The O-substitution pattern of the MoCl5-mediated oxidative aryl-aryl coupling reaction

Article abstract of DOI:10.1055/s-2003-36264

Different protective groups for the phenolic oxygen were investigated in the molybdenum pentachloride-mediated dehydrodimerization reaction. Cyclic acetals and ketals, triisopropylsilyl and alkoxycarbonylmethyl moieties are compatible with the strong acidic reaction conditions.

Full text of DOI:10.1055/s-2003-36264

PAPER
91
The O-substitution Pattern of the MoCl5-Mediated Oxidative Aryl-Aryl
Coupling Reaction
M
oCl -mediate
d
e
Coupling R
a
eaction te Kramer, Roland Fröhlich, Klaus Bergander, Siegfried R. Waldvogel*
5
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: waldvog@uni-muenster.de
Received 12 August 2002; revised 11 October 2002
Abstract: Different protective groups for the phenolic oxygen were
investigated in the molybdenum pentachloride-mediated dehydro-
dimerization reaction. Cyclic acetals and ketals, triisopropylsilyl
and alkoxycarbonylmethyl moieties are compatible with the strong
acidic reaction conditions.
Key words: biaryls, coupling, dimerizations, protective groups,
molybdenum
Scheme 1
The starting materials were synthesized according to
known or standard procedures.8–10 Recently, we reported
on the oxidative coupling reaction of 1a by molybdenum
pentachloride forming the parent tetramethoxy biphenyl
compound 2a.4 The reaction proceeded to completion
within several minutes at room temperature while the evo-
lution of hydrogen chloride was observed. In a first set of
experiments we focused on common protective groups
based on ketals or acetal moieties. The 1,3-benzodioxole
is of particular interest since it is a widely occurring struc-
tural feature in natural products. The conversion of 5-me-
thyl-1,3-benzodioxole (1b) resulted in the known biaryl
2b.7 In order to avoid partial oxidation of the methylene
moiety, performing the reaction at lower temperature is
advantageous. The increased stability of the acetone-de-
rived benzodioxole 1c leads to higher yields. The reaction
can be conducted at ambient temperature without signifi-
cant loss of product. Unfortunately, open-chain acetals
like the methoxymethyl group are not suitable for the mo-
lybdenum pentachloride-mediated transformation. Even
low temperature conditions do not result in any of the de-
sired biaryl system. The starting material 1d undergoes al-
most immediate cleavage and the liberated formaldehyde
equivalent does an electrophilic attack onto the electron
rich aromatic systems (Scheme 2). Beside the known me-
thylene-bridged dimer 3,11 we isolated a significant
amount of the trimeric compound 4. No other isomers of
4 were detected. Higher aggregates were only present in
traces and identified by mass spectrometry. The structure
of 4 was assigned by the X-ray analysis of a single crystal
(Figure 1).17 Remarkably, all phenolic protons form dis-
tinct hydrogen bonds to the adjacent methoxy groups.
The oxidative coupling reaction of electron rich aromatics
by molybdenum pentachloride gives access to novel
structures which are particular useful in supramolecular
chemistry.1 The molybdenum pentachloride mediated de-
hydrodimerization can be exploited for the installation of
the tetramethoxybiaryl moiety resulting in the selective
formation of eight-membered lignans.2 Furthermore, mul-
tiple iodinated substrates are tolerated and can be subject-
ed to coupling without loss of the iodo-substituents.3 In
order to use these particularly interesting structures for
pharmaceutical purposes it is necessary to make them less
lipophilic. This means cleavage or replacement of the me-
thyl protective group.
Molybdenum pentachloride exhibits a substrate selectivi-
ty for 1,2-disubstituted benzenes.4 Due to the strong
Lewis acid character and the oxophilic behaviour of mo-
lybdenum pentachloride, the phenolic oxygen is usually
protected by simple alkyl groups or sterically demanding
ketals. When longer reaction times or additives like sul-
furic acid are applied, a partial loss of the alkyl moieties is
observed.5 Complete removal of the methyl groups how-
ever requires harsh conditions and selective deprotection
of one oxygen is almost impossible.6 To overcome this se-
vere limitation in the molybdenum pentachloride mediat-
ed dehydrodimerization reaction, we were prompted to
investigate a variety of different protective groups for the
phenolic substrates. Subsequent removal or modification
of the O-protective groups should allow an easy tuning of
the physical properties. Differently blocked 4-methylcat-
echols 1a–k were subjected to the molybdenum pen-
tachloride-mediated
dehydrodimerization
reaction
(Table 1). The presence of a methyl group in one para-po-
sition leads normally to exclusive formation of the desired
biaryls, avoiding multiple oxidative coupling (Scheme 1).
