A distinctive method for synthesizing a variety of multisubstituted α-arylnaphthalenes utilizing novel regiocontrolled ipso-type [4 + 2] benzannulation is presented. Ortho- and para-substituted 1-Ar1-1-Ar2-2,2-dichlorocyclopropylmethanols (AACM) were transformed to the corresponding ipso-type α-arylnaphthalenes. (i) The reaction of ortho-AACM using TiCl4 or SnCl4 (1.0 equiv) proceeded smoothly to afford ipso-type α-arylnaphthalenes (seven examples; 49-69% yield) exclusively, without producing conventional benzannulation isomers. (ii) Para-AACM also underwent the reaction successfully to afford the desired ipso-type α-arylnaphthalenes (14 examples; 39-98% yield) without producing conventional benzannulation isomers. (iii) In contrast, meta-AACM underwent the previously reported conventional benzannulation. (iv) The present method exhibited sufficient substrate generality for application to ortho- and para-substituted AACM substrates bearing Me-, Cl-, and MeO- groups. (v) The six key structures were unambiguously confirmed by X-ray structure analyses. (vi) A plausible reaction mechanism for the present ipso-type reaction is proposed and supported by three careful cross-over and comparable experiments. To demonstrate the utility of the present reaction, we achieved the first total synthesis of chaihunaphthone, a uniquely (highly congested) substituted and less accessible natural lignan lactone with three contiguous trimethoxy substituents (total eight steps, overall 6.4% yield).
A distinctive method for synthesizing a variety of multisubstituted α-arylnaphthalenes utilizing novel regiocontrolled ipso-type [4 + 2] benzannulation is presented. Ortho- and para-substituted 1-Ar1-1-Ar2-2,2-dichlorocyclopropylmethanols (AACM) were transformed to the corresponding ipso-type α-arylnaphthalenes. (i) The reaction of ortho-AACM using TiCl4 or SnCl4 (1.0 equiv) proceeded smoothly to afford ipso-type α-arylnaphthalenes (seven examples; 49-69% yield) exclusively, without producing conventional benzannulation isomers. (ii) Para-AACM also underwent the reaction successfully to afford the desired ipso-type α-arylnaphthalenes (14 examples; 39-98% yield) without producing conventional benzannulation isomers. (iii) In contrast, meta-AACM underwent the previously reported conventional benzannulation. (iv) The present method exhibited sufficient substrate generality for application to ortho- and para-substituted AACM substrates bearing Me-, Cl-, and MeO- groups. (v) The six key structures were unambiguously confirmed by X-ray structure analyses. (vi) A plausible reaction mechanism for the present ipso-type reaction is proposed and supported by three careful cross-over and comparable experiments. To demonstrate the utility of the present reaction, we achieved the first total synthesis of chaihunaphthone, a uniquely (highly congested) substituted and less accessible natural lignan lactone with three contiguous trimethoxy substituents (total eight steps, overall 6.4% yield).
Highly
substituted α-arylnaphthalenes have useful applications
as reagents, catalysts, biologically active natural products, pharmaceuticals,
and functionalized materials because of their core structural scaffolds.[1] Regiocontrolled benzannulation strategies provide
distinctive constructions for elaborated α-arylnaphthalenes.[2] Among these strategies, regioselective reactions
starting from accessible monofunctionalized benzene substrates have
a diverse synthetic scope for multisubstituted naphthalene derivatives.Fischer carbene complex-mediated Döts benzannulation[3] and α-diazoketone-mediated Danheiser benzannulation[4] are two pioneering [4 + 2] annulation methods
(Scheme ). Since the
development of these innovative studies, several [4 + 2] approaches
starting from monofunctionalized benzenes have been reported to date.
Five representative benzannulations involve the appropriate alkyne
segments for the construction of multisubstituted naphthalenes: (i)
GaCl3-catalyzed aldehyde–alkyne condensation,[5] (ii) TiCl4-promoted aldehyde–alkyne
condensation,[6] (iii) iron-catalyzed Grignard
coupling with two symmetrical alkynes,[7] (iv) Tf2NH-catalyzed aldehyde–arylated alkyne
condensation,[8] and (v) FeCl3-promoted condensation of alkynyl alcohols concomitant with selenylation.[9]
Scheme 1
[4 + 2]-Type Döts and Danheiser Benzannulations
The present article discloses distinctive ipso-type benzannulations for the syntheses of a variety
of uniquely
substituted and much less accessible α-arylnaphthalenes. Fedorynski
and Anilkumar’s group provided impressive and comprehensive
reviews of the synthetic application of gem-dihalocyclopropanes.[10] Consistent with our longstanding synthetic studies
of regio- and stereoselective gem-dihalocyclopropane
transformations,[11] related drug discovery
and process studies of chiral cyclopropane pyrethroid insecticides,[12] and recent total syntheses of all six chiral
natural pyrethrins,[13] we previously reported
a couple of benzannulation methods (Scheme ).
Scheme 2
Two [4 + 2] Types of Benzannulations
Using Stereodefined AACM-I and
AACM-II
The first-stage non-regiocontrolled
[4 + 2] benzannulation using
(Ar)(Ar)(2,2-dichlorocyclopropyl)methanols (AACM-I) produced symmetrically
substituted α-arylnaphthalenes, including natural lignan lactones,
such as justicidin E and taiwanin C. One representative non-regiocontrolled
benzannulation method using an AACM-I was the subject of a practical
Gram-scale synthetic procedure.[14] The second-stage
regiocontrolled [4 + 2] benzannulation strategy using (Ar1)(Ar2)(2,2-dichlorocyclopropyl)methanols (AACM-II) produced
various unsymmetrically substituted α-arylnaphthalenes. This
strategy was successfully applied for total syntheses of unsymmetrically
substituted natural lignan lactones, such as justicidin B, retrojusticidin
B, and dehydrodesoxypodophyllotoxin.[11e] In addition, chirality exchange [4 + 2] benzannulation using optically
active AACM-II was achieved to produce axially chiral α-arylnaphthalenes
with a nearly complete transfer of chirality.[11d]During the course of our investigations, we recently
encountered
a unique and unusual mode of benzannulation, in which ortho- and para-substituted (Cl-, Me-, and MeO-) and
stereodefined AACM-II 1 and 3 consistently
underwent ipso-type reactions to furnish a variety
of isomeric α-arylnaphthalenes 4 and 5, respectively, which were not produced by hitherto-reported conventional
reactions even under the same reaction conditions, as illustrated
in Scheme .
Scheme 3
General
Mode of Ipso-Type Benzannulations Starting
from Three Stereodefined AACM-II 1–3
The ortho-form AACM-II 1 produced
4-chloro-5-substituted 1-phenylnaphthalene 4 instead
of 4-chloro-8-substituted 1-arylnaphthalene 6 via the
expected conventional benzannulation. However, benzannulation using
the meta-form AACM-II 2 proceeded in
the usual manner to afford 4-chloro-7-substituted 1-arylnaphthalene 5. The para-form AACM-II 3 underwent ipso-type benzannulation to produce 4-chloro-7-substituted
1-arylnaphthalene 5 instead of 4-chloro-6-substituted
1-arylnaphthalene 7 via the expected conventional reaction
pathway.The present eventful mode involves wide substrate generality
as
described in the Results and Discussion section.Application of the present ipso-type benzannulation
to the first total synthesis of chaihunaphthone, an unsymmetrically
substituted lignan lactone, is demonstrated.
