Efficient Synthesis of 3-Alkynyl-2-(hydroxymethyl)cyclohex-2-en-1-ones by a Stork-Danheiser Sequence from Vinylogous Esters and Terminal Alkynes

Article abstract of DOI:10.1055/s-0034-1380451

An efficient Stork-Danheiser sequence has been developed for the preparation of a variety of 3-alkynyl-2-(hydroxymethyl)cyclohex-2-en-1-ones in good to excellent yields from the corresponding 4,6,7,8-tetrahydro-5H-1,3-benzodioxin-5-ones and terminal alkynes. Several of the 3-alkynyl-2-(hydroxymethyl)cyclohex-2-en-1-one products were catalytically cyclized to give the corresponding 3-aryl-1,5,6,7-tetrahydro-8H-isochromen-8-ones.

Full text of DOI:10.1055/s-0034-1380451

SYNTHESIS
0
0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2965–2970
2965
special topic
A. Parida et al.
Special Topic
Synthesis
Efficient Synthesis of 3-Alkynyl-2-(hydroxymethyl)cyclohex-2-en-
1-ones by a Stork–Danheiser Sequence from Vinylogous Esters
and Terminal Alkynes
Amarchand Parida
Mohd. Sharique
Badrinath N. Kakde
Santanu Ghosh
OH
O
O
O
THF, n-BuLi
–78 °C to r.t.
then H3O+
O
O
OH
H
R
R
+
Ar
O
R
R
Alakesh Bisai*
Ar
OH
12 examples
50–79%
R = H, Me
hydranginol
Department of Chemistry, Indian Institute of Science Education
and Research, Bhopal, MP 462066, India
alakesh@iiserb.ac.in
Received: 25.04.2015
Accepted after revision: 24.05.2015
Published online:
Preissia, Reboulia, Monoclea, Ricciocarpos, and Blasia.1 The
compounds are secondary metabolites that show a wide
range of cytotoxic, antibacterial, antifungual, and 5-lipoxy-
genase inhibitory activities.2 Biogenically, dimeric biben-
zyls are formed from lunularic acid (1d) or lunularin (1a)
(Figure 1), which are widely distributed in leafy and thal-
loid liverworts.1
In 1983, Ohta and co-workers isolated prelunularic acid
(1c) (Figure 1) from suspension-cultured cells of Marchan-
tia polymorpha.3a The naturally occurring stilbene carbox-
ylic acid lunularic acid (1d) has been isolated from the liv-
erwort Lunularia cruciate, found in Israel.3b,4 Hydrangeic
acid 4′-O-β-D-glucopyranoside (1e) and 2-hydroxy-6-[2-(4-
hydroxyphenyl)-2-oxoethyl]benzoic acid (1f) were isolated
from the roots of viper’s grass (Scorzonera judaica) from
Jordan.5
DOI: 10.1055/s-0034-1380451; Art ID: ss-2015-c0264-st
Abstract An efficient Stork–Danheiser sequence has been developed
for the preparation of a variety of 3-alkynyl-2-(hydroxymethyl)cyclo-
hex-2-en-1-ones in good to excellent yields from the corresponding
4,6,7,8-tetrahydro-5H-1,3-benzodioxin-5-ones and terminal alkynes.
Several of the 3-alkynyl-2-(hydroxymethyl)cyclohex-2-en-1-one prod-
ucts were catalytically cyclized to give the corresponding 3-aryl-
1,5,6,7-tetrahydro-8H-isochromen-8-ones.
