The synthesis and resolution of 2,2′-, 4,4′-, and 6,6′-substituted chiral biphenyl derivatives for application in the preparation of chiral materials

Article abstract of DOI:10.1021/jo060553d

Various routes were examined for the synthesis of chiral biphenyl species that are substituted at the 2,2′, 4,4′ and 6,6′ positions. Because the biaryl bond is tetrasubstituted, many coupling reactions were not suitable. The most reliable coupling reaction proved to be the Ullmann, which gave the desired product in 82% yield. The products were required as the starting point for the preparation of chiral materials using these as the monomer. For this reason, a route was required that produced large quantities of both enantiomers. The two enantiomers were resolved at the penultimate step by the use of chiral HPLC. A complicating feature proved to be the necessity to have a reactive group at the 4,4′ positions, which would permit polymerization though this point. Ultimately, we employed an Ullmann coupling on a dibrominated arene, which occurred selectively at the more hindered bromine by virtue of the directing effect of an ortho ester substituent.

Full text of DOI:10.1021/jo060553d

The Synthesis and Resolution of 2,2′-, 4,4′-, and 6,6′-Substituted
Chiral Biphenyl Derivatives for Application in the Preparation of
Chiral Materials
Pedro J. Montoya-Pelaez, Yoon-Seo Uh, Christopher Lata, Matthew P. Thompson,
Robert P. Lemieux, and Cathleen M. Crudden*
Department of Chemistry, Queen’s UniVersity, Kingston, Ontario, K7L 3N6
cruddenc@chem.queensu.ca
ReceiVed March 13, 2006
Various routes were examined for the synthesis of chiral biphenyl species that are substituted at the 2,2′,
4,4′ and 6,6′ positions. Because the biaryl bond is tetrasubstituted, many coupling reactions were not
suitable. The most reliable coupling reaction proved to be the Ullmann, which gave the desired product
in 82% yield. The products were required as the starting point for the preparation of chiral materials
using these as the monomer. For this reason, a route was required that produced large quantities of both
enantiomers. The two enantiomers were resolved at the penultimate step by the use of chiral HPLC. A
complicating feature proved to be the necessity to have a reactive group at the 4,4′ positions, which
would permit polymerization though this point. Ultimately, we employed an Ullmann coupling on a
dibrominated arene, which occurred selectively at the more hindered bromine by virtue of the directing
effect of an ortho ester substituent.
Introduction
generally useful ligands developed to date (Figure 1). In addition
to binaphthyls, chiral ligands based on biphenyl architectures
have also been developed, providing some of the most highly
enantioselective catalysts known.4b For example, SEGPHOS (3)
and its derivatives have been used as chiral ligands in Cu(I)-
catalyzed cross-aldol type reactions,5 Ru-mediated hydrogena-
tion of ketones and alkenes,6 and Pd-catalyzed allene formation.7
Biphenyl (4) as well as derivatives of 2 are the key components
of asymmetric Mo-catalyzed ring closing metathesis catalysts.8
Derivatives of BINOL are also employed in materials
chemistry, where they can induce helical structures in certain
nematic liquid crystals. They are particularly effective in liquid
crystals with complementary biphenyl structures, which promote
Although the largest application of chiral organic compounds
is in the synthesis of pharmaceutical compounds, chiral auxil-
iaries, and chiral ligands, the need for chiral molecules/
monomers in materials chemistry is growing. For example, small
quantities of chiral organic compounds can induce technologi-
cally important bulk properties in soft materials such as
polymers, self-assembled monolayers, and liquid crystals. The
propagation of chirality from the chiral dopant to the bulk of
the material is a function of dopant-host complementarity and
molecular recognition. Axially chiral binaphthyl and biphenyl
structures are particularly effective at inducing chiral bulk
properties in a range of materials1,2 and, at the same time, are
widely known as chiral ligands for some of the most efficient
asymmetric catalysts developed to date.
(4) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b) Shimizu,
H.; Nagasaki, I.; Saito, N. Tetrahedron 2005, 61, 5405-5432.
(5) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005, 7,
3757-3760.
In terms of chiral ligands, axially chiral binaphthyl com-
pounds BINOL (1)3 and BINAP (2)4 are two of the most
(6) Jeulin, S.; Duprat de Paule, S. D.; Ratovelomanana-Vidal, V.; Genet,
J.-P.; Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5799-5804.
(1) Lemieux, R. P. Acc. Chem. Res. 2001, 34, 845-853.
(2) Gin, M. S.; Yokozawa, T.; Prince, R. B.; Moore, J. S. J. Am. Chem.
Soc. 1999, 121, 2643-2644.
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5764-5767.
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Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526-8533.
(3) Brunel, J. M. Chem. ReV. 2005, 105, 857-897.
10.1021/jo060553d CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/11/2006
J. Org. Chem. 2006, 71, 5921-5929
5921

Montoya-Pelaez et al.
Dai15 developed a Negishi cross coupling using P(t-Bu)3 as the
ligand of choice. This was quickly followed by other examples
of hindered biaryl syntheses via Negishi,16 Suzuki-Miyaura,17
and Stille couplings.18 More recently, organocuprate oxidation
has been used to couple hindered Grignard reagents,19 as well
as organolithium reagents,20 with encouraging results.
Historically, the classical Ullmann coupling11 and the reduc-
tive coupling of diazonium salts21-23 have been most effective
in the synthesis of hindered biaryls. Neither of these reactions
require the presence of special ligands or expensive reagents.
The apparent simplicity of these last two reactions and the
presence of closely related structures in the literature convinced
us to explore synthetic pathways involving both of these
reactions in the key coupling step.
FIGURE 1.
the propagation of chirality through noncovalent core-core
interactions.9 One of us has shown that axially chiral biphenyl
dopants are very effective at inducing polar order in smectic
liquid crystals with complementary biaryl core structures via
intermolecular chirality transfer.1 For example, a biaryl dopant
has been shown to induce some of the highest ferroelectric
polarizations ever reported in achiral smectic C liquid crystals
with 2-phenylpyrimidine cores. This type of behavior is
particularly relevant to the development of fast switching
ferroelectric liquid crystal microdisplays.10
Route 1: Diazonium Coupling of Bromoaniline Deriva-
tive. Denmark and Matsuhashi21 reported the synthesis of
compound 7 via a reductive coupling of diazonium salts
generated from amine 6.
As part of a project directed toward the synthesis of chiral
materials based on biaryl compounds, we required access to
large quantities of highly functionalized tetra-ortho-substituted
biphenyls of the general structure of 5, Scheme 1. Polar,
hydrogen-bonding groups are required around the axis to
facilitate the organization of the material and as a handle for
further synthetic manipulations. Most critical is the presence
of halogen substituents para to the ring juncture, because these
sites will be employed to incorporate the chiral biphenyl into
various materials. As shown in Scheme 1, using 5 as the starting
point, we will be able to introduce aryl, vinyl, siloxyl, and a
variety of other groups by Pd- or Rh-catalyzed coupling
reactions.
Because large amounts of the target compound were required,
the route to these species has to be efficient and scalable. In
addition, a resolution should be possible as close to the final
target as possible, providing access to both enantiomers. Finally,
the synthesis should be modular to permit the introduction of a
variety of substituents.
For our route, precursor 11, in which the para position is
substituted with a bromine atom, was required. This species
was initially synthesized via isatin intermediate 9,24-26 which
was prepared from o-toluidine, in two steps (Scheme 2).
