Synthesis of a landomycinone skeleton via Masamune-Bergmann cyclization

Article abstract of DOI:10.1039/c4ra04066j

In this report, a synthetic study of landomycinone via Masamune-Bergmann cyclization is described. A 10-membered 1,2-dialkynylbenzene derivative was designated as a key intermediate in the formation of an angular tetracyclic core via Masamune-Bergmann cyclization. Cyclization was expected to proceed under mild heating conditions based on a DFT transition state analysis of the 10-membered enediyne. The enediyne was successfully prepared by intramolecular NHK cyclization in good yield and underwent Masamune-Bergman cyclization at 70 °C for 2 h. However, an undesired β-elimination of the secondary alcohol was involved in the cyclization. In addition, iodination at the 12 position did not occur due to the steric hindrance of two methyl groups. This methodology should be widely applicable to the synthesis of various types of highly oxy-functionalized anthraquinone derivatives as well as landomycinone, and should be a useful way to clarify structure-activity relationships. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra04066j

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Synthesis of a landomycinone skeleton via
Masamune–Bergmann cyclization†
Cite this: RSC Adv., 2014, 4, 32241
a
a
Sho Yamaguchi, Hiroshi Tanaka, Ryo Yamada,b Susumu Kawauchib
*
ac
*
and Takashi Takahashi
In this report, a synthetic study of landomycinone via Masamune–Bergmann cyclization is described. A 10-
membered 1,2-dialkynylbenzene derivative was designated as a key intermediate in the formation of an
angular tetracyclic core via Masamune–Bergmann cyclization. Cyclization was expected to proceed
under mild heating conditions based on a DFT transition state analysis of the 10-membered enediyne.
The enediyne was successfully prepared by intramolecular NHK cyclization in good yield and underwent
Masamune–Bergman cyclization at 70 ꢀC for 2 h. However, an undesired b-elimination of the secondary
alcohol was involved in the cyclization. In addition, iodination at the 12 position did not occur due to the
steric hindrance of two methyl groups. This methodology should be widely applicable to the synthesis of
various types of highly oxy-functionalized anthraquinone derivatives as well as landomycinone, and
should be a useful way to clarify structure–activity relationships.
Received 3rd May 2014
Accepted 30th June 2014
DOI: 10.1039/c4ra04066j
www.rsc.org/advances
difficulty in the formation of an angucyclic skeleton. Roush
Introduction
¨
et al. reported the synthesis of landomycinone based on Dotz
annulation and intramolecular Michael addition under basic
conditions, which involved the formation of a fully aromatized
Landomycin A (1), which was isolated in 1990, is an angucyclic-
type antibiotic that exhibits potent antitumor and antibacterial
activity, as well as inhibition of G1/S cell-cycle progression
resulting in the induction of apoptosis (Scheme 1).1 It is
composed of a highly oxy-functionalized aglycon portion,
namely landomycinone (2), and a structurally unique, complex
deoxyhexasaccharide.2 Biological evaluation of related natural
products varying at the deoxyoligosaccharide revealed the
importance of the length of the saccharide chain. However, the
structure–activity relationships of the aglycon portion have not
been claried due to the low availability of its derivatives.
Therefore, an effective methodology for the synthesis of land-
omycinone and its related compounds is required.
The aglycon portion of landomycinone involves a highly
substituted angular tetracyclic core (Scheme 1, A–D ring). The B
ring would be easily aromatized by b-elimination of the hydroxyl
group at the 6 position. In addition, the steric repulsion
between the oxygen functions at the 1 and 11 positions creates
aDepartment of Applied Chemistry, Graduate School of Science and Engineering, Tokyo
Institute of Technology, 2-12-1-H-101, Ookayama, Meguro-ku, Tokyo 152-8552, Japan.
E-mail: thiroshi@apc.titech.ac.jp; Fax: +81-(0)3-5734-2884; Tel: +81-(0)3-5734-2471
bDepartment of Polymer Chemistry, Graduate School of Science and Engineering,
Tokyo Institute of Technology, 2-12-1-E4-6, Ookayama, Meguro-ku, Tokyo 152-8552,
Japan
cFaculty of Pharmaceutical Sciences, Yokohama College of Pharmacy 601, Matana-cho,
Totsuka-ku, Yokohama-shi, 245-0066, Japan
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, and compounds characterization, including 1H and 13C NMR
spectra. See DOI: 10.1039/c4ra04066j
Scheme 1 Retrosynthetic plan of synthetic target 4.
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byproduct.3 Roulland et al. applied a [2 + 2 + 2] transition-metal-
catalyzed cycloaddition of alkynes to form
a C12 non-
substituted C ring.4 Yu et al. have recently accomplished the
total synthesis of landomycin A, in which the aglycon was
prepared via a modied Roush's method.5 On the other hand,
we recently reported on the synthesis of a landomycin skeleton
3 without substituents at the 1,3,8,11 positions via Masamune–
Bergman cyclization to provide an angucycline tetracyclic skel-
eton possessing 7,12-diiodide without b-elimination of the C6
hydroxyl group.6 The diiodide was converted to quione via
copper-catalyzed etherication followed by oxidation. Hence, in
this work, we report the synthesis of a landomycinone skeleton
via Masamune–Bergmann cyclization.
Fig. 1 DFT calculation at the uB97XD/6-31G* level by Gaussian 09.
