Synthesis of polycyclic isoindoline derivatives via tandem Pd-catalyzed coupling, propargyl-allenyl isomerization, [4 + 2] cycloaddition and aromatization reaction

Article abstract of DOI:10.1021/jo301437k

We report in this paper an interesting sequential reaction involving sequential Sonogashira coupling, propargyl-allenyl isomerization, [4 + 2] cycloaddition and aromatization reaction, which provides a facile method for the synthesis of a variety of polycyclic isoindoline derivatives from easily accessible starting materials.

Full text of DOI:10.1021/jo301437k

Note
pubs.acs.org/joc
Synthesis of Polycyclic Isoindoline Derivatives via Tandem Pd-
Catalyzed Coupling, Propargyl−Allenyl Isomerization, [4 + 2]
Cycloaddition and Aromatization Reaction
Shugao Zhu,‡ Jian Cao,‡ Luling Wu,*,‡ and Xian Huang†,‡,§
‡Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: We report in this paper an interesting
sequential reaction involving sequential Sonogashira coupling,
propargyl−allenyl isomerization, [4 + 2] cycloaddition and
aromatization reaction, which provides a facile method for the
synthesis of a variety of polycyclic isoindoline derivatives from
easily accessible starting materials.
soindolines and their congeners display a remarkable variety
of biological activities.1 Some isoindolines act as selective
sequential reaction to access polycyclic isoindoline derivatives
(Scheme 1).
I
serotonin uptake inhibitors, while others exhibit antitumor,
diuretic, and herbicidal activity.2 Hence, the study on
isoindolines continues to be an active research area, and
continuous efforts have been directed to the development of
new and efficient synthetic methods toward isoindolines
derivatives.3
We initiated this study by conducting the reaction of 3-iodo-
5,5-dimethylcyclohex-2-enone 1a and 2a in THF using 5 mol %
of Pd(PPh3)2Cl2 and 3 mol % of CuI. The reaction with 2 equiv
of DBU as base at room temperature for 2 h afforded the
coupling product exclusively (Scheme 2).
We reasoned that 1 equiv of DBU was consumed in the
Sonogashira coupling reaction, thus, the remaining DBU is not
enough for further reaction. In fact, when 4 equiv of DBU were
applied, the reaction afforded the expected product 3a in 62%
yield (Table 1, entries 1 and 2). t-BuOK was also investigated
as the base; however, no product was detected. In the absence
of an extra base or 1 mL of Et3N was added, the reaction only
afforded the coupling product (Table 1, entry 4), which means
that triethylamine could not be sufficient to induce the
isomerization step. When DBN was used as base, the yield
was improved to 72% (Table 1, entry 5). Other solvents were
also examined; however, no improvement was observed (Table
1, entries 6−10).
With the optimal conditions in hand, we next examined the
reaction scope. Typical results are summarized in Table 2. As
for substrate 2 wherein R3 is an aromatic group such as phenyl,
p-methylphenyl, p-methoxyphenyl and p-fluorophenyl group,
the reactions proceeded smoothly under the established
conditions, delivering the isoindoline derivatives 3 in good
yields (Table 2, entries 1−4). Furthermore, when R3 is an alkyl
group, the reactions gave the expected product as well (Table 2,
entries 5 and 6). The reaction was also applied to 3-
iodocyclohex-2-enone 1b and 3-iodocyclopent-2-enone 1c
(Table 2, entries 7−9). When (E)-ethyl 3-iodoacrylate 1d
The development of novel cascade reactions involving in situ
generation of reactive functional groups such as allene
intermediate is an intensively pursued goal in our group.
Muller et al. pioneered the Sonogashira coupling/propargyl−
̈
allenyl isomerization reactions for the synthesis of a variety of
useful compounds including chalcones, pyrazolines, pyrroles,
fluorescent spirocycles, and some other pharmaceutically
interesting heterocycles.4 In this aspect, we previously
established a series of sequential reactions wherein an allene
intermediate, generated in situ, would undergo cycloaddition
reaction under mild conditions, providing an efficient synthesis
of structurally complex polycycles with 2,3-dihydrofuran units,5
structurally diverse fused dihydroisobenzofuran derivatives,6
and other structurally complex polycycles.7 We anticipated that
this protocol could be further extended to cyclic compounds in
a broader dimension.
As a continuous exploration, herein we envisioned a
sequence of palladium-catalyzed coupling, propargyl−allenyl
isomerization, [4 + 2] cycloaddition and aromatization
reaction: Oxidative addition of alkenyl iodide 1 with Pd(0)
species would form intermediate A. Then it would react with
alkynyl copper intermediate B via transmetalation to generate
intermediate C. After reductive elimination regenerating Pd(0),
enyne D was formed, which was expected to undergo
propargyl−allenyl isomerization with a suitable base to afford
the enyne−allene intermediate E, which may preferentially
cyclize to produce intermediate F via [4 + 2] cycloaddition. In
this paper, we wish to report our results on this Pd-catalyzed
Received: July 9, 2012
Published: October 10, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1. Tandem Pd-Catalyzed Sequential Reaction
product was obtained smoothly and in good yield as well
(Table 3, entries 8 and 9).
Scheme 2
As comparison, we also conducted the reaction of 1-
iodobenzene (4d) or 1-iodo-4-methoxybenzene (4e) with 2a,
which exclusively gave the coupling products E2 and E3 in
excellent yields, without further isomerization to form 5
(Scheme 3).
