,
J¼5.6 Hz, 2H), 2.26 (s, 6H) ppm; 13C NMR (100 MHz, acetone-d6):
Supplementary data
d
169.3, 158.5, 157.3, 141.7, 140.0, 134.8, 134.4, 131.3, 130.7, 128.9,
128.4, 126.0, 116.6, 114.4, 112.2, 66.4, 65.0, 58.3, 41.4, 45.5, 39.0 ppm.
HRMS calcd for C26H29NO4 [MþH] 420.2175, found 420.2177.
Compound characterization data and experimental details on
the biological assays are provided. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tet.2012.04.106.
3.1.9.8. Synthesis of methyl 2-((2,30-dibenzyl-40-(2-(dimethyla-
mino)ethoxy)-[1,10-biphenyl]-4-yl)oxy)acetate (1h). Oil; 1H NMR
(400 MHz, acetone-d6):
d
7.22 (m, 6H), 7.13 (m, 3H), 7.06 (dd, J¼8.0,
References and notes
2.4 Hz, 1H), 7.03 (d, J¼2 Hz, 1H), 6.97 (dd, J¼6.4, 2 Hz, 2H), 6.81 (dd,
J¼8.0, 2.8 Hz, 1H), 6.78 (d, J¼2.8 Hz, 1H), 4.70 (s, 2H), 4.11 (t, J¼6 Hz,
2H), 3.94 (s, 2H), 3.91 (s, 2H), 3.70 (s, 3H), 2.70 (t, J¼6 Hz, 2H), 2.28
1. Henchey, L. K.; Jochim, A. L.; Arora, P. S. Curr. Opin. Chem. Biol. 2008, 12,
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(s, 6H) ppm; 13C NMR (100 MHz, acetone-d6):
d
169.2, 157.5, 155.9,
3. Perez de Vega, M. J.; Martín-Martínez, M.; Gonzalez-Muniz, R. Curr. Top. Med.
ꢀ
ꢀ
~
Chem. 2007, 7, 33e62.
141.6, 141.5, 140.0, 135.5, 133.6, 131.7, 131.4, 129.7,129.2, 128.9, 128.5,
128.4, 128.3, 126.0, 125.9, 116.6, 112.2, 111.4, 66.9, 64.9, 58.5, 51.5,
45.6, 29.1, 36.0 ppm. HRMS calcd for C33H35NO4 [MþH] 510.2644,
found 510.2639.
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3.1.9.9. Synthesis of methyl 2-((20,3-dibenzyl-40-(2-(dimethyla-
mino)ethoxy)-[1,10-biphenyl]-4-yl)oxy)acetate (1i). Oil; 1H NMR
(400 MHz, acetone-d6):
d
7.28 (d, J¼7.2 Hz, 2H), 7.23 (t, J¼7.6 Hz,
2H), 7.18 (d, J¼8.4 Hz, 2H), 7.14 (dd, J¼7.2, 2.4 Hz, 1H), 7.10 (d,
J¼8.0 Hz, 2H), 7.04 (m, 2H), 6.95 (d, J¼7.2 Hz, 2H), 6.91 (d, J¼8.8 Hz,
1H), 6.83 (dd, J¼8.0, 2.0 Hz, 1H), 6.79 (d, J¼2.8 Hz, 1H), 4.80 (s, 2H),
4.05 (t, J¼5.6 Hz, 2H), 4.01 (s, 2H), 3.90 (s, 2H), 3.77 (s, 3H), 2.64 (t,
J¼6.0 Hz, 2H), 2.24 (s, 6H) ppm; 13C NMR (100 MHz, acetone-d6):
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d
169.3, 158.4, 154.9, 141.7, 141.3, 139.9, 134.7, 134.5, 131.9, 131.3,
130.1, 129.2, 128.9, 128.31, 128.4, 125.9, 116.7, 112.2, 111.7, 66.4, 65.4,
58.3, 51.5, 45.5, 39.1, 35.7 ppm. HRMS calcd for C33H35NO4 [MþH]
510.2644, found 510.2639.
3.1.9.10. Synthesis of methyl 2-((2,20-dibenzyl-40-(2-(dimethyla-
mino)ethoxy)-[1,10-biphenyl]-4-yl)oxy)acetate (1j). Oil; 1H NMR
(400 MHz, acetone-d6):
d
7.21 (m, 4H), 7.15 (m, 2H), 7.00 (dd, J¼8.8,
3.2 Hz, 2H), 6.93 (dd, J¼5.6, 1.2 Hz, 4H), 6.83 (dd, J¼8.0, 2.8 Hz, 1H),
6.81 (m, 2H), 6.77 (d, J¼2.8 Hz, 1H), 4.71 (s, 2H), 4.06 (t, J¼5.6 Hz,
2H), 3.72 (s, 3H), 3.57 (m, 4H), 2.64 (t, J¼5.6 Hz, 2H), 2.24 (s, 6H)
ppm; 13C NMR (100 MHz, acetone-d6):
d 158.6, 157.6, 141.5, 141.3,
141.0, 140.9, 131.6, 131.6, 129.2, 128.4, 126.1, 126.0, 116.3, 116.2, 111.8,
111.8, 66.4, 64.9, 58.3, 51.5, 45.5, 39.4, 39.3 ppm. HRMS calcd for
C33H35NO4 [MþH] 510.2644, found 510.2643.
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Acknowledgements
We gratefully acknowledge Donald P. McDonnell and Ching-Yi
Chang at Duke University Medical Center for performing the bi-
ological evaluation of the synthesized compounds. Additionally we
are grateful to the Boston University Chemical Instrumentation
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