Results and Discussion
Basic Investigation of Ipso-Type Regiocontrolled
Benzannulations
Stereodefined AACM-II
and 1 (ortho-form), 2 (meta-form), and 3 (para-form)
were readily prepared through sequential introductions of Ar1 and Ar2 groups by basically following the reported method[11d,11e] (Scheme ). The reaction
of accessible cyclopropanecarbonyl chlorides 9 (derived
from the commercially available acid) and 10 (derived
from methyl angelate) with Ar1MgBr afforded the corresponding
Ar1-substituted ketones 11 and 12, respectively, in good yield (Table ).
Scheme 4
Preparation of Stereodefined AACM-II 1–3
Table 1
Preparation of Ketones 11 and 12
Subsequent addition to ketones 11 and 12 using Ar2Li reagents furnished a variety of
stereodefined
AACM-II 1 and 3 in an acceptable yield with
excellent diastereoselectivity (>95:5) by way of Cram’s
rule[11d,11e] (Table ). The addition
reaction using ketones 11 afforded a wide variety of
AACM-II 1 and 3 in moderate to high yields.
However, ketones 12 smoothly underwent the addition reaction
using para-substituted Ar2Li, resulting
in a good yield, but ortho-substituted Ar2Li resisted the desired addition (no reaction), probably because
of the high stereocongestion.
Table 2
Preparation of Stereodefined
AACM-II 1 and 3
2.2 Equiv of Ar2Li was
used.
2-Me THF solvent was
used instead
of THF.
Prepared by an alternative
reported
method as described in the experimental section.
2.2 Equiv of Ar2Li was
used.2-MeTHF solvent was
used instead
of THF.Prepared by an alternative
reported
method as described in the experimental section.Key regiocontrolled and ipso-type regiocontrolled
benzannulations using AACM-II 1 (ortho-form) and AACM-II 3 (para-form) were
successfully performed (Tables and 4) with the following salient
features. (i) The reaction of AACM-II 1 using TiCl4 (1.0 equiv) or SnCl4 (1.0 equiv) proceeded smoothly
to produce ipso-type products 4 with
nearly exclusive regioselectivity (seven examples; 49–69% yield)
(Table ); compounds 6 were not detected following the conventional benzannulation.
(ii) AACM-II 3 also underwent the reaction successfully
to produce the desired compounds 5 (14 examples; 39–98%
yield) (Table ); compounds 7 were not detected following the conventional benzannulation.
(iii) The present method was consistently applied to 1 and 3 bearing Me–, Cl–, and MeO–
groups.
Table 3
Ipso-Type Regiocontrolled
Benzannulations Using AACM-II 1 (ortho-Form)
SnCl4 was used instead
of TiCl4.
Table 4
Ipso-Type Regiocontrolled
Benzannulations Using AACM-II 3 (para-Form)
SnCl4 was used instead
of TiCl4 in high dilution conditions.
SnCl4 was used instead
of TiCl4.SnCl4 was used instead
of TiCl4 in high dilution conditions.No specific correlation of either
the reactivity or the yield between
EDG (Me– and MeO−) or EWG (Cl−) groups in Ar1 or Ar2 was observed, consistent with the reported
the conventional benzannulation reactions. However, 3,4-dimethoxyphenyl
substrate requires high dilution technique probably because of the
high reactivity (vide infra).Two separate and independent reactions
for ipso-type and conventional benzannulations using
AACM-II 3c and 3m support and justify our
proposed hypothesis
and aforementioned results, in which the same product 5c was obtained with high regioselectivity (Scheme ).
Scheme 5
Two Separate and Independent Reactions
for Ipso-Type
and Conventional Benzannulation
Notably, even (Ar)(2,2-dichlorocyclopropyl)methanols 13 and 16 smoothly underwent a similar ipso-type benzannulation to furnish naphthalenes 14 and 17, respectively, with excellent ipso-regioselectivity
(Scheme ).
Scheme 6
Ipso-Type Benzannulations Using (Ar)(2,2-Dichlorocyclopropyl)methanols
To support the ipso-type benzannulation
pathway
(vide infra, Plausible Reaction Mechanism for Ipso-Type
and Regiocontrolled Benzannulations section), a controlled
reaction was examined using (2,2-dichlorocyclopropyl)(2,4,6-trimethoxyphenyl)methanol 19, which was readily prepared from 9 by AlCl3-catalyzed Friedel–Crafts acylation and LAH reduction
sequence (Scheme ).
The reaction of 19 under identical conditions produced
the expected spiro compound 20 successfully in 70% yield.
Scheme 7
Ipso-Type Reaction Using (2,4,6-Trimethoxyphenyl)methanol
Substrate
Plausible
Reaction Mechanism for Ipso-Type and Regiocontrolled
Benzannulations
Similarly to the
reported conventional benzannulations,[11b][11e] the treatment of ortho-form AACM-II 1 with SnCl4 affords dichloromethylinium
cation A, which in turn forms key benzenonium cationic
intermediate B by the ipso-type mode
through 1,5-cyclization (Scheme ). Reactive dotted carbons adjacent to the R2 position are indicated. In contrast to the conventional benzannulations, ortho- or para-orientation of the R2 substituents contributes to this 1,5-cyclization. Cation B reversibly converts to relatively stable tricyclic carbenium
intermediate C, which immediately rearranges into more
stable cation D by ring fission in a cyclopropane moiety.
Finally, α-arylnaphthalenes 4 are produced by aromatization
with the elimination of HCl.
Scheme 8
Reaction Mechanism for Ipso-Type Benzannulations
Using ortho-Form AACM-II 1 and para-Form AACM-II 3
A similar transformation mechanism for para-form
AACM-II 3 is depicted involving the sequence of cationic
intermediates A′, B′, C′, and D′ for the production of
α-arylnaphthalenes 5. Notably, α-arylnaphthalenes 5 were the very same products derived from meta-form AACM-II 2 through conventional benzannulation.
X-ray Determination of the Structure of Six
Representative α-Arylnaphthalenes
X-ray structure analyses
of six key α-arylnaphthalenes bearing ortho-Me, MeO, and Cl groups, and para-Me, MeO, and Cl
groups were performed to unambiguously confirm the structure. Figure shows the resultant
structures of α-arylnaphthalenes 4a, 4b, 4c, 5a′ (brominated compound derived from 5a), 5b′ (brominated compound derived
from 5b), and 5c. Conformations around the
axial moiety are in good accordance with that of the X-ray structure
of the reported compound.[11b]
Figure 1
X-ray structures
of six key α-arylnaphthalenes.
X-ray structures
of six key α-arylnaphthalenes.
