Selectivity in Garratt-Braverman cyclization of aryl-/heteroaryl- substituted unsymmetrical bis-propargyl systems: Formal synthesis of 7′-desmethylkealiiquinone

Article abstract of DOI:10.1021/jo402749d

Unsymmetrical bis-propargyl ethers and sulfonamides containing various combinations of aryl/heteroaryl substituents at the acetylene termini were synthesized, and their reactivity under basic conditions was studied. Moderate to high (chemo)selectivity was

Full text of DOI:10.1021/jo402749d

Article
pubs.acs.org/joc
Selectivity in Garratt−Braverman Cyclization of Aryl-/Heteroaryl-
Substituted Unsymmetrical Bis-Propargyl Systems: Formal Synthesis
of 7′-Desmethylkealiiquinone
Joyee Das, Raja Mukherjee,* and Amit Basak*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
S
* Supporting Information
ABSTRACT: Unsymmetrical bis-propargyl ethers and sulfonamides
containing various combinations of aryl/heteroaryl substituents at the
acetylene termini were synthesized, and their reactivity under basic
conditions was studied. Moderate to high (chemo)selectivity was
observed, which followed a trend opposite to that reported earlier for
the corresponding sufones. The major products obtained in most
cases (except with indole) were formed via participation of the
heteroaryl ring or the less electron rich aryl ring. The selectivity
observed in imidazole-based systems was exploited to complete a
formal total synthesis of 7′-desmethylkealiiquinone, an analogue of the
marine alkaloid kealiiquinone.
substituted bis-propargyl system, provided proper selectivity is
achieved during GB cyclization. It may be mentioned here that
the selectivity issue addressed in the present cases is close to
chemoselectivity rather than regioselectivity. The two different
aryl rings or the aryl and heteroaryl rings on the two arms of
the bis-propargyl system may be considered as representing two
different functionalities, and thus chemoselectivity is involved in
the two possible GB pathways and is used henceforth.4
INTRODUCTION
■
Garratt−Braverman (GB) cyclization1a−k is the rearrangement
of aryl-substituted bis-allenic sulfone/sulfides, ethers, and
amines/sulfonamides leading to aromatic systems. The reaction
involves formation of two C−C bonds, believed to pass through
a biradical intermediate, and belongs to the class of cyclo-
aromatization reactions.1l The reactive bis-allenic system is
made in situ from the corresponding bis-propargyl counterparts
via a base-mediated isomerization. The GB reaction of
unsymmetrical bis-propargyl sulfones, ethers, and sulfonamides
can follow two pathways, involving either of the two aryl rings
at the termini. It was earlier shown2 by our group that the GB
reaction of such sulfones can be made chemoselective by
suitable perturbation of the electronic character of the terminal
aryl groups (Scheme 1). The reaction follows a pathway in
which the aryl group with greater electron-donating ability
preferentially participates in the rearrangement. The rationale
behind such selectivity was the greater nucleophilic character of
the benzylic radical attached to the aryl ring having electron-
donating properties. This interpretation was also supported by
theoretical calculations. Unlike sulfones, there has been no
systematic study of selectivity of GB cyclization involving bis-
propargyl ethers or sulfonamides. Moreover, the effect of
replacing one of the aryl groups with a heterocyclic ring such as
pyridine, indole, or imidazole or an electronically different aryl
ring such as naphthyl or methoxyphenyl also has not been
evaluated (Scheme 2). Such a study, especially for heteroaryl
systems, is relevant, as natural products of the kealiinine family3
are imidazolyl fused benzenoid systems with a pendant aryl ring
(Figure 1). This skeleton, at least in principle, may be
obtainable via the GB reaction of a suitably heteroaryl
RESULTS AND DISCUSSION
■
With this in mind, we proceeded with the synthesis of target
bis-propargyl ethers and sulfonamides; key synthetic steps
involved Sonogashira coupling5 and O- or N-propargylation.6
As an example, ether 1a was prepared via a NaH-mediated O-
alkylation of the alcohol 4a with the propargyl bromide 7. The
alcohol 4a was prepared by a Sonogashira reaction between N-
benzyl-3-iodoindole (6a) and propargyl alcohol, while the
bromide 7 was obtained via a similar reaction of iodobenzene
with propargyl alcohol followed by bromination via mesylation
and displacement with LiBr. O-alkylation of 4a with the
bromide 7 was achieved using NaH in THF at 0 °C (Scheme
3).
In order to follow the outcome of the Garratt−Braverman
rearrangement, these bis-propargyl ethers/sulfonamides were
treated with base (KOtBu/DBN/DBU depending upon the
substrate) in toluene at reflux. The ratio of the products, as
1
determined from the H NMR spectrum of the crude reaction
mixture by comparing the ratio of integrations for characteristic
Received: December 11, 2013
Published: April 3, 2014
© 2014 American Chemical Society
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Scheme 1. GB Reaction of Sulfone
Scheme 2. GB Reaction of Mixed Propargyl Systems
Figure 1. Kealiinine and kealiiquinone alkaloids and analogues.
signals for the two isomers, showed varying degrees of
selectivity with a definite trend. In some cases, the selectivity
was very high and we failed to see the peaks of the other isomer
in the NMR spectrum. The results of the GB reaction for all of
the substrates are shown in Table 1. As the molecular masses
are the same for the starting material as well as for the products
observed in the DEPT-135 spectrum. The alternate structure
9a would have shown 11 aryl C−H signals (Scheme 4). H
1
NMR in d6-acetone also clearly showed the presence of two
one-proton singlets, which is possible only for structure 12a
(for the spectrum see the Supporting Information)
The greater participation of the imidazole nucleus during the
GB reaction encouraged us to proceed with the synthesis of a
key intermediate, namely the dialdehyde 31 (in an overall yield
of 63% starting from 6c), used en route to the marine alkaloid
analogue 7′-desmethylkealiiquinone (32). In an earlier report,7
1
and H NMR provides very little discriminatory information,
the structures of the products were confirmed on the basis of
13C NMR spectra. For a representative example, the structure
elucidation of product 12a was based upon 13 aryl C−H signals
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Scheme 3. Synthesis of Target Bis-Propargyl Systems
the dialdehyde was obtained by an intramolecular Diels−Alder
reaction of the propargyl ester followed by reduction of the
lactone and subsequent oxidation. We recognized that the same
dialdehyde could be prepared by the HNO3-mediated oxidation
of the phthalan 30,8 obtainable in one step via the GB
cyclization of 29 (Scheme 5). The latter was synthesized from
N-benzyl-4-iodoimidazole (6c) via oxidation to imidazolone 28
following the literature procedure of Lovely et al.9 followed by a
Sonogashira coupling. Here because of the greater electron-
withdrawing character of imidazolone, only the desired isomer
was obtained during GB cyclization in excellent yield. To our
delight, the phthalan could be oxidized directly to the
dialdehyde 31 by a carefully controlled oxidation with nitric
acid. The product matched that reported in the literature in all
respects (the two 13C NMR spectra are shown in Figure 2).7
The rationale behind the observed selectivity for the GB
cyclization was based upon the relative nucleophilic character of
the two radicals in the diradical intermediate. We realized a
basic difference between the sulfone and the ether. Since the
sulfone is an electron-accepting group, captodative stabiliza-
tion10 (16; Figure 3) will increase the nucleophilicity of the
radical adjacent to the donor ring. In the case of ether, the
situation is reverse. The vinyl ether functionality now acts as a
donor and the more nucleophilic radical will be that adjacent to
the electron-withdrawing aryl/heteroaryl group, as that will lead
to captodative stabilization (19; Figure 3). Thus, in this case,
we expect a greater participation of the electron-withdrawing
aryl group in the formation of the product.