Based on the practical significance of benzyl protective
groups, we subjected 1e to the MoCl5-mediated coupling
reaction. The conversion is very sluggish even at low tem-
perature and the only detectable component is the newly
formed benzyl chloride. We investigated the 4-nitro and
4-methoxy benzyl groups as well, leading to the same
sluggish result. Obviously, the oxophilic character of
Synthesis 2003, No. 1, Print: 30 12 2002.
Art Id.1437-210X,E;2003,0,01,0091,0096,ftx,en;T09302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

92
B. Kramer et al.
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Table 1 Oxidative Coupling Reaction of 1 using MoCl5
Entry
1
Substrate
Reaction Conditions
25 °C, 40 min
Yield (%)a
1a
69 (2a) 4
H3CO
H3CO
CH3
2
3
1b
1c8
1d9
1e10
1f
0 °C, 40 min
64 (2b) 7
73 (2c)
–
O
O
CH3
25 °C, 40 min
O
O
CH3
4
–10 °C, 15 min
O
O
H3CO
CH3
5
–10 °C, 15 min
–
BnO
H3CO
CH3
6
0 °C, 40 min
91 (2f)
64 (2g)
62 (2h)
>99 (2i)
96 (2k)
H3COOC
O
H3CO
O
CH3
CH3
7
1g
–10 °C, 15 min argon stream
–35 °C, 8 min argon stream
0 °C, 50 min
H3COOC
H3COOC
TIPSO
O
8
1h
1i
H3CO
Cl
CH3
9
O
H3CO
CH3
10
1k
0 °C, 50 min
O
O
Cl
Cl
CH3
a Yields refer to isolated biaryls 2.
OH
OH
H3CO
OCH3
41 % 3
CH3
CH3
CH3
H3C
MoCl5
1d
+
H3CO
OCH3
HO H3C
OH
OH
18 % 4
OCH3
Figure 1 Solid state structure of 4.
Scheme 2 Reagents and conditions: 1.8 equiv MoCl5, CH2Cl2,
0 °C, 20 min.
Synthesis 2003, No. 1, 91–96 ISSN 0039-7881 © Thieme Stuttgart · New York

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MoCl5-Mediated Coupling Reaction
93
molybdenum pentachloride can be employed to liberate of more complex natural products will be reported in due
the benzyl moiety as benzyl chloride, while the electron course.
rich phenol undergoes degradation processes. Similar re-
sults are obtained when the corresponding allyl derivative
Melting points were determined on a MFB 595 Gallenkamp appa-
ratus (UK) and were uncorrected. Microanalysis was performed us-
is used.12
ing a Vario EL III (Elementar-Analysensysteme, Hanau, D). NMR
Surprisingly, the methoxycarbonylmethyl group, which is
spectra were recorded on a Bruker 300 ARX or on a Varian 600
readily installed,13 turned out to be very stable under the
Unity Plus using TMS as an internal standard. The abbreviation sp
strong acidic reaction conditions. The conversion of 1f to
denotes a septet. Mass spectra were obtained on a MAT8200 system
2f proceeds very quickly in excellent yield. After a few
(Finnigan-MAT, Bremen, D). Exact mass was determined with a
seconds the transformation is accomplished. Possibly the
ester group assists in the recognition of the molybdenum
reagent, similar to the anticipated reaction mechanism for
1,2-dialkoxy-substituted benzenes. When employing two
methoxycarbonylmethyl groups the biaryl 2g is also
readily formed from 1g. A small amount of monochlori-
nated by-product turned out to be almost inseparable.
Alkoxycarbonylmethyl systems are not considered as pro-
tective groups but the ester moiety offers a variety of
transformations, e.g. the conversion to a substituted
amide, and is therefore especially suitable for a tuning of
the physical properties. If the phenolic oxygen is protect-
ed as the acetate or 2-methoxyacetate, no oxidative cou-
pling reaction with molybdenum pentachloride is
observed.
GC-TOF (Micromass, Manchester, UK).
(2-Methoxy-4-methylphenoxy)acetic Acid Methyl Ester (1f)19
4-Methylguaiacol (8.00 g, 0.058 mol) was treated with K2CO3 (8.78
g, 0.064 mol), 2-bromomethylacetate (8.86 g, 0.058 mol) in acetone
(150 mL) and the reaction mixture was heated to reflux over a peri-
od of 4 h. The white inorganic solid was filtered off and washed
with EtOAc (100 mL). Removal of the solvents and subsequent dis-
tillation in vacuo (93 °C; 1.3 102 mbar) provided pure 1f (11.1 g,
91%).
