Radical arylation of phenols, phenyl ethers, and furans

Article abstract of DOI:10.1002/chem.200902927

Radical arylations of parasubstituted phenols and phenyl ethers proceeded with good regioselectivity at the ortho position with respect to the hydroxy or alkoxy group. The reactions were conducted with arenediazonium salts as the aryl radical source, titaniumACHTUNGTRENUNG(III) chloride as the reductant, and diluted hydrochloric acid as the solvent. Substituted biaryls were obtained from hydroxy- and alkoxy-substituted benzylamines, phenethylamines, and aromatic amino acids. The methodology described offers a fast, efficient, and cost-effective new access todiversely functionalized biphenyl alcohols and ethers. Free phenolic hydroxyl groups, aromatic and aliphatic amines, as well as amino acid substructures, are well tolerated. Two examples for the applicability of the methodology are the partial synthesis of a b-secretase inhibitor and the synthesis of a calciumchannel modulator

Full text of DOI:10.1002/chem.200902927

FULL PAPER
DOI: 10.1002/chem.200902927
Radical Arylation of Phenols, Phenyl Ethers, and Furans
Alexander Wetzel,[a] Gerald Pratsch,[b] Roman Kolb,[a] and Markus R. Heinrich*[b]
Abstract: Radical arylations of para-
substituted phenols and phenyl ethers
proceeded with good regioselectivity at
the ortho position with respect to the
hydroxy or alkoxy group. The reactions
were conducted with arenediazonium
salts as the aryl radical source,
titaniumACHTUNGTRENNUNG(III) chloride as the reductant,
and diluted hydrochloric acid as the
solvent. Substituted biaryls were ob-
tained from hydroxy- and alkoxy-sub-
stituted benzylamines, phenethyl-
amines, and aromatic amino acids. The
methodology described offers a fast, ef-
ficient, and cost-effective new access to
diversely functionalized biphenyl alco-
hols and ethers. Free phenolic hydroxy
groups, aromatic and aliphatic amines,
as well as amino acid substructures, are
well tolerated. Two examples for the
applicability of the methodology are
the partial synthesis of a b-secretase in-
hibitor and the synthesis of a calcium-
channel modulator.
Keywords: diazonium
salts
·
biaryls · phenols · phenyl ethers ·
radical reactions
Introduction
noles.[6] Major advantages of the established organometallic
reactions certainly are the broad substrate tolerance and the
unambiguous regioselectivity. Disadvantages can arise from
the need for protecting groups, difficult optimization, chal-
lenging reaction conditions, as well as the limited commer-
cial availability of substrates.
Organometallic cross-coupling reactions are currently popu-
lar strategies for biaryl synthesis.[1] In the widely applied
Suzuki, Stille, Negishi, and Kumada reactions, aromatic bor-
onic acids, aryl tin, aryl zinc, and aryl magnesium com-
pounds are treated with aryl halides, aryl tosylates, or aryl
diazonium salts to give biaryl compounds.[2] Recent studies
revealed that, besides the well-known palladium- or nickel-
based catalysts, cobalt- or iron-containing compounds can
be a useful alternative.[3,4] The newly developed decarboxy-
lative cross-coupling reactions of aryl carboxylic acids and
aryl carboxylates in the presence of copper, nickel, and pal-
ladium catalysts represent another valuable extension of the
synthetic routes towards biaryls.[5] Substrates that are suita-
ble precursors for the formation of biaryls, based on carbon-
centered leaving groups, are benzonitriles and arylcarbi-
ꢀ
Biaryl synthesis based on the activation of C H bonds is
currently an intensively investigated field of research.[7–9] In
contrast to the classical cross-coupling methods, reactions of
this type often only require easily accessible starting materi-
als, although lower regioselectivity and double arylation are
still potential risks.
Very recently, reactions with combined radical and organ-
ometallic mechanisms were shown to be highly efficient
with respect to increased reactivity and selectivity.[10,11]
The classical radical methods for biaryl synthesis are
known as the Gomberg–Bachmann and Pschorr reac-
tions,[12,13] in which aryl diazonium salts serve as precursors
for aryl radicals. New developments in this area include the
use of aryl halides in the presence of organotin, organosili-
con, or samarium compounds.[14] The low regioselectivity of
radical arylations has certainly impeded the broad use of
these reactions in synthetic organic chemistry. Moreover,
the slow addition of aryl radicals to substituted benzenes
often requires the use of the substrates in great excess or
even as solvents, therefore, usually only cheap, easily acces-
sible, and conveniently separable arenes are employed.[15]
For the same reason, intramolecular radical arylation reac-
tions are frequently employed.[16] Improvements and recent
reports on Gomberg–Bachmann-type reactions include
[a] Dipl.-Chem. A. Wetzel, R. Kolb
Department fꢀr Chemie und Biochemie, Organische Chemie 1
Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
[b] G. Pratsch, Prof. Dr. M. R. Heinrich
Department fꢀr Chemie und Pharmazie, Pharmazeutische Chemie
Friedrich-Alexander-Universitꢁt Erlangen-Nꢀrnberg
Schuhstrasse 19, 91052 Erlangen (Germany)
Fax : (+49)9131-85-22585
E-mail: Markus.Heinrich@medchem.uni-erlangen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902927.
Chem. Eur. J. 2010, 16, 2547 – 2556
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2547

phase-transfer variants,[17] the application of oxygen as reoxi-
dant in tin-mediated radical biaryl syntheses,[18] and the ap-
plication of arylhydrazines and Grignard reagents[19,20] as
aryl radical precursors. Biaryl compounds can also be ob-
tained by radical addition to a nonaromatic precursor and
subsequent aromatization.[21]
Radical biaryl syntheses that rely on a chain mechanism,
in the sense of an SRN1-reaction,[22] have, so far, only been
described for a few substrates.[23] In this reaction type the di-
azonium salt A serves as both the aryl radical source and
the oxidizing agent (Scheme 1). Therefore, the rearomatiza-
tion step leads from E to the product F, as well as to a new
aryl diazenyl radical B, which, after loss of nitrogen to aryl
radical C, enters the cycle again. Aryl radical C is captured
by the substrate D to give the cyclohexadienyl intermediate
E.
Scheme 2. Radical arylation of anilines and phenols.
suppressed by low concentrations of the diazonium salt and
a fast reductive step from A to C. In addition to this chal-
lenging aspect, radical arylations of anilines and phenols are
likely to imply the following advantages: 1) effective aryl
radical addition to electron-rich substrates D; 2) increased
regioselectivity; 3) the possibility to use water as a solvent;
4) facilitated reoxidation of the cyclohexadienyl intermedi-
ate E.
The aryl radical addition to electron-rich substrates D can
be considered as more effective than to unsubstituted ben-
zene (k=106 mꢀ1 sꢀ1) due to the electrophilic character of the
aryl radical C. Moreover, hydroxy and amino substituents
attached to an aromatic core exert decisive effects on the
electron density of the positions of the benzene ring of D, as
well as on the stabilization of the resulting cyclohexadienyl
intermediate E, which should lead to good regioselectivity.
The use of water as the solvent can be beneficial in several
ways. First, the aromatic hydroxy and amino groups are
much less prone to hydrogen abstraction by the aryl radical
due to hydrogen bonding.[28] The aryl radical is also practi-
cally unable to abstract hydrogen from water, which is not
true for most common organic solvents.[29] Due to the insolu-
bility of the biaryl products F, the solvent water is, indirectly,
useful to prevent double arylation even when only a compa-
ratively low excess of substrate D is applied.[30] Finally, elec-
tron-donating substituents facilitate the reoxidation of the
cyclohexadienyl intermediate E and can enable the reaction
to run as a radical chain, in which the diazonium salt A acts
as an oxidant for E.
Scheme 1. Radical biaryl coupling by an SRN1-type chain reaction.
Phenolates, as electron-rich substrates, are adequate reac-
tion partners for aryl radicals, but the undesired azo-cou-
pling reaction requires the use of azo sulfides instead of aryl
diazonium salts.[24] The chain reaction can also be put into
effect by the combination of electron-poor aryl diazonium
salts and nonactivated substrates, such as benzene. Several
examples have been described with pentafluorophenyl di-
azonium salts.[25] The perfluorinated diazonium salt, more-
over, had the advantage that no attack of the aryl radical on
the diazonium salt itself, either in the sense of a biaryl cou-
pling or in the sense of an azo coupling, was observed.
A closer look at the factors influencing regioselectivity re-
veals that one suitable substituent in a para-substituted aro-
matic substrate should be sufficient for successful radical ar-
ylation reactions (Scheme 3).