First Total Synthesis of Chaihunaphthone, an
Unsymmetrically Substituted Lignan Lactone
Natural arylnaphthalene
lactones and their analogues have attracted considerable attention
because of their characteristic structures and biologic activities.[2] The total synthesis of unsymmetrically substituted
compounds of β-alkoxy-substituted arylnaphthalene lignan lactones,
such as symmetrically substituted helioxanthin and diphiline, is quite
limited because of their structural complexity. With this background,
we next focused our attention on the total synthesis of chaihunaphthone,
a natural lignan lactone, as a distinctive application for the present ipso-type benzannulation (Scheme ).
Scheme 9
Total Synthesis of Chaihunaphthone
Chaihunaphthone, isolated from the root of Bupleurum scorzonerifolium (Nan-Chai-Hu), exhibits immunosuppressive
effects and a uniquely
(highly congested) substituted α-arylnaphthalene structure.[15] Following a reaction similar to that shown in Scheme , 3,4-methylenedioxyphenylmagnesium
bromide was coupled with acid chloride 10 to afford aryl
cyclopropyl ketone 21 in 94% yield. An addition reaction
of 3,4,5-trimethoxyphenyllithium to 21 led to AACM-II 22 in 66% yield with excellent stereoselectivity.The
key ipso-type benzannulation using 22 was successfully implemented using SnCl4 to produce the
desired α-arylnaphthalene 23 in 60% yield with
excellent regioselectivity.[16] Notably,
undesirable regioisomer 23′ was not detected following
the conventional benzannulation; the orientation effect of the mono para-MeO group toward the ipso-type benzannulation
absolutely predominated over that of the two reactive meta-MeO groups toward the conventional benzannulation. Traditional dibromination
using 23(11) yielded the desired
product 24, including small amounts of poly brominated
byproducts because of highly reactive aromatic rings. Without any
purification, the crude mixture of 24 was treated successively
with KOAc and KOH to yield the diol mixture 25. Mild
but powerful SmI2-mediated debromination[17] of the mixture 25 furnished precursor 26 in a pure form with 21% yield from 22 in three
steps.Final oxidation by Fetizon’s reagent[18] produced chaihunaphthone in 72% yield (total
6.4% yield
from 10). The melting point and spectroscopic data (1H NMR, 13C NMR, and HRMS) of this synthetic specimen
reasonably matched with those of the reported natural product.[15] To the best of our knowledge, this is the first
example of the total synthesis of a stereocongested and less accessible
6,7,8-trimehoxy-substituted natural lignan lactone. We speculate that
the previously reported methodologies are not capable of concise and
straightforward synthesis of β-alkoxy-type lignan lactones.
Conclusions
We achieved a regiocontrolled ipso-type benzannulation
to produce a variety of unique and multisubstituted α-arylnaphthalenes.
The reaction mode apparently differs from the reported conventional
benzannulation mode; ortho- and para-substituted 1,1-diaryl-2,2-dichlorocyclopropylmethanols (AACM) were
transformed to the corresponding ipso-type α-arylnaphthalenes,
whereas the meta-substituted AACM underwent the reaction
in the expected conventional manner. The structure of six multisubstituted
representative α-arylnaphthalenes derived from three ortho-substituted AACM and three para-substituted
AACM was unambiguously established by X-ray analyses.We present
a plausible mechanism supported by three careful cross-over
experiments using AACM and monosubstituted substrates. To demonstrate
the utility of the present reaction, we achieved the first total synthesis
of chaihunaphthone, a stereocongested and less accessible natural
lignan lactone with three contiguous trimethoxy substituents.The present methodology provides diverse syntheses for multisubstituted
and less accessible arylnaphthalenes. Further investigation of the
asymmetric versions of benzannulation using chiral AACM is currently
in progress.
An improved
procedure for the reported method (73%).10e A solution
of acid chloride 9 (1.87 g, 10
mmol) in THF (10 mL) was added to a stirred solution of PhMgBr generated
from Mg (292 mg, 12.0 mmol) and bromobenzene (1.88 g, 12.0 mmol) in
THF (10 mL) at 0–5 °C, and the mixture was stirred at
the same temperature for 1 h and then warmed up to 20–25 °C
for ca. 30 min. Sat. NH4Cl aqueous solution was added to
the mixture, which was extracted twice with Et2O. The combined
organic phase was washed with water and brine, dried (NaSO4) and concentrated. The obtained crude oil was purified by SiO2-column chromatography (hexane/AcOEt = 30:1) to give the desired
product 11a (2.19 g, 96%).Colorless oil; 1H NMR (500 MHz, CDCl3): δ = 1.49 (d, J = 7.5 Hz, 1H), 1.65 (s, 3H), 2.30 (d, J = 7.5 Hz, 1H), 7.52–7.57 (m, 2H), 7.60–7.64 (m, 1H),
7.94–7.98 (m, 2H); 13C{1H} NMR (125 MHz,
CDCl3): δ = 20.7, 29.5, 39.7, 62.4, 128.7 (2C), 129.6
(2C), 133.4, 134.4, 195.4.
nBuLi (1.55 M in hexane, 3.94 mL, 6.1 mmol)
was added to a stirred solution of 2-bromotoluene (104 mg, 6.10 mmol)
in THF (4 mL) at −78 °C under an Ar atmosphere, and the
mixture was stirred at the same temperature for 30 min. A solution
of ketone11a (932 mg, 4.1 mmol) in THF (4 mL) was added
to the mixture at −78 °C, followed by stirring at the
same temperature for 1 h, and then warmed up to 20–25 °C
for 1 h. Sat. NH4Cl aqueous solution was added to the mixture,
which was extracted twice with Et2O. The combined organic
phase was washed with water and brine, dried (NaSO4) and
concentrated. The obtained crude solid was purified by SiO2-column chromatography (hexane/AcOEt = 30:1) to give the desired
product 1a (1.10 g, 84%).Colorless crystals; mp
116–118 °C; 1H NMR (500 MHz, CDCl3): δ = 1.26 (s, 3H), 1.46 (d, J = 7.5 Hz,
1H), 2.40 (s, 3H), 2.51 (d, J = 7.5 Hz, 1H), 2.65
(s, 1H), 6.59–6.70 (m, 1H), 6.92–7.00 (m, 1H), 7.08–7.15
(m, 2H), 7.36–7.45 (m, 3H), 7.50–7.64 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ
= 22.9, 24.1, 30.9, 37.0, 67.2, 82.3, 124.9, 127.4 (2C), 127.8 (2C),
128.5 (2C), 130.3, 132.3, 137.0, 144.0, 145.9; IR (neat): νmax = 3566, 3059, 2940, 1485, 1321, 1217, 1086, 1024, 758,
748, 702 cm–1; HRMS (DART): m/z calcd for C18H18Cl2O [M – OH]+ 303.0707; found: 303.0698.