1H NMR (300 MHz, CDCl3): = 2.23 (s, 3 H, Ar-CH3), 3.71 (s, 3
H, OCH3), 3.79 (s, 3 H, ArOCH3), 4.59 (s, 2 H, OCH2), 6.58–6.71
(m, 3 H, Ar-H).
13C NMR (75 MHz, CDCl3): = 20.7 (Ar-CH3), 51.8 (OCH3), 55.6
(ArOCH3), 66.7 (OCH2), 113.1 (C-6), 114.8 (C-3), 120.7 (C-5),
132.3 (C-4), 145.0 (C-1), 149.3 (C-2), 169.4 (CO).
MS (EI, 70 eV): m/z = 210.0 (100) [M+], 137.0 (90), [M+
–
Silyl protective groups usually show a limited stability in
a strongly acidic environment.14 We found that the triiso-
propylsilyl system is a reliable protective group for the
oxidative coupling reaction (entry 8). Other silyl moieties,
like tert-butyldimethyl and tert-butyldiphenyl lead to
sluggish results. In order to avoid traces of protolytic re-
moval by hydrogen chloride, the dehydrodimerization re-
action is performed at low temperatures and with a gentle
stream of inert gas extracting the hydrogen chloride.
CH2CO2CH3], 91.0 (36) [M+ – CH2CO2CH3 – CH3 – OCH3].
Anal. Calcd for C11H14O4 (210.35): C, 62.85; H, 6.71. Found: C,
62.72; H.6.67.
(2-Methoxycarbonylmethoxy-4-methylphenoxy)acetic Acid
Methyl Ester (1g)
4-Methylcatechol (8 g,0.064 mol) was treated with K2CO3 (26.64,
0.193 mol), 2-bromomethylacetate (29.57 g, 0.193 mol) in acetone
(150 mL) and the reaction mixture was heated to reflux over a peri-
od of 5 h. Standard work-up (see 1f) and fractional distillation in
high vacuum (120 °C; 1.3 102 mbar) gave 1g (14.78 g; 87%).
1H NMR (300 MHz, CDCl3): = 2.22 (s, 3 H, ArCH3), 3.72 (s, 3 H,
OCH3), 3.74 (s, 3 H, OCH3), 4.62 (s, 2 H, OCH2), 4.66 (s, 2 H,
OCH2), 6.67–6.77 (m, 3 H, Ar.-H).
Best results were obtained using 2-chloroethyl as the pro-
tecting group15 for the oxidative coupling reaction with
molybdenum pentachloride. The biaryl 2i was easily iso-
lated in almost quantitative yield, analytically pure with-
out further purification. The removal of the 2-chloroethyl
moiety can be done by the known elimination-hydrolysis
sequence.16 Furthermore, the 2-chloroethyl moieties in 2i
and 2k give access to a variety of modifications by simple
nucleophilic displacement of the chlorine and therefore
another possibility for tuning the physical properties of
the biaryls. Even if two 2-chloroethyl moieties are in-
volved in the starting material 1k, a clean conversion was
found without any chlorinated by-products. Since the de-
hydrodimerization process is slow, an active role of the
protective group during the oxidative coupling process
can be excluded.
13C NMR (75 MHz, CDCl3): = 20.6 (ArCH3), 51.8 (OCH3), 66.5
(OCH2), 66.8 (OCH2), 115.8 (C-6), 116.4 (C-3), 122.7 (C-5), 132.4
(C-4), 145.7 (C-1), 147.9 (C-2), 169.3 (CO).
MS (EI, 70 eV): m/z (%) = 268.1 (73) [M+], 209.1 (6) [M+
–
CO2CH3], 195.1 (12) [M+
[H3CC6H3O2CH3 ], 45.0 (100) [HCO2 ].
–
CH2CO2CH3], 137.0 (47)
+
+
HRMS: m/z calcd for C13H16O6, 268.0947; found, 268.0944.
Triisopropyl-(2-methoxy-4-methylphenoxy)silane (1h)
4-Methylguaiacol (5.1 g, 0.036 mol) was deprotonated with NaH
(60% in oil, 1.71 g , 0.042 mol) in anhyd THF at ambient tempera-
ture. The suspension was treated with chloro-tris(isopropyl)silane
(7 g, 0.036 mol) and stirred for 16 h. Standard work-up (see 1f) and
fractional distillation in high vacuum (105 °C; 4 103 mbar) gave
1h (6.1 g; 58%).