The experimental results are also in conformity with the
above rationale. For example, in the case of pyridine-substituted
systems, the radical adjacent to the pyridine ring is expected to
have greater negative character, as it is more stabilized by the
pyridine nucleus in comparison to the phenyl or 4-
methoxyphenyl group (Figure 4). In the case of a competition
between indole and phenyl, the former (being a better electron
donor) destabilizes the anion adjacent to it. Hence, the major
product was formed via the involvement of the aryl ring. The
results obtained for the naphthyl or methoxyphenyl systems
could also be explained similarly. For the GB reaction of the
imidazole-based bis-propargyl ether, the reason for the
preferential participation of the imidazole ring is not clear. It
may be due to the involvement of the lone pair on the benzyl-
attached nitrogen N(1) preferentially delocalizing with C2
N(3) (shown in structure 26), which reduces the electron-
donating capability of the imidazole ring in comparison to the
aryl ring.11 Replacing the imidazole with a more electron
withdrawing imidazolone ring as in 29 led to the formation of
only the product 30, involving the sole participation of the
imidazolone ring, thus supporting our explanation. The
sulfonamides, expectedly, showed a selectivity trend similar to
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Table 1. Results of GB Cyclization
SM
X
A
R
reaction conditions
yield (%)
product ratio
1a
2a
1b
2b
1c
2c
1d
1e
1f
O
1-benzyl-3-indolyl
1-benzyl-3-indolyl
2-pyridyl
H
110 °C, 5 h, KOtBu
110 °C, 6 h, KOtBu
110 °C, 2 h, KOtBu
110 °C, 3 h, KOtBu
110 °C, 11 h, KOtBu
110 °C, 9 h, KOtBu
60 °C, 1 h, KOtBu
60 °C, 1 h, KOtBu
110 °C, 30 min, KOtBu
80 °C, 2 h, KOtBu
110 °C, 24 h, DBN
110 °C, 18 h, DBN
110 °C, 26 h, DBN
120 °C, 12 h, DBU
120 °C, 12 h, DBU
120 °C, 12 h, DBU
120 °C, 12 h, DBU
83
80
94
97
55
60
97
94
95
94
65
71
51
80
75
73
76
only 12a
O
OMe
H
1:4 10a:13a
only 9b
O
O
2-pyridyl
OMe
H
only 10b
O
1-benzyl-4-imidazolyl
1-benzyl-4-imidazolyl
2-naphthyl
2:1 9c:12c
only 10c
O
OMe
H
O
1.6:1 9d:12d
1:1.25 9e:12e
1:8 9f:12f
O
6-methoxynaphthyl
4-methoxyphenyl
2,4-dimethoxyphenyl
1-benzyl-3-indolyl
2-pyridyl
H
O
H
1g
3a
3b
3c
3d
3e
3f
O
H
1:8 9g:12g
1:4 11a:14a
only 11b
NTs
NTs
NTs
NTs
NTs
NTs
NTs
H
H
1-benzyl-4-imidazolyl
2-naphthyl
H
only 11c
H
1.91:1 11d:14d
2.43:1 11e:14e
1:4.88 11f:14f
1:3.95 11g:14g
6-methoxynaphthyl
4-methoxyphenyl
2,4-dimethoxyphenyl
H
H
3g
H
that of the ethers. However, the selectivity trend is less in case
of the bis-aryl sulfonamides and in some cases the selectivity is
opposite to what has been observed for the corresponding ether
(for 3e and 1e). The differential aromaticity (between
naphthalene and benzene systems) may be a factor here but
needs further exploration.
analogue. Our future research is aimed toward distinguishing
the two mechanisms, namely diradicals vs anionic DA, as well
as the synthesis of other natural products of the kealiinine and
kealiiquinone family, including a study of their biological
activities.
It should be pointed out here that Kudoh et al.12,13 in a
recent paper has proposed an anionic [4 + 2] (Diels−Alder)
mechanism involving a monoallene for the rearrangement of
bis-propargyl ethers to arylnaphthalenes. Although their
proposal was mainly based on the reactivity of a disubstituted
substrate capable of isomerization to monoallene only,
nevertheless, these authors have extended this anionic
mechanism to ethers that also have the possibility of
isomerization to bis-allene. We have considered this mechanism
and realized that our observed selectivity can also be explained
on the basis of this anionic DA reaction involving monoallene,
which will be formed more easily from the propargyl arm
attached to the more electron-withdrawing aryl/heteroaryl ring,
which thus preferentially participates (Scheme 6). We are
presently carrying out computations to evaluate the energetics
for both mechanisms along with the effect of spin traps on the
kinetics of the reaction. The results will be reported in due
course.
EXPERIMENTAL SECTION
■
1
All H and 13C NMR spectra were respectively recorded at 400 and
100 MHz in CDCl3 unless mentioned otherwise. ESI-MS and HRMS
were obtained using a LCT mass spectrometer; solutions of the
compounds were injected directly into the spectrometer via a
Rheodyne injector equipped with a 10 μL loop. A 20 micro LC
syringe pump delivered the solution to the vaporization nozzle of the
electrospray ion source at a flow rate of 3 μL min−1. Nitrogen was used
both as a drying gas and for nebulization with flow rates of
approximately 3 L min−1 and 100 mL min−1, respectively. Pressure
in the analyzer region was usually about 3 × 10−5 Torr. IR spectra were
recorded as thin films, and bands are expressed in cm−1. In all
purifications by silica gel chromatography, ethyl acetate/hexane (68
°C) was used as the eluent.
General Procedure for the Sonogashira Coupling. To a
degassed solution of the respective iodo and bromo aromatic
compounds 6a−g (2 mmol), CuI (20 mol %), and propargyl alcohol
or propargylamine-p-toluenesulfonamide (1.2 equiv) in 20 mL of
triethylamine was added 3 mol % of Pd(PPh3)2Cl2, and the mixture
was stirred for 3 h at room temperature. The reaction mixture was
then poured into ethyl acetate (15 mL), and the organic layer was
washed with saturated NH4Cl solution and brine (30 mL each) and
dried over anhydrous Na2SO4. Evaporation of the solvent left an oily
residue, from which the product was isolated by column chromatog-
raphy (silica gel, hexane/ethyl acetate mixture as eluent).
In conclusion, we have demonstrated the selective nature of
GB reactions of various bis-propargyl ethers and amines
containing combinations of heteroaryl and aryl substituents at
the acetylene ends. A general guideline for achieving the
selectivity for these systems has been formulated. As a followup
of the results, we have achieved the formal synthesis of 7′-
desmethylkealiiquinone, a marine imidazolone natural product
General Procedure for the O- and N-Propargylation. To an
ice-cold solution of the alcohol or propargylamine-p-toluenesulfona-
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Scheme 4. Expected 13C NMR Signals of Products
evaporated and dried (Na2SO4). Silica gel column chromatography
furnished the desired product with ethyl acetate/hexane as eluent.
1-Benzyl-3-(3-(3-phenylprop-2-ynyloxy)prop-1-ynyl)-1H-indole
(1a): state, light yellow oil; Rf = 0.3 (hexane/EtOAc 9/1); yield 292
mg, 78%; IR (neat) νmax 2952, 2360, 2331, 1641, 1490, 1279, 1258,
1081, 749 cm−1; δH 7.79−7.77 (m, 1 H), 7.50−7.47 (m, 2 H), 7.35−
7.25 (m, 8 H), 7.23−7.18 (m, 2 H) 7.14−7.11 (m, 2 H), 5.29 (s, 2 H),
4.64 (s, 2 H), 4.60 (s, 2 H); δC 136.5, 135.7 132.2, 131.8, 129.4, 128.8,
128.4, 128.2, 127.9, 126.9, 122.8, 122.6, 120.6, 120.2, 110.0, 96.9, 86.6,
86.0, 84.7, 80.5, 57.8, 57.1, 50.3; HRMS calcd for C27H21NO + H+
376.1701, found 376.1699.
Scheme 5. Formal Total Synthesis of 7′-
Desmethylkealiiquinone
1-Benzyl-3-(3-(3-(4-methoxyphenyl)prop-2-ynyloxy)prop-1-ynyl)-
1H-indole (2a): state, yellow sticky mass; Rf = 0.4 (hexane/EtOAc 10/
1); yield 307 mg, 76%; IR (neat) νmax 2958, 2360, 2331, 1606, 1464,
1273, 1249, 1077, 764 cm−1; δH 7.80−7.75 (m, 1 H), 7.44−7.42 (m, 2
H), 7.35 (s, 1 H), 7.32−7.28 (m, 4 H), 7.24−7.20 (m, 2 H), 7.14−7.12
(m, 2 H), 6.86−6.84 (m, 2 H), 5.28 (s, 2 H), 4.63 (s, 2 H), 4.58 (s, 2
H), 3.81 (s, 3 H); δC 159.7, 136.5, 135.7,133.3, 132.2, 129.4, 128.9,
127.9, 126.9, 122.8, 120.6, 120.2, 114.7, 113.9, 110.0, 97.0, 86.5, 86.2,
83.0, 80.5, 57.8, 57.2, 55.3, 50.3; HRMS calcd for C28H23NO2 + H+
406.1807, found 406.1811.
2-(3-(3-Phenylprop-2-ynyloxy)prop-1-ynyl)pyridine (1b): state,
brown solid; Rf = 0.4 (hexane/EtOAc 1/1); mp 118−120 °C; yield
224 mg, 91%; IR (neat) νmax 2952, 2355, 2090, 1766, 1633, 1461,
1276, 1050, 764 cm−1; δH 8.56−8.53 (m, 1 H), 7.63−7.58 (m, 1 H),
7.44−7.40 (m, 3 H), 7.30−7.25 (m, 3H), 7.22−7.18 (m, 1 H), 4.55 (d,
J = 2.0 Hz, 2 H), 4.53 (d, J = 2.0 Hz, 2 H); δC 150.0, 142.7, 136.2,
131.8, 128.6, 128.3, 127.2, 123.1, 122.5, 87.0, 86.1, 84.6, 84.3, 57.6,
57.1; HRMS calcd for C17H13NO + H+ 248.1075, found 248.1077.