When the R2 substituent is an electron-donating and radi-
cal-stabilizing substituent (such as hydroxyl), the relative
rate of the ortho attack of radical C on substrate D is in-
creased by the additional stability of intermediate E’. Since
the SOMO energy level of the resulting cyclohexadienyl in-
termediate E’ is much more dependent on the nature of R2
(compare resonance structures of radical E’), reoxidation of
E’ to F’ will be facilitated by electron-donating R2 substitu-
ents, which raise the SOMO energy level.[31] Low regioselec-
tivities, however, must be expected if both R2 and R3 are
competing electron-donating substituents because both
pathways leading to F’ and F’’ are then equally favored.
In our first report on radical arylation, we demonstrated
that the considerations shown above can indeed be put into
Results and Discussion
The main goal of our work is the development of radical ar-
ylation methods for electron-rich aromatics, including ani-
lines and phenols,[26] based on the use of arene diazonium
salts[27] (Scheme 2).
To allow the use of free diazonium salts A as radical pre-
cursors, in combination with anilines and phenols D, the un-
desired azo coupling and triazene formation needs to be
2548
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2547 – 2556

Radical Arylation of Phenols
FULL PAPER
Scheme 3. Substituent effects on regioselectivity.
practice (Scheme 4).[32] With suitable R2 groups, such as
amino, hydroxy, and alkoxy, the radical arylation of anilini-
um salts 1 (R3 =NH3+) to biaryls 3 proceeded with good
yields and acceptable regioselectivities. The ammonium
group as the para substituent nicely fulfils the requirements
for R3, in the sense that R3 is a non-electron-donating sub-
stituent with sufficient polarity to achieve water solubility.
Scheme 5. Radical arylation of para-substituted phenyl ethers.
sired biarylamine (7) in 63% yield accompanied by 6% of
the meta-isomer (Scheme 5a).
Variation of the reaction temperature had shown that
room temperature and 408C gave similar results, but run-
ning the reaction at 08C proved less favorable. The relative-
ly slow (10 to 15 min) and controlled addition of the solu-
tion of diazonium salt to the reaction mixture by syringe
pump was beneficial in the sense that homocoupling reac-
tions (addition of the aryl radical to the diazonium ion)
were largely suppressed.[33] Under the improved conditions,
biarylamine 9 was obtained from 4-methoxyphenethylamine
(8) in 51% yield along with 10% of the meta-product (Sche-
me 5b). The arylation of 3,4-dimethoxyphenethylamine (10)
proceeded with only low regioselectivity and an inseparable
mixture of regioisomers was isolated (Scheme 5c). Analysis
of the product distribution by proton NMR spectroscopy
suggested a ratio of the 2’-, 5’- and 6’-isomers of 1.6:1.0:2.3,
respectively, with the 6’-isomer as the major product.
The results obtained in the arylation reactions are re-
markable because the structures of all substrates possess
benzylic hydrogen atoms, which are known to be labile in
the presence of aryl radicals. Given the reported rate con-
stants for the aryl radical induced abstraction of hydrogen
from toluene (kꢁ106 mꢀ1 sꢀ1)[34] and for aryl radical additions
to benzene (kꢁ106 mꢀ1 sꢀ1),[35] the results shown above clear-
ly indicate that electron-rich aromatic compounds are well-
suited substrates to which aryl radicals add significantly
faster than to benzene. Otherwise, the competing abstrac-
Scheme 4. Radical arylation of (mono)protonated 4-aminophenol (1a),
p-anisidine (1b), and 1,4-phenylene diamine (1c).
Herein, we would like to demonstrate that the radical
ortho-arylation of phenyl ethers 4 and phenols 5 with arene-
diazonium salts is a more generally applicable method with
the partial limitations that the para-substituent R3 is neither
strongly electron donating nor too lipophilic.
The ortho-arylation of phenyl ethers 4 was first investigat-
ed with 4’-methoxybenzylamine
(6) as a substrate (Scheme 5a).
The addition of 4-chlorophenyl-
diazonium chloride (2) to
fivefold excess of and
titanium(III) chloride in dilute
hydrochloric acid led to the de-
a
6
AHCTUNGTRENNUNG
Chem. Eur. J. 2010, 16, 2547 – 2556
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2549

M. R. Heinrich et al.
tion reactions could not be successfully overcome. The
slightly better yield that was obtained in the arylation of 6
compared with that of 8 might also be explained by the dif-
ꢀ
ferent electronic properties of the benzylic C H bonds. Al-
though the proximity of the protonated (under the reaction
ꢀ
conditions) amine in 6 renders the benzylic C H bonds less
electron rich and, therefore, more stable towards hydrogen
ꢀ
abstraction, the properties of the benzylic C H bonds of 8,
in contrast, remain more or less unaffected by the inductive
effect of the ammonium group and are more easily at-
tacked.
Radical arylations of phenols benefit from the use of
aqueous solvents. Although phenols are efficient hydrogen
donors when employed in nonpolar solvents, as exemplified
by the antioxidant vitamin tocopherol,[36] hydrogen bonding
to the phenolic hydroxy group significantly reduces its hy-
drogen atom donor capabilities.
The substrates for the following series of experiments
were chosen to investigate which, potentially even more
ꢀ
labile, C H bonds would be tolerated by the radical aryla-
tion. To enable comparison with the previous experiments,
compound 2 was again used as the aryl radical source. With
respect to the general applicability, several previous studies
have led to the conclusion that the outcome of radical aryla-
tion reactions is, in most cases, only slightly dependent on
the nature of the ring substituents of the aryl radical.[37] An
exchange of the chloro substituent for a multitude of other
functional groups should, therefore, be possible.
Scheme 6. Radical arylation of para-substituted phenols.
The 39% overall yield with 3:1 regioselectivity obtained
from the arylation of tyramine (12; Scheme 6) shows, in
comparison with 8 (Scheme 5), that the phenolic hydroxy
group is indeed not a prohibitive structural element.[38] Due
to the polarity of biarylamine 13, quantitative extraction
from the aqueous phase turned out to be difficult and may
be a reason for the slightly lower yields obtained in these
experiments. Moreover, the usual purification by column
chromatography failed. Instead, compound 13 was purified
by sublimation and preparative HPLC.
The successful arylation of methyl l-tyrosinate (14) dem-
onstrates that amino acids can be functionalized in this
way.[39] The free amino group in 14 is a crucial structural ele-
ment, since formation of the ammonium salt under the
acidic reaction conditions successfully suppresses hydrogen
abstraction from the CH unit, which would otherwise lead
to a radical stabilized by the captodative effect.[40] Even the
rate of hydrogen abstraction from methyl d-4-hydroxyphen-
yl glycinate (16) can be sufficiently reduced by protonation
such that the desired radical arylation of the phenol core
occurs as the main reaction pathway. In the case of 17, we
were unable to detect the meta-regioisomer in the crude
product mixture.
aryl radical based olefin functionalization reactions. Al-
though nonprotonated allylic amines are not suitable sub-
strates due to extensive hydrogen abstraction from the allyl-
ic position, the protonated ammonium salts of these sub-
strates react without difficulties.[41]
The best results from the arylation of heterocycles were
obtained with furan (18),[42] furfurylamine (19), and 2-meth-
ylfuran (24). All three substrates gave the desired biaryls in
good yields and with high regioselectivity (Scheme 7).[43]
Among the diazonium salts used for the arylation of the
furan derivatives, the “electron-neutral” and the acceptor-
substituted salts 2 and 22 led to a more efficient product for-
mation than the donor-substituted diazonium salt 26. Diazo-
nium salt 26 is not as easily reduced as 2 and 22 and the re-
action was, therefore, carried out at 408C instead of room
temperature.
Arylation products could also be obtained from the het-
erocycles benzofuran (28) and indole (30) (Scheme 8). Due
to the additional benzene core in the substrate, small
amounts of the corresponding regioisomers were isolated
along with the desired products 29 and 31, which were only
accessible in moderate to low yields. In contrast to 28, the
arylation of 30 is significantly complicated by the azo cou-
pling of 22 to the 3-position of indole.[44a,b] Further attempts
with pyrrol and N-alkylated pyrrols have, so far, failed due
to the instability of these compounds under strongly acidic
conditions (Fichtenspan reaction).[44c]
ꢀ
The observation that C H bonds, which are usually labile
with respect to hydrogen abstraction, become significantly
more stable by protonation of an adjacent amine can also
be rationalized by the fact that electrophilic aryl radicals are
less likely to attack electron-deficient than -rich bonds.