Importantly, bromination of 9 occurred exclusively para to the
amide moiety. Hydrolysis of 10 provided substrate 11 for the
key coupling step.
Although the coupling of 6 in which the key para position is
unsubstituted could be reliably reproduced using the Denmark
procedure,21 compound 11 gave the desired compound 12 in
extremely low yield. Although the 1H NMR spectrum and
weight of the crude product suggested a clean reaction with a
fairly high yield (about 70%), it soon became obvious that a
large amount of spectroscopically invisible material accompa-
nied the product, complicating purification. When purification
was finally achieved, the yield of the coupling reaction was at
best 13%.
Synthetic Routes
Because the only difference between substrates 6 and 11 is
the para-bromo substituent, we hypothesized that activation of
Despite the large number of coupling reactions that can be
used in the synthesis of biaryls,11-14 only a few are effective at
forming tetra-substituted biaryls. The majority of methods that
are used to prepare these hindered compounds require the
presence of a tether, effectively preorganizing the two aryl
groups.14 Although asymmetric syntheses have been developed
using chiral tethers or chiral catalysts, most suffer from
insufficient generality, cost, or are too lengthy to be employed
for the production of large quantities of the final product.13,14
Certain Pd-catalyzed aryl-aryl coupling reactions can be
employed in the synthesis of sterically hindered biaryls. Fu and
(15) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724.
(16) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028-
13032.
(17) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am.
Chem. Soc. 2004, 126, 15195-15201.
(18) Su, W.; Urgaonkar, S.; McLaughlin, P. A.; Verkade, J. J. Am. Chem.
Soc. 2004, 126, 16433-16439.
(19) Surry, D. S.; Su, X.; Fox, D. J.; Franckevicius, V.; Macdonald, S.
J. F.; Spring, D. R. Angew. Chem., Int. Ed. 2005, 44, 1870-1873.
(20) Surry, D. S.; Fox, D. J.; Macdonald, S. J. F.; Spring, D. R. Chem.
Commun. 2005, 2589-2590.
(21) Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479-
3586.
(22) Atkinson, E. R.; Lawler, H. J. Organic Syntheses; Wiley: New York,
1941; Collect. Vol. No. I, p 222.
(23) Atkinson, E. R.; Lawler, H. J.; Heath, J. C.; Kimball, E. H.; Read,
E. R. J. Am. Chem. Soc. 1941, 63, 730-733.
(24) Marvel, C.; Hiers, G. Organic Syntheses; Wiley: New York, 1941;
Collect. Vol. No. I, p 327.
(25) Kollmar, M.; Parlitz, R.; Oevers, S. R.; Helmchen, G. Organic
Syntheses; Wiley: New York, 2002; Vol. 79, pp 196-204.
(26) Pavia, M. R.; Moos, W. H.; Hershenson, F. M. J. Org. Chem. 1990,
55, 560-564.
(9) Gottarelli, G.; Hibert, M.; Samori, B.; Solladie, G.; Spada, G. P.;
Zimmermann, R. J. Am. Chem. Soc. 1983, 105, 7318-7321.
(10) Lagerwall, S. T. Ferroelectric and Antiferroelectric Liquid Crystals;
Wiley-VCH: Weinhem, Germany, 1999.
(11) Fanta, P. E. Synthesis 1974, 9-21.
(12) Hassan, J.; Sevignon, M.; Gozzi, C.; Schultz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359-1469.
(13) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl.
1990, 29, 977-991.
(14) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.
5922 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Substituted Chiral Biphenyl DeriVatiVes
SCHEME 1. Introduction of Polymerizable Groups on the Biaryl Framework
SCHEME 2
the C-Br bond and subsequent reaction with the amine from
another molecule27 in a Hartwig-Buchwald-type might be
responsible for the polymeric contaminants observed.
In an attempt to simplify the purification, the crude biphenyl,
12, was taken through to the next step, esterified,28 and then
purified on flash silica. This method of purification, while
successful, proved unsatisfactory as we planned to resolve the
biphenyl atropisomers at the acid stage by salt formation with
quinine. The purified diester would, thus, have to be hydrolyzed
(88% yield), resolved, and then re-esterified (85% yield), in
effect adding two unwanted steps to the pathway.
In lieu of the apparent incompatibility of the para-bromo
substituent under coupling conditions, we attempted to introduce
the halogen after the coupling by an electrophilic bromination
(eq 2). Unfortunately, this reaction proved highly unselective,
with the crude 1H NMR showing the presence of at least three
other isomers, all in greater yield than the desired product. The
directing power of the phenyl group is obviously not strong
enough to out-compete that of the methyl group.
Route 2: Diazonium Coupling of Nitroaniline Derivative.
Re-evaluating our synthetic route, we decided to employ a nitro
group as a synthon for the bromo substituent. Even though
conversion of the NO2 group into Br requires two steps
(reduction and Sandmeyer reaction), the improved behavior of
the substrate at problem steps more than compensated for the
additional steps. Furthermore, this route would provide facile
access to the para-diiodo biphenyl derivative, 5b, which would
be the most reactive substrate for a slate of future metal-
catalyzed coupling reactions.
Nitration of methyl isatin 9 proceeded smoothly, as did the
hydrolysis of 14, yielding 2-amino-3-methyl-5-nitrobenzoic acid
15 (Scheme 3).29 As expected, the coupling step proceeded with
higher but still unsatisfactory yields (47%). The crude product
showed the presence of both unreacted starting material as well
(27) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248,
2337-2364.
(28) Hosangadi, B. D.; Dave, R. H. Tetrahedron Lett. 1996, 37, 6375-
6378.
(29) Cassebaum, H. J. Prakt. Chem. 1964, 23, 301.
J. Org. Chem, Vol. 71, No. 16, 2006 5923

Montoya-Pelaez et al.
SCHEME 3
as a small amount of 2-hydroxy-3-methyl-5-nitrobenzoic acid.
The former could be removed by trituration with ether, but final
purification still required exhaustive silica gel chromatography,
which was not desirable on a large scale.
moderate success (yields < 10% for the former and in the 50%
range for the latter). The main difficulty in purification was that
the product was always contaminated with small amounts of
monoiodinated product resulting from reduction of one of the
two diazonium salts. This byproduct had a very similar Rf as
di-iodinated species 5b, making it difficult to remove.
Not content with the extent of time and labor required to
perform this reaction, we examined other options. Moore and
co-workers32-34 have effectively used 1-aryl-3,3-dialkyltriazenes
as masking groups for aryl iodides in the synthesis of phenyl-
acetylene macrocycles.33 Unfortunately, the yield of the triazene
derivatives from aromatic amine 18 was quite low. Finally, a
recently reported procedure35 using DMSO, NaNO2, and HI
gave the highest yield we have obtained to date in this reaction
(65%) along with little to no byproduct, fast reaction times, and
facile workup. It is worth noting that the conversion of aromatic
diamines to the corresponding aromatic dihalogens is often a
poor reaction, and yields below 50% are common.
