Synthesis of hexahydro-1 H-isoindole derivatives from arylacyl bromides via homoallenic bromohydrins

Article abstract of DOI:10.1021/acs.joc.5b00072

A procedure has been developed for the concise synthesis of hexahydro-1H-isoindole derivatives starting from phenacyl bromides. The approach employs a sequence involving an initial indium-mediated allenylation reaction of an arylacyl bromide with propargyl bromide. This process is followed by FeBr₃-mediated S_N2′-type substitution reaction of the formed homoallenic bromohydrin to produce a 2,5-dibromo-4-aryl-1,3-pentadiene, which then is subjected to a sequential, one-pot N-alkylation reaction with N-allyl-N-(p-tosyl)amine and a highly diastereoselective intramolecular Diels-Alder reaction of the formed ene-diene to generate the target hexahydro-1H-isoindole.

Full text of DOI:10.1021/acs.joc.5b00072

Note
pubs.acs.org/joc
Synthesis of Hexahydro‑1H‑isoindole Derivatives from Arylacyl
Bromides via Homoallenic Bromohydrins
Mei-Huey Lin,* Yi-Syuan Li, Chung-Kai Kuo, Chung-Hao Chen, Yen-Chih Huang, Kung-Yu Liang,
Yu-Chun Chen, Chang-Hsien Tsai, and Tsung-Hsun Chuang
Department of Chemistry, National Changhua University of Education, Changhua, Taiwan 50007
S
* Supporting Information
ABSTRACT: A procedure has been developed for the concise synthesis of hexahydro-1H-isoindole derivatives starting from
phenacyl bromides. The approach employs a sequence involving an initial indium-mediated allenylation reaction of an arylacyl
bromide with propargyl bromide. This process is followed by FeBr3-mediated SN2′-type substitution reaction of the formed
homoallenic bromohydrin to produce a 2,5-dibromo-4-aryl-1,3-pentadiene, which then is subjected to a sequential, one-pot N-
alkylation reaction with N-allyl-N-(p-tosyl)amine and a highly diastereoselective intramolecular Diels−Alder reaction of the
formed ene-diene to generate the target hexahydro-1H-isoindole.
ubstances possessing the 3a-phenyl-isoindoline ring system
display potent analgesic activities.1 As a result, methods for
promoted intramolecular Diels−Alder reactions.5 Recently,
the novel cis-octahydro-1H-isoindole 1 was shown to be a
potent triple serotonin, norepinephrine, and dopamine trans-
porter inhibitor for use as a potential drug to treat depression.6
The construction of the skeleton of 1 was accomplished by
employing either a palladium-catalyzed arylation reaction of a
fused γ-lactone or a Diels−Alder reaction of an aryl-maleic
anhydride (c and d, Scheme 1).
S
the preparation of this unique structural scaffold are in high
demand. One obvious approach to construct this fused
heterocyclic framework, by using an intramolecular [4 + 2]
cycloaddition and N-alkylation protocol starting with α-
bromomethylstyrene and pentadienyl amine, failed, owing to
the inherent instability of the amine (a, Scheme 1).1 In another
In the study described below, we explored a new method for
the synthesis of cis-bicyclic-polyhydro-1H-isoindoles containing
a stereogenic, quaternary, aryl-substituted bridgehead carbon.
For this purpose, we designed an approach that relies on an
intramolecular [4 + 2] cycloaddition reaction of an amine
tethered ene-aryldiene. Recently, we described a method for the
efficient synthesis of homoallenic halohydrins 2 (Scheme 2)
that involves an indium-mediated allenylation reaction of
arylacyl halides with propargyl bromide in aqueous media.7 In
a manner that is similar to the reported generation of 2-halo-
1,3-dienes by using halide-ion-promoted SN2′-type substitution
reactions of allenols,8 we observed that 2-aryl-1,4-dibromo-
penta-2,4-dienes 3 can be prepared by reactions of homoallenic
bromohydrins 2 with FeBr3. We envisioned that bromo-dienes
3 would serve as effective substrates in reactions with
allylamines that take place by a one-pot, sequential nucleophilic
substitution and intramolecular [4 + 2] cycloaddition of the
intermediate amine tethered ene-dienes. If valid, the proposed
pathway would serve as a simple method for the synthesis of
7a-aryl-6-bromo-hexahydro-1H-isoindoles 4 (Scheme 2).