1H NMR (300 MHz, CDCl3): = 1.11 (d, 18 H, 3J = 6.9 Hz, CH3),
1.24 (sp, 3 H, 3J = 6.9 Hz, CH), 2.27 (s, 3 H, 7-H), 3.79 (s, 3 H, 8-
H), 6.58–6.67 (m, 2 H, ArH), 6.76–6.78 (s, 1 H, ArH).
In conclusion, several protective groups for the phenolic
oxygen were found to be compatible with the MoCl5-me-
diated oxidative coupling reaction. Clean transformations
are obtained with cyclic acetals or ketals, triisopropylsilyl,
alkoxycarbonylmethyl and 2-chloroethyl systems. There-
fore, the enlarged scope of the molybdenum pentachlo-
ride-mediated transformations is no longer limited to
13C NMR (75 MHz, CDCl3): = 12.9 (CH), 17.9 (CH3), 21.0
(ArCH3), 55.4 (OCH3), 113.4 (C-3), 120.1; 121.0 (C-5, C-6), 130.8
methyl protected phenols. The application to the synthesis (C-4), 143.3 (C-1), 150.5 (C-2).
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94
B. Kramer et al.
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MS (EI, 70 eV): m/z (%) = 294.2 (9) [M+], 251.1 (100) [M+ – iso-
13C NMR (75 MHz, CDCl3): = 19.0 (ArCH3), 30.1 (CH3), 30.3
(CH3), 97.1 (C-2), 113.8 (C-4), 116.2 (C-7), 130.0 (C-5), 142.1 (C-
3a), 144.7 (C-7).
propyl], 236.0 (85) [M+ – isopropyl – CH3].
Anal. Calcd for C17H30O2Si (294.50): C, 69.33; H, 10.27. Found: C,
69.52; H.10.60.
MS (EI, 70 eV): m/z (%) = 326.15 (100) [M+], 311.1 (8) [M+ –
CH3].
1-(2-Chloroethoxy)-2-methoxy-4-methylbenzene (1i)
Anal. Calcd for C20H22O4 (326.38): C, 73.60; H, 6.79. Found: C,
73.42; H, 6.66.
1f (7 g, 0.033 mol) was reduced with NaBH4 (2.52 g , 0.066 mol) in
MeOH (120 mL) at 0 °C providing the alcohol (5.7 g, 95%) which
was then converted into the chloro derivative using Appel’s proce-
dure. For the conversion, PPh3 (9.86 g , 0.038 mol) was dissolved
in CCl4 (25 mL), stirred for 15 min at 0 °C, treated with alcohol
(5.7 g , 0.031 mol), dissolved in CCl4 (15 mL) and toluene (35 mL).
After the reaction mixture was heated 7 h to reflux, all volatile com-
ponents were removed. The residue was fractionated between Et2O
(3 150 mL) and NaHCO3 soln (100 mL). Afterwards the com-
bined organic phases were washed with brine (50 mL), dried and
concentrated. The pure 1i (4.17 g; 67%) was obtained after sublima-
tion in vacuo (60 °C; 5 102 mbar).
(4,4 -Dimethoxy-3 -methoxycarbonylmethoxy-6,6 -dimethyl-bi-
phenyl-3-yloxy)-acetic Acid Methyl Ester (2f)
Mp 132 °C (from MeOH).
1H NMR (300 MHz, CDCl3): = 1.99 (s, 6 H, ArCH3), 3.76 (s, 6 H,
OCH3), 3.90 (s, 6 H, ArOCH3), 4.65 (s, 4 H, OCH2), 6.58 (s, 2 H,
ArH), 6.78 (s, 2 H, ArH).
13C NMR (75 MHz, CDCl3): = 19.3 (ArCH3), 52.0 (OCH3), 55.9
(ArOCH3), 66.7 (OCH2), 113.8 (C-2), 116.3 (C-5), 130.2 (C-6),
133.0 (C-1), 144.8 (C-3), 148.5 (C-4), 169.4 (CO).
MS (EI, 70 eV): m/z (%) = 418.0 (100) [M+], 359.1 (4) [M+
–
Mp 45–46 °C.
1H NMR (300 MHz, CDCl3): = 2.30 (s, 3 H, ArCH3), 3.79 (t, 2 H,
3J = 6.3 Hz, CH2Cl), 3.84 (s, 3 H, OCH3), 4.23 (t, 2 H, 3J = 6.3 Hz,
OCH2), 6.67–6.83 (m, 3 H, ArH).
