Palladium-catalyzed construction of polycyclic heterocycles by an alkyne insertion and direct arylation cascade

Article abstract of DOI:10.1055/s-0030-1260098

Cascade cyclization of bromoenynes bearing an aryl group with catalytic amounts of palladium(II) acetate and cesium carbonate led to the direct construction of tri- or tetracyclic heterocycles. Direct arylation of a pyrrole, furan or thiophene ring in the

Full text of DOI:10.1055/s-0030-1260098

SPECIAL TOPIC
2567
Palladium-Catalyzed Construction of Polycyclic Heterocycles by an Alkyne
Insertion and Direct Arylation Cascade
P
alladium-Catalyz
i
e
d
Ca
s
r
o
lization aki Ohno,*a,b Mio Yamamoto,a Mutsumi Iuchi,a Nobutaka Fujii,b Tetsuaki Tanaka*a
a
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68798214; E-mail: hohno@pharm.kyoto-u.ac.jp; E-mail: t-tanaka@phs.osaka-u.ac.jp
b
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 15 May 2011
R3
R1
cat. Pd
base
Abstract: Cascade cyclization of bromoenynes bearing an aryl
group with catalytic amounts of palladium(II) acetate and cesium
carbonate led to the direct construction of tri- or tetracyclic hetero-
cycles. Direct arylation of a pyrrole, furan or thiophene ring in the
cascade reaction affords the corresponding fused heteroarenes in
moderate to good yields.
N
N
R3
Br
R1
R2
R2
2
1
oxidative addition
C-H bond activation
Key words: tandem reaction, palladium, polycycles, fused-ring
systems, ring closure
R3
N
R3
N
carbopalladation
Pd
H
Pd
R1
Br
R2
R1
Br
R2
The development of cascade reactions that realize step-
economical syntheses of complex compounds by multiple
bond formation represents one of the most attractive sub-
jects in modern organic chemistry.1 A challenge in this
area is to improve atom economy by minimizing waste
product formation.2 C–H bond activation (including direct
arylation), which avoids pre-activation of the substrate
and thus minimizes the production of waste, is an impor-
tant strategy for this purpose.3 As a result, considerable at-
tention has been paid recently to catalytic cascade
reactions involving a C–H bond activation step.4
3
4
Scheme 1 Synthesis of isoindoles by palladium-catalyzed cascade
reaction through C–H bond activation.
The cinnamylamine-type bromoenynes 11 required for
the cascade reaction were prepared according to the gen-
eral route shown in Scheme 2. Carreira asymmetric
alkynylation9 of aldehydes 5 with alkynes 6 gave propar-
gylic alcohols 7, which were converted into the corre-
sponding protected propargylic amines 8 by Mitsunobu
reaction with Boc-amides followed by acid treatment. In
some cases, racemic propargylamines, which were readily
prepared by reaction of lithium acetylide with aldehydes
followed by amination, were used. A second Mitsunobu
condensation with 2-bromocinnamyl alcohols 10, which
were obtained by Wittig reaction of aldehydes 9 followed
by reduction with diisobutylaluminum hydride (DIBAL-
H), afforded the desired bromoenynes 11 in good yields.
Palladium catalysts are known to promote a variety of
transformations, including C–H bond activation. Several
palladium-catalyzed cascade reactions have been reported
recently, including carbopalladation onto a carbon–car-
bon multiple bond, followed by C–H bond activation to
form cyclic products.4,5 Reactions involving carbopalla-
dation onto a carbon–carbon triple bond are especially
useful for the direct construction of fused aromatic ring
systems6,7 such as oxindoles,6a,b fluorenes,6c indoles,6d
phenanthrenes,6e biarylidenes,7a,b acenaphthylenes,7c and
fused fulvenes.7d We recently found that palladium-cata-
lyzed cascade cyclization of bromoenynes 1 provides di-
rect access to benzoisoindole derivatives 2 (Scheme 1).8
This reaction proceeds through oxidative addition of a
bromoenyne 1 to palladium(0), carbopalladation, and aro-
matic C–H bond activation. Herein, our detailed studies
on this cascade cyclization, which includes aromatic C–H
bond activation, for the synthesis of various tri- and tetra-
cyclic heterocycles, are reported. A reaction involving di-
rect arylation with heteroarenes is also described.