In order to evaluate the feasibility of the new strategy for
aryl-hexahydro-1H-isoindole synthesis, homoallenic bromohy-
Scheme 1. Synthesis of Polyhydro-1H-isoindoles
approach to the polyhydro-1H-isoindole scaffold, initial
secondary amine induced ring opening of thiophene-1,1-
dioxide to form the azatriene was found to take place in only
a 31% yield, and the ensuing intramolecular Diels−Alder
reaction was low yielding (11%, b, Scheme 1).2 Other examples
of strategies devised for synthesis of polyhydro-1H-isoindoles
rely on key rhodium(I)-catalyzed,3 thermo,4 and BCl3-
Received: January 11, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00072
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2
drin 2a was subjected to SN2′-type substitution reaction
conditions using various amounts of ferric bromide (Table
1). The results show that bromo-diene 3a is produced as the
Table 2. Preparation of 2-Aryl-1,4-dibromopenta-2,4-dienes
3
ab
,
a
Table 1. FeBr3-Mediated SN2′-Type Substitution Reactions
entry
FeBr3 (mol %)
3a′, yield (%)
3a, yield (%)
1
2
3
4
30
35
40
60
4
5
5
5
60
63
86
86
a
Conditions: 2a (0.5 mmol) and FeBr3 as indicated in CH2Cl2 (4.0
mL) at 25−28 °C for 2 h.
major product in these reactions along with small amounts of
enone 3a′, which can be easily removed by using chromatog-
raphy. Because the yield of 3a is not improved significantly by
using larger amounts of ferric bromide (Table 1, entry 3 vs 4),
ideal conditions for this process involve the use of 40 mol % of
ferric bromide. An examination of the 3a showed that it is
stable when stored below 0 °C but that it slowly decomposes at
room temperature.
The preparation and FeBr3-promoted reactions of a variety of
aryl-substituted homoallenic bromohydrins 2 were explored
next (Table 2). The results show that indium-mediated
allenylation reactions of arylacyl bromides with propargyl
bromide in aqueous media take place to form the desired
homoallenic bromohydrins in high yields along with small
amounts of both the propargyl analogues and corresponding
methylketones, generated by direct reduction of the arylacyl
bromides. Pure homoallenic bromohydrins 2a, 2e, and 2g,
obtained by using the previously described chromatographic
procedure,7 were observed to undergo FeBr3-mediated SN2′-
type substitution reactions to give the respective bromo-dienes
3a, 3e, and 3g in high yields (Table 2, entries 1, 5, and 7).
Alternatively, the crude mixtures generated in the indium-
mediated allenylation reactions were subjected to the FeBr3-
mediated SN2′-type substitution reaction conditions. The
results of these two-step reactions, listed in Table 2 (entries
2−4, 6, and 8), show that bromo-dienes 3 are generated in
modest yields even when purifications of the intermediate
homoallenic bromohydrins 2 are not performed. It is worth
noting that the FeBr3-mediated SN2′-type substitution reactions
of homoallenic bromohydrins 2 not only occur with high levels
of regioselectivity but also form the Z-stereoisomers selectively,
as was demonstrated by using X-ray crystallographic analysis of
3e.9
a
Conditions: 2 (0.5 mmol) and FeBr3 (0.2 mmol) in CH2Cl2 (4.0
mL) at 25−28 °C for 2 h. Two-step overall yield.
b
with N-allyl-N-(p-tosyl)amine in the presence of various bases
and solvents were explored (Table 3). The results show that
the nature of the base plays a crucial role in this process,
exemplified by the observation that the Diels−Alder product 4c
Table 3. Reactions of Bromo-Diene 3c through One-Pot,
Sequential Formation of Ene-Diene, Followed by
a
Intramolecular Diels−Alder Reaction
entry
substrate
base
solvent
4c, yield (%)
1
2
3
4
5
6
7
8
9
3c
3c
3c
3c
3c
3c
3c
3c
3c
Et3N
DBU
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
0
0
guanidine carbonate
Cs2CO3
0
58
70
0
K2CO3
K2CO3
K2CO3
EtOH
41
31
0
K2CO3
dioxane
toluene
The key step in the proposed route for synthesis of 7a-aryl-6-
bromo-hexahydro-1H-isoindoles 4, involving one-pot formation
of ene-diene, followed by intramolecular Diels−Alder cyclo-
addition, was examined next. For this purpose, reactions of 3c
K2CO3
a
Conditions: 3c (0.6 mmol), N-allyl-N-(p-tosyl)amine (0.5 mmol),
and indicated base (1.0 mmol) in solvent (3.0 mL) at reflux for 12 h.
B
DOI: 10.1021/acs.joc.5b00072
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
is not formed when triethylamine, DBU, and guanidine
carbonate are employed (Table 3, entries 1−3). In contrast,
inorganic bases such as cesium carbonate and potassium
carbonate promoted formation of the target 4c in respective
58% and 70% yields (Table 3, entries 4 and 5). A screen of
solvents showed that acetonitrile is an ideal solvent for the two-
step process. Importantly, neither the precursor ene-diene nor
the cyclization product 4c is formed in reactions in dichloro-
ethane or toluene (Table 3, entries 6 and 9) and that 4c is
generated in low yields when ethanol and dioxane are
employed as solvents (Table 3, entries 7 and 8). A single
diastereoisomer is produced in the reaction of 3c with N-allyl-
N-(p-tosyl)amine. The stereochemistry of the fused-bicyclic
ring system in 4c was shown to be cis by using X-ray
crystallographic analysis.10
In conclusion, the studies described above have led to the
development of a simple method for the preparation of (Z)-2-
aryl-1,4-dibromopenta-2,4-dienes 3 from phenacyl bromides
and an application of these dienes to the synthesis of
hexahydro-1H-isoindole derivatives.