Key words alkynylations, Stork–Danheiser sequences, vinylogous es-
ters, alkynes, cyclizations, chromenones
Naturally occurring dimeric bibenzyls containing one or
two diaryl ether or biphenyl bonds have been found in liv-
erworts of such genera as Riccardia, Marchantia, Plagiochila,
O
O
OH
O
OH
O
Glu =
HO
O
H
OH
H
OH
OH
OH
OR
H
H
H
HO
HO
HO
Glu
HO
OH
OH
O
prelunularic acid (1c)
lunularic acid (1d)
lunularin (1a; R = H)
lunularin 4-O-β-D-glucoside (1b; R = Glu)
hydrangeic acid
4'-O-β-D-glucopyranoside (1e)
O
OH
O
OH
O
OH
oxidation
O
OH
O
O
O
H
H
OH
OH
OR
oxidation
OH
OH
3c
1f
thunberginol A (2a; R = H)
phyllodulcin (2b; R = Me)
hydranginol (2c)
common intermediate
OMe
Figure 1 Lunularic acid (1d) and related compounds (1a–c,e,f), dihydroisocoumarins 2a–c, and the common intermediate 3c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2965–2970

2966
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Synthesis
Dihydroisocoumarins are widespread secondary metab-
olites that have been isolated from various organisms and
have some interesting biological activities. Several dihy-
droisocoumarins are being examined as lead drugs in phar-
maceutical research.6,7 Thunberginol A (2a), phyllodulcin
(2b), and hydrangenol (2c) (Figure 1) have been isolated
from the leaves of Hydrangea macrophylla var. thunbergii.
These compounds promote adipogenesis of 3T3-L1 cells
and exhibit antidiabetic properties.8,9 Various other natu-
rally occurring dihydroisocoumarin derivatives isolated
from various species show gastroprotective,10a antibiotic,
antimicrobial, or antibacterial activities and some suppress
inflammation or the activity of ulcers. Some congeners of
this family are active against Gram-positive bacteria.10b
The carbon–carbon triple bond is among the most im-
portant functional groups in organic chemistry, and it has
been used in advanced intermediates in natural-product
synthesis as well as in syntheses of functionalized materi-
als.10 Recently, significant progress has been made in the
construction of heterocyclic rings through intramolecular
annulation of carboxylic acids, amides, alcohols, or amines
to a variety of carbon–carbon triple bonds.11 We surmised
that natural products containing a 3-alkynylcyclohex-2-en-
1-one structure12 might be obtained by a Stork–Danheiser
sequence from the vinylogous esters 4a,b and the appropri-
ate terminal alkynes. Here, we report an efficient Stork–
Danheiser sequence13 that uses lithium acetylides prepared
in situ by the reaction of a terminal aralkyne and n-butyl-
lithium (Scheme 1).
Table 1 Substrate Scope of Bicyclic Vinylogous Esters 4a,ba
O
O
THF, n-BuLi
–78 °C to r.t.
then H3O+
O
OH
R1
R1
R1
+
R2
O
R1
R2
4a R1 = H
4b R1 = Me
3a–l
Entry
R1
R2
Product
Yieldb (%)
1
H
Ph
4-Tol
3a
3b
3c
3d
3e
3f
76
50
72
58
78
75
69
71
67
62
75
79
2
H
H
H
H
H
3
4-MeOC6H4
4-F3CC6H4
3,4-(MeO)2C6H3
3-i-Pr-4-MeOC6H3
Ph
4
5
6
7
Me
Me
Me
Me
H
3g
3h
3i
8
4-Tol
9
4-MeOC6H4
4-F3CC6H4
Bu
10
11
12
3j
3k
3l
H
c-Pr
a Reaction conditions: 4a,b (1.5 mmol), THF (10 mL), –78 °C to r.t., 10 h
then 4 M aq HCl, 0 °C, 2 h.
b Isolated yield after column chromatography.
synthesizing core structures of naturally occurring dihy-
droisocoumarins.15 We initially chose compound 3g as a
model substrate and examined the activation of its alkyne
functionality with various catalysts (Table 2). We hoped
that a Lewis acid might activate the carbonyl carbon to
form the tetrahydroisochromenone 5b by a 6-endo-dig cy-
clization rather than the less-preferred 5-exo-dig cycliza-
tion.
O
O
THF, n-BuLi
–78 °C to r.t.
