Cross-Dehydrogenative-Coupling of Alkoxybenzenes with Toluenes: Copper(II) Halide Mediated Tandem Halo/Benzylation of Arenes

Article abstract of DOI:10.1002/chem.201603783

A cross-dehydrogenative-coupling of alkoxybenzenes and toluenes with concomitant halogenation is reported. Conditions employed were the use of stoichiometric copper halide salts and dialkylperoxides to afford a range of bromoalkoxydi- and triarylmethanes. Preliminary mechanistic studies suggest that the in situ production of haloarenes (or dihaloarenes) followed by a copper-mediated coupling of a benzylic radical is operational.

Full text of DOI:10.1002/chem.201603783

DOI: 10.1002/chem.201603783
Full Paper
&
Organic Synthesis
Cross-Dehydrogenative-Coupling of Alkoxybenzenes with
Toluenes: Copper(II) Halide Mediated Tandem Halo/Benzylation of
Arenes
Thomas E. Storr, Christopher J. Teskey, and Michael F. Greaney*[a]
Abstract: A cross-dehydrogenative-coupling of alkoxyben-
zenes and toluenes with concomitant halogenation is re-
ported. Conditions employed were the use of stoichiometric
copper halide salts and dialkylperoxides to afford a range of
bromoalkoxydi- and triarylmethanes. Preliminary mechanistic
studies suggest that the in situ production of haloarenes (or
dihaloarenes) followed by a copper-mediated coupling of
a benzylic radical is operational.
Introduction
The synthesis of diarylmethanes is generally carried out
using nucleophilic substitution or cross-coupling of an a-(pseu-
do)halide bearing benzylic unit.[11] Unfortunately, these meth-
ods sometimes require the use of forcing conditions (high tem-
peratures) or the use of an expensive transition-metal catalyst
and ligand systems. There has been growing interest in CÀH
functionalization approaches to directly functionalize benzylic
C(sp3)ÀH bonds, cutting out pre-functionalization steps and
improving overall atom economy.[12] Despite a number of
recent reports disclosing the direct substitution of benzylic
C(sp3)ÀH bonds for various functional groups,[13] reports of the
analogous arylations are rare. Early work from Miura on this
transformation demonstrated that para-nitrotoluenes could be
effectively cross-coupled with arylhalides to generate diarylme-
thanes.[14] These findings have been extended to a number of
Pd-catalyzed benzylic-C(sp3)ÀH direct arylations, but all require
significant acidification of the benzylic position through elec-
tron-withdrawing groups (Scheme 1a),[15] along with pre-func-
tionalized aryl components (arylhalide or arylorganometallic).
Within our research group, we have a continued interest in the
use of cross-dehydrogenative-coupling reactions (CDC),[16] in
which two disparate CÀH components can be coupled to gen-
erate a new CÀC bond.[17] This approach has limited precedent
for benzhydryl synthesis; the homo-dehydrogenative-coupling
(HDC) of C(sp2)ÀC(sp3) positions is known for simple arenes
such as para-xylene and mesitylene,[18] and the CDC of C(sp2)À
H and benzylic C(sp3)ÀH bonds has been the subject of a small
number of reports. The groups of Shi, Song and Chen have de-
scribed iron-catalyzed di- and triarylmethane syntheses using
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant
(Scheme 1b),[19] and Duan and Zhang/Wen have described
copper-catalyzed CDC benzylation of coumarins and indoles,
respectively.[20]
Diarylmethanes, also known as benzhydryls, are privileged
structural motifs[1] found in pharmaceuticals,[2] supramolecular
chemistry,[3] functional molecules,[4] polymers,[5] ligands,[6] cata-
lysts[7] and dyestuffs.[8] A number of pharmacologically active
natural products contain the diarylmethane subunit,[9] such as
the vidalols A and B; halogenated diarylmethanes recently iso-
lated from marine algae have been shown to possess a wide
range of biological activities, such as inhibition of carbonic an-
hydrase and phospholipase A2 (Figure 1).[10]
Figure 1. Representative pharmaceuticals and algae-derived diarylmethane
natural products.
[a] Dr. T. E. Storr, Dr. C. J. Teskey, Prof. M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
We were thus interested in exploring the potential of CDC
coupling to access alternative benzhydryls based on electron-
rich arene components. During our investigations into the fea-
sibility of a CDC protocol we uncovered an unprecedented
E-mail: michael.greaney@manchester.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603783.
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Table 1. Screening of copper salts to mediate a CDC formation of diaryl-
methanes.
Entry
Copper salt
Yield of 3 [%]
Yield of 4 [%]
1
2
3
4
5
6
7
Cu(OTf)2
Cu(OAc)2
CuSO4
CuBr2
CuCl2
0
0
0
0
0
0
0
0
0
0
49
24
0
CuF2
[Cu(acac)2][a]
Scheme 1. Benzylic C(sp3)ÀH arylation protocols.
0
[a] acac=acetylacetone.
tandem reaction, the halo-benzylation of alkoxyarenes
(Scheme 1c), which is the subject of this report.
Results and Discussion
Reaction discovery
We began by studying the reaction of toluene derivatives with
various arenes under oxidative conditions. We were surprised
to find that treatment of 1,3,5-trimethoxybenzene (1a, as a lim-
iting reagent) with para-xylene (2a, as the solvent and cou-
pling partner), in the presence of stoichiometric copper(II) bro-
mide and di-tert-butyl peroxide (DTBP), gave the brominated
benzhydryl compound 4 (X=Br) as the major product along
with small amounts of mono- and dibrominated 1,3,5-trime-
thoxybenzene (5 and 6; Table 1, entry 4, see the Supporting In-
formation for full details). These reaction conditions have
brought about the formation of the desired C(sp2)ÀC(sp3)
bond as well as concomitant formation of a C(sp2)ÀBr bond.
The reaction also occurred, albeit in poorer yield, with copper(-
II) chloride (Table 1, entry 5).
Given the striking similarity of the benzhydryl products of
this tandem reaction to a number of marine natural products
and pharmaceuticals, we were interested in further investigat-
ing this process. Optimization of the reaction conditions (see
the Supporting Information for details) established the general
method of para-xylene (25 equiv), CuBr2 (2.0 equiv), and either
Luperoxꢁ 101 (2,5-bis(tert-butylperoxy)-2,5-dimethylhexane,
2.25 equiv: conditions A) or DTBP (4.5 equiv: conditions B) at
110 8C for 18 h, providing 4a in serviceable yields of 52 and
48% respectively.
