Homo- and hetero-oxidative coupling of benzyl anions

Article abstract of DOI:10.1021/jo3000805

The regioselective benzylic metalation of substituted toluenes using BuLi/KO-t-Bu/TMP(H) (LiNK metalation conditions) with subsequent in situ oxidative C-C coupling has been developed for the facile generation of 1,2-diarylethanes. A range of oxidants can be used for the oxidative coupling step, with 1,2-dibromoethane proving optimal. Heterocouplings can be achieved starting from a mixture of two different toluenes with a bias toward cross coupling achievable by using a 2-fold excess of one toluene starting material. The utility of this approach is illustrated by the synthesis of several biologically active natural products. A distinct advantage is that the synthetic steps typically required to preactivate the coupling substrates are eliminated and no transition metal is required to facilitate the C-C bond formation.

Full text of DOI:10.1021/jo3000805

Article
pubs.acs.org/joc
Homo- and Hetero-oxidative Coupling of Benzyl Anions
Marco Blangetti, Patricia Fleming, and Donal F. O’Shea*
School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: The regioselective benzylic metalation of
substituted toluenes using BuLi/KO-t-Bu/TMP(H) (LiNK
metalation conditions) with subsequent in situ oxidative C−C
coupling has been developed for the facile generation of 1,2-
diarylethanes. A range of oxidants can be used for the oxidative
coupling step, with 1,2-dibromoethane proving optimal.
Heterocouplings can be achieved starting from a mixture of
two different toluenes with a bias toward cross coupling achievable by using a 2-fold excess of one toluene starting material. The
utility of this approach is illustrated by the synthesis of several biologically active natural products. A distinct advantage is that the
synthetic steps typically required to preactivate the coupling substrates are eliminated and no transition metal is required to
facilitate the C−C bond formation.
Scheme 1. Selective Benzylic Metalation of Toluene
INTRODUCTION
■
The repertoire of carbon−carbon bond formation reactions
utilizing oxidative coupling, while limited, continues to expand.1
As might be expected, the majority of these transformations are
transition-metal catalyzed, but some transition-metal-free
variants have been accomplished. Recent examples include
the coupling of Grignard reagents using TEMPO or 3,3′,5,5′-
tetra-tert-butyldiphenoquinone as oxidants.2 As oxidative C−C
coupling requires the combining of two carbon nucleophiles,
this approach would have enhanced synthetic efficiency if the
nucleophiles could be generated via a direct C−H deprotona-
tion of readily available inexpensive starting substrates and the
oxidative coupling could be achieved without a transition metal.
We have recently described use of the reagent triad BuLi/
KO-t-Bu/TMP(H) (LiNK metalation) to in situ generate a
mixed Li/K metal TMP amide as a general method for benzylic
metalations with excellent selectivity.3 We now report the use
of this benzylic metalation strategy in tandem with an in situ
oxidative coupling for Csp3−Csp3 bond formation.4 Oxidative
homocoupling of benzyl anions has previously been noted, but
it has remained relatively unexplored as a synthetic procedure.5
prompted us to combine this with a tandem oxidative C−C
bond-forming strategy.
Having established our metalation approach could selectively
provide 2a, a variety of oxidants were examined to achieve its
homocoupling to 1,2-diphenylethane (3a) (Table 1). Encour-
agingly, treatment of 2a at −78 °C for 5 min with oxygen, ceric
ammonium nitrate (CAN), or iodine all gave the coupled
product 3a in 62, 35, and 47% yields, respectively (Table 1,
entries 1−3). The inexpensive oxidant 1,2-dibromoethane
proved optimal giving a product yield of 71% (entry 4).7 In
this case, oxidative coupling occurred immediately upon
addition of dibromoethane based upon the disappearance of
the characteristic organometallic color. Interestingly, when
TEMPO was used as oxidant at −78 °C and the reaction
worked up after 5 min, only a trace of 3a was observed. Yet,
RESULTS AND DISCUSSION
■
Prior to this study, we first established the regioselectivity of
LiNK metalation of toluene by its sequential treatment with 1.2
equiv of BuLi/KOtBu/TMP(H) in THF at −78 °C and
quenching with CD3OD (Scheme 1). 1H and 2H NMR analysis
of the product showed that deuterium (73% D) was solely
incorporated into the benzylic position with no aryl deuterium
observed, confirming that organometallic 2a could be
selectively generated (Scheme 1). The apparent simplicity of
this metalation belies the fact achieving this deprotonation with
complete selectivity without the use of an excess of toluene at
elevated temperatures can be challenging.6 The ability of LiNK
metalation conditions to provide routine low temperature
access to the thermodynamically favored benzyl anion
Received: January 13, 2012
Published: February 13, 2012
© 2012 American Chemical Society
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Table 1. LiNK Metalation and Oxidative Coupling of
Toluene
Table 2. Metalation and Homo-oxidative Coupling of
Substituted Toluenes
a
a
entry
substrates
R
product
yield (%)
entry
substrate
1a
oxidant
O2
temp (°C)
3a, yield (%)
1
2
1a
1b
1c
1d
1e
1f
H
3a
3b
3c
3d
3e
3f
71
78
58
53
63
68
46
83
1
2
3
4
5
6
7
8
−78
−78
−78
−78
−78
rt/2 h
62
35
47
71
trace
58
0
2-F
1a
CAN
3
2-NMe2
1a
I2
4
2-CO2H
1a
Br(CH2)2Br
TEMPO
TEMPO
Br(CH2)2Br
5
2-OMe
1a
6
3-OMe
1a
7
1g
1h
1i
3-OMOM
4-CONiPr
3,5-(OMe)2
2-OMe-4-Me
3g
3h
3i
PhCH2MgCl
PhCH2MgCl
−78
rt/2 h
b
8
Br(CH2)2Br
81
b
a
b
9
80
Yield refers to isolated product. The possibility of Grignard reagent
bromination with Br(CH2)2Br with in situ coupling of PhCH2Br and
PhCH2MgBr also exists.
10
11
1j
3j
88
69
1k
3,4,5-(OMe)3
3k
a
b
Yield refers to isolated product. Substrate added to a premixed
upon warming the reaction to rt for 2 h, coupling product was
efficiently formed in a 58% yield. In comparison, benzylmagne-
sium chloride was also examined for its ability to oxidatively
couple with dibromoethane. No reaction was found to occur
at −78 °C, yet upon reaction for 2 h at rt a 81% yield of 3a was
obtained (entries 7 and 8). This shows a general ability of
benzylic organometallics to undergo transition-metal-free
oxidative couplings with the enhanced low temperature
reactivity of 2a versus the Grignard reagent attributable to
the more ionic character of 2a. While the exact mechanism of
the dibromoethane-mediated coupling of 2a has not been
investigated, two general possibilities could be envisaged. The
first was the one electron oxidation of 2a by dibromoethane
with subsequent dimerization to 3a. Alternatively, bromination
of 2a by dibromoethane could form benzyl bromide which
could generate 3a by in situ reaction with unreacted 2a. As
oxygen is capable of oxidizing 2a to produce 3a, this
mechanism could also be viable with dibromoethane as it is a
known oxidant (Table 1, entry 1). However, to illustrate that a
bromination/coupling pathway could also be in operation when
a solution of 2a was treated with with benzyl bromide, 3a was
obtained in a comparable yield.
The generality of this metalation/coupling method was next
examined for a series of substituted toluene derivatives. The
reaction sequence proved very general and tolerant of fluoro,
amino, carboxy, ether and amido functional groups in ortho,
meta, and para positions relative to the methyl group (Table 2,
entries 1−8). Di- and trisubstituted toluenes and xylenes were
also successfully dimerized in good yields (entries 9 and 10). Of
particular note is the hexamethoxylated natural product
brittonin A 3k which can be synthesized with 69% yield in a
single step (Table 2, entry 11).8
solution of BuLi/KO-t-Bu/TMP(H).
Table 3. Hetero-oxidative Coupling of Toluenes
a
entry
substrates
1a:1f (equiv)
product
yield (%)
1
2
3
1a/1f
1a/1f
1a/1f
1:1
2:1
1:2
4a
4a
4a
24
41
39
a
Yield refers to isolated product based on limiting reagent.
