Synthesis of phenol derivatives from cyclohex-2-enones bearing an alkyne through lewis acid-catalyzed enolization and intramolecular Alder-Rickert reaction

Article abstract of DOI:10.1021/jo301554z

A cationic rhodium(I) complex- or In(OTf)₃-catalyzed synthesis of phenol derivatives from cyclohex-2-enone having an ethoxycarbonyl-substituted alkyne has been achieved. This reaction proceeds via enolization and an intramolecular Alder-Rickert reaction.

Full text of DOI:10.1021/jo301554z

Article
pubs.acs.org/joc
Synthesis of Phenol Derivatives from Cyclohex-2-enones Bearing an
Alkyne through Lewis Acid-Catalyzed Enolization and Intramolecular
Alder−Rickert Reaction
Atsushi Kinbara,† Takehiro Yamagishi,† Naoko Hanzawa,† Etsuko Kawashima,‡ and Hiroaki Miyaoka*,‡
†School of Pharmaceutical Sciences, Ohu University, Misumido 31-1, Tomita-machi, Koriyama, Fukushima 963-8611, Japan
‡School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
S
* Supporting Information
ABSTRACT: A cationic rhodium(I) complex- or In(OTf)3-catalyzed
synthesis of phenol derivatives from cyclohex-2-enone having an
ethoxycarbonyl-substituted alkyne has been achieved. This reaction proceeds
via enolization and an intramolecular Alder−Rickert reaction.
INTRODUCTION
■
The powerful synthetic method for generating highly
substituted benzene derivatives by a cascade reaction
comprising a Diels−Alder reaction of cyclohexa-1,3-dienes
with alkynes and a retro Diels−Alder reaction accompanied by
extrusion of ethylene gas is referred to as the Alder−Rickert
reaction.1 This method has also been applied to the synthesis of
phenol derivatives, which are present in biologically active
compounds,2 natural products,3 and chiral catalysts,4 by
utilizing siloxy-1,3-cyclohexadienes and related compounds as
substrates (eq 1). While these starting materials could be
RESULTS AND DISCUSSION
■
Preparation of requisite cyclohex-2-enone derivatives 6a−d is
shown in Scheme 1. Cyclohexenones 6a and 6c were prepared
by a similar synthetic pathway from known alcohol 1.5 Alcohol
1 was converted to malonate derivative 4 via tosylate 2 and
acetal 3. Malonate derivative 4 was treated with 3-
bromopropyne to give alkyne 5. Cyclohexeone 6a was obtained
by ethoxycarbonylation of 5 and then removal of the acetal.
Cyclohexeone 6c was obtained by using 4-iodobut-1-yne (10)6
in lieu of 3-bromopropyne of the above-mentioned pathway.
Preparation of cyclohexeone 6b was completed from known
ketone 77 in five steps via THP ether 8 and secondary alcohol
9. Cyclohexeone 6d was synthesized from tosylate 2 in six
prepared from 1,3-cyclohexanedione in several steps, it is
synthetically convenient and useful to generate hydroxy-1,3-
cyclohexadienes from appropriate precursors in situ, which are
then subjected to the Alder−Rickert reaction. This approach
obviates the need to isolate the reactive dienes. To the best our
knowledge, performing such a sequence in tandem has not
been previously reported. In the course of our studies
concerning Rh-catalyzed Pauson−Khand reactions, we chanced
upon a remarkable observation in that a one-pot synthesis of
phenol derivatives was achieved starting from cyclohex-2-enone
having an activated alkyne. This reaction proceeded via in situ
steps. Tosylate 11 was treated with 4-methyl-N-2-propyn-1-
ylbenzenesulfonamide (12)8 to give sulfonamide 13. Sulfona-
mide 13 was converted to cyclohexeone 6d via ester 14 and
secondary alcohol 15 according to the above similar method.
We first expected that the Pauson−Khand reaction of enyne
6a would proceed in the presence of Rh catalyst. However,
treatment of 6a with 5 mol % [RhCl(CO)2]2, 20 mol %
P(C6F5)3, and 40 mol % Ag(OTf) in toluene at 100 °C under
CO atmosphere afforded only a trace amount of desired
tricyclic product 16, in addition to phenol derivative 17a
unexpectedly obtained in 56% yield (Scheme 2). A similar
generation of a cyclohexa-1,3-dien-1-ol derivative by Lewis acid-
mediated enolization followed by an intramolecular Alder−
Rickert reaction (eq 2). We describe the experimental results in
this paper.
Received: July 23, 2012
Published: September 24, 2012
© 2012 American Chemical Society
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a
Scheme 1. Preparation of Cyclohex-2-enone Derivatives 6a−d
a
Reagents and conditions: (a) TsCl, Et3N, DMAP, CH2Cl2, rt, 68%; (b) 1,2-bis(trimethylsiloxy)ethane, TMSOTf, CH2Cl2, −70 °C, 96%; (c) diethyl
malonate, NaH, NaI, DMF, 100 °C, 67%; (d) 3-bromopropyne, NaH, NaI, THF, rt, 99%; (e) LDA, ClCO2Et, THF, −78 °C to rt; (f) p-TsOH·H2O,
H2O, acetone, rt, 71% for two steps; (g) NaBH4, CeCl3·7H2O, MeOH, rt; (h) DHP, PPTS, CH2Cl2, rt, 70% for two steps; (i) LDA, ClCO2Et, THF,
−78 °C to rt; (j) PPTS, EtOH, rt, 84% for two steps; (k) Dess−Martin periodinane, pyridine, CH2Cl2, rt, 99%; (l) 4-iodobut-1-yne (10), NaH,
DMF, 50 °C; (m) LDA, ClCO2Et, THF, −78 °C to rt; (n) p-TsOH·H2O, H2O, acetone, rt, 34% for three steps; (o) NaBH4, CeCl3·7H2O, MeOH,
rt; (p) DHP, PPTS, CH2Cl2, rt, 86% for two steps; (q) 4-methyl-N-2-propyn-1-ylbenzenesulfonamide (12), NaH, DMF, 50 °C, 60%; (r) n-BuLi,
ClCO2Et, THF, −78 to 40 °C, 62%; (s) PPTS, EtOH, rt, quant.; (t) Dess−Martin periodinane, pyridine, CH2Cl2, rt, 98%.
Scheme 2. Reaction of Enyne 6a in the Presence of Rh(I)
Catalyst
Table 1. Examination of Catalysts and Screening of
Phosphine Ligands for One-Pot Synthesis of Phenol
Derivative 17a
yield
b
a
entry
catalyst
additive
no
ligand (mol %)
(%)
c
1
[RhCl(CO)2]2
no
no
0
2
AgOTf no
AgOTf no
0
3
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
[RhCl(CO)2]2
50
81
45
37
51
39
12
36
16
31
4
AgOTf P(2-furyl)3 (20)
AgOTf P[O(2-MeC6H4)]3 (20)
AgOTf PPh3 (20)
5
reaction under an Ar atmosphere in lieu of CO gave 17a in 62%
yield. Because we took an interest in the one-pot synthesis of
phenol derivative 17a from 6a, reaction conditions were then
examined in an effort to improve the chemical yield of 17a. The
results are summarized in Table 1.