Results and discussion
Retrosynthetic analysis
As shown in Scheme 1, we planned Masamune–Bergman
cyclization of the dialkynylbenzene 6 toward the synthesis of a
fully functionalized landomycin skeleton 4. The dia-
lkynylbenzene 7 would generate the biradical 6 via Masamune–
Bergman cyclization. The biradical 6 could react with 1,2-di-
iodoethane to provide aryl dihalide 5,7 which can be converted
to the naphthoquione derivative 4 via copper-catalyzed Ullmann
etherication followed by oxidation. Highly reactive radical
species could enable oxidation at the sterically hindered 12
position. The 10-membered 1,2-dialkynyl-benzene derivative 7
could be prepared from the intramolecular Nozaki–Hiyama–
Kishi (NHK) cyclization precursor 8, possessing both the
iodoacetylene and aldehyde moieties. The palladium-catalyzed
Sonogashira coupling with benzaldehyde unit 9 (A ring) and
phenylacetylene unit 10 (D ring) could furnish the biaryl alkyne.
Benzaldehyde unit 9 and phenylacetylene 10 could be prepared
from commercially available 3,5-dimethylphenol 17 and 2,5-
dimethoxybenzaldehyde 15 respectively.
Scheme 2 Synthesis of A ring 9.
The synthesis of the substrate 10 (D ring), which is a
precursor of Sonogashira coupling, was shown in Scheme 3. A
benzyl alcohol 18 was prepared from 3,5-dimethylphenol 17 in 3
steps, as noted in a previous report.10 The iodination with n-
BuLi and I2 followed by the oxidation of benzyl alcohol provided
the 2-iodobenzaldehyde 20. Next, hydrolysis under acidic
Computational analysis
We performed transition state analysis of the Masamune–
Bergman cyclization of the 10-membered 1,2-dialkynyl-benzene
derivatives 7 and 12 to biradicals 11 and 13 based on DFT
calculation at the B3LYP/6-31G(d) level by Gaussian 03 (Fig. 1).8
The two types of activation energy for the Masamune–Bergman
reactions were approximately equal to each other at
26.1 kJ mmolꢁ1 and 26.9 kJ mmolꢁ1, respectively. These results
indicate that the 10-membered 1,2-dialkynyl-benzene deriva-
tives 7 and 12 both would undergo Masamune–Bergman cycli-
zation under mild heating conditions.
Scheme and discussion
The synthesis of benzaldehyde unit 9 (A ring) is shown in
Scheme 2.9 The aldehyde moiety of 2,5-dimethoxybenzaldehyde
15 was protected as a 6-membered ring acetal with 1,3-propane
diol and p-toluenesulfonic acid to give the desired substrate in a
72% yield. Then, the bromination with (BrCF2)2 followed by the
deprotection of an acetal afforded the desired A ring unit 9 in 2
steps in a 34% yield.
Scheme 3 Synthesis of D ring 10.
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Scheme 4 Intermolecular NHK cyclization and Masamune–Bergman cyclization.
conditions, following the Wittig reaction with MeOCH2PPh3Cl,
The NHK cyclization was examined. Treatment of the
afforded the aldehyde 21 in an 80% yield in 2 steps.11 Then, the precursor 8 with 9.0 equivalents of CrCl2 and 0.64 equiv. of
aldehyde moiety was converted to a TBS protected primary NiCl2 provided the 10-membered 1,2-dialkynylbenzene deriva-
alcohol by the reduction of the aldehyde and protection of the tive 7 in a 68% yield. Derivative 7 was stable under ambient
primary alcohol in a 72% yield in 2 steps. The treatment of conditions and during silica-gel chromatography. Then, Masa-
iodobenzene 22 with n-BuLi and DMF provided benzaldehyde in mune–Bergman cyclization was examined under our optimized
an 87% yield. Finally, the conversion of the aldehyde moiety to reaction conditions.6 Treatment of the 10-membered 1,2-dia-
an acetylene unit was accomplished with the Ohira–Bestmann lkynylbenzene derivative 7 with 1,2-diiodoethane as a I-source
reagent in a 45% yield.12
The synthesis of intramolecular NHK cyclization precursor 8 ted aromatization compound 28 in a 25% yield.
was examined (Scheme 4).13 Although we initially attempted the
In contrast with a DFT transition state analysis, the actual
and CH3CN as a solvent provided the undesired mono-I inser-
coupling reaction of alkynyl-H 10 and Aryl-Br 9, only an unde- stability of the 10-membered 1,2-dialkynyl-benzene derivative 7
sired homo-coupling product14 was obtained; therefore, a was quite different from 12 in our previous work. The
stannylation of alkynyl-H 10 with n-BuLi and n-Bu3SnCl was compound 7 was stable under ambient air and on silica gel
performed to prevent a homo coupling reaction of alkynyl-H 10. chromatography, and the cycloaromatization proceeded under
The alkynyl-Sn 24, however, was unstable during silica gel harsh conditions. This difference in reactivity seemed to be
chromatography, so the residue was used in situ for the next dependent on the bulky methoxy groups adjacent to the dir-
reaction without purication. The Sonogashira coupling reac- adical. An unexpected compound 28 might be given as a
tion of alkynyl-Sn 24 and Aryl-Br 9 with Pd2(dba)3 and PtBu3 product of the b-elimination of the hydroxyl group in the C-ring
resulted in the desired biaryl coupling product 25 in an efficient followed by cycloaromatization.
manner. Then, treatment of the benzaldehyde 25 with CBr4 and
PPh3 afforded a dibromoalkenyl compound, and conversion of
the dibromoalkenyl to an acetylene with n-BuLi followed by the
Conclusions
deprotection of TBS-groups with TBAF furnished a 41% yield of
the desired substrate 26 in 5 steps from 10. Finally, the iodin-
ation of acetylene followed by the oxidation of primary alcohol
afforded the intramolecular NHK cyclization precursor 8 in an
85% yield.