When 3-iodocyclohex-2-enone 1b reacted with 2i in 3 mL of
THF and 1 mL of Et3N using 5 mol % of Pd(PPh3)2Cl2 and 3
mol % of CuI, the reaction afforded polycyclic isoindoline
derivative 3l in 35% yield (Scheme 4).
Table 1. Optimization of the Reaction Conditions for the
Sequential Reaction of 1a and 2a
a
In summary, we have developed a convenient sequential
Sonogashira coupling, propargyl−allenyl isomerization, [4 + 2]
cycloaddition and aromatization reaction, leading to a facile and
efficient synthesis of polycyclic isoindoline derivatives. In
respect to the easy availability of the starting materials, simple
manipulation, mild conditions and high efficiency, this reaction
will be synthetically useful in organic chemistry.
b
entry
solvent
base/equiv
temp
time
yield of 3a (%)
1
2
THF
DBU/2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2.5 h
2.5 h
1 d
0
THF
DBU/4
62
0
EXPERIMENTAL SECTION
■
3
THF
t-BuOK/4
General Methods. All reactions were performed under a N2
atmosphere. Anhydrous solvents were distilled prior to use: THF
was distilled from sodium-benzophenone; DMF was distilled from
CaH2. Petroleum ether refers to the fraction with the boiling point in
the range 60−90 °C. All 1H NMR and 13C NMR spectra were
measured in CDCl3 with TMS as the internal standard. Chemical shifts
are expressed in ppm, and J values are given in Hz.
c
4
THF
1 d
0
5
THF
DBN/4
DBN/4
DBN/4
DBN/4
DBN/4
DBN/4
2.5 h
2.5 h
2.5 h
2.5 h
2.5 h
2.5 h
72
36
53
45
39
46
6
toluene
CH3CN
DMF
CH2Cl2
DCE
7
8
9
1. Sequential Reactions Involving Coupling, Rearrange-
ment, Intramolecular [4 + 2] Cycloaddtion, and Aromatizaiton
for the Synthesis of Isoindoline Derivatives 3. (1). 7,7-Dimethyl-
4-phenyl-2-tosyl-2,3,7,8-tetrahydro-1H-benzo[f ]isoindol-5(6H)-one
(3a). Typical Procedure. An oven-dried Schlenk tube containing a
Teflon-coated stirring bar was charged with PdCl2(PPh3)2 (9 mg, 5
mol %) and CuI (2 mg, 3 mol %). The Schlenk tube was sealed,
evacuated and backfilled with N2 (3 cycles). A solution of 1a (63 mg,
0.25 mmol) and 2a (97 mg, 0.3 mmol) in THF (3.0 mL) was
subsequently injected to the Schlenk tube, and then 0.1 mL of Et3N
was injected. The reaction mixture was stirred at rt for 0.5 h, and then
4 equiv of DBN was added, and the resulting mixture was stirred for 2
h. When the reaction was complete as determined by TLC analysis,
the resulting mixture was quenched with a saturated aqueous solution
of ammonium chloride, and the mixture was extracted with Et2O. The
combined organic extracts were washed sequentially with water and
brine. The organic layers were dried over Na2SO4 and filtered.
Solvents were evaporated under reduced pressure. The residue was
purified by chromatography on silica gel (eluent: petroleum ether/
ethyl acetate = 4/1) to afford 78 mg (72%) of 3a. Pale solid: mp 180−
10
a
The reaction was carried out using 1 (0.25 mmol) and 2 (0.3 mmol)
in the presence of 5 mol % of Pd(PPh3)2Cl2 and 3 mol % of CuI in 3
mL of solvent and 0.1 mL of Et3N at rt for 30 min, and then 4 equiv of
b
c
base was added. Isolated yields. 1 mL of Et3N was added; the
reaction only afforded the coupling product as well.
was employed, the reactions occurred to give the expected
products in good yields (Table 2, entries 10 and 11).
To further expand the scope of this reaction, we also
investigated a range of electron-deficient aromatic halides. The
reaction of 2 with methyl 4-iodobenzoate 4a proceeded
smoothly to afford the corresponding isoindoline derivatives
5 in 57−76% yields at 60 °C. For R3, aromatic groups including
p-Me, p-MeO, p-F, and p-Cl substituted phenyl groups and
alkyl groups are all applicable (Table 3, entries 1−6). When
methyl 2-iodobenzoate 4b and 1-(4-iodophenyl)ethanone 4c
were employed under the established conditions, the expected
1
184 °C; H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H),
7.44−7.34 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.06−6.98 (m, 3H), 4.66
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Note
Table 2. Sequential Reactions Involving Coupling,
Table 3. Sequential Reactions Involving Coupling,
Rearrangement, Intramolecular [4 + 2] Cycloadditon, and
Aromatizaiton for the Synthesis of Isoindoline Derivatives
Rearrangement, Intramolecular [4 + 2] Cycloadditon, and
Aromatizaiton for the Synthesis of Isoindoline Derivatives
a
a
3
5
a
The reaction was carried out using 4 (0.5 mmol) and 2 (0.6 mmol) in
the presence of 5 mol % of Pd(PPh3)2Cl2 and 3 mol % of CuI in 6 mL
of THF and 0.2 mL of Et3N at rt for 30 min, and then 4 equiv of DBN
was added, and the resulting mixture was stirred at 60 °C for 8 h.
b
Isolated yields.