While complete selectivity for 4a was not achieved, this
single-step approach from the simplest toluene starting
materials remains favorable if alternative multistep routes are
considered. For example, multistep approaches to 4a would
require synthesis of suitably functionalized starting substrates
such as benzyl phosphonium ylide and aryl aldehyde for Wittig
olefination followed by alkene reduction.9 This approach
requires five individual reactions from toluene starting materials
and the use of a transition-metal catalyst (i.e., oxidation of one
toluene substrate to its aromatic aldehyde, bromination of the
other toluene substate to its benzyl bromide, conversion to its
phosphonium salt, Wittig olefination, and alkene reduction)
versus one for the hetero-oxidative coupling with no transition
metal required. Other reported multistep approaches include
the Pd-catalyzed coupling of 2-phenylethyltrifluoroborate and
aryl bromide and arylzinc chloride and triphenylethanylin-
dium.10,11
1,2-Diarylethane (bibenzyl) is a particularly common natural
product scaffold isolated from numerous plants such as
liverwort and orchids.12 Use of these plants has a long history
in traditional medicine, and ongoing analysis of individual
extracted bibenzyls has shown diverse biological activities
including antifungal, antimicrobial, antioxidant, antiprolifera-
tive, and multidrug resistance reversal properties. Typical
substituent patterns for this natural product class include
varying degrees of methoxy or phenolic substituents on the
aromatic rings. Exploiting our cross-coupling approach, it was
In an effort to optimize conditions for heterocouplings,
toluene (1a) and 3-methylanisole (1f) were used as test
substrates (Table 3). It was found that metalation and oxidative
coupling of a 1:1 ratio of each substrate gave a 24% yield of
heterodimer 4a following chromatographic separation from the
two homodimers 3a (25%) and 3f (19%). This yield could be
improved to 41% if a 2:1 ratio of 1a:1f was used and a
comparable yield was obtained if the ratio was reversed with an
excess of 1f employed (Table 3, entries 2 and 3).
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possible to synthesize numerous examples of these natural
products in a single synthetic operation (Table 4).
reaction with methyl iodide (Scheme 2). Substrate 5 presents
an elevated selectivity challenge for a LiNK metalation as it
contains two nonequivalent methyl groups with oxidative coupl-
ing at the 5-methyl required for the natural product syntheses. As
we have previously shown, it could be anticipated, based upon
relative CH acidities of both methyl groups, that this could be
achieved.3a The desired 5-methyl selectivity was confirmed by
2H NMR product analysis following LiNK metalation and treat-
ment with CD3OD, with the spectrum showing one triplet corres-
ponding to D-5 and no aryl deuteration (Scheme 2, Supporting
Information). With the desired regioselective metalation
established, oxidative cross-coupling of 5 with toluene gave
stilbostemin M in a 41% yield. Demethylation of 6 with
BBr3 gave the corresponding diphenol natural product 7,
stilbostemin B, which has been shown to be a biologically active
isolate from the roots of Stemona japonica and Stemona tuberosa
and has numerous cited uses in Chinese medicine.17 In addition
to being natural products in themselves, the bibenzyls we have
described are common intermediates in the synthesis of prenyl-,
pyranyl-, furan-, and glycoside-substituted analogues.18 For
example, conversion of 7 into bauhinol D (8) by ethylen-
ediaminediacetate (EDDA) catalyzed reaction with 3-
methyl-2-butenal has recently been shown.19
Table 4. Synthesis of Ether- and Phenolic-Substituted 1,2-
Diarylethane (Bibenzyl) Natural Products
a
entry substrates equiv ratio
R/R1
H/3-OMe
product yield (%)
1
2
3
4
5
6
1a/1f
1a/1g
1a/1i
1a/1k
1f/1i
2:1
2:1
2:1
2:1
2:1
2:1
4a
4b
4d
4e
41
43
40
46
58
52
b
c
H/3-OMOM
H/3,5-(OMe)2
H/3,4,5-(OMe)3
3-OMe/3,5-(OMe)2
3-OMe/3,4,5-(OMe)3
c
4f
1f/1k
4g
a
b
Yield refers to isolated product based on limiting reagent. OMOM
deprotected to 4c (R/R1 = H/3-OH) with HCl/MeOH in 83% yield.
c
Substrate added to a premixed solution of BuLi/KOtBu/TMP(H).
Compound 4b was synthesized in a 43% yield from toluene
and 3-OMOM-toluene (1g). Acidic deprotection to 3-phenethyl-
phenol (4c) was readily achieved providing the phenolic-
substituted natural product 4c.13 Oxidative cross-coupling of
toluene was equally successful with 3,5-dimethoxytoluene and
3,4,5-trimethoxytoluene to give natural products 4d and 4e
(entries 3 and 4).14 Similarly, the tri- and tetramethoxy-sub-
stituted bibenzyls 4f (batatasin III dimethyl ether) and 4g
(aloifol I dimethyl ether) were obtained in 58 and 52% yields
from 3-methoxytoluene with 1i and 1k, respectively.15
The synthesis of stilbostemin M (6), stilbostemin B (7), and
bauhinol D (8) from 1,3-dimethoxy-5-methylbenzene (1i)
provided an illustration of how the complementary metalation
selectivity achievable with classic superbase conditions of BuLi/
KO-t-Bu16 and LiNK (BuLi/KO-t-Bu/TMP(H)) can be
exploited for targeted synthesis (Scheme 2). As described
CONCLUSION
■
In summary, regioselective benzylic metalation with BuLi/KO-
t-Bu/TMP(H) can be used in conjunction with 1,2-dibromo-
ethane-mediated oxidative coupling to allow direct access to the
bibenzyl scaffold. This one-pot synthetic operation from
toluene starting materials allows easy access to this biologically
important natural product class without requiring additional
synthetic steps to preactivate the coupling partners or the use of
a transition-metal catalyst. A distinct advantage is that the
synthetic steps typically required to preactivate the coupling
toluene substrates are eliminated thereby dramatically reducing
the number of synthetic step. Further synthetic applications
utilizing LiNK metalation are under development and will be
reported in due course.
Scheme 2. Synthesis of Stilbostemin M (6), Stilbostemin B
(7), and Bauhinol D (8)
EXPERIMENTAL SECTION
■
General Methods. All reactions involving air-sensitive reagents
were performed under nitrogen in oven-dried glassware using syringe-
septum cap technique. All solvents were purified and degassed before
use. Unless it is specified, all reagents were used as received without
further purifications. TMP was distilled from CaH2 prior to use and
THF was obtained from a solvent purification system. BuLi was
purchased as a 2.5 M solution in hexanes. KOtBu was purchased as a 1
M solution in THF. The exact concentration of the organolithium
solution was determined by titration with diphenylacetic acid in THF
prior to use.20
Deuteriomethylbenzene (D-1a).
21
A solution of toluene (1a)
(1.00 mL, 9.38 mmol) in THF (5 mL) at −78 °C was treated
dropwise with BuLi (2.50 M, 4.50 mL, 11.20 mmol) and stirred for
5 min. KO-t-Bu (1.0 M in THF, 11.20 mL, 11.20 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (1.60 mL, 9.38
mmol). The reaction mixture was stirred for 1 h at −78 °C and
CD3OD (0.60 mL) added. The reaction mixture was allowed to warm
to room temperature and portioned between diethyl ether (30 mL)
and water (30 mL). The organic layer was washed several times with
water, and the combined organic extracts were dried over magnesium
sulfate and distilled with a fractionating column. The fraction boiling
between 110 and 115 °C was collected to give D-1a as a colorless oil
above, the benzylic metalation of 1i under LiNK conditions
could be used for synthesis of natural product 4d (Table 4,
entry 3). In contrast, selective kinetic metalation of 1i at the
C-2 aryl position (between the two methoxy groups) with
BuLi/KO-t-Bu was confirmed by deuteration and exploited for
the synthesis of 1,3-dimethoxy-2,5-dimethylbenzene 5 by
1
(73% D incorporation). H NMR (500 MHz, CDCl3): δ 7.29−7.22
(m, 2H), 7.21−7.12 (m, 3H), 2.37−2.30 (m, 2H). 13C NMR (125 MHz,
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2
CDCl3): δ 137.8, 129.0, 128.2, 127.3, 125.3, 21.1 (t, J = 19.1 Hz). H
NMR (92.07 MHz, CH2Cl2): δ 2.35 (t, J = 2.2 Hz).