Comparable results have been obtained in earlier studies of
Although several advantages arise from the fact that
water and hydrochloric acid are used as solvents for aryla-
2550
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2547 – 2556

Radical Arylation of Phenols
FULL PAPER
Scheme 9. Single and double arylation of 18.
Table 1. Solvent effects on the arylation of 18.
Solvent
Yield 20
Yield 32
Product ratio 20/32
[%][a]
[%][a]
no additive
86
55
58
59
50
<2
24
12
18
14
>40:1
4:1
10:1
6:1
2,2,2-trifluoroethanol
acetonitrile
acetic acid
acetone
7:1
[a] Yields based on the diazonium salt 2.
The monoarylated furan 20, which is usually not attacked by
a second 4-chlorophenyl radical due to its low solubility, is
now partially converted to 32. This observation in turn
proves that under the modified conditions rather lipophilic
substrates, such as 20, can be used as reactants. Second, the
total recovery of the 4-chlorophenyl group decreases in the
presence of organic solvents in the following order: water>
trifluoroethanol, acetic acid>acetonitrile>acetone. The
loss of the chlorophenyl radicals is most probably due to hy-
drogen abstraction, which occurs most easily from acetone,
and leads to the formation of volatile chlorobenzene. Final-
ly, among the organic additives, acetonitrile was shown to
give the most favorable ratio of mono- versus doubly arylat-
ed product.
Scheme 7. Radical arylation of 18, 19, and 24.
The radical arylation was finally applied to the synthesis
of bioactive substructures and compounds. Aminobenzocou-
marin 33 has been reported as a substructure of the b-secre-
tase (BACE-1) inhibitor 34 (Scheme 10).[45] b-Secretase rep-
resents a target enzyme for the treatment of Alzheimerꢃs
disease. By using a radical biaryl coupling, fragment 33 is
now conveniently accessible in three steps from methyl an-
thranilate (35) and 4-aminophenol (36).
Benzylamine 39 has been examined with respect to bio-
logical activity against the human parathyroid cell Ca2+ re-
ceptor (hPCaR).[46] Pharmaceutical compositions of 39 and
its derivatives should, therefore, be useful for the treatment
or prophylaxis of diseases associated with bone disorders,
such as osteoporosis. Racemic 39 can be obtained from 4-
chloroaniline (37) by diazotization, biaryl coupling with 4’-
methoxybenzylamine (6) (see compound 7, Scheme 5), con-
densation with acetophenone (38), and lithium aluminum
hydride reduction. The simple four-step protocol gave 39 in
40% overall yield without intermediate purification
(Scheme 11).
Scheme 8. Radical arylation of 28 and 30.
tion, this also has to be considered as a significant drawback
because the large group of potential nonpolar substrates is
excluded by this choice of conditions. We therefore exam-
ined a series of organic solvents with respect to their applic-
ability in the arylation procedure. For this purpose, the func-
tionalization of 18 with 2 (Scheme 7) was carried out in
2.5:1 mixtures of an organic solvent and the original aque-
ous titaniumACHTUNGTRENNUNG(III) chloride solution (Scheme 9 and Table 1).
The dominant fraction (>70 vol%) of the organic solvent
was chosen to extend the substrate range significantly to-
wards more lipophilic reactants.
Three conclusions can be drawn from the results shown in
Table 1. First, the organic solvent leads to double arylation.
Chem. Eur. J. 2010, 16, 2547 – 2556
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2551

M. R. Heinrich et al.
and amino acids often appear as substructures in compounds
possessing significant biological activity, our ongoing studies
on radical arylation reactions focus on the application and
establishment of this reliable methodology as a new tool for
the synthesis of compound libraries for biological screen-
ing.[47]
Experimental Section
General: Solvents and reagents were degassed with argon prior to use in
radical reactions. 1H NMR spectra were recorded on 250, 360, and
600 MHz spectrometers with CDCl3 and CD3OD as solvents referenced
to CHCl3 (d=7.26 ppm) and CHD2OD (d=3.31 ppm), respectively.
Chemical shifts are reported in parts per million (ppm). Coupling con-
stants (J) are in hertz. The following abbreviations are used for the de-
scription of signals: s (singlet), d (doublet), dd (double doublet), t (trip-
let), q (quadruplet), and m (multiplet). 13C NMR spectra were recorded
at 63, 91, and 151 MHz in CDCl3 and CD3OD with the residual solvent
CHCl3 (d=77.0 ppm) and CHD2OD (d=49.5 ppm) as internal standards.
Chemical shifts are given in parts per million (ppm). Analytical TLC was
carried out on Merck silica-gel plates by using short wave (254 nm) UV
light to visualize components. Silica gel (Kieselgel 60, 40–63 mm, Merck)
was used for flash column chromatography. Purification by preparative
HPLC was carried out by using a YMC ODS-A column (RP-18, 250ꢄ
20 mm, 5 mm particle size, 12 nm pore size) and UV detection (Dionex
P580, UVD-170U).
Scheme 10. Synthesis of aminobenzocoumarin 33.
General procedure for the radical arylation
Preparation of the arenediazonium chloride: A degassed solution of
sodium nitrite (1.38 g, 20.0 mmol) in water (10 mL) was added dropwise
over a period of 10 min to an ice-cooled degassed solution of the aniline
(20.0 mmol) in 3n hydrochloric acid (20 mL) and water (20 mL). After
stirring for a further 20 min at 08C, the clear solution was used for the
biaryl coupling reactions (20 mmol/50 mL=0.4m).
Scheme 11. Synthesis of the calcium receptor ligand 39 (MS=molecular
sieves).
Biaryl coupling: A 5 mL aliquot of the 0.4m arenediazonium chloride so-
lution (2 mmol) was added dropwise by using a syringe pump to a vigo-
rously stirred solution of the substrate (10.0 mmol) in water (6 mL) and
Conclusion
titaniumACHTUNTRGNEU(GN III) chloride (4 mL, approximately 1m solution in 3n hydrochlo-
Biaryl syntheses, which proceed by the addition of aryl radi-
cals to phenols and phenyl ethers, provided a fast, efficient,
cost-effective, and, so far, unexploited access to functional-
ized biphenyls. Side reactions of the aryl radicals were mini-
mized by the controlled addition of arenediazonium salts to
ric acid, 4 mmol) under an argon atmosphere within 10–15 min. After the
addition was complete, the mixture was left to stir for a further 10 min
and a solution of sodium hydroxide (2.0 g) and sodium sulfite (2.0 g) in
water (20 mL) was added. After extraction with diethyl ether or ethyl
acetate (3ꢄ50 mL), the combined organic phases were washed with satu-
rated aqueous sodium chloride and dried over sodium sulfate. Concentra-
tion in vacuo and purification by various methods (as described with
each product) gave the desired biaryls.
a solution of the phenolic substrate and titaniumACTHNUTRGENUG(N III) chlo-
ride in diluted hydrochloric acid. All of the para-substituted
phenols and phenyl ethers included in our study were con-
verted to biphenyls with synthetically useful yields and re-
gioselectivities. Only small amounts of doubly arylated prod-
ucts were observed. An adjustment of the general procedure
to specific substrates was not necessary. Successful coupling
reactions with tyrosine and phenylglycine showed that the
aryl radical addition step was effective enough so that the
reaction was not significantly impeded by hydrogen abstrac-
tion from benzylic positions. For the conversion of more lip-
ophilic substrates, organic cosolvents, such as acetonitrile,
can be added to the reaction mixture without a major de-
crease in product yield. Purification of the polar products
was often difficult by column chromatography, but could, in
most cases, be achieved by distillation, sublimation, or ex-
traction. Not surprisingly, the best results in purification
were obtained by employing preparative HPLC on re-
versed-phase columns. Since functionalized arylalkylamines
C-(4’-Chloro-6-methoxybiphen-3-yl)methylamine (7): Compound 7 was
prepared from 37 and 6 according to the general procedure described
above. Purification by distillation in vacuo (approximately 0.03 mbar) at
1208C gave 7 as an orange oil (312 mg, 1.26 mmol, 63%) and unreacted
6 (875 mg, 6.38 mmol, 74% of unconverted starting material). Rf =0.5
(CH2Cl2/MeOH=10:3+10% AcOH); 1H NMR (250 MHz, CDCl3): d=
1.42 (s, 2H), 3.71 (s, 3H), 3.77 (s, 2H), 6.86 (d, J=8.3 Hz, 1H), 7.14–7.22
(m, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.38 ppm (d, J=8.7 Hz, 2H); 13C NMR
(63 MHz, CDCl3): d=45.8 (CH2), 55.7 (CH3), 111.3 (CH), 127.5 (CH),
128.1 (2ꢄCH), 129.4 (Cq), 129.6 (CH), 130.7 (2ꢄCH), 132.8 (Cq), 135.7
(Cq), 136.8 (Cq), 155.2 ppm (Cq); MS (EI): m/z (%): 249 (32) [37ClꢀM+],
248 (42), 247 (100) [M+], 246 (73), 230 (18), 216 (55), 205 (55), 184 (9),
181 (12), 168 (16), 152 (23), 136 (41), 122 (14), 105 (13), 98 (17), 78 (27),
63 (27), 44 (56); HRMS (EI): m/z: calcd for C14H14NO35Cl: 247.0764 [M+];
found: 247.0758; calcd for C14H13NO35Cl: 246.0686 [M+ꢀH]; found:
246.0682.