Although this route provided access to the desired compound,
a critical look at the synthetic pathway revealed two major
problems that still had to be addressed. First, the isatin route to
15 did not have a very high overall yield (17%), and the
acquisition of large quantities of chloral hydrate was compli-
cated, as it is a controlled substance. Substitution of the chloral
hydrate with the brominated analogue gave slightly lower yields
of the isonitrosoacetanilide. In addition, scale-up of the coupling
reaction was anticipated to be problematic because the reaction
requires low temperatures, carefully controlled addition of
concentrated HCl to the reaction to form the diazonium salt,
followed by another controlled addition of the latter, and the
Compound 16 could be resolved by selective crystallization
of one of the diastereomeric salts with quinine. The enantiomeric
excess of the M-isomer was determined both by chiral SFC and
1H NMR shift reagents (europium tris-3-(heptafluoropropyhy-
droxymethylene)-(+)-camphorate in a 3:1 ratio with (M)-17)
to be >95%. However, the yields after resolution were less than
satisfactory, normally being on the order of 30% for high purity
material. The supernatant afforded an enriched solution of
P-isomer that could not be further resolved, as quinine has no
natural enantiomers (resolution of racemic 16 with quinidine, a
diastereomer of quinine, was not successful). This was prob-
lematic because both enantiomers are ultimately required for
the preparation of chiral materials of both handedness.
Carrying on with the rest of the route, the reduction of nitro
ester 17 with SnCl2 proceeded smoothly and in quantitative
yield. However, the workup of the SnCl2 reduction proved
tedious due to the formation of emulsions. Reduction with Pd/C
and H2 was faster, just as high yielding, and the workup was
trivial. Some care had to be taken in storing the diamino
biphenyl 18, which became oxidized, most likely to the N-oxide,
if left exposed to air. However, the amine could be stored under
nitrogen or argon in the fridge for up to two weeks without
any noticeable degradation.
The final step in the synthesis, conversion of the diamine to
diiodo biphenyl ester 5b was also problematic. Normal aqueous
conditions for the Sandmeyer reaction provided very little
product (10%). This could have been due to the insolubility of
18, as well as the possible loss of product due to the unwanted
hydrolysis of the esters to acids, but no free iodinated acids
were detected. Furthermore, using the free acid as the starting
material still gave poor results. Nonaqueous methods using iso-
amyl nitrite30 and tert-butyl nitrite31 were attempted with
(31) Read, M. W.; Escobedo, J. O.; Willis, D. M.; Beck, P. A.; Strongin,
R. M. Org. Lett. 2000, 2, 3201-3204.
(32) Moore, J. S.; Wienstein, E. J.; Wu, Z. Tetrahedron Lett. 1991, 32,
2465-2466.
(33) Zhang, J.; Pesak, D. J.; Ludwick, J. L.; Moore, J. S. J. Am. Chem.
Soc. 1994, 116, 4227-4239.
(34) Ku, H.; Barrio, J. R. J. Org. Chem. 1981, 46, 5239-5241.
(35) Baik, W.; Luan, W.; Lee, H. J.; Yoon, C. H.; Koo, S.; Kim, B. H.
Can. J. Chem. 2005, 83, 213-219.
(30) Smith, W. B.; Ho, O. C. J. Org. Chem. 1990, 55, 2543-2545.
5924 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Substituted Chiral Biphenyl DeriVatiVes
SCHEME 4
SCHEME 5
at this stage, because acids are known to interfere with the
coupling reaction. Remarkably, the Ullmann coupling proved
to be far superior to our previous coupling attempts in terms of
yield (82%), ease of reaction, reproducibility, and scalability.
The only complication in this route is that hydrolysis of the
ester to the corresponding acid was necessary to perform the
resolution with quinine, as previously described. Rather than
add more steps to the synthesis, chiral chromatography was
examined. In fact, diamino biphenyl 18 could be resolved on
Chiralpak AS column eVen as the ester. Although the maximum
amount of the amine that could be separated in a given run
was limited by the solubility of 18, this method enabled us to
perform the separation at the penultimate step, without additional
synthetic steps. In addition, complete baseline separation was
achieved, providing both enantiomers in pure form. Thus, using
a column of 5 × 50 cm, we were able to obtain 100 mg of
each enantiomer in 100 minutes.
As one final alternative for the coupling reaction, we
examined the recently published organocuprate oxidation of
Grignard reagents.19 Reported yields for the reaction (24 to 25,
eq 3) are comparable to that of the Ullmann (75%), and the
reaction time is much shorter (30 min). However, our substrate
(23) reacted with very low yield (10%), illustrating the sensitiv-
ity of the reaction to variations in substrate. In addition, the
requirement for one full equivalent of Grignard reagent and
oxidant 26, as well as low temperatures, make this method
unappealing for large scale applications.
subsequent evolution of large quantities of gas. With these
considerations in mind, in addition to literature evidence36,37
suggesting that the Ullmann coupling would occur in high yield,
we attempted the synthesis of 5 via an Ullmann coupling.
Route 3: Ullmann Coupling of Iodonitro Derivative. Our
success in the reduction of the nitro group in 17 to the
corresponding amine led us to attempt the reduction of com-
mercially available 2-nitro-3-methyl benzoic acid (NMBA) to
2-amino-3-methyl benzoic acid 19 (Scheme 4). The reduction,
using Pd/C and H2, proceeded smoothly and in quantitative
yield. Direct nitration of 19 is complicated by the protonation
of the amine with concentrated HNO3, so 19 was first protected
as an acetamide. During nitration, the reaction temperature could
not be allowed to rise above 10 °C, otherwise two regioisomers
were observed corresponding to nitration para to the amine and
ortho to the carboxyl substituent,38 respectively (9:1). At 0 °C,
the reaction was selective for the para-nitro isomer, but
significant decreases in rate were observed. Ultimately, we found
that increasing the concentration of the nitrating reagent by using
fuming nitric acid and keeping the reaction temperature at 0
°C gave a selective and fast reaction, providing 21 in 99% yield.
Poor yields in the deprotection of the acetamide were
observed under basic conditions (50-66%).39 However, reflux-
ing 21 in concentrated HCl resulted in efficient removal of the
amide, and 15 precipitated out of solution in high yield.
Although we expected to isolate compound 15 as the HCl salt,
an infrared spectrum of the material shows both the presence
of a primary amine (two peaks at 3473 and 3362 cm-1) as well
as hydrogen bonding between this amine and the carboxylic
acid (very broad peak at 3000 cm-1), implying that internal
hydrogen bonding takes place between the acid and the amine.
Conversion of the amine group in 15 into an iodide via a
Sandmeyer reaction proceeded smoothly (85% yield, Scheme
5). It was necessary to initially add the NaNO2 in a basic solution
of 15, before acidifying, to ensure that no significant hydroxy-
lation side product of the diazonium salt occurred. Fisher
esterification of the acid yielded the Ullmann coupling precursor
23. Protection of the carboxylic acid as an ester was necessary
Route 4: Ullmann Coupling of Dibromo Derivative. One
final pathway investigated for the synthesis of 5a takes
advantage of the observation that Ullmann reactions take place
preferentially at halogens that are ortho to an electron-
withdrawing group such as methoxycarbonyl. Thus, if it were
possible to differentiate between the two bromines in compound
28, we would have a significantly shorter route to the desired
compound, as outlined in Scheme 6.
The synthesis of 28 begins with selective bromination of 19
without prior protection of the latter, using DMSO and HBr.40
The second bromine is then added via the modified Sandmeyer
reaction, and the crude acid is finally esterified. Gratifyingly
the Ullmann coupling proceeded with high selectivity giving
(36) Kanoh, S.; Muramoto, H.; Kobayashi, N. Bull. Chem. Soc. Jpn. 1987,
60, 3659-3662.
(37) Yang, K.; Campbell, B.; Birch, G.; Williams, V. E.; Lemieux, R.
P. J. Am. Chem. Soc. 1996, 118, 9557-9561.
(38) The identity of the minor isomer was determined using two-
dimensional NMR, namely, HMQC and HMBC experiments.