Scheme 2. Bromo-benzylation of 1,3,5-trimethoxybenzene.
son to using di-tert-butylperoxide so this oxidant was used for
the majority of the future experiments performed. Other poly-
methylbenzenes, including mesitylene, durene and preheni-
tine, were tolerated (4d–f) along with tert-butylmethylben-
zenes (4g and 4h; Scheme 2). Both para-bromotoluene and
para-chlorotoluene were found to be poor coupling partners
generating 4i and 4j in 28 and 25% yields, respectively
(Scheme 2). Surprisingly, toluene itself could not be effectively
used to generate the desired product 4k. The reason for this
observed phenomenon is not yet understood. The use of satu-
rated heterocycles and cycloalkanes as coupling partners was
attempted to no avail (Scheme 2). Due to the high crystallinity
of many of the bromodiarylmethanes produced it was possible
Substrate scope
We began by varying the substitution pattern and functionality
of the benzylic component (Scheme 2). All xylene substitution
patterns were tolerated providing the respective bromodiaryl-
methanes 4a–c in moderate yields (Scheme 2). In general, Lu-
perox 101ꢁ was found to give slightly higher yields in compari-
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Scheme 4. Scope of the aryl coupling partner for halobenzylation. [a] CuCl2
used in place of CuBr2. [b] 2,4,6-Trimethoxybenzoic acid used as the sub-
strate.
hexa-substituted aromatic product 4s in a 12% yield. 1,3-Di-
methoxybenzene was also reacted to yield compound 4t in
a yield of 43%. We could also access chloride 4u in 38% yield
from 1,3,5-trimethoxybenzene by using CuCl2 in place of CuBr2,
demonstrating that alternative copper ions were viable in the
transformation. 2,4,6-Trimethoxybenzoic acid was productive in
the reaction, giving the bromide 4a in 44% yield through
copper-mediated protodecarboxylation.[21]
Figure 2. ORTEP diagrams for compounds 4a (top) and 4 f (bottom); ther-
mal ellipsoids shown at 50% probability.
to grow single crystals of 4a and 4 f suitable for X-ray diffrac-
tion analysis (Figure 2).
It was possible to produce a tertiary benzylic carbon center
from the respective secondary benzylic coupling partner: By
using conditions A with diphenylmethane the synthesis of tri-
phenylmethane 4m was accomplished in 40% yield; 1,4-dieth-
ylbenzene and indane generated 4n and 4o in 41 and 20%
yields, respectively (Scheme 3). Interestingly, when using fluo-
rene as the coupling partner with 1,3,5-trimethoxybenzene the
des-halo product 4p was obtained, which is in contrast to the
halo-substituted product obtained with diphenylmethane.
By using the general protocol with Luperox 101ꢁ as the oxi-
dant, an assessment of the electron-rich component was per-
formed. A number of 1,3-di- and trialkoxybenzenes were sub-
jected to the tandem bromination–xylylation reaction condi-
tions, all of which generated the desired product (Scheme 4).
With an increase in steric congestion of the alkyl groups a de-
crease in chemical yield from 52 to 20% was observed (Me>
Et>iPr). When using 3,4,5-trimethoxytoluene as the substrate,
it was possible to generate the respective highly-functionalized
During our studies, we found that not all alkoxybenzenes
will undergo the tandem functionalization process; in general
these are substrates that already bear an electron-withdrawing
substituent at the 2-position (Scheme 5). To exemplify this
single CÀH functionalization process, 2-nitro-1,3,5-trimethoxy-
benzene gave the product 4v in a good 76% yield. 2-Fluoro-
and 2-formyl-1,3,5-trimethoxybenzene were xylylated in 18 and
20% yields, respectively, although a number of minor byprod-
ucts were observed in these reactions. Some alkoxybenzenes
were also found to only produce the des-halo product, namely
1,2,3-trimethoxybenzene, 1,2,4,5-tetramethoxybenzene, and
1,4-dimethoxybenzene (4y: 29%, 4z: 22% and 4aa: 21%).
As a demonstration of the applicability of this methodology,
we set out to synthesize penta-O-methyl vidalol A (8), which
has shown moderate carbonic anhydrase inhibitory activity, in
a single step.[10i] The polysubstituted toluene 7 was prepared
and used as the benzylic component under our tandem reac-
Scheme 3. Scope of an a-substituted benzyl coupling partner. [a] Reaction carried out with 15 equiv of fluorene and benzene (1 mL) as solvent.
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Scheme 5. Scope of the aryl coupling partner for benzylation.
tion conditions with 1a. To render the reaction more economic
with respect to the benzylic component, it was found possible
to reduce the stoichiometry of 7 to 5.0 equivalents using ben-
zene as a co-solvent. Pleasingly, the target compound 8 was
produced under the reaction conditions, albeit in a low yield
of 19% (Scheme 6). A number of attempts at demethylation to
give the natural product were performed; but, due to the ap-
parent instability of vidalol A, we were not able to isolate
a sample of the natural product.
Scheme 6. Synthesis of penta-O-methyl vidalol A.
Mechanistic probes
With a functioning protocol for this unusual reaction in hand,
our attention was turned to experiments that would allow us
to speculate on a plausible mechanism for the tandem process
(Figure 3). Firstly, a number of control experiments were per-
formed: 1) It was found that the tandem process does not
function if the peroxide is omitted; 2) stoichiometric copper(II)
bromide is also necessary and cannot be substituted for cop-
per(I) bromide; and 3) adventitious oxygen is also detrimental
to the efficacy of the reaction. We next examined the possibili-
ty of benzyl bromide being formed in situ from the respective
toluene and copper(II) bromide in a similar process to the
Wohl–Ziegler bromination.[22] Mixtures of para-xylene and cop-
per(II) bromide (at the same concentration and stoichiometry
as the tandem reaction protocol) gave only small amounts
(14%) of the benzyl bromide in the presence of excess perox-
ide (Figure 3a). On treatment of 1,3,5-trimethoxybenzene with
an equivalent of a-bromo-para-xylene in benzene at 1108C for
18 h, little to none of the desired product was formed (Fig-
ure 3b), which suggests that this reaction does not proceed
via a benzyl halide intermediate.
Figure 3. Mechanistic experiments and control reactions.
Second, we studied the bromination of 1,3,5-trimethoxyben-
zene as it is well known that copper(II) bromide can be used
as an effective electrophilic brominating agent.[23] Treatment of
1a with 2.0 equivalents of copper(II) bromide, with and with-
out the peroxide oxidant, afforded the mono- (5) and dibromi-
nated (6) products, in an approximately 1:2 ratio, respectively
(Figure 3c). The assertion of electrophilic bromination is also
supported by the observation that a flocculent white precipi-
tate, attributed to copper(I) salts, is formed relatively rapidly
during the initial stages of the reaction.