OH
R2
Zn(OTf)2, (–)-NME, Et3N
R1CHO
R1
+
toluene
R2
5
6
7
NHR3
R1
1) R3NHBoc, Ph3P
DIAD
Ar
NR3
R1
Ph3P, DIAD
Br
2) 3 M HCl, EtOAc
(R3 = Ms or Ts)
R2
R2
8
11
1) Ph3P=C(Br)CO2Me
CHCl3
Ar
OH
ArCHO
2) DIBAL-H, THF
Br
9
10
SYNTHESIS 2011, No. 16, pp 2567–2578
Advanced online publication: 08.07.2011
DOI: 10.1055/s-0030-1260098; Art ID: C50911SS
x
x.
x
x
.
2
0
1
1
Scheme 2 General syntheses of substrates; NME = N-methyl-
ephedrine, DIAD = diisopropyl azodicarboxylate
© Georg Thieme Verlag Stuttgart · New York

2568
H. Ohno et al.
SPECIAL TOPIC
Other substrates were also prepared using a similar proto- 7–11); unfortunately, substitution with a phenyl group
col (see the Supporting Information).
was not tolerated (entry 7). The presence of a relatively
bulky substituent at this position, such as an isopropyl or
1-siloxyethyl group, decreased the reaction yield (entries
10 and 11). When tert-butyl derivative 11j was used
(Scheme 3), only the monocyclization product 13j was
obtained (7% yield); the desired bis-cyclization product
did not form. These bulky substituents might hamper ac-
cess of the palladium(II) intermediate of type 3 to the
alkyne moiety (Scheme 1). It should be noted that enynes
11m and 11n, without propargylic or nitrogen substitu-
tion, formed elimination products 14 (Scheme 3).12 From
these observations, the presence of a substituent with ap-
propriate steric bulk at the propargylic position and at the
nitrogen atom are both important for the cascade cycliza-
tion to proceed. Methoxy substitution at the para-position
of the benzene ring decreased the reaction yield (37%; en-
try 13), whereas meta-methoxy substitution was tolerated
(57%; entry 12).
First, the reaction conditions were optimized using bro-
moenyne 11a (Table 1). After considerable experimenta-
tion, it was found that the conditions used by Oh et al.10
[Pd(PPh3)4 (cat.), Cs2CO3, EtOH] for a cascade cycliza-
tion–cross-coupling reaction of 2-bromo-1,6-enynes with
an arylboronic acid promoted the desired bis-cyclization
to give 12a, albeit in low yield (26%; entry 1). Fortunate-
ly, use of palladium(II) acetate instead of Pd(PPh3)4 pro-
duced 12a in 74% yield (entry 2). Decreasing the catalyst
loading to 2 mol% slightly decreased the yield (64%;
entry 3).
A
similar result was obtained using
Pd2(dba)3·CHCl3 as the catalyst (entry 5). Among several
solvents examined, ethanol was the most effective (entries
3, 6, and 7). Bases, such as potassium carbonate and sodi-
um acetate, proved to be ineffective for the reaction.11
Table 1 Optimization of Reaction Conditions with Bromoenyne
11aa
Ph
NMs
palladium catalyst
NMs
Pd(OAc)2 (2 mol%)
Cs2CO3
H
H
Cs2CO3 (2 equiv)
NTs
t-Bu
Br
NTs
t-Bu
c-Hex
Br
solvent, reflux
c-Hex
EtOH
reflux, 7 h
NOE
HO
n-Bu
13j (7%)
OH
12a
n-Bu
11j
11a
Entry
Catalyst (mol%)
Pd(PPh3)4 (6)
Pd(OAc)2 (6)
Pd(OAc)2 (2)
Pd(dppf)2Cl2 (2)
Solvent
EtOH
EtOH
EtOH
EtOH
Time (h) Yield (%)b
Pd(OAc)2 (2 mol%)
Cs2CO3
NTs
1
2
3
4
5
6c
7
1
26
74
64
38
59
35
27
Br
NTs
EtOH
reflux, 0.5 h
2.5
7
11m
14m (54%)
3.5
5
Pd(OAc)2 (2 mol%)
Cs2CO3
NH
Pd2(dba)3·CHCl3 (2)
Pd(OAc)2 (2)
EtOH
DMF
Br
NH
c-Hex
c-Hex
EtOH
reflux, 2.5 h
n-Bu
14n (26%)
21
21
n-Bu
11n
Pd(OAc)2 (2)
dioxane
a Reactions were performed using Cs2CO3 (2 equiv).
b Isolated yields.
