Synthesis of amino- and hydroxybiphenyls by radical chain reaction of arenediazonium salts

Article abstract of DOI:10.1002/anie.200803785

Radically shortened: In the propagation step of the title reaction, the cyclohexadienyl radical intermediate is oxidized by an arenediazonium ion to give the biaryl product (see scheme) while simultaneously a new aryl radical and nitrogen are formed. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200803785

Communications
DOI: 10.1002/anie.200803785
Biaryls
Synthesis of Amino- and Hydroxybiphenyls by Radical Chain Reaction
of Arenediazonium Salts**
Alexander Wetzel, Varinia Ehrhardt, and Markus R. Heinrich*
Dedicated to Professor Dr. Wolfgang Steglich on the occasion of his 75th birthday
A wide range of organometallic methods have been devel-
oped for the mild and efficient synthesis of biaryl com-
pounds.[1–5] In this context,addition reactions of aryl radicals
to aromatic substrates have so far only rarely been applied.[6]
Complications in intermolecular radical aryl–aryl couplings
occur as a result of the relatively slow addition of aryl radicals
to common substrates such as substituted benzenes,[7] which in
turn gives rise to side reactions. Successful aryl–aryl couplings
therefore often require special conditions; for example,the
substrate is used as the solvent[8] or the reaction is modified to
an intramolecular conversion.[9]
to employ the diazonium salt A both as the source of C and as
an oxidant for intermediate E.[16]
Given that the reactivity of aryl radicals is more controlled
in water than in most other organic solvents,[17,18] we decided
to evaluate homolytic aromatic substitution reactions in
aqueous solution. Our first results on the synthesis of
amino- and hydroxybiphenyls are reported herein.
For reasons of solubility and unambiguous regioselectiv-
ity,4-chlorophenyldiazonium chloride ( 1a) and 1,4-phenyl-
enediamine (2a) were chosen for the initial study (Table 1).
Aryl–aryl couplings using arenediazonium salts A as
precursors are known as Gomberg–Bachmann[10,11] or
Pschorr[12] reactions (Scheme 1). These reactions are compli-
cated by the fact that a reductant is needed for the generation
of radicals B and C,[13] whereas oxidizing conditions are
required for the rearomatization of the cyclohexadienyl
intermediate E.[14,15] To date,only a few studies have proposed
Table 1: Coupling reaction of 4-chlorophenyldiazonium chloride (1a)
with 1,4-phenylenediamine hydrochloride (2a).
Entry
Equiv TiCl3
(relative to 1a)
Addition of 1a
over x min
3aa[a]
Yield [%][b]/[%][c]
1
2
2.5
2.5
0
3
56/54
59/–
3
4
5
6
2.5
2.5
2.5
1.0
6
65/58
54/–
50/–
11
23
6
65/–
7
8
9
10
0.5
6
6
6
6
70/70
71/–
66/64
59/60
0.25
0.0
0.0[d]
[a] Reactions conducted according to Method A, see the Supporting
Information. [b] Yield determined by GC (internal standard: tetrade-
cane). [c] Yield after purification by column chromatography. [d] Experi-
ment with 10 equiv 2a instead of 20 equiv.
Scheme 1. Radical chain mechanism for biaryl synthesis.
The fact that substoichiometric amounts of titanium(III)
chloride suffice for the full conversion of the diazonium salt
supports the proposed chain mechanism (Scheme 1). Because
of its reduction potential 2a alone can initiate the chain
reaction (Table 1,entries 9 and 10). Comparable properties
have been observed for 1,4-dimethoxybenzene.[19] The exis-
tence of an optimum rate of addition of 1a to the reaction
mixture (Table 1,entries 1–5) is also consistent with general
considerations. High concentrations of the diazonium salt,
which are created by fast addition,lead to undesired
homocoupling of aryl radicals to diazonium salts.[20] Low
[*] Dipl.-Chem. A. Wetzel, V. Ehrhardt, Dr. M. R. Heinrich
Organische Chemie 1, Technische Universität München
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (49)89-289-13329
E-mail: Markus.Heinrich@ch.tum.de
Homepage: http://www.ch.tum.de/oc1/MHeinrich/
[**] This work was supported by the Fonds der Chemischen Industrie
(Liebig fellowship) and the Deutsche Forschungsgemeinschaft
(DFG). We thank Prof. Dr. Thorsten Bach and his group for support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803785.