Thirdly we subjected the pre-brominated compounds, 5 and
6, individually to the reaction conditions and successfully dem-
onstrated that they are competent substrates for the synthesis
of the benzhydyl product 4a in the presence of either
copper(II) bromide or copper(I) bromide, albeit in decreased
yield (Figure 3d and e). In the absence of any copper salts no
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reaction product was observed, and upon using substoichio-
metric quantities of both copper(II) bromide and copper(I) bro-
mide a significantly decreased yield was observed (<10%). In-
terestingly, it was possible to further promote CÀC bond for-
mation (Figure 3 f). If the reaction was run under the standard
conditions for 20 hours, then an additional one equivalent of
copper(I) bromide was added to the reaction vessel, followed
by further heating for a further 24 hours, then 43% of the ex-
pected product 4a was isolated along with a considerable
quantity of dixylylated product 10 (25%).
of copper to generate the new C(sp2)ÀC(sp3) bond and the
product. The exact role and intermediacy of the organocopper
intermediates in this final step still remains to be established,
but a benzylic radical could possibly react with a copper(II) salt
generating a highly reactive alkyl copper(III) species. Studies to
elucidate the mechanism of this interesting tandem reaction
are on-going.
Conclusions
Fourth, it is well known that the generation of radicals is
possible from DTBH and benzylic CÀH groups and heating;[24]
with this in mind, the role of these radicals was assessed.
When carrying out the benchmark reaction in the presence of
2.0 equivalents of radical trapping agents, TEMPO and galvi-
noxyl radical, no diphenylmethane product 4a was observed
(Figure 3g; only halogenated starting materials were detected).
These results support the hypothesis that a benzylic radical is
generated as a key intermediate during the course of the reac-
tion.
In summary, a new approach to the synthesis of highly substi-
tuted halodiarylmethanes has been demonstrated. The proto-
col employs stoichiometric copper(II) halides and dialkyl perox-
ides to promote the tandem halogenation/cross-dehydrogena-
tive benzylation of electron-rich alkoxyarenes. Despite moder-
ate yields being observed in many cases, the protocol is opera-
tionally simple and enables the one-step production of
polysubstituted diarylmethanes from bulk commodity chemi-
cals. The facility for rapidly generating high-value functional-
ized arenes of biological interest was demonstrated in the
one-step preparation of penta-O-methoxy vidalol A (8). Initial
studies have revealed that this reaction likely proceeds by pri-
mary dihalogenation followed by a copper-mediated coupling
of a benzylic radical. Studies to further the understanding of
this tandem reaction are on-going, with the aim of further de-
veloping and exploiting this novel cascade process in synthe-
sis.
It is important to note that there is a significant dependence
upon the electronics of the substrate; an electron-withdrawing
group on the alkoxybenzene substrate (at the meta-position
with respect to the reactive position) is almost always necessa-
ry for the benzylation reaction to proceed, hence why no des-
halogenated products such as 3 are observed in most cases.
With the information gained from the control reactions and
mechanistic probes, a plausible mechanism for the formation
of 4a in this tandem process can be proposed (Scheme 7). The
primary step involves the bromination of 1a with copper(II)
bromide to generate 5, and the presence of the peroxide oxi-
dant is able to accomplish a second bromination generating 6.
Di-tert-butylperoxide undergoes a thermal homolysis of the OÀ
O bond to generate reactive radicals, which abstract a hydro-
gen atom from the benzylic position of para-xylene. The ben-
zylic radical produced is then reacted with 6 under the action
Experimental Section
General considerations
NMR spectra were recorded on 500, 400 or 300 MHz Bruker NMR
spectrometers in CDCl3 at 300 K (unless stated otherwise). For
proton NMR, samples were prepared using ca. 10 mg of compound
dissolved in 1.0 mL of CDCl3 and for carbon NMR using ca. 20 mg
Scheme 7. A plausible reaction mechanism.
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of compound dissolved in 1.0 mL of CDCl3. All spectra were refer-
enced to the residual solvent peak CHCl3 (d=7.26 ppm) for
1H NMR and the CDCl3 solvent peak (d=77.0 ppm) for 13C{1H} NMR.
NMR chemical shifts (d) are reported in ppm; coupling constants
(J) are reported in Hz; splitting patterns are assigned s=singlet,
d=doublet, t=triplet, q=quartet, br=broad signal and app=the
apparent multiplicity. Where possible, when mixtures of isomers
2-Bromo-1,3,5-trimethoxy-4-(3-methylbenzyl)benzene (4b): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and meta-
xylene (764 mL), the title compound was obtained as a light-yellow
1
solid crystalline solid (35.5 mg, 101 mmol, 40%). H NMR (400 MHz,
CDCl3): d=7.11 (t, J=7.5, 1H), 7.02 (s, 1H), 6.99 (d, J=7.5, 1H),
6.95 (d, J=7.5, 1H), 6.36 (s, 1H), 3.97 (s, 2H), 3.91 (s, 3H), 3.81 (s,
3H), 3.70 (s, 3H), 2.29 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d=
158.2, 156.9, 155.8, 141.2, 137.6, 129.0, 127.9, 126.4, 125.3, 116.9,
98.1, 92.8, 61.1, 56.4, 55.9, 29.5, 21.4 ppm; MS (ESI): m/z (%): 182.1
[trimethoxytoluene cation] (32.5), 357.2 [M(Br79)ÀCH5+Na+] (15.1),
1
were isolated, the H NMR spectrum was used to assign the substi-
tution patterns and the ratio of isomers using comparison to litera-
ture data and authentic compounds. When purified compounds
had inseparable residual starting material present, the 1H NMR
spectrum was used to calculate the quantity and mass of the prod-
uct and is quoted in the characterization data. HRMS was mea-
sured using electrospray ionization (ESI) or electron impact ioniza-
tion (EI) using a 0.5–1.0 mMoldmÀ3 solution of compound in aceto-
nitrile. Solvents, unless otherwise stated, were purchased in re-
agent grade or anhydrous quality and used as received. Reagents
were either purchased directly from commercial suppliers or pre-
pared according to literature procedures. All reactions were carried
out in glass microwave vials equipped with aluminium crimpcaps
or a round-bottomed flask and sealed with a glass stopper and
heated in oil baths with a thermocouple temperature control.
Flash column chromatography was performed manually on silica
gel eluting with hexane/ethyl acetate under pressurized air flow.
1,3,5-trialkoxyarenes were synthesized from 1,3,5-trifluorobenzene
and the respective alcohol according to the procedure described
by Jalalian and Olofsson[25] or from phloroglucinol or 3,5-dimethox-
yphenol and alkylhalides by using literature protocols.[26]
359.2 [M(Br81)ÀCH5+Na+] (19.6), 373.0 [M(Br79)+Na+] (31.0), 375.0
[M(Br81)+Na+] (31.0); HRMS (ESI): m/z: calcd for C17H19Br79NaO3
:
+
373.0410; found: 373.0400.