We have described the synthesis of the landomycinone skeleton
via Masamune–Bergman cyclization. The 10-membered ene-
diyne, which was stable under ambient conditions and during
silica-gel chromatography, was prepared via intermolecular
Sonogashira coupling followed by intramolecular NHK
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cyclization. As expected by the DFT transition state analysis, the same temperature for 10 h, (BrCF2)2 (1.22 mL, 10.3 mmol) in
Masamune–Bergman cyclization proceeded under mild heating THF was added. Aer being stirred at 0 ꢀC for 0.5 h, the reaction
conditions and successfully provided an angular tetracyclic core mixture was concentrated in vacuo. The residue was used for the
with a foothold for the synthesis of 1,4-benzoquinone. This next reaction without further purication.
synthetic method suggests a new approach for the synthesis of
To a stirred solution of the above residue in THF (10.0 mL),
natural products containing the anthraquinone skeleton and conc. HCl (10.0 mL) was added at room temperature. Aer
the synthesis of the more complex oxy-functionalized aromatic being stirred at the same temperature for 10 min, the reaction
derivatives is in progress and will be reported in time.
mixture was poured into diethyl ether. The aqueous layer was
extracted with two portions of diethyl ether. The combined
extract was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was chromatographed on silica gel
with 70 : 30 hexane : ethyl acetate to give 2-bromo-3,6-
dimethoxybenzaldehyde (9) (627 mg, 0.391 mmol, in 2 steps at
34%). 1H NMR (400 MHz, CDCl3) d 10.4 (s, 1H), 7.01 (s, 1H), 6.93
(s, 1H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d
190.9, 155.4, 150.4, 124.8, 117.1, 114.7, 111.4, 57.2, 56.6; IR
(neat): 1696, 1479, 1264, 1032, 806 cmꢁ1; HRMS (ESI-TOF) [M +
H]+ calcd 244.9815, found 244.9787.
Experimental
General
NMR spectra were recorded on a JEOL Model EX-270 (270 MHz
for 1H, 67.8 MHz for 13C) and a JEOL Model ECP-400 (400 MHz
for 1H, 100 MHz for 13C) instrument using the indicated solvent.
Chemical shis are reported in units of parts per million (ppm)
relative to the signal for internal tetramethylsilane (0 ppm for
1H) for solutions in CDCl3. NMR spectral data are reported as
follows: chloroform (7.26 ppm for 1H) or chloroform-d (77.1
ppm for 13C) when the internal standard is not indicated.
Multiplicities are reported by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
and, J, coupling constants in Hertz. IR spectra were recorded on
a Perkin Elmer Spectrum One FT-IR spectrophotometer. Only
the strongest and/or structurally important absorption is
reported as the IR data in cmꢁ1. All reactions were monitored by
thin-layer chromatography carried out on 0.2 mm E. Merck
silica gel plates (60F-254) with UV light, visualized by p-ani-
saldehyde solution, ceric sulfate or 10% ethanolic phospho-
molybdic acid. Merck silica gel 60 (0.063–0.200 mm) was used
for column chromatography. ESI TOF Mass spectra were
measured with Waters LCT Premier TM XE. HRMS (ESI-TOF)
was calibrated with leucine enkephalin (SIGMA) as an internal
standard.
(3-Methoxy-5-methylphenyl)methanol (18)
To a stirred solution of 3,5-dimethoxyanisole (17) (707 mL, 5.00
mmol, 1.00 eq.) in CCl4 (10.0 mL), NBS (890 mg, 5.00 mmol, 1.00
eq.) and a catalytic amount of (PhCOO)2 were added at room
temperature under argon. Aer being stirred at reux for 4 h,
the reaction mixture was poured into diethyl ether and H2O.
The aqueous layer was extracted with two portions of diethyl
ether. The combined extract was washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was used for the
next reaction without further purication.
To a stirred solution of the above residue in dioxane
(10.0 mL) and H2O (10.0 mL), CaCO3 (1.00 g, 10.0 mmol,
2.00 eq.) were added at room temperature under argon. Aer
being stirred at reux for 12 h, the reaction mixture was poured
into diethyl ether and 1 N HCl. The aqueous layer was extracted
with two portions of diethyl ether. The combined extract was
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was chromatographed on silica gel with
70 : 30 hexane : ethyl acetate to give (3-methoxy-5-methyl-
phenyl)methanol (18) (320 mg, 2.10 mmol, 2 steps 42%). 1H
NMR (400 MHz, CDCl3) d 6.76 (s, 1H), 6.72 (s, 1H), 6.65 (s, 1H),
4.61 (s, 2H), 3.79 (s, 3H), 2.32 (s, 3H), 1.90 (br-s, 1H); 13C NMR
(100 MHz, CDCl3) d 159.8, 142.3, 139.7, 120.0, 114.0, 109.2, 69.2,
55.2, 21.4; IR (neat): 3377, 2940, 1613, 1463, 1297, 1166, 1042,
2-(2,5-Dimethoxyphenyl)-1,3-dioxane (16)
To a stirred solution of 2,5-dimethoxybenzaldehyde (15) (3.00 g,
43.3 mmol) in toluene (30.0 mL), 1,3-propane diol (3.00 mL,
43.3 mmol) and a catalytic amount of p-toluenesulfonic acid
were added. Aer being stirred at reux for 12 h, the reaction
mixture was poured into aq. Na2S2O3. The aqueous layer was
extracted with two portions of diethyl ether. The combined
extract was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was chromatographed on silica gel
with 80 : 20 hexane : ethyl acetate to give 2-(2,5-dimethoxy-
phenyl)-1,3-dioxane (16) (2.92 g, 13.0 mmol, 72%). 1H NMR (400
MHz, CDCl3) d 7.19 (d, 1H, J ¼ 2.9 Hz), 6.84–6.77 (m, 2H), 5.83
(s, 1H), 4.21 (m, 2H), 3.97 (m, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 2.20
(m, 1H), 1.38 (m, 1H); 13C NMR (100 MHz, CDCl3) d 153.6, 150.4,
127.5, 115.5, 112.0, 111.7, 96.5, 67.3, 56.1, 55.5, 25.6.