nBuLi (1.57 M in hexane, 8.4 mL, 13.2 mmol)
was added to a stirred solution of 2-bromo-1-chlorobenzene (276 mg,
14.4 mmol) in THF (13 mL) at −78 °C under an Ar atmosphere,
and the mixture was stirred at the same temperature for 1 h. Acid
chloride 9 (562 mg, 3.0 mmol) in THF (6.5 mL) was added
to the mixture, which was stirred at the same temperature for 1 h
and then warmed up to 20–25 °C during 1 h. Sat. NH4Cl aqueous solution was added to the mixture, which was extracted
twice with Et2O. The combined organic phase was washed
with water and brine, dried (NaSO4) and concentrated. The
obtained crude solid was purified by SiO2-column chromatography
(hexane/AcOEt = 30:1) to give the desired product 1f (931
mg, 82%).Colorless crystals; mp 102–108 °C; 1H NMR (500 MHz, CDCl3): δ = 1.17 (s, 3H ×
1/3), 1.23 (d, J = 7.5 Hz, 1H × 2/3), 1.43 (s,
3H × 2/3), 1.52 (d, J = 7.5 Hz, 1H × 1/3),
2.55 (d, J = 7.5 Hz, 1H × 2/3), 2.81 (d, J = 7.5 Hz, 1H × 1/3), 3.24 (s, 1H × 2/3), 3.75
(s, 1H × 1/3), 6.57–6.59 (m, 1H × 1/3), 7.21–7.23
(m, 1H), 7.35–7.49 (m, 5H), 7.74–7.76 (m, 1H), 7.90–7.91
(m, 1H × 2/3); these two atropisomers were settled to one isomer
at high temperature. 1H NMR (500 MHz, DMSO-d6, 150 °C): δ = 1.36 (s, 3H), 1.47 (br s, 1H),
2.66 (br s, 1H), 4.52 (br s, 1H), 7.30–7.51 (m, 7H), 7.75–7.78
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 21.7, 24.1, 27.9, 31.3, 36.0, 39.1, 67.1, 68.0, 78.9,
82.4, 126.1, 126.7, 127.0, 127.5, 128.9, 129.0, 129.2, 129.6, 129.7,
131.1, 130.4, 130.9, 131.2, 131.5, 132.5, 131.6.
TiCl4 (1.0 M in CH2Cl2,
1.4 mL, 1.4 mmol) was added to a stirred solution of AACM 1c (452 mg, 1.34 mmol) in CH2Cl2 (1.4 mL) at
−78 °C under an Ar atmosphere, and the mixture was stirred
at the same temperature for 30 min. Water was added to the mixture,
which was extracted twice with AcOEt. The combined organic phase was
washed with water and brine, dried (Na2SO4)
and concentrated. The obtained crude product was purified by SiO2-column chromatography (hexane) to give the desired product 4c (211 mg, 56%).Colorless crystals; mp 153–154
°C; 1H NMR (500 MHz, CDCl3): δ =
2.14 (s, 3H), 3.97 (s, 3H), 6.84–6.85 (m, 1H), 6.95–6.97
(m, 1H), 7.19–7.23 (m, 3H), 7.40–7.44 (m, 1H), 7.46–7.50
(m, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ = 20.3, 56.1, 106.3, 119.7, 121.3, 126.2, 127.2, 128.4,
128.5 (2C), 130.0 (2C), 131.1, 134.0, 136.6, 137.4, 139.7, 156.3;
IR (neat): νmax = 3001, 2961, 1587, 1570, 1373, 1260,
1086, 770, 746 cm–1; HRMS (DART): m/z calcd for C18H15ClO [M +
H]+ 283.0890; found: 283.0885.
4,5-Dichloro-2-methyl-1-(o-tolyl)naphthalene
(4d)
Following a similar procedure for the preparation of naphthalene4c, the reaction using AACM 1d (356 mg, 1.0 mmol)
and TiCl4 (1.0 M in CH2Cl2, 1.0 mL,
1.0 mmol) in CH2Cl2 (2.0 mL) gave the crude
oil, which was purified by SiO2-column chromatography (hexane)
to give the desired product 4d (153 mg, 51%).Colorless
oil; 1H NMR (500 MHz, CDCl3): δ = 1.88
(s, 3H), 2.09 (s, 3H), 7.04–7.05 (m, 1H), 7.15–7.19
(m, 2H), 7.29–7.33 (m, 1H), 7.34–7.41 (m, 2H), 7.53–7.56
(m, 1H), 7.60–7.61 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ = 19.4, 19.8, 125.99, 126.05,
126.1, 126.2, 127.9, 129.1, 129.7, 130.2, 130.5, 133.2, 134.4, 136.3,
136.5, 137.8, 138.4.; IR (neat): νmax = 3059, 3017,
2918, 1585, 1437, 1373, 910, 812, 764, 752, 733 cm–1; HRMS (DART): m/z calcd for C18H14Cl2 [M]+ 300.0473;
found: 300.0478.
Following a similar procedure for the preparation of naphthalene4c, the reaction using AACM 1g (351 mg, 1.0 mmol)
and TiCl4 (1.0 M in CH2Cl2, 1.0 mL,
1.0 mmol) in CH2Cl2 (2.0 mL) gave the crude
solid, which was purified by SiO2-column chromatography
(hexane) to give the desired product 4g (158 mg, 53%).Colorless crystals; mp 105–107 °C; 1H NMR
(500 MHz, CDCl3): δ = 2.11 (s, 3H), 3.08 (s, 3H),
3.67 (s, 3H), 7.04–7.09 (m, 3H), 7.14–7.17 (m, 1H),
7.21–7.24 (m, 2H), 7.41–7.45 (m, 1H), 7.51–7.52
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 19.9, 26.1, 55.5, 111.1, 120.8, 125.6, 125.7, 128.3,
128.7, 129.0, 129.5, 131.3, 131.6, 133.9, 134.9, 135.8, 157.2; IR
(neat): νmax = 2934, 1506, 1489, 1458, 1435, 1256.
1246, 1026, 907, 754, 737 cm–1; HRMS (DART): m/z calcd for C19H17ClO [M + H]+ 297.1046; found: 297.1041.
4-Chloro-2,7-dimethyl-1-phenylnaphthalene
(5a)
A solution of AACM 3a (577 mg, 1.8 mmol) in
CH2Cl2 (1.8 mL) was added to a stirred solution
TiCl4 (1.0 M in CH2Cl2, 1.8 mL, 1.8
mmol) in CH2Cl2 (1.8 mL) at −78 °C,
and the mixture was stirred at the same temperature for 30 min. Water
was added to the mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The obtained crude product
was purified by SiO2-column chromatography (hexane) to
give the desired product 5a (361 mg, 75%).Colorless
oil; 1H NMR (500 MHz, CDCl3): δ = 2.17
(s, 3H), 2.36 (s, 3H), 7.14–7.15 (m, 1H), 7.22–7.15
(m, 2H), 7.33–7.36 (m, 1H), 7.42–7.46 (m, 2H), 8.15–8.17
(m, 2H), 7.14–7.15 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ = 20.6, 21.8, 124.1, 125.5, 127.2,
127.4, 127.6, 128.0 (2C), 130.1 (2C), 130.7, 133.6, 134.3, 136.3,
136.9, 139.2; IR (neat): νmax = 3055, 2920, 2859,
1030, 907, 868, 814, 758, 702 cm–1; HRMS (DART): m/z calcd for C18H16Cl [M + H]+ 267.0941; found: 267.0937.
