Anti-friedel-crafts-type substitution to form biaryl linkages

Article abstract of DOI:10.1055/s-0033-1339682

The ipso-substitution of one (or two) hydroxy groups of phloroglucinol with arene nucleophiles (e.g., o-xylene, tetralin, biphenyl) can be achieved easily under Friedel-Crafts-type conditions with or without the use of organic solvents affording a variety of 3,5-dihydroxybiphenyls (57-89% yields). The new method has significant practical advantages compared to classical biaryl-coupling routes. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339682

3038▌
PAPER
paper
Anti-Friedel–Crafts-Type Substitution To Form Biaryl Linkages
Anti-Friedel–Crafts-Type Substitution To Form Biaryl Linkages
Gergely Gulyas-Fekete,a,b Carlos J. Boluda,a Bernhard Westermann,*a,c Ludger A. Wessjohann*a,c
a
Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, 06120 Halle, Germany
Fax +49(345)55821309; E-mail: bernhard.westermann@ipb-halle.de
b
University of Pécs, Medical School, Department of Biochemistry and Medical Chemistry, Szigeti út 12, 7624 Pécs, Hungary
c
Institute of Organic Chemistry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, Germany
E-mail: wessjohann@ipb-halle.de
Received: 19.06.2013; Accepted after revision: 08.08.2013
derivatives. This tedious procedure results the appropriate
biaryl component 1 in low yields. Other routes take ad-
vantage of a preformed aromatic ring [e.g., phloroglucinol
(4)] with a substitution pattern that has to be transformed
Abstract: The ipso-substitution of one (or two) hydroxy groups of
phloroglucinol with arene nucleophiles (e.g., o-xylene, tetralin, bi-
phenyl) can be achieved easily under Friedel–Crafts-type condi-
tions with or without the use of organic solvents affording a variety
of 3,5-dihydroxybiphenyls (57–89% yields). The new method has selectively.4i,7
significant practical advantages compared to classical biaryl-
As expected, powerful palladium-catalyzed reactions7,8
coupling routes.
offer another way to 5-aryl-substituted resorcinols. How-
ever, activation of resorcinol by substitution at the meta-
position, e.g. bromination to 1-bromo-3,5-dimethoxyben-
zene (5) by direct halogenation is not very effective, and
thus these starting materials are rather expensive and not
amenable to large-scale synthesis. The same applies for a
similar boron-containing coupling reagent7c and the cata-
lysts themselves, which also limits the applicability in
scale-up procedures.
Key words: biaryls, dendrimers, arylations, umpolung, Friedel–
Crafts
The biaryl moiety is a structural motif that can be found in
numerous examples of biologically active compounds.1
Furthermore, applications in material sciences have also
been reported.2 During our studies towards unbiased
Fréchet-type dendrimers with biaryls as the branching
units (Figure 1), a high yielding multigram synthesis of bi-
aryl building blocks of type 1 and 2 with 3,5-dihydroxy
substituents was required. The preparation of derivatives
with this substitution pattern turned out to be a challeng-
ing task. Here, we present a simple and powerful synthetic
route to a variety of derivatives from readily available and
affordable starting materials.