838, 756 cmꢁ1
.
(2-Iodo-3-methoxy-5-methylphenyl)methanol (19)
To a stirred solution of (3-methoxy-5-methylphenyl)methanol
(18) (793 mg, 5.21 mmol) in Et2O (26.0 mL), a 1.63 M solution of
n-BuLi in hexane (7.00 mL, 11.5 mmol) was added at ꢁ78 ꢀC
under argon. Aer being stirred at room temperature for 4 h,
the solution was cooled to 0 ꢀC. THF (13.0 mL) was then added
to the solution and the reaction mixture was stirred for 1 h,
2-Bromo-3,6-dimethoxybenzaldehyde (9)
To a stirred solution of 2-(2,5-dimethoxyphenyl)-1,3-dioxane followed by the slow addition of I2 (1.59 g, 6.25 mmol) dissolved
(16) (1.15 g, 5.14 mmol) in hexane (25.0 mL) and benzene (10.0 in THF (6.50 mL). Aer being stirred at 0 ꢀC for 30 min, the
mL), a 1.63 M solution of n-BuLi in hexane (7.00 mL, 11.5 mmol) reaction mixture was poured into aq. Na2S2O3. The combined
was added at ꢁ25 ꢀC under argon. Aer being stirred at the extract was washed with brine, dried over MgSO4, and
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concentrated in vacuo. The residue was chromatographed on
silica gel with 70 : 30 hexane : ethyl acetate to give (2-iodo-3-
methoxy-5-methylphenyl)methanol (19) (855 mg, 3.07 mmol,
59%). 1H NMR (400 MHz, CDCl3) d 6.91 (s, 1H), 6.58 (s, 1H), 4.65
(d, 2H, J ¼ 5.9 Hz), 3.87 (s, 3H), 2.34 (s, 3H), 1.90 (t, 1H, J ¼ 5.9
Hz); 13C NMR (100 MHz, CDCl3) d 207.7, 157.8, 143.9, 139.7,
121.9, 111.2, 69.5, 56.5, 21.3; IR (neat): 3274, 2912, 1576, 1457,
1309, 1169, 1041, 838 cmꢁ1; HRMS (ESI-TOF) [M + H]+ calcd
556.9698, found 556.9683.
tert-Butyl(2-iodo-3-methoxy-5-methylphenethoxy)dimethyl
silane (22)
To a stirred solution of NaBH4 (167 mg, 4.38 mmol) in EtOH
(5.00 mL), 2-(2-iodo-3-methoxy-5-methylphenyl) acetaldehyde
(21) (635 mg, 2.19 mmol) in EtOH (5.00 mL) was added at 0 C
under argon. Aer being stirred at the same temperature for 1 h,
the reaction mixture was poured into saturated aq. NH4Cl. The
aqueous layer was extracted with two portions of diethyl ether.
The combined extract was washed with brine, dried over MgSO4
and concentrated in vacuo. The residue was used for the next
reaction without further purication.
ꢀ
2-Iodo-3-methoxy-5-methylbenzaldehyde (20)
To a stirred solution of the above residue in DMF (10.0 mL),
TBSCl (396 mg, 2.63 mmol) and imidazole (224 mg, 3.29 mmol)
were added at 0 ꢀC under argon. Aer being stirred at the same
temperature for 1 h, the reaction mixture was poured into 1 N
HCl. The aqueous layer was extracted with two portions of
diethyl ether. The combined extract was washed with saturated
aq. NaHCO3, brine, dried over MgSO4, ltered and concentrated
in vacuo. The residue was chromatographed on silica gel with
90 : 10 hexane : ethyl acetate to give tert-butyl(2-iodo-3-
methoxy-5-methylphenethoxy)dimethylsilane (22) (641 mg, 1.58
mmol, 2 steps 72%). 1H NMR (400 MHz, CDCl3) d 9.75 (t, 1H, J ¼
1.9 Hz), 6.69 (s, 1H), 6.58 (s, 1H), 3.89–3.87 (m, 5H), 2.32 (s, 3H);
13C NMR (100 MHz, CDCl3) d 198.8, 158.5, 139.7, 137.5, 124.2,
110.9, 89.2, 56.4, 54.7, 21.2; IR (neat): 3274, 2912, 1723, 1457,
1309, 1169, 1041, 838 cmꢁ1; HRMS (ESI-TOF) [M + H]+ calcd
407.0903, found 407.0901.
To a stirred solution of (2-iodo-3-methoxy-5-methylphenyl)-
methanol (19) (730 mg, 2.63 mmol) in CH2Cl2 (10.0 mL), a large
amount of MnO2 was added at room temperature under argon.
Aer being stirred at room temperature for 24 h, the solution
was ltered through a pad of Celite and concentrated in vacuo.
The residue was chromatographed on silica gel with 80 : 20
hexane : ethyl acetate to give 2-iodo-3-methoxy-5-methyl-
benzaldehyde (20) (668 mg, 2.42 mmol, 92%). 1H NMR (400
MHz, CDCl3) d 10.2 (s, 1H), 7.30 (s, 1H), 6.87 (s, 1H), 3.92 (s, 3H),
2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 196.5, 158.1, 139.9,
136.1, 132.8, 122.8, 117.1, 56.7, 21.1; IR (neat): 3274, 2912, 1576,
1457, 1309, 1169, 1041, 838 cmꢁ1; HRMS (ESI-TOF) [M + H]+
calcd 276.9726, found 276.9729.