4,7-Dichloro-2-methyl-1-phenylnaphthalene
(5b)
Following a similar procedure for the preparation of naphthalene5a, the reaction using AACM 3b (226 mg, 0.66
mmol) and TiCl4 (1.0 M in CH2Cl2,
0.7 mL, 0.7 mmol) in CH2Cl2 (1.4 mL) gave the
crude oil, which was purified by SiO2-column chromatography
(hexane) to give the desired product 5b (160 mg, 84%).Colorless crystals; mp 58–60 °C; 1H NMR
(500 MHz, CDCl3): δ = 2.20 (s, 3H), 7.20–7.22
(m, 2H), 7.37–7.38 (m, 1H), 7.44–7.48 (m, 2H), 7.50–7.53
(m, 3H), 8.20–8.21 (m, 1H), 7.14–7.15 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
= 20.6, 125.4, 126.0, 126.6, 127.5, 127.6, 128.7 (2C), 128.8, 130.0
(2C), 130.8, 132.8, 134.8, 135.0, 136.9, 138.1; IR (neat): νmax = 3075, 2938, 1609, 1597, 1406, 1346, 1088, 945, 907, 874,
815, 702 cm–1; HRMS (DART): m/z calcd for C17H12Cl2 [M]+ 286.0316; found: 286.0339.
A solution of AACM 3c (337 mg, 1.0 mmol) in
CH2Cl2 (5 mL) was added to a stirred solution
SnCl4 (1.0 M in CH2Cl2, 1 mL, 1.0
mmol) in CH2Cl2 (15 mL; Caution: this high dilution was necessary) at 20–25 °C, and
the mixture was stirred at the same temperature for 30 min. Water
was added to the mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The obtained crude product
was purified by SiO2-column chromatography (hexane) to
give the desired product 5c (163 mg, 57%).Colorless
crystals; mp 83–84 °C; 1H NMR (500 MHz, CDCl3): δ = 2.18 (s, 3H), 3.66 (s, 3H), 6.68–6.69
(m, 1H), 7.16–7.18 (m, 1H), 7.23–7.25 (m, 2H), 7.37–7.39
(m, 1H), 7.41–7.45 (m, 1H), 7.48–7.52 (m, 2H), 8.17–8.18
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 20.7, 55.1, 105.5, 117.8, 124.6, 125.9, 126.3, 127.3,
128.6 (2C), 130.0 (2C), 130.7, 134.2, 135.5, 136.5, 139.2, 158.0;
IR (neat) νmax = 3001, 2934, 1620, 1506, 1416, 1227,
1115, 1028, 908, 822, 758, 702 cm–1; HRMS (DART): m/z calcd for C18H16ClO [M + H]+ 283.0890; found: 283.0866.
4-Chloro-2,7-dimethyl-1-(o-tolyl)naphthalene
(5d)
Following a similar procedure for the preparation of naphthalene5a, the reaction using AACM 3d (335 mg, 2.0 mmol)
and TiCl4 (1.0 M in CH2Cl2, 1.0 mL,
1.0 mmol) in CH2Cl2 (2.0 mL) gave the crude
solid, which was purified by SiO2-column chromatography
(hexane) to give the desired product 5d (335 mg, 64%).Colorless oil; 1H NMR (500 MHz, CDCl3): δ
= 1.91 (s, 3H), 2.10 (s, 3H), 2.36 (s, 3H), 6.98–7.00 (m, 1H),
7.07–7.08 (m, 1H), 7.29–7.37 (m, 4H), 7.46–7.47
(m, 1H), 8.15–8.17 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ = 19.5, 20.1, 21.8, 124.2, 125.0,
126.0, 127.52, 127.57, 127.65, 128.1, 130.0, 130.1, 130.6, 133.6,
133.8, 136.2, 136.5, 136.7, 138.5; IR (neat): νmax = 3019, 2918, 2859, 868, 814, 756 cm–1; HRMS (DART): m/z calcd for C19H17Cl [M + H]+ 281.1097; found: 281.1100.
Following a similar procedure for the preparation of naphthalene5a, the reaction using AACM 3h (372 mg, 1.0 mmol)
and TiCl4 (1.0 M in CH2Cl2, 1.0 mL,
1.0 mmol) in CH2Cl2 (2.0 mL) gave the crude
solid, which was purified by SiO2-column chromatography
(hexane) to give the desired product 5h (280 mg, 88%).Colorless crystals; mp 87–91 °C; 1H NMR
(500 MHz, CDCl3): δ = 2.21 (s, 3H), 3.85 (s, 3H),
6.74–6.76 (m, 1H), 6.78–6.81 (m, 1H), 6.98–7.02
(m, 1H), 7.40–7.46 (m, 3H), 7.51–7.52 (m, 1H), 8.19–8.21
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 20.6, 55.3, 113.0, 115.6, 122.4, 125.4, 126.0, 126.7,
127.5, 128.8, 129.8, 130.8, 132.8, 134.7, 136.8, 139.6, 159.8; IR
(neat): νmax = 3001, 2920, 1607, 1578, 1495, 1431,
1285, 1047, 924, 874, 816, 735 cm–1; HRMS (DART): m/z calcd for C18H14Cl2O [M + H]+ 317.0500; found: 317.0480.
4-Chloro-2,7-dimethyl-1-(p-tolyl)naphthalene
(5i)
nBuLi (1.57 M in hexane, 2.8 mL, 4.4 mmol)
was added to a stirred solution of 4-bromotoluene (855 mg, 5.0 mmol)
in THF (2.0 mL) at −78 °C under an Ar atmosphere, and
the mixture was stirred at the same temperature for 0.5 h. Methyl
(S*)-2,2-dichloro-1-methylcyclopropane-1-carboxylate[10b] (366 mg, 2.0 mmol) in THF (2.0 mL) was added
to the mixture, which was stirred at the same temperature for 1 h
and then warmed up to 20–25 °C during 1 h. Sat. NH4Cl aqueous solution was added to the mixture, which was extracted
twice with Et2O. The combined organic phase was washed
with water and brine, dried (NaSO4) and concentrated. The
obtained crude oil in CH2Cl2 (2.0 mL) was added
to stirred solution of TiCl4 (1.0 M in CH2Cl2, 2.0 mL, 2.0 mmol) in CH2Cl2 (2.0 mL)
at −78 °C under an Ar atmosphere, and the mixture was
stirred at the same temperature for 0.5 h. Water was added to the
mixture, which was extracted twice with AcOEt. The combined organic
phase was washed with water and brine, dried (NaSO4) and
concentrated. The obtained crude oil was purified by SiO2-column chromatography (hexane) to give the desired product 5i (287 mg, 51%).Colorless oil; 1H NMR (500
MHz, CDCl3): δ = 2.18 (s, 3H), 2.37 (s, 3H), 2.47
(s, 3H), 7.10–7.12 (m, 2H), 7.18–7.19 (m, 1H), 7.30–7.34
(m, 3H), 7.44–7.45 (m, 1H), 8.14–8.16 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
= 20.6, 21.3, 21.8, 124.1, 125.6, 127.5, 127.6, 128.0, 129.2 (2C),
130.0 (2C), 133.7, 134.4, 136.1, 136.2, 136.7, 137.0; IR (neat): νmax = 3021, 2918, 1624, 1514, 1429, 1356, 1204, 1043, 908,
868, 812, 735 cm–1; HRMS (DART): m/z calcd for C19H17Cl [M + H]+ 281.1097; found: 281.1103.