The simplest starting material would be inexpensive phlo-
roglucinol (4), in which the third hydroxy group would
become a handle for selective activation to form biaryl
building blocks 1 and 2. Instead of using costly protection
and activation reagents (e.g., monotriflate formation), di-
HO
AcO
Current methods to achieve 5-substituted resorcinols em-
ploy multistep procedures3 or transition-metal-catalyzed
coupling protocols4 that require precursors activated in
the uncomfortable meta-position of the phenols, e.g. aryl
iodides. The majority of the biaryl motif syntheses in-
volve transition-metal-catalyzed cross coupling of an aryl
halide and an aryl organometallic compound (e.g., magne-
sium, tin, silicon, zinc).5 Gold-catalyzed arylation with ar-
ylsilanes is notable for its mild conditions, low loadings,
and site selectivity,6a while electrochemical C–C cross-
coupling allows syntheses of highly reactive intermedi-
ates.6b
OH
Br
1
2
HO
AcO
head
head
n
n
branching
units
biaryl
head
n
head
n
core
O
To achieve the formation of congeners of the dihydroxy-
aryl ring, a Michael addition of a β-dicarboxy
component4a–f or a sulfinyl-acetate4g,h to an α,β-unsaturat-
ed ester or ketone has been described (Scheme 1). The re-
sulting cyclohexanedione intermediate 3 has to be
transformed in further steps4c,j,k to the desired resorcinol
O
=
head
O
n–1
n–1
head
head
from 1 or 2
n–1
n–1
SYNTHESIS 2013, 45, 3038–3043
head
Advanced online publication: 02.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339682; Art ID: SS-2013-T0425-OP
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Fréchet-type dendrimers with biaryl branching units

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Anti-Friedel–Crafts-Type Substitution To Form Biaryl Linkages
3039
ture of the reactive species between phloroglucinol (4)
and certain nucleophiles in the anti-Friedel–Crafts substi-
tution has not been undoubtedly solved yet.9c–e,10
O
O
O
+
OMe
RO
Ph
In order to generate a practical process, the conditions un-
der which the normal Friedel–Crafts is displaced by an
anti-Friedel–Crafts substitution were studied. Indeed, in
the additional presence of a standard Friedel–Crafts-type
electrophile like benzoyl chloride, and depending on the
conditions, mixtures of both types of products are formed,
revealing the Janus-type behavior of phloroglucinol (4) in
such reactions. Phloroglucinol (4), under similar condi-
tions, can react as a nucleophile with benzoyl chloride (in
nitrobenzene), although with low yield.11 Additionally,
the scope and limitations of this method regarding the cat-
alyst, solvent, and the type of coupling reagents needed to
be investigated.
RO2C
O
Ph
O
OH
OH
OMe
OMe
HO
Br
5
3
4
OH
OH
HO
1
Scheme 1 Synthesis of biaryl Fréchet-type branching units
R2
HO
R2
HO
AlCl3
R1
R1
rect ipso-substitution of one hydroxy group by Lewis acid
activation causing an ‘Umpolung’ of the aromatic rings
electronic status would be most feasible (for a putative
mechanism see Scheme 2). Indeed, Lewis acid catalyzed
ipso-substitutions of phenols by Lewis acid hyperactiva-
tion have already been described, but only used infre-
quently.9,10 In principle, the same type of activation used
in Friedel–Crafts reactions can be assumed, but the spe-
cial constellation and multiple activation causes an invert-
ed reactivity: the phloroglucinol–aluminum complex now
can be seen as a highly activated vinylogous acid (or acti-
vated keto tautomer) acting much like a Friedel–Crafts ac-
ylating agent on an electrophilic benzene. As a
consequence, not the ortho (or para) hydrogen of the orig-
inally nucleophilic phenol is substituted, but one of the
hydroxy groups. This requires an activated hydroxy group
to be a better leaving group than a proton, and accordingly
very strong activation is required to achieve a reaction in
this ‘anti-Friedel–Crafts’ sense, with the phloroglucinol
acting as the electrophile and, for example, toluene as the
nucleophile. The mechanism of the reaction and the struc-
OH
+
no solvent
or PhCl
HO
HO
4
6a–e
7a–e
R1
Me
Me
Ph
R2
H
Me
H
a
b
c
d
e
-(CH2)4-
-O(CH2)2O-
Scheme 3 Biaryls by anti-Friedel–Crafts substitution
In contrast to a reported procedure7c we started our at-
tempts with toluene (6a) as the nucleophilic substrate,
which at the same time can serve as solvent (Scheme 3,
Table 1, entry 1). The reaction parameters were modified
in order to optimize the yield of the desired anti-Friedel–
Crafts products. Increasing the amount of aluminum tri-
chloride from one to five equivalents revealed that two
equivalents of Lewis acid delivered the best yield with re-
spect to the monosubstituted product 4′-methylbiphenyl-
3,5-diol (7a), which was formed in 89% yield with high
regioselectivity (no ortho- or para-substitution product
could be detected). When using four equivalents of alumi-
num trichloride, 3,5-bis(4-methylphenyl)phenol (7a′) is
formed additionally, i.e. two ipso-substitutions occurred,
however, in much lower yield. Applying five equivalents
of aluminum trichloride led to extensive side reactions
and very apolar and inseparable mixtures.