EXPERIMENTAL SECTION
■
General Information and Materials. All commercially available
chemicals were used without further purification. TLC analyses were
run on a TLC glass plate (Silica gel 60 F254) and were visualized using
UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-
anisaldehyde stain. Flash chromatography was performed using silica
gel (70−230 mesh). 1H spectra were recorded on a 300 MHz
spectrometer. 13C NMR spectra were recorded on a 75 MHz with
complete proton decoupling spectrometer. Chemical shifts are
reported relative to CHCl3 [δH 7.24, δC (central line) 77.0]. Mass
spectra were recorded under electron impact ionization (EI)
conditions, and high-resolution mass spectra were recorded by
electron impact ionization with magnetic sector.
An exploration of the scope of the one-pot reaction of
bromo-dienes 3 with N-allyl-N-(p-tosyl)amine showed that it
serves as a general method for the synthesis of a variety of 7a-
aryl-6-bromo-hexahydro-1H-isoindoles 4 (Scheme 3).11 Finally,
General Procedure for the Synthesis of Bromo-Dienes 3
from Homoallenic Bromohydrins 2. A mixture of homoallenic
bromohydrin 2 (0.5 mmol)7 and FeBr3 (59 mg, 0.2 mmol) in CH2Cl2
(4 mL) was stirred at ambient temperature (25−28 °C), After 2 h,
CH2Cl2 (2 mL) and 2 N HCl aqueous solution (2 mL) were added to
the reaction, and the mixture was transferred to a separatory funnel.
The aqueous layer was back extracted with CH2Cl2 (2 mL × 2). The
combined organic layers were dried over MgSO4 and concentrated in a
rotary evaporator. The residue was purified by silica gel chromatog-
raphy using hexanes as eluent to give the product 3.
Scheme 3. Scope of One-Pot Formation of Ene-Diene,
a
Followed by an Intramolecular Diels−Alder Reaction
(Z)-(1,4-Dibromopenta-2,4-dien-2-yl)benzene (3a). Following the
general procedure, the title compound was obtained (130 mg, 86%). A
yellow oil; TLC (Et2O/hexanes (1:5)) Rf = 0.70; 1H NMR (300 MHz,
CDCl3) δ 4.52 (s, 2 H), 5.89 (d, J = 1.8 Hz, 1 H), 6.17 (t, J = 1.8 Hz, 1
H), 6.43 (d, J = 1.8 Hz, 1 H), 7.34−7.40 (m, 3 H), 7.48 (d, J = 8.7 Hz,
2 H); 13C NMR (75 MHz, CDCl3) δ 28.8 (CH2), 121.0 (CH2), 125.1
(C), 126.4 (CH × 2), 128.6 (CH × 2), 128.7 (CH), 130.7 (CH),
137.9 (C), 139.1 (C); IR (neat) 3068, 1688, 1595 cm−1; EI-MS m/z
(rel intensity) 300 ([M]+, 0.1), 223 (11), 141 (100), 115 (20); HRMS
[M]+ calcd for C11H10Br2: 299.9149, found 299.9142.
(Z)-1-(1,4-Dibromopenta-2,4-dien-2-yl)-4-methoxybenzene (3e).
Following the general procedure, the title compound was obtained
(116 mg, 70%). A yellow solid, mp 58−59 °C; TLC (Et2O/hexanes
(1:4)) Rf = 0.60; 1H NMR (300 MHz, CDCl3) δ 3.81 (s, 3 H), 4.50 (s,
2 H), 5.85 (d, J = 1.8 Hz, 1 H), 6.13 (t, J = 1.8 Hz, 1 H), 6.37 (d, J =
1.8 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 28.9 (CH2), 52.2 (CH3), 113.9 (CH × 2),
120.6 (CH2), 125.4 (C), 127.5 (CH × 2), 129.0 (CH), 129.8 (C),
138.4 (C), 159.9 (C); IR (KBr) 3030, 1607, 1506 cm−1; EI-MS m/z
(rel intensity) 332 ([M + 2]+, 7), 330 ([M]+, 4), 251 (100), 172 (88);
HRMS [M]+ calcd for C12H12Br2O: 329.9255, found 329.9265.
(Z)-1-(1,4-Dibromopenta-2,4-dien-2-yl)-2-methoxybenzene (3g).
Following the general procedure, the title compound was obtained
a
Conditions: 3 (0.6 mmol), N-allyl-N-(p-tosyl)amine (0.5 mmol), and
K2CO3 (1.0 mmol) in CH3CN (3.0 mL) at reflux for 12 h.
in contrast to these processes, reaction of bromo-diene 3c with
allylamine leads to formation of the N-allyl-pyrrole 5c (Scheme
4). The formation of 5c likely occurs by intramolecular N-
vinylation of the secondary amine 4c′ formed by initial
substitution reaction of bromo-diene 3c with allylamine.