2-(4’-Chloro-6-methoxybiphen-3-yl)ethylamine (9): Compound 9 was pre-
pared from 37 and 8 according to the general procedure described above.
Purification by column chromatography (silica gel, CH2Cl2/MeOH/
AcOH=10:1:1) gave 9 as a colorless oil (267 mg, 1.02 mmol, 51%). Rf =
2552
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2547 – 2556

Radical Arylation of Phenols
FULL PAPER
0.3 (CH2Cl2/MeOH=20:1+10% AcOH); 1H NMR (360 MHz, CDCl3):
d=1.78 (s, 2H), 2.75 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 3.79 (s,
3H), 6.92 (d, J=8.2 Hz, 1H), 7.15–7.23 (m, 2H), 7.36 (d, J=7.8 Hz, 2H),
7.46 ppm (d, J=7.8 Hz, 2H); 13C NMR (90 MHz, CDCl3): d=38.9 (CH2),
43.6 (CH2), 55.7 (CH3), 111.5 (CH), 128.1 (2ꢄCH), 129.1 (CH), 129.4
(Cq), 130.8 (2ꢄCH), 131.0 (CH), 132.0 (Cq), 132.9 (Cq), 136.9 (Cq),
154.9 ppm (Cq); MS (EI): m/z (%): 263 (4) [37ClꢀM+], 261 (9) [35ClꢀM+],
234 (22), 233 (15), 232 (67), 220 (32), 206 (22), 205 (100), 181 (13), 145
(9), 83 (17), 57 (39), 43 (15); HRMS (EI): m/z: calcd for C15H1635ClNO:
261.0920 [M+]; found: 261.0915.
CD3OD): d=39.9 (CH2), 49.9 (CH3), 56.4 (CH), 117.3 (CH), 128.6 (Cq),
128.7 (Cq), 129.0 (CH), 130.7 (CH), 131.9 (CH), 132.4 (CH), 133.6 (Cq),
138.7 (Cq), 154.6 (Cq), 175.3 ppm (Cq); MS (ESI): m/z: 306 [35ClꢀM+
+H]; MS (EI): m/z (%): 307 (3) [37ClꢀM+], 305 (8) [35ClꢀM+], 248 (4)
[37ClꢀM+ꢀ59], 246 (10) [35ClꢀM+ꢀ59], 219 (42) [37ClꢀM+ꢀ88], 217
(100) [35ClꢀM+ꢀ88], 181 (15), 152 (10), 136 (10), 107 (58), 88 (58), 70
(9), 57 (21), 43 (60); HRMS (EI): m/z: calcd for C16H16NO335Cl: 305.0819
[M+]; found: 305.0806.
Methyl 2-amino-2-(4’-chloro-6-hydroxybiphen-3-yl)acetate (17): Com-
pound 17 was prepared from 37 and 16 according to the general proce-
dure described above. Before threefold extraction with ethyl acetate, sa-
turated aqueous sodium carbonate was used to adjust the pH of the
crude mixture to a value of 9–10. After concentration in vacuo the crude
product was purified by column chromatography (silica gel, CH2Cl2/
MeOH=10:1) to give 17 as a colorless solid (333 mg, 1.14 mmol, 57%).
Rf =0.4 (CH2Cl2/MeOH=10:1); 1H NMR (360 MHz, CD3OD): d=3.71
(s, 3H), 4.63 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 7.20 (dd, J=2.4, 8.4 Hz,
1H), 7.29 (d, J=2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.55 ppm (d, J=
8.7 Hz, 2H); 13C NMR (90.6 MHz, CD3OD): d=53.0 (CH), 58.6 (CH3),
117.4 (CH), 128.8 (CH), 128.9 (Cq), 129.1 (2ꢄCH), 130.5 (CH), 131.0
(Cq), 131.9 (2ꢄCH), 133.8 (Cq), 138.5 (Cq), 155.8 (Cq), 175.0 ppm (Cq);
MS (EI): m/z (%): 293 [37ClꢀM+] (1), 291 [35ClꢀM+] (2), 234 [37ClꢀM+
ꢀ59] (35), 232 [35ClꢀM+ꢀ59] (100), 205 (6), 187 (3), 170 (9), 152 (13),
141 (6), 122 (11), 116 (5), 98 (11), 43 (16); HRMS (EI): m/z: calcd for
C13H11NO35Cl: 232.0529 [M+ꢀ59]; found: 232.0522.
2-(4’-Chloro-5-methoxybiphen-2-yl)ethylamine (9’): Colorless oil; Rf =0.4
(CH2Cl2/MeOH=20:1+10% AcOH); 1H NMR (360 MHz, CDCl3): d=
2.62–2.67 (m, 2H), 2.70–2.75 (m, 2H), 3.80 (s, 1H), 6.73 (d, J=2.7 Hz,
1H), 6.87 (dd, J=2.7, 8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.24 (d, J=
8.4, 2H), 7.38 ppm (d, J=8.4 Hz, 2H); 13C NMR (91 MHz, CDCl3): d=
36.4 (CH2), 43.4 (CH2), 55.3 (CH3), 113.4 (CH), 115.4 (CH), 128.3 (2ꢄ
CH), 129.2 (Cq), 130.4 (2ꢄCH), 130.7 (CH), 133.0 (Cq), 140.1 (Cq), 142.0
(Cq), 157.7 ppm (Cq); MS (EI): m/z (%): 261 (1) [M+], 234 (32), 233
(21), 232 (100), 231 (18), 196 (28), 181 (12), 165 (18), 152 (24).
2-(4,4’’-Dichloro-5’-methoxy[1,1’;4’,1’’]terphen-2’-yl)ethylamine (double
arylation product of 8): Colorless oil; Rf =0.5 (CH2Cl2/MeOH=20:1+
10% AcOH); 1H NMR (360 MHz, CDCl3): d=2.66–2.80 (m, 4H), 3.79
(s, 3H), 6.79 (s, 1H), 7.21 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.39 (d, J=
8.5 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.50 ppm (d, J=8.5 Hz, 2H); MS
(ESI) m/z: 374 [37Cl35ClꢀM++H], 372 [35Cl2ꢀM++H].
2-(4-Chlorophenyl)furan (20):[48] Compound 20 was prepared from 37
and furan according to the general procedure described above. Purifica-
tion by distillation in vacuo gave 20 as a light yellow oil (306 mg,
1.72 mmol, 86%). 1H NMR (250 MHz, CDCl3): d=6.47 (dd, J=1.8,
3.4 Hz, 1H), 6.64 (dd, J=0.7, 3.4 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.47
(dd, J=0.7, 1.8 Hz, 1H), 7.60 ppm (d, J=8.8 Hz, 2H); 13C NMR
(63 MHz, CDCl3): d=105.4 (CH), 111.8 (CH), 125.0 (2ꢄCH), 128.9 (2ꢄ
CH), 129.4 (Cq), 133.0 (Cq), 142.3 (CH), 152.9 ppm (Cq); All analytical
data are in agreement with those reported in ref. [48].