nucleophile
HO
OH
HO
– HCl
OH
HO
n AlCl3 (n ≥ 2)
aromatization
elimination
Umpolung
Bromo-, chloro-, and 1,2-dichlorobenzene proved to be
inert under these conditions, rendering them potential sol-
vents for the reaction. In other common solvents for elec-
OAlCl2
AlCl3
OAlCl2
H
trophilic
substitutions
(sulfolane,
nitromethane,
nitroethane, nitrobenzene) no reaction occurred, likely
due to a complexation–deactivation of the aluminum salt
by the solvent. In addition to aluminum trichloride, some
other Lewis acid catalysts such as silicon tetrachloride (2–
4 equiv), scandium(III) triflate (catalytic amount),
iron(III) chloride (0.5–3 equiv), and indium(III) chloride
(0.5–3 equiv) were examined in the presence of toluene,
Cl2AlO
O
H
Cl2AlO
AlCl3
Cl
AlCl2
O
electrophile
(mono-keto-mesomer shown)
Scheme 2 A putative mechanism for the anti-Friedel–Crafts substi-
tution of polyhydroxybenzenes, with only one of the possible Lewis
acid hyperactivated phloroglucinol intermediates and mesomers
shown
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3038–3043

3040
G. Gulyas-Fekete et al.
PAPER
but they were ineffective for this reaction, or in case of electronically highly activated substrates like anisole12 or
iron(III) chloride did not lead to any improvement.
naphthalene and derivatives, the reaction works too, but
turned out to be difficult to control and can yield complex
mixtures under standard conditions. For example, in the
case of diphenyl- and triphenylmethane, a competitive
Scholl reaction might be a cause for the weak perfor-
mance.10,13
Other arene nucleophiles proved to be suitable for this re-
action. In the case of o-xylene, the corresponding biaryl
7b was formed in 67%. The reaction is highly regioselec-
tive forming 7b as the only isomer. Biphenyl and tetralin
were also applied successfully, yielding 7c (57%) and 7d
(64%) in acceptable yields. The dioxolane-annulated ben- With the substituted resorcinol 7a available in large quan-
zene 6e gave the corresponding coupled product 7e tities, the synthesis of building blocks 1 and 2 suitable for
(61%), demonstrating the utility of this approach even in Fréchet-type dendrimers with a biaryl unit was straight-
the presence of functionalized subunits.
forward (Scheme 4). Acetylation to 8 and bromination in
the presence of N-bromosuccinimide following classical
protocols led to the first key intermediate, the 4′-bromo
compound 2 in 76% yield overall. Treatment with dimeth-
yl sulfoxide, depending on the conditions, can directly
give either 1,14 or the aldehyde 9 (Kornblum oxidation)
Deactivating substituents on the aromatic ring (formyl,
acetyl, cyano, alkoxycarbonyl, halogeno, acylamino)
show no useful reactivity. Obviously, the electrophilic in-
termediate from phloroglucinol (4) and aluminum trichlo-
ride is too weak to initiate the reaction. In the cases of
Table 1 Products of the Reaction of Phloroglucinol with (Substituted) Arenes
Entry
Arene
Product
Method
Aa
Yield (%)
HO
1
89
HO
6a
7a
OH
2
Ab
24
6a
7a′
HO
3
4
5
6
A
Ba
A
B
67
57
64
61
HO
6b
6c
7b
HO
HO
7c
HO
HO
6d
7d
HO
O
O
O
O
HO
6e
7e
a Conditions A: solvent-free, 4, 6, 10 min, AlCl3 (2 equiv), r.t., 1 d; Conditions B: 4, AlCl3 (2 equiv), PhCl, 10 min, 6, r.t., 1 d.
b AlCl3 (4 equiv), 50 °C, 3 d.
Synthesis 2013, 45, 3038–3043
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Anti-Friedel–Crafts-Type Substitution To Form Biaryl Linkages
3041
Phenols 7, With-Solvent Method; General Procedure B
that can be reduced in one step to the biphenylic congener
Phloroglucinol 4 (1.26 g, 10 mmol) was stirred in chlorobenzene
(30 mL) with AlCl3 (2.67 g, 20 mmol, 2 equiv) for 30 min. Then the
substrate 6c or 6e was added (15 mmol) and the suspension was
stirred (applied reaction times and temperatures are given in Table
1). Ice and EtOAc (50 mL) were added, the phases were separated,
and the aqueous phase was washed with EtOAc (2 × 50 mL). The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated under reduced pressure. The resulting red oil was sub-
jected to column chromatography (PE–EtOAc, 2:1).
1 of Fréchet’s building units in 92% yield.
AcO
HO
Ac2O
quant.