2-Bromo-1,3,5-trimethoxy-4-(2-methylbenzyl)benzene (4c): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and ortho-
xylene (755 mL), the title compound was obtained as a white crys-
talline solid (45.0 mg, 128 mmol, 51%). 1H NMR (400 MHz, CDCl3):
d=7.15 (d, J=7.4, 1H), 7.06 (td, J=7.4, 1.6, 1H), 7.02 (td, J=7.4,
1.6, 1H), 6.77 (dd, J=7.4, 1H), 6.39 (s, 1H), 3.94 (s, 2H), 3.93 (s,
3H), 3.77 (s, 3H), 3.61 (s, 3H), 2.43 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=158.4, 157.0, 155.9, 139.2, 135.9, 129.6, 127.2, 125.7,
125.5, 116.2, 98.1, 92.7, 61.0, 56.4, 55.9, 26.8, 19.8 ppm; MS (ESI):
m/z (%): 182.1 [trimethoxytoluene cation] (34.6), 357.2
[M(Br79)ÀCH5+Na+] (12.7), 359.2 [M(Br81)ÀCH5+Na+] (16.9), 373.0
[M(Br79)+Na+] (17.1), 375.0 [M(Br81)+Na+] (15.6); HRMS (ESI): m/z:
calcd for C17H19Br79NaO3+: 373.0410; found: 373.0401.
2-Bromo-1,3,5-trimethoxy-4-(3,5-dimethylbenzyl)benzene (4d):
By using the general procedure with Luperox101ꢁ (186 mL), cop-
per(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and
mesitylene (869 mL), the title compound was obtained as an off-
white solid (38.3 mg, 105 mmol, 42%). 1H NMR (500 MHz, CDCl3):
d=6.81 (s, 2H), 6.78 (s, 1H), 6.36 (s, 1H), 3.94 (s, 2H), 3.92 (s, 3H),
3.82 (s, 3H), 3.71 (s, 3H), 2.26 ppm (s, 6H); 13C NMR (126 MHz,
CDCl3): d=158.3, 156.9, 155.8, 141.2, 137.4, 127.3, 126.0, 117.1,
98.2, 92.9, 61.0, 56.4, 55.9, 29.4, 21.3 ppm; MS (ESI): m/z (%): 182.1
General procedure
To a 10 mL reaction tube, equipped with a magnetic stirrer bar,
was added the alkoxybenzene (0.25 mmol, 1.0 equiv), vacuum-
dried copper(II) bromide (111.7 mg, 0.5 mmol, 2.0 equiv) and a sub-
stituted toluene (6.25 mmol, 25 equiv). The reaction vessel was
then purged with N2, Luperoxꢁ 101 (186 mL, 0.56 mmol, 2.25 equiv)
or di-tert-butylperoxide (207 mL, 1.13 mmol, 4.5 equiv) was added
and the reaction vessel was immediately sealed under a N2 atmos-
phere with a crimp cap seal and placed into a pre-heated oil bath
at 1108C. The reaction was heated for 18 h, after which time the
reaction was allowed to cool, diluted with dichloromethane (ca.
10 mL), analysed by thin layer chromatography and filtered
through a cotton wool plug. The reaction mixture was then ad-
sorbed onto the minimum amount of silica gel and purified by
silica gel chromatography (gradient elution with ethyl acetate/
hexane 2:98 to 3.5:96.5 to 5:95 and higher for the phenols). The
product-containing fractions were evaporated in vacuo to yield the
product.
[trimethoxytoluene cation] (30.2), 387.1 [M(Br79)+Na+] (82.3), 389.1
[M(Br81)+Na+] (78.0); HRMS (ESI): m/z: calcd for C18H21Br79NaO3
:
+
387.0566; found: 387.0560.
2-Bromo-1,3,5-trimethoxy-4-(2,3–4-trimethylbenzyl)benzene
(4e) and 2-bromo-1,3,5-trimethoxy-4-(2,3–6-trimethylbenzyl)-
benzene (4e’): By using the general procedure with Luperox101ꢁ
(186 mL), copper(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene
(42.2 mg) and prehenitene (932 mL), the two isomeric title com-
pounds were obtained (in a ca. 2:1 ratio of 4e/4e’) as an off-white
solid (53.3 mg, 141 mmol, 56%) (samples of the isomers were isolat-
1
ed separately for characterization purposes). 4e: H NMR (400 MHz,
2-Bromo-1,3,5-trimethoxy-4-(4-methylbenzyl)benzene (4a): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and para-
xylene (771 mL), the title compound was obtained as an off-white
CDCl3): d=6.81 (d, J=7.8, 1H), 6.47 (d, J=7.8, 1H), 6.38 (s, 1H),
3.94 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 3.61 (s, 3H), 2.34 (s, 3H), 2.24
(s, 3H), 2.22 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d=158.5,
157.1, 155.8, 136.4, 134.7, 134.3, 133.6, 126.8, 124.4, 116.4, 98.2,
92.7, 61.1, 56.5, 55.9, 27.6, 20.8, 16.0, 15.5 ppm; MS (ESI): m/z (%):
182.1 [trimethoxytoluene cation] (8.6), 401.1 [M(Br79)+Na+ (100),
1
crystalline solid (44.4 mg (126 mmol, 51%). Tm =110–1128C; H NMR
(400 MHz, CDCl3): d=7.10 (d, J=8.0, 2H), 7.03 (d, J=8.0, 2H), 6.35
(s, 1H), 3.97 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 3.71 (s, 3H), 2.29 ppm
(s, 3H); 13C NMR (101 MHz, CDCl3): d=158.2, 156.8, 155.7, 138.2,
134.9, 128.8, 128.1, 117.1, 98.1, 92.8, 61.1, 56.4, 55.9, 29.2,
21.0 ppm; MS (ESI): m/z: (%):182.1 [trimethoxytoluene cation]
(39.5), 357.2 [M(Br79)ÀCH5+Na+] (18.1), 359.2 [M(Br81)ÀCH5+Na+]
(23.5), 373.0 [M(Br79)+Na+] (14.9), 375.0 [M(Br81)+Na+] (14.2); HRMS
(ESI): m/z: calcd for C17H19Br79NaO3+: 373.0410; found: 373.0415.
403.1 [M(Br81)+Na+] (99.1); HRMS (ESI): m/z: calcd for
C19H23Br79NaO3
:
401.0723; found: 401.0719; 4e’: 1H NMR
+
(400 MHz, CDCl3): d=6.88 (s, 2H), 6.30 (s, 1H), 4.02 (s, 2H), 3.88 (s,
3H), 3.70 (s, 3H), 3.29 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 2.13 ppm (s,
3H); 13C NMR (101 MHz, CDCl3): d=158.2, 157.1, 155.4, 138.2,
135.8, 135.1, 133.9, 127.2, 127.1, 117.5, 98.5, 93.1, 60.6, 56.4, 56.0,
&
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25.1, 20.8, 20.6, 15.7 ppm; MS (ESI): m/z (%): 182.1 [trimethoxyto-
luene cation] (8.6), 401.1 [M(Br79)+Na+] (100), 403.1 [M(Br81)+Na+]
(99.1); HRMS (ESI): m/z: calcd for C19H23Br79NaO3+: 401.0723; found:
401.0719.