(39) Fanta, P.; Tarbell, D. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. No. 3, p 78.
(40) Srivastava, S. K.; Chauhan, P. M. S.; Bhaduri, A. P. Chem. Commun.
1996, 279-280.
J. Org. Chem, Vol. 71, No. 16, 2006 5925

Montoya-Pelaez et al.
SCHEME 6
spectrometer. TLC was performed using glass- or aluminum-backed
Silica Gel 60 F254. Column purification was achieved through
normal flash silica or using the flash chromatography cartridges.
Analytical SFC chromatography was performed on a SFC HPLC
using a Daicel ChiralPak AD-H column and methanol as the co-
eluent. Preparative chiral stationary-phase HPLC separations were
performed using a 5 × 50 cm Chiralpak AS column. Melting points
(uncorrected) were determined using a Fisher-Jones melting point
apparatus.
Materials. All reagents and chemicals were used without further
purification unless otherwise noted.
Synthesis of o-Isonitrosoacetotoluidide (8).26 A three-neck 2-L
round-bottom flask was charged with chloral hydrate (39.9 g, 241
mmol, 1.1 equiv), anhydrous sodium sulfate (312.2 g, 1.75 mol, 8
equiv), and 880 mL of H2O. The solution was stirred with a
mechanical stirrer and heated to 40 °C until the mixture became
clear.
Solution A: Distilled o-toluidine (23.4 g, 219 mmol) was
dissolved in 135 mL of H2O and concentrated HCl (22.7 g, 19.0
mL, 230 mmol, 1.05 equiv).
Solution B: Hydroxylamine (50.2 g, 723 mmol, 3.3 equiv) was
dissolved in 225 mL of H2O.
Solutions A and B were added to the mixture in order, under
vigorous stirring. The resulting solution was heated to reflux,
allowed to reflux for 2 min, and then cooled to room temperature.
The product precipitated out of solution, and after standing for 16
h, the solid was collected and dried: 28.8 g (74%); mp 117-118
°C (lit.41 119-121 °C). 1H NMR (CDCl3): δ 8.21 (s, 1H), 8.01 (s,
1H), 7.97 (d, J ) 8 Hz, 1H), 7.62 (s, 1H), 7.24 (t, J ) 8 Hz, 1H),
7.21 (d, J ) 8 Hz, 1H), 7.10 (t, J ) 8 Hz, 1H), 2.30 (s, 3H). 13C
NMR (CDCl3): δ 160.5, 144.6, 134.6, 130.6, 129.2, 126.9, 125.7,
122.8, 17.4.
only the desired coupled product. Although the yield is moderate
(55% with activated Cu), the shortness of the route compensates
for this.
Comparison of Routes
The various synthetic routes that have been examined for the
synthesis of 5 are compared in Table 1. The first route examined,
which involves the coupling of para-bromo aniline (11) as the
key step, is only six steps, but the low yield in the coupling
step makes this route untenable, with an overall yield of 2.7%.
Proceeding through the nitro derivative 15, even though it adds
an additional two steps, gives an average yield per step of 68%,
but the overall yield is still only 4.6%. The big improvement in
the synthesis came with the use of NMBA as the starting
material instead of chloral hydrate. The diazonium coupling in
this route is still the lowest yielding step, but the overall yield
increases to 18.9%. The initial Ullmann route is longer by one
step but is the most scalable and highest yielding, with an overall
yield of 30.2% and an average yield per step of 87%. Finally,
the Ullmann route using precursor 28 is only five steps long
but suffers from two low yielding steps, giving an overall yield
that is lower (21.1%) than the previous pathway, with an average
yield of 77.2%.
Synthesis of 7-Methyl-1H-indole-2,3-dione (9).26 To a preheated
(50 °C) solution of concentrated sulfuric acid (33 mL), under rapid
stirring, compound 8 (8.40 g, 0.053 mol) was slowly added, keeping
the temperature of the reaction between 60 and 70 °C. Once the
addition was complete, the reaction mixture was heated to 80 °C
and stirred for 20 min. The reaction mixture was then allowed to
cool to rt and poured over crushed ice (200 g), yielding a crude
rust-colored precipitate that was collected by suction filtration. The
crude product was purified by initial suspension in 15 mL of hot
water, followed by dissolution in NaOH (1.4 g in 5 mL of H2O).
This solution was then acidified using 4 M HCl until a slight
precipitate appeared (around pH 3-4), at which point it was filtered
and the filtrate was acidified below pH 0. The pure product
precipitated out as an orange solid that was collected and air-
dried: 3.185 g (32%); mp 273 °C (lit.26,41 270-273 and 266-268
°C, respectively). 1H NMR (DMSO-d6): δ 11.09 (s, 1H), 7.43 (d,
J ) 8 Hz), 7.34 (d, J ) 8 Hz, 1H), 6.98 (t, J ) 8 Hz, 1H), 2.19 (s,
3H). 13C NMR (DMSO-d6): δ 185.2, 160.4, 149.7, 140.0, 123.1,
122.5, 122.1, 117.9, 15.9.
Conclusions
In conclusion, the synthesis of chiral biphenyl 5 has been
achieved by a variety of routes. Difficulties were encountered
in the coupling and iodination steps. The most reliable coupling
reaction proved to be the Ullmann, which gave the desired
product in 82% yield. The overall yield for this sequence was
30.2%, with an average yield per step of 87.5%. The two
enantiomers were resolved at the penultimate step by the use
of chiral HPLC. The preparation of analogues of 5 and
conversion of these compounds into chiral materials is currently
underway in our lab.
Synthesis of 5-Bromo-7-methyl-1H-indole-2,3-dione (10). To
a solution of 7-methyl-1H-indole-2,3-dione, 9 (2.15 g, 0.013 mol),
in CHCl3 (200 mL) was added dropwise to a solution of Br2 (2.6
g) in 30 mL of CHCl3. The resulting solution was heated to reflux
and stirred for 24 h. It was then cooled to 0 °C (ice bath), which
resulted in the precipitation of the product as a red solid. The
precipitate was collected by suction filtration and dried under
vacuum to yield 3.75 g of 10 (88%): mp 262 °C dec (lit.42 180
Experimental Section
1
°C). H NMR (DMSO-d6): δ 11.20 (s, 1H), 7.64 (s, 1H), 7.48 (s,
1H), 2.20 (s, 3H). 13C NMR (DMSO-d6): δ 184.0, 160.0, 148.9,
141.2, 124.8, 124.6, 119.5, 114.7, 15.7. MS (EI+): m/z 239 [M+];
HRMS calcd for C9H6O2NBr, 238.9582; found, 238.9590.
Synthesis of 2-Amino-5-bromo-3-methylbenzoic Acid (11).
Method 1. Compound 10 (7.6 g, 0.032 mol), NaCl (4.2 g, 0.073
General. All nonhydrolytic reactions were performed in oven-
or flame-dried glassware under a dry nitrogen or argon atmosphere.
The 1H and 13C NMR spectra were recorded using 300-, 400-, 500-,
and 600-MHz spectrometers. Proton chemical shifts are given
relative to those of internal standards chloroform, methanol, DMSO,
and acetone: δ ) 7.26, 3.30, 2.50, or 2.05 ppm, respectively.
Carbon chemical shifts are given relative to those of chloroform,
methanol, DMSO, and acetone: 77.0, 49.0, 39.5, or 29.8 ppm,
respectively. Mass spectra were obtained using a QStar XL
(41) Boa, A. N.; Canavan, S. P.; Hirst, P. R.; Ramsey, C.; Stead, A. M.