Scheme 3 Unsuccessful results using bromoenynes 11j, 11m, and
11n
c The reaction was performed at 100 °C.
To expand the reaction to construct various heterocyclic
ring systems, the direct arylation13 of heterocyclic sub-
strates 15a–e was investigated (Table 3). The reaction of
furan-substituted enyne 15a was complete within two
hours, to afford furo[2,3-f]isoindole 16a in moderate yield
(43%, entry 1). Bromoenynes 15b–e, bearing a pyrrole
ring, exhibited relatively low reactivity and thus required
an increased loading of the palladium catalyst (entries 2–
9). For example, the reaction of tosylamide 15b with 10
mol% palladium(II) acetate and cesium carbonate in N,N-
dimethylformamide did not reach completion within 72
hours, giving the desired tetrahydropyrrolo[3,4-f]indole
16b in 27% yield, along with recovered starting material
(entry 2). In contrast, the yield of 16b was improved to
75% when 20 mol% catalyst was used (entry 3). Similar
results were obtained using N-Mts derivative 15c
(Mts = 2,4,6-trimethylbenzenesulfonyl; entries 4 and 5).
The reactions of various cinnamylamine-type enynes 11
under the optimized reaction conditions shown in entry 3
(Table 1) were investigated; the results are summarized in
Table 2. The influence of the substituent at the alkyne ter-
minus was examined by using N-tosylamides 11b–f. 2-
Hydroxypropan-2-yl, n-butyl, and unsubstituted deriva-
tives 11b–d gave the corresponding bis-cyclization prod-
ucts 12b–d in 56–79% yield (entries 1–3). In contrast,
benzyloxymethyl derivative 11e gave a complex mixture
of unidentified products (entry 4). For reasons that are not
yet clear, phenyl substitution also had a negative effect on
the reaction, giving 12f in just 27% yield (entry 5). The
type of sulfonamide moiety used (Ts vs. Ms) was relative-
ly unimportant (Table 2, entry 3 vs. 6, and Table 2, entry
1 vs. Table 1, entry 3). In contrast, the reaction was sensi-
tive to the substituent at the propargylic position (entries
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

SPECIAL TOPIC
Palladium-Catalyzed Cascade Cyclization
2569
Table 2 Synthesis of Benzoisoindole Derivativesa
Entry
Substrate
Time (h)
Product (yield)b
NTs
c-Hex
NTs
Br
c-Hex
R
R
1
2
3
4
5
11b (R = CMe2OH)
( )-11c (R = n-Bu)
( )-11d (R = H)
11e (R = CH2OBn)
11f (R = Ph)
2.5
6
2
1.5
6
12b (64%)
( )-12c (79%)
( )-12d (56%)
12e (0%)c
12f (27%)
NMs
c-Hex
NMs
Br
c-Hex
6
11g
6
12g (46%)
NTs
R
NTs
R
Br
n-Bu
n-Bu
7
8
11h (R = Ph)
( )-11i (R = n-Pent)
1
3
12h (0%)c
( )-12i (65%)
NTs
R
NTs
R
Br
9
10
( )-11k (R = n-Pent)
11l (R = i-Pr)
1.5
4
( )-12k (48%)
12l (24%)
NTs
Br
NTs
H
OTBDPS
OTBDPS
11d
11o
24
12o (39%)
R1
R1
NTs
c-Hex
NTs
Br
R2
R2
c-Hex
n-Bu
n-Bu
12
13
11p (R1 = OMe, R2 = H)
5
8
12p (57%)
12q (37%)
11q (R1 = H, R2 = OMe)
a Reaction conditions (unless otherwise noted): Pd(OAc)2 (2 mol%), Cs2CO3 (2 equiv), EtOH, reflux.
b Isolated yield.
c A complex mixture of unidentified products formed.
d An increased amount of Pd(OAc)2 (4 mol%) was used.