2-(2-Iodo-3-methoxy-5-methylphenyl)acetaldehyde (21)
2-(2-(tert-Butyldimethylsilyloxy)ethyl)-6-methoxy-4-methyl-
benzaldehyde (23)
To a suspension of (methoxymethyl)triphenylphosphonium
chloride (2.41 g, 5.86 mmol) in anhydrous THF (10.0 mL), a 0.5
M solution of KHMDS in toluene (12.9 mL, 6.45 mmol) was
added at ꢁ78 ꢀC. The mixture was stirred at ꢁ78 ꢀC for 1 h, and
then a solution of 2-iodo-3-methoxy-5-methylbenzaldehyde (20)
(1.62 g, 5.86 mmol) in anhydrous THF (10.0 mL) was added. The
reaction was allowed to warm to 0 ꢀC over 3 h, and then hexane
was added (50.0 mL). The resultant mixture was ltered through
Celite and thoroughly washed with hexane. The ltrate was
concentrated in vacuo and the residue was diluted with hexane
(50.0 mL). The resultant mixture was ltered through Celite
again to remove the remaining triphenylphosphine oxide. Aer
evaporation, the residue was used for the next reaction without
further purication.
The residue was taken up in THF (5.00 mL)–H2O (5.00 mL)
and 3 M HCl (5.00 mL) was added. The mixture was reuxed for
2 h, and then quenched with saturated aqueous Na2CO3. The
aqueous layer was extracted with two portions of EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed on silica gel with 5–6% EtOAc–hexane to give 2-(2-iodo-
3-methoxy-5-methylphenyl) acetaldehyde (21) (1.36 mg, 4.69
mmol, 2 steps 80%). 1H NMR (400 MHz, CDCl3) d 9.75 (t, 1H, J ¼
1.9 Hz), 6.69 (s, 1H), 6.58 (s, 1H), 3.89–3.87 (m, 5H), 2.32 (s, 3H);
13C NMR (100 MHz, CDCl3) d 198.8, 158.5, 139.7, 137.5, 124.2,
110.9, 89.2, 56.4, 54.7, 21.2; IR (neat): 3274, 2912, 1723, 1457,
To a stirred solution of tert-butyl(2-iodo-3-methoxy-5-methyl-
phenethoxy)dimethylsilane (22) (504 mg, 1.24 mmol) in Et2O
(3.00 mL), a 1.63 M solution of n-BuLi in hexane (836 mL, 1.36
mmol) was added at ꢁ78 ꢀC under argon. The mixture was stirred
at the same temperature for 30 min, then dimethylformamide
(192 mL, 2.48 mmol) was added. Aer being stirred at same
temperature for 1 h, the reaction mixture was poured into satu-
rated aq. NH4Cl. The aqueous layer was extracted with two
portions of diethyl ether. The combined extract was washed with
saturated aq. NaHCO3, brine, dried over MgSO4, ltered and
concentrated in vacuo. The residue was chromatographed on
silica gel with 90 : 10 hexane : ethyl acetate to give 2-(2-(tert-
butyldimethylsilyloxy)ethyl)-6-methoxy-4-methylbenzaldehyde
1
(23) (333 mg, 1.08 mmol, 87%). H NMR (400 MHz, CDCl3) d
10.5 (s, 1H), 6.68 (s, 1H), 6.65 (s, 1H), 3.86 (s, 3H), 3.80 (t, 2H, J ¼
6.3 Hz), 3.24 (t, 2H, J ¼ 6.3 Hz), 2.34 (s, 3H), 0.84 (s, 9H), ꢁ0.05
(s, 6H); 13C NMR (100 MHz, CDCl3) d 191.5, 163.4, 145.3, 142.7,
125.9, 120.9, 110.2, 63.7, 55.7, 37.3, 25.9, 22.1, 18.2, ꢁ5.50; IR
(neat): 2956, 1721, 1608, 1460, 1257, 1091, 837, 709 cmꢁ1; HRMS
(ESI-TOF) [M + H]+ calcd 309.1886, found 309.1884.
tert-Butyl(2-ethynyl-3-methoxy-5-methylphenethoxy)dimethyl
silane (10)
1309, 1169, 1041, 838 cmꢁ1; HRMS (ESI-TOF) [M + H]+ calcd To a stirred solution of 2-(2-(tert-butyldimethyl silyloxy)ethyl)-6-
290.9882, found 290.9885.
methoxy-4-methylbenzaldehyde (23) (437 mg, 1.42 mmol) in
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MeOH (7.10 mL), Ohira–Bestmann Reagent (300 mg, 1.56
To a stirred solution of the above residue in THF (1.00 mL),
mmol) in MeOH (7.10 mL) and K2CO3 (236 mg, 1.70 mmol) were TBAF (46.8 mg, 0.181 mmol) was added at 0 ꢀC under argon.