2-(4’-Chloro-6-hydroxybiphen-3-yl)ethylamine (13): Compound 13 was
prepared from 37 and 12 according to the general procedure described
above. Excess 12 was removed by sublimation. The residue was dissolved
in diluted hydrochloric acid, extracted twice with Et2O, and basified to
pH 10 with sodium carbonate. Extraction with EtOAc gave 13 along with
the regioisomer 13’ (193 mg, 0.78 mmol, 39%). Separation of the re-
gioisomers was achieved by preparative HPLC (MeOH/(H2O+0.1%
CF3COOH)=50:50). Colorless oil; Rf =0.2 (CH2Cl2/MeOH/AcOH=
10:1:1); 1H NMR (360 MHz, CD3OD): d=2.68 (t, J=6.9 Hz, 2H), 2.84
(t, J=6.3 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 7.00 (dd, J=2.0, 8.1 Hz, 1H),
7.08 (brs, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.54 ppm (d, J=8.5 Hz, 2H);
1H NMR (360 MHz, CD3OD, regioisomer 13’): d=2.60 (brs, 4H), 6.60
(d, J=2.5 Hz, 1H), 6.73 (dd, J=2.5, 8.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H),
C-(5-(4-Chlorophenyl)furan-2-yl)methylamine (21): Compound 21 was
prepared from 37 and 19 according to the general procedure described
above. Purification by distillation in vacuo gave 21 as an orange solid
(305 mg, 1.47 mmol, 74%). Rf =0.4 (CH2Cl2/MeOH/AcOH=10:1:1);
1H NMR (360 MHz, CDCl3): d=1.56 (s, 2H), 3.88 (s, 2H), 6.22 (d, J=
3.3 Hz, 1H), 6.56 (d, J=3.3 Hz, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.57 ppm
(d, J=8.6 Hz, 2H); 13C NMR (91 MHz, CDCl3): d=39.5 (CH2), 106.1
(CH), 107.4 (CH), 124.8 (2ꢄCH), 128.8 (2ꢄCH), 129.4 (Cq), 132.7 (Cq),
152.0 (Cq), 156.8 ppm (Cq); MS (EI): m/z (%): 209 (29) [37ClꢀM+], 208
(24), 207 (80) [35ClꢀM+], 206 (47), 193 (18), 192 (38), 191 (58), 190
(100), 149 (12), 139 (18), 128 (24), 111 (16), 96 (42), 78 (8), 68 (80);
HRMS (EI): m/z: calcd for C11H10NO35Cl: 207.0451 [M+]; found:
207.0449.
7.24 (d, J=8.4 Hz, 2H), 7.38 ppm (d,
J =
8.4 Hz, 2H); 13C NMR
(91 MHz, CD3OD, mixture of regioisomers 13 and 13’): d=36.5 (CH2),
39.2 (CH2), 43.9 (CH2), 44.3 (CH2), 116.4 (CH), 117.4 (CH), 118.3 (CH),
128.6 (Cq), 129.0 (CH), 129.3 (CH), 130.1 (CH), 131.7 (CH), 131.8 (CH),
131.9 (CH), 132.0 (CH), 133.4 (Cq), 133.9 (Cq), 139.1 (Cq), 142.1 (Cq),
143.2 (Cq), 154.3 (Cq), 157.9 ppm (Cq), (two Cq signals missing due to
overlap); MS (ESI): m/z: 248 [M++H]; HRMS (ESI): m/z: calcd for
C14H1535ClNO: 248.0837 [M++H]; found: 248.0830.
5’-(2-Aminoethyl)-4,4’’-dichloro-[1,1’;3’,1’’]terphenyl-2’-ol (double aryla-
tion product of 12): Yellow oil; Rf =0.6 (CH2Cl2/MeOH/AcOH=10:1:1);
1H NMR (360 MHz, CD3OD): d=2.94 (t, J=7.5 Hz, 2H), 3.17 (t, J=
7.5 Hz, 2H), 7.15 (s, 2H), 7.42 (d, J=8.3 Hz, 4H), 7.53 ppm (d, J=
8.3 Hz, 4H); 13C NMR (91 MHz, CD3OD): 34.1 (CH2), 42.2 (CH2), 129.5
(CH), 131.5 (Cq), 131.6 (CH), 132.2 (CH), 134.2 (Cq), 138.6 (Cq),
150.9 ppm (Cq) (one Cq signal missing); MS (ESI): m/z: 360 [37Cl35ClꢀM+
+H], 358 [35Cl2ꢀM++H].
Methyl 4-(furan-2-yl)benzoate (23)[49] was prepared from methyl 4-ami-
nobenzoate and 18 by using the modified procedure described below.
Preparation of the arenediazonium chloride: A degassed solution of
sodium nitrite (0.69 g, 10.0 mmol) in water (5 mL) was added dropwise
over 10 min to an ice-cooled degassed solution of methyl 4-aminoben-
zoate (1.51 g, 10.0 mmol) in 3n hydrochloric acid (10 mL), water
(10 mL), and acetonitrile (4 mL). After stirring for a further 20 min at
08C, the light yellow solution was used for the biaryl coupling reactions
(10 mmol/29 mL=0.35m).
Methyl
2-amino-3-(4’-chloro-6-hydroxybiphen-3-yl)propanoate
(15):
Compound 15 was prepared from 37 and 14 according to the general pro-
cedure described above. Before threefold extraction with ethyl acetate,
saturated aqueous sodium carbonate was used to adjust the pH of the
crude mixture to a value of 9–10. After concentration in vacuo, the crude
product was purified by column chromatography (silica gel, CH2Cl2/
MeOH=10:1) to give 15 as a white solid (269 mg, 0.88 mmol, 44%)
along with minor amount of its regioisomer. Separation of the regioisom-
ers was achieved by preparative HPLC (MeOH/(H2O+0.1%
Biaryl coupling: A 5.8 mL aliquot of the arenediazonium chloride solu-
tion (0.35m, 2 mmol) was added dropwise by using a syringe pump to a
vigorously stirred solution of 18 (10.0 mmol) in water (6 mL) with
titaniumACTHNUTRGNE(NUG III) chloride (4 mL, of an approximately 1m solution in 3n hy-
drochloric acid, 4 mmol) under argon atmosphere within 10–15 min.
After the addition was complete, the mixture was left to stir for a further
10 min and the pH was adjusted to a value of 9–10 with saturated aque-
ous sodium carbonate. After extraction with diethyl ether (2ꢄ50 mL)
and ethyl acetate (2ꢄ50 mL), the combined organic phases were washed
with saturated aqueous sodium chloride and dried over sodium sulfate.
Purification by distillation in vacuo gave the light orange solid 23
(336 mg, 1.66 mmol, 83%). Orange solid; Rf =0.8 (ethyl acetate);
CF3COOH)=50:50).
Rf =0.4
(CH2Cl2/MeOH=10:1);
1H NMR
(360 MHz, CD3OD): d=2.94 (dd, J=6.0, 13.9 Hz, 1H), 3.02 (dd, J=7.0,
13.9 Hz, 1H), 3.71 (s, 3H), 3.83 (dd, J=6.0, 7.0 Hz, 1H), 6.85 (d, J=
8.3 Hz, 1H), 7.01 (dd, J=2.2, 8.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.37
(d, J=8.6 Hz, 2H), 7.54 ppm (d, J=8.6 Hz, 2H); 13C NMR (91 MHz,
Chem. Eur. J. 2010, 16, 2547 – 2556
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2553

M. R. Heinrich et al.
1H NMR (360 MHz, CDCl3): d=3.92 (s, 3H), 6.49–6.51 (m, 1H), 6.79 (d,
J=3.3 Hz, 1H), 7.52 (brs, 1H), 7.73 (d, J=8.7 Hz, 2H), 8.05 ppm (d, J=
8.7 Hz, 2H); 13C NMR (91 MHz, CDCl3): d=52.1 (CH3), 107.2 (CH),
112.0 (CH), 123.4 (2ꢄCH), 128.5 (Cq), 130.1 (2ꢄCH), 134.8 (Cq), 143.1
(CH), 152.9 (Cq), 166.8 ppm (Cq); MS (EI): m/z (%): 203 (11), 202 (78),
172 (12), 171 (100), 143 (15), 115 (33). All analytical data are in agree-
ment with those reported in ref. [49].
Methyl 4-(5-methylfuran-2-yl)benzoate (25):[50] Compound 25 was pre-
pared from methyl 4-aminobenzoate and 24 according to the modified
procedure described for the preparation of 23. To increase the solubility
of 24 in the aqueous phase, CH3CN (18 mL) was added. Purification by
distillation in vacuo gave 25 as a brown solid (342 mg, 1.58 mmol, 80%).