CO2CH3].
Anal. Calcd for C22H26O8 (418.44): C, 63.15; H, 6.26. Found: C,
63.01; H, 6.00.
13C NMR (75 MHz, CDCl3): = 21.0 (ArCH3), 41.8 (CH2Cl), 56.0
(OCH3), 70.0 (OCH2), 113.5 (C-3), 115.7 (C-6), 121.1 (C-5), 132.4
(C-4), 145.5 (C-1), 149.9 (C-2).
MS (EI, 70 eV): m/z (%) = 200.0 (100) [M+], 137.0 (89) [M+
CH2CH2Cl].
4,4 -Dimethoxy-2,2 -dimethyl-5,5 -bis-triisopropylsilanyloxy-
biphenyl (2h)
Mp 100–101 °C (from MeOH).
1H NMR (300 MHz, CDCl3): = 1.06 (d, 36 H, 3J = 6.9 Hz, CH3),
1.19 (sp, 6 H, 3J = 6.9 Hz, CH), 1.95 (s, 6 H, ArCH3), 3.80 (s, 6 H,
OCH3), 6.58 (s, 2 H, ArH), 6.68 (s, 2 H, ArH).
13C NMR (75 MHz, CDCl3): = 12.9 (CH), 17.9 (CH3), 19.3
(ArCH3), 55.7 (OCH3), 113.8 (C-3), 121.9 (C-6), 128.8 (C-2), 133.8
(C-1), 142.9 (C-5), 149.6 (C-4).
Anal. Calcd for C10H13ClO2 (200.66): C, 59.86; H, 6.53. Found: C,
59.80; H, 6.35.
1,2-Bis-(2-chloroethoxy)-4-methylbenzene (1k)
It was prepared in an analogous manner to 1i, using 1g as starting
material and reagents (2.5 equiv). The pure 1k (60%) was obtained
after sublimation in vacuo (85 °C; 5 102 mbar).
MS (EI, 70 eV): m/z (%) = 586.3 (47) [M+], 543.3 (100) [M+ – iso-
propyl], 470.1 (61) [M+ – 2 isopropyl – 2 CH3].
Mp 56–57 °C (from MeOH).
Anal. Calcd for C34H58O4Si2 (586.99): C, 69.57; H, 9.96. Found: C,
69.27; H, 9.94.
1H NMR (300 MHz, CDCl3): = 2.26 (s, 3 H, ArCH3), 3.73 (t, 2 H,
3J = 6.0 Hz, CH2Cl), 3.77 (t, 2 H, 3J = 6.0 Hz, CH2Cl), 4.17 (t, 2 H,
3J = 6.0 Hz, CH2O), 4.24 (t, 2 H, 3J = 6.0 Hz, CH2O), 6.72–6.84 (m,
3 H, ArH).
13C NMR (75 MHz, CDCl3): = 20.8 (ArCH3), 42.1 (CH2Cl), 42.1
(CH2Cl), 69.9 (OCH2), 70.4 (OCH2), 116.9; 117.2 (C-3, C-6), 122.9
(C-5), 132.7 (C-4), 146.4 (C-1), 148.6 (C-2).
(4,3 ,4 -Tris-(methoxycarbonylmethoxy)-6,6 -dimethylbiphe-
nyl-3-yloxy)-acetic Acid Methyl Ester (2g)
1H NMR (300 MHz, CDCl3): = 1.94 (s, 6 H, ArCH3), 3.76 (s, 6 H,
OCH3), 3.81 (s, 6 H, OCH3), 4.67 (s, 4 H, OCH2), 4.74 (s, 4 H,
OCH2), 6.60 (s, 2 H, ArH), 6.75 (s, 2 H, ArH).
13C NMR (75 MHz, CDCl3): = 19.3 (ArCH3), 52.1 (OCH3), 52.1
(OCH3), 66.8 (OCH2), 66.9 (OCH2), 117.1 (C-2), 117.2 (C-5),
130.4 (C-6), 134.8 (C-1), 145.6 (C-3), 147.0 (C-4), 169.4 (CO),
169.6 (CO).
MS (EI, 70 eV): m/z (%) = 248.0, 250.0 (71) [M+], 213.1 (5) [M+
Cl], 186.0 (35) [M+ – CHCH2Cl], 123.0 (100) [M+ – 2(CHCH2Cl)].
Anal. Calcd for C11H14Cl2O2 (249.13): C, 53.03; H, 5.66. Found: C,
53.00; H, 5.41.