OH
O
then H3O+
R1
R1
R1
+
O
50–79%
R2
R1
R2
4a R1 = H
4b R1 = Me
3a–l
We found that 10 mol% of bismuth(III) triflate16 in vari-
ous solvents gave tetrahydroisochromenone 5b in yields of
up to 30% (Table 2, entries 1–5), whereas 10 mol% of scandi-
um(III) triflate gave 5b in 50% yield (entry 6). Interestingly,
10 mol% of iron(III) chloride was a better Lewis acid cata-
lyst, giving 5b in 72% yield when the reaction was carried
out in dichloromethane (entry 7). On changing the catalysts
from a Lewis acid to a transition metal,17 we found that 10
mol% of palladium(II) acetate gave product 5b in up to 82%
yield at room temperature (entries 8–11).
Similar treatment of the 3-alkynyl-2-(hydroxymeth-
yl)cyclohex-2-en-1-ones 3c, 3i, and 3j under the optimized
conditions gave the corresponding to dihydroisocoumarin
5a, 5c, and 5d, respectively, in 63–84% isolated yield (Table
3).
Scheme 1 Stork–Danheiser sequence from 4a,b
We treated one equivalent of the vinylogous ester 4a or
4b14 with a lithium acetylide, prepared in situ by adding 1.3
equivalents of n-butyllithium to 1.2 equivalents of the ap-
propriate terminal alkyne in tetrahydrofuran at –78 °C, to
give the corresponding 3-alkynyl-(2-hydroxymethyl)cyclo-
hex-2-en-1-ones 3a–l in up to 79% yield (Table 1). Com-
pounds 3a–f, which have a hydroxymethyl group in the 2-
position, are potentially useful as advanced intermediates
for the synthesis of various lunularic acid derivatives or di-
hydroisocoumarins through synthetic elaboration of the
triple bond and hydroxymethyl functionalities.
We were also interested in activating the triple-bond
functionality of the 3-alkynyl-2-(hydroxymethyl)cyclohex-
2-en-1-ones 3 in the presence of a Lewis acid with aim of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2965–2970

2967
A. Parida et al.
Special Topic
Synthesis
Table 2 Optimization of the Cyclization of 2-(Hydroxymethyl)-5,5-di-
methyl-3-(phenylethynyl)cyclohex-2-en-1-one (3g)a
riched intermediate that might be useful in organic synthe-
sis. Further studies on applications of our method in the
syntheses of natural products are currently underway in
our laboratory.
LA
O
O
cat.
(10 mol%)
6-endo-dig
cyclization
O
OH
solvent
temp
Me
Me
Unless otherwise stated, reactions were performed in oven-dried
glassware fitted with rubber septa under a nitrogen atmosphere and
were stirred with Teflon-coated magnetic stirring bars. Liquid re-
agents and solvents were transferred via syringe using standard
Schlenk techniques. Tetrahydrofuran (THF) and diethyl ether (Et2O)
were distilled over sodium/benzophenone ketyl. Dichloromethane
(CH2Cl2), toluene, and benzene were distilled over calcium hydride.
All other solvents such as DCE, DMF, 2,2,2-trifluoroethanol and re-
agents were used as received.