Scheme 4. Formation of N-Allyl-Pyrrole 5c
C
DOI: 10.1021/acs.joc.5b00072
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(125 mg, 75%). An off-white solid, mp 47−49 °C; TLC (Et2O/
1.8 Hz, 1 H), 6.16 (t, J = 1.8 Hz, 1 H), 6.42 (d, J = 1.8 Hz, 1 H), 6.87−
6.90 (m, 1 H), 7.00−7.07 (m, 2 H), 7.29 (d, J = 8.1 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 28.8 (CH2), 55.1 (CH3), 112.2 (CH),
113.8 (CH), 118.6 (CH), 121.0 (CH2), 124.9 (C), 129.5 (CH), 130.7
(CH), 138.9 (C), 139.2 (C), 159.5 (C); IR (KBr) 2938, 1616, 1487
cm−1; EI-MS m/z (rel intensity) 332 ([M + 2]+, 4), 330 ([M]+, 2),
251 (100), 172 (73); HRMS [M]+ calcd for C12H12Br2O: 329.9255,
found 329.9260.
(Z)-2-(1,4-Dibromopenta-2,4-dien-2-yl)naphthalene (3h). Follow-
ing the general procedure, the title compound was obtained (1.3 g,
46%). A yellow solid, mp 57−58 °C; TLC (Et2O/hexanes (1:5)) Rf =
0.70; 1H NMR (300 MHz, CDCl3) δ 4.63 (s, 2 H), 5.91 (d, J = 1.8 Hz,
1 H), 6.21 (t, J = 1.8 Hz, 1 H), 6.57 (d, J = 1.8 Hz, 1 H), 7.47−7.60
(m, 3 H), 7.80−7.87 (m, 3 H), 7.95 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 28.8 (CH2), 121.1 (CH2), 123.7 (CH), 125.1 (C), 125.9
(CH), 126.4 (CH), 126.5 (CH), 127.5 (CH), 128.3 (CH × 2), 131.0
(CH), 133.1 (C), 133.2(C), 134.9 (C), 138.9 (C); IR (KBr) 3067,
1601, 1217 cm−1; EI-MS m/z (rel intensity) 352 ([M + 2]+, 3), 350
([M]+, 1), 271 (33), 192 (100); HRMS [M]+ calcd for C15H12Br2:
349.9306, found 349.9315.
General Procedure for the Synthesis Hexahydro-1H-iso-
indoles 4. A mixture of bromo-diene 3 (0.6 mmol), N-allyl-N-(p-
tosyl)amine (110 mg, 0.5 mmol), and K2CO3 (138 mg, 1.0 mmol) in
CH3CN (3.0 mL) was stirred at 87 °C overnight. The mixture was
cooled to ambient temperature (25−28 °C) and filtered through a
filter paper. The filtrate was transferred to a separatory funnel,
followed by addition of CH2Cl2 (10 mL) and water (10 mL). The
aqueous layer was back extracted with CH2Cl2 (5 mL × 2). The
combined organic layers were washed with brine (10 mL), dried over
MgSO4, and concentrated in a rotary evaporator. The crude product
was triturated with Et2O (5 mL), followed by filtration to give the
product 4.
1
hexanes (1:5)) Rf = 0.70; H NMR (300 MHz, CDCl3) δ 3.83 (s, 3
H), 4.67 (s, 2 H), 5.89 (d, J = 1.8 Hz, 1 H), 6.17 (t, J = 1.8 Hz, 2 H),
6.90 (d, J = 7.8 Hz, 1 H), 6.99 (t, J = 7.8 Hz, 1 H), 7.22 (d, J = 7.8 Hz,
1 H), 7.35 (d, J = 7.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 30.2
(CH2), 55.2 (CH3), 110.5 (CH), 120.5 (CH), 120.8 (CH2), 124.7
(C), 127.8 (C), 129.7 (CH), 131.0 (CH), 132.4 (CH), 139.7 (C),
156.3 (C); IR (KBr) 3003, 1590, 1488 cm−1; EI-MS m/z (rel
intensity) 330 ([M]+, 0.2), 298 (39), 251 (100), 172 (55); HRMS
[M]+ calcd for C12H12Br2O: 329.9255, found 329.9245.
General Procedure for the 2-Step Sequence To Form
Bromo-dienes 3 from Arylacyl Bromides. A mixture of propargyl
bromide (1.0 mL, 14.4 mmol), indium powder (325 mesh, 1.4 g, 12.0
mmol), and arylacyl bromide (8.0 mmol) in THF/H2O (12.0 mL/4.0
mL) was stirred at ambient temperature (25−28 °C). Reaction was
monitored by TLC until no starting material was observed, and
normally the reaction was stirred at rt overnight. Et2O (20 mL) and
water (20 mL) was then added to the reaction, and the mixture was
transferred to a separatory funnel. The aqueous layer was back
extracted with Et2O (20 mL × 2). The combined organic layers were
washed with brine (20 mL), dried over MgSO4, and concentrated in a
rotary evaporator. The residue was purified by a short silica gel plug
with using hexanes (100 mL) and then Et2O/hexanes (1:20, 100 mL)
as eluent to give the crude product 2. The crude mixture was dissolved
in CH2Cl2 (42 mL), and then FeBr3 (612 mg, 2.1 mmol)) was added.