It is worth noting that N,N-dimethylformamide was the The synthesis of tetracyclic fused-ring systems was then
solvent of choice for the reaction of protected pyrroles investigated (Table 4). Among the protected indole-
15b and 15c because the reaction in ethanol was relatively derived bromoenynes 17a–c (entries 1–4), tosylate 17a
inefficient and caused decomposition of the starting mate- proved to be the most efficient substrate for the cascade
rial (entry 6). When using electron-rich sulfonamide 15d, reaction, giving the desired tetrahydropyrrolo[3,4-b]car-
the decomposition of the substrate in ethanol was sup- bazole 18a upon reaction in N,N-dimethylformamide
pressed to some extent, and the desired fused indole 16d (entry 1). The reaction of carbamate 17c in ethanol only
was produced in 52% yield (entry 7). The 2-position of the promoted demethoxycarbonylation of the substrate (entry
pyrrole was less reactive toward direct arylation than the 4). Interestingly, the electron-rich N-methylindole-
3-position in this cascade reaction (entry 3 vs. entry 9).
derived enyne 17d was less reactive, affording 18d in
43% yield using an increased loading of the palladium
catalyst (10 mol%, entry 5). These results suggest that the
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

2570
H. Ohno et al.
SPECIAL TOPIC
Table 3 Synthesis of Tricyclic Heterocyclesa
Entry
Substrate
Conditionsb
Product (yield)c
O
O
NTs
c-Hex
NTs
Br
Br
c-Hex
n-Bu
n-Bu
1
15a
2 mol%, EtOH, 2 h
16a (43%)
R
N
R
N
NTs
c-Hex
NTs
c-Hex
n-Bu
n-Bu
2
3
4
5
6
7
8
15b (R = Ts)
15b (R = Ts)
15c (R = Mts)e
15c (R = Mts)e
15c (R = Mts)e
15d (R = SO2NMe2)
15d (R = SO2NMe2)
10 mol%, DMF, 72 h
20 mol%, DMF, 2 h
10 mol%, DMF, 2 h
20 mol%, DMF, 2 h
10 mol%, EtOH, 12 h
10 mol%, EtOH, 12 h
10 mol%, DMF, 3 h
16b (27%)d
16b (75%)
16c (42%)
16c (81%)
16c (36%)
16d (52%)
16d (33%)
NTs
NTs
Br
N
N
c-Hex
Ts
Ts
c-Hex
n-Bu
n-Bu
9
15e
20 mol%, DMF, 4 h
16e (42%)
a Reaction conditions: Pd(OAc)2, Cs2CO3 (2 equiv), EtOH (reflux) or DMF (120 °C).
b Catalyst loading, reaction solvent, and reaction time are shown.
c Isolated yield.
d Starting material (27%) was recovered.
e Mts = 2,4,6-trimethylbenzenesulfonyl.
direct arylation of indole derivatives 17 proceeds through zothiophene- and benzofuran-fused isoindoles 18e and
a concerted metalation–deprotonation (CMD) pathway 18f, respectively, in moderate yields (entries 6 and 7). 2,3-
rather than electrophilic aromatic substitution (SEAr).14 Dihydronaphtho[2,3-f]isoindole 18g was obtained in 43%
The reaction of benzothiophen-3-yl- and benzofuran-2- yield by activation of the naphthalene C–H bond (entry 8).
ylenynes 17e and 17f produced the corresponding ben-
Table 4 Synthesis of Tetracyclic Heterocyclesa
Entry
Substrate
Conditionsb
Product (yield)c
NTs
c-Hex
NTs
Br
N
R
N
R
c-Hex
n-Bu
n-Bu
1
2
3
4
5
17a (R = Ts)
17b (R = Mts)
17c (R = CO2Me)
17c (R = CO2Me)
17d (R = Me)
5 mol%, DMF, 18 h
5 mol%, DMF, 3 h
5 mol%, DMF, 4 h
5 mol%, EtOH, 1 h
10 mol%, EtOH, 36 h
18a (51%)
18b (31%)
18c (0%)d
18c (0%)e
18d (43%)
NTs
c-Hex
NTs
Br
S
S
c-Hex
n-Bu
n-Bu
6
17e
2 mol%, EtOH, 3 h
18e (49%)
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

SPECIAL TOPIC
Palladium-Catalyzed Cascade Cyclization
Product (yield)c
2571
Table 4 Synthesis of Tetracyclic Heterocyclesa (continued)
Entry
Substrate
Conditionsb
O
O
NTs
c-Hex
NTs
Br
c-Hex
n-Bu
n-Bu
7
8
17f
2 mol%, EtOH, 1 h
5 mol%, DMF, 5 hf
18f (59%)
NTs
c-Hex
NTs
Br
c-Hex
n-Bu
n-Bu
17g
18g (43%)
a Reaction conditions: Pd(OAc)2, Cs2CO3 (2 equiv), EtOH (reflux) or DMF (120 °C).
b Catalyst loading, reaction solvent, and reaction time are shown.
c Isolated yield.
d A complex mixture of unidentified products formed.
e The demethoxycarbonylation product was obtained (67%).
f 2 h with 2 mol% catalyst and a further 3 h with an additional 3 mol% catalyst.