2-Bromo-1,3,5-trimethoxy-4-(4-chlorobenzyl)benzene (4j): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and para-
chlorotoluene (1.08 mL), the title compound was obtained as an
1
off-white solid (23.0 mg; 62 mmol, 32%). H NMR (400 MHz, CDCl3):
d=7.18 (d, J=8.5, 2H), 7.12 (d, J=8.5, 2H), 6.34 (s, 1H), 3.94 (s,
2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.71 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=158.1, 156.8, 156.0, 139.9, 131.3, 129.7, 128.2, 116.4,
98.1, 92.8, 61.1, 56.5, 55.9, 29.1 ppm; MS (ESI): m/z (%): 182.1 [tri-
methoxytoluene cation] (32.9), 392.1 [M(Br79/Cl35)+Na+] (28.2),
394.1 [M(Br81/Cl35 or Br79/Cl37)+Na+] (36.6), 396.1 [M(Br81/Cl37)+Na+]
(8.2); HRMS (ESI): m/z: calcd for C19H23Br79L3NaO3+: 392.9864;
found: 392.9870.
2-Bromo-1,3,5-trimethoxy-4-(2,4,5-trimethylbenzyl)benzene (4 f):
By using the general procedure with Luperox101ꢁ (186 mL), cop-
per(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and
durene (1.00 mL), the title compound was obtained as a white
crystalline solid (51.5 mg, 136 mmol, 54%); 1H NMR (500 MHz,
CDCl3): d=6.93 (s, 1H), 6.53 (s, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.89
(s, 2H), 3.79 (s, 3H), 3.64 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H), 2.10 ppm
(s, 3H); 13C NMR (126 MHz, CDCl3): d=158.5, 157.1, 155.8, 136.3,
133.4, 133.4, 133.0, 131.1, 128.6, 116.7, 98.2, 92.8, 61.0, 56.4, 55.9,
26.3, 19.3, 19.1, 19.1 ppm; MS (ESI): m/z (%): 182.1 [trimethoxyto-
luene cation] (30.5), 401.1 [M(Br79)+Na+] (47.6), 403.1 [M(Br81)+Na+
] (48.4); HRMS (ESI): m/z: calcd for C19H23Br79NaO3+: 401.0723;
found: 401.0701.
[(3-Bromo-2,4,6-trimethoxyphenyl)methylene]dibenzene (4m):
By using the general procedure with Luperox101ꢁ (186 mL), cop-
per(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and
diphenylmethane (1.05 g), the title compound obtained an off-
white solid 41.2 mg (100 mmol, 40%); 1H NMR (400 MHz, CDCl3):
d=7.31–7.23 (m, 4H), 7.22–7.11 (m, 6H), 6.34 (s, 1H), 6.06 (s, 1H),
3.90 (s, 3H), 3.51 (s, 3H), 3.44 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=158.5, 157.0, 156.2, 143.4, 129.1, 127.8, 125.7, 120.5,
98.6, 94.0, 91.6, 60.9, 56.3, 55.8, 46.8 ppm; MS (ESI): m/z (%): 182.1
2-Bromo-4-(3-tert-butyl-5-methylbenzyl)-1,3,5-trimethoxy-ben-
zene (4g): By using the general procedure with Luperox101ꢁ
(186 mL), copper(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene
(42.2 mg) and 1-tert-butyl-3,5-dimethylbenzene (1.17 mL), the title
compound was obtained as an off-white solid (27.7 mg, 68 mmol,
[trimethoxytoluene cation] (12.0), 435.1 [M(Br79)+Na+] (100), 437.1
[M(Br81)+Na+] (97.7); HRMS (ESI): m/z: calcd: for C22H21Br79NaO3
:
+
1
27%). H NMR (400 MHz, CDCl3): d=7.08 (s, 1H), 6.97 (s, 1H), 6.80
435.0566; found: 435.0560 .
(s, 1H), 6.35 (s, 1H), 3.96 (s, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 3.69 (s,
3H), 2.27 (s, 3H), 1.28 ppm (s, 9H); 13C NMR (101 MHz, CDCl3): d=
158.3, 156.9, 155.7, 150.6, 140.8, 137.1, 126.1, 123.4, 122.7, 117.3,
98.1, 92.8, 61.1, 56.4, 55.9, 34.4, 31.4, 29.8, 21.7 ppm; MS (ESI): m/z
(%): 429.1 [M(Br79)+Na+] (8.4), 431.1 [M(Br81)+Na+] (8.5), 475.2
[M(Br79)+ImidazoleH+] (99.1), 477.2 [M(Br81)+ImidazoleH+] (100);
HRMS (ESI): m/z: calcd for C21H27Br79NaO3+: 429.1036; found:
429.1034.
2-Bromo-4-[1-(4-ethylphenyl)ethyl]-1,3,5-trimethoxybenzene
(4n): By using the general procedure with Luperox101ꢁ (186 mL),
copper(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg)
and para-diethylbenzene (839 mL), the title compound was ob-
tained as a light-yellow solid (39.0 mg; 103 mmol, 41%); 1H NMR
(400 MHz, CDCl3): d=7.18 (d, J=8.0, 2H), 7.07 (d, J=8.0, 2H), 6.31
(s, 1H), 4.67 (q, J=7.2, 1H), 3.88 (s, 3H), 3.67 (s, 3H), 3.59 (s, 3H),
2.59 (q, J=7.6, 2H), 1.66 (d, J=7.2, 3H), 1.20 ppm (t, J=7.6, 3H);
13C NMR (101 MHz, CDCl3): d=158.5, 156.6, 155.6, 142.9, 141.0,
127.2, 127.1, 122.9, 98.5, 93.7, 61.1, 56.4, 55.8, 34.1, 28.4, 18.1,
15.7 ppm; MS (ESI): m/z (%): 182.1 [trimethoxytoluene cation] (8.0),
401.1 [M(Br79)+Na+] (100), 403.1 [M(Br81)+Na+] (97.7); HRMS (ESI):
m/z: cacld for C19H23Br79NaO3+: 401.0723; found: 401.0725.
2-Bromo-1,3,5-trimethoxy-4-(4-tert-butylbenzyl)benzene (4h): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and para-
tert-butyltoluene (1.08 mL), the title compound was obtained as an
1
off-white solid (31.0 mg, 79 mmol, 32%). H NMR (500 MHz, CDCl3):
d=7.24 (d, J=8.4, 2H), 7.14 (d, J=8.4, 2H), 6.35 (s, 1H), 3.97 (s,
2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H), 1.28 ppm (s, 9H);
13C NMR (126 MHz, CDCl3): d=158.2, 156.9, 155.8, 148.3, 138.2,
127.9, 125.0, 117.2, 98.2, 92.9, 61.0, 56.5, 55.9, 34.3, 31.4, 29.1 ppm;
MS (ESI): m/z (%): 182.1 [trimethoxytoluene cation] (9.8), 415.1
[M(Br79)+Na+] (97.4), 403.1 [M(Br81)+Na+] (100); HRMS (ESI): m/z:
calcd for C19H23Br79NaO3+: 415.0879; found: 415.0909.