Rf =0.7 (pentane/ethyl acetate=10:1); 1H NMR (250 MHz, CDCl3): d=
2.22 (d, J=0.7 Hz, 3H), 3.75 (s, 3H), 5.94 (dd, J=3.3, 0.7 Hz, 1H), 6.52
(d, J=3.3 Hz. 1H), 7.51 (d, J=8.7 Hz, 1H), 7.87 ppm (d, J=8.7 Hz, 1H);
13C NMR (63 MHz, CDCl3): d=13.5 (CH3), 51.7 (CH3), 108.1 (CH),
108.2 (CH), 122.5 (2ꢄCH), 127.6 (Cq), 129.8 (2ꢄCH), 134.8 (Cq), 151.0
(Cq), 153.0 (Cq), 166.6 ppm (Cq); MS (EI): m/z (%): 216 (100), 185 (88),
157 (13), 128 (23). All analytical data are in agreement with those report-
ed in ref. [50].
sified (pH 10) with Na2CO3 and aqueous NH3 (25%). After extraction
with ethyl acetate (2ꢄ50 mL), the combined organic phases were washed
with brine and dried over sodium sulfate. Concentration in vacuo and pu-
rification by column chromatography (EtOAc/pentane=1:1!ethyl ace-
tate) gave 33 as a light yellow solid (1.50 g, 7.11 mmol, 36%). Rf =0.3
(pentane/EtOAc=1:1); 1H NMR (360 MHz, CDCl /
3 ACHTUNRGTNEUNG(CD3)2SO): d=6.00
(dd, J=2.7, 8.7 Hz, 1H), 6.29 (d, J=8.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H),
6.67–6.72 (m, 1H), 6.93 (ddd, J=1.4, 7.3, 8.1 Hz, 1H), 7.71 (d, J=8.1 Hz,
1H), 7.47 ppm (ddd, J=0.6, 1.4, 8.0 Hz, 1H); 13C NMR (91 MHz,
CDCl3/ACHTUNGTRENUNG(CD3)2SO): d=98.2 (CH), 108.8 (CH), 109.0 (Cq), 109.1 (CH),
111.6 (Cq), 112.2 (CH), 119.2 (CH), 120.8 (CH), 125.3 (CH), 125.4 (Cq),
133.8 (Cq), 135.0 (Cq), 152.6 ppm (Cq). All analytical data are in agree-
ment with those reported in ref. [53].
(4’-Chloro-6-methoxybiphen-3-ylmethyl)(1-phenylethyl)amine (39): Com-
pound 7 was prepared from 2 (8.00 mmol) and 6 (5.49 g, 40.0 mmol) ac-
cording to the general procedure described above (4-fold quantities). Pu-
rification by distillation in vacuo (approximately 0.03 mbar) at 1208C
gave 7 along with minor amounts of remaining benzylamine 6. A flame-
dried round-bottomed flask was charged with molecular sieves (3 ꢅ, 6 g)
and dry CH2Cl2 (10 mL). Acetophenone (38; 1.18 g, 9.81 mmol) and biar-
ylamine 7 (1.62 g, 6.54 mmol) were added under argon and the resulting
mixture was stirred for 6 d in the presence of p-toluenesulfonic acid
(92.0 mg, 0.53 mmol). The molecular sieves were separated from the mix-
ture by filtration and the solvent was removed under reduced pressure.
Without further purification, the intermediate imine was dissolved in dry
C-(5-(4-Methoxyphenyl)furan-2-yl)methylamine (27): Compound 27 was
prepared from p-anisidine and 19 according to the modified procedure
described for the preparation of 23. Purification by distillation in vacuo
gave 27 as an orange solid (210 mg, 1.03 mmol, 52%). Rf =0.5 (CH2Cl2/
MeOH/AcOH=10:1:1); 1H NMR (600 MHz, CDCl3): d=3.83 (s, 3H),
3.86 (s, 2H), 6.18 (d, J=2.9 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 6.91 (d, J=
8.6 Hz, 2H), 7.58 ppm (d, J=8.6 Hz, 2H); 13C NMR (150.9 MHz,
CDCl3): d=39.5 (CH2), 55.3 (CH3), 104.0 (CH), 107.1 (CH), 114.1 (2ꢄ
CH), 124.1 (Cq), 125.0 (2ꢄCH), 153.1 (Cq), 155.7 (Cq), 158.9 ppm (Cq);
MS (EI): m/z (%): 204 (14), 203 (100) [M+], 202 (32), 188 (12), 187 (87),
186 (46), 159 (10), 145 (11), 144 (12), 135 (12), 96 (10), 85 (10), 83 (15),
68 (25); HRMS (EI): m/z: calcd for C12H13NO2: 203.0946 [M+]; found:
203.0946.
Methyl 4-(benzofuran-2-yl)benzoate (29)[51] was prepared from methyl 4-
aminobenzoate and 28 according to the modified procedure described for
the preparation of 23. To increase the solubility of 28 in the aqueous
phase CH3CN (18 mL) was added. Purification by column chromatogra-
phy (silica gel, pentane/ethyl acetate=10:1) gave 29 as a white solid
(199 mg, 0.79 mmol, 39%). Rf =0.6 (pentane/ethyl acetate=10:1);
1H NMR (250 MHz, CDCl3): d=3.80 (s, 3H), 6.99 (s, 1H), 7.38–7.45 (m,
4H), 7.77 (d, J=8.63, 1H), 7.97 ppm (d, J=8.63, 1H); 13C NMR
(63 MHz, CDCl3): d=52.1 (CH3), 103.4 (CH), 111.3 (CH), 121.2 (CH),
123.2 (CH), 124.5 (2ꢄCH), 125.0 (CH), 128.3 (Cq), 129.6 (Cq), 130.1 (2ꢄ
CH), 134.4 (Cq), 154.6 (Cq), 155.1 (Cq), 166.6 (Cq); MS (EI): m/z (%):
252 (100), 221 (57), 193 (10), 165 (31), 110 (8), 82 (10). All analytical
data are in agreement with those reported in ref. [51].
diethyl ether (20 mL) and added to
a solution of LiAlH4 (1.25 g,
32.7 mmol) in dry diethyl ether (280 mL). After heating at reflux for 19 h
under argon the reaction mixture was cooled to 08C and was quenched
with acetone and water. The solution was extracted with diethyl ether
(3ꢄ200 mL). The combined organic phases were washed with water
(200 mL) and saturated aqueous sodium chloride (200 mL) and were
dried over Na2SO4. After removing the solvent under reduced pressure,
the crude product was purified by column chromatography (silica gel,
CH2Cl2/MeOH=10:1). Biarylamine 39 (1.13 g, 3.20 mmol, 40%) was ob-
tained as a colorless solid along with minor amounts of (4-methoxyben-
zyl)(1-phenylethyl)amine. Separation of the byproduct was achieved by
preparative HPLC (MeOH/(H2O+0.1% CF3COOH)=60:40). Rf =0.6
(CH2Cl2/MeOH=10:1); 1H NMR (360 MHz, CDCl3): d=1.28 (d, J=
6.8 Hz, 3H), 1.96–2.05 (m, 1H), 3.58–3.67 (m, 2H), 3.65 (s, 3H), 4.10–
4.20 (m, 1H), 6.79 (d, J=9.0 Hz, 1H), 7.17 (d, J=7.2 Hz, 2H), 7.29 (d,
J=8.6 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.36–7.45 ppm (m, 5H);
13C NMR (91 MHz, CDCl3) d=20.0 (CH3), 49.1 (CH2), 55.7 (CH3), 58.5
(CH), 111.6 (CH), 123.2 (Cq), 127.9 (2ꢄCH), 128.4 (2ꢄCH), 129.5 (CH),
129.6 (2ꢄCH), 129.81 (Cq), 130.9 (2ꢄCH), 131.1 (CH), 132.80 (CH),
133.4 (Cq), 136.0 (Cq), 136.4 (Cq), 157.2 ppm (Cq); MS (ESI): m/z: 352
[35ClꢀM++H]; HRMS (ESI): m/z: calcd for C22H2335ClNO: 352.1463 [M+
+H]; found: 352.1452; HRMS (EI): m/z: calcd for C22H2235ClNO:
351.1390 [M+]; found: 351.1379.
Methyl 4-(indol-2-yl)benzoate (31):[52] Compound 31 was prepared from
methyl 4-aminobenzoate and 30 according to the modified procedure de-
scribed for the preparation of 23. White solid; Rf =0.3 (pentane/ethyl
1
acetate=6:1); H NMR (360 MHz, CDCl3): d=3.96 (s, 3H), 6.97 (s, 1H),
7.14 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H),
7.67 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.3 Hz, 2H), 8.11 (d, J=8.3 Hz, 2H),
8.67 ppm (brs, 1H); 13C NMR (91 MHz, CDCl3): d=52.0 (CH3), 101.3
(CH), 111.2 (CH), 120.8 (CH), 122.5 (CH), 123.3 (CH), 124.7 (2ꢄCH),
128.9 (Cq), 130.1 (2ꢄCH), 133.0 (Cq), 136.7 (Cq), 137.5 (Cq), 146.1 (Cq),
166.7 ppm (Cq); MS (EI): m/z (%): 251 (100), 220 (23), 192 (28), 165
(13), 96 (14); All analytical data are in agreement with those reported in
ref. [52].