Finally, construction of an indane skeleton using malonate In conclusion, we have developed a palladium-catalyzed
congeners 19 was investigated (Table 5). The reaction of cascade reaction for the cyclization of bromoenynes. The
19a with palladium(II) acetate in ethanol produced tricy- reaction proceeds through carbopalladation onto a car-
clic carbocycle 20a in 68% yield (entry 2). Other palladi- bon–carbon triple bond and C–H bond activation of a ben-
um catalysts, such as Pd2(dba)3·CHCl3 (entry 3) and zene ring, leading to the direct construction of isoindole
Pd(PPh3)4 (entry 4), were less effective. The presence of a derivatives. The presence of a propargylic substituent is
substituent at the propargylic position was also important important for the progress of the reaction. Direct arylation
to promote the desired cascade cyclization using malonate of heteroarenes, such as pyrrole, furan, thiophene and
derivatives.12 The reaction of pyrrole-derived malonate their benzene-fused rings, allows various types of tri- and
19b in N,N-dimethylformamide at 140 °C resulted in the tetracyclic heterocycles to be produced from readily pre-
formation of cyclopenta[f]indole derivative 20b in low pared enynes.
yield (35%, entry 5).
Table 5 Synthesis of Indane Derivativesa
Entry
Substrate
Conditionsb
Product (yield)c
CO2Et
CO2Et
n-Pent
CO2Et
CO2Et
Br
n-Pent
n-Bu
n-Bu
1
2
3
4
19a
19a
19a
19a
5 mol%, DMF, 6 h
5 mol%, EtOH, 2 h
5 mol%, DMF, 4 he
5 mol%, DMF, 4 hf
20a (0%)d
20a (68%)
20a (34%)
20a (17%)
CO2Et
Ts
N
Ts
N
CO2Et
CO2Et
CO2Et
n-Pent
Br
n-Pent
n-Bu
n-Bu
5
19b
5 mol%, DMF, 24 hg
20b (35%)
a Reaction conditions (unless otherwise stated): Pd(OAc)2, Cs2CO3 (2 equiv), EtOH (reflux) or DMF (120 °C).
b Catalyst loading, reaction solvent, and reaction time are shown.
c Isolated yield.
d A complex mixture of unidentified products formed.
e Pd2(dba)3·CHCl3 was used.
f Pd(PPh3)4 was used.
g The reaction was conducted at 140 °C.
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

2572
H. Ohno et al.
SPECIAL TOPIC
(1R)-1-Cyclohexyl-9-(2-hydroxypropan-2-yl)-2-(4-methylphe-
nylsulfonyl)-2,3-dihydro-1H-benzo[f]isoindole (12b)
Bromoenyne 11b (124 mg, 0.227 mmol) was converted into 12b
and a minor product in 2.5 h.
Melting points are uncorrected. Nominal (LRMS) and exact mass
(HRMS) spectra were recorded with a JEOL JMS-700 or JMS-600
mass spectrometer. 1H NMR spectra were recorded in CDCl3.
Chemical shifts are reported in parts per million downfield from in-
ternal Me4Si (s = singlet, d = doublet, dd = double doublet,
ddd = doublet of double doublet, t = triplet, dt = double triplet,
tt = triple triplet, q = quartet, m = multiplet). Optical rotations were
measured in CHCl3 with a JASCO DIP-360 digital polarimeter. For
flash chromatography, silica gel 60 H (silica gel for thin-layer chro-
matography, Merck) or silica gel 60 (finer than 230 mesh, Merck)
was employed.
Compound 12b
Yield: 67.6 mg (64%); colorless oil; [a]D23 +50.6 (c 0.60, CHCl3).
