A new approach for fused isoindolines via hexadehydro-Diels-Alder reaction (HDDA) by Fe(0) catalysis

Article abstract of DOI:10.1039/c4ra12376j

A simple method has been developed for the synthesis of fused isoindolines via a cascade HDDA approach catalyzed by Fe₂(CO)₉. In this work, a 1,3-diyne was involved in a [4 + 2] cycloisomerization with a diynophile to give an aryne intermediate, which was subsequently trapped with -OH nucleophile to beget the fused isoindolines in high yields.

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A New Approach for Fused Isoindolines via
hexadehydro-Diels-Alder Reaction (HDDA) by Fe
(0) Catalysis
Cite this: DOI: 10.1039/x0xx00000x
Jaya Kishore Vandavasi,a WanꢀPing Hu,b ChengꢀTien Hsiao,a Gopal Chandru
Senadi,a JehꢀJeng Wang*,a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A simple method has been developed for the synthesis of fused isoindolines via a cascade HDDA
www.rsc.org/
approach catalyzed by Fe2(CO)9. In this work, 1, 3ꢀdiyne was involved in
a [4+2]
cycloisomerization with a diynophile to give aryne intermediate, which was subsequently trapped
with –OH nucleophile to beget the fused isoindolines in high yields.
Introduction
Fused heterocycles are important class of compounds mostly in
pharmaceutical and natural products. Among them, nitrogen
and oxygen containing molecules have more potent role in
medicinal chemistry. In particular, isoindolines belonging to
nitrogen heterocycles exhibit a number of biological functions
such as diuretic, antitumor, selective serotonin uptake
inhibitors, herbicidal activities,1,2 antipsychotic agents I (Fig.
1)3 and Alzheimer’s disease II.4 On other hand, the
dihydrobenzofuran structural motif from oxygen heterocycles
also play a pivotal role in many bioꢀactive natural products III
& IV (Fig. 1), as well as synthetic drugs used in the treatment
of hypertension, central nervous system trauma, pulmonary,
and atherosclerotic peripheral arterial disease.5,6 Hence, the
study on isoindolines and 2,3ꢀdihydrobenzofurans continue to
be an interesting research field.
Fig. 1 Pharmaceutical and natural compounds.
In general, synthesis of isoindolines and 2,3ꢀ
dihydrobenzofurans have been described by several
approaches.7,8 The most common methods include the
utilization of transition metal catalysts9 and bases.10 By
knowing the biological importance of these two cores, we
hereby designed a new synthetic protocol to convert both the
cores in one molecule as shown in Scheme 1E.
The synthesis of complex heterocyclic compounds via a
cascade process has been a captivating area in organic
chemistry. In this view, many researchers have focused on
triynes A (Scheme 1) as potential precursor for building fused
ring systems. For representative examples, the combined use of
enyne metathesis and metallotropic [1,3]ꢀshift of alkynyl
ruthenium carbenes is used to construct enediynes and
oligoenynes (scheme 1, B).11 In a similar way, the construction
of fused yneꢀsubstituted aryl halides were developed with Pd
and Ag (Scheme 1, C & D).12,13 Very recently, Hoye and Lee
Scheme 1 Synthetic approaches with triyne molecule.
individually developed HDDA for constructing fused ring
systems by using triynes.14ꢀ16 In this context, and following our
ongoing interest in the synthesis of bicyclic[1,2,3]ꢀtriazole
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from alkynols, we envisioned the possibility of exploring new substrates in Table 2, which follows a [4+2] cycloisomerization
reagents and development of a catalytic cascade reactions with of 1,3ꢀdiyne with a ‘diynophile’ to give a reactive aryne
alkynols to undergo the HDDA reaction. Herein, we have intermediate which was subsequently trapped with –OH
developed a new synthetic pathway to afford fused isoindolines nucleophiles was studied (entry 1, 92%). We conducted
through generation of oꢀarynes via Fe(0) catalysis for the first reactions with EDG as –OMe/Me on phenyl ring and the
time with broad substrate scope in high yields (Scheme 1E).
reactions produced with high yields (entries 2b and 2e).