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Table 3: Coupling reactions of 1a with anilinium hydrochlorides 2b–2g.
concentrations of the diazonium salt do not effectively
propagate the radical chain (E!F,Scheme 1).
The results obtained with various arenediazonium salts
1a–1e are summarized in Table 2. Since not all diazonium
precursors can be prepared as chloride salts in aqueous
Table 2: Coupling reactions of arenediazonium salts 1a–1e with 2a.
2
R
Method
3
Yield [%][b]
Selectivity
ortho/meta
2b
OMe
A (458C)
3ab
3ab
3ab
3ab
3ac
3ac
3ac
3ad
3ad
3ae
3ae
3af
64
66
57
68
75
64
50
18
23
22
19
10
28
35
15:85
16:84
37:63
22:78
15:85
A
A (08C)
B
1
R
Method
3
Yield [%][b]
2c
OH
A (458C)
A
13:87
21:79
1a
p-Cl
A
B
C
A
B
C
B
A
B
A
B
C
3aa
3aa
3aa
3ba
3ba
3ba
3ca
3da
3da
3ea
3ea
3ea
70[c]
56
A (08C)
2d
2e
2 f
2g
F
A
B
A
B
A
B
B
>95:5[c]
>95:5[c]
80:20
22
1b
p-F
70[c]
60
Cl
78:22
35
CO2Me
COMe
>95:5[c]
>95:5[c]
>95:5[c]
1c
1d
o-Cl
o-Br
39
3af
3ag
45[c]
48
75[c]
49
[a] Reactions conducted according to procedures described in the
Experimental Section. [b] Yields after purification by column chromatog-
raphy. [c] The meta isomer was not detected by GC-MS nor by NMR
spectroscopy.
1e
p-MeO
58
[a] Reactions conducted according to procedures described in the
Supporting Information. [b] Yield after purification by column chroma-
tography. [c] Yield over two steps, based on the aniline precursor of the
diazonium salt.
ineffective rearomatization (E!F,Scheme 1) of the cyclo-
hexadienyl intermediates arising from the meta attack.
Examples for applications of this methodology to poly-
hydroxylated biaryls are sumarized in Table 4. Method A,
which proceeded with substoichiometric amounts of titanium-
(III) chloride,was found to be less effective than method B,in
which an excess of titanium was used. In contrast to 1,4-
phenylendiamine,hydroquinones 4 are unable to initiate the
chain reaction.[19,23] 4’-Chlorobiphenyl-2,3-diol (5ab),which is
solution (method A) owing to insufficient solubility,we also
conducted the reactions by adding diazonium tetrafluorobo-
rates either as solids (method B) or dissolved in acetonitrile
(method C). Given that the diazonium chloride can be
prepared as an aqueous solution,method A is the procedure
of choice. If this is not the case,method B can be applied
instead. Acetonitrile as cosolvent (method C) is suitable only
for donor-substituted diazonium salts. Previous syntheses of
biaryl-2,5-diamines required a five-step sequence including a
Suzuki cross-coupling of doubly benzylidene-protected 2-
iodo-1,4-phenylenediamine.[21]
Table 4: Coupling reactions of arenediazonium salts 1a–c,f with hydro-
quinones 4a,b.
In the following series of experiments,4-chlorophenyldia-
zonium salts 1a were reacted with different para-substituted
anilines (Table 3). The best results were obtained with the
donor-substituted anilines anisidine (2b) and 4-aminophenol
(2c); this suggests that the substitution mechansim can also be
classified as SRN1 type.[22] In contrast,the reactions of the less
electron-rich anilines 2d–2g were significantly complicated
by homocoupling reactions,[20] indicating that the aryl radical
addition step (C!E,Scheme 1) is too slow. These reactions
therefore require more than fivefold excess of the aniline to
be efficient.
The predominating meta selectivity in the reactions with
2b and 2c points to a preferred attack of the aryl radical at
positions ortho to the more electron-donating group.