6
7
AgOTf P(o-tolyl)3 (20)
AgOTf dppe (10)
8
9
AgOTf dppp (10)
10
11
12
AgOTf dppb (10)
When the reaction was performed in the absence of AgOTf,
the desired reaction did not proceed and 72% of starting
material 6a was recovered (entry 1). Furthermore, no reaction
was observed when AgOTf was used in the absence of
[RhCl(CO)2]2, which indicated that cationic Rh(I) is an
essential catalyst. The reaction without P(C6F5)3 ligand
afforded product 17a in 50% yield (entry 3). Investigation of
monodentate phosphine ligands (entries 4−7) revealed that
using P(2-furyl)3 was optimal, giving 17a in 81% yield (entry
AgOTf (rac)-BINAP (10)
AgOTf P(C6F5)2C2H4P(C6F5)2
(10)
a
b
All reactions were carried out under an Ar atmosphere. Isolated
c
yields. 72% of starting material 6a was recovered.
4). Although several bidentate ligands were also examined, the
chemical yields were not improved (entries 8−12).
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It was important to employ high temperature conditions in
order for the present reactions to proceed smoothly. When the
reaction was conducted by lowering the temperature from 100
to 80 °C, 17a was formed in poor yield (37%) with diene 18 in
11% yield (Scheme 3). Reaction at 60 °C resulted in no
As shown in Scheme 4, it was assumed that the cationic
rhodium(I) complex acts as a Lewis acid in this reaction.
Therefore, we investigated other Lewis acid catalysts for the
production of phenol derivative 17a from 6a (Table 2). The
Table 2. Screening of Lewis Acid Catalysts and the Control
Experiment Using Triflic Acid
Scheme 3. Optimization of Reaction Temperature and
Conversion of Intermediate 18 to 17a
Lewis acid (10 mol %)
(0.052−60.a10 mmol) ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ 17a
toluene, 100 ◦C, 2 h
a
entry
Lewis acid
BF3·OEt2
yield (%)
b
1
0
2
3
4
5
6
7
SnCl4
0
TiCl4
0
AlCl3
0
InCl3
0
Al(OTf)3
Cu(OTf)2
Yb(OTf)3·xH2O
In(OTf)3
TfOH
12
27
0
c
8
9
61
a
b
Isolated yields. 31% of starting material 6a was recovered.
10
16
a
b
c
Isolated yields. 80% of starting material 6a was recovered. 79% of
formation of phenol 17a and gave 18 in 11% yield, and 31% of
starting material 6a was recovered. The formation of diene 18
might be accounted for by an intramolecular Diels−Alder
reaction of the diene generated from 6a. Compound 18 was
converted to 17a by heating at 100 °C in toluene. The results
suggested that diene 18 was an intermediate of the present
reaction.
starting material 6a was recovered.
reaction of 6a in toluene at 100 °C with 10 mol % Lewis acid,
which is generally utilized for the Diels−Alder reaction, did not
give desired product 17a (entries 1−5). Interestingly, the use of
Al(OTf)3 and Cu(OTf)2 produced desired product 17a in 12%
and 27% yields, respectively (entries 6 and 7), although use of
Yb(OTf)3 did not produce 17a (entry 8). When In(OTf)3 was
used as the Lewis acid catalyst, the yield of 17a was
considerably improved to 61% (entry 9). Incidentally, although
the use of triflic acid which is a known contaminant of the
Lewis acid-bearing triflate as counterion produced 17a in 16%
yield, the yield was remarkably low in comparison with the
reaction which used In(OTf)3 (entry 10). Thus, cationic
rhodium(I) complex and In(OTf)3 were shown to be two
effective Lewis acid catalysts in this reaction.
We propose a plausible mechanism of this reaction based on
the aforementioned results (Scheme 4). Starting material 6a is
Scheme 4. Proposed Reaction Pathway
Having established two types of suitable conditions for the
present reactions, the use of other cyclohex-2-enone derivatives
as substrates was then investigated (Table 3). Upon treatment
of 6b with [RhCl(CO)2]2 (5 mol %), P(2-furyl)3 (20 mol %),
and Ag(OTf) (40 mol %) in toluene at 100 °C (method A),
product 17b was formed in good yield (83%) (entry 1, method
A). However, the treatment of 6b with In(OTf)3 (10 mol %) in
toluene at 100 °C (method B) gave 17b in low yield (12%)
(entry 1, method B). The reaction of 6c, having a one-carbon
elongated tether moiety compared to 6a, under the conditions
of method A gave 17c in 12% yield (entry 2, method A), and in
the case of method B, 17c was not obtained (entry 2, method
B). The reaction of 6d bearing a tosyl amide under the
conditions of method A gave 17d, albeit with 24% yield (entry
3, method A). On the other hand, the reaction of 6d under the
conditions of method B led to improved chemical yields by up
to 57% (entry 3, method B). Furthermore, also in the case of
the reaction employing excess reaction substrate 6a (1.2 mmol)
under the conditions of methods A and B, 17a was obtained in
82% yield and 65% yield, respectively, similar to chemical yields
of the present reaction which employed 6a on a small scale
(entry 4).
converted into dienol 20 via complex 19, wherein cationic
Rh(I) might act as Lewis acid to activate the ketone and
promote enolization. The intramolecular Diels−Alder reaction
of generated 20 then proceeds under thermal conditions to
afford diene 21, and subsequent retro-Diels−Alder reaction
would give phenol derivative 17a and ethylene gas. With
respect to the transformation of 21 to 17a, it is known that the
retro Diels−Alder reaction is accelerated by the presence of
alkoxide and trimethylsilyloxy substituents at the bridgehead of
bicyclo[2.2.2]octa-2,5-diene.9 The present one-pot synthesis of
phenol derivative 17a can be achieved via enolization of 6a and
subsequent Alder−Rickert reaction.
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of saturated aqueous NaHCO3 solution and stirred for 20 min. The
mixture was extracted with AcOEt, and the organic layer was washed
with H2O and brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by a silica gel
column chromatography (hexane/AcOEt = 1:1) to give tosylate 2
(2.22 g, 68% yield) as a white solid. Tosylate 2 is unstable under air at
room temperature. mp 63−64 °C; IR (KBr) 1680, 1597, 1493, 1451,
1356, 1172 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 7.80 (2H, d, J
= 8.3 Hz), 7.37 (2H, d, J = 8.1 Hz), 6.74 (1H, ddd, J = 10.1, 2.5, 1.5
Hz), 6.04 (1H, dd, J = 10.1, 2.5 Hz), 4.00−4.07 (2H, m), 2.82 (1H,
m), 2.48 (1H, m), 2.46 (3H, s), 2.37 (1H, m), 2.09 (1H, m), 1.78 (1H,
m); 13C NMR (100 MHz, CDCl3) δ ppm: 198.2, 148.0, 145.2, 132.4,
131.0, 129.9, 129.9, 127.8, 127.8, 71.1, 36.1, 35.8, 25.1, 21.6; HRMS
(ESI) m/z calcd for C14H17O4S (M + H)+ 281.0848, found 281.0830;
Anal. Calcd for C14H16O4S: C, 59.98; H, 5.75. Found: C, 59.72; H,
5.79.