W.; McConkey, G. A. Bioorg. Med. Chem. 2005, 13, 1945-1967.
(42) Ressy, M.; Ortodocsu, A. Bull. Soc. Chim. Fr. 1923, 33, 637-640.
5926 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Substituted Chiral Biphenyl DeriVatiVes
TABLE 1. Comparison of Various Synthetic Pathways
coupling precursor/
starting material
coupling
method
number
of steps
lowest yielding
step (%)
overall
yield (%)
yield per
step (%)
Br (11)/toluidine
NO2 (15)/toluidine
NO2 (15)/NMBA
NO2 (15)/NMBA
Br (28)/NMBA
diazonium
diazonium
diazonium
Ullmann
6
8
8
9
5
13
47
47
65
55
2.66
4.61
18.9
30.2
21.1
54.6
68.1
81.2
87.5
77.2
Ullmann
mol), and NaOH (2.9 g, 0.073 mol) were dissolved in water (75
mL) with stirring to give a yellow solution after 0.5 h. This mixture
was cooled to 0 °C, to which a solution made up of 30% H2O2
(5.5 mL) and NaOH (4.9 g) in water (65 mL) was slowly added.
The reaction mixture was stirred for another 1.5 h and then
quenched with glacial acetic acid, yielding the product as a tan
precipitate. The solid was collected by suction filtration, washed
thoroughly with cold water, and dried under vacuum to yield 7.20
g (99%).
Method 2. To a solution of compound 19 (1.36 g, 9.00 mmol)
in 10 mL of DMSO was added 48% HBr (5 equiv, 3.64 g, 2.44
mL, 45 mmol), and the resulting mixture was stirred for 16 h. A
white precipitate formed during the course of the reaction. The
reaction was quenched with NaCO3(satd), yielding a white solid that
was filtered and dried under vacuum to yield 1.83 g of product
(88%): mp 218-220 °C. IR (KBr): 3511, 3379 (NH2), 2800 (br,
OH), 1680 (CdO). 1H NMR (DMSO-d6): δ 7.68 (s, 1H), 7.32 (s,
1H), 2.10 (s, 3H). 13C NMR (DMSO-d6): δ 168.8, 149.0, 136.3,
130.6, 126.2, 111.0, 104.5, 17.2. MS (EI+): m/z 229 [M+]; HRMS
calcd for C8H8O2NBr, 228.9738; found, 228.9747.
General Synthetic Procedure for Biphenyl Compounds (12)
and (16).21 The requisite amine (10 mmol) was taken up in 18 mL
of 2.5 M NaOH (4.5 equiv), followed by 18 mL of H2O, to give a
fine suspension. This suspension was stirred and cooled in an ice
bath (0-4 °C) for 10 min, then NaNO2 (2.5 equiv, 1.71 g, 25 mmol)
was added. After an additional 15 min of stirring, the dropwise
addition of cold 4 M HCl (33 equiv, 94 mL), while keeping the
temperature between 0 and 5 °C, was performed. The solution was
stirred for an additional 1.5 h to ensure formation of the diazonium
species. In a separate flask, CuSO4 (1.7 equiv, 4.25 g, 17 mmol)
was dissolved in 40 mL of H2O and stirred for 10 min in an ice
bath. NH4OH (230 equiv, 30 mL) was then added to the solution,
and the resulting deep purple solution was stirred at 0 °C for an
additional 1.5 h. A solution of NH2OH, prepared by dissolving NH2-
OH‚HCl (1.9 equiv, 1.32 g, 19 mmol) in 2.5 M NaOH (2 equiv,
15.2 mL), was then added to the copper solution. The diazonium
solution was then added dropwise into the copper solution, at all
times maintaining the temperature below 10 °C. Once the addition
was complete, the reaction solution was stirred for 5 min then heated
at reflux for 0.5 h. The reaction was cooled to room temperature,
had 37.5 mL of 12 M HCl added dropwise, and then was stirred
for 12 h. The crude brown product precipitate was collected by
suction filtration, washed with H2O, and dried in vacuo.
Purification of 4,4′-Dibromo-6,6′-dimethyl[1,1′-biphenyl]-2,2′-
dicarboxylic Acid (12). Using the general procedure, 5.19 g of
amine 11 (22.6 mmol) afforded 3.51 g of crude biphenyl 12.
Trituration of the crude product in ether, followed by filtration and
removal of the solvent, yielded 2.80 g of still impure product. Final
purification was achieved by column chromatography using an
ether/hexanes/acetic acid (29.75:70:0.25) solvent mixture. The
impure product was added as a silica plug (5 g) to a 60 g silica
column affording 0.617 g of pure product (13%): mp 151-152
°C. IR (KBr): 3000 (br, OH), 1687 (CdO). 1H NMR (CD3-
COCD3): δ 7.99 (d, J ) 1.6 Hz, 2H), 7.69 (d, J ) 1.6 Hz, 2H),
1.92 (s, 6H). 13C NMR (CD3COCD3): δ 166.7, 140.6, 140.2, 136.8,
132.6, 131.3, 121.0, 19.9. MS (ES-): m/z 427 [M - H]-; HRMS
calcd for C16H11O4Br2, 424.9024; found, 424.9019.
amine 15 (37.8 mmol) afforded 5.32 g of crude biphenyl 16.
Trituration of the crude in ether, followed by filtration and removal
of the solvent, yielded 4.21 g of still impure product. Final
purification was achieved by column chromatography using an
ether/hexanes/acetic acid (59.5:40:0.5) solvent mixture. The impure
product was added as a silica plug (10 g) to a 200 g silica column,
affording 3.17 g of pure product (47%): mp 84-185 °C. IR
1
(KBr): 3000 (br, OH), 1712 (CdO). H NMR (CD3COCD3): δ
8.76 (s, 2H), 8.42 (s, 2H), 2.10 (s, 6H). 13C NMR (CD3COCD3):
δ 165.1, 147.1, 147.0, 139.0, 130.6, 127.8, 123.0, 19.3. MS (EI-):
m/z 358.9 [M - H]-; HRMS calcd for C16H11O8N2, 359.0514;
found, 359.0530.
Classical Resolution of 16.43 To 12 (1.81 g, 5.02 mmol),
dissolved in 25 mL of acetone, was added quinine (1.81 g, 5.02
mmol, 1 equiv), and then the mixture was refluxed for 30 min.
Once the solution had cooled, the precipitated salt was collected,
washed once with cold acetone, and dried under vacuum to yield
1.71 g. This salt was dissolved into 10 mL of 4 N HCl solution
that was subsequently extracted with ether (3 × 10 mL). The
organic solvent was dried with MgSO4, filtered, and concentrated
to yield 594 mg of (+)-12 (33%), mp 187-191 °C, [R]D ) +2.5°
(c 1.7, MeOH). The supernatant was concentrated, treated with HCl,
and subsequently extracted with ether, yielding enriched (-)-12,
upon concentration, 853 mg (47%).
Synthesis of Dimethyl 4,4′-Dibromo-6,6′-dimethyl[1,1′-bi-
phenyl]-2,2′-dicarboxylate (5a).28 Method 1. Compound 5 (26 mg,
0.610 mmol) was dissolved in 2 mL of methanol, resulting in a
homogeneous solution, and cooled to 0 °C. SOCl2 (0.026 mL, 1.83
mmol, 6 equiv) was then added dropwise to the reaction mixture,
which was heated at reflux for 2 h. The reaction was cooled to
room temperature and concentrated in vacuo. The resulting solid
was triturated with EtOAc and discarded. The organic solution was
washed with H2O, dried with MgSO4, and concentrated to afford
27.8 mg of a white solid (99%).