THF (15 mL) at −78 °C was treated dropwise with BuLi (2.37
M, 0.51 mL, 1.20 mmol) and stirred for 5 min. KO-t-Bu (1.0 M
in THF, 1.20 mL, 1.20 mmol) was added dropwise followed by
2,2,6,6-tetramethylpiperidine (0.17 mL, 1.00 mmol). The
reaction mixture was stirred for 15 min at −78 °C, benzyl
bromide added (0.12 mL, 1.00 mmol), and the mixture stirred
for a further 5 min. The reaction mixture was warmed to rt and
the solvent removed under reduced pressure. Diethyl ether
(30 mL) was added to the residue, which was then washed with
HCl (2 M, 3 × 10 mL), dried over sodium sulfate, and
concentrated to dryness. Purification by silica gel chromatog-
raphy eluting with 92:8 cyclohexane/diethyl ether gave 1,2-
diphenylethane (3a) (Rf = 0.80, 135 mg) contaminated by
2-Deuterio-1,3-dimethoxy-5-methylbenzene (D-1i). A solution of
3,5-dimethoxytoluene (1i) (121 mg, 0.80 mmol) in THF (10 mL)
at −78 °C was treated dropwise with BuLi (2.50 M in hexanes, 0.35 mL,
0.88 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF, 0.88 mL,
0.88 mmol) was added dropwise, and the reaction mixture was stirred
for 1 h at −78 °C. Then CD3OD (0.20 mL) was added, and the
reaction mixture was stirred at −78 °C for an additional time of 5 min.
The reaction mixture was warmed to room temperature and the
solvent removed under reduced pressure. Diethyl ether (30 mL) was
added to the residue, washed with HCl (2 M, 3 × 10 mL), dried over
sodium sulfate, and concentrated to dryness to give D-1i as a colorless
oil (105 mg, 86%, 85% D incorporation). 1H NMR (500 MHz,
CDCl3): δ 6.33 (s, 2H), 3.77 (s, 6H), 2.30 (s, 3H). 13C NMR
benzyl bromide.
1,2-Diphenylethane (3a).
22
A solution of toluene (1a) (46 mg,
2
0.50 mmol) in THF (15 mL) at −78 °C was treated dropwise with
BuLi (2.37 M, 0.25 mL, 0.60 mmol) and stirred for 5 min. KO-t-Bu
(1.0 M in THF, 0.60 mL, 0.60 mmol) was added dropwise followed by
2,2,6,6-tetramethylpiperidine (84 μL, 0.50 mmol). The reaction
mixture was stirred for 15 min at −78 °C, and 1,2-dibromoethane
added (0.13 mL, 1.50 mmol) and stirred for a further 5 min. The
reaction mixture was warmed to rt and the solvent removed under
reduced pressure. Diethyl ether (30 mL) was added to the residue,
which was then washed with HCl (2 M, 3 × 10 mL), dried over
sodium sulfate, and concentrated to dryness. Purification by silica gel
chromatography eluting with 92:8 cyclohexane/diethyl ether gave 1,2-
diphenylethane (3a) as a colorless solid (Rf = 0.80, 32 mg, 71%), mp
(125 MHz, CDCl3): δ 159.7, 139.2, 106.1, 96.5 (bs), 54.2, 20.8. H
NMR (92.07 MHz, CH2Cl2): δ 6.28 (s). HRMS [M]+: 153.0900,
C9H11DO2 requires 153.0900.
5-(Deuteriomethyl)-1,3-dimethoxy-2-methylbenzene (D-5). A
solution of 1,3-dimethoxy-2,5-dimethylbenzene (5) (75 mg, 0.45
mmol) in THF (10 mL) at −78 °C was treated dropwise with BuLi
(2.50 M in hexanes, 0.20 mL, 0.50 mmol) and stirred for 5 min. KO-
t-Bu (1.0 M in THF, 0.50 mL, 0.50 mmol) was added dropwise
followed by 2,2,6,6-tetramethylpiperidine (76 μL, 0.45 mmol). The
reaction mixture was stirred for 15 min at −78 °C, CD3OD (0.20 mL)
added, and the mixture stirred for a further 5 min. The reaction
mixture was warmed to room temperature and the solvent removed
under reduced pressure. Diethyl ether (30 mL) was added to the
residue, washed with HCl (2 M, 3 × 10 mL), dried over sodium
sulfate, and concentrated to dryness to give D-5 as a colorless solid (65
mg, 86%, 70% D incorporation, mp 48−49 °C). 1H NMR (500 MHz,
CDCl3): δ 6.36 (s, 2H), 3.80 (s, 6H), 2.33−2.29 (m, 2H), 2.05
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 158.2, 136.2, 136.1, 111.4,
104.5, 55.7, 21.6 (t, J = 19.4 Hz), 7.8. 2H NMR (92.07 MHz, CH2Cl2):
δ 2.31 (t, J = 2.2 Hz). HRMS [M]+: 167.1055, C10H13DO2 requires
167.1057.
General Procedure for the Optimization of Homocoupling
Reaction. A solution of toluene (1a) (46 mg, 0.50 mmol) in THF
(15 mL) at −78 °C was treated dropwise with BuLi (2.37 M, 0.25 mL,
0.60 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF, 0.60 mL,
0.60 mmol) was added dropwise followed by 2,2,6,6-tetramethylpiper-
idine (84 μL, 0.50 mmol). The reaction mixture was stirred for 15 min
at −78 °C, oxidant added, and the mixture stirred for a further 5 min.
The reaction mixture was warmed to room temperature and the
solvent removed under reduced pressure. Diethyl ether (30 mL) was
added to the residue, washed with HCl (2 M, 3 × 10 mL), dried over
sodium sulfate, and concentrated to dryness. Purification by silica gel
chromatography eluting with 92:8 cyclohexane/diethyl ether gave 1,2-
diphenylethane (3a) as a colorless solid (Rf = 0.80).
50−51 °C (lit.22b mp 51−53 °C). H NMR (500 MHz, CDCl3): δ
1
7.29−7.23 (m, 4H), 7.20−7.15 (m, 6H), 2.91 (s, 4H). 13C NMR (125
MHz, CDCl3): δ 141.8, 128.5, 128.3, 125.9, 37.9. HRMS [M]+:
182.1092, C14H14 requires 182.1096.
1,2-Bis(2-fluorophenyl)ethane (3b).
23
A solution of 2-fluoroto-
luene (1b) (165 mg, 1.50 mmol) in THF (15 mL) at −78 °C was
treated dropwise with BuLi (2.37 M, 0.76 mL, 1.80 mmol) and stirred
for 5 min. KO-t-Bu (1.0 M in THF, 1.80 mL, 1.80 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (0.25 mL,
1.50 mmol). The reaction mixture was stirred for 15 min at −78 °C,
1,2-dibromoethane (0.37 mL, 4.50 mmol) added, and the mixture stirred
for a further 5 min. The reaction mixture was warmed to rt and the sol-
vent removed under reduced pressure. Diethyl ether (30 mL) was added
to the residue, which was then washed with HCl (2 M, 3 × 10 mL), dried
over sodium sulfate, and concentrated to dryness. Purification by silica gel
chromatography eluting with 90:10 cyclohexane/diethyl ether gave 3b
as a colorless solid (Rf = 0.80, 128 mg, 78%), mp 40−41 °C (lit.23b mp
1
40−41 °C). H NMR (500 MHz, CDCl3): δ 7.21−7.09 (m, 4H),
7.04−6.98 (m, 4H), 2.94 (s, 4H). 13C NMR (125 MHz, CDCl3):
δ 161.2 (d, J = 244.9 Hz), 130.7 (d, J = 5.0 Hz), 128.3 (dd, J = 18.8,
15.0 Hz), 127.7 (d, J = 8.1 Hz), 123.8 (d, J = 3.6 Hz), 115.2 (d, J =
22.1 Hz), 29.7−29.6 (m). HRMS [M]+: 218.0912, C14H12F2 requires
218.0907.
O2 (bubbling): 28 mg, 62%.
2,2′-(Ethane-1,2-diyl)bis(N,N-dimethylaniline) (3c). A solution of
N,N-dimethyl-o-toluidine (1c) (203 mg, 1.50 mmol) in THF (15 mL)
at −78 °C was treated dropwise with BuLi (2.37 M, 0.76 mL,
1.8 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF, 1.80 mL,
1.80 mmol) was added dropwise followed by 2,2,6,6-tetramethylpiper-
idine (0.25 mL, 1.50 mmol). The reaction mixture was stirred for
15 min at −78 °C, 1,2-dibromoethane (0.37 mL, 4.50 mmol) added,
and the mixture stirred for a further 5 min. The reaction mixture was
warmed to rt and the solvent removed under reduced pressure. Diethyl
ether (30 mL) was added to the residue, which was then washed with
water (3 × 10 mL), dried over sodium sulfate, and concentrated to
dryness. Purification by silica gel chromatography eluting with 80:20
cyclohexane/diethyl ether (0.5% Et3N) gave 3c as a colorless solid
(Rf = 0.60, 116 mg, 58%), mp 53−54 °C. 1H NMR (500 MHz,
CDCl3): δ 7.28 (d, J = 7.5 Hz, 2H), 7.17 (t, J = 7.5 Hz, 2H), 7.11 (d,
J = 7.9 Hz, 2H), 7.02 (t, J = 7.4 Hz, 2H), 3.03 (s, 4H), 2.68 (s, 12H).