Table 3. Rhodium or In(OTf)3-Catalyzed One-Pot Synthesis
of phenol Derivatives 17b−d from Cyclohex-2-enones 6b−d
1,4-Dioxaspiro[4.5]dec-6-en-8-ylmethyl 4-Methylbenzene-
sulfonate (3). To a solution of 2 (2.22 g, 7.93 mmol) in CH2Cl2
(60 mL) was added 1,2-bis(trimethylsilyloxy)ethane (9.0 mL, 36.7
mmol) at −78 °C under an Ar atmosphere. TMSOTf (0.29 mL, 1.59
mmol) was added dropwise to the mixture at the same temperature,
and the mixture was stirred at −70 °C for 30 h. The reaction mixture
was treated with addition of pyridine (1.0 mL). After concentration of
solvent under reduced pressure, the residue was purified by a silica gel
column chromatography (hexane/AcOEt = 1:1) to give acetal 3 (2.47
g, 96% yield) as a colorless oil. Acetal 3 is unstable under air at room
temperature. IR (neat) 1598, 1495, 1452, 1361, 1177 cm−1; 1H NMR
(400 MHz, CD3OD) δ ppm: 7.76 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J =
8.0 Hz), 5.67 (1H, dd, J = 10.4, 1.5 Hz), 5.60 (1H, dd, J = 10.4, 1.5
Hz), 3.82−3.93 (6H, m), 2.43 (3H, s), 2.40 (1H, m), 1.73−1.81 (2H,
m), 1.62 (1H, m), 1.44 (1H, m); 13C NMR (100 MHz, CD3OD) δ
ppm: 146.6, 134.3, 131.8, 131.3, 131.1, 131.1, 129.0, 129.0, 106.2, 73.9,
65.6, 65.4, 36.6, 32.9, 24.4, 21.6; HRMS (ESI) m/z calcd for
C16H21O5S (M + H)+ 325.1110, found 325.1124.
a
In the presence of [RhCl(CO)2]2 (5 mol %), AgOTf (40 mol %),
b
and P(2-furyl)3 (20 mol %). In the presence of In(OTf)3 (10 mol %).
c
d
Isolated yields. Reactions were carried out using 0.057−0.10 mmol
of reaction substrates.
Diethyl 2-(1,4-Dioxaspiro[4.5]dec-6-en-8-ylmethyl)malonate
(4). To a solution of diethyl malonate (1.3 mL, 8.37 mmol) in DMF
(15 mL) was added NaH (365 mg, 8.37 mmol) at 0 °C under an Ar
atmosphere. After stirring at room temperature for 1 h, to the mixture
were added a solution of 3 (2.47 g, 7.61 mmol) in DMF (10 mL) via a
cannula and NaI (1.14 g, 7.61 mmol) at 0 °C. The mixture was stirred
at 100 °C for 14 h. After cooling the reaction mixture to room
temperature, the reaction mixture was quenched by addition of
saturated aqueous NH4Cl solution, the mixture was extracted with
AcOEt, and the organic layer was washed with H2O and brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by a silica gel column chromatography (hexane/
AcOEt = 3:1) to give 4 (1.59 g, 67% yield) as a colorless oil: IR (neat)
CONCLUSION
■
In summary, we have achieved the one-pot synthesis of phenol
derivatives from compounds possessing cyclohex-2-enone and
ethoxycarbonyl-substituted alkyne moieties. This cascade
reaction proceeds via enolization and an intramolecular
Alder−Rickert reaction. Furthermore, the cationic rhodium(I)
complex and In(OTf)3 were found to be two effective Lewis
acid catalysts in this reaction. It is possible to synthesize phenol
derivatives which have an indane unit, a 1,2,3,4-tetrahydronaph-
thalene unit, or an isoindoline unit from the corresponding
substrates using this reaction.
1
1732 cm−1; H NMR (400 MHz, CDCl3) δ ppm: 5.81 (1H, dd, J =
EXPERIMENTAL SECTION
General Information. All reagents were obtained from
commercial sources and used as received unless stated otherwise. H
10.1, 2.5 Hz), 5.60 (1H, dd, J = 10.1, 1.6 Hz), 4.17−4.23 (4H, m),
3.88−4.02 (4H, m), 3.45 (1H, t, J = 7.6 Hz), 1.99−2.13 (2H, m),
1.85−1.92 (3H, m), 1.72 (1H, m), 1.48 (1H, m), 1.26 (6H, t, J = 7.1
Hz); 13C NMR (100 MHz, CDCl3) δ ppm: 169.3, 169.2, 135.4, 128.0,
105.4, 64.6, 64.4, 61.4, 61.4, 49.6, 34.0, 33.2, 32.3, 26.6, 14.0, 14.0;
HRMS (ESI) m/z calcd for C16H24O6Na (M + Na)+ 335.1471, found
335.1486; Anal. Calcd for C16H24O6: C, 61.52; H, 7.74. Found: C,
61.75; H, 7.85.
■
1
and 13C NMR spectra were recorded on a 400 MHz spectrometer.
Chemical shifts are given on the δ (ppm) scale using tetramethylsilane
(TMS) as the internal standard (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad). Coupling constants (J) are reported
in hertz (Hz). Infrared spectra were recorded on a Fourier transform
infrared (FTIR) spectrometer. Absorption band positions are reported
in reciprocal centimeters (cm−1). High resolution mass spectra were
obtained on a time-of-flight (TOF) mass instrument equipped with
electrospray ionization (ESI) interface. Melting points were
determined on a melting point apparatus and are uncorrected. Flash
column chromatography was performed using silica gel 60, 40−50 μm.
Thin-layer chromatography analysis was performed on commercial
silica gel 60 F254 glass-backed plates.