2-(3-(3-(4-Methoxyphenyl)prop-2-ynyloxy)prop-1-ynyl)pyridine
(2b): state, brown semisolid; Rf = 0.4 (hexane/EtOAc 1/1); yield 217
mg, 88%; IR (neat) νmax 2950, 2361, 2331, 1644, 1460, 1273, 1249,
mide derivatives (1 mmol) in dry THF or dry DMF (5 mL) was added
NaH (2 equiv, 60% suspension in mineral oil) or dry K2CO3 (2 equiv),
and the mixture was stirred. With the temperature maintained in ice,
1.1 equiv of the respective propargyl bromide (7, 8, 5d−g) was added
dropwise as a solution in THF or DMF (1 mL) and the reaction
mixture was stirred at room temperature for 1 h. It was then quenched
by slow addition of NH4Cl solution (2 mL) and then partitioned
between water and ethyl acetate (3 × 20 mL). The organic layer was
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Figure 2. 13C NMR spectra of the dialdehyde 31 (prepared via the route described here and reported).
Figure 3. Captodative stabilization of the nucleophilic radical.
Figure 4. Radical stabilization for pyridine and imidazole systems.
Scheme 6. Explanation of Selectivity Based on Anionic Diels−Alder Mechanism As Proposed by Kudoh et al.12
764 cm−1; δH 8.56−8.54 (m, 1 H), 7.64−7.59 (m, 1 H), 7.43−7.40 (m,
1 H), 7.39−7.35 (m, 2 H), 7.22−7.19 (m, 1 H), 6.82−6.79 (m, 2 H),
4.54 (m, 2 H), 4.52 (m, 2 H), 3.76 (m, 3 H); δC 159.9, 150.1, 142.8,
136.2, 133.4, 127.3, 123.2, 144.6, 144.0, 87.0, 86.0, 84.8, 82.9, 57.8,
57.1, 55.3; HRMS calcd for C18H15NO2 + H+ 278.1181, found
278.1187.
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1-Benzyl-4-(3-(3-phenylprop-2-ynyloxy)prop-1-ynyl)-1H-imida-
zole (1c): state, yellow viscous liquid; Rf = 0.3 (hexane/EtOAc 8/1);
yield 221 mg, 68%; IR (neat) νmax 2976, 2952, 2850, 2360, 2078, 1644,
1487, 1258, 1075, 757 cm−1; δH 7.51 (s, 1 H), 7.45−7.43 (m, 2 H),
7.37−7.29 (m, 6 H), 7.17−7.08 (m, 2 H), 6.97 (s, 1 H), 5.08 (s, 2 H),
4.51 (s, 4 H); δC 139.0, 137.5, 135.4, 132.0, 129.3, 128.8, 128.6, 128.4,
127.7, 127.6, 125.0, 124.2, 123.8, 122.7, 86.8, 84.8, 84.6, 80.5, 57.5,
57.4, 51.4; HRMS calcd for C22H18N2O + H+ 327.1497, found
327.1499.
1-Benzyl-4-(3-(3-(4-methoxyphenyl)prop-2-ynyloxy)prop-1-ynyl)-
1H-imidazole (2c): state, orange liquid; Rf = 0.3 (hexane/EtOAc 8/1);
yield 249 mg, 70%; IR (neat) νmax 2978, 2950, 2848, 2362, 2078, 1640,
1487, 1259, 1075, 756 cm−1; δH 7.47 (s, 1 H), 7.37−7.35 (m, 5 H),
7.18−7.14 (m, 2 H), 7.08 (s, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 5.07 (s, 2
H), 4.50 (s, 2 H), 4.49 (s, 2 H), 3.80 (s, 3 H); δC 159.8, 137.4, 133.4,
129.2, 128.7, 128.6, 127.6, 127.5, 114.7, 113.9, 86.7, 84.7, 83.1, 80.4,
57.4, 57.3, 55.3, 51.2; HRMS calcd for C23H20N2O2 + H+ 357.1603,
found 357.1607.
2-[3-(3-Phenylprop-2-ynyloxy)prop-1-ynyl]naphthalene (1d):
state, brown liquid; Rf = 0.5 (hexane/EtOAc 30/1); yield 180 mg,
61%; IR (neat) νmax 3061, 2926, 2851, 2232, 1723, 1493, 1079, 754
cm−1; δH 8.06 (s, 1 H), 7.86−7.81 (m, 3 H), 7.56−7.52 (m, 5 H),
7.37−7.36 (bs, 3 H), 4.65 (s, 2 H), 4.64 (s, 2 H); δC (50 MHz): 133.0,
131.9, 128.7, 128.6, 128.5, 128.2, 127.9, 126.9, 126.7, 122.7, 119.9,
87.3, 87.0, 84.9, 84.6, 57.7; HRMS calcd for C22H16O + Na+ 319.1099,
found 319.1099.
2-Methoxy-6-[3-(3-phenylprop-2-ynyloxy)prop-1-ynyl]-
naphthalene (1e): state, gummy liquid; Rf = 0.5 (hexane/EtOAc 20/
1); yield 195 mg, 60%; IR (neat) νmax 3066, 2971, 2851, 2223, 1628,
1488, 1079, 759 cm−1; δH 7.96 (s, 1 H), 7.72−7.69 (m, 2 H), 7.54
(app s, 3 H), 7.37−7.35 (comp, 3 H), 7.19 (d, J = 8.0 Hz, 1 H), 7.12
(s, 1 H), 4.64 (s, 4 H), 3.92 (s, 3 H); δC (50 MHz): 158.5, 134.4,
131.9, 131.8, 129.4, 129.1, 128.6, 128.4, 126.9, 122.6, 119.5, 117.4,
105.8, 87.5, 86.9, 84.6, 84.1, 57.7, 57.5, 55.4; HRMS calcd for
C23H18O2 + Na+ 349.1204, found 349.1205.
127.4, 123.4, 122.3, 86.2, 85.0, 82.3, 81.6, 37.8, 37.4, 21.5; HRMS calcd
for C24H20N2O2S + H+ 401.1324, found 401.1324.
N-(3-(1-Benzyl-1H-imidazol-4-yl)prop-2-ynyl)-4-methyl-N-(3-phe-
nylprop-2-ynyl)benzenesulfonamide (3c): state, dark red gummy oil;
Rf = 0.3 (hexane/EtOAc 3:2); yield 239 mg, 50%; IR (neat) νmax 2958,
2856, 2360, 1635, 1457, 1279, 1159, 764 cm−1; δH 7.75 (d, J = 8.0 Hz,
2 H), 7.45 (s, 2 H), 7.35−7.34 (m, 3 H), 7.23−7.19 (m, 5 H), 7.15−
7.12 (m, 3 H), 6.89 (s, 1 H), 5.02 (s, 2 H), 4.41 (s, 2 H), 4.36 (s, 2 H),
2.24 (s, 3 H); δC 143.9, 137.5, 135.7, 135.5, 132.3, 132.2, 131.9, 129.8,
129.4, 128.8, 128.7, 128.6, 128.3, 128.2, 127.7, 86.0, 82.1, 81.8, 79.6,
51.4, 37.7, 37.5, 21.6; HRMS calcd for C29H25N3O2S + H+ 480.1746,
found 480.1751.
4-Methyl-N-(3-naphthalen-2-ylprop-2-ynyl)-N-(3-phenylprop-2-
ynyl)benzenesulfonamide (3d): state, yellow solid; Rf = 0.5 (hexane/
EtOAc 5/1); yield 314 mg, 70%; IR (neat) νmax 3061, 2926, 2856,
2237, 1603, 1493, 1363, 1169, 754 cm−1; δH 7.87−7.81 (m, 4 H), 7.33
(app d, J = 4.0 Hz, 2 H), 7.52−7.50 (m, 2 H), 7.28−7.26 (m, 7 H),
7.15 (app d, J = 4.0 Hz, 1 H), 4.53 (s, 2 H), 4.52 (s, 2 H), 2.31 (s, 3
H); δC 143.9, 135.4, 132.9, 132.8, 131.8, 131.7, 131,6, 129.7, 128.6,
128.5, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.5, 126.9, 126.7,
122.2, 119.5, 86.3, 85.9, 82.0, 81.8, 37.8, 37.7, 21.5; HRMS calcd for
C29H23NO2S + Na+ 472.1347, found 472.1348.
N-[3-(6-Methoxynaphthalen-2-yl)prop-2-ynyl]-4-methyl-N-(3-
phenylprop-2-ynyl)benzenesulfonamide (3e): state, gummy oil; Rf =
0.5 (hexane/EtOAc 5/1); yield 350 mg, 73%; IR (neat) νmax 3051,
2966, 2926, 2856, 2232, 1633, 1488, 1348, 1163, 1094, 759 cm−1; δH
7.82 (d, J = 8.0 Hz, 2 H), 7.64−7.60 (m, 3 H), 7.30−7.24 (m, 8 H),
7.21−7.09 (m, 1 H), 7.08 (s, 1 H), 4.48 (s, 4 H), 3.92 (s, 3 H), 2.30 (s,
3 H); δC 158.5, 143.9, 135.5, 134.3, 131.8, 131.6, 129.8, 129.7, 129.3,
128.9, 128.6, 128.3, 128.2, 128.1, 127.6, 126.7, 122.3, 119.6, 117.2,
105.8, 86.4, 85.9, 81.9, 81.3, 55.4, 37.8, 37.7, 21.6; HRMS calcd for
C30H25NO3S + Na+ 502.1453, found 502.1453.