Reaction were also tested with electron withdrawing groups
like Cl/Br/Ts/CF3 and all of them are progressed well to
Results and discussion
produce high yields (entries 2c
strategy was extended to construct fused chromane scaffolds
(entries 2h ). The electronic effects were also studied for this
reaction with various functionalities such as ꢀOMe/Me (entries
2i and 2n) at o/m/p positions. In similar way, electron
ꢀd and 2fꢀg). The synthetic
To optimize the reaction condition, compound 1a was
synthesized and used as a model substrate. The initial
investigation of 1a with AgOTf failed to produce the desired
compound 2a (Table 1, entry 1). We next evaluated the
feasibility of the reaction with various metal salts (entries 2ꢀ12).
Among them Fe salts shown good results compared with other
metal salts (entries 10ꢀ12). In particular, Fe2(CO)9 underwent
smooth reaction to give compound 2a in best yield 92% (entry
11). Further, the reaction was carried out with lower catalyst
loading and there was no any substantial change in the reaction
yield (entry 13). According to the observations from the
ꢀ
p
ꢀ
k
withdrawing groups such as Cl/Br/Ts/CF3 obeyed the reaction
condition to produce the desired compounds in good yields
(entries 2lꢀm and 2oꢀp). It is noteworthy to mention that this
method is the first example for HDDA reaction with EDG on
phenyl ring attached to nitrogen.
optimizing studies, the best condition was found to be with 5 Table 2 Investigation of reaction with Fe2(CO)9 to synthesize fused
Isoindolines.a
mol% of Fe2(CO)9 in toluene at 80oC for 2h to afford the
compound 2a in 92% yield (entry 13).
R1/R2
Fe2(CO)9 (5mol %)
R1/R2
R
N
2h, 80oC
toluene
N
R
n
Table 1 Optimizing conditions to construct fused heterocycles.
O
OH
1
2
H
n
R1
R1
R1
H
N
N
Cl
N
O
O
O
O
O
H
H
2b, 90%
R1
2c, 91%
R1
2a, 92%
N
R1
Br
N
Ts N
O
O
S.No
1
catalyst
AgOTf
time
6h
4h
2h
24h
6h
6h
6h
6h
6h
2h
2h
2h
2h
Yield (%)d
ꢀꢀꢀꢀꢀa
82
H
H
H
2d, 89%
2e, 91%
2f, 93%
N
R2
R2
R1
2
ZnCl2
N
O
F3C
N
O
3
Pd(OAc)2
Pd(OAc)2
PPh3AuCl
Cu(OTf)2
Fe(OTf)3
Sc(OTf)3
Zn(OTf)2
FeCl3
ꢀꢀꢀꢀꢀ a
O
O
O
O
H
H
H
2i, 88%
2g, 85%
2h, 90%
4b
5b
6
80
R2
R2
R2
72
N
N
Cl
N
O
79
O
O
H
H
H
2l, 85%
R2
2j, 86%
2k, 89%
R2
7
83
R2
8
75
N
Br
N
Ts
N
O
O
O
O
9
73
H
H
H
2m, 87%
2n, 86%
2o, 91%
10
11
12
13c
88
R2
Fe2(CO)9
FeBr3
92
R1
=
R2
=
F3C
N
OH
85
OH
H
2p, 86%
Fe2(CO)9
92
a Reaction Condition: Comp 1 (0.5 mmol), Fe2(CO)9 (5 mol%), toluene (3
mL), temp 80oC and time 2h.
Reaction conditions: Compound 1 (0.5 mmol), catalyst (10 mol%), toluene (3
mL), temp at 80oC and time (h). a Complex mixture. b 28oC. c 5 mol%. d
Isolated yields.