Diethyl 2-(1,4-Dioxaspiro[4.5]dec-6-en-8-ylmethyl)-2-(prop-
2-ynyl)malonate (5). To a solution of 4 (500 mg, 1.60 mmol) in
DMF (8.0 mL) was added NaH (69.8 mg, 1.60 mmol) at 0 °C under
an Ar atmosphere, and the mixture was stirred at room temperature for
1 h. To the mixture were added 3-bromopropyne (0.15 mL, 1.92
mmol) and NaI (1.14 g, 7.61 mmol) at 0 °C. The mixture was stirred
at room temperature for 3 h. The reaction mixture was quenched by
addition of saturated aqueous NH4Cl solution, and the mixture was
extracted with AcOEt. The organic layer was washed with H2O and
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by a silica gel column
chromatography (hexane/AcOEt = 3:1) to give 5 (553 mg, 99%
(4-Oxocyclohex-2-enyl)methyl 4-Methylbenzenesulfonate
(2). To a solution of 1 (1.50 g, 11.9 mmol) in CH2Cl2 (60 mL)
were added triethylamine (1.8 mL, 13.1 mmol), p-toluenesulfonyl
chloride (2.50 g, 13.1 mmol), and DMAP (727 mg, 5.95 mmol) at 0
°C under an Ar atmosphere, and the mixture was stirred at room
temperature for 4 h. The reaction mixture was quenched by addition
1
yield) as a colorless oil: IR (neat) 3281, 2122, 1735 cm−1; H NMR
(400 MHz, CDCl3) δ ppm: 5.76 (1H, dd, J = 10.1, 2.0 Hz), 5.55 (1H,
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d, J = 10.1 Hz), 4.15−4.25 (4H, m), 3.89−4.00 (4H, m), 2.88 (2H, t, J
= 2.8 Hz), 2.08−2.27 (3H, m), 2.02 (1H, t, J = 2.8 Hz), 1.81−1.90
(2H, m), 1.70 (1H, m), 1.49 (1H, m), 1.25 (6H, t, J = 7.1 Hz); 13C
NMR (100 MHz, CDCl3) δ ppm: 170.3, 170.1, 136.7, 127.3, 105.1,
78.6, 71.7, 64.5, 64.4, 61.6, 61.6, 56.0, 36.8, 32.4, 31.3, 27.9, 23.1, 13.9,
13.9; HRMS (ESI) m/z calcd for C19H27O6 (M + H)+ 351.1808, found
351.1805; Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C,
64.83; H, 7.54.
Triethyl 5-(4-Oxocyclohex-2-enyl)pent-1-yne-1,4,4-tricar-
boxylate (6a). To a solution of LDA, which was prepared in situ
by mixing i-Pr2NH (0.39 mL, 2.77 mmol) and n-BuLi (1.65 M hexane
solution, 1.60 mL, 2.63 mmol) in THF (8.0 mL) at 0 °C for 30 min,
was added a solution of 5 (462 mg, 1.32 mmol) in THF (5.0 mL) at
−78 °C under an Ar atmosphere. The mixture was stirred at the same
temperature for 1 h. To the mixture was added ethyl chloroformate
(0.38 mL, 3.96 mmol) at −78 °C, and the mixture was stirred at room
temperature for 12 h. The reaction mixture was quenched by addition
of saturated aqueous NH4Cl solution, and the mixture was extracted
with AcOEt. The organic layer was washed with H2O and brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
crude product was used for the next reaction without further
purification.
To a solution of the above crude product in acetone (13 mL) and
H2O (0.9 mL) was added p-TsOH·H2O (25.0 mg, 0.132 mmol) at 0
°C, and the mixture was stirred at room temperature for 18 h. The
reaction mixture was extracted with AcOEt, and the organic layer was
washed with saturated aqueous NaHCO3 solution, H2O, and brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by a silica gel column chromatography
(hexane/AcOEt = 4:1) to give 6a (355 mg, 71% yield, two steps) as a
pale yellow solid: mp 49−50 °C; IR (KBr) 2244, 1753, 1730, 1674
cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 6.77 (1H, dd, J = 10.1, 2.3
Hz), 5.96 (1H, dd, J = 10.1, 2.3 Hz), 4.18−4.29 (6H, m), 3.06 (2H, d,
J = 3.5 Hz), 2.47−2.54 (2H, m), 2.31−2.39 (2H, m), 2.21 (1H, m),
2.10 (1H, m), 1.77 (1H, m), 1.26−1.31 (9H, m); 13C NMR (100
MHz, CDCl3) δ ppm: 198.7, 169.5, 169.4, 153.7, 153.0, 129.3, 82.5,
76.2, 62.2, 62.2, 62.0, 55.8, 36.8, 36.5, 32.1, 29.7, 23.7, 13.9, 13.9, 13.9;
HRMS (ESI) m/z calcd for C20H27O7 (M + H)+ 379.1757, found
379.1744; Anal. Calcd for C20H26O7: C, 63.48; H, 6.98. Found: C,
63.50; H, 7.07.
mmol) and n-BuLi (2.69 M hexane solution, 1.26 mL, 3.38 mmol) in
THF (10 mL) at 0 °C for 30 min under an Ar atmosphere, was added
a solution of 8 (419 mg, 1.69 mmol) in THF (7.0 mL) at −78 °C, and
the mixture was stirred at the same temperature for 1 h. To the
mixture was added ethyl chloroformate (0.48 mL, 5.07 mmol) at −78
°C, and the mixture was stirred at room temperature for 21 h. The
reaction mixture was quenched by addition of saturated aqueous
NH4Cl solution, the mixture was extracted with AcOEt, and the
organic layer was washed with saturated aqueous NaHCO3 solution,
H2O, and brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was used for the next reaction
without further purification.
To a solution of the above crude product in EtOH (10 mL) was
added PPTS (50.0 mg, 0.198 mmol) at 0 °C, and the mixture was
stirred at room temperature for 18 h. The reaction mixture was
quenched by addition of saturated aqueous NaHCO3 solution, and the
mixture was extracted with AcOEt. The organic layer was washed with
H2O and brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by a silica gel column
chromatography (hexane/AcOEt = 2:1) to give 9 (211 mg, 84% yield,
1
two steps) as a colorless oil: IR (neat) 3393, 2235, 1713 cm−1; H
NMR (400 MHz, CDCl3) δ ppm: 5.64−5.81 (2H, m), 4.14−4.24 (3H,
m), 2.32−2.36 (2H, m), 2.04−2.10 (2H, m), 1.19−1.88 (11H, m); 13C
NMR (100 MHz, CDCl3) δ ppm: 153.8, 135.2, 133.7, 130.7, 129.0,
88.9, 73.4, 66.9, 64.4, 61.8, 35.0, 34.9, 34.8, 34.7, 31.8, 30.3, 26.6, 25.0,
24.8, 23.8, 18.8, 14.0; HRMS (ESI) m/z calcd for C14H20O3Na (M +
Na)+ 259.1310, found 259.1310; Anal. Calcd for C14H20O3: C, 71.16;
H, 8.53. Found: C, 70.99; H, 8.44.
Ethyl 6-(4-Oxocyclohex-2-enyl)hex-2-ynoate (6b). To a
solution of 9 (170 mg, 0.765 mmol) in CH2Cl2 (7.7 mL) were
added Dess−Martin periodinane (389 mg, 0.918 mmol) and NaHCO3
(321 mg, 3.83 mmol) at 0 °C under an Ar atmosphere, and the
mixture was stirred at room temperature for 18 h. The reaction
mixture was quenched by addition of 1:1 mixture saturated aqueous
Na2S2O3 solution and saturated aqueous NaHCO3 solution, and the
mixture was extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by a silica gel column
chromatography (hexane/AcOEt = 1:1) to give 6b (166 mg, 99%
1
yield) as a colorless oil: IR (neat) 2234, 1708, 1683 cm−1; H NMR
2-(4-(Pent-4-ynyl)cyclohex-2-enyloxy)tetrahydro-2H-pyran
(8). To a solution of 7 (390 mg, 2.40 mmol) in MeOH (24 mL) were
added CeCl3·7H2O (983 mg, 2.64 mmol) and NaBH4 (100 mg, 2.64
mmol) at 0 °C, and the mixture was stirred at room temperature for 2
h. The reaction mixture was quenched by addition of saturated
aqueous NH4Cl solution, and the mixture was extracted with AcOEt.