1-(3-Bromo-2,4,6-trimethoxyphenyl)-2,3-dihydro-1H-indene (4o):
By using the general procedure with Luperox101ꢁ (186 mL), cop-
per(II) bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and
indane (766 mL), the title compound was obtained as a yellow solid
(19.3 mg; 53 mmol, 21%). Tm =110–1128C; 1H NMR (500 MHz,
CDCl3): d=7.24 (d, J=7.4 Hz, 1H), 7.11 (appt, J=7.4 Hz, 1H), 7.04
(app t, J=7.4 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 6.32 (s, 1H), 4.89
(appt, J=8.1 Hz, 1H), 3.90 (s, 3H), 3.56 (brs, 6H), 3.15–3.11 (m,
1H), 3.04–2.97 (m, 1H), 2.41–2.29 ppm (m, 2H); 13C NMR (126 MHz,
CDCl3): d=159.0, 157.5, 155.9, 147.5, 143.7, 125.9, 125.8, 124.2,
123.2, 120.9, 98.6, 94.0, 56.5, 56.1, 41.8, 32.4, 31.8 ppm; MS (EI): m/
2-Bromo-1,3,5-trimethoxy-4-(4-bromobenzyl)benzene (4i): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg) and para-
bromotoluene (769 mL), the title compound was obtained as a mix-
ture with 1-bromo-2,4,6-trimethoxybenzene (in a 1:2 ratio of 4i/5)
as a brown solid (63.1 mg; this equates to 28.8 mg of the title com-
pound; 70 mmol, 28%). 1H NMR (500 MHz, CDCl3): d=7.32 (d, J=
8.4, 2H), 7.07 (d, J=8.4, 2H), 6.33 (s, 1H), 3.92 (s, 2H), 3.90 (s, 3H),
3.79 (s, 3H), 3.71 ppm (s, 3H); 13C NMR (126 MHz, CDCl3): d=158.1,
156.8, 156.0, 140.4, 131.1, 130.1, 119.3, 116.3, 98.1, 92.8, 61.1, 56.5,
55.8, 29.1 ppm; MS (ESI): m/z (%): 182.1 [trimethoxytoluene cation]
(37.2), 436.1 [M(Br79/Br79)+Na+] (22.4), 438.1 [M(Br79/Br81)+Na+]
(44.5), 440.1 [M(Br81/Br81)+Na+] (22.0); HRMS (ESI): m/z: calcd for
C16H16Br792NaO3+: 436.9358; found: 436.9359.
z: 283.0 [MÀBr] (48), 362.0 [M(Br79)] (100), 364.0 [M(Br81)] (99);
HRMS (ESI): m/z: calcd for C18H19Br79O3
: 365.0518; found:
+
362.0508.
9-(2,4,6-Trimethoxyphenyl)-9H-fluorene (4p): By using the gener-
al procedure with Luperox101ꢁ (186 mL), copper(II) bromide
(111.7 mg), 1,3,5-trimethoxybenzene (42.2 mg), fluorene (623 mg)
and degassed benzene (1.0 mL) as the co-solvent, the title com-
pound was obtained as a yellow solid (17.8 mg; 53 mmol, 21%).
Tm =98–1008C; 1H NMR (500 MHz, CDCl3): d=7.79 (d, J=7.5 Hz,
2H), 7.34–7.29 (m, 2H), 7.24–7.17 (m, 4H), 6.31 (d, J=2.3 Hz, 1H),
Chem. Eur. J. 2016, 22, 1 – 11
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5.95 (d, J=2.3 Hz, 1H), 5.61 (s, 1H), 3.98 (s, 3H), 3.80 ppm (s, 3H),
2.97 (s, 3H); 13C NMR (125 MHz, CDCl3): d=160.2, 159.9, 159.8,
148.9, 141.2, 126.6, 126.2, 123.7, 119.5, 110.7, 92.7, 91.1, 56.4, 55.9,
55.4, 43.8 ppm; MS (EI): m/z (%): 165.1 [MÀC9H11O3] (13), 332.1 [M]
(100); HRMS (APCI): m/z: calcd for C22H21O3+: 333.1470; found:
333.1485.
2-Chloro-1,3,5-trimethoxy-4-(4-methylbenzyl)benzene (4u): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
chloride (67.2 mg), 1,3,5-trimethoxybenzene (42.2 mg) and para-
xylene (771 mL), the title compound was yielded as a white solid
1
(29.5 mg; 96 mmol, 38%); H NMR (400 MHz, CDCl3): d=7.10 (d, J=
7.9, 2H), 7.04 (d, J=7.9, 2H), 6.36 (s, 1H), 3.95 (s, 2H), 3.91 (s, 3H),
3.81 (s, 3H), 3.72 (s, 3H), 2.29 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=157.1, 155.8, 154.8, 138.3, 135.0, 128.8, 128.1, 116.9,
108.5, 92.7, 60.9, 56.4, 55.9, 28.9, 21.0 ppm; MS (ESI): m/z (%): 182.1
2-Bromo-1,3,5-triethoxy-4-(4-methylbenzyl)benzene (4q): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-triethoxybenzene (52.5 mg) and para-
xylene (771 mL), the title compound was obtained as an off-white
solid (32.9 mg; 84 mmol, 33%); Tm =74–768C; 1H NMR (400 MHz,
CDCl3): d=7.12 (d, J=7.9 Hz, 2H), 7.02 (d, J=7.9 Hz, 2H), 6.29 (s,
1H), 4.06 (q, J=7.0 Hz, 2H), 3.96 (q, J=7.0 Hz, 2H), 3.94 (s, 2H),
3.86 (q, J=7.0 Hz, 2H), 2.28 (s, 3H), 1.46 (t, J=7.0 Hz, 3H), 1.40 (t,
J=7.0 Hz, 3H), 1.34 ppm (t, J=7.0 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d=157.6, 156.1, 155.2, 138.8, 135.0, 128.8, 128.5, 117.9,
99.1, 95.1, 69.5, 65.3, 64.3, 29.7, 21.1, 15.7, 14.9, 14.9 ppm; MS (EI):
m/z (%): 392.1 [M(Br79)] (100), 394.1 [M(Br81)] (97); HRMS (EI): m/z:
calcd C20H25O379Br+ for 392.0982; found: 392.0983.
[trimethoxytoluene cation] (4.6), 329.1 [M(Cl35)+Na+] (100), 331.1
[M(Cl37)+Na+] (33.7); HRMS (ESI): m/z: calcd for C17H19Cl35NaO3
:
+
329.0915; found: 329.0914.