(s, 2H), 4.24 (s, 2H), 2.86 (s, 2H), 2.40 (s, 3H), 2.38 (s, 2H), 1.04 (s,
6H) ppm; 13C NMR (100 MHz, CDCl3) δ 197.7, 143.9, 143.7, 140.7,
139.8, 138.6, 135.5, 133.5, 129.8, 129.4, 128.4, 127.5, 127.0, 126.9,
122.7, 54.0, 53.8, 53.1, 44.7, 33.4, 28.0, 21.5 ppm; MS (EI, 70ev) m/z
(%) 445 (M+, 10.42), 290 (100); IR (neat) 2962, 1696, 1602, 1511,
1458, 1343, 1268, 1222, 1158, 1092, 1057 cm−1; HRMS (EI) calcd. for
C27H27NO3S (M+) 445.1712, found 445.1715.
a
The reaction was carried out using 1 (0.25 mmol) and 2 (0.3 mmol)
in the presence of 5 mol % of Pd(PPh3)2Cl2 and 3 mol % of CuI in 3
mL of THF and 0.1 mL of Et3N at rt for 30 min, and then 4 equiv of
DBN was added, and the resulting mixture was stirred for 2 h.
b
Isolated yields.
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Note
Scheme 3
127.5, 121.2, 54.6, 54.0, 52.8, 45.1, 33.0, 32.0, 31.6, 27.9, 23.3, 21.5,
13.9 ppm; MS (EI, 70ev) m/z (%) 425 (M+, 18.75), 270 (100); IR
(neat) 2957, 1685, 1605, 1513, 1453, 1343, 1245, 1159, 1096, 1057
cm−1; HRMS (EI) calcd. for C25H31NO3S (M+) 425.2025, found
425.2028.
Scheme 4
(6). 4-Cyclopropyl-7,7-dimethyl-2-tosyl-2,3,7,8-tetrahydro-1H-
benzo[f ]isoindol- 5(6H)-one (3f). Yield: 61% (62 mg). Pale solid:
mp 138−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz,
2H), 7.33 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 4.68 (s, 2H), 4.57 (s, 2H),
2.77 (s, 2H), 2.48 (s, 2H), 2.41 (s, 3H), 2.15−2.06 (m, 1H), 1.04−
0.95 (m, 8H), 0.26−0.18 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
δ 198.7, 143.7, 143.6, 140.3, 139.7, 136.9, 133.4, 132.8, 129.8, 127.5,
121.3, 54.2, 53.5, 53.0, 44.6, 33.7, 28.1, 21.4, 13.8, 8.2 ppm; MS (EI,
70ev) m/z (%) 409 (M+, 6.65), 254 (100); IR (neat) 2964, 1686,
1605, 1513, 1452, 1338, 1279, 1245, 1158, 1094, 1056, 1029 cm−1;
HRMS (EI) calcd. for C24H27NO3S (M+) 409.1712, found 409.1715.
(7). 4-Phenyl-2-tosyl-2,3,7,8-tetrahydro-1H-benzo[f ]isoindol-
5(6H)-one (3g). Yield: 78% (81 mg). Pale solid: mp 188−191 °C;
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.44−7.33
(m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 7.01 (d, J = 6.4 Hz,
2H), 4.65 (s, 2H), 4.23 (s, 2H), 2.96 (t, J = 5.8 Hz, 2H), 2.53 (t, J =
6.4 Hz, 2H), 2.40 (s, 3H), 2.11−2.02 (m, 2H) ppm; 13C NMR (100
MHz, CDCl3) δ 197.6, 145.7, 143.7, 140.3, 139.8, 138.9, 135.5, 133.4,
130.3, 129.8, 128.3, 127.4, 126.9, 126.8, 122.1, 54.0, 53.1, 40.3, 30.9,
22.8, 21.4 ppm; MS (EI, 70ev) m/z (%) 397 (M+, 16.90), 242 (100);
IR (neat) 2958, 1686, 1604, 1513, 1453, 1343, 1244, 1159, 1095, 1056,
1028 cm−1; HRMS (EI) calcd. for C25H23NO3S (M+) 417.1399, found
417.1394.
The following compounds were prepared according to this
procedure.
(2). 7,7-Dimethyl-4-p-tolyl-2-tosyl-2,3,7,8-tetrahydro-1H-benzo-
[f]isoindol-5(6H)- one (3b). Yield: 75% (86 mg). Pale solid: mp
188−192 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H),
7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 7.00 (s, 1H), 6.91
(d, J = 7.6 Hz, 2H), 4.64 (s, 2H), 4.25 (s, 2H), 2.85 (s, 2H), 2.39 (s,
3H), 2.38 (s, 3H), 2.37 (s, 2H), 1.03 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 197.8, 143.9, 143.7, 140.5, 138.6, 136.7, 136.4, 135.5,
133.4, 129.7, 129.5, 129.0, 127.4, 126.7, 122.5, 54.0, 53.8, 53.2, 44.6,
33.3, 27.9, 21.4, 21.2 ppm; MS (EI, 70ev) m/z (%) 459 (M+, 13.45),
304 (100); IR (neat) 2957, 1690, 1602, 1512, 1438, 1345, 1287, 1224,
1161, 1094, 1055, 1017 cm−1; HRMS (EI) calcd. for C28H29NO3S
(M+) 459.1868, found 459.1864.