MS (EI, 70 eV): m/z (%) = 534.3 (100) [M+], 475.2 (2) [M+
–
CO2CH3].
Oxidative Coupling Reaction; General Procedure
HRMS: m/z calcd mass for C26H30O12, 534.1737; found, 534.1739.
The substrate (9–10 mmol) in anhyd CH2Cl2 (30 mL) was placed in
a well dried flask and after the temperature was adjusted, MoCl5
(2.73 g, 10 mmol) was added. The reaction mixture was quenched
after the time given in Table 1 with NaHCO3 soln (50 mL). The aq
phase was partitioned with EtOAc (3 100 mL). Subsequent wash-
ings of the combined organic fractions with H2O (100 mL) as well
as brine (100 mL) and concentration provided crude product that
was purified either by column chromatography on silica (cyclohex-
ane–ethyl acetate) or recrystallization.
5,5 -Bis-(2-chloro-ethoxy)-4,4 -dimethoxy-2,2 -dimethylbiphe-
nyl (2i)
Mp 132–134 °C (from EtOAc).
1H NMR (300 MHz, CDCl3): = 2.01 (s, 6 H, ArCH3), 3.80 (t, 4 H,
3J = 6.3 Hz, CH2Cl), 3.90 (s, 6 H, OCH3), 4.24 (dt, 4 H, 2J = 1.8 Hz,
3J = 6.3 Hz, OCH2), 6.68 (s, 2 H, 3-H), 6.79 (s, 2 H, 6-H).
13C NMR (75 MHz, CDCl3): = 19.4 (ArCH3), 41.8 (CH2Cl), 56.1
(OCH3), 69.8 (OCH2), 114.0 (C-6), 116.9 (C-3), 130.0 (C-2), 133.4
(C-1), 145.2 (C-5), 148.8 (C-4).
2,2,6,2 ,2 ,6 -Hexamethyl-[5,5 ]bi(benzo[1,3]dioxolyl) (2c)
Mp 121 °C (from MeOH).
1H NMR (300 MHz, CDCl3): = 1.81 (s, 6 H, CH3), 1.89 (s, 6 H,
CH3), 2.01 (s, 6 H,), 6.56, 6.79 (s, 4 H, ArH) .
MS (EI, 70 eV): m/z (%) = 397.9, 399.3 (100, 68) [M+], 335.0 (6)
[M+ – CH2CH2Cl].
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MoCl5-Mediated Coupling Reaction
95
Anal. Calcd for C20H24Cl2O4 (399.31): C, 60.16; H, 6.06. Found: C,
59.93; H, 6.35.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) and the European Graduate College ‘Template Directed
Chemical Synthesis’. The gift of MoCl5 by H.C. Starck (Goslar,
Germany) was very helpful.
4,5,4 ,5 -Tetrakis-(2-chloroethoxy)-2,2 -dimethylbiphenyl (2k)
Mp 93–94 °C (from MeOH).
1H NMR (300 MHz, CDCl3): = 1.91 (s, 6 H, ArCH3), 3.71–3.79
(m, 8 H, CH2Cl), 4.15 (m, 8 H, CH2O), 6.63 (s, 2 H, 3-H), 6.76 (s,
2 H, 6-H).
13C NMR (75 MHz, CDCl3): = 19.2 (ArCH3), 41.9 (CH2Cl), 42.2
(CH2Cl), 70.1 (CH2O), 70.3 (CH2O), 117.8; 117.9 (C-3, C-6), 130.4
(C-2), 135.0 (C-1), 146.2 (C-5), 147.6 (C-4).
References
(1) (a) Waldvogel, S. R.; Fröhlich, R.; Schalley, C. A. Angew.
Chem. Int. Ed. 2000, 39, 2472. (b) Waldvogel, S. R.;
Wartini, A. R.; Rasmussen, P. H.; Rebek, J. Jr. Tetrahedron
Lett. 1999, 40, 3515.
(2) Kramer, B.; Averhoff, A.; Waldvogel, S. R. Angew. Chem.
Int. Ed. 2002, 41: in press.
(3) Waldvogel, S. R.; Aits, E.; Holst, C.; Fröhlich, R. Chem.
Commun. 2002, 1278.
(4) Waldvogel, S. R. Synlett 2002, 622.
MS (EI, 70 eV): m/z (%) = 494.0; 496.0; 498.0 (76, 100, 50) [M+],
63.0 (31) [CHCH2Cl+].
Anal. Calcd for C22H26Cl4O4 (496.25): C, 53.25; H, 5.28. Found: C,
52.79; H, 5.16 (Calcd for C22H26Cl4O4 0.25 CH3OH (504.25.): C,
53.00; H, 5.40).