The organic layer was washed with H2O and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude product
was used for the next reaction without further purification.
To a solution of the above crude product in CH2Cl2 (12 mL) were
added 3,4-dihydro-2H-pyran (DHP) (0.65 mL, 7.20 mmol) and PPTS
(302 mg, 1.20 mmol) at 0 °C under an Ar atmosphere, and the
mixture was stirred at room temperature for 18 h. The reaction
mixture was quenched by addition of saturated aqueous NaHCO3
solution, and the mixture was extracted with AcOEt. The organic layer
was washed with H2O and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by a
silica gel column chromatography (hexane/AcOEt = 20:1) to give 8
(419 g, 70% yield, two steps) as a colorless oil: IR (neat) 3294, 2116
cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 5.69−5.78 (2H, m), 4.74
(1H, m), 4.19 (1H, m), 3.93 (1H, m), 3.51 (1H, m), 1.16−2.21 (18H,
m); 13C NMR (100 MHz, CDCl3) δ ppm: 135.6, 135.2, 134.3, 134.1,
129.5, 128.2, 128.0, 126.8, 98.1, 97.9, 96.9, 96.6, 84.4, 84.4, 77.2, 72.1,
70.8, 69.8, 68.6, 68.3, 68.3, 62.8, 62.7, 62.5, 35.1, 35.0, 35.0, 34.6, 34.5,
31.3, 31.2, 31.2, 31.1, 30.0, 28.5, 27.9, 27.2, 26.8, 26.5, 26.1, 25.7, 25.7,
25.5, 24.6, 24.4, 19.9, 19.9, 19.8, 19.7, 18.6; HRMS (ESI) m/z calcd for
C16H24O2Na (M + Na)+ 271.1674, found 271.1689; Anal. Calcd for
C16H24O2: C, 77.38; H, 9.74. Found: C, 77.47; H, 9.83.
(400 MHz, CDCl3) δ ppm: 6.83 (1H, ddd, J = 10.4, 2.5, 1.3 Hz), 5.99
(1H, dd, J = 10.4, 1.9 Hz), 4.22 (2H, q, J = 7.1 Hz), 2.32−2.54 (5H,
m), 2.13 (1H, m), 1.50−1.75 (5H, m), 1.31 (3H, t, J = 7.1 Hz); 13C
NMR (100 MHz, CDCl3) δ ppm: 199.5, 154.1, 153.6, 129.3, 88.2,
73.7, 61.8, 36.8, 35.6, 33.6, 28.4, 24.9, 18.7, 14.0; HRMS (ESI) m/z
calcd for C14H19O3 (M + H)+ 235.1334, found 235.1329; Anal. Calcd
for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.55; H, 7.76.
Triethyl 6-(4-Oxocyclohex-2-enyl)hex-1-yne-1,5,5-tricarbox-
ylate (6c). To a solution of 4 (300 mg, 0.960 mmol) in DMF (6.0
mL) was added NaH (50.2 mg, 1.15 mmol) at 0 °C under an Ar
atmosphere, and the mixture was stirred at room temperature for 1 h.
To the mixture was added a solution of 4-iodo-1-butyne (10) (931 mg,
4.80 mmol) in DMF (3.6 mL) via a cannula at 0 °C, and the mixture
was stirred at 50 °C for 15 h. After cooling to room temperature, the
reaction mixture was quenched by addition of saturated aqueous
NH4Cl solution, and the mixture was extracted with AcOEt. The
organic layer was washed with H2O and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by a silica gel column chromatography (hexane/AcOEt = 2:1)
to give unseparable mixture (288 mg) of the desired product and
unidentified byproduct.
To a solution of LDA, which was prepared in situ by mixing i-
Pr2NH (0.30 mL, 2.09 mmol) and n-BuLi (1.65 M hexane solution,
1.2 mL, 2.02 mmol) in THF (4.7 mL) at 0 °C for 30 min under an Ar
atmosphere, was added a solution of the aforementioned mixture in
THF (2.0 mL) at −78 °C, and the mixture was stirred at the same
temperature for 1 h. To the mixture was added ethyl chloroformate
(0.26 mL, 2.69 mmol) at −78 °C, and the mixture was stirred at room
temperature for 14 h. The reaction mixture was quenched by addition
of saturated aqueous NH4Cl solution, and the mixture was extracted
6-(4-Hydroxycyclohex-2-enyl)hex-2-ynoate (9). To a solution
of LDA, which was prepared in situ by mixing i-Pr2NH (0.50 mL, 3.55
9003
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Article
with AcOEt. The organic layer was washed with H2O and brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
crude product was used for the next reaction without further
purification.
135.8, 135.7, 131.4, 131.2, 130.8, 130.5, 130.4, 130.2, 130.1, 129.8,
129.4, 129.4, 127.8, 127.7, 98.0, 96.9, 77.2, 76.4, 76.3, 74.0, 73.9, 71.5,
70.4, 69.7, 68.7, 62.7, 62.6, 50.8, 50.6, 50.2, 50.2, 37.0, 36.8, 33.6, 33.6,
33.5, 33.5, 31.1, 31.1, 29.1, 27.8, 27.1, 25.7, 25.5, 25.4, 24.7, 24.1, 22.0,
21.5, 19.8, 19.7, 19.7; HRMS (ESI) m/z calcd for C22H29NO4NaS (M
+ Na)+ 426.1715, found 426.1686.
To a solution of the above crude product in acetone (6.7 mL) and
H2O (0.5 mL) was added p-TsOH·H2O (12.8 mg, 0.0673 mmol) at 0
°C, and the mixture was stirred at room temperature for 4 h. The
reaction mixture was extracted with AcOEt, and the organic layer was
washed with saturated aqueous NaHCO3 solution, H2O, and brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by a silica gel column chromatography
(hexane/AcOEt = 5:1) to give 6c (127 mg, 34% yield, three steps) as a
white solid: mp 62−63 °C; IR (KBr) 2237, 1721, 1708, 1681 cm−1; 1H
NMR (400 MHz, CDCl3) δ ppm: 6.74 (1H, dd, J = 10.1, 2.0 Hz), 5.96
(1H, dd, J = 10.1, 2.0 Hz), 4.19−4.24 (6H, m), 2.45−2.52 (2H, m),
2.04−2.39 (8H, m), 1.72 (1H, m), 1.25−1.32 (9H, m); 13C NMR
(100 MHz, CDCl3) δ ppm: 198.5, 170.6, 170.5, 153.6, 153.4, 129.3,
87.1, 73.9, 61.8, 61.8, 61.8, 56.4, 37.9, 36.5, 32.3, 31.7, 29.9, 14.5, 14.0,
14.0, 14.0; HRMS (ESI) m/z calcd for C21H29O7 (M + H)+ 393.1913,
found 393.1911.