AcO
AcO
HO
8
7a
NBS
(BzO)2
4′-Methylbiphenyl-3,5-diol (7a)
Light yellow solid; yield: 1.78 g (89%); Rf = 0.34 (PE–EtOAc, 2:1);
mp 165 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.26 (s, 3 H), 6.21 (s, 1 H),
6.43 (s, 2 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.42 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 19.1, 101.3, 104.6, 126.3,
129.4, 136.6, 137.7, 142.1, 158.6.
DMSO
Br
HO
HO
AcO
AcO
2 76%
DMSO
NaOAc
OH
1 92%
HRMS (ESI): m/z [M – H]– calcd for C13H11O2: 199.0764; found:
199.0768.
O
LiAlH4
H
4,4′′-Dimethyl-1,1′:3′,1′′-terphenyl-5′-ol (7a′)
AcO
9 85%
The double ipso-substituted compound 7a′ was obtained using pre-
parative HPLC with a purity of >95%. White solid; yield: 0.66 g
(24%); Rf = 0.79 (CH2Cl2)9; mp 318 °C.
Scheme 4 Formation of dendrimer-branching units 1 and 2
1H NMR (400 MHz, CD3OD): δ = 2.34 (s, 6 H, CH3), 6.97 (d,
J = 1.6 Hz, 2 H, HAr), 7.26 (d, J = 7.8 Hz, 4 H, HAr), 7.27 (s, 1 H,
HAr), 7.57 (d, J = 8.1 Hz, 4 H, HAr).
13C NMR (100 MHz, CDCl3): δ = 21.1, 112.6, 118.6, 127.0, 129.4,
137.3, 137.8, 143.2, 156.0.
HRMS (ESI): m/z [M – H]– calcd for C20H17O: 273.1279; found:
273.1286.
In conclusion, the reaction of phloroglucinol with (donor-
substituted) benzenes in the presence of aluminum tri-
chloride seems to be superior to other methods to prepare
3,5-dihydroxybiaryls. Furthermore, it is an inexpensive
and simple method, suitable to yield pure products in large
quantities.
3′,4′-Dimethylbiphenyl-3,5-diol (7b)
Light yellow solid; yield: 1.43 g (67%); Rf = 0.32 (PE–EtOAc, 2:1);
mp 79 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.23 (s, 3 H), 2.26 (s, 3 H),
6.19 (s, 1 H), 6.43 (s, 2 H), 7.16 (d, J = 7.4 Hz, 1 H), 7.22 (d, J = 7.4
Hz, 1 H), 7.29 (s, 1 H), 9.29 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 19.0, 19.5, 101.2, 104.6,
123.7, 127.5, 129.8, 135.3, 136.4, 138.1, 142.2, 158.5.
HRMS (ESI): m/z [M – H]– calcd for C14H13O2: 213.0921; found:
213.0924.
1H and 13C NMR spectra were obtained in CDCl3, CD3OD acetone-
d6 or DMSO-d6 and recorded with a Varian Mercury 300 spectrom-
eter with respect to TMS as an internal standard (1H NMR) and to
the solvent (13C NMR). HRMS ESI were obtained from a Bruker
Apex III FT ion cyclotron resonance (FT-ICR) mass spectrometer
equipped with an Infinity™ cell, a 7.0 Tesla superconducting mag-
net, an RF-only hexapole ion guide, and an external electrospray ion
source (Agilent, off axis spray). Column chromatography was car-
ried out using Merck silica gel 60 (0.040–0.063 nm) and analytical
TLC was performed using Merck silica gel 60 F254 aluminum
sheets. All commercially available chemicals were used without
further purification. When required, preparative HPLC was per-
formed on an Agilent Infinity 1260 equipped with quaternary ana-
lytical pump, column oven, preparative fraction collector,
preparative autosampler, preparative binary pumps and single Quad
MS detector. Preparative HPLC separations were performed using
a Zorbax column (extend-C18 PrepHT 21, 5 μm, 2 × 150 mm) at a
flow rate of 17 mL/min. For the HPLC a gradient system was used
starting from H2O–MeOH, 20:80 to 0:100, hold time 10 min; 600
μL was injected into HPLC-system; detection: MS: m/z = 100–
1000; UV: 210 and 254 nm. Petroleum ether = PE.
1,1′;4′,1′′-Terphenyl-3,5-diol (7c)
Light yellow solid; yield: 1.49 g (57%); Rf = 0.40 (PE–EtOAc, 2:1);
mp 57 °C.