1,3,5-Trimethoxy-2-(4-methylbenzyl)-4-nitrobenzene (4v): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 2,4,6-trimethoxynitrobenzene (53.3 mg) and
para-xylene (771 mL), the title compound was obtained as a yellow
1
solid 60.0 mg (189 mmol, 76%); Tm =104–1068C; H NMR (500 MHz,
CDCl3): d=7.05 (s, 4H), 6.32 (s, 1H), 3.93 (s, 2H), 3.90 (s, 3H), 3.84
(s, 3H), 3.72 (s, 3H), 2.29 ppm (s, 3H); 13C NMR (126 MHz, CDCl3):
160.2, 152.0, 151.5, 137.4, 135.4, 129.0, 128.1, 116.1, 91.7, 63.2, 56.6,
56.1, 28.6, 21.1 ppm; MS (EI): m/z (%): 270.1 [MÀOCH3O] (22), 317.1
[M] (100); HRMS (APCI): m/z: cacld for C17H19NO5+: 317.1258;
found: 317.1246.
2-Bromo-1,3,5-triisopropyl-4-(4-methylbenzyl)benzene (4r): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3,5-triisopropylbenzene (63.0 mg) and para-
xylene (771 mL), the title compound was obtained as a yellow oil
1
2-Fluoro-1,3,5-trimethoxy-4-(4-methylbenzyl)benzene (4w): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 2-fluoro1,3,5-trimethoxybenzene (46.6 mg) and
para-xylene (771 mL), the title compound was obtained as a white
solid (12.8 mg; 44 mmol, 18%) (note: a sample of 1-bromo-3-
fluoro-2,4,6-trimethoxy-5-(4-methylbenzyl)benzene and 4,4’-(5-
fluoro-2,4,6-trimethoxy-1,3-phenylene)bis(methylene)bis(methyl-
benzene) was also obtained as an inseparable mixture (11.3 mg,
7% and 4%) as determined by GCMS and 1H NMR). 1H NMR
(400 MHz, CDCl3): d=7.10 (d, J=7.9 Hz, 2H), 7.03 (d, J=7.9 Hz,
2H), 6.29 (d, J=6.5 Hz, 1H), 3.90 (s, 2H), 3.88 (s, 3H), 3.81 (d, J=
1.9 Hz, 3H), 3.77 (s, 3H), 2.28 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=153.3 (d, J=2.6 Hz), 147.1 (d, J=17 Hz), 147.0 (d, J=
17 Hz), 141.3 (d, J=240 Hz), 138.6, 135.1, 128.9, 128.4, 115.9, 93.2,
61.4 (d, J=6.5 Hz), 56.9, 56.3, 28.6 (d, J=1.5 Hz), 21.1 ppm; MS (EI):
m/z (%): 199.1 [MÀC7H7] (28), 275.1 [MÀCH3] (15), 290.1 [M] (100);
HRMS (EI): m/z: calcd for C17H19O3F+: 290.1318; found: 290.1317.
(22.3 mg, 51 mmol, 20%); H NMR (400 MHz, CDCl3): d=7.09 (d, J=
7.8 Hz, 2H), 6.99 (d, J=7.8 Hz, 2H), 6.28 (s, 1H), 4.53 (quint, J=
6.2 Hz, 1H), 4.45 (quint, J=6.1 Hz, 1H), 4.41 (quint, J=6.0 Hz, 1H),
3.93 (s, 2H), 2.27 (s, 3H), 1.36 (d, J=6.1 Hz, 6H), 1.30 (d, J=6.2 Hz,
6H), 1.18 ppm (d, J=6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3): d=
156.1, 154.8, 154.2, 138.8, 134.8, 128.6, 119.9, 101.1, 98.5, 76.1, 72.9,
70.2, 30.3, 22.5, 22.3, 22.0, 21.1 ppm; MS (EI): m/z (%): 392.1
[M(Br79)ÀCH2CHCH3] (71), 394.1 [M(Br81)ÀCH2CHCH3] (43), 436.1
[M(Br79)] (100), 436.1 [M(Br81)] (100); HRMS (EI): m/z: calcd for
C22H31O379Br+: 434.1451; found: 434.1447.
1-Bromo-2,3,4-trimethoxy-6-methyl-5-(4-methylbenzyl)benzene
(4s): By using the general procedure with Luperox101ꢁ (186 mL),
copper(II) bromide (111.7 mg), 3,4,5-trimethoxytoluene (45.6 mg)
and para-xylene (839 mL), the title compound was obtained as
1
a yellow oil (11.0 mg, 30 mmol, 12%); H NMR (500 MHz, CDCl3): d=
7.06 (d, J=7.7 Hz, 2H), 6.97 (d, J=7.7 Hz, 2H), 4.04 (s, 2H), 3.92 (s,
3H), 3.90 (s, 3H), 3.74 (s, 3H), 2.29 (s, 3H), 2.28 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=151.6, 149.6, 145.2, 137.3, 135.4,
132.9, 129.6, 129.2, 128.0, 115.7, 61.2, 61.1, 61.0, 32.8, 21.1,
19.9 ppm; MS (EI) m/z (%): 349.0 [M(Br79)ÀCH3] (13), 351.0
[M(Br81)ÀCH3] (11), 364.1 [M(Br79)] (100), 366.1 [M(Br81)] (97); HRMS
(EI): m/z: calcd for C18H21O379Br+: 364.0674; found: 364.0665.
2,4,6-Trimethoxy-3-(4-methylbenzyl)benzaldehyde (4x): By using
the general procedure with Luperox101ꢁ (186 mL), copper(II) bro-
mide (111.7 mg), 2,4,6-trimethoxybenzaldehyde (49.1 mg) and
para-xylene (771 mL), the title compound was obtained as a color-
less oil 14.9 mg (50 mmol, 20%). 1H NMR (500 MHz, CDCl3): d=
10.33 (s, 1H), 7.09 (d, J=7.9 Hz, 2H), 7.03 (d, J=7.9 Hz, 2H), 6.27
(s, 1H), 3.92 (s, 3H), 3.91 (s, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 2.28 ppm
(s, 3H); 13C NMR (125 MHz, CDCl3): d=188.1, 164.3, 163.0, 162.2,
138.2, 135.2, 129.0, 128.3, 116.3, 112.4, 91.1, 63.3, 56.2, 55.9, 28.1,
21.1 ppm; MS (ESI): m/z (%): 105.1 [MÀC10H11O4] (100), 195.1
[MÀC8H9] (65), 285.1 [MÀCH3] (75), 300.1 [M] (43); HRMS (APCI): m/
z: calcd for C18H21O4+: 301.1434; found: 301.1422.