(4-(Tetrahydro-2H-pyran-2-yloxy)cyclohex-2-enyl)methyl 4-
Methylbenzenesulfonate (11). To a solution of 2 (500 mg, 1.78
mmol) in MeOH (18.0 mL) were added CeCl3·7H2O (730 mg, 1.96
mmol) and NaBH4 (74.2 mg, 1.96 mmol) at 0 °C, and the mixture was
stirred at room temperature for 3 h. The reaction mixture was
quenched by addition of saturated aqueous NH4Cl solution and the
mixture was extracted with AcOEt. The organic layer was washed with
H2O and brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was used for the next reaction
without further purification.
Ethyl 4-(4-Methyl-N-((4-(tetrahydro-2H-pyran-2-yloxy)-
cyclohex-2-enyl)methyl)phenylsulfonamido)but-2-ynoate
(14). To a solution of 13 (235 mg, 0.582 mmol) in THF (5.8 mL) was
added n-BuLi (1.69 M hexane solution, 0.41 mL, 0.698 mmol) at −78
°C under an Ar atmosphere, and the mixture was stirred at the same
temperature for 1 h. To the mixture was added ethyl chloroformate
(0.11 mL, 01.16 mmol) at −78 °C, and the mixture was stirred at
room temperature for 1 h and stirred at 40 °C for 15 h. After cooling
to room temperature, the reaction mixture was quenched by addition
of saturated aqueous NH4Cl solution at 0 °C, and the mixture was
extracted with AcOEt. The organic layer was washed with H2O and
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by a silica gel column
chromatography (hexane/AcOEt = 5:1) to give 14 (172 mg, 62%
yield) as a colorless oil: IR (neat) 2240, 1713, 1598, 1495, 1448, 1351,
1162 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 7.70−7.72 (2H, m),
7.29−7.31 (2H, m), 5.67−5.91 (2H, m), 4.73 (1H, m), 4.12−4.34
(5H, m), 3.91 (1H, m), 3.51 (1H, m), 3.00−3.20 (2H, m), 2.34−2.41
(4H, m), 2.09 (1H, m), 1.47−1.92 (8H, m), 1.25−1.42 (4H, m); 13C
NMR (100 MHz, CDCl3) δ ppm: 152.4, 152.4, 143.8, 143.8, 135.2,
135.2, 131.7, 130.9, 130.7, 130.5, 130.4, 130.1, 129.9, 129.7, 129.4,
127.7, 127.6, 98.0, 97.9, 96.9, 79.9, 79.8, 77.4, 77.2, 71.4, 70.3, 69.6,
68.6, 62.7, 62.6, 62.0, 51.3, 51.1, 50.8, 50.8, 37.1, 36.9, 33.7, 33.6, 33.6,
31.1, 31.1, 29.1, 27.8, 27.0, 25.7, 25.4, 24.7, 24.1, 22.3, 22.0, 21.5, 19.8,
19.7, 19.7, 13.9; HRMS (ESI) m/z calcd for C25H33NO6NaS (M +
Na)+ 498.1926, found 498.1924.
To a solution of the above crude product in CH2Cl2 (9.0 mL) were
added DHP (0.48 mL, 5.34 mmol) and PPTS (224 mg, 0.890 mmol)
at 0 °C under an Ar atmosphere, and the mixture was stirred at room
temperature for 60 h. The reaction mixture was quenched by addition
of saturated aqueous NaHCO3 solution, and the mixture was extracted
with AcOEt. The organic layer was washed with H2O and brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by a silica gel column chromatography (hexane/
AcOEt = 3:1) to give 11 (564 mg, 86% yield, two steps) as a colorless
Ethyl 4-(N-((4-Hydroxycyclohex-2-enyl)methyl)-4-
methylphenylsulfonamido)but-2-ynoate (15). To a solution of
14 (142 mg, 0.299 mmol) in EtOH (3.0 mL) was added PPTS (15.0
mg, 0.0598 mmol) at 0 °C, and the mixture was stirred at room
temperature for 42 h. The reaction mixture was extracted with AcOEt,
and the organic layer was washed with saturated aqueous NaHCO3
solution, H2O, and brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by a silica gel
column chromatography (hexane/AcOEt = 1:1) to give 15 (117 mg,
quant.) as a colorless oil: IR (neat) 3530, 3403, 2239, 1711, 1598,
1
oil: IR (neat) 1598, 1496, 1450, 1361, 1177 cm−1; H NMR (400
MHz, CDCl3) δ ppm: 7.77−7.79 (2H, m), 7.33−7.35 (2H, m), 5.85
(1H, m), 5.61 (1H, m), 4.70 (1H, m), 4.16 (1H, m), 3.81−3.92 (3H,
m), 3.49 (1H, m), 2.39−2.52 (4H, m), 1.23−2.06 (10H, m); 13C
NMR (100 MHz, CDCl3) δ ppm: 144.7, 144.7, 133.0, 132.6, 131.4,
131.2, 130.2, 129.8, 129.0, 128.6, 128.2, 127.9, 127.8, 98.1, 97.9, 97.0,
96.8, 77.2, 73.0, 72.9, 72.6, 72.5, 71.1, 70.0, 69.4, 68.3, 62.8, 62.7, 62.6,
62.5, 35.2, 35.2, 35.1, 35.1, 31.1, 31.1, 31.0, 31.0, 30.6, 28.7, 27.5, 26.7,
25.6, 25.4, 25.4, 23.4, 22.9, 21.6, 21.2, 20.9, 19.8, 19.7, 19.6; HRMS
(ESI) m/z calcd for C19H26O5NaS (M + Na)+ 389.1399, found
389.1384; Anal. Calcd for C19H26O5S: C, 62.27; H, 7.15. Found: C,
62.27; H, 7.20.
1
1495, 1450, 1353, 1161 cm−1; H NMR (400 MHz, CDCl3) δ ppm:
7.71−7.74 (2H, m), 7.30−7.32 (2H, m), 5.68−5.84 (2H, m), 4.13−
4.31 (5H, m), 3.06−3.14 (2H, m), 2.42−2.46 (4H, m), 2.11 (1H, m),
1.91 (1H, m), 1.35−1.54 (3H, m), 1.26−1.29 (3H, m); 13C NMR
(100 MHz, CDCl3) δ ppm: 152.4, 143.9, 135.2, 132.6, 129.8, 129.7,
127.7, 127.6, 79.8, 77.5, 77.2, 66.4, 62.0, 51.1, 51.0, 37.0, 33.6, 30.9,
24.1, 21.8, 21.5, 14.0; HRMS (ESI) m/z calcd for C20H25NO5NaS (M
+ Na)+ 414.1351, found 414.1350.