4-Chloro-2,3,7-trimethyl-1-phenylnaphthalene
(5j)
Following a similar procedure for the preparation of naphthalene5a, the reaction using AACM 3i (335 mg, 1.0 mmol)
and TiCl4 (1.0 M in CH2Cl2, 1.0 mL,
1.0 mmol) in CH2Cl2 (2.0 mL) gave the crude
oil, which was purified by SiO2-column chromatography (hexane)
to give the desired product 5j (275 mg, 98%).Colorless
crystals; mp 119–121 °C; 1H NMR (500 MHz, CDCl3): δ = 2.14 (s, 3H). 2.34 (s, 3H), 2.59 (s, 3H), 7.03–7.05
(m, 1H), 7.19–7.22 (m, 2H), 7.31–7.32 (m, 1H), 7.42–7.45
(m, 1H), 7.48–7.51 (m, 2H), 8.20–8.22 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
= 17.9, 18.9, 21.6, 124.3, 125.7, 127.0, 127.7, 128.1, 128.4 (2C),
130.2 (2C), 130.4, 132.1, 132.6, 133.7, 135.2, 136.8, 140.2; IR (neat):
νmax = 3057, 2920, 1441, 907, 814, 737, 704 cm–1; HRMS (DART): m/z calcd for C18H16Cl [M + H]+ 281.1083;
found: 281.1097.
nBuLi (1.57 M in hexane, 2.8 mL, 4.4 mmol)
was added to a stirred solution of 4-bromotoluene (855 mg, 5.0 mmol)
in THF (2.0 mL) at −78 °C under an Ar atmosphere, and
the mixture was stirred at the same temperature for 0.5 h. Methyl
(1S*,3S*)-2,2-dichloro-1,3-dimethylcyclopropane-1-carboxylate[10b] (394 mg, 2.0 mmol) in THF (2.0 mL) was added
to the mixture, which was stirred at the same temperature for 1 h
and then warmed up to 20–25 °C during 1 h. Sat. NH4Cl aqueous solution was added to the mixture, which was extracted
twice with Et2O. The combined organic phase was washed
with water and brine, dried (NaSO4) and concentrated. The
obtained crude oil in CH2Cl2 (2.0 mL) was added
to stirred solution of TiCl4 (1.0 M in CH2Cl2, 2.0 mL, 2.0 mmol) in CH2Cl2 (2.0 mL)
at −78 °C under an Ar atmosphere, and the mixture was
stirred at the same temperature for 0.5 h. Water was added to the
mixture, which was extracted twice with AcOEt. The combined organic
phase was washed with water and brine, dried (NaSO4) and
concentrated. The obtained crude oil was purified by SiO2-column chromatography (hexane) to give the desired product 3n (447 mg, 76%).Colorless oil; 1H NMR (500
MHz, CDCl3): δ = 2.15 (s, 3H), 2.34 (s, 3H), 2.47
(s, 3H), 2.58 (s, 3H), 7.07–7.11 (m, 3H), 7.29–7.33
(m, 3H), 8.19–8.21 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ = 17.9, 19.0, 21.3, 21.6, 124.3,
125.7, 127.7, 128.0, 129.1 (2C), 130.1 (2C), 130.3, 132.1, 132.7,
133.9, 135.1, 136.6, 136.9, 137.1; IR (neat): νmax = 3021, 2918, 2864, 1514, 1494, 1454, 1317, 1043, 1022, 908, 812,
735 cm–1; HRMS (DART): m/z calcd
for C20H19Cl [M + H]+ 331.0657; found: 311.0634.
NaBH4 (125 mg, 3.3 mmol) was added to a stirred
solution ketone 11d (777 mg, 3.0 mmol) in MeOH (3.0 mL)
at room temperature under an Ar atmosphere, and the mixture was stirred
at the same temperature for 1 h. Water was added to the mixture, which
was extracted twice with ether. The combined organic phase was washed
with water and brine, dried (Na2SO4) and concentrated.
The obtained crude product was purified by SiO2-column
chromatography (hexane/AcOEt = 20:1) to give the desired product 13 (654 mg, 84%).Colorless crystals; mp 57–59
°C; 1H NMR (500 MHz, CDCl3): δ =
1.21 (d, J = 7.5 Hz, 1H), 1.25 (s, 3H), 1.93 (d, J = 7.5 Hz, 1H), 2.42 (br s, 1H), 3.80 (s, 3H), 5.13 (s,
1H), 6.87–6.89 (m, 1H), 7.00–7.04 (m, 1H), 7.25–7.29
(m, 1H), 7.56–7.38 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ = 15.0, 31.7, 35.1, 55.2, 67.4,
71.8, 110.3, 120.6, 128.0, 128.5, 129.0, 155.9; IR (neat): νmax = 3532, 2940, 2878, 2839, 1487, 1462, 1234, 1092, 1028,
916, 814, 756, 735 cm–1; HRMS (DART): m/z calcd for C12H14Cl2O2 [M – OH]+ 243.0344; found: 243.0326.
Following a similar procedure for the preparation of alcohol 13, the reaction using ketone 15 (777 mg, 3.0
mmol) and NaBH4 (125 mg, 3.3 mmol) in MeOH (3.0 mL) gave
the crude oil, which was purified by SiO2-column chromatography
(hexane/AcOEt = 20:1) to give the desired product 16 (605
mg, 77%).Colorless crystals; mp 68–71 °C; 1H NMR (500 MHz, CDCl3): δ = 1.22 (s, 3H),
1.31 (d, J = 7.5 Hz, 1H), 1.70 (d, J = 7.5 Hz, 1H), 2.24 (br s, 1H), 3.82 (s, 3H), 4.73 (s, 1H), 6.89–6.92
(m, 2H), 7.30–7.96 (m, 2H); 13C{1H} NMR
(125 MHz, CDCl3): δ = 14.5, 31.7, 36.2, 55.2, 66.7,
76.8, 113.6(2C), 127.1(2C), 132.8, 159.0; IR (neat): νmax = 3566, 3466, 2938, 1611, 1512, 1385, 1302, 1072, 1034, 959, 831,
770, 752 cm–1; HRMS (DART): m/z calcd for C12H12Cl2O [M – OH]+ 243.0344; found: 243.0363.