(3). 4-(4-Fluorophenyl)-7,7-dimethyl-2-tosyl-2,3,7,8-tetrahydro-
1H- benzo[f ]isoindol-5(6H)-one (3c). Yield: 83% (96 mg). Pale
1
solid: mp 217−220 °C; H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
7.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.16−7.07 (m, 3H), 6.99 (t, J =
6.0 Hz, 2H), 4.66 (s, 2H), 4.22 (s, 2H), 2.87 (s, 2H), 2.44−2.35 (m,
5H), 1.04 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 197.8, 161.8
(d, J = 244.1 Hz), 144.1, 143.8, 140.7, 137.5, 135.6, 133.3, 129.8,
129.4, 128.6 (d, J = 8.4 Hz), 127.4, 123.0, 115.5, 115.2, 53.9, 53.8, 53.0,
44.6, 33.3, 27.9, 21.4 ppm; MS (EI, 70ev) m/z (%) 463 (M+, 12.32),
308 (100); IR (neat) 2958, 1690, 1604, 1508, 1451, 1344, 1267, 1225,
1157, 1092, 1052 cm−1; HRMS (EI) calcd. for C27H26NO3SF (M+)
463.1617, found 463.1620.
(8). 4-Butyl-2-tosyl-2,3,7,8-tetrahydro-1H-benzo[f ]isoindol-
5(6H)-one (3h). Yield: 64% (64 mg). Pale solid: mp 165−168 °C;
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J =
8.0 Hz, 2H), 6.92 (s, 1H), 4.61 (s, 4H), 2.89 (t, J = 6.0 Hz, 2H), 2.84
(t, J = 6.8 Hz, 2H), 2.61 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H), 2.06−1.96
(m, 2H), 1.43 (d, J = 1.8 Hz, 4H), 0.95 (t, J = 6.4 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 199.4, 146.2, 143.8, 141.0, 140.3, 135.1,
133.4, 130.1, 129.8, 127.4, 120.5, 54.0, 52.8, 41.0, 32.0, 31.7, 31.3, 23.2,
22.7, 21.4, 13.8 ppm; MS (EI, 70ev) m/z (%) 425 (M+, 18.75), 270
(100); IR (neat) 2951, 1685, 1605, 1512, 1457, 1344, 1289, 1239,
1157, 1096, 1019 cm−1; HRMS (EI) calcd. for C23H27NO3S (M+)
397.1712, found 397.1714.
(4). 4-(4-Methoxyphenyl)-7,7-dimethyl-2-tosyl-2,3,7,8-tetrahy-
dro-1H- benzo[f ]isoindol-5(6H)-one (3d). Yield: 65% (77 mg). Pale
1
solid: mp 190−195 °C; H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
8.0 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.03 (s, 1H), 6.94 (t, J = 9.6 Hz,
4H), 4.65 (s, 2H), 4.26 (s, 2H), 3.86 (s, 3H), 2.86 (s, 2H), 2.44−2.35
(m, 5H), 1.04 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 197.9,
158.5, 143.9, 143.7, 140.5, 138.4, 135.9, 133.4, 131.8, 129.8, 129.6,
128.1, 127.5, 122.5, 113.8, 55.2, 54.0, 53.9, 53.2, 44.7, 33.3, 28.0, 21.5
ppm; MS (EI, 70ev) m/z (%) 475 (M+, 48.43), 320 (100); IR (neat)
2962, 1687, 1606, 1513, 1455, 1345, 1268, 1244, 1160, 1095, 1052,
1029 cm−1; HRMS (EI) calcd. for C28H29NO4S (M+) 475.1817, found
475.1813.
(9). 4-Phenyl-2-tosyl-2,3,6,7-tetrahydrocyclopenta[f ]isoindol-
5(1H)-one (3i). Yield: 62% (61 mg). Pale solid: mp 234−237 °C;
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.42 (d, J =
4.8 Hz, 3H), 7.32 (d, J = 7.6 Hz, 2H), 7.24 (s, 1H), 7.17 (t, J = 3.6 Hz,
2H), 4.68 (s, 2H), 4.39 (s, 2H), 3.08 (t, J = 5.6 Hz, 2H), 2.64 (t, J =
5.8 Hz, 2H), 2.41 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 204.5,
156.5, 143.8, 143.0, 136.1, 135.4, 135.3, 133.32, 133.26, 129.9, 128.2,
128.1, 127.5, 119.8, 53.7, 52.4, 37.1, 25.0, 21.5 ppm; MS (EI, 70ev) m/
z (%) 403 (M+, 8.82), 248 (100); IR (neat) 1705, 1603, 1452, 1341,
1269, 1247, 1159, 1091, 1091, 1055 cm−1; HRMS (EI) calcd. for
C24H21NO3S (M+) 403.1242, found 403.1247.