Based on the previous literature reports18 and our observed
results, a plausible mechanism was outlined in Scheme 3. The
initial coꢀordination of Fe to compound
1 resulted in the
formation of intermediate 1A. Further, the intermediate 1A
underwent [4+2] cycloaddition to afford the key aryne
With the optimal reaction conditions (Table 1, entry 13) in
hand, we have conducted HDDA reaction with various
2 | J. Name., 2012, 00, 1-3
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Instrument Center of NSC at NCHU. Flash chromatography was
carried out on silica gel 60 (E. Merck, 230ꢀ400 mesh).
intermediate 1C via ironꢀcomplex compound 1B and Fe was
regenerated for the next catalytic cycle. Finally, the compound
1C was trapped by intramolecular –OH nucleophile followed
General Procedure to Synthesis Compound 2:
A 50 mL roundꢀbottomed flask was charged with the comp 1 (0.5
mmol) and toluene (4 mL). To this, Fe2(CO)9 (5 mol%) was added.
After stirring at 90oC for 2 h under air the completion of reaction
was monitored by TLC. Removal of the solvent in vacuo and
purification of the residue by silica gel column chromatography
afforded the desired product 2.
by [1, 3]ꢀH shift to achieve the desired fused isoindolines 2.
The 1, 3ꢀshift was explored previously by using –OTBS
(scheme 2), deuterium labelling and DFT experiments.14a, 16a By
this results, we also predict that our reaction was followed a
1,3ꢀshift to beget the desired compound.
4-(6-phenyl-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-
yn-1-ol (2a): According to general procedure, title compound was
synthesized (2a). The product was purified by silica gel flash column
chromatography (hexane→hexane/AcOEt = 5/1) to afford 2a as offꢀ
Scheme 2. HDDA reaction 1,3-shift.
1
white solid (140.3 mg, 92% yield). Melting Point: 105ꢀ107oC. H
NMR (400 MHz, CDCl3): δ 7.29 (t, J = 7.8 Hz, 2H), 6.75ꢀ6.65 (m,
4H), 4.61 (t, J = 8.8 Hz, 2H), 4.56 (s, 4H), 3.86 (t, 6.4 Hz, 2H), 3.23
(t, 8.8 Hz, 2H), 2.77 (t, 6.4 Hz, 2H), 1.83 (brs, 1H). 13C NMR (100
MHz, CDCl3): δ 159.5, 147.0, 137.6, 131.8, 129.3, 128.7, 116.0,
114.7, 111.4, 103.7, 92.9, 78.0, 71.6, 61.2, 54.2, 53.1, 29.4, 24.0.
HRMS (ESI): calculated for [C20H20NO2]+ requires 306.14886,
found 306.14884.
R1
R1
R
N
RN
Fe
O
OR2
R2
1
1C
aryne generation
R1
Fe
R1
4-(6-(3-methoxyphenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-
R1
R
N
RN
RN
[1,3]-H shift
f]isoindol-4-yl)but-3-yn-1-ol (2b): According to general procedure,
title compound was synthesized (2b). The product was purified by
silica gel flash column chromatography (hexane→hexane/AcOEt =
5/1) to afford 2b as a light yellow sticky mass (142.3 mg, 85%
yield). 1H NMR (400 MHz, CDCl3): δ 7.18 (t, J = 8.4 Hz, 1H), 6.64
(s, 1H), 6.284 (dddd, J = 2.4 Hz, 2H), 6.17 (t, J = 2.4 Hz, 1H), 4.57
(t, J = 8.4 Hz, 2H), 4.50 (s, 4H), 3.84 (t, J = 6.4 Hz, 2H), 3.82 (s,
3H), 3.18 (t, J = 8.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 160.8, 159.5, 148.4, 137.5, 131.6, 130.0,
128.6, 114.7, 104.6, 103.5, 101.0, 97.8, 93.0, 77.9, 71.6, 61.2, 55.1,
54.2, 53.1, 29.3, 23.9. HRMS (ESI): calculated for [C21H22NO3]+
requires 336.15942, found 336.15941.