Ethyl 4-(4-Methyl-N-((4-oxocyclohex-2-enyl)methyl)-
phenylsulfonamido)but-2-ynoate (6d). To a solution of 15
(78.0 mg, 0.199 mmol) in CH2Cl2 (4.0 mL) were added Dess−
Martin periodinane (118 mg, 0.279 mmol) and NaHCO3 (83.6 mg,
0.995 mmol) at 0 °C under an Ar atmosphere, and the mixture was
stirred at room temperature for 12 h. The reaction mixture was
quenched by addition of 1:1 mixture saturated aqueous Na2S2O3
solution and saturated aqueous NaHCO3 solution, and the mixture
was extracted with Et2O. The organic layer was washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by a silica gel column chromatography
(hexane/AcOEt = 1:1) to give 6d (75.9 mg, 98% yield) as a white
solid: mp 98−99 °C; IR (neat) 2238, 1718, 1681, 1596, 1496, 1450,
1350, 1162 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 7.73 (2H, d, J
= 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz), 6.92 (1H, ddd, J = 10.4, 2.5, 1.3
Hz), 6.08 (1H, dd, J = 10.4, 2.5 Hz), 4.22−4.34 (2H, m), 4.17 (2H, q,
J = 7.1 Hz), 3.16−3.28 (2H, m), 2.78 (1H, m), 2.57 (1H, dt, J = 16.9,
4.8 Hz), 2.35−2.43 (4H, m), 2.17 (1H, m), 1.80 (1H, m), 1.28 (3H, t,
J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ ppm: 198.8, 152.3, 149.7,
144.3, 134.8, 130.5, 129.9, 129.9, 127.7, 127.7, 79.4, 77.8, 62.2, 50.3,
4-Methyl-N-(prop-2-ynyl)-N-((4-(tetrahydro-2H-pyran-2-
yloxy)cyclohex-2-enyl)methyl)benzenesulfonamide (13). To a
solution of amide 12 (314 mg, 1.50 mmol) in DMF (3.0 mL) was
added NaH (65.5 mg, 1.50 mmol) at 0 °C under an Ar atmosphere,
and the mixture was stirred at room temperature for 1 h. To the
mixture was added a solution of 11 (500 mg, 1.36 mmol) in DMF (3.8
mL) via a cannula at 0 °C, and the mixture was stirred at 50 °C for 18
h. After cooling to room temperature, the reaction mixture was
quenched by addition of saturated aqueous NH4Cl solution at 0 °C,
and the mixture was extracted with AcOEt. The organic layer was
washed with H2O and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by a
silica gel column chromatography (hexane/AcOEt = 3:1) to give 13
(331 mg, 60% yield) as a colorless oil: IR (neat) 3276, 2118, 1598,
1
1495, 1452, 1349, 1163 cm−1; H NMR (400 MHz, CDCl3) δ ppm:
7.70−7.79 (2H, m), 7.27−7.35 (2H, m), 5.68−5.90 (2H, m), 4.74
(1H, m), 4.06−4.28 (3H, m), 3.88 (1H, m), 3.51 (1H, m), 3.01−3.21
(2H, m), 2.37−2.50 (4H, m), 2.00−2.13 (2H, m), 1.47−1.91 (8H, m),
1.31 (1H, m); 13C NMR (100 MHz, CDCl3) δ ppm: 143.5, 143.4,
9004
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37.4, 36.3, 34.6, 26.4, 21.5, 14.0; HRMS (ESI) m/z calcd for
C20H23NO5NaS (M + Na)+ 412.1195, found 412.1187; Anal. Calcd for
C20H23NO5S: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.47; H, 5.94; N,
3.65.
suspension was added a solution of 6a (38.9 mg, 0.103 mmol) in
anhydrous toluene (0.9 mL) via a cannula at room temperature, and
the mixture was stirred at 80 °C for 12 h. After cooling to room
temperature, the reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane/EtOAc = 3:1) to give 17a (13.4 mg, 37% yield) and 18
(4.3 mg, 11% yield) as a colorless oil. 18: IR (neat) 3429, 1732, 1681,
1645 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 6.33 (1H, d, J = 7.6
Hz), 6.32 (1H, s), 5.98 (1H, d, J = 7.6 Hz), 4.16−4.29 (6H, m), 3.43
(1H, d, J = 19.2 Hz), 3.30 (1H, d, J = 19.2 Hz), 2.90 (1H, d, J = 13.9
Hz), 2.59 (1H, d, J = 13.9 Hz), 1.45−1.61 (4H, m), 1.20−1.35 (9H,
m); 13C NMR (100 MHz, CDCl3) δ ppm: 171.4, 171.1, 166.6, 164.2,
140.2, 133.1, 126.2, 79.6, 62.0, 61.9, 61.9, 60.7, 53.4, 41.2, 38.5, 36.1,
31.7, 14.3, 14.0, 14.0; HRMS (ESI) m/z calcd for C20H27O7 (M + H)+
379.1757, found 379.1747; Anal. Calcd for C20H26O7: C, 63.48; H,
6.93. Found: C, 63.50: H, 6.97.
Conversion of Triethyl 6-Hydroxy-3a,6-ethanoindene-2,2,7-
(1H,3H,6H)-tricarboxylate (18) to Triethyl 5-Hydroxy-1H-in-
dene-2,2,4(3H)-tricarboxylate (17a) (Scheme 3). A solution of 18
(1.2 mg, 0.00317 mmol) in anhydrous toluene (0.5 mL) was stirred at
100 °C for 2 h under an Ar atmosphere. After cooling to room
temperature, the solution was concentrated under reduced pressure.
The residue was purified by preparative TLC (hexane/EtOAc = 2:1)
to give 17a (1.0 mg, 90% yield).
Typical Procedure for Rhodium(I)-Catalyzed Synthesis of
Triethyl 5-Hydroxy-1H-indene-2,2,4(3H)-tricarboxylate (17a)
(Table 1, entry 4). A solution of [RhCl(CO)2]2 (1.8 mg, 0.00463
mmol) and P(2-furyl)3 (4.3 mg, 0.0185 mmol) in anhydrous toluene
(0.4 mL) was stirred at room temperature for 20 min under an Ar
atmosphere. To the solution was added AgOTf (9.5 mg, 0.0370
mmol) at room temperature, and the mixture was stirred at the same
temperature for 30 min. To the suspension was added a solution of 6a
(35.0 mg, 0.0926 mmol) in anhydrous toluene (0.8 mL) via a cannula
at room temperature, and the mixture was stirred at 100 °C for 12 h.
After cooling to room temperature, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/EtOAc = 3:1) to give 17a
(26.2 mg, 81% yield) as a white solid. mp 76−77 °C; IR (KBr) 1731,
1
1667, 1604, 1468 cm−1; H NMR (400 MHz, CDCl3) δ ppm: 11.1
(1H, s), 7.24 (1H, d, J = 8.3 Hz), 6.82 (1H, d, J = 8.3 Hz), 4.43 (2H, q,
J = 7.1 Hz), 4.21 (4H, q, J = 7.1 Hz), 3.86 (2H, s), 3.49 (2H, s), 1.43
(3H, t, J = 7.1 Hz), 1.26 (6H, t, J = 7.1 Hz); 13C NMR (100 MHz,
CDCl3) δ ppm: 171.7, 171.7, 170.7, 161.8, 141.9, 131.4, 130.6, 116.7,
109.7, 61.7, 61.7, 61.6, 60.0, 42.9, 39.4, 14.3, 14.0, 14.0; HRMS (ESI)
m/z calcd for C18H22O7Na (M + Na)+ 373.1263, found 373.1260;
Anal. Calcd for C18H22O7: C, 61.71; H, 6.33. Found: C, 61.95: H, 6.42.