N-[3-(2,4-Dimethoxyphenyl)prop-2-ynyl]-4-methyl-N-(3-phenyl-
prop-2-ynyl)benzenesulfonamide (3g): state, viscous liquid; Rf = 0.5
(hexane/EtOAc 5/1); yield 298 mg, 65%; %; IR (neat) νmax 3052,
2961, 2926, 2854, 2231, 1635, 1470, 1349, 1161, 1094, 754 cm−1; δH
7.79 (d, J = 8.0 Hz, 2 H), 7.26−7.17 (comp, 6 H), 7.06 (d, J = 8.0 Hz,
2 H), 6.37 (app d, J = 8.0 Hz, 2 H), 4.46 (s, 4 H), 3.80 (s, 6 H), 2.30
(s, 3 H); δC 161.4, 143.7, 137.5, 135.6, 134.4, 131.7, 130.3, 129.5,
128.4, 128.2, 128.0, 122.4, 104.7, 104.1, 98.3, 85.6, 84.2, 82.4, 81.9,
55.8, 55.5, 37.9, 37.3, 21.5; HRMS calcd for C27H25NO4S + Na+
482.1402, found 482.1402.
1-Methoxy-4-[3-(3-phenylprop-2-ynyloxy)prop-1-ynyl]benzene
(1f): state, yellow viscous liquid; Rf = 0.5 (hexane/EtOAc 20/1); yield
165 mg, 60%; IR (neat) νmax 3061, 2972, 2851, 2232, 1620, 1482,
1049, 754 cm−1; δH 7.51−7.50 (bm, 2 H), 7.44 (d, J = 8.4 Hz, 2 H),
7.34 (bs, 3 H), 6.86 (d, J = 8.4 Hz, 2 H), 4.57(s, 4 H), 3.79 (s, 3 H);
δC 159.9, 138.3, 133.4, 131.9, 128.4, 122.6, 116.5, 114.7, 114.0, 86.8,
84.7, 83.2, 57.6, 57.4, 55.3; HRMS calcd for C19H16O2 + Na+
299.1048, found 299.1049.
N-[3-(4-Methoxyphenyl)prop-2-ynyl]-4-methyl-N-(3-phenylprop-
2-ynyl)benzenesulfonamide (3f): state, gummy liquid; Rf = 0.5
(hexane/EtOAc 5/1); yield 300 mg, 69%; IR (neat) νmax 3061, 2926,
2851, 2242, 1603, 1463, 1348, 1158, 1089, 749 cm−1; δH 7.81 (d, J = 8
Hz, 2 H), 7.28−7.21 (comp, 7 H), 7.18 (d, J = 8.0 Hz, 2 H), 6.80 (d, J
= 8.0 Hz, 2 H), 4.46 (s, 2 H), 4.44 (s, 2 H), 3.82 (s, 3 H), 2.35 (s, 3
H); δC (50 MHz): 159.9, 143.9, 135.6, 133.3, 131.8, 129.7, 128.6,
128.3, 128.1, 122.4, 114.4, 113.9. 85.9, 81.9, 80.4, 55.4, 37.7, 37.6, 21.5;
HRMS calcd for C26H23NO3S + Na+ 452.1296, found 452.1297.
General Procedure for the GB Rearrangement of the Bis-
Propargyl Ether and Sulfonamide. To an ice-cold solution of the
ether (0.3 mmol) or amine (0.3 mmol) in dry toluene (10 mL) was
added 2 equiv of KOtBu (for the ether) or DBN/DBU (for the
amine). After removal of the ice bath, the reaction mixture was
warmed to room temperature and heated gradually to reflux for 5−6 h
in a preheated oil bath at 110 °C. The solvent was then evaporated,
and the crude mass was purified via silica gel column filtration with
hexane/ethyl acetate as eluent.
1-Benzyl-3-(1,3-dihydronaphtho[2,3-c]furan-4-yl)-1H-indole
(12a). state, colorless liquid; Rf = 0.3 (hexane/EtOAc 9/1); yield 93
mg, 83%; IR (neat) νmax 2957, 2921, 2850, 2310, 2342, 1630, 1218,
1052, 772 cm−1; δH 7.98 (d, J = 8.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H),
7.74 (s, 1 H), 7.52 (dt, J = 8.0, 1.6 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H),
7.43−7.34 (m, 6 H), 7.31 (dt, J = 7.4, 1.2 Hz, 1H), 7.24 (dd, J = 6.8
Hz, 1 H), 7.22 (s, 1 H), 7.15 (dt, J = 8.0, 1.2 Hz, 1 H), 5.44 (s, 2 H),
5.38 (s, 2 H), 5.15 (dd, J = 12.8, 10.4 Hz, 2 H); δC 138.4, 137.9, 137.4,
136.7, 133.9, 132.9, 129.0, 128.2, 127.9, 127.5, 126.9, 126.5, 122.3,
2,4-Dimethoxy-1-[3-(3-phenylprop-2-ynyloxy)prop-1-ynyl]-
benzene (1g): state, Yellow liquid; Rf = 0.5 (hexane/EtOAc 20/1);
yield 199 mg, 65%; %; IR (neat) νmax 3016, 2931, 2851, 2227, 1613,
1508, 1079, 764 cm−1; δH 7.47−7.45 (m, 2 H), 7.36 (d, J = 8.0 Hz, 2
H), 7.32−7.30 (m, 2 H), 6.45 (app d, J = 4.0 Hz, 1 H), 6.43 (s, 1 H),
4.58 (s, 2 H), 4.56 (s, 2 H), 3.86 (s, 3 H), 3.81 (s, 3 H); δC 161.6,
161.5, 134.8, 131.9, 128.4, 122.8, 104.9, 104.4, 98.6, 87.1, 86.7, 84.9,
83.4, 57.9, 57.4, 55.9, 55.6; HRMS calcd for C20H18O3 + Na+
329.1154, found 329.1154.
N-(3-(1-Benzyl-1H-indol-3-yl)prop-2-ynyl)-4-methyl-N-(3-phenyl-
prop-2-ynyl)benzenesulfonamide (3a): state, light yellow semisolid;
Rf = 0.3 (hexane/EtOAc 1/1); yield 324 mg, 61%; IR (neat) νmax
2958, 2952, 2358, 2084, 1637, 1460, 1276, 1080, 764 cm−1; δH 7.81 (d,
J = 7.6 Hz, 2 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.31−7.27 (m, 4 H), 7.26−
7.20 (m, 8 H), 7.17−7.10 (m, 4 H), 5.25 (s, 2 H), 4.52 (s, 2 H), 4.50
(s, 2 H), 2.22 (s, 3 H); δC 143.7, 136.5, 135.7, 135.6, 132.0, 131.7,
129.7, 129.6, 129.3, 128.9, 128.4, 128.2, 128.0, 126.9, 122.9, 122.4,
120.6, 120.1, 115.7, 110.1, 96.8, 85.7, 83.3, 82.0, 79.6, 50.3, 38.0, 37.4,
21.4; MS: m/z = 529 [MH+]. HRMS calcd for C34H28N2O2S + H+
529.1950, found 529.1956.
4-Methyl-N-(3-phenylprop-2-ynyl)-N-(3-(pyridin-2-yl)prop-2-
ynyl)benzenesulfonamide (3b): state, brown gummy liquid; Rf = 0.5
(hexane/EtOAc 1/1); yield 260 mg, 65%; IR (neat) νmax 2956, 2361,
1644, 1463, 1259, 1079, 762 cm−1; δH 8.51 (d, J = 4.0 Hz, 1 H), 7.77
(d, J = 7.6 Hz, 2 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.28−7.20 (m, 5 H),
7.18−7.13 (m, 4 H), 4.46 (s, 2 H), 4.44 (s, 2 H), 2.26 (s, 3 H); δC
150.0, 144.1, 142.4, 136.3, 135.5, 131.8, 129.8, 128.7, 128.3, 128.1,
3795
dx.doi.org/10.1021/jo402749d | J. Org. Chem. 2014, 79, 3789−3798

The Journal of Organic Chemistry
Article
120.7, 120.0, 118.6, 112.6, 110.1, 73.7, 73.6, 61.5, 50.3; HRMS calcd
for C27H21NO + H+ 376.1701, found 376.1663.
0.5 (hexane/EtOAc 20/1); yield 86 mg, 97%; IR (neat) νmax 2924,
2854, 1657, 1462, 1051, 753 cm−1; δH 8.00−7.68 (comp, 10 H, major
+ minor), 7.59−7.34 (comp, 13 H, major + minor), 7.12 (td, J = 8.0,
4.0 Hz, 1 H, major), 5.38 (s, 2 H, major), 5.34 (s, 2 H, minor), 5.12,
5.04 (ABq, J = 12.0 Hz, 2 H, minor), 4.96 (s, 2 H, major); δC (major +
minor) 142.6, 139,7, 137.7, 137.4, 137.2, 135.7, 133.7, 133.6, 133.5,
132.8, 132.5, 131.9, 130.8, 130.1, 129.6, 128.8, 128.5, 128.4, 128.3,
128.2, 127.9, 127.7, 127.6, 127.5, 126.5, 126.4, 125.9, 125.8, 125.7,
125.2, 120.3, 74.0,73.9, 73.4, 72.9; HRMS calcd for C22H16O + Na+
319.1099, found 319.1099.