13C NMR (125 MHz, CDCl3): δ 152.9, 137.4, 129.8, 126.6, 123.4,
119.6, 45.2, 31.9. HRMS [M]+: 268.1937, C18H24N2 requires
268.1939. Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N, 10.44.
Found: C, 80.49; H, 8.86; N, 10.17.
Ceric ammonium nitrate: (822 mg, 1.50 mmol): 16 mg, 35%.
Iodine: (380 mg, 1.50 mmol): 21 mg, 47%.
1,2-Dibromoethane (0.13 mL, 1.50 mmol): 32 mg, 71%.
TEMPO (158 mg, 1.00 mmol). After the addition of TEMPO the
reaction mixture was stirred for 2 h at room temperature: 26 mg, 58%.
Coupling Reaction of Benzylmagnesium Chloride. 1,2-
Diphenylethane (3a). Benzyl chloride (60 mg, 0.47 mmol) was
added dropwise to a stirred suspension of magnesium powder
(12 mg, 0.50 mmol) in dry THF (4 mL), and the reaction
mixture was refluxed under nitrogen. After 30 min, the resulting
Grignard reagent was cooled to room temperature, and 1,2-
dibromoethane (0.13 mL, 1.50 mmol) was added. The reaction
mixture was stirred for 2 h, quenched with water, and extracted
with diethyl ether (2 × 10 mL). The combined organic layer
was dried over sodium sulfate and concentrated to dryness.
Purification by silica gel chromatography eluting with 92:8
cyclohexane/diethyl ether gave 1,2-diphenylethane (3a )as a
colorless solid (35 mg, 81%).
Coupling Reaction of 2a with Benzyl Bromide. 1,2-Diphenyl-
ethane (3a). A solution of toluene (1a) (92 mg, 1.00 mmol) in
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2,2′-(Ethane-1,2-diyl)dibenzoic Acid (3d). 24 A solution of o-toluic
acid (1d) (272 mg, 2.00 mmol) in THF (18 mL) at −78 °C was
treated dropwise with BuLi (2.30 M, 1.74 mL, 4.00 mmol) and stirred
for 5 min. KO-t-Bu (1.0 M in THF, 4.00 mL, 4.00 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (0.34 mL,
2.00 mmol). The reaction mixture was stirred for 15 min at −78 °C, 1,2-
dibromoethane (0.52 mL, 6.00 mmol) added, and the mixture stirred
for a further 5 min. The reaction mixture was warmed to rt and the
solvent removed under reduced pressure. Diethyl ether (30 mL) was
added to the residue, washed with HCl (2 M, 3 × 10 mL), dried over
sodium sulfate, and concentrated to dryness. Trituration from diethyl
ether with cooling gave 3d as a pale yellow solid (144 mg, 53%), mp
4,4′-(Ethane-1,2-diyl)bis(N,N-diisopropylbenzamide) (3h). A sol-
ution of N,N-diisopropyl-4-methylbenzamide (1h) (219 mg, 1.00 mmol)
in THF (15 mL) at −78 °C was treated dropwise with BuLi (2.50 M,
0.48 mL, 1.20 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF,
1.20 mL, 1.20 mmol) was added dropwise followed by 2,2,6,6-
tetramethylpiperidine (0.17 mL, 1.00 mmol). The reaction mixture
was stirred for 15 min at −78 °C, 1,2-dibromoethane (0.26 mL,
3.00 mmol) added, and the mixture stirred for a further 5 min. The
reaction mixture was warmed to rt and the solvent removed under
reduced pressure. Diethyl ether (30 mL) was added to the residue,
which was washed with 2 M HCl (3 × 10 mL), dried over sodium
sulfate, and concentrated to dryness. Purification by silica gel chroma-
tography eluting with 15:85 cyclohexane/diethyl ether gave 3h as a
228−229 °C (lit.24b mp 229−231 °C). H NMR (500 MHz, DMSO-
1
1
d6): δ 12.86 (bs, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.45 (td, J = 7.5, 1.1 Hz,
2H), 7.31−7.24 (m, 4H), 3.19 (s, 4H). 13C NMR (125 MHz,
DMSO-d6): δ 169.2, 143.2, 132.1, 131.0, 130.9, 130.7, 126.5, 36.0.
HRMS [M + Na]+: 293.0796, C16H14O4Na requires 293.0790.
colorless solid (Rf = 0.60, 96 mg, 88%), mp 144−145 °C. H NMR
(500 MHz, CDCl3): δ 7.23 (d, 4H, J = 7.9 Hz), 7.17 (d, 4H, J =
7.9 Hz), 3.69 (bs, 4H), 2.93 (s, 4H), 1.33 (bs, 24H). 13C NMR
(125 MHz, CDCl3): δ 171.1, 142.1, 136.7, 128.4, 125.8, 37.4, 20.8.
(Note: i-Pr tertiary C not observed). HRMS [M + H]+: 437.3188,
C28H41N2O2 requires 437.3168. Anal. Calcd for C28H40N2O2: C,
77.02; H, 9.23; N, 6.42. Found: C, 76.73; H, 9.34; N, 6.30.
25
1,2-Bis(2-methoxyphenyl)ethane (3e). A solution of 2-methyl-
anisole (1e) (122 mg, 1.00 mmol) in THF (15 mL) at −78 °C was
treated dropwise with BuLi (2.50 M, 0.48 mL, 1.20 mmol) and stirred
for 5 min. KO-t-Bu (1.0 M in THF, 1.20 mL, 1.20 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (0.17 mL,
1.00 mmol). The reaction mixture was stirred for 15 min at −78 °C, 1,2-
dibromoethane (0.26 mL, 3.00 mmol) added, and the mixture stirred
for a further 5 min. The reaction mixture was warmed to rt and the
solvent removed under reduced pressure. Diethyl ether (30 mL) was
added to the residue, washed with HCl (2 M, 3 × 10 mL), dried over
sodium sulfate, and concentrated to dryness. Purification by silica gel
chromatography eluting with 98:2 cyclohexane/diethyl ether gave 3e
as a colorless solid (Rf = 0.70, 76 mg, 63%), mp 78−79 °C (lit.25 mp
81−82 °C). 1H NMR (500 MHz, CDCl3): δ 7.16 (t, J = 7.8 Hz, 2H),
7.11 (d, J = 7.3 Hz, 2H), 6.90−6.78 (m, 4H), 3.80 (s, 6H), 2.89 (s,
4H). 13C NMR (125 MHz, CDCl3): δ 156.5, 129.8, 128.7, 125.9,
119.3, 109.2, 54.3, 29.4. HRMS [M]+: 242.1298, C16H18O2 requires
27
1,2-Bis(3,5-dimethoxyphenyl)ethane (3i). A solution of 2,2,6,6-
tetramethylpiperidine (0.22 mL, 1.31 mmol) in THF (10 mL) at
−78 °C was treated dropwise with BuLi (2.35 M, 0.67 mL,
1.57 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF,
1.57 mL, 1.57 mmol) was added dropwise and stirred for 5 min. A
solution of 3,5-dimethoxytoluene (1i) (200 mg, 1.31 mmol) in THF
(5 mL) at −78 °C was added dropwise to the reaction mixture and
stirred for 15 min at −78 °C. Then 1,2-dibromoethane (0.34 mL,
3.93 mmol) was added, and the mixture was stirred for a further 5 min.
The reaction mixture was warmed to rt and the solvent removed under
reduced pressure. The residue was dissolved in diethyl ether (30 mL),
washed with 2 M HCl (3 × 10 mL), dried over sodium sulfate, and
concentrated to dryness to give 3i as a colorless solid (160 mg, 80%),
mp 96−97 °C (lit.27b mp 99−100 °C). 1H NMR (400 MHz, CDCl3):
δ 6.36−6.35 (m, 4H), 6.33−6.32 (m, 2H), 3.77 (s, 12H), 2.85 (s, 4H).
13C NMR (100 MHz, CDCl3): δ 160.7, 144.1, 106.5, 98.0, 55.3, 38.0.
HRMS [M + H]+: 303.1600, C18H23O4 requires 303.1596.