1-Bromo-2,4-dimethoxy-5-(4-methylbenzyl)benzene (4t): By
using the general procedure with Luperox101ꢁ (186 mL), copper(II)
bromide (111.7 mg), 1,3-dimethoxybenzene (32.7 mL) and para-
xylene (771 mL), the title compound was yielded as an off-white
solid (34.8 mg; 108 mmol, 43%). Tm =81–838C; 1H NMR (400 MHz,
CDCl3): d=7.20 (s, 1H), 7.08 (s, 4H), 6.47 (s, 1H), 3.89 (s, 3H), 3.83
(s, 2H), 3.82 (s, 3H), 2.31 ppm (s, 3H); 13C NMR (101 MHz, CDCl3):
d=157.6, 155.2, 137.7, 135.5, 134.0, 129.2, 128.8, 123.9, 101.7, 96.8,
56.6, 55.9, 34.6, 21.2 ppm; MS (EI): m/z (%): 305.0 [M(Br79)ÀCH3]
(71), 307.0 [M(Br81)ÀCH3] (43), 320.0 [M(Br79)] (100), 322.0 [M(Br81)]
(97); HRMS (EI): m/z: calcd for C16H17O279Br+: 320.0412; found:
320.0400.
1,2,3-Trimethoxy-4-(4-methylbenzyl)benzene (4y): By using the
general procedure with Luperox101ꢁ (186 mL), copper(II) bromide
(111.7 mg), 1,2,3-trimethoxybenzene (42.1 mg) and para-xylene
(771 mL), the title compound was obtained as
a yellow oil
(19.7 mg; 72 mmol, 29%); 1H NMR (400 MHz, CDCl3): d=7.08 (s,
4H), 6.78 (d, J=8.5 Hz, 2H), 6.60 (d, J=8.5 Hz, 2H), 3.88 (s, 2H),
3.87 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H), 2.31 ppm (s, 3H); 13C NMR
&
&
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1,2,4,5-Tetramethoxy-3-(4-methylbenzyl)benzene (4z): By using
the general procedure with Luperox101ꢁ (186 mL), copper(II) bro-
mide (111.7 mg), 1,2,4,5-tetramethoxybenzene (49.6 mg) and para-
xylene (771 mL), the title compound was obtained as an off-white
solid (16.5 mg; 55 mmol, 22%). Tm =57–598C; 1H NMR (500 MHz,
CDCl3): d=7.14 (d, J=7.6 Hz, 2H), 7.02 (d, J=7.60 Hz, 2H), 6.46 (s,
1H), 3.99 (s, 2H), 3.85 (s, 6H), 3.63 (s, 6H), 2.27 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=149.1, 141.3, 138.5, 135.1, 129.6,
128.9, 128.6, 97.6, 60.9, 56.4, 29.9, 21.1 ppm; MS (EI): m/z (%): 287.1
+
[MÀCH3] (20), 302.2 [M] (100); HRMS (EI): m/z: calcd for C18H22O4
:
302.1513; found: 302.1512.
1,4-Dimethoxy-2-(4-methylbenzyl)benzene (4aa):[27] By using the
general procedure with Luperox101ꢁ (186 mL), copper(II) bromide
(111.7 mg), 1,4-dimethoxybenzene (34.5 mg) and para-xylene
(771 mL), the title compound was obtained as an off-white solid
1
(12.6 mg; 52 mmol, 21%). H NMR (400 MHz, CDCl3): d=7.10 (d, J=
8.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 6.79 (d, J=8.8 Hz, 1H), 6.70
(dd, J=8.8, 3.1 Hz, 1H), 6.65 (d, J=3.1 Hz, 1H), 3.90 (s, 2H), 3.77 (s,
3H), 3.72 (s, 3H), 2.30 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
153.6, 151.8, 137.7, 135.4, 131.3, 129.1, 128.9, 116.9, 111.5, 111.2,
56.2, 55.8, 35.6, 21.2 ppm; MS (EI): m/z (%): 227.1 [MÀCH3] (26),
242.1 [M] (100); HRMS (EI): m/z: calcd for C16H18O2+: 242.1301;
found: 242.1313.
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Penta-O-methyl vidalol A (8):[10i] To
a 10 mL reaction tube,
equipped with a magnetic stirrer bar, was added 1,3,5-trimethoxy-
benzene (55.0 mg, 0.327 mmol, 1.0 equiv), copper(II) bromide
(147 mg, 0.5 mmol, 2.0 equiv) and 2,3-dibromo-4,5-dimethoxy-1-
methylbenzene (507 mg, 1.64 mmol, 5.0 equiv) in degassed ben-
zene (1.0 mL). The reaction vessel was then purged with N2 and lu-
perox 101 (244 mL, 0.838 mmol, 2.25 equiv) was added and the re-
action vessel was immediately sealed under an N2 atmosphere
with a crimp cap seal and placed directly into a preheated oil bath
at 1108C. The reaction was heated for 18 h, after which time, the
reaction was allowed to cool, diluted with dichloromethane (ca.
10 mL), analyzed by thin layer chromatography and filtered
through a cotton wool plug. The reaction mixture was then puri-
fied by automated column chromatography to give the product as
1
a yellow oil (38.4 mg, 69 mmol, 19%). H NMR (400 MHz, CDCl3): d=
6.37 (s, 1H), 6.31 (s, 1H), 4.05 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.78
(s, 3H), 3.70 (s, 3H), 3.61 ppm (s, 3H); 13C NMR (101 MHz, CDCl3):
d=158.5, 157.3, 156.5, 152.4, 145.7, 137.9, 121.6, 117.5, 114.9, 111.9,
98.2, 92.5, 61.3, 60.6, 56.6, 56.2, 56.1, 32.0 ppm; MS (ESI): m/z (%):
588.9 [M(79Br)+ClÀ] (100), 590.8 [M(81Br)+ClÀ] (90); HRMS (ESI): m/z:
calcd (%) for C18H20Br379O5+: 552.8855; found: 552.8857.
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Acknowledgements
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We thank the University of Manchester and the EPSRC (Leader-
ship Fellowship to M.F.G. and studentship to C.J.T.) for funding.
Keywords: CÀH activation · cross-dehydrogenative-coupling ·
diarylmethane · homogeneous catalysis · tandem reactions
Chem. Eur. J. 2016, 22, 1 – 11
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Published online on && &&, 0000
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FULL PAPER
Two steps away: A copper-mediated
cross-dehydrogenative-coupling of alk-
oxybenzenes and toluenes with con-
comitant halogenation is reported (see
figure). A range of bromoalkoxydi- and
triarylmethanes are synthesized and
a plausible mechanism is proposed.
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Organic Synthesis
T. E. Storr, C. J. Teskey, M. F. Greaney*
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Cross-Dehydrogenative-Coupling of
Alkoxybenzenes with Toluenes:
Copper(II) Halide Mediated Tandem
Halo/Benzylation of Arenes
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
11
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