IR (KBr): 3525 (OH), 1599 (naphthalene), 1340 (NHSO2), 1161
(NHSO2) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.86–1.94 (m, 11 H), 1.76 (s, 3 H,
CCH3), 1.96 (s, 3 H, CCH3), 2.12 (s, 3 H, ArCH3), 4.62 (d,
J = 16.5 Hz, 1 H, NCHH), 4.75 (d, J = 16.5 Hz, 1 H, NCHH), 6.08
(d, J = 1.5 Hz, 1 H, 1-H), 7.00 (d, J = 7.9 Hz, 2 H, ArH), 7.35–7.40
(m, 3 H, ArH), 7.64–7.70 (m, 3 H, ArH), 8.14 (d, J = 8.5 Hz, 1 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 21.3, 26.27, 26.30, 26.8 (2C), 31.5,
32.3, 33.7, 47.3, 53.5, 72.2, 75.1, 120.2, 124.6, 124.7, 126.4 (2C),
127.5, 128.8 (2C), 129.1, 130.1, 134.3, 135.1, 136.5, 137.4, 138.0,
143.0.
Synthesis of Bromoenynes (11) by Condensation of Propargyl
Amine Derivatives (8) with 3-Aryl-2-bromoprop-2-en-1-ols
(10); General Procedure
To a stirred mixture of protected propargylic amine 8 (ca. 3 mmol),
alcohol 10 (2.2 equiv), and Ph3P (2.2 equiv) in THF (30 mL), was
added dropwise diisopropyl azodicarboxylate (DIAD; 2.2 equiv) at
0 °C. The mixture was stirred for 4 h at r.t. and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy over silica gel (n-hexane–EtOAc) to give 11.
MS (FAB): m/z (%) = 464 (38) [M + H+], 380 (100).
HRMS (FAB): m/z [M + H]+ calcd for C28H34NO3S: 464.2259;
found: 464.2270.
Palladium-Catalyzed Cascade Cyclization of Bromoenynes:
Synthesis of (1R)-1-Cyclohexyl-9-(2-hydroxypropan-2-yl)-2-
methylsulfonyl-2,3-dihydro-1H-benzo[f]isoindole (12a) (Table
1, Entry 3); Typical Procedure
A mixture of 11a (124 mg, 0.265 mmol), Cs2CO3 (173 mg, 0.531
mmol), and Pd(OAc)2 (1.2 mg, 0.0531 mmol; 2 mol%) in EtOH (1.5
mL) was heated under reflux for 7 h. After cooling, sat. aq NH4Cl
(10 mL) was added. The mixture was then extracted with EtOAc
(2 × 50 mL) and dried over MgSO4. Concentration under reduced
pressure gave an oily residue, which was purified by column chro-
matography over silica gel (n-hexane–EtOAc, 10:1) to give 12a and
an unidentified minor product.
Minor Product
Yield: 17.1 mg (16%); colorless crystals; mp 152–154 °C (n-hex-
ane–EtOAc); [a]D23 +280 (c 0.33, CHCl3).
IR (KBr): 3523 (OH), 1344 (NHSO2), 1166 (NHSO2) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.86–1.98 (m, 11 H), 1.00 (s, 3 H,
CCH3), 1.20 (s, 3 H, CCH3), 2.41–2.43 (m, 1 H), 2.53 (s, 3 H,
ArCH3), 4.36 (s, 1 H), 4.41 (s, 1 H), 5.93 (s, 1 H, C = CH), 6.66 (d,
2 H, J = 7.3 Hz, ArH), 7.13–7.35 (m, 5 H, ArH), 7.66 (d, 2 H,
J = 8.5 Hz, Ph).
13C NMR (67.8 MHz, CDCl3): d = 21.8, 26.2, 26.35, 26.42, 27.8,
29.0, 29.1, 29.2, 43.1, 49.4, 67.3, 70.6, 114.0, 127.2, 127.4 (2C),
128.0 (2C), 128.2 (2C), 129.4 (2C), 133.2, 137.1, 138.5, 143.3,
148.5, 149.1.
MS (FAB): m/z (%) = 464 (56) [M + Na+], 154 (100).
HRMS (FAB): m/z [M + Na]+ calcd for C28H33NNaO3S: 486.2074;
Compound 12a
Yield: 65.7 mg (64%); colorless oil; [a]D28 +31.4 (c 0.62, CHCl3).