6-Amino-3,4-benzocoumarin (33):[53] NaNO2 (20 mmol, 1.38 g) in de-
gassed water (10 mL) was added to a solution of methyl anthranilate (35)
(20 mmol, 3.02 g) in degassed water (20 mL) and hydrochloric acid (3n,
20 mL) over a period of 10 min at 08C. The solution was left to stir for
further 10 min at 08C. A 50 mL aliquot of the arenediazonium chloride
solution (0.4m) was added to a solution of 4-aminophenol (36; 100 mmol,
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie (Liebig
fellowship) and the Deutsche Forschungsgemeinschaft (DFG). The help
of Prof. Dr. Thorsten Bach (TU Mꢀnchen) and his group is gratefully ac-
knowledged. We would like to thank Olaf Ackermann from Prof. Bachꢃs
group for his technical assistance with preparative HPLC and Dr. Werner
Spahl (LMU Mꢀnchen) for ESI–HRMS spectra.
[1] For an overview, see: a) M. Beller, C. Bolm, Transition Metals for
Organic Synthesis, 2nd ed., Wiley-VCH, Weinheim, 2004; b) A. de
Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions,
2nd ed., Wiley-VCH, Weinheim, 2004; c) L. Ackermann, Modern
Arylation Methods, 1st ed., Wiley-VCH, Weinheim, 2009.
10.9 g) in degassed water (160 mL) with titaniumACTHNUTRGNEUG(N III) chloride (40 mmol,
40 mL, of an approximately 1m solution in 3n hydrochloric acid) drop-
wise at room temperature over a period of 15 min. After the addition
was complete the solution was left to stir for 10 min. The solution was ba-
[2] S. P. Stanforth, Tetrahedron 1998, 54, 263–303.
2554
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2547 – 2556

Radical Arylation of Phenols
FULL PAPER
[3] M. Amatore, C. Gosmini, Angew. Chem. 2008, 120, 2119–2122;
Angew. Chem. Int. Ed. 2008, 47, 2089–2092.
[20] M. S. Maji, T. Pfeifer, A. Studer, Angew. Chem. 2008, 120, 9690–
9692; Angew. Chem. Int. Ed. 2008, 47, 9547–9550.
[4] a) T. Hatakeyama, M. Nakamura, J. Am. Chem. Soc. 2007, 129,
9844–13863; b) I. Sapountzis, W. Lin, C. C. Kofink, C. Despotopou-
lou, P. Knochel, Angew. Chem. 2005, 117, 1682–1685; Angew.
Chem. Int. Ed. 2005, 44, 1654–1658; c) A. Fꢀrstner, A. Leitner, M.
Mendez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856–13863.
[5] a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662–664;
b) L. J. Goossen, N. Rodriguez, B. Melzer, C. Linder, G. Deng,
L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824–4833; c) L. J. Goos-
sen, N. Rodriguez, K. Goossen, Angew. Chem. 2008, 120, 3144–
3164; Angew. Chem. Int. Ed. 2008, 47, 3100–3120; d) L. J. Goossen,
B. Zimmermann, T. Knauber, Angew. Chem. 2008, 120, 7211–7214;
Angew. Chem. Int. Ed. 2008, 47, 7103–7106; e) L. J. Goossen, K.
Goossen, C. Stanciu, Angew. Chem. 2009, 121, 3621–3624; Angew.
Chem. Int. Ed. 2009, 48, 3569–3571.
[21] B. Quiclet-Sire, G. Revol, S. Z. Zard, Org. Lett. 2009, 11, 2832–
2835.
[22] For reviews on SRN1-type reactions, see: a) R. A. Rossi in Synthetic
Organic Photochemistry, Vol. 12 (Eds.: A. Griesbeck, J. Mattay),
Marcel Dekker, New York, 2005, pp. 495–527; b) R. A. Rossi, A. B.
Pierini, A. B. PeÇꢆÇory, Chem. Rev. 2003, 103, 71–167; c) R. A.
Rossi, A. B. Pierini, A. N. Santiago in Organic Reactions (Eds.:
L. A. Paquette, R. Bittman), Wiley, New York, 1999, pp. 1–272.
[23] R. Bolton, G. H. Williams, Chem. Soc. Rev. 1986, 15, 261–289.
[24] G. Petrillo, M. Novi, C. DellꢃErba, C. Tavani, Tetrahedron 1991, 47,
9297–9304.
[25] D. Kosynkin, T. M. Bockman, J. K. Kochi, J. Am. Chem. Soc. 1997,
119, 4846–4855.
[26] For a first report on the radical arylation of phenol, see: R. Hirsch,
Chem. Ber. 1890, 23, 3705–3710.
[27] For a recent report on the use of arenediazonium salts in cross-cou-
pling reactions, see: a) F.-X. Felpin, E. Fouquet, C. Zakri, Adv.
Synth. Catal. 2009, 351, 649–655; b) M. Mahesh, J. A. Murphy, F.
LeStrat, H. P. Wessel, Beilstein J. Org. Chem. 2009, 5, No. 1.
[28] a) P. Mulder, H.-G. Korth, D. A. Pratt, G. A. DiLabio, L. Valgimigli,
G. F. Pedulli, K. U. Ingold, J. Phys. Chem. A 2005, 109, 2647–2655;
b) L. Valgimigli, J. T. Banks, J. Lusztyk, K. U. Ingold, J. Org. Chem.
1999, 64, 3381–3383.
[29] S. J. Garden, D. V. Avila, A. L. J. Beckwith, V. W. Bowry, K. U.
Ingold, J. Lusztyk, J. Org. Chem. 1996, 61, 805–809.
[30] For radical polyarylation of 1,4-phenylenediamine, see: Z. J. Allan,
F. Muzik, Chem. Listy 1954, 18, 52–60.
[6] S. M. Bonesi, M. Fagnoni, A. Albini, Angew. Chem. 2008, 120,
10172–10175; Angew. Chem. Int. Ed. 2008, 47, 10022–10025.
ꢀ
[7] For an overview on C H activation reactions, see: a) G. Dyker,
ꢀ
Handbook of C H Transformations, Wiley-VCH, Weinheim, 2005;
b) L. Ackermann, Top. Organomet. Chem. 2008, 24, 35–60.
ꢀ
[8] For recent reports on C H activation reactions, see: a) T. Vogler, A.
Studer, Org. Lett. 2008, 10, 129–131; b) L. Ackermann, R. Vicente,
A. Althammer, Org. Lett. 2008, 10, 2299–2302; c) M. Shimizu, K.
Mochida, T. Hiyama, Angew. Chem. 2008, 120, 9906–9910; Angew.
Chem. Int. Ed. 2008, 47, 9760–9764; d) V. S. Thirunavukkarasu, K.
Parthasarathy, C.-H. Cheng, Angew. Chem. 2008, 120, 9604–9607;
Angew. Chem. Int. Ed. 2008, 47, 9462–9465; e) J. Wen, J. Zhang, S.-
Y. Chen, J. Li, X.-Q. Yu, Angew. Chem. 2008, 120, 9029–9032;
Angew. Chem. Int. Ed. 2008, 47, 8897–8900; f) L. Ackermann, A.
Althammer, S. Fenner, Angew. Chem. 2009, 121, 207–210; Angew.
Chem. Int. Ed. 2009, 48, 201–204; g) W. Jin, Z. Yu, W. He, W. Ye,
W.-J. Xiao, Org. Lett. 2009, 11, 1317–1320.
[31] For kinetic studies on the reaction of phenyl radicals with chloro-
benzene, see: Y. Gao, P. Marshall, Proc. Combust. Inst. 2009, 32,
351–357.
[32] A. Wetzel, V. Ehrhardt, M. R. Heinrich, Angew. Chem. 2008, 120,
9270–9273; Angew. Chem. Int. Ed. 2008, 47, 9130–9133.
[33] For products of homocoupling reactions, see: F. Minisci, F. Coppa, F.
Fontana, G. Pianese, L. Zhao, J. Org. Chem. 1992, 57, 3929–3933.
[34] R. H. Chen, S. A. Kafafi, S. E. Stein, J. Am. Chem. Soc. 1989, 111,
1418–1423.