1-Chloro-8-methoxy-3-methylnaphthalene
(14)
SnCl4 (1.0 M in CH2Cl2,
1.0 mL, 1.0 mmol) was added to a stirred solution of alcohol 13 (261 mg, 1.0 mmol) and MS4A (1.0 g) in 1,2-dichloroethane
(10 mL) at 80 °C under an Ar atmosphere, and the mixture was
stirred at the same temperature for 30 min. Water was added to the
mixture, which was extracted twice with AcOEt. The combined organic
phase was washed with water and brine, dried (Na2SO4) and concentrated. The obtained crude product was purified
by SiO2-column chromatography (hexane) to give the desired
product 14 (97 mg, 47%).Colorless oil; 1H NMR (500 MHz, CDCl3): δ = 2.43 (s, 3H), 3.95 (s,
3H), 6.82–6.84 (m, 1H), 7.33–7.35 (m, 2H), 7.44–7.46
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 20.9, 55.9, 106.3, 120.7, 121.0, 126.4, 126.6, 129.2,
130.8, 135.8, 137.2, 156,3; IR (neat): νmax = 3063,
3001, 2962, 1587, 1570, 1389, 1373, 1260, 1086, 770, 706 cm–1; HRMS (DART): m/z calcd for C12H11ClO [M + H]+ 207.0577; found:
207.0552.
1-Chloro-6-methoxy-3-methylnaphthalene (17)
Following a similar procedure for the preparation of naphthalene 14, the reaction using alcohol 16 (131 mg, 0.5
mmol), MS4A (0.5 g), and SnCl4 (1.0 M in CH2Cl2, 0.5 mL, 0.5 mmol) in 1,2-dichloroethane (5.0 mL)
gave the crude oil, which was purified by SiO2-column chromatography
(hexane) to give the desired product 17 (53 mg, 51%).Colorless oil; 1H NMR (500 MHz, CDCl3): δ
= 2.46 (s, 3H), 3.92 (s, 3H), 7.05–7.06 (m, 1H), 7.15–7.18
(m, 1H), 7.26–7.28 (m, 1H), 7.41–7.43 (m, 1H), 8.09–8.10
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 21.4, 55.3, 105.5, 118.6, 124.4, 125.1, 125.8, 125.9,
131.5, 136.0, 136.4, 158.2; IR (neat): νmax = 2920,
1628, 1504, 1441, 1265, 1238, 1036, 858, 820 cm–1; HRMS (DART): m/z calcd for C12H11ClO [M – OH]+ 207.0577;
found: 207.0554.
A mixture of naphthalene5a (84 mg, 0.3 mmol), N-bromosuccinimide (53 mg, 0.3
mmol), and AIBN (1 mg, 0.015
mmol) in benzene (0.6 mL) was refluxed for 2 h. After cooling down,
water was added to the mixture, which was extracted twice with AcOEt.
The combined organic phase was washed with water and brine, dried
(Na2SO4) and concentrated. The obtained crude
product was purified by SiO2-column chromatography (hexane)
to give the desired product 5a′ (49 mg, 45%).Colorless crystals; mp 123–124 °C, 1H NMR
(400 MHz, CDCl3): δ = 2.38 (s, 3H), 4.34 (s, 2H),
7.16–7.17 (m, 1H), 7.34–7.36 (m, 2H), 7.42–7.43
(m, 1H), 7.50–7.54 (m, 2H), 7.635–7.642 (m, 1H), 8.18–8.20
(m, 1H).
Following a similar procedure for the preparation of naphthalene5a′, the reaction using naphthalene 5b (229 mg, 0.8 mmol), N-bromosuccinimide (142 mg,
0.8 mmol), and AIBN (7 mg, 0.04 mmol) in benzene (0.6 mL) gave the
crude oil, which was purified by SiO2-column chromatography
(hexane) to give the desired product 5b′ (176
mg, 69%).Colorless crystals; mp 139–140 °C, 1H NMR (500 MHz, CDCl3): δ = 4.33 (s, 2H),
7.33–7.34 (m, 2H), 7.386–7.391 (m, 1H), 7.50–7.57
(m, 4H), 7.70–7.72 (m, 1H), 8.23–8.25 (m, 1H).
AlCl3 (480 mg, 3.6 mmol) and acid chloride 9 (187 mg, 1.0 mmol) was added to a stirred solution 1,3,5-trimethoxybenzene
(505 mg, 3.0 mmol) in CH2Cl2 (2.0 mL) at 0–5
°C under an Ar atmosphere, and the mixture was stirred at the
same temperature for 2 h, and then warmed up to 20–25 °C
for 1 h. 10% NaOH aqueous solution was added to the mixture, which
was extracted three times with CH2Cl2. The combined
organic phase was washed with brine, dried (Na2SO4) and concentrated. The obtained crude product was purified by SiO2-column chromatography (hexane/AcOEt = 5:1) to give the desired
product 18 (221 mg, 69%)Colorless crystals; mp
85–89 °C; 1H NMR (400 MHz, CDCl3): δ = 1.34 (d, J = 7.3 Hz, 1H), 1.49 (s,
3H), 2.50 (d, J = 7.3 Hz, 1H), 3.85 (s, 9H), 6.12
(s, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ = 19.4, 30.6, 41.2, 55.4, 55.9 (2C), 66.0, 90.6 (2C),
110.1, 159.9 (2C), 163.4, 195.5; IR (neat): νmax =
3003, 2941, 1684, 1605, 1585, 1456, 1416, 1229, 1207, 1157, 1132,
974, 756 cm–1; HRMS (DART): m/z calcd for C14H16Cl2O4 [M + H]+ 319.0504; found: 319.0503.
Ketone 18 (848 mg, 2.65 mmol) in THF (5.3 mL)
was added to a stirred solution LiAlH4 (101 mg, 3.0 mmol)
in THF (5.3 mL) at 0–5 °C under an Ar atmosphere, and
the mixture was stirred at the same temperature for 1 h. 15% NaOH
aqueous solution was added to the mixture, which was extracted twice
with AcOEt. The combined organic phase was washed with water and brine,
dried (Na2SO4) and concentrated. The obtained
crude product was purified by SiO2-column chromatography
(hexane/AcOEt = 10:1–5:1) to give the desired product 19 (322 mg, 38%)Colorless crystals; mp 134–137
°C; 1H NMR (500 MHz, CDCl3): δ =
1.05 (d, J = 7.3 Hz, 1H), 1.36 (s, 3H), 1.81 (d, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.83 (s, 6H), 4.85 (d, J = 11.0 Hz, 1H), 5.20 (d, J = 11.0 Hz,
1H), 6.12 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ = 15.9, 30.8, 36.1, 55.3, 55.6 (2C), 67.9, 71.5,
91.1 (2C), 109.0, 158.5 (2C), 160.5; IR (neat): νmax = 3501, 2943, 1609, 1591, 1418, 1217, 1150, 1121, 1032, 754 cm–1; HRMS (DART): m/z calcd for C14H18Cl2O4 [M – OH]+ 303.0555; found: 303.0560.