The resulting mixture was stirred at ambient temperature (25−28 °C)
for 2 h. Then, CH2Cl2 (20 mL) and 2 N HCl aqueous solution (20
mL) were added to the reaction, and the mixture was transferred to a
separatory funnel. The aqueous layer was back extracted with CH2Cl2
(20 mL × 2). The combined organic layers were dried over MgSO4
and concentrated in a rotary evaporator. The residue was purified by
silica gel chromatography using hexanes as eluent to give the product
3.
6-Bromo-7a-phenyl-2-tosyl-2,3,3a,4,5,7a-hexahydro-1H-isoin-
dole (4a). Following the general procedure, the title compound was
obtained (176 mg, 68%). A yellow solid, mp 86−87 °C; TLC (Et2O/
(Z)-1-Bromo-4-(1,4-dibromopenta-2,4-dien-2-yl)benzene (3b).
Following the general procedure, the title compound was obtained
1
1
(1.8 g, 58%). A yellow oil; TLC (Et2O/hexanes (1:5)) Rf = 0.75; H
hexanes (1:2)) Rf = 0.50; H NMR (300 MHz, CDCl3) δ 1.36−1.60
NMR (300 MHz, CDCl3) δ 4.46 (s, 2 H), 5.89 (d, J = 1.8 Hz, 1 H),
6.15 (t, J = 1.8 Hz, 1 H), 6.40 (d, J = 1.8 Hz, 1 H), 7.34 (d, J = 8.7 Hz,
2 H), 7.48 (d, J = 8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 28.4
(CH2), 121.3 (CH2), 122.9 (C), 124.7 (C), 128.0 (CH × 2), 131.0
(CH), 131.8 (CH × 2), 136.8 (C), 138.0 (C); IR (neat) 3030, 1587,
1496 cm−1; EI-MS m/z (rel intensity) 378 ([M]+, 0.3), 303 (22), 221
(33), 141 (100); HRMS [M]+ calcd for C11H9Br3: 377.8254, found
377.8253.
(m, 2 H), 2.32−2.43 (m, 3 H), 2.45 (s, 3 H), 3.14 (dd, J = 9.9, 7.5 Hz,
1 H), 3.42 (d, J = 10.5 Hz, 1 H), 3.50 (dd, J = 9.9, 7.5 Hz, 1 H), 3.72
(d, J = 10.5 Hz, 1 H), 5.76 (s, 1 H), 7.15−7.35 (m, 7 H), 7.71 (d J =
8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 21.5 (CH3), 22.2 (CH2),
31.0 (CH2), 42.5 (CH), 49.8 (CH2), 52.4 (C), 58.3 (CH2), 123.5 (C),
126.3 (CH × 2), 127.0 (CH × 2), 127.2 (CH), 128.5 (CH × 2), 129.7
(CH × 2), 131.3 (CH), 133.4 (C), 142.2 (C), 143.6 (C); IR (neat)
2931, 1596, 1339 cm−1; EI-MS m/z (rel intensity) 431 ([M]+, 3), 352
(34), 239 (33), 198 (100); HRMS [M]+ calcd for C21H22BrNO2S:
431.0555, found 431.0559.
(Z)-1-Chloro-4-(1,4-dibromopenta-2,4-dien-2-yl)benzene (3c).
Following the general procedure, the title compound was obtained
(1.3 g, 49%). A yellow solid, mp 42−44 °C; TLC (Et2O/hexanes
6-Bromo-7a-(4-bromophenyl)-2-tosyl-2,3,3a,4,5,7a-hexahydro-
1H-isoindole (4b). Following the general procedure, the title
compound was obtained (233 mg, 76%). A yellow solid, mp 188−
1
(1:5)) Rf = 0.75; H NMR (300 MHz, CDCl3) δ 4.47 (s, 2 H), 5.89
(d, J = 1.8 Hz, 1 H), 6.15 (t, J = 1.8 Hz, 1 H), 6.40 (d, J = 1.8 Hz, 1
H), 7.35 (d, J = 8.7 Hz, 2 H), 7.41 (d, J = 8.7 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 28.5 (CH2), 121.3 (CH2), 124.7 (C), 127.7 (CH ×
2), 128.8 (CH × 2), 131.0 (CH), 134.7 (C), 136.3 (C), 138.0 (C); IR
(KBr) 3030, 1597, 1440 cm−1; EI-MS m/z (rel intensity) 334 ([M]+,
4), 257 (68), 176 (99), 141 (100); HRMS [M]+ calcd for C11H9Br2
Cl: 333.8760, found 333.8761.