1,2-Bis(3-methoxy-4-methylphenyl)ethane (3j). A solution of 2,5-
dimethylanisole (1j) (209 mg, 1.50 mmol) in THF (15 mL) at
−78 °C was treated dropwise with BuLi (2.50 M in hexanes, 0.72 mL,
1.80 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF, 1.80 mL,
1.80 mmol) was added dropwise followed by 2,2,6,6-tetramethylpiper-
idine (0.26 mL, 1.50 mmol). The reaction mixture was stirred for
15 min at −78 °C, 1,2-dibromoethane (0.37 mL, 4.50 mmol) added,
and the mixture stirred for a further 5 min. The reaction mixture was
warmed to rt and the solvent removed under reduced pressure. The
residue was dissolved in diethyl ether (30 mL), washed with 2 M HCl
(3 × 10 mL), dried over sodium sulfate, and concentrated to dryness.
Purification by silica gel chromatography eluting with 98:2 cyclo-
hexane/EtOAc gave 3j as a colorless solid (Rf = 0.50, 178 mg, 88%, mp
70−71 °C. 1H NMR (500 MHz, CDCl3): δ 7.03 (d, J = 7.5 Hz, 2H),
6.71 (d, J = 7.5 Hz, 2H), 6.62 (s, 2H), 3.78 (s, 6H), 2.88 (s, 4H), 2.18
(s, 6H). 13C NMR (125 MHz, CDCl3): δ 157.6, 140.7, 130.4, 124.0,
120.1, 110.4, 55.2, 38.1, 15.8. HRMS [M + H]+: 271.1708, C18H23O2
requires 271.1698. Anal. Calcd for C18H22O2: C, 79.96; H, 8.20.
242.1307.
26
1,2-Bis(3-methoxyphenyl)ethane (3f).
A solution of 3-methyl-
anisole (1f) (122 mg, 1.00 mmol) in THF (15 mL) at −78 °C was
treated dropwise with BuLi (2.50 M, 0.48 mL, 1.20 mmol) and stirred
for 5 min. KO-t-Bu (1.0 M in THF, 1.20 mL, 1.20 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (0.17 mL,
1.00 mmol). The reaction mixture was stirred for 15 min at −78 °C, 1,2-
dibromoethane (0.26 mL, 3.00 mmol) added, and the mixture stirred
for a further 5 min. The reaction mixture was warmed to rt and the
solvent removed under reduced pressure. Diethyl ether (30 mL) was
added to the residue, which was washed with HCl (2 M, 3 × 10 mL),
dried over sodium sulfate, and concentrated to dryness. Purification by
silica gel chromatography eluting with 96:4 cyclohexane/diethyl ether
gave 3f as a colorless oil (Rf = 0.60, 82 mg, 68%). 1H NMR (500 MHz,
CDCl3): δ 7.19 (t, J = 7.7 Hz, 2H), 6.79−6.71 (m, 6H), 3.77 (s, 6H),
2.89 (s, 4H). 13C NMR (125 MHz, CDCl3): δ 159.6, 143.4, 129.3,
120.9, 114.2, 111.3, 55.1, 37.8. HRMS [M + H]+: 243.1377, C16H19O2
requires 243.1385.
1,2-Bis(3-(methoxymethoxy)phenyl)ethane (3g). A solution of
1-methoxymethoxy-3-methylbenzene (1g) (250 mg, 1.64 mmol) in
THF (20 mL) at −78 °C was treated dropwise with BuLi (2.40 M,
0.82 mL, 1.97 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF,
1.97 mL, 1.97 mmol) was added dropwise followed by 2,2,6,6-tetra-
methylpiperidine (0.28 mL, 1.64 mmol). The reaction mixture was
stirred for 15 min at −78 °C, 1,2-dibromoethane (0.42 mL, 4.92 mmol)
added, and the mixture stirred for a further 5 min. The reaction
mixture was warmed to rt and the solvent removed under reduced
pressure. The residue was dissolved in diethyl ether (30 mL), washed
with 2 M HCl (3 × 10 mL), dried over sodium sulfate, and con-
centrated to dryness. Purification by alumina gel chromatography
eluting with 99:1 cyclohexane/ethyl acetate gave 3g as a colorless oil
(Rf = 0.60, 115 mg, 46%). 1H NMR (400 MHz, CDCl3): δ 7.22−7.18
(m, 2H), 6.89−6.84 (m, 6H), 5.16 (s, 4H), 3.48 (s, 6H), 2.90 (s, 4H).
13C NMR (100 MHz, CDCl3): δ 157.34, 143.39, 129.30, 122.07,
116.44, 113.78, 94.50, 55.95, 37.73. HRMS [M]+: 302.1519, C18H22O4
requires 302.1518.
Found: C, 79.68; H, 8.27.
1,2-Bis(3,4,5-trimethoxyphenyl)ethane (3k) (Brittonin A).
28
A
solution of 3,4,5-trimethoxytoluene (1k) (182 mg, 1.00 mmol) in
THF (15 mL) at −78 °C was treated dropwise with BuLi (2.50 M in
hexanes, 0.48 mL, 1.20 mmol) and stirred for 5 min. KO-t-Bu (1.0 M
in THF, 1.20 mL, 1.20 mmol) was added dropwise followed by
2,2,6,6-tetramethylpiperidine (0.17 mL, 1.00 mmol). The reaction mix-
ture was stirred for 15 min at −78 °C, 1,2-dibromoethane (0.26 mL,
3.00 mmol) added, and the mixture stirred for a further 5 min. The
reaction mixture was warmed to rt and the solvent removed under
reduced pressure. The residue was dissolved in diethyl ether (30 mL),
washed with 2 M HCl (3 × 10 mL), dried over sodium sulfate, and
concentrated to dryness. Triturating from diethyl ether with cool-
ing gave 3k as a colorless solid (125 mg, 69%), mp 138−139 °C (lit.28b
1
mp 138−139 °C). H NMR (500 MHz, CDCl3): 6.36 (s, 4H), 3.82
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(s, 18H), 2.85 (s, 4H). 13C NMR (125 MHz, CDCl3): δ 153.0, 137.3,
136.3, 105.6, 60.8, 56.1, 38.4. HRMS [M + Na]+: 385.1637,
C20H26O6Na requires 385.1627.
(t,
J = 7.4 Hz, 2H), 7.21−7.12 (m, 4H), 6.76 (d, J = 7.4 Hz, 1H), 6.68−
6.63 (m, 2H), 4.70 (s, 1H), 2.94−2.84 (m, 4H). 13C NMR (125 MHz,
CDCl3): δ 155.5, 143.7, 141.6, 129.5, 128.4, 128.3, 125.9, 121.0, 115.4,
112.8, 37.7, 37.6. HRMS [M]+: 198.1060, C14H14O requires 198.1045.
1,3-Dimethoxy-5-phenethylbenzene (4d). 30 A solution of 2,2,6,6-
tetramethylpiperidine (0.25 mL, 1.50 mmol) in THF (20 mL) at
−78 °C was treated dropwise with BuLi (2.37 M, 0.69 mL,
1.65 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF,
1.65 mL, 1.65 mmol) was added dropwise and stirred for 5 min. A
solution of 3,5-dimethoxytoluene (1i) (76 mg, 0.50 mmol) and
toluene (1a) (92 mg, 1.00 mmol) in THF (5 mL) at −78 °C was
added dropwise to the reaction mixture and stirred for 15 min at
−78 °C. Then 1,2-dibromoethane (0.22 mL, 2.50 mmol) was added,
and the mixture was stirred for a further 5 min. The reaction mixture
was warmed to rt and the solvent removed under reduced pressure.
Diethyl ether (30 mL) was added to the residue, washed with HCl
(2 M, 3 × 10 mL), dried over sodium sulfate, and concentrated to
dryness. Purification by silica gel chromatography eluting with 96:4
cyclohexane/diethyl ether gave 4d as a colorless oil (Rf = 0.40, 49 mg,
40%). 1H NMR (500 MHz, CDCl3): δ 7.29−7.26 (m, 2H), 7.20−7.16
(m, 3H), 6.36−6.29 (m, 3H), 3.75 (s, 6H), 2.94−2.83 (m, 4H). 13C
NMR (125 MHz, CDCl3): δ 160.7, 144.2, 141.7, 128.4, 128.3, 125.9,
106.5, 98.0, 55.2, 38.2, 37.6. HRMS [M + H]+: 243.1397, C16H19O2
requires 243.1385.