SnCl4 (1.0 M in CH2Cl2,
1.0 mL, 1.0 mmol) was added to a stirred solution of alcohol 19 (127 mg, 10.4 mmol) in 1,2-dichloroethane (10 mL) at 80
°C under an Ar atmosphere, and the mixture was stirred at the
same temperature for 30 min. Sat. NaHCO3 aqueous solution
was added to the mixture, which was extracted twice with AcOEt. The
combined organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The obtained crude product
was purified by SiO2-column chromatography (hexane/AcOEt
= 2:1) to give the desired product 20 (81 mg, 70%).Colorless crystals; mp 182–184 °C; 1H NMR
(500 MHz, CDCl3): δ = 1.89 (d, J = 1.4 Hz, 3H), 3.35 (s, 2H), 3.69 (s, 6H), 5.24 (q, J = 1.4 Hz, 1H), 5.56 (s, 2H); 13C{1H} NMR (125
MHz, CDCl3): δ = 16.9, 55.9(2C), 60.0, 69.5, 95.1,
103.2 (2C), 122.2, 143.0, 169.8 (2C), 187.9; IR (neat): νmax = 3065, 2978, 2938, 2918, 1668, 1651, 1622, 1591, 1360,
1238, 1211, 1098, 864, 847, 743 cm–1; HRMS (DART): m/z calcd for C13H14Cl2O3 [M + H]+ 289.0398; found:
289.0413.
nBuLi (1.63 M in hexane, 8.2 mL, 13.4 mmol)
was added to a stirred solution of 5-bromo-1,2,3-trimethoxybenzene
(3.21 g, 13.4 mmol) in THF (15 mL) at −78 °C, and the
mixture was stirred at the same temperature for 1 h. A solution of
ketone 21 (2.49 g, 8.67 mmol) in THF (7.5 mL) was added
to the mixture at −78 °C and warmed up to 20–25
°C during about 4 h. Sat. NH4Cl aqueous solution was
added to the mixture, which was extracted twice with Et2O. The combined organic phase was washed with water and brine, dried
(Na2SO4) and concentrated. The obtained crude
product was purified by silica-gel column chromatography (hexane/AcOEt
= 4:1) to give the desired product 22 (2.60 g, 66%).Colorless crystals; mp 150–152 °C; 1H NMR
(500 MHz, CDCl3): δ = 1.19 (s, 3H), 1.52 (q, J = 6.87 Hz, 1H), 1.77 (d, J = 6.87 Hz,3H),
2.74 (s, 1H), 3.78 (s, 6H), 3.86 (s, 3H), 6.01 (d, J = 1.15 Hz, 1H), 6.02 (d, J = 1.15 Hz, 1H), 6.47
(s, 2H), 6.87 (d, J = 8.02 Hz, 1H), 6.96 (d, J = 1.72 Hz, 1H), 7.05 (dd, J = 1.72, 8.02
Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 11.1, 27.0, 36.2, 38.3, 56.1 (2C), 60.8, 73.7, 83.8,
101.2, 106.0 (2C), 107.5, 109.7, 122.3, 137.1, 138.1, 141.9, 147.1,
147.4, 152.2 (2C); IR (neat): νmax = 2936, 1589,
1504, 1454, 1414, 1335, 1232, 1124 cm–1; HRMS (ESI): m/z calcd for C22H24Cl2O6 [M + Na]+ 477.0848; found:
477.0878.
A mixture of α-arylnaphthalene 23 (361
mg, 0.90 mmol), N-bromosuccinimide (641 mg, 3.60
mmol), and AIBN (15 mg, 0.09 mmol) in CCl4 (9 mL) was refluxed
for 2 h. After cooling down, water was added to the mixture, which
was extracted twice with CHCl3. The combined organic phase
was washed with 1 M HCl aqueous solution, water, 3% Na2S2O3 aqueous solution, and brine, dried (Na2SO4) and concentrated. The obtained crude product 25 was used in the next step without any purification. A suspension
of the obtained crude product 25 (672 mg) and KOAc (353
mg, 3.60 mmol) in DMF (3.6 mL) was stirred at room temperature for
2 h. KOH (303 mg, 5.40 mmol) in water (1.8 mL) and MeOH (3.4 mL) was
added to the stirred mixture at 20–25 °C, and the mixture
was stirred at the same temperature for 2 h. 1 M HCl aqueous solution
was added to the mixture, which was extracted twice with Et2O. The combined organic phase was washed three times with water and
brine, dried (Na2SO4) and concentrated. The
obtained crude product 25 was used in the next step without
any purification. HMPA (1.53 mL, 8.80 mmol) was added to a solution
of SmI2 in THF (ca. 0.1 M, 22 mL), which
was stirred at 20–25 °C for 15 min. To the resultant solution,
a solution of the crude solid 26 (238 mg) in THF (1.0
mL) and the mixture was stirred for 15 min. Then, 2-propanol (0.34
mL, 4.40 mmol) was added to the mixture, and the mixture was stirred
at the same temperature for 1 h. 1 M HCl aqueous solution was added
to the mixture, which was extracted twice with Et2O. The
combined organic phase was washed with water, 3% Na2S2O3 aqueous solution, and brine, dried (Na2SO4) and concentrated. The obtained crude product was
purified by silica-gel column chromatography (hexane/AcOEt = 1:2)
to give the desired product 26 (75 mg, 21%).Colorless
crystals; mp 184–187 °C; 1H NMR (500 MHz, CDCl3): δ = 2.36 (s, 1H), 3.14 (s, 1H), 3.34 (s, 3H), 3.86
(s, 3H), 3.98 (s, 3H), 4.52 (d, J = 12.0 Hz, 1H),
4.56 (d, J = 12.0 Hz, 1H), 4.88 (d, J = 12.6 Hz, 1H), 4.92 (d, J = 12.6 Hz, 1H), 6.02
(d, J = 1.7 Hz, 1H), 6.04 (d, J =
1.7 Hz, 1H), 6.70 (dd, J = 1.7, 7.5 Hz, 1H), 6.78
(d, J = 1.7 Hz, 1H), 6.86 (d, J =
7.5 Hz, 1H), 6.98 (s, 1H), 7.72 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ = 55.9, 60.0, 60.8, 61.0,
65.2, 101.0, 103.1, 107.3, 109.9, 121.7, 123.2, 128.2, 131.2, 134.3,
135.9, 137.1, 137.7, 143.1, 146.1, 146.8, 150.2, 153.4; IR (neat):
νmax = 3343, 2937, 1607, 1562, 1487, 1379, 1227,
1138 cm–1; HRMS (ESI): m/z calcd
for C22H22O7 [M +
Na]+ 421.1263; found: 421.1263.
Authors: Gerhard Bringmann; Anne J Price Mortimer; Paul A Keller; Mary J Gresser; James Garner; Matthias Breuning Journal: Angew Chem Int Ed Engl Date: 2005-08-26 Impact factor: 15.336
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