(5). 4-Butyl-7,7-dimethyl-2-tosyl-2,3,7,8-tetrahydro-1H-benzo[f ]-
isoindol- 5(6H)-one (3e). Yield: 68% (72 mg). Pale solid: mp 130−
134 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.33
(d, J = 8.0 Hz, 2H), 6.88 (s, 1H), 4.61 (s, 4H), 2.86 (t, J = 7.2 Hz,
2H), 2.79 (s, 2H), 2.45 (s, 2H), 2.41 (s, 3H), 1.42 (t, J = 3.6 Hz, 4H),
1.02 (s, 6H), 0.95 (t, J = 6.6 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 199.6, 144.5, 143.8, 140.9, 140.6, 135.1, 133.5, 129.8, 129.2,
(10). Ethyl 4-phenyl-2-tosylisoindoline-5-carboxylate (3j). Yield:
1
76% (80 mg). Pale solid: mp 170−174 °C; H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.39 (d, J
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Note
= 6.8 Hz, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1H),7.12
(t, J = 7.6 Hz, 2H), 4.69 (s, 2H), 4.37 (s, 2H), 3.99 (q, J = 7.2 Hz,
2H), 2.40 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 167.4, 143.7, 139.5, 138.5, 137.9, 136.3, 133.4, 130.6, 129.9,
129.8, 128.2, 127.6, 127.5, 127.4, 121.4, 60.8, 54.0, 53.3, 21.5, 13.5
ppm; MS (EI, 70ev) m/z (%) 421 (M+, 9.85), 266 (100); IR (neat)
2955, 1701, 1603, 1512, 1459, 1344, 1286, 1224, 1159, 1127, 1095,
1061, 1017 cm−1; HRMS (EI) calcd. for C24H23NO4S (M+) 421.1348,
found 421.1349.
CDCl3) δ 167.0, 162.5 (d, J = 245.8 Hz), 143.9, 136.8, 135.5, 134.6 (d,
J = 11.9 Hz), 133.1, 132.5 (d, J = 3.0 Hz), 131.0, 130.9, 129.8, 128.4,
128.2, 127.7, 127.6, 125.4, 120.8, 116.2, 116.0, 53.5, 52.9, 52.2, 21.5
ppm; MS (EI, 70ev) m/z (%) 475 (M+, 11.54), 319 (100); 2953,
1711, 1602, 1513, 1446, 1339, 1286, 1261, 1222, 1150, 1119, 1096,
1067, 1001 cm−1; HRMS (EI) calcd. for C27H22NO4SF (M+)
475.1254, found 475.1257.
(4). Methyl 4-(4-methoxyphenyl)-2-tosyl-2,3-dihydro-1H-benzo-
[f]isoindole-6- carboxylate (5d). Yield: 76% (185 mg). Pale solid: mp
217−220 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.00 (d, J =
8.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.63 (s,
1H), 7.29 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0
Hz, 2H), 4.78 (s, 2H), 4.50 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.37 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.0, 159.4, 143.7, 136.8,
135.6, 134.6, 133.3, 131.2, 130.4, 129.7, 128.7, 128.1, 127.53, 127.46,
125.2, 120.2, 114.3, 55.3, 53.5, 53.0, 52.1, 21.4 ppm; MS (EI, 70ev) m/
z (%) 487 (M+, 7.56), 331 (100); IR (neat) 2951, 1714, 1608, 1513,
1442, 1338, 1285, 1253, 1226, 1155, 1098, 1025 cm−1; HRMS (EI)
calcd. for C28H25NO5S (M+) 487.1453, found 487.1453.
(11). Ethyl 4-(4-fluorophenyl)-2-tosylisoindoline-5-carboxylate
1
(3k). Yield: 72% (79 mg). Pale solid: mp 152−155 °C; H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 7.2
Hz, 4H), 4.69 (s, 2H), 4.34 (s, 2H), 4.03 (q, J = 7.2 Hz, 2H), 2.40 (s,
3H), 0.98 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
167.1, 162.2 (d, J = 245.4 Hz), 143.8, 139.7, 136.9, 136.5, 134.4 (d, J =
3.6 Hz), 133.3, 130.5, 130.1, 129.8, 129.4 (d, J = 9.0 Hz), 127.4, 121.6,
115.3 (d, J = 21.2 Hz), 60.9, 54.0, 53.2, 21.4, 13.6 ppm; MS (EI, 70ev)
m/z (%) 439 (M+, 8.90), 284 (100); IR (neat) 2960, 1700, 1602,
1511, 1462, 1367, 1321, 1286, 1224, 1160, 1127, 1092, 1057, 1014
cm−1; HRMS (EI) calcd. for C24H22NO4SF (M+) 439.1254, found
439.1258.