added at 0 ꢀC under argon. Aer being stirred at room Aer being stirred at the same temperature for 1 h, the reaction
temperature for 3 h, the reaction mixture was poured into 1 N mixture was poured into saturated aq. NH4Cl. The aqueous
HCl. The aqueous layer was extracted with two portions of layer was extracted with two portions of diethyl ether. The
diethyl ether. The combined extract was washed with brine, combined extract was washed with brine, dried over MgSO4 and
dried over MgSO4, and concentrated in vacuo. The residue was concentrated in vacuo. The residue was chromatographed on
chromatographed on silica gel with 85 : 15 hexane : ethyl silica gel with 85 : 15 toluene : ethyl acetate to give 2-(2-((2-
acetate
to
give
tert-butyl(2-ethynyl-3-methoxy-5-methyl- ethynyl-3,6-dimethoxyphenyl)ethynyl)-3-methoxy-5-methyl-
phenethoxy)dimethyl silane (10) (195 mg, 0.639 mmol, 45%). 1H phenyl)ethanol (26) (13.0 mg, 37.1 mmol, 5 steps 41%). 1H NMR
NMR (400 MHz, CDCl3) d 6.68 (s, 1H), 6.57 (s, 1H), 3.87 (s, 3H), (400 MHz, CDCl3) d 6.85 (d, 1H, J ¼ 9.2 Hz), 6.78 (d, 1H, J ¼ 9.2
3.83 (t, 2H, J ¼ 7.3 Hz), 3.46 (s, 1H), 2.99 (t, 2H, J ¼ 7.3 Hz), 2.32 Hz), 6.70 (s, 1H), 6.60 (s, 1H), 3.94 (t, 2H, J ¼ 6.8 Hz), 3.91 (s, 3H),
(s, 3H), 0.88 (s, 9H), 0.00 (s, 6H); IR (neat): 3312, 2958, 2102, 3.90 (s, 3H), 3.87 (s, 3H), 3.64 (s, 1H), 3.18 (t, 2H, J ¼ 6.8 Hz), 2.35
1609, 1463, 1217, 1091, 837, 771, 668 cmꢁ1; HRMS (ESI-TOF) (s, 3H); 13C NMR (100 MHz, CDCl3) d 160.3, 155.1, 154.1, 142.5,
[M + H]+ calcd 305.1937, found 305.1935.
140.0, 129.0, 128.2, 125.3, 122.8, 118.2, 114.1, 112.3, 110.9,
109.8, 93.7, 91.5, 85.3, 79.0, 63.4, 56.7, 56.4, 56.0, 38.2, 29.7,
22.0; IR (neat): 3446, 3020, 1651, 1217, 771, 669 cmꢁ1; HRMS
(ESI-TOF) [M + H]+ calcd 351.1596, found 351.1593.
2-((2-(2-(tert-Butyldimethylsilyloxy)ethyl)-6-methoxy-4-
methylphenyl) ethynyl)-3,6-dimethoxybenzaldehyde (26)
To
a stirred solution of tert-butyl(2-ethynyl-3-methoxy-5-
2-(2-((2-(Iodoethynyl)-3,6-dimethoxyphenyl)ethynyl)-3-
methoxy-5-methylphenyl)ethanol (27)
methylphenethoxy)dimethylsilane (10) (27.6 mg, 0.0905 mmol)
in THF (1.00 mL), a 1.63 M solution of n-BuLi in hexane (66.6 mL,
0.109 mmol) was added at ꢁ78 ꢀC under argon. The mixture was
stirred at the same temperature for 1 h, then n-Bu3SnCl (29.6 mL,
0.109 mmol) was added. Aer being stirred at the same
temperature for 1 h, the reaction mixture was poured into satu-
rated aq. NH4Cl. The aqueous layer was extracted with two
portions of diethyl ether. The combined extract was washed with
saturated aq. NaHCO3, brine, dried over MgSO4, and was then
ltered and concentrated in vacuo. The residue was ltered
through a pad of alumina and concentrated in vacuo. The residue
was used for the next reaction without further purication.
To a stirred solution of the residue and 2-bromo-3,6-
dimethoxybenzaldehyde (9) (22.2 mg, 0.0905 mmol) in toluene
(1.50 mL), Pd2(dba)3 (0.470 mg, 0.453 mmol, 0.00500 eq.) and
PtBu3 (0.240 mg, 0.996 mmol, 0.0110 eq.) were added at room
temperature under argon. The mixture was stirred at the same
temperature for 12 h, then the residue was ltered through a
pad of Celite and concentrated in vacuo. The residue was used
for the next reaction without further purication.
To a stirred solution of 2-(2-((2-ethynyl-3,6-dimethoxyphenyl)-
ethynyl)-3-methoxy-5-methylphenyl)ethanol (26) (10.2 mg,
0.0291 mmol) in toluene (1.00 mL), morpholine (38.0 mL, 0.437
mmol) and I2 (37.0 mg, 0.146 mmol) were added at room
temperature under argon. Aer being stirred at 50 ꢀC for 1 h, the
reaction mixture was poured into 10% aq. Na2S2O3. The
aqueous layer was extracted with two portions of diethyl ether.
The combined extract was washed with brine, dried over MgSO4
and concentrated in vacuo. The residue was chromatographed
on silica gel with 80 : 20 hexane : ethyl acetate to give 2-(2-((2-
(iodoethynyl)-3,6-dimethoxyphenyl)ethynyl)-3-methoxy-5-methyl-
phenyl)ethanol (27) (11.7 mg, 0.0247 mmol, 85%). 1H NMR (400
MHz, CDCl3) d 6.81 (d, 1H, J ¼ 9.2 Hz), 6.75 (d, 1H, J ¼ 9.2 Hz),
6.72 (s, 1H), 6.61 (s, 1H), 3.97 (t, 2H, J ¼ 6.3 Hz), 3.96 (s, 3H), 3.88
(s, 3H), 3.84 (s, 3H), 3.18 (t, 2H, J ¼ 6.3 Hz), 2.35 (s, 3H); 13C
NMR (68.7 MHz, CDCl3) d 160.6, 155.7, 154.0, 142.7, 140.0,
122.8, 118.3, 115.3, 112.1, 110.8, 109.8, 93.7, 91.4, 89.2, 63.5,
56.7, 56.5, 56.3, 38.2, 22.0, 14.1; IR (neat): 3446, 3020, 1638,
1218, 772, 661 cmꢁ1; HRMS (ESI-TOF) [M + H]+ calcd 477.0563,
found 477.0564.