1
190 °C; TLC (Et2O/hexanes (1:5)) Rf = 0.75; H NMR (300 MHz,
CDCl3) δ 1.41−1.61 (m, 2 H), 2.32−2.38 (m, 3 H), 2.43 (s, 3 H),
3.12 (dd, J = 9.9, 7.2 Hz, 1 H), 3.38 (d, J = 10.8 Hz, 1 H), 3.49 (dd, J =
9.9, 7.5 Hz, 1 H), 3.69 (d, J = 10.8 Hz, 1 H), 5.72 (s, 1 H), 7.04 (d, J =
8.4 Hz, 2 H), 7.32−7.39 (m, 4 H), 7.69 (d J = 8.4 Hz, 2 H); 13C NMR
(75 MHz, CDCl3) δ 21.6 (CH3), 22.5 (CH2), 31.2 (CH2), 42.8 (CH),
50.0 (CH2), 52.2 (C), 58.1 (CH2), 121.1 (C), 124.0 (C), 127.2 (CH ×
2), 128.2 (CH × 2), 129.8 (CH), 130.7 (CH × 2), 131.6 (CH × 2),
133.4 (C), 141.5 (C), 143.8 (C); IR (neat) 2931, 1474, 1340 cm−1;
EI-MS m/z (rel intensity) 509 ([M]+, 2), 411 (25), 343 (38), 198
(100); HRMS [M]+ calcd for C21H21Br2NO2S: 508.9660, found
508.9654.
(Z)-1-(1,4-Dibromopenta-2,4-dien-2-yl)-4-methylbenzene (3d).
Following the general procedure, the title compound was obtained
1
(1.3 g, 50%). A yellow oil; TLC (Et2O/hexanes (1:5)) Rf = 0.75; H
NMR (300 MHz, CDCl3) δ 2.40 (s, 3 H), 4.54 (s, 2 H), 5.91 (d, J =
1.8 Hz, 1 H), 6.19 (t, J = 1.8 Hz, 1 H), 6.46 (d, J = 1.8 Hz, 1 H), 7.22
(d, J = 7.8 Hz, 2 H), 7.42 (d, J = 7.8 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 21.1 (CH3), 28.8 (CH2), 120.7 (CH2), 125.2 (C), 126.1
(CH × 2), 129.3 (CH × 2), 129.8 (CH), 134.7 (C), 138.6 (C), 138.8
(C); IR (neat) 3038, 1605, 1441 cm−1; EI-MS m/z (rel intensity) 314
([M]+, 5), 251 (36), 237 (82), 156 (100); HRMS [M]+ calcd for
C12H12Br2: 313.9306, found 313.9303.
6-Bromo-7a-(4-chlorophenyl)-2-tosyl-2,3,3a,4,5,7a-hexahydro-
1H-isoindole (4c). Following the general procedure, the title
compound was obtained (196 mg, 70%). A white solid, mp 169−
1
171 °C; TLC (Et2O/hexanes (1:2)) Rf = 0.38; H NMR (300 MHz,
CDCl3) δ 1.38−1.59 (m, 2 H), 2.31−2.39 (m, 3 H), 2.42 (s, 3 H),
3.11 (dd, J = 9.9, 7.2 Hz, 1 H), 3.38 (d, J = 10.5 Hz, 1 H), 3.47 (dd, J =
9.9, 7.2 Hz, 1 H), 3.68 (d, J = 10.5 Hz, 1 H), 5.72 (s, 1 H), 7.09 (d, J =
8.1 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.68
(d, J = 8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 21.5 (CH3), 22.4
(Z)-1-(1,4-Dibromopenta-2,4-dien-2-yl)-3-methoxybenzene (3f).
Following the general procedure, the title compound was obtained
1
(1.2 g, 45%). A yellow oil; TLC (Et2O/hexanes (1:5)) Rf = 0.63; H
NMR (300 MHz, CDCl3) δ 3.82 (s, 3 H), 4.49 (s, 2 H), 5.87 (d, J =
D
DOI: 10.1021/acs.joc.5b00072
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(CH2), 31.1 (CH2), 42.7 (CH), 49.9 (CH2), 52.1 (C), 58.2 (CH2),
124.0 (C), 127.2 (CH × 2), 127.8 (CH × 2), 128.6 (CH × 2), 129.7
(CH × 2), 130.7 (CH), 132.9 (C), 133.4 (C), 140.9 (C), 143.7 (C);
IR (KBr) 2967, 1569, 1474 cm−1; EI-MS m/z (rel intensity) 465
([M]+, 1), 386 (11), 284 (15), 198 (100); HRMS [M]+ calcd for
C21H21BrClNO2S: 465.0165, found 465.0154.