IR (KBr): 3545 (OH), 1336 (NSO2), 1153 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90–1.28 (m, 5 H), 1.58–1.85 (m,
6 H), 1.96 (s, 3 H, CCH3), 2.03 (s, 3 H, CCH3), 2.55 (s, 3 H,
SO2CH3), 4.65 (dd, J = 16.8, 1.2 Hz, 1 H, NCHH), 4.80 (dd,
J = 16.8, 1.2 Hz, 1 H, NCHH), 5.97 (d, J = 1.2 Hz, 1 H, 1-H), 7.42–
7.50 (m, 2 H, ArH), 7.61 (s, 1 H, ArH), 7.79–7.82 (m, 1 H, ArH),
8.25 (dd, J = 9.9, 2.7 Hz, 1 H, ArH).
13C NMR (67.5 MHz, CDCl3): d = 26.2, 26.3, 26.7 (2C), 31.4, 32.6,
34.2 (2C), 47.0, 53.4, 71.9, 75.2, 120.8, 125.0, 125.1, 126.5, 129.0,
130.3, 134.6, 136.4, 137.3, 139.0.
found: 486.2079.
Anal. Calcd for C28H33NO3S: C, 72.54; H, 7.17; N, 3.02. Found: C,
72.50; H, 7.19; N, 2.99.
( )-9-Butyl-1-cyclohexyl-2-(4-methylphenylsulfonyl)-2,3-dihy-
dro-1H-benzo[f]isoindole (12c)
Bromoenyne 11c (130 mg, 0.240 mmol) was converted into 12c in
6 h.
MS (FAB): m/z (%) = 388 (53) [M + H]+, 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C22H30NO3S: 388.1946;
Yield: 87.8 mg (79%); colorless oil.
IR (KBr): 1346 (NSO2), 1163 (NSO2) cm–1.
found: 388.1948.
Minor product
1H NMR (300 MHz, CDCl3): d = 0.90–2.16 (m, 18 H), 2.38 (s, 3 H,
ArCH3), 2.81–2.91 (m, 1 H, 1¢-CHH), 2.95–3.05 (m, 1 H, 1¢-CHH),
4.71 (d, J = 16.2 Hz, 1 H, 3-CHH), 4.83 (d, J = 16.2 Hz, 1 H, 3-
CHH), 5.12 (s, 1 H, 1-H), 6.99 (d, J = 8.1 Hz, 2 H, ArH), 7.34–7.46
(m, 3 H, ArH), 7.57 (d, J = 8.1 Hz, 2 H, Ph), 7.70 (d, J = 7.5 Hz,
1 H, ArH), 7.92 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.0, 21.3, 23.2, 26.1, 26.4, 26.5,
26.7, 29.5, 31.5, 32.9, 45.4, 54.9, 70.4, 118.6, 124.0, 125.3, 125.4,
127.2 (2C), 128.5, 129.3 (2C), 131.5, 132.6, 133.6, 135.1, 135.8,
136.8, 143.1.
Yield: 2.5 mg (3%); colorless oil; [a]D22 –114 (c 0.14, CHCl3).
IR (KBr): 3519 (OH), 1338 (NSO2), 1159 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 (s, 3 H, CCH3), 1.15–1.96 (m,
12 H), 1.31 (s, 3 H, CCH3), 2.79 (s, 3 H, SO2CH3), 4.47 (d,
J = 1.2 Hz, 2 H), 5.84 (s, 1 H, C=CH), 7.13–7.27 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.1, 26.2, 26.3, 27.5, 28.8, 29.1,
29.4, 34.5, 43.2, 49.7, 67.6, 70.8, 113.8, 127.4 (2C), 127.6, 128.7
(2C), 136.7, 138.6, 148.9, 149.3.
MS (FAB): m/z (%) = 410 (40) [M + Na+], 176 (100).
HRMS (FAB): m/z [M + Na]+ calcd for C22H29NNaO3S: 410.1766;
MS (FAB): m/z (%) = 462 (60) [M + H+], 378 (100).
HRMS–FAB: m/z [M + H]+ calcd for C29H36NO2S: 462.2467;
found: 410.1789.
found: 462.2467.
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

SPECIAL TOPIC
Palladium-Catalyzed Cascade Cyclization
2573
( )-1-Cyclohexyl-2-(4-methylphenylsulfonyl)-2,3-dihydro-1H-
benzo[f]isoindole (12d)
( )-9-Butyl-2-(4-methylphenylsulfonyl)-1-pentyl-2,3-dihydro-
1H-benzo[f]isoindole (12i)
Bromoenyne 11d (63.9 mg, 0.131 mmol) was converted into 12d in
2 h.