O
O
OR2
R2
Fe
1A
R2
1D
1B
R1
aromatization
RN
O
R2
2
R2 = H
Scheme 3. A Plausible mechanism
Conclusions
In conclusion, we have developed a simple method for the
synthesis of fused isoindolines via a cascade HDDA approach
catalyzed by Fe2(CO)9. The key features of this reaction are
easy handling, atom efficiency, time economic and good
reaction yields with broad substrate scope irrespective of
electronic factors. It is noteworthy to mention that this method
is the first example for HDDA reaction with EDG on phenyl
ring attached to nitrogen. Further, extension of this method for
trapping with other carbo or hetero nucleophiles are under
progress.
4-(6-(4-chlorophenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-
4-yl)but-3-yn-1-ol (2c): According to general procedure, title
compound was synthesized (2c). The product was purified by silica
gel flash column chromatography (hexane→hexane/AcOEt = 5/1) to
afford 2c as white solid (149.1 mg, 88% yield). Melting Point: 116ꢀ
118oC. 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.8 Hz, 2H), 6.65
(s, 1H), 6.53 (d, J = 9.2 Hz, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.49 (s,
4H), 3.85 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 8.8 Hz, 2H), 2.77 (t, J = 6.4
Hz, 2H), 1.90 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ 159.6,
145.6, 137.3, 131.4, 129.0, 128.8, 120.9, 114.7, 112.3, 103.6, 93.0,
77.9, 71.6, 61.2, 54.3, 53.2, 29.3, 23.9. HRMS (ESI): calculated for
[C20H18NO2Cl]+ requires 339.1026, found 339.1025.
Experimental Section
General Information:
Melting points are uncorrected. 1H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively, using CDCl3 as a
4-(6-(4-bromophenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-
4-yl)but-3-yn-1-ol (2d): According to general procedure, title
compound was synthesized (2d). The product was purified by silica
gel flash column chromatography (hexane→hexane/AcOEt = 5/1) to
afford 2d as offꢀwhite solid (160.8 mg, 84% yield). Melting Point:
1
solvent. H NMR chemical shifts are referenced to TMS or CDCl3
(7.26 ppm). 13C NMR was referenced to CDCl3 (77.0 ppm).
Multiplicities were determined by the DEPT sequence as s, d, t, q.
Mass spectra and highꢀresolution mass spectra (HRMS) were
measured using the ESIꢀIon trap technique by Taichung Regional
1
85ꢀ87oC. H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 9.2 Hz, 2H),
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6.64 (s, 1H), 6.48 (d, J = 9.2 Hz, 2H), 4.59 (t, J = 8.8 Hz, 2H), 4.47 31.6, 23.8, 22.1, 16.2. HRMS (ESI): calculated for [C22H23NO2]+
(s, 4H), 3.85 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H), 2.76 (t, J = requires 333.1729, found 333.1727.
6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 159.6, 145.9, 137.2,
131.8, 131.3, 128.8, 114.7, 112.9, 107.9, 103.5, 93.1, 77.8, 71.6,
5-(7-(4-methoxyphenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-
61.2, 54.2, 53.1, 29.3, 23.9. HRMS (ESI): calculated for f]isoindol-5-yl)pent-4-yn-1-ol (2i): According to general procedure,
[C20H18BrNO2+Na]+ requires 406.0413, found 406.0411.
title compound was synthesized (2i). The product was purified by
silica gel flash column chromatography (hexane→hexane/AcOEt =
5/1) to afford 2i as a light yellow sticky mass (157.9 mg, 87% yield).