General Procedure for the Optimization of Heterocoupling
Reaction. A solution of toluene (1a) and 3-methylanisole (1f) in
THF (20 mL) at −78 °C was treated dropwise with BuLi (2.37 M)
and stirred for 5 min. KO-t-Bu (1.0 M in THF) was added dropwise
followed by 2,2,6,6-tetramethylpiperidine. The reaction mixture was
stirred for 15 min at −78 °C, 1,2-dibromoethane (0.22 mL, 5.00 equiv)
added, and the mixture stirred for a further 5 min. The reaction mixture
was warmed to room temperature and the solvent removed under
reduced pressure. Diethyl ether (30 mL) was added to the residue,
which was then washed with HCl (2 M, 3 × 10 mL), dried over sodium
sulfate, and concentrated to dryness. Purification by silica gel chroma-
tography eluting with 96:4 cyclohexane/diethyl ether gave 1-methoxy-
3-phenethylbenzene (4a) as a colorless oil (Rf = 0.60).
Tabulated results:
entry 1a (mg, 1f (mg, Li/K/TMP 4a (mg, mmol, 3a (mg,
mmol) mmol) (equiv) yield, %) mmol)
3f (mg,
mmol)
1
2
3
46, 0.50 61, 0.50 2.2:2.2:2
92, 1.00 61, 0.50 3.3:3.3:3
26, 0.121, 24 21, 0.115 23, 0.094
43, 0.202, 41 72, 0.395 23, 0.095
46, 0.50 122, 1.00 3.3:3.3:3
41, 0.195, 39 25, 0.139 60, 0.248
11
1-Methoxy-3-phenethylbenzene (4a).
A solution of 3-
methylanisole (1f) (61 mg, 0.50 mmol) and toluene (1a) (92 mg,
1.00 mmol) in THF (20 mL) at −78 °C was treated dropwise with
BuLi (2.37 M, 0.69 mL, 1.65 mmol) and stirred for 5 min. KO-t-Bu
(1.0 M in THF, 1.65 mL, 1.65 mmol) was added dropwise followed by
2,2,6,6-tetramethylpiperidine (0.25 mL, 1.50 mmol). The reaction
mixture was stirred for 15 min at −78 °C, 1,2-dibromoethane (0.22 mL,
2.50 mmol) added, and the mixture stirred for a further 5 min. The
reaction mixture was warmed to rt and the solvent removed under
reduced pressure. Diethyl ether (30 mL) was added to the residue, which
was washed with HCl (2 M, 3 × 10 mL), dried over sodium sulfate, and
concentrated to dryness. Purification by silica gel chromatography eluting
with 96:4 cyclohexane/diethyl ether gave 1-methoxy-3-phenethylbenzene
1,2,3-Trimethoxy-5-phenethylbenzene (4e). 31 A solution of 3,4,5-
trimethoxytoluene (1k) (91 mg, 0.50 mmol) and toluene (1a) (92 mg,
1.00 mmol) in THF (20 mL) at −78 °C was treated dropwise with
BuLi (2.50 M, 0.66 mL, 1.65 mmol) and stirred for 5 min. KO-t-Bu
(1.0 M in THF, 1.65 mL, 1.65 mmol) was added dropwise followed by
2,2,6,6-tetramethylpiperidine (0.25 mL, 1.50 mmol). The reaction
mixture was stirred for 15 min at −78 °C, 1,2-dibromoethane
(0.22 mL, 2.50 mmol) added, and the mixture stirred for a further 5
min. The reaction mixture was warmed to rt and the solvent removed
under reduced pressure. Diethyl ether (30 mL) was added to the
residue, which was then washed with HCl (2 M, 3 × 10 mL), dried
over sodium sulfate, and concentrated to dryness. Purification by silica
gel chromatography eluting with 80:20 cyclohexane/diethyl ether gave
1
4a as a colorless oil (Rf = 0.60, 43 mg, 41%). H NMR (500 MHz,
CDCl3): δ 7.29−7.25 (m, 2H), 7.21−7.16 (m, 4H), 6.80−6.70 (m, 3H),
3.77 (s, 3H), 2.95−2.86 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 159.6,
143.4, 141.7, 129.3, 128.4, 128.3, 125.9, 120.9, 114.2, 111.3, 55.1, 37.9,
1
4e as a colorless oil (Rf = 0.50, 63 mg, 46%). H NMR (500 MHz,
CDCl3): δ 7.28 (t, J = 7.4 Hz, 2H), 7.21−7.15 (m, 3H), 6.36 (s, 2H), 3.82
(s, 3H), 3.81 (s, 6H), 2.94−2.84 (m, 4H). 13C NMR (125 MHz, CDCl3):
δ 153.0, 141.6, 137.4, 136.3, 128.5, 128.3, 125.9, 105.5, 60.8, 56.1, 38.3,
37.9. HRMS [M + H]+: 273.1484, C17H21O3 requires 273.1491.
37.8. HRMS [M]+: 212.1209, C15H16O requires 212.1201.
29
1-(Methoxymethoxy)-3-phenethylbenzene (4b).
A solution of
1-(methoxymethoxy)-3-methylbenzene (1g) (76 mg, 0.50 mmol) and
toluene (1a) (92 mg, 1.00 mmol) in THF (20 mL) at −78 °C was
treated dropwise with BuLi (2.50 M, 0.66 mL, 1.65 mmol) and stirred
for 5 min. KO-t-Bu (1.0 M in THF, 1.65 mL, 1.65 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (0.25 mL,
1.50 mmol). The reaction mixture was stirred for 15 min at −78 °C, 1,2-
dibromoethane (0.22 mL, 2.50 mmol) added, and the mixture stirred
for a further 5 min. The reaction mixture was warmed to rt and the
solvent removed under reduced pressure. Diethyl ether (30 mL) was
added to the residue, which was then washed with HCl (2 M, 3 ×
10 mL), dried over sodium sulfate, and concentrated to dryness.
Purification by silica gel chromatography eluting with 94:6 cyclo-
hexane:diethyl ether (0.25% Et3N) gave 4b as a colorless oil (Rf = 0.60,
1,3-Dimethoxy-5-(3-methoxyphenethyl)benzene (4f) (Batatasin
15
III Dimethyl Ether).
A solution of 2,2,6,6-tetramethylpiperidine
(0.25 mL, 1.50 mmol) in THF (20 mL) at −78 °C was treated
dropwise with BuLi (2.35 M, 0.70 mL, 1.65 mmol) and stirred for
5 min. KO-t-Bu (1.0 M in THF, 1.65 mL, 1.65 mmol) was added
dropwise and stirred for 5 min. A solution of 3,5-dimethoxytoluene
(1i) (76 mg, 0.50 mmol) and 3-methylanisole (1f) (122 mg,
1.00 mmol) in THF (5 mL) at −78 °C was added dropwise to the reac-
tion mixture and stirred for 15 min at −78 °C. Then 1,2-dibromoethane
(0.22 mL, 2.50 mmol) was added, and the mixture was stirred for a
further 5 min. The reaction mixture was warmed to rt and the solvent
removed under reduced pressure. Diethyl ether (30 mL) was added to
the residue, washed with HCl (2 M, 3 × 10 mL), dried over sodium sulfate,
and concentrated to dryness. Purification by silica gel chromatography
eluting with 85:15 pentane/diethyl ether gave 4f as a pale yellow solid (Rf =
0.60, 79 mg, 58%), mp 41−42 °C. 1H NMR (500 MHz, CDCl3): δ 7.19
(td, J = 7.9, 1.9 Hz, 1H), 6.80−6.72 (m, 3H), 6.36−6.30 (m, 3H), 3.77 (s,
3H), 3.75 (s, 6H), 2.91−2.82 (m, 4H). 13C NMR (125 MHz, CDCl3): δ
160.8, 159.7, 144.1, 143.3, 129.3, 120.8, 114.2, 111.3, 106.5, 98.0, 55.2, 55.1,
38.1, 37.7. HRMS [M + H]+: 273.1501, C17H21O3 requires 273.1491.
1
53 mg, 43%). H NMR (500 MHz, CDCl3): δ 7.30−7.26 (m, 2H),
7.22−7.17 (m, 4H), 6.90−6.82 (m, 3H), 5.15 (s, 2H), 3.48 (s, 3H),
2.95−2.87 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 157.3, 143.5,
141.7, 129.3, 128.4, 128.3, 125.9, 122.1, 116.4, 113.7, 94.5, 55.9, 37.9,
37.8. HRMS [M + Na]+: 265.1204, C16H18O2Na requires 265.1204.
13
3-Phenethylphenol (4c). A solution of 1-(methoxymethoxy)-3-
phenethylbenzene (4b) (52 mg, 0.22 mmol) in methanol (15 mL) was
treated dropwise with concd HCl (0.50 mL) and stirred overnight at
reflux. The reaction mixture was cooled to rt, extracted into ethyl
acetate (3 × 30 mL), and washed with water. The combined organic
material was dried over sodium sulfate and concentrated to dryness.