Method 2. A mixture of 27 (1.444 g, 4.69 mmol) and activated
Cu powder (1.2 g, 18.8 mmol, 4 equiv) in 20 mL of dry DMF was
refluxed with stirring for 16 h. Once the solution was cool, it was
filtered, and the residue was washed with ethyl acetate (50 mL).
The filtrate was washed successively with 1 M HCl (3 × 20 mL),
H2O (3 × 20 mL), and satd NaHCO3 (3 × 20 mL), dried with
MgSO4, and concentrated to give a crude brown solid. The product
was purified by column chromatography (Biotage) using a gradient
solvent system (3% EtOAc/hexanes to 25% EtOAc/hexanes). The
isolated yield of 5a was 0.591 g (55%): mp 163-164 °C. IR
(KBr): 1737, 1715 (CdO). 1H NMR (CDCl3): δ 8.01 (d, J ) 1.5
Hz, 1H), 7.58 (d, J ) 1.5 Hz, 1H), 3.63 (s, 3H), 1.88 (s, 3H). 13C
NMR (CDCl3): δ 165.9, 139.3, 138.8, 136.5, 130.8, 121.0, 52.2,
19.9. MS (EI+): m/z 455 [M+]; HRMS calcd for C18H16O4Br2,
455.9396; found, 455.9410.
Synthesis of 7-Methyl-5-nitro-1H-indole-2,3-dione (14). Com-
pound 9 (10.9 g, 67.7 mmol) was added to a cooled (6 °C) solution
of concentrated H2SO4 (60 mL) and stirred for 5 min. A solution
of concentrated HNO3 (5 mL) and H2SO4 (0.5 mL) was then added
dropwise, keeping the temperature between 10 and 14 °C. Once
the addition was complete, the reaction was stirred for another 10
min and poured onto 360 g of crushed ice. The resulting orange
Purification of 4,4′-Dinitro-6,6′-dimethyl[1,1′-biphenyl]-2,2′-
dicarboxylic Acid (16). Using the general procedure, 7.42 g of
(43) Williams, V. E.; Lemieux, R. P. Chem. Commun. 1996, 2259-
2260.
J. Org. Chem, Vol. 71, No. 16, 2006 5927

Montoya-Pelaez et al.
precipitate was filtered, washed with H2O (3 × 20 mL), and dried
under vacuum, 12.21 g (87%): mp 255-256 (lit.29 256-257 °C).
1H NMR (CD3COCD3): δ 10.68 (br s, 1H), 8.38 (s, 1H), 8.16 (s,
1H), 3.44 (br s, 2H), 2.45 (s, 3H). 13C NMR (CD3COCD3): δ 183.5,
160.3, 154.9, 144.3, 134.4, 124.1, 118.4, 118.2, 15.7. MS (EI+):
m/z 206 [M+]; HRMS calcd for C9H6O4N2, 206.0328; found,
206.0336.
equiv) was slowly added, under constant stirring, so that the
temperature of the reaction was kept between 0 and 5 °C. Once
the addition was complete, the resulting mixture was kept between
0 and 5 °C for another 8 h. The resulting yellow solution was then
poured into a flask containing 300 g of crushed ice. The flask was
shaken vigorously, resulting in an off-white solid precipitate. The
solid was collected by suction filtration, washed thoroughly with
cold water, and further dried under vacuum to give pure product,
9.19 g (99%): mp 201-202 °C. IR (KBr): 3258 (NH), 1700, 1665
(CdO). 1H NMR (CD3COCD3): δ 9.54 (s, 1H), 8.59 (s, 1H), 8.34
(s, 1H), 2.43 (s, 3H), 2.19 (s, 3H). 13C NMR (CD3COCD3): δ 168.1,
166.1, 144.3, 142.8, 137.3, 128.5, 126.3, 123.2, 22.8, 18.4. MS
(ESI-): m/z 237 [M - H]-, 475 [M2 - H]-, 712 [M3 - H]-;
HRMS (ESI+) calcd for C10H11N2O5, 239.0668 [M + H]+; found,
237.0664.
Synthesis of 2-Iodo-3-methyl-5-nitrobenzoic Acid (22). Com-
pound 15 (4.02 g, 20.5 mmol) and NaNO2 (2 equiv, 41 mmol, 2.83
g) were added to 20 mL of 2 M NaOH and 20 mL of H2O that was
cooled in an ice bath to 4 °C. HCl (4 M) in the amount of 25 mL
was then added dropwise, ensuring that the temperature did not
surpass 8 °C. This was then followed by the dropwise addition of
50 mL of 12 M HCl, once again ensuring that the temperature
stayed below 8 °C. The solution was then left stirring, at 4 °C, for
90 min. Urea (2.00 g) was then added to the solution until all the
excess nitrite had been consumed (tested using starch iodide paper).
A solution of KI (5 equiv, 200 mmol, 17 g), with a small amount
of Cu (2 mg), in 15 mL of H2O was added to the reaction carefully
(vast quantities of N2 evolved) under vigorous stirring. The reaction
was allowed to reach room temperature and left stirring overnight.
The brown precipitate was collected, washed with water (2 × 50
mL), and dried to yield 5.25 g (85%) of product: mp 198 °C (lit.29
199 °C). 1H NMR (CD3OD/CDCl3): δ 8.20 (s, 1H), 8.15 (s, 1H),
2.62 (s, 3H). 13C NMR (CD3OD/CDCl3): δ 168.4, 147.3, 145.9,
140.6, 124.5, 120.9, 107.8, 29.2. MS (EI-): m/z 305.8 [M - H]-;
HRMS calcd for C8H5O4NI, 305.9263; found, 305.9265.
Synthesis of Methyl 2-Iodo-3-methyl-5-nitrobenzoate (23).
Acid 22 (5.25 g, 17.1 mmol) was added to a solution containing
60 mL of MeOH and 6 mL of concentrated H2SO4, and the mixture
was refluxed for 16 h. Once the solution was cooled (ice bath), the
product began to precipitate out. The precipitate was collected by
filtration and washed with H2O (3 × 50 mL). The supernatant had
another 100 mL of H2O added to induce another crop of product.
This was also collected and added to the second crop, 5.02 g
(91%): mp 108-109 °C. IR (KBr): 1737 (CdO). 1H NMR
(CDCl3): δ 8.23 (s, 1H), 8.16 (s, 1H), 3.99 (s, 3H), 2.65 (s, 3H).
13C NMR (CDCl3): δ 30.0, 53.2, 108.6, 121.6, 125.1, 139.7, 145.9,
147.3, 166.8. MS (CI+): m/z 322 [M + 1]+; HRMS calcd for C9H9-
NO4I, 321.9576; found, 321.9576.
Synthesis of Dimethyl 6,6′-Dimethyl-4,4′-dinitro[1,1′-bi-
phenyl]-2,2′-dicarboxylate (17). Method 1. To a solution of acid
16 (75 mg, 0.208 mmol) and K2CO3 (173 mg, 1.25 mmol, 6 equiv)
in 10 mL of dry acetone was added MeI (177 mg, 1.25 mmol, 6
equiv). The mixture was heated to reflux and stirred for 16 h. The
solvent was then removed, under reduced pressure, and EtOAc was
added. This solution was washed with H2O, dilute HCl, and brine
and dried with MgSO4. It was then filtered and concentrated to
yield 69 mg of pure product (85%).