(5). Methyl 4-butyl-2-tosyl-2,3-dihydro-1H-benzo[f ]isoindole-6-
carboxylate (5e). Yield: 57% (125 mg). Pale solid: mp 182−185 °C;
1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H),
2. Sequential Reactions Involving Coupling, Rearrange-
ment, Intramolecular [4 + 2] Cycloaddtion, and Aromatizaiton
for the Synthesis of Isoindoline Derivatives 5. (1). Methyl 4-
phenyl-2-tosyl-2,3-dihydro-1H-benzo[f ]isoindole-6-carboxylate
(5a). Typical Procedure. An oven-dried Schlenk tube containing a
Teflon-coated stirring bar was charged with PdCl2(PPh3)2 (18 mg, 5
mol %) and CuI (3 mg, 3 mol %). The Schlenk tube was sealed,
evacuated and backfilled with N2 (3 cycles). A solution of 4a (131 mg,
0.5 mmol) and 2a (194 mg, 0.6 mmol) in THF (6.0 mL) was
subsequently injected to the Schlenk tube, and then 0.2 mL of Et3N
was injected. The reaction mixture was stirred at rt for 0.5 h, and then
4 equiv of DBN (248 mg, 2 mmol) were added, and the resulting
mixture was stirred at 60 °C for 8 h. When the reaction was complete
as determined by TLC analysis, the resulting mixture was quenched
with a saturated aqueous solution of ammonium chloride, and the
mixture was extracted with Et2O. The combined organic extracts were
washed sequentially with water and brine. The organic layers were
dried over Na2SO4 and filtered. Solvents were evaporated under
reduced pressure. The residue was purified by chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 4/1) to afford 142
7.86−7.74 (m, 3H), 7.51 (s, 1H), 7.33 (d, J = 7.6 Hz, 2H), 4.76 (s,
2H), 4.74 (s, 2H), 3.98 (s, 3H), 2.95 (t, J = 7.8 Hz, 2H), 2.39 (s, 3H),
1.68−1.56 (m, 2H), 1.52−1.41 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 167.2, 143.8, 136.9, 135.9, 134.9,
133.9, 133.3, 130.4, 129.8, 128.7, 127.6, 127.2, 126.7, 124.9, 119.2,
53.5, 52.6, 52.3, 32.5, 29.6, 23.0, 21.5, 13.9 ppm; MS (EI, 70ev) m/z
(%) (M+, 10.84), 281 (100); IR (neat) 2952, 1713, 1612, 1447, 1402,
1346, 1284, 1259, 1226, 1162, 1096, 1063 cm−1; HRMS (EI) calcd. for
C25H27NO4S (M+) 437.1661, found 437.1666.
(6). Methyl 4-(4-chlorophenyl)-2-tosyl-2,3-dihydro-1H-benzo[f ]-
isoindole-6-carboxylate (5g). Yield: 61% (150 mg). Pale solid: mp
238−241 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.04 (d, J =
8.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.69 (s,
1H), 7.52 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 7.2
Hz, 2H), 4.80 (s, 2H), 4.46 (s, 2H), 3.88 (s, 3H), 2.40 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 166.9, 143.9, 140.2, 136.9, 135.6,
135.0, 134.53, 134.49, 134.35, 133.1, 130.8, 130.6, 129.9, 129.3, 128.3,
127.8, 127.6, 125.5, 120.9, 53.5, 52.9, 52.3, 21.5 ppm; MS (EI, 70ev)
m/z (%) 493 (M+(37Cl), 2.38), 491 (M+(35Cl), 6.27), 335 (100); IR
(neat) 3090, 1713, 1614, 1496, 1445, 1339, 1286, 1260, 1227, 1201,
1151, 1093, 1066, 1004 cm−1; HRMS (EI) calcd. for C27H22NO4S35Cl
(M+) 491.0958, found 491.0952.
1
mg (62%) of 5a. Pale solid: mp 195−198 °C; H NMR (400 MHz,
CDCl3) δ 8.32 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz,
1H), 7.74 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.57−7.47 (m, 3H), 7.34−
7.23 (m, 4H), 4.80 (s, 2H), 4.49 (s, 2H), 3.85 (s, 3H), 2.38 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 167.0, 143.8, 136.8, 136.6,
135.8, 135.5, 134.4, 133.1, 130.9, 129.8, 129.2, 128.9, 128.7, 128.2,
128.1, 127.6, 125.3, 120.5, 53.5, 53.0, 52.2, 21.4 ppm; MS (EI, 70ev)
m/z (%) 457 (M+, 4.41), 301 (100); IR (neat) 2954, 1717, 1599,
1508, 1443, 1342, 1284, 1259, 1226, 1161, 1058, 1000 cm−1; HRMS
(EI) calcd. for C27H23NO4S (M+) 457.1348, found 457.1342.
(7). Methyl 4-(4-(methoxycarbonyl)phenyl)-2-tosyl-2,3-dihydro-
1H- benzo[f ]isoindole-6-carboxylate (5h). Yield: 35% (90 mg). Pale
1
solid: mp 172−175 °C; H NMR (400 MHz, CDCl3) δ 8.22 (d, J =
8.4 Hz, 3H), 8.04 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.73 (t,
J = 8.2 Hz, 3H), 7.36 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H),
4.80 (s, 2H), 4.45 (s, 2H), 4.01 (s, 3H), 3.86 (s, 3H), 2.39 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 166.8, 166.6, 143.9, 141.4,
136.9, 135.5, 134.6, 134. 3, 133.0, 130.5, 130.2, 130.0, 129.8, 129.4,
128.3, 128.1, 127.8, 127.5, 125.5, 121.1, 53.4, 52.7, 52.3, 52.2, 21.4
ppm; MS (EI, 70ev) m/z (%) 515 (M+, 6.05), 359 (100); IR (neat)
2954, 1713, 1610, 1440, 1401, 1347, 1284, 1259, 1163, 1095, 1063
cm−1; HRMS (EI) calcd. for C29H25NO6S (M+) 515.1403, found
515.1408.