Purification by silica gel chromatography eluting with 80:20 cyclohexane/
ethyl acetate gave 4c as a white solid (Rf = 0.50, 36 mg, 83%), mp 74−
1,2,3-Trimethoxy-5-(3-methoxyphenethyl)benzene (4g) (Aloifol I
32
Dimethyl Ether).
A solution of 3,4,5-trimethoxytoluene (1k)
(91 mg, 0.50 mmol) and 3-methylanisole (1f) (122 mg, 1.00 mmol) in
THF (20 mL) at −78 °C was treated dropwise with BuLi (2.50 M,
0.66 mL, 1.65 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF,
1.65 mL, 1.65 mmol) was added dropwise followed by 2,2,6,6-
tetramethylpiperidine (0.25 mL, 1.50 mmol). The reaction mixture
75 °C (lit.13 mp 75−76 °C). H NMR (500 MHz, CDCl3): δ 7.28
1
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was stirred for 15 min at −78 °C, 1,2-dibromoethane (0.22 mL,
2.50 mmol) added, and the mixture stirred for a further 5 min. The re-
action mixture was warmed to rt and the solvent removed under reduced
pressure. Diethyl ether (30 mL) was added to the residue, which was
washed with HCl (2 M, 3 × 10 mL), dried over sodium sulfate, and
concentrated to dryness. Purification by silica gel chromatography eluting
with 70:30 cyclohexane/diethyl ether gave 4g as a colorless oil (Rf =
0.40, 79 mg, 52%). 1H NMR (500 MHz, CDCl3): δ 7.20 (t, J = 7.8 Hz,
1H), 6.80−6.71 (m, 3H), 6.37 (s, 2H), 3.82 (s, 3H), 3.82 (s, 6H), 3.78
(s, 3H), 2.91−2.83 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 159.6,
153.0, 143.2, 137.4, 136.3, 129.3, 120.9, 114.3, 111.3, 105.5, 60.8, 56.1,
55.1, 38.2, 38.0. HRMS [M + Na]+: 325.1409, C18H22O4Na requires
CD3OD): δ 7.22 (t, J = 7.5 Hz, 2H), 7.17−7.10 (m, 3H), 6.17 (s, 2H),
4.81 (s, 2H), 2.86−2.66 (m, 4H), 2.00 (s, 3H). 13C NMR (125 MHz,
CD3OD): δ 157.1, 143.3, 141.2, 129.4, 129.2, 126.7, 109.6, 107.8, 39.0,
38.9, 8.3. HRMS [M + H]+: 229.1228, C15H17O2 requires 229.1229.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 2H, and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: donal.f.oshea@ucd.ie.
■
325.1416.
33
1,3-Dimethoxy-2,5-dimethylbenzene (5).
A solution of 3,5-
dimethoxytoluene (1i) (228 mg, 1.50 mmol) in THF (20 mL) at
−78 °C was treated dropwise with BuLi (2.50 M, 0.66 mL,
1.65 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF,
1.65 mL, 1.65 mmol) was added dropwise, and the reaction mixture
was stirred for 1 h at −78 °C. Methyl iodide (0.10 mL, 1.65 mmol)
was added, and the reaction mixture was stirred at −78 °C for 30 min.
The reaction was quenched with HCl (2 M, 20 mL), warmed to rt,
and extracted with diethyl ether (3 × 15 mL). The combined organic
layers were washed with a saturated solution of sodium thiosulphate
(2 × 10 mL), dried over sodium sulfate, and concentrated to dryness.
Purification by silica gel chromatography eluting with 20:1 cyclo-
hexane/diethyl ether gave 5 as a colorless solid (Rf = 0.70, 181 mg,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Science Foundation Ireland, The Irish Research Council for
Science, Engineering and Technology, and ERA-Chemistry are
acknowledged for financial support. We thank Dr. J. Muldoon
for NMR analysis.
REFERENCES
73%), mp 47−48 °C (lit.33b mp 49−50 °C). H NMR (500 MHz,
1
■
CDCl3): δ 6.36 (s, 2H), 3.80 (s, 6H), 2.33 (s, 3H), 2.05 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 158.2, 136.1, 111.4, 104.5, 55.7, 21.9, 7.8.
HRMS [M + H]+: 167.1069, C10H15O2 requires 167.1072.
(1) For a recent review, see: Liu, C.; Jin, L.; Lei, A. Synlett 2010, 17,
2527−2536.
(2) (a) Maji, M. S.; Murarka, S.; Studer, A. Org. Lett. 2010, 12, 3878−
3881. (b) Maji, M. S.; Pfeifer, T.; Studer, A. Angew. Chem., Int. Ed.
2008, 47, 9547−9550. (c) Maji, M. S.; Studer, A. Synthesis 2009, 14,
2467−2470. (d) Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 5010−5014.
(e) Nishiyama, T.; Seshita, T.; Shodai, H.; Aoki, K.; Kameyama, H.;
Komura, K. Chem. Lett. 1996, 549−550.
(3) (a) Fleming, P.; O’Shea, D. F. J. Am. Chem. Soc. 2011, 133,
1698−1701. (b) Blangetti, M.; Fleming, P.; O’Shea, D. F. Beilstein J.
Org. Chem. 2011, 7, 1249−1254. (c) Tricotet, T.; Fleming, P.; Cotter, J.;
Hogan, A.-M. L.; Strohmann, C.; Gessner, V. H.; O’Shea, D. F. J. Am.
Chem. Soc. 2009, 131, 3142−3143.
(4) For recent reviews on the synthetic uses of mixed metal amides
see (a) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9794−9824. (b) Mulvey, R. E. Acc. Chem. Res.
2009, 42, 743−755. For structural evidence of related lithium−
potassium−TMP compositions, see: (c) Armstrong, D. R.; Kennedy,
A. R.; Mulvey, R. E.; Robertson, S. D. Chem.Eur. J. 2011, 17, 8820−
8831.
(5) (a) MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem.
2001, 66, 3662−3670. (b) Bates, R. B.; Ogle, C. A. J. Org. Chem. 1982,
47, 3949−3952. (c) Kaes, C.; Hosseini, W.; De Cian, A.; Fischer, J.
Tetrahedron Lett. 1997, 38, 4389−4392.
1,3-Dimethoxy-2-methyl-5-phenethylbenzene (6) (Stilbostemin M). 34
Solution A. A solution of 1,3-dimethoxy-2,5-dimethylbenzene (5)
(83 mg, 0.50 mmol) in THF (10 mL) at −78 °C was treated dropwise
with BuLi (2.50 M in hexanes, 0.42 mL, 1.05 mmol) and stirred for
5 min. KO-t-Bu (1.0 M in THF, 1.05 mL, 1.05 mmol) was added
dropwise followed by 2,2,6,6-tetramethylpiperidine (84 μL,
0.50 mmol). The reaction mixture was stirred for 15 min at −78 °C.
Solution B. A solution of toluene (1a) (92 mg, 1.00 mmol) in THF
(10 mL) at −78 °C was treated dropwise with BuLi (2.50 M, 0.44 mL,
1.10 mmol) and stirred for 5 min. KO-t-Bu (1.0 M in THF, 1.10 mL,
1.10 mmol) was added dropwise followed by 2,2,6,6-tetramethylpiper-
idine (0.17 mL, 1.00 mmol). The reaction mixture was stirred for
15 min at −78 °C and transferred via cannula into the solution of
metalated 1,3-dimethoxy-2,5-dimethylbenzene (solution A). The
resulting mixture was immediately quenched with 1,2-dibromoethane
(0.22 mL, 2.50 mmol) and stirred for a further 5 min at −78 °C. The
reaction mixture was warmed to rt and the solvent removed under
reduced pressure. Diethyl ether (30 mL) was added to the residue,
washed with HCl (2 M, 3 × 10 mL), dried over sodium sulfate, and
concentrated to dryness. Purification by silica gel chromatography
eluting with 98:2 pentane/ddiethyl ether gave 6 as a colorless solid
(Rf = 0.50, 52 mg, 41%), mp 77−78 °C, lit.34 mp 77−79 °C).
1H NMR (500 MHz, CDCl3): δ 7.30−7.26 (m, 2H), 7.22−7.16
(m, 3H), 6.34 (s, 2H), 3.77 (s, 6H), 2.95−2.85 (m, 4H), 2.06 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 157.2, 140.8, 139.2, 127.5, 127.3,
124.9, 111.0, 102.9, 54.7, 37.4, 37.0, 6.9. HRMS [M + H]+: 257.1531,
(6) For alternative toluene deprotonations, see: (a) Hage, M.; Ogle,
C. A.; Rathman, T. L.; Hubbard, J. L. Main Group Met. Chem. 1998,
21, 777−782. (b) Broaddus, C. D. J. Am. Chem. Soc. 1966, 88, 4174−
4178. (c) Broaddus, C. D. J. Org. Chem. 1970, 35, 10−15.