1H NMR (400 MHz, CDCl3): δ 6.91 (d, J = 9.2 Hz, 2H), 6.71(s,
1H), 6.61 (d, J = 9.2 Hz, 2H), 4.52 (s, 4H), 4.15 (t, J = 5.2 Hz, 2H),
3.87 (t, J = 6.4 Hz, 2H), 3.78 (s, 3H), 2.85 (t, J = 6.8 Hz, 2H), 2.64
(t, J = 6.8 Hz, 2H), 2.04ꢀ1.98 (m, 2H), 1.91 (quint, J = 6.4 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 154.3, 151.0, 142.1, 136.6, 132.7,
122.7, 118.3, 115.1, 112.2, 110.5, 97.7, 66.1, 61.7, 55.9, 54.5, 53.9,
31.6, 23.7, 22.1, 16.2. HRMS (ESI): calculated for [C23H26NO3]+
requires 364.1834, found 364.1831.
4-(6-(p-tolyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-
3-yn-1-ol (2e): According to general procedure, title compound was
synthesized (2e). The product was purified by silica gel flash column
chromatography (hexane→hexane/AcOEt = 5/1) to afford 2e as a
1
light yellow sticky mass (135 mg, 85% yield). H NMR (400 MHz,
CDCl3): δ 7.10 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 6.57 (d, J = 8.8 Hz,
2H), 4.60 (t, J = 8.8 Hz, 2H), 4.53 (s, 4H), 3.85 (t, J = 6.4 Hz, 2H),
3.22 (t, J = 8.8 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.28 (s, 3H), 1.81
(brs, 1H). 13C NMR (100 MHz, CDCl3): δ 159.4, 145.0, 137.8,
132.0, 129.8, 128.5, 125.1, 114.6, 111.4, 103.7, 92.8, 78.1, 71.6,
61.2, 54.4, 53.2, 29.4, 24.0, 20.2. HRMS (ESI): calculated for
[C21H22NO2]+ requires 320.1645, found 320.1644.
5-(7-(3-methoxyphenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-
f]isoindol-5-yl)pent-4-yn-1-ol (2j): According to general procedure,
title compound was synthesized (2j). The product was purified by
silica gel flash column chromatography (hexane→hexane/AcOEt =
5/1) to afford 2j as offꢀwhite solid (156 mg, 86% yield). Melting
4-(6-tosyl-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-
yn-1-ol (2f): According to general procedure, title compound was
synthesized (2f). The product was purified by silica gel flash column
chromatography (hexane→hexane/AcOEt = 5/1) to afford 2f as a
light yellow sticky mass (178 mg, 93% yield). Spectral data are in
1
Point: 123ꢀ125oC. H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 8.4
Hz, 1H), 6.70 (s, 1H), 6.32ꢀ6.27 (m, 2H), 6.19 (t, J = 2.4 Hz, 1H),
4.53 (s, 4H), 4.14 (t, J = 5.2 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 3.83
(s, 3H), 2.83 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.03ꢀ1.98
(m, 2H), 1.91 (quint, J = 6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3):
δ 160.8, 154.3, 148.4, 136.1, 132.3, 130.0, 122.8, 118.4, 110.4,
104.6, 100.9, 97.8, 66.1, 61.6, 55.1, 54.0, 53.4, 31.6, 23.7, 22.1,
16.2. HRMS (ESI): calculated for [C23H25NO3]+ requires 363.1834,
found 363.1831.
1
agreement with the literature. H NMR (400 MHz, CDCl3): δ 7.76
(d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.47 (s, 1H), 4.58ꢀ4.52
(m, 6H), 3.82 (t, J = 6.4 Hz, 2H), 3.16 (t, J = 8.4 Hz, 2H), 2.72 (t, J =
6.4 Hz, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.9,
143.6, 135.7, 133.7, 129.8, 129.4, 127.5, 115.0, 103.4, 93.8, 71.7,
61.1, 54.1, 53.2, 29.6, 29.2, 23.8, 21.4. HRMS (ESI): calculated for
[C21H21NO4S+Na]+ requires 406.10835, found 406.10837.