ASSOCIATED CONTENT
* Supporting Information
X-ray crystallographic data (3e, 4c) and complete character-
ization data (1H and 13C{1H} NMR data) for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
6-Bromo-7a-(p-tolyl)-2-tosyl-2,3,3a,4,5,7a-hexahydro-1H-isoin-
dole (4d). Following the general procedure, the title compound was
obtained (174 mg, 65%). A white solid, mp 164−165 °C; TLC (Et2O/
AUTHOR INFORMATION
Corresponding Author
*E-mail: mhlin@cc.ncue.edu.tw (M.-H.L.).
Notes
■
1
hexanes (1:2)) Rf = 0.38; H NMR (300 MHz, CDCl3) δ 1.43−1.62
(m, 2 H), 2.31 (s, 3 H), 2.32−2.43 (m, 3 H), 2.46 (s, 3 H), 3.13 (dd, J
= 9.9, 7.2 Hz, 1 H), 3.39 (d, J = 10.5 Hz, 1 H), 3.50 (dd, J = 9.9, 7.2
Hz, 1 H), 3.70 (d, J = 10.5 Hz, 1 H), 5.75 (s, 1 H), 7.06 (m, 4 H), 7.34
(d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 20.7 (CH3), 21.4 (CH3), 22.1 (CH2), 31.9 (CH2), 42.4
(CH), 49.8 (CH2), 52.1 (C), 58.4 (CH2), 123.3 (C), 126.1 (CH × 2),
127.1 (CH × 2), 129.1 (CH × 2), 129.7 (CH × 2), 131.4 (CH), 133.4
(C), 136.6 (C), 139.0 (C), 143.5 (C); IR (KBr) 2933, 1329, 1172
cm−1; EI-MS m/z (rel intensity) 445 ([M]+, 2), 366 (31), 290 (42),
198 (100); HRMS [M]+ calcd for C22H24BrNO2S: 445.0711, found
445.0701.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and Technology
of the Republic of China, Taiwan, is gratefully acknowledged.
We are also thankful for the assistance from Chang-Chih Hsieh
and Hung-Chang Hsiao for the X-ray structure determination.
REFERENCES
6-Bromo-7a-(4-methoxyphenyl)-2-tosyl-2,3,3a,4,5,7a-hexa-
hydro-1H-isoindole (4e). Following the general procedure, the title
compound was obtained (225 mg, 81%). A yellow solid, mp 164−166
°C; TLC (Et2O/hexanes (1:2)) Rf = 0.38; 1H NMR (300 MHz,
CDCl3) δ 1.38−1.59 (m, 2 H), 2.33−2.38 (m, 3 H), 2.41 (s, 3 H),
3.11 (dd, J = 9.9, 7.2 Hz, 1 H), 3.38 (d, J = 10.5 Hz, 1 H), 3.46 (dd, J =
9.9, 7.2 Hz, 1 H), 3.66 (d, J = 10.5 Hz, 1 H), 3.73 (s, 3 H), 5.72 (s, 1
H), 6.77 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 8.7 Hz, 2 H), 7.32 (d, J = 8.4
Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
21.4 (CH3), 22.1 (CH2), 30.9 (CH2), 42.6 (CH), 49.8 (C), 51.8
(CH2), 55.1 (CH3), 58.4 (CH2), 113.7 (CH × 2), 123.3 (C), 127.1
(CH × 2), 127.4 (CH × 2), 129.7 (CH × 2), 131.4 (CH), 133.4 (C),
133.9 (C), 143.5 (C), 158.3 (C); IR (KBr) 2925, 1329, 1172 cm−1; EI-
MS m/z (rel intensity) 461 ([M]+, 8), 306 (58), 242 (33), 198 (100);
HRMS [M]+ calcd for C22H24BrNO3S: 461.0660, found 461.0657.
6-Bromo-7a-(3-methoxyphenyl)-2-tosyl-2,3,3a,4,5,7a-hexa-
hydro-1H-isoindole (4f). Following the general procedure, the title
compound was obtained (191 mg, 69%). A yellow solid, mp 164−166
°C; TLC (Et2O/hexanes (1:2)) Rf = 0.38; 1H NMR (300 MHz,
CDCl3) δ 1.41−1.62 (m, 2 H), 2.31−2.49 (m, 6 H), 3.14 (dd, J = 9.6,
7.8 Hz, 1 H), 3.41 (d, J = 10.8 Hz, 1 H), 3.50 (dd, J = 9.6, 7.8 Hz, 1
H), 3.68 (d, J = 10.8 Hz, 1 H), 3.75 (s, 3 H), 5.74 (s, 1 H), 6.72−6.76
(m, 3 H), 7.15−7.21 (m, 1 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.70 (d, J =
8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 21.6 (CH3), 22.2 (CH2),
31.0 (CH2), 42.4 (CH), 49.9 (CH2), 52.5 (C), 55.2 (CH3), 58.7
(CH2), 111.7 (CH), 113.2 (CH), 118.7 (CH), 123.7 (C), 127.3 (CH
× 2), 129.7 (CH), 129.9 (CH × 2), 131.3 (CH), 133.5 (C), 143.8
(C), 143.9 (C), 159.7 (C); IR (KBr) 2946, 1143, 1573 cm−1; EI-MS
m/z (rel intensity) 461 ([M]+, 7), 382 (34), 306 (56), 198 (100);
HRMS [M]+ calcd for C22H24BrNO3S: 461.0660, found 461.0657.