3g
Ph
Ph
5b
Entry
Catalyst
Solvent
Temp (°C) Time
Yieldb,c (%)
1
2
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Sc(OTf)3
FeCl3
DCE
80
110
80
25
40
40
40
25
25
25
25
3 h
6 h
21
–
DMF
MeCN
3
24 h
10 h
15 h
10
30
22
50
72
66
64
82
63
Thin-layer chromatography was performed using Merck Silicagel 60
F-254 precoated plates (0.25 mm) and visualized by UV irradiation,
anisaldehyde stain and other stains. Silica gel from Merck (100–200
mesh) was used for flash chromatography. Melting points were re-
corded on a digital melting point apparatus from Jyoti Scientific (AN
ISO 9001:2000) and are uncorrected. 1H and 13C NMR spectra were re-
corded on Bruker 400 and 500 MHz spectrometers with 13C operating
frequencies of 100 and 125 MHz, respectively. Chemical shifts (δ) are
reported in ppm relative to the residual solvent signal (δ = 7.26 for 1H
NMR and δ = 77.0 for 13C NMR). Data for 1H NMR spectra are reported
as follows: chemical shift (multiplicity, coupling constants, number of
hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad). IR spectra were record-
ed on an FT-IR system (Spectrum BX) from PerkinElmer and are re-
ported in frequency of absorption (cm–1). Only selected IR absorben-
cies are reported. High-resolution mass spectral data were obtained
from the Central Instrumentation Facility (CIF) at IISER Bhopal.
4
F3CCH2OH
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
5
6
40 min
10 h
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
18 h
9
DCE
24 h
10
11
CH2Cl2
F3CCH2OH
24 h
24 h
a Reactions were carried out with 0.2 mmol of 3g in 2 mL of solvent.
b Isolated yield after column chromatography.
c 10–52% of the starting material 3g was recovered as a result of incomplete
reaction.
Table 3 Substrate Scope of the Isomerization of Enones 3a
3-Alkynyl-2-(hydroxymethyl)cyclohex-2-en-1-ones 3; General
Procedure
O
O
Pd(OAc)2
A 2.0 M soln of n-BuLi in cyclohexane (1.95 mmol, 1.3 equiv) was add-
ed to a stirred solution of the appropriate terminal alkyne (1.8 mmol,
1.2 equiv) in THF (5 mL) at – 78 °C, and the mixture was stirred for 1
h. A solution of vinylogous ester 4 (1.5 mmol, 1.0 equiv) in THF (5 mL)
was then slowly added over 5 min. The mixture was allowed to warm
to r.t. and stirred for 10 h. The reaction was then quenched with 4 M
aq HCl (5 mL) at 0 °C and the mixture was stirred for 2 h. The resulting
mixture was extracted with EtOAc (3 × 25 mL) and the organic layers
were combined, dried (Na2SO4), and concentrated under reduced
pressure to give a crude product that was purified by column chroma-
tography.
OH
(10 mol%)
CH2Cl2, 25 °C
O
R
R
X
R
X
R
3
5
R
X
Product
Yieldb (%)
H
4-MeOC6H4
Ph
5a
5b
5c
5d
84
82
79
63
Me
Me
Me
4-MeOC6H4
4-F3CC6H4
2-(Hydroxymethyl)-3-(phenylethynyl)cyclohex-2-en-1-one (3a)
Yellow oil; yield: 258 mg (76%; 1.5 mmol scale); Rf = 0.39 (30% EtOAc–
hexanes).
a Reaction conditions: 3 (0.2 mmol), CH2Cl2 (2 mL), r.t.
b Isolated yield after column chromatography.
IR (film): 3432, 2928, 2197, 1661, 1643, 1361, 1311, 1187, 1010, 759
cm–1
.
In conclusion, we have developed an efficient Stork–
1H NMR (400 MHz, CDCl3): δ = 7.46–7.48 (m, 2 H), 7.34–7.37 (m, 3 H),
5.20 (br s, 1 H), 4.59 (s, 2 H), 2.61 (t, J = 6.02 Hz, 2 H), 2.49 (t, J = 6.44
Hz, 2 H), 2.02–2.07 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 200.1, 140.13, 140.10, 131.9, 129.7,
128.6, 121.9, 104.7, 86.7, 60.2, 37.9, 31.3, 22.3.
Danheiser sequence starting from vinylogous esters and
terminal alkynes. The resulting 3-alkynyl-2-(hydroxymeth-
yl)cyclohex-2-en-1-ones 3 might be useful as building
blocks for synthesis of the isocoumarin skeleton. We also
believe that a Corey–Bakshi–Shibata reduction18 of the 3-
alkynylcyclohex-2-en-1-ones 3 should give an enantioen-
HRMS (ESI): m/z [M + Na]+ calcd for C15H14NaO2: 249.0886; found:
249.0905.