(5) Kumar, S.; Manickham, M. Chem. Commun. 1997, 1615.
(6) Green, T. W.; Wuts, G. M. In Protective Groups in Organic
Synthesis; Wiley-Interscience: New York, 1999.
(7) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma,
H.; Kita, Y. J. Org. Chem. 1998, 63, 7698.
(8) Ogura, K.; Tsuchihashi, G. Tetrahedron Lett. 1971, 12,
3151.
(9) Weertunga, G.; Jaworska-Sobiesiak, A.; Horne, S.; Russell,
R. Can. J. Chem. 1987, 65, 2019.
(10) Benigni, J. D.; Minnis, R. L. J. Heterocycl. Chem. 1965, 2,
307.
(11) Arcoleo, A.; Garofano, T. Ann. Chim. (Rome, Italy) 1957,
47, 1142.
(12) Srikishna, A.; Rao, M. S. Tetrahedron Lett. 2001, 42, 5781.
(13) Larock, R. C.; Babu, S. Tetrahedron 1987, 43, 2013.
(14) (a) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(b) Davies, J. S.; Higginbotham, C. L.; Tremeer, E. J.;
Brown, C.; Treadgold, R. C. J. Chem. Soc., Perkin Trans. 1
1992, 3043.
(15) Laatsch, H. Liebigs Ann. Chem. 1980, 140.
(16) Laatsch, H. Z. Naturforsch., B: Chem. Sci. 1985, 40, 534.
(17) X-ray crystal structure analysis of 4: formula C26H30O6
M = 438.50 colorless crystal 0.35 0.30 0.10 mm
a = 11.923(2) b = 12.352(2) c = 16.974(2) Å = 96.80(1)
= 92.64(2) = 112.76(1)° V = 2277.4(6) Å3 calc = 1.279
gcm–3 = 7.34 cm–1 empirical absorption correction via
2,3-Bis-(5-hydroxy-4-methoxy-2-methylbenzyl)-6-methoxy-4-
methylphenol Hemihydrate (4)18
Mp 200–202 °C (from hexane).
1H NMR (600 MHz, CDCl3): = 1.64 (s, 1 H, 0.5 H2O), 2.11 (s, 3
H, 7-H), 2.16 (s, 3 H, 8 -H), 2.17 (s, 3 H, 8 -H), 3.54 (s, 2 H, 1 -H),
3.67 (s, 2 H, 1 -H), 3.82 (s, 3 H, 9 -H), 3.83 (s, 3 H, 9 -H), 3.89 (s,
3 H, 8-H), 5.31 (s, 2 H, 4 -OH; 4 -OH), 5.54 (s, 1 H, 1-OH), 6.18
(s, 1 H, 3 -H), 6.33 (s, 1 H, 3 -H), 6.63 (s, 1 H, 6 -H), 6.65 (s, 1 H,
6 -H), 6.66 (s, 1 H, 3-H).
13C NMR (150 MHz, CDCl3): = 19.2 (C-8 ), 19.3 (C-8 ), 19.8 (C-
7), 28.5 (C-1 ), 31.3 (C-1 ), 55.9 (C-8; C-9 ; C-9 ), 111.2 (C-3),
112.5 (C-6’), 112.6 (C-6 ), 113.4 (C-3 ), 113.6 (C-3 ), 125.2 (C-6),
127.2 (C-7 ), 127.3 (C-7 ), 128.2 (C-4), 130.1 (C-5), 131.4 (C-2 ),
131.6 (C-2 ), 142.3 (C-1), 143.3 (C-4 ), 143.4 (C-4 ), 144.1 (C-5 ;
C-5 ), 144.6 (C-2).
GCOSY (600 MHz / 600 MHz, CDCl3): (13C) / (1H) = 2.11 (7-
H) / 6.66 (3-H), 2.16 (8 -H) / 3.54 (1 -H) / 6.65 (6 -H), 2.17 (8 -H)
/ 3.67 (1 -H) / 6.63 (6 -H), 2.16 (8 -H) / 3.54 (1 -H) / 6.18 (3 -H),
2.17 (8 -H) / 3.67 (1 -H) / 6.33 (3 -H).