Synthesis of 2-Amino-3-methyl-5-nitrobenzoic Acid (15).
Method 1. Compound 14 (4.00 g, 34 mmol) was dissolved in 500
mL of a freshly made 0.90 M NaOH (18 g) solution and stirred at
rt for 1.5 h. Then 193 mL of 3% H2O2 in H2O was added to the
solution, and it was stirred for an additional hour at rt. The reaction
was quenched by adding 50 mL of glacial acetic acid, yielding a
yellow precipitate that was collected via filtration, washed with
H2O (2 × 50 mL), and dried under vacuum, 5.79 g (87%).
Method 2. Concentrated HCl (150 mL) was added to compound
21 (10.0 g, 42.0 mmol), and the resulting solution was refluxed
for 2 h. Toward the end of the reaction, the product started to
precipitate out as a yellow solid. The solution was cooled, added
to a beaker containing crushed ice (100 g), and filtered once the
ice had melted. The solid was then washed with H2O (3 × 50 mL)
and dried to yield 6.70 g. The supernatant was diluted by adding
50% more water and allowed to stand for 24 h, at which point the
second crop of product was filtered and washed with H2O, 0.408
1
g. Overall yield: 7.11 g (86%). Mp 268-269 (lit.29 268 °C). H
NMR (CD3COCD/DMSO): δ 8.65 (s, 1H), 8.02 (s, 1H), 7.50 (br
s, 1H), 2.27 (s, 3H). 13C NMR (CD3COCD/DMSO): δ 169.8, 155.6,
136.4, 129.2, 127.4, 124.8, 109.4, 17.6. MS (ESI+): m/z 197 [M
+ H]+, 219 [M + Na]+; HRMS calcd for C8H9NO4, 197.0562;
found, 197.0555.
Synthesis of 2-Amino-3-methyl-benzoic Acid (19). An auto-
clave was charged with 2-nitro-3-methylbenzoic acid (25.0 g, 0.14
mol) in ethanol (160 mL). Palladium on activated carbon (10%
Pd, 2.5 g) was then added. After sequentially evacuating and
purging with hydrogen three times, the autoclave was charged to
approximately 500 psi, and the reaction mixture was stirred at
ambient temperature until further hydrogen uptake ceased. Once
the reaction was finished, the catalyst was removed by filtration
through a sintered-glass funnel containing a pad of Celite, which
was washed with 500 mL of ethanol. The solvent was removed
under reduced pressure, and the product was then further dried under
vacuum, yielding a pinkish-white solid, 20.5 g (99%): mp 175-
1
176 °C (lit.44 174-176 °C). H NMR (CD3COCD3): δ 7.76 (d, J
) 8.0 Hz, 1H), 7.20 (d, J ) 8.0 Hz, 1H), 6.53 (t, J ) 8.0 Hz), 2.17
(s, 3H). 13C NMR (CD3COCD3): δ 169.7, 150.1, 134.7, 129.4,
123.0, 114.7, 109.3, 16.7. MS (ESI-): m/z 150 [M - H]-.
Synthesis of 2-Acetylamino-3-methyl-benzoic Acid (20).
2-Amino-3-methylbenzoic acid 19 (37.3 g, 0.25 mol) and acetic
anhydride (70 mL, 0.75 mol) were added to a 300-mL round-bottom
flask, and the resulting suspension was heated to reflux for 2 h
under constant stirring. The hot solution was then poured into a
flask containing 500 g of crushed ice, resulting in a white
precipitate. The suspension was stirred for an additional 10 h, and
then the beige-white solid was collected by suction filtration, washed
with cold water, and further dried under vacuum, 41.4 g (87%):
1
mp 204-205 °C (lit.45 204-205 °C). H NMR (CD3COCD3): δ
9.47 (s, 1H), 7.59 (d, J ) 7.2 Hz, 1H), 7.42 (d, J ) 6.8 Hz, 1H),
7.21 (t, J ) 7.2 Hz, 1H), 2.20 (s, 3H), 2.01 (s, 3H). 13C NMR
(CD3COCD3): δ 168.8, 168.4, 136.1, 136.0, 133.9, 129.5, 128.0,
126.1, 23.5, 18.5. MS (TOF-): m/z 192 [M - H]-; HRMS calcd
for C10H10NO3, 192.0661; found, 192.0660.
Method 2. A mixture of 23 (0.559 g, 1.74 mmol) and Cu powder
(1.10 g, 17.4 mmol, 10 equiv) in 5 mL of dry DMF was refluxed
with stirring for 16 h. Once the solution was cool, it was filtered,
and the residue was washed with ethyl acetate (50 mL). The filtrate
was washed successively with 1 M HCl (3 × 20 mL), H2O (3 ×
20 mL), and satd NaHCO3 (3 × 20 mL), dried with MgSO4, and
concentrated to give a crude brown solid (313.3 mg). The product
was purified by column chromatography (Biotage) using a gradient
solvent system (3% EtOAc/hexanes to 25% EtOAc/hexanes). The
reduced starting material and the product 18 have Rf values of 0.64
and 0.54 (1:3 EtOAc/hexanes), respectively. The isolated yields of
Synthesis of 2-Acetylamino-3-methyl-5-nitrobenzoic Acid
(21). 2-Acetylamino-3-methyl-benzoic acid 20 (5.95 g, 31.0 mmol)
was dissolved in concentrated H2SO4 (75 mL), and the resulting
mixture was cooled to 0 °C. Fuming HNO3 (90%, 186 mmol, 6
(44) Newman, M. S.; Kannan, R. J. Org. Chem. 1976, 41, 3356-3359.
(45) Cremin, D. J.; Hegarty, A. F. J. Chem. Soc., Perkin Trans. 2 1978,
3, 208-212.
5928 J. Org. Chem., Vol. 71, No. 16, 2006

Synthesis of Substituted Chiral Biphenyl DeriVatiVes
18 and the reduced starting material were 247 mg (73%) and 26
mg, respectively.
crude product. Final purification was achieved by column chro-
matography (gradient elution of toluene/hexanes 96:4 to 100%),
yielding 0.410 g (49%) of product.
This method was improved by activating the copper powder using
the following procedure. Cu in the amount of 10 g was stirred into
a solution of iodine (2 g) in 50 mL of acetone. As soon as the
mixture became colorless, the liquid was decanted and the copper
powder was washed once with HCl(concd)/acetone (1:1), followed
by acetone (5 × 50 mL). The copper powder was then dried in a
vacuum at 170 °C for 2 h and used immediately. The reaction
requires 2.5 times less Cu than the unactivated version, and the
final yield is increased to 82% (with an 8% yield of deaminated
Method 2.35 A solution made up of dissolved 18 (1.67 g, 5.08
mmol) and NaNO2 (8 equiv, 2.80 g, 40.6 mmol) in 35 mL of DMSO
was heated to 40 °C, under constant stirring. A freshly made
solution containing HI (8 equiv, 55%, 5.56 mL, 40.6 mmol), CuI
(0.2 equiv, 0.193 g, 1.02 mmol), and 25 mL of DMSO was then
added, and the mixture was stirred for 30 min. It was then poured
into a flask containing satd NaCO3/crushed ice, and the crude
product precipitate was collected via filtration, washed with H2O,
and the redissolved in EtOAc. The organic layer was washed with
H2O and brine, dried over MgSO4, and concentrated under vacuum.