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Synthesis
2-(Hydroxymethyl)-3-(4-tolylethynyl) cyclohex-2-en-1-one (3b)
13C NMR (100 MHz, CDCl3): δ = 200.0, 158.2, 140.7, 139.1, 137.6,
131.1, 130.0, 113.6, 110.3, 106.3, 85.7, 60.4, 55.4, 37.9, 31.4, 26.6,
22.4, 22.3.
HRMS (ESI): m/z [M + Na]+ calcd for C19H22NaO3: 321.1461; found:
321.1459.
Yellow oil; yield: 180 mg (50%; 1.5 mmol scale); mp 55–58 °C;
Rf = 0.52 (30% EtOAc–hexane).
IR (film): 3401, 1647, 922, 745 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.07 Hz, 2 H), 7.19 (d,
J = 8.03 Hz, 2 H), 4.63 (s, 2 H), 3.00 (br s, 1 H), 2.65 (t, J = 6.02 Hz, 2 H),
2.52 (t, J = 6.45 Hz, 2 H), 2.40 (s, 3 H), 2.0–2.11 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 200.1, 140.4, 140.2, 139.7, 131.9,
129.4, 118.8, 105.3, 86.3, 60.3, 37.9, 31.3, 22.3, 21.7.
2-(Hydroxymethyl)-5,5-dimethyl-3-(phenylethynyl)cyclohex-2-
en-1-one (3g)
Yellow gel; yield: 263 mg (69%; 1.5 mmol scale); Rf = 0.45 (20% EtOAc–
hexanes).
IR (film): 3435, 2962, 2197, 1653, 1012, 759, 475 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.49–7.52 (m, 2 H), 7.35–7.41 (m, 3 H),
.
2-(Hydroxymethyl)-3-[(4-methoxyphenyl)ethynyl]cyclohex-2-en-
1-one (3c)
4.64 (s, 2 H), 3.03 (br s, 1 H), 2.53 (s, 2 H), 2.37 (s, 2 H), 1.10 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 200.2, 139.1, 137.8, 131.9, 129.6,
Yellow solid; yield: 276 mg (72%; 1.5 mmol scale); mp 89–95 °C;
Rf = 0.38 (30% EtOAc–hexane).
IR (film): 3421, 2936, 2191, 1645, 1296, 1252, 1176, 1025, 835 cm–1
.
128.6, 121.9, 104.1, 87.0, 60.0, 51.5, 44.9, 33.5, 28.0.
HRMS (ESI): m/z [M + Na]+ calcd for C17H18NaO2: 277.1199; found:
277.1202.
1H NMR (500 MHz, CDCl3): δ = 7.44 (m, 2 H), 6.89 (m, 2 H), 4.61 (s, 2
H), 3.83 (s, 3 H), 3.09 (br s, 1 H), 2.62 (t, J = 6.02 Hz, 2 H), 2.50 (m, 2 H),
2.03–2.08 (m, 2 H).
2-(Hydroxymethyl)-5, 5-dimethyl-3-(4-tolylethynyl)cyclohex-2-
en-1-one (3h)
13C NMR (100 MHz, CDCl3): δ = 199.9, 160.8, 140.6, 139.3, 133.7,
114.2, 113.9, 105.4, 86.0, 60.2, 55.4, 37.9, 31.3, 22.3.
Colorless solid; yield: 286 mg (71%; 1.5 mmol scale); mp 90–92 °C;
Rf = 0.51 (20% EtOAc–hexane).
IR (film): 3396, 2190, 1641, 1364, 780 cm–1
2-(Hydroxymethyl)-3-{[4-(trifluoromethyl)phenyl]ethynyl}cyclo-
hex-2-en-1-one (3d)
.