To a stirred solution of the above residue in CH2Cl2 (1.00
mL), CBr4 (67.6 mg, 0.181 mmol) and PPh3 (94.7 mg, 0.362
mmol) were added at room temperature under argon. Aer
being stirred at the same temperature for 30 min, the reaction
mixture was poured into saturated aq. NaHCO3. The aqueous
2-(2-((2-(Iodoethynyl)-3,6-dimethoxyphenyl)ethynyl)-3-
methoxy-5-methylphenyl)acetaldehyde (8)
layer was extracted with two portions of diethyl ether. The To a stirred solution of 2-(2-((2-(iodoethynyl)-3,6-dimethoxy-
combined extract was washed with brine, dried over MgSO4 and phenyl)ethynyl)-3-methoxy-5-methyl phenyl)ethanol (27) (11.7
concentrated in vacuo. The residue was used for the next reac- mg, 0.0245 mmol) in CH2Cl2 (0.500 mL), NaHCO3 (10.3 mg,
tion without further purication.
0.123 mmol) and Dess–ꢀMartin periodinane (21.0 mg, 0.0490
To a stirred solution of the above residue in THF (2.00 mL), a mmol) were added at 0 C under argon. Aer being stirred at
1.63 M solution of n-BuLi in hexane (138 mL, 0.226 mmol) was room temperature for 1 h, the reaction mixture was poured into
added at ꢁ78 ꢀC under argon. Aer being stirred at the same saturated aq. NaHCO3. The aqueous layer was extracted with
temperature for 30 min, the reaction mixture was poured into two portions of diethyl ether. The combined extract was washed
saturated aq. NH4Cl. The aqueous layer was extracted with two with brine, dried over MgSO4 and concentrated in vacuo. The
portions of diethyl ether. The combined extract was washed with residue was chromatographed on silica gel with 80 : 20
brine, dried over MgSO4 and concentrated in vacuo. The residue hexane : ethyl acetate to give 2-(2-((2-(iodoethynyl)-3,6-dime-
was used for the next reaction without further purication.
thoxyphenyl)ethynyl)-3-methoxy-5-methylphenyl)acetaldehyde
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(8) (7.60 mg, 0.0160 mmol, 65%). H NMR (400 MHz, CDCl3) d 7.61 (d, 1H, J ¼ 9.7 Hz), 7.30 (s, 1H), 7.05 (s, 1H), 6.95 (d, 1H, J ¼
9.80 (t, 1H, J ¼ 1.9 Hz), 6.79 (d, 1H, J ¼ 9.2 Hz), 6.76 (d, 1H, J ¼ 8.2 Hz), 6.77 (d, 1H, J ¼ 8.2 Hz), 4.19 (s, 3H), 4.08 (s, 3H), 3.99 (s,
9.2 Hz), 6.67 (d, 2H, J ¼ 8.2 Hz), 4.02 (d, 2H, J ¼ 1.9 Hz), 3.99 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) d 172.0, 158.6,
3H), 3.84 (s, 6H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.6, 137.7, 134.4, 134.2, 134.1, 132.2, 130.3, 129.7, 123.3,
200.0, 160.6, 155.5, 154.1, 140.4, 136.1, 123.1, 117.7, 115.2, 121.4, 111.4, 107.6, 102.5, 77.6, 56.2, 56.0, 29.7, 21.6; IR (neat):
111.8, 111.1, 110.6, 110.4, 93.1, 92.5, 89.1, 56.4, 56.3, 49.2, 21.9, 3734, 2923, 2851, 1731, 1615, 1560, 1452, 1265, 1099, 801 cmꢁ1
;
14.2; IR (neat): 3453, 1722, 1607, 1463, 1255, 1065, 736 cmꢁ1
HRMS (ESI-TOF) [M + H]+ calcd 475.0406, found 475.0401.
;
HRMS (ESI-TOF) [2 ꢂ M] calcd 917.0836, found 917.0835.
Acknowledgements
1,2-Dialkynylbenzene derivative (7)
This work was nancially supported by a JSPS Research
Fellowship for Young Scientists (DC2).
To a stirred solution of 2-(2-((2-(iodoethynyl)-3,6-dimethoxy-
phenyl)ethynyl)-3-methoxy-5-methyl phenyl)acetaldehyde (8)
(5.40 mg, 0.0114 mmol) in THF (2.80 mL), CrCl2 (12.7 mg, 0.103
mmol) and NiCl2 (0.940 mg, 0.00730 mmol) were added at room
temperature under argon. Aer being stirred at the same
temperature for 10 min, the reaction mixture was poured into
H2O. The aqueous layer was extracted with two portions of
diethyl ether. The combined extract was washed with brine,
dried over MgSO4 and concentrated in vacuo. The residue was
chromatographed on silica gel with 50 : 50 hexane : ethyl
acetate to give 1,2-dialkynylbenzene derivative (7) (2.70 mg,
0.00776 mmol, 68%, rotamer 55 : 45). The ratio of rotamers was
determined by 1H NMR analysis. Major: 1H NMR (400 MHz,
CDCl3) d 6.81–6.62 (m, 4H), 4.87 (br-s, 1H), 3.97 (m, 1H), 3.89–
3.84 (m, 9H), 3.29 (dd, 1H, J ¼ 8.8 Hz, J ¼ 13.7 Hz), 2.37 (s, 3H).