6-Bromo-7a-(naphthalen-2-yl)-2-tosyl-2,3,3a,4,5,7a-hexahydro-
1H-isoindole (4h). Following the general procedure, the title
compound was obtained (200 mg, 69%). A yellow solid, mp 71−72
°C; TLC (Et2O/hexanes (1:2)) Rf = 0.33; 1H NMR (300 MHz,
CDCl3) δ 1.45−1.63 (m, 2 H), 2.36−2.40 (m, 2 H), 2.41 (s, 3 H),
2.50−2.59 (m, 1 H), 3.20 (dd, J = 9.9, 7.5 Hz, 1 H), 3.49 (d, J = 10.8
Hz, 1 H), 3.55 (dd, J = 9.9, 7.5 Hz, 1 H), 3.86 (d, J = 10.8 Hz, 1 H),
5.87 (s, 1 H), 7.27−7.49 (m, 5 H), 7.56 (s, 1 H), 7.70−7.79 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ 21.2 (CH3), 21.9 (CH2), 30.8 (CH2),
■
104.
(1) Gschwend, H. W.; Hillman, M. J.; Kisis, B. J. Org. Chem. 1976, 41,
(2) Tsirk, A.; Gronowitz, S.; Hornfeldt, A. B. Tetrahedron 1995, 51,
̈
7035.
(3) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Org. Biomol.
Chem. 2003, 1, 2038.
(4) (a) Tsirk, A.; Gronowitz, S.; Hornfeldt, A. B. Tetrahedron 1998,
̈
54, 9529. (b) Clary, K. N.; Parvez, M.; Back, T. G. Org. Biomol. Chem.
2009, 7, 1226. (c) Thomas, E. J. Acc. Chem. Res. 1991, 24, 229.
(d) Flores, B.; Molinski, T. Org. Lett. 2011, 13, 3932.
(5) Hyodo, K.; Nakamura, S.; Shibata, N. Angew. Chem., Int. Ed.
2012, 51, 10337.
(6) Shao, L.; Hewitt, M. C.; Malcolm, S. C.; Wang, F.; Ma, J.;
Campbell, U. C.; Spicer, N. A.; Engel, S. R.; Hardy, L. W.; Jiang, Z. D.;
Schreiber, R.; Spear, K. L.; Varney, M. A. J. Med. Chem. 2011, 54, 5283.
(7) Lin, M.-H.; Huang, Y.-C.; Kuo, C.-K.; Tsai, C.-H.; Li, Y.-S.; Hu,
T.-C.; Chuang, T.-H. J. Org. Chem. 2014, 79, 2751.
(8) (a) Ma, S.; Wang, G. Tetrahedron Lett. 2002, 43, 5723. (b) Cho,
Y. S.; Jun, B. K.; Pae, A. N.; Cha, J. H.; Koh, H. Y.; Chang, M. H.; Han,
S. Y. Synthesis 2004, 16, 2620. (c) Deng, Y.; Jin, X.; Ma, S. J. Org.
Chem. 2007, 72, 5901. (d) A, J. M.; Lee, P. H. Bull. Korean Chem. Soc.
2009, 30, 471. (e) Eom, D.; Kim, H.; Lee, P. H. Bull. Korean Chem.
Soc. 2010, 31, 645. (f) Alcaide, B.; Almendros, P.; Luna, A.; Prieto, N.
J. Org. Chem. 2012, 77, 11388.
(9) The structure has been deposited with the Cambridge
Crystallographic Data Centre (3e: CCDC 1042388). These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(10) The structure has been deposited with the Cambridge
Crystallographic Data Centre (4c: CCDC 1042387). These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(11) Reaction of bromo-dienes 3 with N-propargyl-N-(p-tosyl)amine
under the same condition gave the cyclization precursor yne-dienes,
but no cyclization product was observed.
41.8 (CH), 49.6 (CH2), 52.3 (C), 58.0 (CH2), 123.4 (C), 123.8 (CH),
125.1 (CH), 125.8 (CH), 125.9 (CH), 126.8 (CH × 2), 127.0 (CH),
127.5 (CH), 128.1 (CH), 129.4 (CH × 2), 130.9 (CH), 131.7 (C),
132.5 (C), 133.1 (C), 139.1 (C), 143.2 (C); IR (KBr) 2933, 1643,
1341 cm−1; EI-MS m/z (rel intensity) 481 ([M]+, 9), 402 (21), 326
(56), 198 (100); HRMS [M]+ calcd for C25H24BrNO2S: 481.0711,
found 481.0706.
E
DOI: 10.1021/acs.joc.5b00072
J. Org. Chem. XXXX, XXX, XXX−XXX