5-(7-(2-methoxyphenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-
4-(6-(4-(trifluoromethyl)phenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-
f]isoindol-4-yl)but-3-yn-1-ol (2g): According to general procedure,
title compound was synthesized (2g). The product was purified by
silica gel flash column chromatography (hexane→hexane/AcOEt =
5/1) to afford 2g offꢀwhite solid (152.9 mg, 82% yield). Melting
Point: 156ꢀ158oC. 1H NMR (400 MHz, CDCl3): 7.50 (d, J = 8.8 Hz,
2H), 6.68 (s, 1H), 6.64 (D, J = 8.8 Hz, 2H), 4.64ꢀ4.59 (m, 6H), 3.87
(t, J = 6.4 Hz, 2H), 3.23 (t, J = 8.4 Hz, 2H), 2.78 (J = 6.4 Hz, 2H).
13C NMR (100 MHz, CDCl3): 159.8, 149.0, 136.9, 130.9, 129.1,
126.5 (q, J = 3.8 Hz), 117.7, 117.4, 114.8, 110.7, 103.6, 93.3, 77.8,
71.7, 61.2, 54.2, 53.1, 29.4, 24.0. HRMS (ESI): calculated for
[C21H19NO2F3]+ requires 374.1290, found 374.1292.
f]isoindol-5-yl)pent-4-yn-1-ol (2k): According to general
procedure, title compound was synthesized (2k). The product was
purified by silica gel flash column chromatography
(hexane→hexane/AcOEt = 5/1) to afford 2k as a light yellow sticky
1
mass (161.5 mg, 89% yield). H NMR (400 MHz, CDCl3): δ 6.96ꢀ
6.80 (m, 4H), 6.68 (s, 1H), 4.71 (s, 2H), 4.67 (s, 2H), 4.14 (t, J = 5.2
Hz, 2H), 3.86ꢀ3.84 (m, 5H), 2.84 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 6.8
Hz, 2H), 2.04ꢀ1.98 (m, 2H), 1.89 (quint, J = 6.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 154.0, 149.8, 138.6, 137.2, 133.1, 122.3,
121.6, 119.0, 117.9, 115.3, 112.7, 110.1, 97.3, 77.0, 66.1, 61.6, 56.5,
56.0, 55.6, 31.5, 23.7, 22.1, 16.2. HRMS (ESI): calculated for
[C23H25NO3]+ requires 363.1834, found 363.1833.
5-(7-phenyl-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-
5-(7-(4-chlorophenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-
yl)pent-4-yn-1-ol (2h): According to general procedure, title
compound was synthesized (2h). The product was purified by silica
gel flash column chromatography (hexane→hexane/AcOEt = 5/1) to
afford 2h as offꢀwhite solid (148 mg, 89% yield). Melting Point:
124ꢀ126oC. 1H NMR (400 MHz, CDCl3): δ 7.29 (t, J = 8.0 Hz, 2H),
6.75ꢀ6.72 (m, 2H), 6.66 (d, J = 8.0 Hz, 2H), 4.56 (s,4H), 4.15 (t, J =
5.2 Hz, 2H), 3.87 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.65
(t, J = 7.2 Hz, 2H), 2.05ꢀ1.99 (m, 2H), 1.92 (quint, J = 6.8 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 154.4, 147.1, 136.3, 132.4, 129.3,
122.8, 118.4, 115.9, 111.4, 110.5, 97.8, 76.8, 66.2, 61.7, 54.0, 53.4,
f]isoindol-5-yl)pent-4-yn-1-ol (2l): According to general procedure,
title compound was synthesized (2l). The product was purified by
silica gel flash column chromatography (hexane→hexane/AcOEt =
5/1) to afford 2l as a light yellow solid (157.8 mg, 86% yield).