́
(d) Lochmann, L.; Petranek, J. Tetrahedron Lett. 1991, 32, 1483−1486.
C17H21O2 requires 257.1542.
2-Methyl-5-phenethylbenzene-1,3-diol (7) (Stilbostemin B).
35
(7) For the use of dibromoethane as an oxidant in conjunction with
transition-metal catalysts, see: (a) Dong, C.-G.; Yeung, P.; Hu, Q.- S.
Org. Lett. 2007, 9, 363−366. (b) Nagano, T.; Hayashi, T. Chem. Lett.
2005, 34, 1152−1153.
A
solution of 1,3-dimethoxy-2-methyl-5-phenethylbenzene (6) (30 mg,
0.12 mmol) in dichloromethane (10 mL) at −78 °C was treated
dropwise with BBr3 (1.0 M in dichloromethane, 0.70 mL, 0.70 mmol).
The reaction mixture was warmed to rt and stirred for 3.5 h. The
reaction was then poured into a saturated solution of sodium
bicarbonate (10 mL) and stirred vigorously for 30 min. The product
was extracted with CH2Cl2, washed with a saturated solution of
sodium bicarbonate (20 mL) and brine (20 mL). The organic layer
was dried over sodium sulfate and concentrated to dryness.
Purification by silica gel chromatography eluting with 1:1 cyclo-
hexane/ethyl acetate gave 7 as a colorless solid (Rf = 0.70, 20 mg,
73%), mp 152−153 °C (lit.35b mp 153−154 °C). 1H NMR (500 MHz,
(8) Guo, D.-X.; Xiang, F.; Wang, X.-N.; Yuan, H.-Q.; Xi, G.-M.;
Wang, Y.-Y.; Yu, W.-T.; Lou, H.-X. Phytochemistry 2010, 71, 1573−
1578.
(9) Alonso, F.; Riente, P.; Yus, M. Eur. J. Org. Chem. 2009, 34, 6034−
6042.
(10) Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org.
Chem. 2003, 68, 5534−5539.
(11) Jin, L.; Zhao, Y.; Zhu, L.; Zhang, H.; Lei, A. Adv. Synth. Catal.
2009, 351, 630−634.
2876
dx.doi.org/10.1021/jo3000805 | J. Org. Chem. 2012, 77, 2870−2877

The Journal of Organic Chemistry
Article
(12) For recent reviews and publications, see: (a) Asakawa, Y.;
Ludwiczuk, A.; Nagashima, F.; Toyota, M.; Hashimoto, T.; Tori, M.;
Fukuyama, Y.; Harinantenaina, L. Heterocycles 2009, 77, 99−150.
(b) Gutierrez, R. M. P. J. Med. Plant. Res. 2010, 4, 592−638. (c) Laclef, S.;
́
Anderson, K.; White, A. J. P.; Barrett, A. G. M. Tetrahedron Lett. 2012, 53,
225−227.
(13) Schultz, T. P.; Boldin, W. D.; Fisher, T. H.; Nicholas, D. D.;
McMurtrey, K. D.; Pobanz, K. Phytochemistry 1992, 31, 3801−3806.
(14) Yamaki, M.; Kato, T.; Bai, L.; Inoue, K.; Shuzo, T.
Phytochemistry 1991, 30, 2759−2760.
(15) Hernandez-Romero, Y.; Rojas, J.-I.; Castillo, R.; Rojas, A.; Mata,
R. J. Nat. Prod. 2004, 67, 160−167.
(16) For reviews, see: (a) Schlosser, M. Mod. Synth. Methods 1992, 6,
227−271. (b) Lochmann, L. Eur. J. Inorg. Chem. 2000, 1115−1126.
(17) (a) Adams, M.; Pacher, T.; Greger, H.; Bauer, R. J. Nat. Prod.
2005, 68, 83−85. (b) Kostecki, K.; Engelmeier, D.; Pacher, T.; Hofer, O.;
Vajrodaya, S.; Greger, H. Phytochemistry 2004, 65, 99−106. (c)
Pharmacopoeia of the Peoples Republic of China, English Ed.; Chemical
Industry Press: Beijing, 2000; p 162.
(18) (a) Song, Y.; Hwang, S.; Gong, P.; Kim, D.; Kim, S. Org. Lett.
2008, 10, 269−271. (b) Crombie, L. W.; Cromcie, W. M. L.; Firth, D. F.
J. Chem. Soc., Perkin Trans. 1 1988, 1263−1270. (c) Tajima, R.; Oozeki,
H.; Muraoka, S.; Tanaka, S.; Motagi, Y.; Nihei, H.; Yamada, Y.; Masuoka,
N.; Nihei, K. Eur. J. Med. Chem. 2011, 46, 1374−1381.
(19) Park, B. H.; Lee, Y. R.; Kim, S. H. Bull. Korean Chem. Soc. 2011,
32, 566−570.
(20) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879−
1880.
(21) Savino, T. G.; Soundararajan, N.; Platz, M. S. J. Phys. Chem.
1986, 60, 919−923.
(22) (a) Sloan, M. E.; Staubitz, A.; Lee, K.; Manners, I. Eur. J. Org.
Chem. 2011, 4, 672−675. (b) Alonso, F.; Riente, P.; Yus, M.
Tetrahedron 2009, 65, 10637−10643.
(23) (a) Aitken, R. A.; Hodgson, P. K. G.; Morrison, J. J.; Oyewale, A.
O. J. Chem. Soc., Perkin Trans. 1 2002, 3, 402−415. (b) Cauber
̀
e, P.;
Moreau, J. Tetrahedron 1970, 26, 2637−2645.
(24) (a) Hannemann, K.; Wirz, J.; Riesen, A. Helv. Chim. Acta 1988,
71, 1841−1857. (b) Gilman, A. J. Org. Chem. 1963, 28, 2906−2907.
(25) Azzena, U.; Pisano, L.; Antonello, S.; Maran, F. J. Org. Chem.
2009, 74, 8064−8070.
(26) Fischer, F. R.; Nuckolls, C. Angew. Chem., Int. Ed. 2010, 49,
7257−7260.
(27) (a) Suh, Y.; Lee, J.; Kim, S.-H.; Rieke, R. D. J. Organomet. Chem.
2003, 684, 20−36. (b) Kricka, L. J.; Ledwith, A. J. Chem. Soc., Perkin
Trans. 1 1973, 294−297.
(28) (a) Barrero, A. F.; Herrador, M. M.; Moral, J. F.; Quilez del
Arteaga, P.; Akssira, M.; Hanbali, F.; Arteaga, J. F.; Dieguez, H. R.;
Sanchez, E. M. J. Org. Chem. 2007, 72, 2251−2254. (b) Iyoda, M.;
Sakaitani, M.; Otsuka, H.; Oda, M. Chem. Lett. 1985, 127−130.
(29) Esumi, T.; Wada, M.; Mizushima, E.; Sato, N.; Kodama, M.;
Asakawa, Y.; Fukuyama, Y. Tetrahedron Lett. 2004, 45, 6941−6946.
(30) Molander, G. A.; Sandrock, D. L. Org. Lett. 2009, 11, 2369−
2372.
(31) Asakawa, Y.; Hashimoto, T.; Takikawa, K.; Tori, M.; Ogawa, S.
Phytochemistry 1991, 30, 235−251.
(32) Juneja, R. K.; Sharma, S. C.; Tandon, J. S. Phytochemistry 1987,
26, 1123−1126.
(33) (a) Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org.
Chem. 1990, 55, 5386−5390. (b) Ridley, D. D.; Ritchie, E.; Taylor, W.
C. Aust. J. Chem. 1968, 21, 2979−2988.
(34) Yang, X.; Lin, L.; Tang, C.; Liu, Y.; Ye, Y. Helv. Chim. Acta 2007,
90, 318−325.
(35) (a) Zhao, W.; Qin, G.; Ye, Y.; Xu, R.; Le, X. Phytochemistry
1995, 38, 711−714. (b) Pacher, T.; Seger, C.; Engelmeier, D.;
Vajrodaya, S.; Hofer, O.; Greger, H. J. Nat. Prod. 2002, 65, 820−827.
2877
dx.doi.org/10.1021/jo3000805 | J. Org. Chem. 2012, 77, 2870−2877