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.06 Hz, 2 H), 7.18 (d,
J = 7.94 Hz, 2 H), 4.64 (s, 2 H), 3.05 (br s, 1 H), 2.52 (s, 2 H), 2.39 (s, 3
H), 2.37 (s, 2 H), 1.11 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 200.3, 140.1, 138.7, 138.0, 131.9,
129.3, 118.9, 104.7, 86.6, 60.1, 51.5, 45.0, 33.5, 28.0, 21.6.
Yellow solid; yield: 256 mg (58%; 1.5 mmol scale); mp 95–97 °C;
Rf = 0.42 (30% EtOAc–hexane).
IR (film): 3399, 2097, 1660, 1648, 780 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.60–7.66 (m, 4 H), 4.62 (s, 2 H), 2.97
(br s, 1 H), 2.66 (t, J = 5.99 Hz, 2 H), 2.55 (m, 2 H), 2.07–2.13 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 200.0, 140.9, 139.1, 132.1, 131.3,
125.6 (m), 125.5 (q, J = 3.82 Hz), 122.6, 102.3, 88.4, 60.3, 37.9, 31.1,
22.3.
HRMS (ESI): m/z [M + K]+ calcd for C18H20KO2: 307.1095; found:
307.1110.
2-(Hydroxymethyl)-3-[(4-methoxyphenyl)ethynyl]-5,5-dimethyl-
cyclohex-2-en-1-one (3i)
3-[(3,4-Dimethoxyphenyl)ethynyl]-2-(hydroxymethyl)cyclohex-2-
en-1-one (3e)
Yellow solid; yield: 286 mg (67%; 1.5 mmol scale); mp 95–100 °C;
Rf = 0.39 (20% EtOAc–hexane).
Yellow gel; yield: 335 mg (78%; 1.5 mmol scale); Rf = 0.32 (30% EtOAc–
hexanes).
IR (film): 3470, 2960, 2187, 1645, 1592, 1511, 1365, 1292, 1253,
1021, 835 cm–1
.
IR (film): 3419, 2935, 2360, 2340, 2186, 1650, 1515, 1252, 1022 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.45 (m, 2 H), 6.90 (m, 2 H), 4.63 (s, 2
H), 3.85 (s, 3 H), 3.08 (br s, 1 H), 2.52 (s, 2 H), 2.36 (s, 2 H), 1.10 (s, 6
H).
1H NMR (400 MHz, CDCl3): δ = 7.08 (dd, J = 8.31, 1.65 Hz, 1 H), 6.93 (d,
J = 1.53 Hz, 1 H), 6.81 (d, J = 8.31 Hz, 1 H), 4.58 (s, 2 H), 3.87 (s, 3 H),
3.86 (s, 3 H), 2.98 (t, J = 7.54 Hz, 1 H), 2.60 (t, J = 5.89 Hz, 2 H), 2.47 (t,
J = 6.67 Hz, 2 H), 1.99–2.05 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 200.3, 160.8, 138.3, 138.2, 133.7,
13C NMR (100 MHz, CDCl3): δ = 200.0, 150.7, 148.8, 140.4, 139.4,
125.9, 114.3, 114.0, 111.1, 105.5, 85.8, 60.3, 56.0, 37.9, 31.3, 29.7,
22.3.
114.3, 113.9, 105.0, 86.4, 60.1, 55.4, 51.5, 45.0, 33.5, 28.1.
HRMS (ESI): m/z [M + K]+ calcd for C18H20KO3: 323.1044; found:
323.1031.
2-(Hydroxymethyl)-3-[(3-isopropyl-4-methoxyphenyl)ethynyl]cy-
clohex-2-en-1-one (3f)
2-(Hydroxymethyl)-5,5-dimethyl-3-{[4-(trifluoromethyl)phe-
nyl]ethynyl}cyclohex-2-en-1-one (3j)
Colorless gel; yield: 336 mg (75%; 1.5 mmol scale); Rf = 0.35 (30%
Yellow solid; yield: 300 mg (62%; 1.5 mmol scale); mp 70–72 °C;
EtOAc–hexanes).