ꢀ
[9] For recent examples of oxidative (C H activation) couplings, see:
a) Y. Kita, K. Morimoto, M. Ito, C. Ogawa, A. Goto, T. Dohi, J.
Am. Chem. Soc. 2009, 131, 1668–1669; b) S. Chaudhary, S. Pecic, O.
Le Gendre, W. W. Harding, Tetrahedron Lett. 2009, 50, 2437–2439;
c) A. Kar, N. Mangu, H. M. Kaiser, M. K. Tse, J. Organomet. Chem.
2009, 694, 524–537; d) K. Wang, M. Lu, A. Yu, X. Zhu, Q. Wang, J.
Org. Chem. 2009, 74, 935–938.
[35] C. Galli, Chem. Rev. 1988, 88, 765–792.
[36] M. Leopoldini, T. Marino, N. Russo, M. Toscano, J. Phys. Chem. A
2004, 108, 4916–4922.
[10] a) G. Manolikakes, P. Knochel, Angew. Chem. 2009, 121, 211–215;
Angew. Chem. Int. Ed. 2009, 48, 205–209; b) W.-Y. Yu, W. N. Sit, Z.
Zhou, A. S.-C. Chan, Org. Lett. 2009, 11, 3174–3177.
[11] For an overview, see: L. Ford, U. Jahn, Angew. Chem. 2009, 121,
6504–6507; Angew. Chem. Int. Ed. 2009, 48, 6386–6389.
[12] M. Gomberg, W. E. Bachmann, J. Am. Chem. Soc. 1924, 46, 2339–
2343.
[37] a) M. R. Heinrich, A. Wetzel, M. Kirschstein, Org. Lett. 2007, 9,
3833–3835; b) M. R. Heinrich, O. Blank, S. Wçlfel, Org. Lett. 2006,
8, 3323–3325; c) M. R. Heinrich, O. Blank, D. Ullrich, M. Kirsch-
stein, J. Org. Chem. 2007, 72, 9609–9616; d) M. R. Heinrich, O.
Blank, A. Wetzel, J. Org. Chem. 2007, 72, 476–484; e) O. Blank, A.
Wetzel, D. Ullrich, M. R. Heinrich, Eur. J. Org. Chem. 2008, 3179–
3189.
[38] For the synthesis and biological evaluation of 3-aryl-4-hydroxyphe-
nethyl amines, see: A. Kuglstatter, M. Stahl, J.-U. Peters, W. Huber,
M. Stihle, D. Schlatter, J. Benz, A. Ruf, D. Roth, T. Enderle, M.
Hennig, Bioorg. Med. Chem. Lett. 2008, 18, 1304–1307.
[39] Previous syntheses of aromatic substituted phenylalanines: a) S.
Knçr, B. Laufer, H. Kessler, J. Org. Chem. 2006, 71, 5625–5630;
b) W. Wang, J. Zhang, C. Xiong, V. J. Hruby, Tetrahedron Lett. 2002,
43, 2137–2140; c) M. J. Burk, J. R. Lee, J. P. Martinez, J. Am. Chem.
Soc. 1994, 116, 10847–10848; d) M. J. Burk, M. F. Gross, T. G. P.
Harper, C. S. Kalberg, J. R. Lee, J. P. Martinez, Pure Appl. Chem.
1996, 68, 37–44; e) W. Wang, C. Xiong, J. Zhang, V. J. Hruby, Tetra-
hedron 2002, 58, 3101–3110; f) W. Wang, M. Cai, C. Xiong, J.
Zhang, D. Trivedi, V. J. Hruby, Tetrahedron 2002, 58, 7365–7374;
g) S. Kotha, K. Lahiri, Biopolymers 2003, 69, 517–528.
[13] R. Pschorr, Chem. Ber. 1896, 29, 496–501.
[14] For recent reports on radical biaryl syntheses, see: a) A. Studer, M.
Brossart in Radicals in Organic Synthesis, Vol. 2, 1st ed. (Eds.: P.
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, pp. 62–80;
b) W. R. Bowman, J. M. D. Storey, Chem. Soc. Rev. 2007, 36, 1803–
1822; c) J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic
Chemistry, Wiley, New York, 1995, pp. 167–180.
[15] a) A. Nunez, A. Sanchez, C. Burgos, J. Alvarez-Builla, Tetrahedron
2004, 60, 6217–6224; b) P. T. F. McLoughlin, M. A. Cline, F. Aldab-
bagh, Tetrahedron 2004, 60, 8065–8071.
[16] For recent examples, see: a) T. Lanza, R. Leardini, M. Minozzi, D.
Nanni, P. Spagnolo, G. Zanardi, Angew. Chem. 2008, 120, 9581–
9584; Angew. Chem. Int. Ed. 2008, 47, 9439–9442; b) H. Iwasaki, T.
Eguchi, N. Tsutsui, H. Ohno, T. Tanaka, J. Org. Chem. 2008, 73,
7145–7152.
[17] J. R. Beadle, S. H. Korzeniowski, D. E. Rosenberg, B. J. Garcia-
Slanga, G. W. Gokel, J. Org. Chem. 1984, 49, 1594–1603.
[18] D. P. Curran, A. I. Keller, J. Am. Chem. Soc. 2006, 128, 13706–
13707.
[40] For radicals stabilized by the captodative effect, see: a) H. Birkhof-
er, J. Hꢁdrich, H. D. Beckhaus, C. Ruechardt, Angew. Chem. 1987,
99, 592–594, Angew. Chem. Int. Ed. 1987, 26, 573–575; b) L. Stella,
J. N. Harvey in Radicals in Organic Synthesis, Vol. 1 (Eds. P.
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, pp. 360–378.
[41] A. Wetzel, M. R. Heinrich, unpublished results.
[19] a) A. S. Demir, O. Reis, E. Oezguel-Karaaslan, J. Chem. Soc. Perkin
Trans. 1 2001, 3042–3045; b) H. Firouzabadi, D. Mohajer, M. Ente-
zari-Moghadam, Bull. Chem. Soc. Jpn. 1988, 61, 2185–2190.
Chem. Eur. J. 2010, 16, 2547 – 2556
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2555

M. R. Heinrich et al.
[42] For a recent example of the radical arylation of furan, see: R. Cella,
R. L. O. R. Rodrigo, A. E. Reis, D. C. Pimenta, C. F. Klitzke, H. A.
Stefani, J. Org. Chem. 2006, 71, 244–250.
[47] For modified amino acids with biaryl substructures, see referen-
ce [39a] and references therein.
[48] A. R. Katritzky, J. Li, M. F. Gordeev, J. Org. Chem. 1993, 58, 3038–
3041.
[49] C.-Y. Zhou, P. W. H. Chan, C.-M. Che, Org. Lett. 2006, 8, 325–328.
[50] S. J. Pridmore, P. A. Slatford, J. M. J. Williams, Tetrahedron Lett.
2007, 48, 5111–5114.
[51] A. Arcadi, S. Cacchi, M. Del Rosario, G. Fabrizi, F. Marinelli, J.
Org. Chem. 1996, 61, 9280–9288.
[43] The regioisomer was not detected in the 1H NMR spectra of the
crude product. From the experiments reported by A. W. Johnson, J.
Chem. Soc. 1946, 895–899, the relative rate of the aryl radical addi-
tion to the 2- and 3-position of furan can be estimated to 40:1.
[44] a) For compounds resulting from the azo coupling at the 3-position
of indole, see: H. A. Albar, A. S. Shawali, M. A. Abdaliah, Can. J.
Chem. 1993, 71, 2144–2149; b) the dominant regioisomer of 31 re-
sults from the arylation at the 4-position of 30; c) H. J. Teuber, D.
Cornelius, U. Woelcke, Liebigs Ann. Chem. 1966, 696, 116–135.
[45] N. Pietrancosta, G. Quelever, Y. Laras, C. Garino, S. Burlet, J. L.
Kraus, Aust. J. Chem. 2005, 58, 585–594.
[52] F. Liu, D. Ma, J. Org. Chem. 2007, 72, 4844–4855.
1
[53] For H and 13C NMR data of compound 22, see Sigma–Aldrich spec-
tral database.
[46] M. G. Kelly, S. Xu, N. Xi, P. Miller, J. F. Kincaid, C. Ghiron, T.
Coulter, PCT Int. Appl. WO2003099776, 2003; [Chem. Abstr. 2003,
140, 4840].
Received: October 22, 2009
Published online: January 11, 2010
2556
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2547 – 2556