4-(6-Methoxynaphthalen-2-yl)-1,3-dihydronaphtho[2,3-c]furan
(12e, major) and 3-methoxy-11-phenyl-8,10-dihydro-9-
oxacyclopenta[b]phenanthrene (9e, minor) (9e:12e = 1:1.25):
state, yellow gummy mass; Rf = 0.5 (hexane/EtOAc 15/1); yield 92
mg, 94%; IR (neat) νmax 2924, 2852, 1608, 1460, 1049, 751 cm−1; δH
7.88 (t, J = 8.0 Hz, 2 H, major), 7.78−7.72 (m, 6 H, minor), 7.65 (d, J
= 8.0 Hz, 1 H, minor), 7.55−7.44 (m, 5 H, major, 1 H, minor), 7.38
(d, J = 8.0 Hz, 1 H, minor), 7.33 (d, J = 8.0 Hz, 2 H, major), 7.25 (d, J
= 8.0 Hz, 2 H, major), 7.21 (t, J = 4.0 Hz, 1 H, minor), 6.72 (dd, J =
8.0 Hz, 4 Hz, 1 H, minor), 5.35−5.30 (m, 4 H, major + minor), 5.09,
5.02 (ABq, J = 12.0 Hz, 2 H, major), 4.92 (s, 2 H, minor), 3.98 (s, 3 H,
major), 3.88 (s, 3 H, minor); δC (50 MHz) (major + minor) 158.2,
157.5, 142.7, 137.9, 137.3, 136.6, 134.1, 133.9, 133.5, 132.9, 132.7,
132.2, 129.8, 129.3, 129.1, 128.5, 128.4, 128.3, 127.7, 127.2, 126.0,
125.9, 125.8, 120.5, 119.5, 118.9, 115.3, 109.0, 105.9, 74.1, 73.6, 73.2,
55.6, 55.4; HRMS calcd for C23H18O2 + Na+ 349.1204, found
349.1204.
4-(4-Methoxyphenyl)-1,3-dihydronaphtho[2,3-c]furan (12f,
major) and 6-methoxy-4-phenyl-1,3-dihydronaphtho[2,3-c]furan
(9f, minor) (9f:12f = 1:8): state, gummy yellow solid; Rf = 0.5
(hexane/EtOAc 10/1); yield 79 mg, 95%; IR (neat) νmax 2923, 2853,
1634, 1462, 1053, 752 cm−1; δH 7.86 (d, J = 8.0 Hz, 1 H, major), 7.72
(d, J = 8.0 Hz, 1 H, major), 7.67 (s, 1 H, major), 7.46 (t, J = 8.0 Hz, 1
H, major), 7.38 (t, J = 8.0 Hz, 1 H, major), 7.29 (d, J = 8.0 Hz, 2 H,
major), 7.04 (d, J = 8.0 Hz, 2 H, major), 5.29 (s, 2 H, major), 5.27 (s, 2
H, minor), 5.03 (s, 2 H, major), 5.00 (s, 2 H, minor), 3.90 (s, 6 H,
major + minor); δC (50 MHz) (major + minor) 159.3, 137.8, 137.2,
133.9, 132.5, 132.3, 130.8, 130.5, 128.3, 125.9, 125.8, 125.7, 118.7,
114.2, 73.6, 73.2, 55.5; HRMS calcd for C19H16O2 + Na+ 299.1048,
found 299.1048.
4-(2,4-Dimethoxyphenyl)-1,3-dihydronaphtho[2,3-c]furan (12g,
major) and 6,8-dimethoxy-4-phenyl-1,3-dihydronaphtho[2,3-
c]furan (9g, minor) (9g:12g = 1:8): state, pale yellow gummy solid;
yield 86 mg, 94%; δH 7.85 (d, J = 8.0 Hz, 1 H, major), 7.67 (s, 1 H,
major), 7.58 (d, J = 12 Hz, 1 H, major), 7.44 (td, J = 8.0, 4.0 Hz, 1 H,
major), 7.35 (app td, J = 8.0, 4.0 Hz, 1 H, major), 7.12 (d, J = 8.0 Hz, 1
H, major), 6.64 (m, 1 H, major), 6.61 (d, J = 4.0 Hz, 1 H, major), 6.56
(s, 1 H, minor), 6.52 (s, 1 H, minor), 5.30 (s, 4 H, major + minor),
4.98 (app s, 4 H, major + minor), 3.90 (s, 6 H, major + minor), 3.69
(s, 6 H, major + minor); HRMS calcd for C20H18O3 + Na+ 329.1154,
found 329.1154.
1-Benzyl-3-(6-methoxy-1,3-dihydronaphtho[2,3-c]furan-4-yl)-
1H-indole (13a). state, yellow gummy mass; Rf = 0.2 (hexane/EtOAc
9/1); yield 78 mg, 64%; IR (neat) νmax 2958, 2922, 2851, 2361, 2343,
1628, 1219, 1052, 772 cm−1; δH 7.78 (d, J = 9.2 Hz, 1 H), 7.63 (s, 1
H), 7.44 (d, J = 8.4 Hz, 1 H), 7.35−7.31 (m, 3 H), 7.29−7.24 (m, 3
H), 7.22−7.19 (m, 3 H) 7.16−7.09 (m, 2 H), 5.46, 5.43 (Abq, J =
16.0, 4.4 Hz, 2 H), 5.30 (s, 2 H), 5.06 (s, 2 H), 3.60 (s, 3 H); δC 157.7,
138.9, 137.6, 136.9, 135.6, 134.1, 129.6, 129.5, 129.1, 128.0, 127.7,
127.5, 127.0, 124.5, 122.4, 120.9, 120.0, 118.5, 118.3, 112.9, 110.2,
105.2, 73.8, 73.7, 55.2, 50.3; HRMS calcd for C28H23NO2 + H+
406.1807, found 406.1783.
9-Benzyl-10-phenyl-3,9-dihydro-1H-2-oxa-9-azacyclopenta[b]-
fluorene (10a): state, orange oil; Rf = 0.4 (hexane/EtOAc 9/1); yield
20 mg, 16%; IR (neat) νmax 2956, 2922, 2851, 2360, 2342, 1627, 1508,
1458, 1246, 1176, 1055, 772 cm−1; δH 8.12 (d, J = 8.0 Hz, 1 H), 7.96
(s, 1 H), 7.37 (dt, J = 8.4, 1.2 Hz, 1 H), 7.27−7.20 (m, 3 H), 7.13−
7.03 (m, 3 H), 7.02−7.00 (m, 2 H) 6.75−6.73 (m, 2 H), 6.56 (d, J =
7.6 Hz, 2 H), 5.33 (s, 2 H), 5.10 (s, 2 H), 4.88 (s, 2 H), 3.82 (s, 3 H);
δC 159.2, 142.3, 138.5, 138.0, 137.9, 130.5, 130.3, 129.2, 128.3, 126.9,
126.1, 125.7, 124.6, 122.8, 120.0, 119.6, 119.4, 113.8, 11.4, 109.6, 74.2,
73.7, 55.4, 47.8; HRMS calcd for C28 H23NO2 + H+ 406.1807, found
406.1809.
5-Phenyl-6,8-dihydrofuro[3,4-g]quinoline (9b): state, yellow solid;
Rf = 0.4 (hexane/EtOAc 1/1); mp 144−145 °C; yield 70 mg, 94%; IR
(neat) νmax 2959, 2922, 2851, 2361, 2343, 1767, 1609, 1508, 1289,
1219, 1168, 1056, 772 cm−1; δH 8.85−8.82 (m, 1 H), 8.01−7.97 (m, 1
H), 7.94 (s, 1 H), 7.49−7.40 (m, 3 H), 7.30−7.24 (m, 3 H), 5.29 (s, 2
H), 5.01 (s, 2 H); δC 149.7, 148.3, 141.7, 137.4, 136.8, 134.1, 132.5,
129.4, 128.7, 128.0, 126.7, 120.7, 120.1, 73.3, 72.6; HRMS calcd for
C17H13NO + H+ 248.1075, found 248.1091.