Minor: 1H NMR (400 MHz, CDCl3) d 6.81–6.62 (m, 4H), 4.65 (d,
1H, J ¼ 10.2 Hz), 4.08 (m, 1H), 3.89–3.84 (m, 9H), 3.01 (d, 1H, J ¼
13.2 Hz), 2.37 (s, 3H).; 13C NMR (100 MHz, CDCl3) d 173.7, 160.3,
159.9, 152.8, 152.6, 152.3, 146.9, 146.8, 140.8, 140.0, 139.7,
138.0, 127.2, 124.7, 120.7, 118.3, 112.4, 112.0, 111.6, 110.7,
110.3, 105.8, 105.3, 98.5, 98.2, 95.6, 95.1, 85.0, 84.0, 83.0, 65.2,
60.4, 59.4, 56.4, 55.9, 48.8, 44.1, 29.7, 21.9, 14.2; IR (neat): 3393,
2929, 1493, 1260, 1101, 771 cmꢁ1; HRMS (ESI-TOF) [M + H]+
calcd 349.1440, found 349.1447.
Notes and references
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T. Takahashi, Synlett, 2012, 23, 1327.
7-Iodo-1,8,11-trimethoxy-3-methyltetraphene (28)
To a stirred solution of 2-(2-((2-(iodoethynyl)-3,6-dimethoxy-
phenyl)ethynyl)-3-methoxy-5-methyl phenyl)acetaldehyde (7)
(7.60 mg, 0.0160 mmol) in THF (3.20 mL), CrCl2 (17.7 mg, 0.144
mmol) and NiCl2 (1.33 mg, 0.0102 mmol) were added at room
temperature under argon. Aer being stirred at the same
temperature for 10 min, the reaction mixture was poured into
H2O. The aqueous layer was extracted with two portions of
diethyl ether. The combined extract was washed with brine,
dried over MgSO4 and concentrated in vacuo. The residue was
used for the next reaction without further purication.
To a stirred solution of the residue in CH3CN (3.20 mL), a
large amount of 1,2-diiodoethane was added at room temper-
ature under argon. Aer being stirred at 70 ꢀC for 2 h, the
reaction mixture was poured into H2O. The aqueous layer was
extracted with two portions of diethyl ether. The combined
extract was washed with brine, dried over MgSO4 and concen-
trated in vacuo. The residue was chromatographed on silica gel
with 80 : 20 hexane : ethyl acetate to give 7-iodo-1,8,11-trime-
thoxy-3-methyltetraphene (28) (1.64 mg, 0.00272 mmol, 25%).
1H NMR (400 MHz, CDCl3) d 10.7 (s, 1H), 8.68 (d, 1H, J ¼ 9.7 Hz),
7 (a) N. Darby, C. U. Kim, J. A. Salaun, K. W. Shelton, S. Takada
and S. Masamune, J. Chem. Soc. D, 1971, 23, 1516; (b)
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Int. Ed. Engl., 1996, 35, 1835; (f) I. A. Maretina and
B. A. Tromov, Russ. Chem. Rev., 2006, 75, 825; (g)
H. Tanaka, Y. Tanaka, M. Minoshima, S. Yamaguchi,
S. Fuse, T. Doi, S. Kawauchi, H. Sugiyama and
T. Takahashi, Chem. Commun., 2010, 46, 5942.
8 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
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X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr,
This journal is © The Royal Society of Chemistry 2014
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Paper
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, 13 K. C. Nicolaou, A. Liu, Z. Zeng and S. McComb, J. Am. Chem.
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K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, 14 Data of homo-coupling product: to a stirred solution of
J. Tomasi, M. Cossi, N. Rega, N. J. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
PdCl2(PPh3)2 (4.60 mg, 0.00649 mmol, 0.0100 eq.) and CuI
(3.70 mg, 0.0195 mmol, 0.0300 eq.) was added DMF (1.50
mL), Et2NH (134 mL, 1.30 mmol, 2.00 eq.), 2-bromo-3,6-
dimethoxy benzaldehyde (9) (159 mg, 0.649 mmol, 1.00
eq.) and tert-butyl(2-ethynyl-3-methoxy-5-methylphenethoxy)-
dimethyl silane (10) (129 mg, 0.423 mmol, 0.652 eq.) at
¨
J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas,
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10 G. Qabaja, E. M. Perchellet, J. Perchellet and G. B. Jones,
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12 (a) S. Ohira, Synth. Commun., 1989, 19, 561; (b) S. Muller,
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Synthesis, 2004, 59.
room temperature under argon. Aer being stirred at 80 C
for 6 h, the reaction mixture was poured into 1 N HCl. The
aqueous layer was extracted with two portions of diethyl
ether. The combined extract was washed with brine, dried
over MgSO4 and concentrated in vacuo. The residue was
chromatographed on silica gel with 85 : 15 hexane : ethyl
acetate to give homocoupling product (90.8 mg, 0.149
1
mmol, 23%). H NMR (400 MHz, CDCl3) d 6.69 (s, 2H), 6.55
(s, 2H), 3.86 (s, 6H), 3.84 (t, 4H, J ¼ 6.8 Hz), 2.99 (t, 4H, J ¼
6.8 Hz), 2.32 (s, 6H), 0.87 (s, 18H), 0.01 (s, 12H); IR (neat):
3688, 2857, 1607, 1463, 1255, 1090, 775 cmꢁ1; HRMS (ESI-
TOF) [M + H]+ calcd 624.3904, found 624.3921.
32248 | RSC Adv., 2014, 4, 32241–32248
This journal is © The Royal Society of Chemistry 2014