(2). Methyl 4-p-tolyl-2-tosyl-2,3-dihydro-1H-benzo[f ]isoindole-6-
carboxylate (5b). Yield: 67% (158 mg). Pale solid: mp 233−237 °C;
1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H),
7.81 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 7.34−
7.25 (m, 4H), 7.13 (d, J = 7.6 Hz, 2H), 4.78 (s, 2H), 4.49 (s, 2H), 3.85
(s, 3H), 2.47 (s, 3H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 167.0, 143.7, 137.8, 136.8, 135.8, 135.5, 134.4, 133.5, 133.1,
131.0, 129.7, 129.5, 129.0, 128.7, 128.1, 127.5, 127.4, 125.2, 120.3,
53.5, 53.0, 52.1, 21.4, 21.2 ppm; MS (EI, 70ev) m/z (%) 471 (M+,
15.81), 315 (100); IR (neat) 2953, 1714, 1597, 1447, 1338, 1314,
1285, 1262, 1226, 1161, 1095, 1059 cm−1; HRMS (EI) calcd. for
C28H25NO4S (M+) 471.1504, found 471.1508.
(3). Methyl 4-(4-fluorophenyl)-2-tosyl-2,3-dihydro-1H-benzo[f ]-
isoindole-6- carboxylate (5c). Yield: 72% (171 mg). Pale solid: mp
196−200 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.03 (d, J =
8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.68 (s,
1H), 7.32 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 6.0 Hz, 4H), 4.80 (s, 2H),
4.47 (s, 2H), 3.87 (s, 3H), 2.39 (s, 3H) ppm; 13C NMR (100 MHz,
(8). Methyl 9-phenyl-2-tosyl-2,3-dihydro-1H-benzo[f ]isoindole-5-
carboxylate (5i). Yield: 54% (123 mg). Pale solid: mp 196−200 °C;
1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H),
7.74 (t, J = 7.6 Hz, 3H), 7.56−7.44 (m, 3H), 7.36−7.26 (m, 3H), 7.22
(d, J = 6.8 Hz, 2H), 4.82 (s, 2H), 4.48 (s, 2H), 3.98 (s, 3H), 2.36 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.8, 143.7, 137.2, 136.1,
134.6, 133.6, 133.1, 132.1, 131.3, 130.9, 130.0, 129.7, 129.2, 128.7,
127.9, 127.5, 126.7, 124.4, 118.6, 53.8, 53.0, 52.2, 21.4 ppm; MS (EI,
70ev) m/z (%) 457 (M+, 7.61), 301 (100); IR (neat) 2952, 1712,
1597, 1509, 1426, 1343, 1315, 1257, 1184, 1157, 1094, 1065, 1013
cm−1; HRMS (EI) calcd. for C27H23NO4S (M+) 457.1348, found
457.1346.
10413
dx.doi.org/10.1021/jo301437k | J. Org. Chem. 2012, 77, 10409−10415

The Journal of Organic Chemistry
Note
(9). Methyl 9-phenyl-2-tosyl-2,3-dihydro-1H-benzo[f ]isoindole-5-
carboxylate (5j). Yield: 57% (126 mg). Pale solid: mp 190−193 °C;
1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H),
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for 3, 5, E. This material is
7.86 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.58−
7.46 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 4.80
(s, 2H), 4.50 (s, 2H), 2.49 (s, 3H), 2.39 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 197.9, 143.8, 137.1, 136.5, 136.0, 135.6, 134. 53,
134.46, 133.1, 131.0, 129.8, 129.2, 128.9, 128.4, 128.3, 127.9, 127.6,
123.9, 120.5, 53.5, 52.9, 26.5, 21.5 ppm; MS (EI, 70ev) m/z (%) 441
(M+, 12.20), 285 (100); IR (neat) 3058, 1715, 1686, 1602, 1494, 1344,
1339, 1310, 1285, 1254, 1223, 1157, 1091, 1056 cm−1; HRMS (EI)
calcd. for C27H23NO3S (M+) 441.1399, found 441.1394.
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Wululing@zju.edu.cn.
Notes
The authors declare no competing financial interest.
†Prof. Xian Huang passed away on March 6, 2010. He had been
fully in charge of this project. At this moment, Prof. Luling Wu
is helping him to finish all the projects with the help from Prof.
Shengming Ma.
3. Reactions Affording the Direct Coupling Products E1, E2,
and E3. (1). N-(3-(5,5-Dimethyl-3-oxocyclohex-1-en-1-yl)prop-2-yn-
1-yl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide
1
(E1). Yield: 93% (103 mg). Oil: H NMR (400 MHz, CDCl3) δ 7.78
(d, J = 8.0 Hz, 2H), 7.33−7.18 (m, 7H), 5.95 (s, 1H), 4.44 (s, 2H),
4.39 (s, 2H), 2.38 (s, 3H), 2.20 (s, 2H), 2.11 (s, 2H), 0.99 (s, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 198.6, 144.0, 139.9, 135.2,
131.9, 131.5, 129.6, 128.6, 128.1, 127.9, 127.8, 121.9, 92.0, 89.0, 84.8,
81.2, 50.8, 43.7, 37.7, 37.5, 33.4, 27.9, 21.4 ppm; MS (EI, 70ev) m/z
(%) 445 (M+, 6.43), 91(100); IR (neat) 2958, 1663, 1596, 1491, 1440,
1351, 1305, 1277, 1243, 1161, 1093 cm−1; HRMS (EI) calcd. for
C27H27NO3S (M+) 445.1712, found 445.1717.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Projects No. 20872127, 20732005 and J0830431),
National Basic Research Program of China (973 Program,
2009CB825300), and CAS Academician Foundation of
Zhejiang Province and the Fundamental Research Funds for
the Central Universities for financial support.