5-(4-Methoxyphenyl)-6,8-dihydrofuro[3,4-g]quinoline (10b).
state, brown solid; Rf = 0.3 (hexane/EtOAc 1/1); mp 150−152 °C;
yield 81 mg, 97%; IR (neat) νmax 2961, 2851, 2360, 1628, 1508, 1458,
1351, 1246, 1219, 1163, 1053, 772 cm−1; δH 8.87 (dd, J = 4.0, 1.6 Hz,
1 H), 8.08 (dd, J = 5.4, 1.6 Hz, 1 H), 7.96 (s, 1 H), 7.32 (dd, J = 6.2,
4.0 Hz, 1 H), 7.28−7.24 (m, 2 H), 7.06−7.02 (m, 2 H), 5.33 (s, 2 H),
5.06 (s, 2 H), 3.89 (s, 3 H); δC 159.5, 149.8, 148.7, 141.8, 137.6, 134.2,
132.4, 130.7, 129.1, 127.0, 120.7, 120.1, 114.3, 73.4, 72.8, 55.4; HRMS
calcd for C18H15NO2 + H+ 278.1181, found 278.1198.
1-Benzyl-8-phenyl-3a,5,7,8a-tetrahydro-1H-isobenzofuro[5,6-d]-
imidazole (9c). state, whitish gum; Rf = 0.3 (hexane/EtOAc 1/1);
yield 36 mg, 37%; IR (neat) νmax 2955, 2921, 2851, 2360, 2342, 1636,
1219, 1055, 772 cm−1; δH 7.87 (s, 1 H), 7.64 (s, 1 H), 7.34 (t, J = 7.2
Hz, 1 H), 7.26 (t, J = 7.6 Hz, 2 H), 7.16−7.09 (m, 3 H), 7.04 (d, J =
7.2 Hz, 2 H) 6.47 (d, J = 7.6 Hz, 2 H), 5.24 (s, 2 H), 4.92 (s, 2 H),
4.84 (s, 2 H); HRMS calcd for C22H18N2O + H+ 327.1497, found
327.1495.
1-Benzyl-4-(1,3-dihydronaphtho[2,3-c]furan-4-yl)-1H-imidazole
(12c). state, white gum; Rf = 0.3 (hexane/EtOAc 1/1); yield, 18%; IR
(neat) νmax 2958, 2922, 2851, 2361, 2343, 1628, 1219, 1053, 772 cm−1;
δH 8.31−8.29 (m, 1 H), 7.87−7.81 (m, 1 H), 7.72 (s, 1 H), 7.62 (s, 1
H), 7.44−7.34 (m, 5 H), 7.28 (s, 2 H), 7.06 (s, 1 H), 5.26 (s, 2 H),
5.24 (s, 2 H), 5.23 (s, 2 H); δC 139.1, 138.1, 137.8, 137.5, 136.1, 134.0,
131.6, 129.7, 129.3, 128.7, 128.4, 127.5, 125.9, 125.6, 125.0, 119.2,
119.0, 115.5, 73.9, 73.3, 51.3; HRMS calcd for C22H18N2O + H+
327.1497, found 327.1494.
1-Benzyl-8-(4-methoxyphenyl)-3a,5,7,8a-tetrahydro-1H-
isobenzofuro[5,6-d]imidazole (10c): state, yellow oil; Rf = 0.4
(hexane/EtOAc 3:2); yield 64 mg, 60%; IR (neat) νmax 2956, 2922,
2851, 2365, 2344, 1628, 1219, 1053, 772 cm−1; δH 7.87 (s, 1 H), 7.63
(s, 1 H), 7.18−7.14 (m, 4 H), 6.97 (d, J = 8.0 Hz, 2 H), 6.79 (d, J = 8.0
Hz, 2 H), 6.55 (d, J = 8.0 Hz, 2 H), 5.25 (s, 2 H), 4.95 (s, 2 H), 4.85
(s, 2 H), 3.84 (s, 3 H); δC 159.4, 145.3, 145.0, 136.4, 135.3, 134.1,
130.4, 128.6, 127.9, 127.8, 126.2, 120.2, 113.8, 114.4, 73.9, 73.0, 55.5,
50.1; HRMS calcd for C23H20N2O2 + H+ 357.1603, found 357.1633.
11-Phenyl-8,10-dihydro-9-oxacyclopenta[b]phenanthrene (9d,
major) and 4-naphthalen-2-yl-1,3-dihydronaphtho[2,3-c]furan
(12d, minor) (9d:12d = 1.6:1): state, pale yellow sticky mass; Rf =
4-(2,4-Dimethoxyphenyl)-1,3-dihydronaphtho[2,3-c]furan (12g):
state, yellow solid; Rf = 0.5 (hexane/EtOAc 10/1); yield 76 mg, 82%;
IR (neat) νmax 2924, 2853, 1610, 1461, 1048, 754 cm−1; δH (DMSO-
d6): 7.91 (d, J = 8.0 Hz, 1 H), 7.78 (s, 1 H), 7.46−7.33 (m, 3 H), 7.09
(d, J = 8.0 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 8.2 Hz, 2.4
Hz,1 H), 5.17 (s, 2 H), 4.82, 4.73 (ABq, J = 12.0 Hz, 2 H), 3.83 (s, 3
H), 3.63 (s, 3 H); δC (DMSO-d6) 161.0, 158.1, 137.9, 133.7, 132.3,
131.9, 129.1, 128.6, 126.1, 125.9, 125.7, 119.1, 118.3, 105.8, 99.3, 72.9,
72.4, 55.9, 55.8; HRMS calcd for C20H18O3 + Na+ 329.1154, found
329.1154.
4-(1-Benzyl-1H-indol-3-yl)-2-tosyl-2,3-dihydro-1H-benzo[f ]-
isoindole (14a): state, light yellow sticky mass; Rf = 0.3 (hexane/
EtOAc 2/3); yield 83 mg, 52%; IR (neat) νmax 2957, 2921, 2850, 2361,
2342, 1628, 1508, 1458, 1249, 1159, 1054, 772 cm−1; δH 7.80 (t, J =
9.6 Hz, 2 H), 7.70 (d, J = 7.2 Hz, 2 H), 7.63 (s, 1 H), 7.45−7.36 (m, 4
H), 7.33−7.21 (m, 7 H), 7.14 (s, 1 H), 7.10−7.06 (m, 2 H); δC 143.6,
137.1, 129.7, 128.9, 127.9, 127.8, 127.6, 127.4, 126.9, 126.3, 125.8,
125.7, 122.3, 120.4, 120.3, 119.9, 111.7, 111.1, 53.8, 53.7, 50.2, 21.1;
HRMS calcd for C34 H28N2O2S + Na+ 551.1769, found 551.1768.
3796
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5-Phenyl-7-tosyl-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline (11b):
state, yellow solid; Rf = 0.4 (hexane/EtOAc 3/2); mp 204−206 °C;
yield 85 mg, 70%; IR (neat) νmax 2956, 2919, 2361, 2337, 1728, 1463,
1259, 963, 749 cm−1; δH 8.84 (s, 1 H), 7.91−7.89 (m, 2 H), 7.74 (d, J
= 7.6 Hz, 2 H), 7.53−7.47 (m, 3 H), 7.31−7.22 (m, 5 H), 4.82 (s, 2
H), 4.51 (s, 2 H), 2.37 (s, 3 H); δC 150.4, 148.4, 144.1, 138.4, 136.4,
134.6, 134.4, 134.3, 134.2, 133.5, 130.1, 129.5, 129.1, 128.5, 127.8,
127.0, 122.4, 121.2, 53.8, 53.1, 21.7; HRMS calcd for C24H20N2O2S +
H+ 401.1324, found 401.1351.
1-Benzyl-8-phenyl-6-tosyl-1,3a,5,6,7,8a-hexahydroimidazo[4,5-
f]isoindole (11c): state, brown sticky mass; Rf = 0.2 (hexane/EtOAc
1/1); yield 73 mg, 51%; IR (neat) νmax 2959, 2921, 2851, 2361, 2342,
1701, 1611, 1516, 1465, 1364, 1273, 1219, 1052, 842, 772 cm−1; δH
8.13 (d, J = 7.2 Hz, 1 H), 7. 78−7.72 (m, 4 H), 7.56 (s, 1 H), 7.45−
7.36 (m, 4 H), 7.29−7.26 (m, 4 H), 7.07 (s, 1 H), 5.23 (s, 2 H), 4.76
(s, 2 H), 4.73 (s, 2 H), 2.37 (s, 3 H); δC 143.8, 134.7, 134.6, 133.8,
133.7, 130.0, 129.4, 128.7, 128.2, 127.9, 127.7, 126.2, 125.9, 125.8,
120.9, 119.3, 115.5, 54.2, 53.6, 51.4, 21.6; HRMS calcd for
C29H25N3O2S + H+ 480.1746, found 480.1735.