1H NMR (400 MHz, DMSO-d6): δ = 6.26 (s, 1 H), 6.54 (d, J = 2.0
Hz, 2 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.62 (d,
J = 8.5 Hz, 2 H), 7.70 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 101.7, 104.7, 126.5, 127.0,
127.1, 127.5, 129.0, 139.1, 139.6, 139.7, 141.6, 158.7.
HRMS (ESI): m/z [M – H]– calcd for C18H13O2: 261.0916; found:
261.0922.
Phenols 7, Solvent-Free Method; General Procedure A
Phloroglucinol 4 (1.26 g, 10 mmol) was stirred in the appropriate
substrate 6 (50 mL) for 10 min. Then AlCl3 (2.67 g, 20 mmol, 2
equiv) was added and the suspension was stirred (applied reaction
times and temperatures are given in Table 1). Ice and EtOAc (50
mL) were added, the phases were separated, and the aqueous phase
was washed with EtOAc (2 × 50 mL). The combined organic layers
were dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The resulting red oil was subjected to column chroma-
tography (PE–EtOAc, 2:1).
5-(5,6,7,8-Tetrahydronaphthalen-2-yl)benzene-1,3-diol (7d)
Brown oil; yield: 1.54 g (64%); Rf = 0.30 (PE–EtOAc, 2:1).
1H NMR (400 MHz, CD3OD): δ = 1.62 (s, 4 H), 2.59 (d, J = 7.0 Hz,
4 H), 6.18 (d, J = 2.2 Hz, 1 H), 6.43 (d, J = 2.2 Hz, 2 H), 6.87 (d,
J = 7.9 Hz, 1 H), 7.07 (s, 1 H), 7.09 (d, J = 7.9 Hz, 2 H).
13C NMR (100 MHz, CD3OD): δ = 24.3, 30.0, 30.4, 102.1, 106.4,
124.9, 128.2, 130.3, 137.3, 138.1, 139.5, 144.8, 159.6.
HRMS (ESI): m/z [M – H]– calcd for C16H15O2: 239.1072; found:
239.1080.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3038–3043

3042
G. Gulyas-Fekete et al.
PAPER
5-(2,3-Dihydro-1,4-benzodioxin-6-yl)benzene-1,3-diol (7e)
Light yellow solid; yield: 1.49 g (61%); Rf = 0.25 (PE–EtOAc, 2:1);
mp 131 °C.
1H NMR (400 MHz, acetone-d6): δ = 4.24 (s, 4 H), 6.36 (t, J = 2.2
Hz, 1 H), 6.59 (d, J = 2.2 Hz, 2 H), 6.83 (d, J = 7.8 Hz, 1 H), 7.01
(s, 1 H), 7.04 (d, J = 2.0 Hz, 2 H).
13C NMR (100 MHz, acetone-d6): δ = 65.2, 102.1, 106.0, 116.1,
118.1, 120.3, 135.4, 143.5, 144.3, 144.7, 159.7.
HRMS (ESI): m/z [M – H]– calcd for C14H11O4: 243.0657; found:
243.0650.
subsequently extracted with EtOAc (3 × 150 mL). The combined
organic layers were washed with H2O (3 × 150 mL) and brine, and
then dried (MgSO4), and the solvent was removed in vacuo. Flash
chromatography (PE–EtOAc, 1:1) delivered pure 1. Colorless oil;
yield: 6.7 g (92%); Rf = 0.27 (PE–EtOAc, 1:1).
1H NMR (300 MHz, DMSO-d6): δ = 4.52 (d, J = 4.98 Hz, 2 H), 5.20
(s, 1 H), 6.22 (s, 1 H), 6.47 (d, J = 1.9 Hz, 2 H), 7.36 (d, J = 8.1 Hz,
2 H), 7.48 (d, J = 8.1 Hz, 2 H), 9.33 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 62.6, 101.5, 104.7, 126.1,
126.9, 139.0, 141.6, 142.1, 158.7.
HRMS (ESI): m/z [M – H]– calcd for C13H11O3: 215.0708; found:
215.0717.