GHSQC (150 MHz / 600 MHz, CDCl3): (13C) / (1H) = 19.2 /
2.16 (C-8 / 8 -H), 19.3 / 2.17 (C-8 / 8 -H), 19.8 / 2.11 (C-7 / 7-H),
28.5 / 3.67 (C-1 / 1 -H), 31.3 / 3.54 (C-1 / 1 -H), 55.9 / 3.82 (C-8,
C-9 , C-9 / 9 -H), 55.9 / 3.83 (C-8, C-9 , C-9 / 9 -H), 55.9 (C-8,
C-9 , C-9 / 8-H), 111.2 / 6.66 (C-3 / 3-H), 112.5 / 6.65 (C-6 / 6 -
H), 112.57 / 6.61 (C-6 / 6 -H), 113.4 / 6.18 (C-3 / 3 -H), 113.61 /
6.33 (C-3 / 3 -H).
scan data (0.783
T
0.930) Z = 4 triclinic space group
P1bar (No. 2) = 1.54178 Å T = 223 K /2 scans 9478
reflections collected (+h k l) [(sin )/ ] = 0.62 Å-1 9040
independent (Rint = 0.026) and 7595 observed reflections [I
GHMBC (50 MHz / 600 MHz, CDCl3): (13C) / (1H) = 28.5 (C-
1 ); 127.3 (C-7 ); 143.3 (C-4 ); 144.1 (C-5 ; C-5 ) / 6.33 (3 -H),
31.3 (C-1 ); 127.2 (C-7 ); 143.4 (C-4 ); 144.1 (C-5 ; C-5 ) / 6.18 (3 -
H), 125.2 (C-6); 127.2 (C-7 ); 128.2 (C-4); 130.1 (C-5); 131.4 (C-
2 ) / 3.54 (1 -H), 125.2 (C-6); 127.3 (C-7 ), 130.1 (C-5), 131.6 (C-
2 ) / 3.67 (1 -H), 125.2 (C-6) / 5.54 (1-OH), 127.2 (C-7 ) / 6.18 (3 -
H), 127.3 (C-7 ) / 6.33 (3 -H), 128.2 (C-4); 130.1.(C-5) / 2.11 (7-
H), 143.3 (C-4 ); 144.1 (C-5 C-5 ) / 6,33 (3 -H), 143.4 (C-4 );
144.1 (C-5 ; C-5 ) / 6.18 (3 -H).
2
(I)] 595 refined parameters R = 0.047 wR2 = 0.134
max. residual electron density 0.30 (–0.24) e Å–3 two
independent molecules in the asymmetric unit hydrogens
calculated and refined as riding atoms.
Data set was collected with an Enraf Nonius CAD4
diffractometer. Programs used: data collection Express
(Nonius B.V. 1994) data reduction MolEN (K. Fair 1990)
structure soln SHELXS-97 (Sheldrick, G. M. Acta Cryst.
1990, A46, 467) structure refinement SHELXL-97
(Sheldrick, G. M. Universität Göttingen, 1997) graphics
POV-Ray 3.2.
Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication CCDC 191456. Copies of the data can be
obtained free of charge on application to The Director
CCDC 12 Union Road CambridgeCB2 1EZ UK [fax:
+44(1223)336033 e-mail: deposit@ccdc.cam.ac.uk].
1D-NOE (600 MHz, CDCl3): Irradiation at = 2.11 (7-H), NOE-
signal at 3.54 (1 -H), 6.18 (3 -H), 6.66 (3-H); irradiation at = 3.53
(1 -H), NOE-signal at 2.11 (7-H), 2.16 (8 -H), 3.67 (1 -H), 6.18 (3 -
H), 6.33 (3 -H); irradiation at = 3.66 (1 -H), NOE-signal at 2.17
(8 -H), 3.54 (1 -H), 6.18 (3 -H), 6.33 (3 -H); irradiation at = 3.89
(8-H), NOE-signal at 6.66 (3-H).
MS (EI, 70 eV): m/z (%) = 438.2 (100) [M+], 285.1 (86) [M+ –
+
C9H13O2], 151.1 (37) [C9H12O2 ].
Anal. Calcd for C26H30O6 0.5 H2O (447.52): C, 69.78; H, 6.98.
Found: C, 70.02; H, 6.74.
Synthesis 2003, No. 1, 91–96 ISSN 0039-7881 © Thieme Stuttgart · New York

96
B. Kramer et al.
PAPER
(18) Structure of 4: The chemical shifts for the structure were
assigned by long range coupling experiments and refer to the
following numbering (Figure 2).
(19) For a multi-step synthesis of 1f, see: Freudenberg, K.;
Müller, H. G. Liebigs Ann. Chem. 1953, 584, 40.
Figure 2
Synthesis 2003, No. 1, 91–96 ISSN 0039-7881 © Thieme Stuttgart · New York