Final purification was achieved by gradient elution (1 to 20%
EtOAc/hexanes) on the Biotage, 1.816 g (65%): mp 123-125 °C.
IR (KBr): 1734, 1714 (CdO). 1H NMR (CDCl3): δ 8.19 (s, 2H),
7.78 (s, 2H), 3.62 (s, 6H), 1.85 (s, 6H). 13C NMR (CDCl3): δ 165.7,
142.4, 140.0, 138.7, 136.7, 130.7, 92.5, 52.2, 19.7. MS (TOF
EI+): 550 [M]+; HRMS calcd for C18H16I2O4, 550.9216; found,
550.9194. [R]D for (+)-5b: +8.15° (c 0.91, EtOAc); mp 82-83
°C. [R]D for (-)-5b: -8.15° (c 1.1, EtOAc); mp 82-83 °C.
Synthesis of Methyl 2,5-Dibromo-3-methylbenzoic Acid (27).
To a solution of 19 (0.575 g, 2.50 mmol), NaNO2 (4 equiv, 0.690
g, 10 mmol), and CuBr (1 equiv, 0.360 g, 2.5 mmol) in 12.5 mL
of DMSO was added dropwise a solution of 48% HBr (4 equiv,
1.86 g, 1.25 mL, 10 mmol), and this solution was left to stir at 40
°C for 3 h. The reaction was quenched with NaHCO3/ice, and the
green copper residue was filtered off through a pad of Celite. The
filtrate was reacidified to yield a white precipitate that was filtered
and dried under vacuum to give 0.404 g of product (55%): mp
1
product): mp 136-137 °C. IR (KBr): 1736 (CdO). H NMR
(CDCl3): δ 8.79 (d, 2H, J ) 2.5 Hz), 8.35 (d, 2H, J ) 2.5 Hz),
3.72 (s, 6H), 2.04 (s, 6H). 13C NMR (CDCl3): δ 164.9, 147.1, 146.6,
138.5, 129.9, 128.2, 123.4, 52.6, 19.9. MS (TOF EI+): m/z 388
[M]+; HRMS calcd for C18H16N2O8, 388.0907; found, 388.0908.
Synthesis of Dimethyl 4,4′-Diamino-6,6′-dimethyl[1,1′-bi-
phenyl]-2,2′-dicarboxylate (18). Method 1. A mixture of 17 (0.218
g, 0.561 mmol) and SnCl2‚2H2O (10 equiv, 5.61 mmol, 1.26 g) in
10 mL of absolute ethanol was heated at 70 °C for 2.5 h. Once the
solution was cool, it was poured onto 50 g of crushed ice, and the
pH of the solution was adjusted to 7-8 by adding satd NaHCO3.
It was then extracted with EtOAc (4 × 50 mL), and the organic
layer was washed with brine (1 × 50 mL), dried over MgSO4, and
concentrated to give a pale yellow solid (184 mg, 100%).
Method 2. Compound 17 (4.33 g, 11.2 mmol) was dissolved in
300 mL of a mixture of deoxygenated 95% EtOH/EtOAc (1:1).
500 mg of 10% Pd/C was then added to the solution and set up on
a Parr hydrogenater. The system was charged with H2 (40 PSI)
and shaken until no more was being absorbed (3 h). The solution
was then filtered through a bed of Celite, and the solvent was
removed to yield the product as a pale yellow solid, 3.65 g (99%):
mp 136-138 °C: 1H NMR (CDCl3): δ 7.26 (s, 2H), 6.72 (s, 2H),
3.67 (br s, 4H), 3.55 (s, 6H), 1.84 (s, 6H). 13C NMR (CDCl3): δ
168.1, 144.8, 138.5, 131.1, 130.9, 120.1, 113.8, 51.6, 20.2. MS
(TOF EI+): 329 [M + H]+; 351 [M + Na]+; 367 [M + K]+; HRMS
calcd for C18H21N2O4, 329.15013; found, 329.1512.
1
170-171 °C. IR (KBr): 3000 (br, OH), 1718, 1684 (CdO). H
NMR (CDCl3/CD3OD): δ 7.67 (s, 1H), 7.46 (s, 1H), 4.01 (br s,
1H), 2.41 (s, 3H). 13C NMR (CDCl3/CD3OD): δ 167.7, 141.7,
135.6, 130.9, 122.0, 120.4, 23.5. MS (TOF-): m/z 292.8 [M -
H]-; HRMS calcd for C8H5O2Br2, 290.8656; found, 290.8645.
Synthesis of Methyl 2,5-Dibromo-3-methylbenzoate (28).
Compound 28 (0.404 g, 1.37 mmol) was dissolved in a solution of
1:6 MeOH/H2SO4 (6.6 mL) and heated to reflux for 16 h. After
most of the MeOH was then removed under reduced pressure, water
was added, followed by EtOAc. The organic layer was then
separated, dried with brine, followed by MgSO4, filtered, and
concentrated to give 0.367 g of product as a white solid: mp 34-
35 °C. IR (KBr): 1737 (CdO). 1H NMR (CDCl3): δ 7.61 (s, 1H),
7.49 (s, 1H), 3.93 (s, 3H), 2.44 (s, 3H). 13C NMR (CDCl3): δ 166.3,
141.8, 135.7, 135.2, 130.8, 122.1, 120.5, 52.8, 23.7. MS (EI+): m/z
307.9 [M+]; HRMS calcd for C9H8Br2O2, 305.8891; found,
305.8882.
Chiral Column Resolution of 18. A 20 mL loop containing
200 mg of racemic 18 dissolved in 60:40 EtOH/hexanes was
injected into the preconditioned Chiralpak AS using an 18:82 EtOH/
hexanes solvent mixture. At a flow rate of 50 mL min-1, (-)-18
(100 mg) and (+)-18 (95 mg) had retention times of 64 and 85
min, respectively. [R]D for (-)-18: -32.2° (c 1.3, MeOH); mp 153-
154 °C. [R]D for (+)-18: +32.2° (c 1.2, MeOH); mp 153-154
°C.
Synthesis of Dimethyl 4,4′-Diiodo-6,6′-dimethyl[1,1′-bi-
phenyl]-2,2′-dicarboxylate (5b). Method 1.31 Compound 18 (0.500
g, 1.52 mmol) and I2 (3 equiv, 1.16 g, 4.57 mmol) were dissolved
in 75 mL of dry benzene, then the solution was cooled in an ice
bath to 0-4 °C, under constant stirring to prevent the benzene from
freezing. Freshly distilled tert-butyl nitrite (3 equiv, 0.471 g, 0.543
mL, 4.57 mmol) was then added to the solution, it was allowed to
reach rt, and stirred for 16 h. The solution was then heated to 70
°C for 1.5 h, then allowed to cool to rt. Once cool, H2O (75 mL)
was added, and the two layers were separated. The aqueous layer
was washed with EtOAc (3 × 75 mL). The organic layers were
combined and washed with NaHSO3 (3 × 50 mL), dried with
MgSO4, and the solvent was removed under vacuo to yield the
Acknowledgment. The Natural Sciences and Engineering
Council of Canada are acknowledged for support for this project
in terms of an NSERC Strategic grant to C.M.C. and R.P.L.
NSERC is also acknowledged for USRA fellowships to C.L.
Supporting Information Available: 1H and 13C NMR spectra
of all new compounds synthesized. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO060553D
J. Org. Chem, Vol. 71, No. 16, 2006 5929