3,5-Diacetoxy-4′-methylbiphenyl (8)
4′-Methylbiphenyl-3,5-diol (7a, 56.3 g, 0.28 mol) was dissolved in
Ac2O (100 mL) and pyridine (1 mL) was added; the mixture was
stirred overnight at r.t. The mixture was concentrated under reduced
pressure, whereupon it was poured into H2O (400 mL) and extracted
with Et2O (3 × 150 mL). The combined organic phases were
washed with H2O, sat. NaHCO3, and with H2O again, and then dried
(MgSO4), and the solvent was removed in vacuo. The crude product
was used for the next step without further purification. Colorless oil;
yield: 80.2 g (100%); Rf = 0.41 (hexane–CH2Cl2, 1:1).
Acknowledgment
C.B. thanks the Canarian Foundation Dr. Manuel Morales for a
postdoctoral fellowship. Financial support from the University of
Paderborn (G.G.-F.) and the state of Saxony-Anhalt (HWP-
program – G.G.-F.) is gratefully acknowledged. C.J.B. and G.G.-F.
contributed equally to this paper.
1H NMR (300 MHz, CDCl3): δ = 2.29 (s, 6 H), 2.37 (s, 3 H), 6.88
(s, 1 H), 7.18 (d, J = 2.1 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.44 (d,
J = 8.2 Hz, 2 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
13C NMR (75 MHz, DMSO-d6): δ = 21.2, 22.2, 113.7, 117.4, 126.8,
129.4, 136.3, 137.8, 143.2, 151.0, 168.8.
References
3,5-Diacetoxy-4′-(bromomethyl)biphenyl (2)
3,5-Diacetoxy-4′-methylbiphenyl (8, 68.1 g, 0.24 mol) and NBS
(44.8 g, 0.25 mol) were dissolved in CCl4 (600 mL). (BzO)2 (1.0 g,
4.1 mmol) was added and the mixture was refluxed (TLC monitor-
ing). When starting material 8 had been consumed, the mixture was
cooled to r.t. and filtered. Crude product was obtained from the fil-
trate by solvent removal under vacuum, and the solid residue was
subjected to flash chromatography (PE–EtOAc 4:1). Colorless oil;
yield: 66.1 g (76%); Rf = 0.29 (PE–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): δ = 2.30 (s, 6 H), 4.51 (s, 2 H), 6.92
(s, 1 H), 7.19 (d, J = 2.0 Hz, 2 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.51 (d,
J = 8.3 Hz, 2 H).
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13C NMR (75 MHz, DMSO-d6): δ = 21.2, 33.1, 114.3, 117.5, 127.3,
129.4, 137.4, 139.2, 142.4, 151.1, 168.8.
Applications; Wiley-VCH: Weinheim, 2001. (c) Marcos,
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4-(3,5-Diacetoxyphenyl)benzaldehyde (9)
3,5-Diacetoxy-4′-(bromomethyl)biphenyl (2, 40.0 g, 0.11 mol) and
NaOAc (32.8 g, 4 equiv) were suspended in DMSO (100 mL) and
the mixture was stirred at 70 °C overnight. Then, mixture was
cooled to r.t. and poured into H2O (500 mL). After extraction with
Et2O (3 × 150 mL), the combined organic phases were washed with
H2O (5 ×) and then with brine, dried (MgSO4), the solvent was re-
moved in vacuo, and the crude substance subjected to flash chroma-
tography (PE–EtOAc, 3:1). Colorless oil; yield: 27.9 g (85%); Rf =
0.32 (PE–EtOAc, 3:1).
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1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 6 H), 6.96 (s, 1 H), 7.20
(d, J = 1.8 Hz, 2 H), 7.61 (d, J = 8.1 Hz, 2 H), 7.85 (d, J = 8.1 Hz, 2
H), 9.94 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 20.7, 114.9, 117.5, 127.1,
129.7, 135.2, 141.4, 144.3, 151.0, 168.3, 191.1.
HRMS (ESI): m/z [M + Na]+ calcd for C17H14O5Na: 321.0739;
found: 321.0733.
4-(3,5-Dihydroxyphenyl)benzyl Alcohol (1)
4-(3,5-Diacetoxyphenyl)benzaldehyde (9, 10.0 g, 33.5 mmol) dis-
solved in THF (50 mL) was added dropwise to a stirred suspension
of LiAlH4 (2.60 g, 68.5 mmol) in THF (200 mL). The mixture was
refluxed for 1 h and cooled to r.t. EtOAc (100 mL), H2O (80 mL),
and then 37% HCl (25 mL) were added to the mixture, which was
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Anti-Friedel–Crafts-Type Substitution To Form Biaryl Linkages
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Synthesis 2013, 45, 3038–3043