Attempts to increase the selectivity by running the reaction
at 08C or 458C failed. The virtually complete ortho selectivity
in the reactions with 2d, 2 f,and 2g can be explained by the
1
R1, R2
4
R3, R4
Method
5
Yield Selectivity
[%][b] ortho/meta
1a p-Cl, H
4a OH, H
A
B
B
B
B
A
B
5aa
5aa
5ba
5ca
5 fa
5ab
5ab
60
79
85
81
80
54
63
–
–
–
–
1b p-F, H
1c o-Cl, H
1 f p-Cl, m-Cl 4a OH, H
1a p-Cl, H 4b H, OH
4a OH, H
4a OH, H
–
70:30
75:25
[a] Yields after purification by column chromatography. Reactions
conducted according to procedures described in the Supporting
Information.
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Communications
obtained as the main product from the arylation of ortho-
are difficult to accomplish with electron-rich aromatics.
Regarding the availability and price of the starting materials,
the radical chain reactions offer an economically interesting
new pathway to many biarylamines and alcohols. Further
investigations in the control of regioselectivity in reactions of
para-subsituted anilinium salts are currently underway and
will be reported in due course.
hydroquinone (4b),was previously synthesized by a signifi-
cantly more demanding four-step procedure from 1,2-dime-
thoxybenzene and 4-chloroiodobenzene.[24] Photochemically
initiated SRN1-type reactions of phenoxides with azosulfides
in dimethylsulfoxide have been reported by Petrillo et al.[25]
To demonstrate the synthetic potential of the described
method,we converted the biarylamines 3aa and 3ac into the
fungizide Boscalid[26,27] (industrial production exceeds
1000 tons annually) and the antimalarial agent tebuquine, Experimental Section
respectively.[28]
Method A for the radical arylation of anilines (Table 3): a) Prepara-
tion of the arenediazonium chloride: An ice-cooled degassed solution
of the aniline (20.0 mmol) in 10% hydrochloric acid (20 mL) and
water (20 mL) was stirred,and a degassed solution of sodium nitrate
(1.38 g,20.0 mmol) in water (10 mL) was added dropwise over
10 min. After the reaction mixture had been stirred an additional
20 min at 08C,the solution was used for the aryl–aryl coupling
Monoprotection of diamine 3aa with di-tert-butyl pyro-
carbonate (Boc2O) gave 6,which upon reaction with 2-
chloronicotinic acid chloride (7) furnished amide
8
(Scheme 2). Boscalid (9) was accessible in a one-pot proce-
dure consisting of deprotection,diazotization,and reduction.
reaction. b) Aryl–aryl coupling:
A mixture of the aniline 2
(10.0 mmol) in degassed water (16 mL) and titanium(III) chloride
(4 mL,ca. 1 m solution in 10% hydrochloric acid) was stirred,and the
solution of the arenediazonium chloride (5 mL,ca. 2.00 mmol) was
added by syringe pump over 5 min. The resulting mixture was left to
stir for 15 min,and a solution of sodium hydroxide (2.0 g) and sodium
sulfite (2.0 g) in water (20 mL) was added. The crude product mixture
was extracted three times with diethyl ether (3 ” 30 mL),and the
combined organic phases were subsequently washed with saturated
sodium chloride solution (30 mL) and dried over sodium sulfate.
Concentration in vacuo and purification by column chromatography
furnished the biphenylamines 3.
Scheme 2. Three-step synthesis of the fungizide Boscalid (9) from
4’-chlorobiphenyl-2,5-diamine (3aa).
Received: August 1,2008
Published online: October 21,2008
ꢀ
Keywords: aromatic substitution · biaryls · C C coupling ·
radical reactions · titanium
.
Starting from aminophenol 3ac,tebuquine ( 11) was
accessible by a simple sequence (Scheme 3). Nucleophilic
aromatic substitution of 4,7-dichloroquinoline (10) followed
by Mannich aminomethylation led to the desired target
compound 11 after acidic workup. Tebuquine (11) has shown
subnanomolar activity against chloroquine-resistant strains of
Plasmodium falciparum and represents a lead structure for
the development of new antimalarial drugs.[28–30]
In summary,we have developed a previously unknown
access to functionalized biarylamines and alcohols. Electron-
rich phenols and aniline derivatives were shown to be best
suited precursors. This methodology is of particular value
since conventional organometallic cross-coupling reactions
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