11-Phenyl-9-(toluene-4-sulfonyl)-9,10-dihydro-8H-9-
azacyclopenta[b]phenanthrene (11d, major) and 4-naphthalen-2-
yl-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[f ]isoindole (14d,
minor) (11d:14d = 1.9:1): state, light brown sticky mass; Rf = 0.5
(hexane/EtOAc 4/1); yield 108 mg, 80%; IR (neat) νmax 2924, 2856,
1598, 1448, 1346, 1163, 1097, 748 cm−1; δH 7.99 (t, J = 8.0 Hz, 1 H,
major), 7.84−7.58 (complex, 20 H, major + minor), 7.56−7.25 (comp,
10 H, major + minor), 7.08 (t, J = 8.0 Hz, 1 H, major), 4.87 (s, 2 H,
major), 4.84 (s, 2 H, minor), 4.48−4.58 (m, 2 H, minor), 4.44 (s, 2 H,
major), 2.40 (s, 6 H, major + minor); δC (50 MHz) (major + minor)
143.9, 142.0, 136.3, 135.3, 134.3, 133.8, 133.6, 130.6, 130.0, 128.7,
128.5, 128.4, 128.0, 127.8, 127.7, 127.5, 127.4, 126.7, 126.2, 125.5,
122.1, 120.9, 54.3, 54.1, 53.3, 21.7; HRMS calcd for C29H23NO2S +
Na+ 472.1347, found 472.1344.
3-Methoxy-11-phenyl-9-(toluene-4-sulfonyl)-9,10-dihydro-8H-9-
azacyclopenta[b]phenanthrene (11e, major) and 4-(6-methoxy-
naphthalen-2-yl)-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[f ]-
isoindole (14e, minor) (11e:14e = 2.4:1). state, Gummy solid; yield
108 mg, 75%; δH 7.89 (d, J = 8.0 Hz, 1 H, minor), 7.85 (d, J = 8.0 Hz,
1 H, minor), 7.75 (d, J = 8.0 Hz, 2 H, major, 3 H, minor), 7.69−7.62
(m, 3 H, major, 3 H minor), 7.57−7.52 (m, 3 H, major), 7.45 (app d, J
= 9.6 Hz, 1 H, major, 1 H, minor), 7.37−7.25 (m, 4 H, major, 5 H,
minor), 7.19 (d, J = 2.4 Hz, 1 H, major), 6.72 (dd, J = 8.4 Hz, 2 Hz, 1
H, major), 4.85 (s, 4 H, major + minor), 4.52−4.54 (m, 2 H, minor),
4.43 (s, 2 H, major), 4.02 (s, 3 H, minor), 3.88 (s, 3 H, major), 2.41 (s,
6 H, major + minor); HRMS calcd for C30H25NO3S + H+ 480.1633,
found 480.1614.
114.4, 100.2, 55.6, 53.8, 53.4, 21.7; HRMS calcd for C26H23NO3S +
Na+ 452.1296, found 452.1293.
4-(2,4-Dimethoxyphenyl)-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-
benzo[f]isoindole (14g, major) and 6,8-dimethoxy-4-phenyl-2-
(toluene-4-sulfonyl)-2,3-dihydro-1H-benzo[f ]isoindole (11g,
minor) (11g:14g = 1:4): state, sticky mass; yield 105 mg, 76%; δH
(DMSO-d6): 7.93 (s, 1 H, minor), 7.85 (d, J = 8.0 Hz, 1 H, major),
7.74−7.68 (complex, 5 H, major, 2 H, minor), 7.40−7.24 (complex, 3
H, major, 7 H, minor), 7.01 (d, J = 8.0 Hz, 1 H, major), 6.74 (s, 1 H,
major), 6.67 (d, J = 8.0 Hz, 1 H, major), 6.60 (s, 1 H, minor), 6.33 (s,
1 H, minor), 4.73 (s, 2 H, major), 4.69 (s, 2 H, minor), 4.34−4.19 (m,
4 H, major + minor), 3.92 (s, 3 H, minor), 3.85 (s, 3 H, major), 3.57
(app s, 6 H, major + minor), 2.48 (s, 6 H, major + minor), 2.35 (s, 3
H, minor), 2.32 (s, 3 H, major); HRMS calcd for C27H25NO4S + Na+
482.1402, found 482.1402.
4-(2,4-Dimethoxyphenyl)-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-
benzo[f ]isoindole (14g): state, pale yellow solid; Rf = 0.5 (hexane/
EtOAc 4/1); yield 83 mg, 60%; IR (neat) νmax, 2922, 2852, 1604,
1461, 1349, 1161, 1032, 754 cm−1 δH 7.81 (d, J = 8.0 Hz, 1 H), 7.78
(d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.60 (s, 1 H), 7.50 (d, J
= 8.0 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.34−7.28 (m, 2 H), 7.01 (d,
J = 8.0 Hz, 1 H), 6.61 (app d, J = 7.6 Hz, 2 H), 4,81−4.75 (m, 2 H),
4.46 (s, 2 H), 3.91 (s, 3 H), 3.64 (s, 3 H), 2.38 (s, 3 H); δC (50 MHz)
161.2, 158.0, 143.8, 134.8, 134.2, 133.8, 133.7, 132.6, 131.9, 130.8,
129.9, 128.1, 127.9, 126.7, 126.0, 125.9, 120.7, 118.4, 105.0, 99.2, 55.7,
53.9, 53.6, 21.7; HRMS calcd for C27H25NO4S + Na+ 482.1402, found
482.1402.
Procedure for the Synthesis of 1-Benzyl-4-iodo-3-methyl-
1H-imidazol-2(3H)-one (28). 1-Benzyl-4-iodoimidazole (6c; 85 mg,
0.3 mmol) was taken up in 5 mL of toluene, MeI (1.5 equiv) was
added to it, and the mixture was heated to reflux for 3 h. Toluene was
then evaporated off, and the yellow gummy mass was triturated with
petroleum ether (3 × 5 mL) to free the mass from the excess MeI
trapped. The yellow gum 27 (112 mg, 0.27 mmol) was dried and
dissolved in 5 mL of THF, 1 mL of 1 M NaOH was added to that
solution, and subsequently 500 μL of 5% NaOCl was added slowly.
After that the reaction mixture was partitioned between ethyl acetate
(2 × 10 mL) and water. The combined organic layers were washed
with brine (15 mL) and dried (anhydrous MgSO4). Ethyl acetate was
evaporated under vacuum, and the crude product was subjected to
chromatography to give the pure product: state, yellow semisolid; Rf =
0.3 (hexane/EtOAc 1/1); yield 76 mg, 81% (based on 0.3 mmol of
6e); IR (neat) νmax 2952, 2853, 2923, 2856, 2343, 1709, 1674, 1463,
1273, 1077, 750 cm−1; δH 7.34−7.30 (m, 3 H), 7.29−7.24 (m, 2 H),
6.29 (s, 1 H), 4.76 (s, 2 H), 3.23 (s, 3 H); δC 152.8, 136.4, 128.8,
128.1, 128.0, 116.8, 60.6, 47.5, 31.4; HRMS calcd for C11H11N2OI +
H+ 314.9994, found 314.9999.
3-Methoxy-11-phenyl-9-(toluene-4-sulfonyl)-9,10-dihydro-8H-9-
azacyclopenta[b]phenanthrene (11e): state, pale yellow solid; Rf =
0.5 (hexane/EtOAc 4/1); yield 76 mg, 52%; IR (neat) νmax, 2922,
2851, 1628, 1480, 1349, 1161, 1092, 750 cm−1; δH 7.73 (d, J = 8.0 Hz,
2 H), 7.67−7.61 (m, 3 H), 7.56−7.50 (m, 3 H), 7.42 (d, J = 9.6 Hz, 1
H), 7.30 (d, J = 8.0 Hz, 2 H), 7.24−7.22 (m, 2 H), 7.17 (d, J = 2.8 Hz,
1 H), 6.69 (dd, J = 9.6 Hz, 2.8 Hz, 1 H), 4.84 (s, 2 H), 4.40 (s, 2 H),
3.86 (s, 3 H), 2.39 (s, 3 H); δC (50 MHz) 157.7, 143.9, 142.1, 136.4,
135.3, 134.6, 133.9, 133.4, 132.9, 130.1, 129.3, 128.6, 128.5, 128.1,
128.0, 127.9, 127.8, 127.6, 124.9, 122.2, 115.5, 109.1, 55.5, 54.4, 54.2,
21.7); HRMS calcd for C30H25NO3S + H+ 480.1633, found 480.1614.