Rf = 0.40 (20% EtOAc–hexane).
IR (film): 3425, 1647, 1322, 1130, 844 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.61–7.66 (m, 4 H), 4.63 (s, 2 H), 2.95
.
IR (film): 3444, 2962, 2360, 2340, 2189, 1660, 1587, 1495, 1290,
1248, 1186, 1024, 816 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.31 (m, 2 H), 6.78 (d, J = 9.0 Hz, 1
H), 4.60 (s, 2 H), 3.83 (s, 3 H), 3.21–3.30 (m, 1 H), 2.95 (br s, 1 H), 2.60
(t, J = 5.92 Hz, 2 H), 2.47 (t, J = 6.55, 2 H), 1.99–2.06 (m, 2 H), 1.18 (d,
J = 6.81, 6 H).
(br s, 1 H), 2.55 (s, 2 H), 2.40 (s, 2 H), 1.13 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 200.2, 139.9, 136.8, 132.1, 132.1,
131.3, 125.6 (m), 125.5 (q, J = 3.7 Hz), 101.8, 88.8, 60.1, 51.5, 44.7,
33.5, 28.0.
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HRMS (ESI): m/z [M + Na]+ calcd for C18H17F3NaO2: 345.1073; found:
13C NMR (125 MHz, CDCl3): δ = 194.6, 159.2, 151.6, 135.5, 135.3,
345.1073.
128.5, 128.4, 126.7, 102.7, 74.7, 52.0, 35.5, 35.1, 28.5.
HRMS (ESI): m/z [M – H]+ calculated for C17H17O2: 253.1223; found:
253.1213.
3-Hex-1-yn-1-yl-2-(hydroxymethyl)cyclohex-2-en-1-one (3k)
Brown liquid; yield: 232 mg (75%; 1.5 mmol scale); Rf = 0.50 (20%
EtOAc–hexane).
3-(4-Methoxyphenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-8H-iso-
IR (film): 3440, 2935, 2874, 2213, 1655, 1360, 1015 cm–1
.
chromen-8-one (5c)
Yellow oil; yield: 45 mg (79%; 0.2 mmol scale); Rf = 0.70 (20% EtOAc–
hexane).
1H NMR (400 MHz, CDCl3): δ = 4.52 (s, 2 H), 2.97 (br s, 1 H), 2.51 (t,
J = 5.96 Hz, 2 H), 2.47 (m, 4 H), 1.97–2.04 (m, 2 H), 1.55–1.62 (m, 2 H),
1.41–1.50 (m, 2 H), 0.95 (t, J = 7.35 Hz, 3 H).
IR (film): 2930, 1664, 1251, 1177, 1033, 840 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 200.3, 141.3, 139.6, 107.7, 78.7, 60.2,
37.9, 31.6, 30.3, 22.2, 22.0, 19.7, 13.5.
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.72 Hz, 2 H), 6.90 (d,
J = 8.80 Hz, 2 H), 5.63 (s, 1 H), 5.23 (m, 2 H), 3.84 (s, 3 H), 2.39 (s, 2 H),
2.38 (s, 2 H), 1.15 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 194.5, 158.4, 157.6, 151.7, 134.6,
129.8, 128.1, 114.0, 112.6, 74.5, 55.3, 51.9, 35.4, 35.1, 28.5.
3-(Cyclopropylethynyl)-2-(hydroxymethyl)cyclohex-2-en-1-one
(3l)
HRMS (ESI): m/z [M + H]+ calcd for C18H21O3: 285.1485; found:
285.1475.
Yellow gel; yield: 225 mg (79%; 1.5 mmol scale); Rf = 0.32 (20% EtOAc–
hexane).
IR (film): 3400, 3013, 2945, 2875, 2205, 1649, 1595, 1371, 1219,
1188, 1110, 1011, 942 cm–1
.