Ethyl 5-Hydroxy-2,3-dihydro-1H-indene-4-carboxylate
(17b). White solid; mp 47−48 °C; IR (KBr) 1657, 1604, 1466
cm−1; 1H NMR (400 MHz, CDCl3) δ ppm: 11.1 (1H, s), 7.27 (1H, d,
J = 8.4 Hz), 6.79 (1H, d, J = 8.4 Hz), 4.36 (2H, q, J = 7.1 Hz), 3.21
(2H, t, J = 7.6 Hz), 2.83 (2H, t, J = 7.6 Hz), 2.06 (2H, quintet, J = 7.6
Hz), 1.43 (3H, t, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ ppm:
171.3, 161.1, 146.5, 135.6, 130.7, 115.5, 110.0, 61.3, 35.6, 31.9, 25.1,
14.2; HRMS (ESI) m/z calcd for C12H15O3 (M + H)+ 207.1021, found
207.1015.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: miyaokah@toyaku.ac.jp.
■
Triethyl 2-Hydroxy-7,8-dihydronaphthalene-1,6,6(5H)-tri-
Notes
carboxylate (17c). White solid; mp 104−105 °C; IR (KBr) 1735,
The authors declare no competing financial interest.
1
1659, 1592, 1466 cm−1; H NMR (400 MHz, CDCl3) δ ppm: 11.0
(1H, s), 7.16 (1H, d, J = 8.6 Hz), 6.81 (1H, d, J = 8.6 Hz), 4.43 (2H, q,
J = 7.1 Hz), 4.19 (4H, q, J = 7.1 Hz), 3.20 (2H, s), 3.13 (2H, t, J = 6.7
Hz), 2.27 (2H, t, J = 6.7 Hz), 1.42 (3H, t, J = 7.1 Hz), 1.23 (6H, t, J =
7.1 Hz); 13C NMR (100 MHz, CDCl3) δ ppm: 171.4, 171.3, 171.3,
161.3, 137.3, 135.6, 125.5, 116.9, 112.1, 61.6, 61.4, 61.4, 52.9, 35.1,
28.4, 26.4, 14.2, 14.0, 14.0; HRMS (ESI) m/z calcd for C19H24O7 (M
+ H)+ 365.1600, found 365.1588.
REFERENCES
■
(1) For a review, see (a) Wang, Z. In Comprehensive Organic Name
Reactions and Reagents; Wiley: New York, 2009; Vol. 1, p 41.
(b) Rickborn, B. In Organic Reaction; Paquette, L. A.; Ed.; Wiley: New
York, 1998; Vol. 52, p 1. (c) Kanakam, C. C.; Ramanathan, H.; Rao, G.
S. R. S.; Birch, A. J. Curr. Sci. 1982, 51, 400−2.
(2) Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. J.
Org. Chem. 2007, 72, 9857−9865.
(3) For recent reports, see (a) Katoh, N.; Nakahata, T.; Kuwahara, S.
Tetrahedron 2008, 64, 9073−9077. (b) Yang, Z. Q.; Geng, X.; Solit,
D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
126, 7881−7889. (c) Yang, Z. Q.; Danishefsky, S. J. J. Am. Chem. Soc.
2003, 125, 9602−9603. (d) Subba Rao, G. S. R. Pure Appl. Chem.
2003, 75, 1443−1451.
(4) (a) Perkins, J. R.; Carter, R. G. J. Am. Chem. Soc. 2008, 130,
3290−3291. (b) Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. J. Am.
Chem. Soc. 2007, 129, 9109−9116. (c) Ashburn, B. O.; Carter, R. G.
Angew. Chem., Int. Ed. 2006, 45, 6737−6741.
(5) Kozmin, S. A.; He, S. W.; Rawal, V. H. Org. Synth. 2002, 78, 160−
168.
(6) Tashima, T.; Toriumi, Y.; Mochizuki, Y.; Nonomura, T.;
Nagaoka, S.; Furukawa, K.; Tsuru, H.; Adachi-Akahane, S.; Ohwada,
T. Bioorg. Med. Chem. 2006, 14, 8014−8031.
(7) Kende, A. S.; Newbold, R. C. Tetrahedron Lett. 1989, 30, 4329−
4332.
Ethyl 5-Hydroxy-2-tosylisoindoline-4-carboxylate (17d).
1
White solid; mp 204−205 °C; IR (KBr) 1657, 1604, 1466 cm−1; H
NMR (400 MHz, CDCl3) δ ppm: 11.1 (1H, s), 7.76 (2H, d, J = 8.1
Hz), 7.32 (2H, d, J = 8.1 Hz), 7.20 (1H, d, J = 8.3 Hz), 6.88 (1H, d, J
= 8.3 Hz), 4.83 (2H, s), 4.53 (2H, s), 4.44 (2H, q, J = 7.1 Hz), 2.40
(3H, s), 1.44 (3H, t, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ
ppm: 169.7, 162.2, 143.7, 143.7, 137.9, 134.0, 129.8, 129.8, 129.0,
127.5, 127.5, 117.8, 108.4, 62.0, 55.8, 52.9, 21.5, 14.3; HRMS (ESI)
m/z calcd for C18H20NO5S (M + H)+ 362.1062, found 362.1074.
Typical Procedure for In(OTf)3-Catalyzed Synthesis of
Triethyl 5-Hydroxy-1H-indene-2,2,4(3H)-tricarboxylate (17a)
(Table 2, entry 9). To a solution of 6a (19.6 mg, 0.0518 mmol) in
anhydrous toluene (0.7 mL) was added In(OTf)3 (2.9 mg, 0.00518
mmol) at room temperature under an Ar atmosphere, and the mixture
was stirred at 100 °C for 12 h. After cooling to room temperature, the
reaction mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/
EtOAc = 3:1) to give 17a (11.0 mg, 61% yield).
Synthesis of Triethyl 6-Hydroxy-3a,6-ethanoindene-2,2,7-
(1H,3H,6H)-tricarboxylate (18) (Scheme 3, entry 1). A solution of
[RhCl(CO)2]2 (2.0 mg, 0.00514 mmol) and P(2-furyl)3 (4.8 mg,
0.0206 mmol) in anhydrous toluene (0.4 mL) was stirred at room
temperature for 20 min under an Ar atmosphere. To the solution was
added AgOTf (10.6 mg, 0.0411 mmol) at room temperature, and the
mixture was stirred at the same temperature for 30 min. To the
(8) Trost, B, M.; Machacek, M, R.; Faulk, B, D. J. Am. Chem. Soc.
2006, 128, 6745−6754.
(9) Papies, O.; Grimme, W. Tetrahedron Lett. 1980, 21, 2799−2802.
9005
dx.doi.org/10.1021/jo301554z | J. Org. Chem. 2012, 77, 8999−9005