4-(4-Methoxyphenyl)-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-
benzo[f]isoindole (14f, major) and 6-methoxy-4-phenyl-2-(tol-
uene-4-sulfonyl)-2,3-dihydro-1H-benzo[f ]isoindole (11f, minor)
(11f:14f = 1:4.9): state, gummy solid; Rf = 0.5 (hexane/EtOAc 4/
1); yield 94 mg, 0.73 mmol, 73%; IR (neat) νmax 2924, 2856, 1662,
1465, 1352, 1162, 1093, 755 cm−1; δH 7.80 (d, J = 8.0 Hz, 1 H, major),
7.75 (d, J = 8.0 Hz, 2 H, major), 7.60 (app d, J = 8.0 Hz, 2 H, major),
7.43 (t, J = 8.0 Hz, 1 H, major), 7.35 (app t, J = 8.0 Hz, 1 H, major),
7.30 (d, J = 8.0 Hz, 2 H, major), 7.18 (d, J = 12.0 Hz, 2 H, major), 7.03
(d, J = 12.0 Hz, 2 H, major), 6.85 (d, J = 2.4 Hz, 1 H, minor), 4.79 (s,
2 H, major), 4.77 (s, 2 H, minor), 4.50 (s, 2 H, major), 4.46 (s, 2 H,
minor), 3.91 (s, 3 H, major), 3.69 (s, 3 H, minor), 2.39 (s, 6 H, major
+ minor); δC (50 MHz) (major + minor) 159.5, 143.9, 134.5, 133.9,
132.3, 130.7, 130.0, 129.5, 129.1, 128.1, 127.9, 126.2, 126.1, 120.6,
Procedure for the Synthesis of 1-Benzyl-4-(3-(3-(4-
methoxyphenyl)prop-2-ynyloxy)prop-1-ynyl)-3-methyl-1H-
imidazol-2(3H)-one (29). 28 (79 mg, 0.25 mmol), CuI (0.2 mol %),
and 1-methoxy-4-(3-(prop-2-ynloxy)prop-1-ynyl)benzene (1.2 equiv)
were taken u in dry degassed triethylamine (8 mL), to this solution
was added Pd(PPh3)2Cl2 (0.03 mol %), and the mixture was stirred for
4 h. Triethylamine was evaporated in a rotavap, and the crude mixture
was subjected to silica gel column chromatography to give the
coupling product: state, yellow liquid; Rf = 0.4 (hexane/EtOAc 1/2);
yield 87 mg, 90% (based on 0.25 mmol of 28); IR (neat) νmax 2952,
2361, 2331, 1710, 1605, 1460, 1249, 1080, 767 cm−1; δH 7.34−7.27
(m, 5 H), 7.21−7.19 (m, 3 H), 6.79 (d, J = 8.8 Hz, 2 H), 6.38 (s, 1 H),
4.74 (s, 2 H), 4.46 (s, 2 H), 4.42 (s, 2 H), 3.76 (s, 3 H), 3.24 (s, 3 H);
δC 159.9, 152.3, 136.2, 133.3, 128.9, 128.1, 128.0, 116.1, 114.1, 114.0,
106.8, 90.8, 87.1, 82.6, 82.6, 75.0, 57.6, 57.1, 55.3, 47.3, 28.5; HRMS
calcd for C24H22N2O3 + H+ 387.1709, found 387.1714.
Procedure for the GB Cyclization of 1-Benzyl-4-(3-(3-(4-
methoxyphenyl)prop-2-ynyloxy)prop-1-ynyl)-3-methyl-1H-
imidazol-2(3H)-one (29). To a solution of 29 (77 mg, 0.2 mmol) in
8 mL dry THF was added KOtBu (2 equiv), and the mixture was
heated to 50 °C for 2 h. After the completion of the reaction THF was
evaporated off and the crude mixture was purified by silica gel column
filtration: state, whitish gum; Rf = 0.3 (hexane/EtOAc 1/5); yield 73
mg, 94% (based on 0.2 mmol of 29); IR (neat) νmax 2924, 2852, 2359,
3797
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Article
1755, 1705, 1612, 1518, 1494, 1468, 1287, 1053, 1032, 839, 747 cm−1;
δH 7.07−7.04 (m, 3 H), 6.86−6.83 (m, 3 H), 6.72 (d, J = 8.2 Hz, 2 H),
6.55−6.52 (m, 2 H), 5.16 (s, 2 H). 4.77 (s, 2 H), 4.73 (s, 2 H), 3.79(s,
3 H), 3.48 (s, 3 H); δC 159.2, 155.5, 136.9, 132.6, 131.5, 131.0, 130.4,
128.0, 127.3, 126.8, 126.0, 125.9, 118.9, 113.5, 99.4, 74.3, 73.4, 55.3,
45.4, 27.5; HRMS calcd for C24H22N2O3 + H+ 387.1709, found
387.1714.
Procedure for the Conversion of Phthalan 30 to Dialdehyde
31. To an ice-cold solution of the phthalan 30 (77 mg, 0.2 mmol) in 2
mL of dry DCM was added slowly a pre cooled solution of HNO3 (2
equiv) in 1 mL of DCM. After the completion (approximately 15 min)
of the reaction, the mixture was diluted with DCM (5 mL) and basic
alumina was added. After filtration the solvent was removed in a liquid
nitrogen trap. The dialdehyde was obtained pure via crystallization
from ethyl acetate/hexane.
3-Benzyl-4-(4-methoxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazole-5,6 dicarbaldehyde (31): state, light yellow solid;
mp 151−156 °C (Reported 152−155 °C) yield 74 mg; 92% (based on
0.2 mmol of 30); δH 10.3 (s, 1 H), 9.70 (s, 1 H), 7.12−7.06 (m, 3 H),
6.91 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.6 Hz, 2 H), 6.53 (d, J = 6.4 Hz,
2 H), 4.73 (s, 2 H), 3.82 (s, 3 H), 3.57 (s, 3 H); δC 192.6, 191.9, 160.1,
155.6, 136.1, 133.7, 132.2, 131.9, 131.7, 130.1, 128.3, 128.0, 127.2,
125.5, 123.5, 113.7, 106.5, 55.5, 45.8, 27.9; HRMS calcd for
C24H20N2O4 + H+ 401.1501, found 401.1527.
1229−1234. (c) Lewis, J. R. Nat. Prod. Rep. 1992, 9, 81−101.
(d) Faulkner, D. J. Nat. Prod. Rep. 1992, 9, 323−364. (e) Hassan, W.;
Edrada, R.; Ebel, R.; Wray, V.; Berg, A.; Van Soest, R.; Wiryowidagdo,
S.; Proksch, P. J. Nat. Prod. 2004, 67, 817−822. Synthesis:
(f) Kawasaki, I.; Taguchi, N.; Yamamoto, T.; Yamashita, N.; Ohta,
S. Tetrahedron Lett. 1995, 36, 8251−8254. (g) Gibbons, J. B.;
Gligorich, K. M.; Welm, B. E.; Looper, R. E. Org. Lett. 2012, 14, 4734−
4737. (h) Das, J.; Koswatta, P. B.; Jones, J. D.; Yousufuddin, M.;
Lovely, C. J. Org. Lett. 2012, 14, 6210−6213. (i) Nakamura, S.; Tsuno,
N.; Yamashita, M.; Kawasaki, I.; Ohta, S.; Ohishi, Y. J. Chem. Soc.,
Perkin Trans. 1 2001, 429−436. (j) Kawasaki, I.; Taguchi, N.;
Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1997, 45, 1393−1398.
(k) Das, J.; Bhan, A.; Mandal, S.; Lovely, C. J. Bioorg. Med. Chem. Lett.
2013, 23, 6183−6187.
(4) We thank one of the reviewers for pointing out this aspect of the
GB process.
(5) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467−4470. (b) Takahashi, K.; Kuroyama, Y.; Sonogashira,
K.; Hagihara, N. Synthesis 1980, 627−630. (c) For a general review,
see: Sonogashira, K. In Metal Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany,
1998; Chapter 5.
(6) (a) Mukherjee, R.; Basak, A. Synlett 2012, 23, 877. (b) Addy, P.
S.; Dutta, S.; Biradha, K.; Basak, A. Tetrahedron Lett. 2012, 53, 19.
(7) Sivappa, R.; Yousufuddin, M.; Lovely, C. J. Org. Lett. 2012, 14,
2274−2277.
(8) Strazzolini, P.; Runcio, A. Eur. J. Org. Chem. 2003, 3, 526−536.
(9) Lima, H. M.; Lovely, C. J. Org. Lett. 2011, 13, 5736−39.
(10) Viehe, H. G.; Janousek, Z.; Merenyi, R.; Stella, L. Acc. Chem. Res.
1985, 18, 148−154.
(11) N-alkylation of imidazole weakens the electron donation ability
of the alkylated nitrogen. This is reflected by the higher pKa of N-
methylimidazole (pKa 7.45) in comparison to that of imidazole (pKa
6.95): Bruice, T. C.; Schmir, G. L. J. Am. Chem. Soc. 1958, 80, 148−
156.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H and 13C NMR spectra of GB precursors and
products and HRMS spectra of GB products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for R.M.: rajamukherg@gmail.com.
*E-mail for A.B.: absk@chem.iitkgp.ernet.in.
■
(12) Kudoh, T.; Mori, T.; Shirahama, M.; Yamada, M.; Ishikawa, T.;
Saito, S.; Kobayashi, H. J. Am. Chem. Soc. 2007, 129, 4939−4947.
(13) A very recent report on the total synthesis of 7′-
desmethylkealiiquinone, 4′-desmethoxykealiiquinone, and 2-deoxykea-
liiquinone has appeared: Lima, H. M.; Rasapalli, S.; Yousufuddin, M.;
Lovely, C. J. J. Org. Chem. 2014, 79, 2481−2490.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. A. Anoop and Mr. S. Jana for helpful discussion.
R.M. and J.D. are grateful to the CSIR for fellowship. The DST
is thanked for SERC funds and for a J. C. Bose Fellowship
awarded to A.B.. The Department of Organic Chemistry, IISc,
Bangalore, India, is thanked for extending their HRMS facility.
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