6,6-Dimethyl-3-[4-(trifluoromethyl)phenyl]-1,5,6,7-tetrahydro-
1H NMR (400 MHz, CDCl3): δ = 4.41 (s, 2 H), 3.00 (br s, 1 H), 2.38–2.44
(m, 4 H), 1.91–1.97 (m, 2 H), 1.41–1.47 (m, 1 H), 0.89–0.94 (m, 2 H),
0.76–0.81 (m, 2 H).
8H-isochromen-8-one (5d)
Yellow oil; yield: 41 mg (63%; 0.2 mmol scale); Rf = 0.72 (20% EtOAc–
hexane).
13C NMR (100 MHz, CDCl3): δ = 200.0, 141.4, 139.3, 111.2, 74.1, 59.9,
IR (film): 2945, 1664, 1328, 1115, 827 cm–1
.
37.8, 31.5, 22.2, 9.6, 0.8.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.23 Hz, 2 H), 7.58 (d,
J = 8.36 Hz, 2 H), 5.67 (s, 1 H), 5.28 (m, 2 H), 2.43 (t, J = 2.29 Hz, 2 H),
2.42 (s, 2 H), 1.18 (s, 6 H).
3-Aryl-1,5,6,7-tetrahydro-8H-isochromen-8-ones 5; General Pro-
cedure
13C NMR (100 MHz, CDCl3): δ = 194.5, 160.9, 151.0, 138.8 (d, J = 1.38
Hz), 136.7, 128.3, 125.3 (q, J = 3.83 Hz, CF3), 101.0, 75.1, 52.0, 35.5,
35.1, 28.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H18F3O2: 323.1253; found:
323.1260.
Pd(OAc)2 (0.02 mmol, 0.1 equiv) was added to a stirred solution of
enone 3 (0.20 mmol, 1.0 equiv) in CH2Cl2 (2 mL) at r.t. under an inert
atmosphere. When the starting material had been consumed (TLC),
most of the volatiles were evaporated in a rotary evaporator under re-
duced pressure. The crude product was purified by column chroma-
tography (silica gel, EtOAc–hexane).
Acknowledgements
3-(4-Methoxyphenyl)-1,5,6,7-tetrahydro-8H-isochromen-8-one
(5a)
A.B. thanks the BRNS, DAE, India, for a research grant through a Young
Scientist Research Award (YSRA). We also thank the Department of
Science and Technology (DST Sanction No.: SR/S1/OC-54/2011) for
generous funding. B.N.K. and S.G. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi, for doctoral fellowships. A.P.
thanks the UGC for a JRF fellowship. M.S. thanks the DST for an
INSPIRE fellowship. We thank the Department of Chemistry, IISER,
Bhopal for provision of infrastructure.
Yellow oil; yield: 43 mg (84%; 0.2 mmol scale); Rf = 0.65 (30% EtOAc–
hexane).
IR (film): 3445, 2100, 1642, 1254, 1176, 835 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.67–7.70 (m, 2 H), 6.92–6.95 (m, 2 H),
5.88 (s, 1 H), 5.05 (s, 2 H), 3.87 (s, 3 H), 2.48 (t, J = 6.08 Hz, 2 H), 2.44–
2.47 (m, 2 H), 2.04–2.09 (m, 2 H).
.
13C NMR (125 MHz, CDCl3): δ = 195.3, 161.6, 160.6, 152.6, 127.9,
125.3, 116.2, 113.9, 99.4, 64.2, 55.4, 37.5, 28.4, 22.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O3: 257.1172; found:
257.1182.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380451.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
6,6-Dimethyl-3-phenyl-1,5,6,7-tetrahydro-8H-isochromen-8-one
(5b)
Yellow oil; yield: 42 mg (82%; 0.2 mmol scale); Rf = 0.5 (15% EtOAc–
hexane).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2965–2970

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2965–2970