(2). 4-Methyl-N,N-bis(3-phenylprop-2-yn-1-yl)benzene-
1
sulfonamide (E2). Yield: 88% (176 mg). Oil: H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.29−7.16 (m, 12H), 4.44 (s, 4H),
2.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 143.8, 135.2, 131.5,
129.5, 128.4, 128.1, 127.8, 122.0, 85.7, 81.5, 37.4, 21.3 ppm; MS (EI,
70ev) m/z (%) 399 (M+, 2.23), 243 (100); IR (neat) 3058, 1597,
1490, 1440, 1350, 1256, 1160, 1093, 1070, 1026 cm−1; HRMS (EI)
calcd. for C25H21NO2S (M+) 399.1293, found 399.1296.
REFERENCES
■
(1) (a) Jiang, W.-T.; Chen, Y.-S.; Hsu, T.; Wu, S.-H.; Chien, C.-H.;
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W.; Paul, R.; Powell, D. J. Med. Chem. 1999, 42, 2145. (c) Cornish, E.
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Goethem, S.; Matheeussen, V.; Joossens, J.; Lambeir, A. M.; Chen, X.;
De Meester, I.; Haemers, A.; Augustyns, K.; Van der Veken, P. J. Med.
Chem. 2007, 50, 5568. (e) Shultz, M.; Fan, J.; Chen, C.; Cho, Y. S.;
Davis, N.; Bickford, S.; Buteau, K.; Cao, X.; Holmqvist, M.; Hsu, M.;
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(3). N-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)-4-methyl-N-(3-phe-
nylprop-2-yn-1-yl) benzenesulfonamide (E3). Yield: 91% (195 mg).
1
Oil: H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.32−
7.12 (m, 9H), 6.77 (d, J = 8.8 Hz, 2H), 4.44 (s, 2H), 4.42 (s, 2H), 3.77
(s, 3H), 2.31 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.7,
143.7, 135.3, 133.1, 131.6, 129.5, 128.4, 128.1, 127.8, 122.1, 114.2,
113.7, 85.7, 81.6, 80.1, 55.2, 37.5, 37.4, 21.4 ppm; MS (EI, 70ev) m/z
(%) 429 (M+, 16.12), 273 (100); IR (neat) 2926, 1603, 1509, 1440,
1349, 1291, 1247, 1160, 1093 cm−1; HRMS (EI) calcd. for
C26H23NO3S (M+) 429.1399, found 429.1394.
Synthesis of 6,6-Dimethyl-3-phenyl-2-tosyl-4,5,6,7,9,9a-hex-
ahydro-1H-benzo-[f ]isoindol-8(2H)-one (3l). An oven-dried
Schlenk tube containing a Teflon-coated stirring bar were charged
with PdCl2(PPh3)2 (9 mg, 5 mol %) and CuI (2 mg, 3 mol %). The
Schlenk tube was sealed, evacuated and backfilled with N2 (3 cycles). A
solution of 1a (63 mg, 0.25 mmol) and 2i (97 mg, 0.3 mmol) in THF
(3.0 mL) was subsequently injected to the Schlenk tube, and then 1
mL of Et3N was injected. The reaction mixture was stirred at rt for 3 h.
When the reaction was complete as determined by TLC analysis, the
resulting mixture was quenched with a saturated aqueous solution of
ammonium chloride, and the mixture was extracted with Et2O. The
combined organic extracts were washed sequentially with water and
brine. The organic layers were dried over Na2SO4 and filtered.
Solvents were evaporated under reduced pressure. The residue was
purified by chromatography on silica gel (eluent: petroleum ether/
ethyl acetate = 6/1) to afford 39 mg (35%) of 3l. Oil: 1H NMR (400
MHz, CDCl3) δ 7.54 (d, J = 8.8 Hz, 2H), 7.46−7.33 (m, 5H), 7.27−
7.24 (m, 2H), 4.24 (dd, J1 = 8.8 Hz, J2 = 12.8 Hz, 1H), 3.57 (dd, J1 =
9.2 Hz, J2 = 12.4 Hz, 1H), 3.01−2.84 (m, 3H), 2.52−2.39 (m, 4H),
2.21 (s, 2H), 2.17−1.99 (m, 2H), 1.64−1.55 (m, 1H), 0.95 (s, 3H),
0.93 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 198.2, 151.4, 143.7,
135.5, 133.7, 132.5, 129.4, 129.1, 128.9, 128.3, 127.9, 127.8, 126.2,
56.8, 51.2, 44.8, 38.5, 33.0, 32.0, 28.7, 28.3, 28.1, 21.6. ppm; MS (EI,
70ev) m/z (%) 447 (M+, 4.08), 292 (100); IR (neat) 2961, 1670,
1443, 1301, 1243, 1162, 1093 cm−1; HRMS (EI) calcd. for
C27H29NO3S (M+) 447.1868, found 447.1865.
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10414
dx.doi.org/10.1021/jo301437k | J. Org. Chem. 2012, 77, 10409−10415

The Journal of Organic Chemistry
Note
(4) (a) Braun, R. U.; Ansorge, M.; Muller, T. J. J. Chem.Eur. J.
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