1
Melting Point: 144ꢀ146oC. H NMR (400 MHz, CDCl3): 7.22 (d, J
= 8.8 Hz, 2H), 6.71 (s, 1H), 6.56 (d, J = 9.6 Hz, 2H), 4.53 (s, 4H),
4.15 (t, J = 5.2 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.8 Hz,
2H), 2.65 (t, J = 6.8 Hz, 2H), 2.053ꢀ1.99 (m, 2H), 1.92 (quint, J =
6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): 154.4, 145.6, 136.0,
4 | J. Name., 2012, 00, 1-3
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DOI: C10O.1M03M9/CU4NRAIC12A3T76IOJ N
132.0, 129.0, 123.0, 120.8, 118.4, 112.4, 110.5, 97.9, 76.7, 66.2, CDCl3): 154.6, 149.1, 135.5, 131.6, 126.5 (d, J = 3.8 Hz), 123.2,
61.7, 54.1, 53.5, 31.6, 29.6, 23.7, 22.0, 16.2. HRMS (ESI): 118.6, 110.8, 110.5, 98.2, 66.2, 61.7, 54.0, 53.4, 31.6, 23.8, 22.0,
calculated for [C22H23ClNO2]+ requires 368.14118, found 363.14119. 16.3. HRMS (ESI): calculated for [C23H23NO2F3]+ requires
402.1603, found 401.1605.
5-(7-(4-bromophenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-
f]isoindol-5-yl)pent-4-yn-1-ol (2m): According to general Acknowledgements
The authors gratefully acknowledge the Ministry of Science and
Technology (MOST), Taiwan for financial support.
procedure, title compound was synthesized (2m). The product was
purified by silica gel flash column chromatography
(hexane→hexane/AcOEt = 5/1) to afford 2m as offꢀwhite solid
Notes and references
1
(172.6 mg, 84% yield). Melting Point: 142ꢀ144oC. H NMR (400
a Department of Medicinal and Applied chemistry, Kaohsiung Medical
University, Kaohsiung, Taiwan.
MHz, CDCl3): 7.35 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H), 6.52 (d, J = 8.8
Hz, 2H), 4.52 (s, 4H), 4.15 (t, J = 5.2 Hz, 2H), 3.86 (t, J = 6.4 Hz,
2H), 2.85 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 2.05ꢀ1.99 (m,
2H), 1.92 (quint, J = 6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3):
154.5, 146.0, 135.9, 132.0, 131.9, 123.0, 118.5, 113.0, 110.5, 107.9,
97.9, 76.7, 66.2, 61.7, 54.1, 53.5, 31.6, 23.8, 22.0, 16.2. HRMS
(ESI): calculated for [C22H22NO2Br]+ requires 411.0834 found
411.0837.
b
Department of Biotechnology, Kaohsiung Medical University,
Kaohsiung, Taiwan.
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
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yl)pent-4-yn-1-ol (2n): According to general procedure, title
compound was synthesized (2n). The product was purified by silica
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afford 2n as offꢀwhite solid (150.9 mg, 87% yield). Melting Point:
1
128ꢀ130oC. H NMR (400 MHz, CDCl3): 7.09 (d, J = 8.4 Hz, 2H),
2. (a) E. J. Cornish, G. E. Lee and W. R. Wragg, Nature, 1963,
6.70 (s, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.52 (s, 4H), 4.14 (t, J = 5.2
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= 6.8 Hz, 2H), 2.27 (s, 3H), 2.03ꢀ1.98 (m, 2H), 1.90 (quint, J = 6.4
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4-yn-1-ol (2o): According to general procedure, title compound was
synthesized (2o). The product was purified by silica gel flash column
chromatography (hexane→hexane/AcOEt = 5/1) to afford 2o as a
light yellow sticky mass (184.9 mg, 90% yield). 1H NMR (400
MHz, CDCl3): 7.76 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H),
6.52 (s, 1H), 4.54 (d, J = 8.0 Hz, 4H), 4.10ꢀ4.07 (m, 2H), 3.82 (t, J =
6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.40
(s, 3H), 1.98ꢀ1.93 (m, 2H), 1.87 (quint, 2H). 13C NMR (100 MHz,
CDCl3): 154.8, 143.5, 134.4, 133.7, 130.4, 129.8, 127.5, 123.5,
118.7, 110.3, 98.6, 76.1, 66.2, 61.6, 54.0, 53.6, 31.5, 29.6, 23.7,
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requires 434.1396, found 434.1397.
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