Bromoenyne 11i (72.0 mg, 0.136 mmol) was converted into 12i in
3 h.
Yield: 29.7 mg (56%); colorless oil.
Yield: 39.9 mg (65%); colorless oil.
IR (KBr): 1346 (NSO2), 1161 (NSO2) cm–1.
IR (KBr): 1346 (NSO2), 1161 (NSO2) cm–1.
1H NMR (270 MHz, CDCl3): d = 0.89–1.34 (m, 5 H), 1.50–1.75 (m,
6 H), 2.24 (s, 3 H, ArCH3), 4.74 (d, J = 15.5 Hz, 1 H, 3-CHH), 4.78
(d, J = 15.5 Hz, 1 H, 3-CHH), 5.02 (d, J = 4.3 Hz, 1 H, 1-H), 7.10
(d, J = 8.4 Hz, 2 H, ArH), 7.41–7.44 (m, 2 H, ArH), 7.53 (d,
J = 9.5 Hz, 2 H, ArH), 7.64 (d, J = 8.4 Hz, 2 H, ArH), 7.71–7.79
(m, 2 H, ArH).
13C NMR (68 MHz, CDCl3): d = 21.5, 26.2, 26.3, 26.5, 28.2, 28.8,
45.9, 53.8, 70.6, 120.4, 121.8, 125.7, 125.8, 127.0 (2C), 127.5,
127.9, 129.4 (2C), 132.6, 132.8, 135.2, 135.8, 137.9, 143.1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 7.2 Hz, 3 H, CCH3),
0.97 (t, J = 7.2 Hz, 3 H, CCH3), 1.15–1.28 (m, 5 H), 1.39–1.54 (m,
5 H), 1.74–1.85 (m, 1 H), 1.98–2.10 (m, 1 H), 2.24 (s, 3 H, ArCH3),
2.88 (dt, J = 13.8, 3.3 Hz, 1 H, 1¢-CHH), 2.98 (dt, J = 13.8, 3.3 Hz,
1 H, 1¢-CHH), 4.78 (d, J = 16.5 Hz, 1 H, 3-CHH), 4.84 (d,
J = 16.5 Hz, 1 H, 3-CHH), 5.29 (dd, J = 5.7, 3.3 Hz, 1 H, 1-H), 7.09
(d, J = 8.7 Hz, 2 H, ArH), 7.39–7.47 (m, 3 H, ArH), 7.64 (d,
J = 8.7 Hz, 2 H, ArH), 7.73 (dd, J = 7.8, 1.8 Hz, 1 H, ArH), 7.93
(dd, J = 7.5, 1.8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.0, 14.1, 21.3, 22.5, 23.3, 24.1,
29.2, 31.8, 32.8, 36.4, 53.3, 65.4, 119.1, 123.9, 125.4, 125.5, 127.0
(2C), 128.5, 129.5 (2C), 131.5, 132.5, 133.7, 135.2, 135.6, 137.1,
143.2.
MS (FAB): m/z (%) = 406 (70) [M + H+], 322 (100).
HRMS (FAB): m/z [M + H]+ calcd for C25H28NO2S: 406.1841;
found: 406.1823.
MS (FAB): m/z (%) = 450 (62) [M + H+], 378 (100).
HRMS (FAB): m/z [M + H]+ calcd for C28H36NO2S: 450.2467;
(1R)-1-Cyclohexyl-2-(4-methylphenylsulfonyl)-9-phenyl-2,3-di-
hydro-1H-benzo[f]isoindole (12f)
Bromoenyne 11f (64.0 mg, 0.114 mmol) was converted into 12f in
6 h.
found: 450.2458.
( )-2-(4-Methylphenylsulfonyl)-1-pentyl-2,3-dihydro-1H-ben-
zo[f]isoindole (12k)
Bromoenyne 11k (94.2 mg, 0.199 mmol) was converted into 12k in
Yield: 15.0 mg (27%); colorless oil; [a]D25 –46.5 (c 0.60, CHCl3).
IR (KBr): 1346 (NSO2), 1163 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83–1.05 (m, 6 H), 1.22–1.64 (m,
5 H), 2.25 (s, 3 H, ArCH3), 4.75 (d, J = 16.5 Hz, 1 H, 3-CHH), 4.93
(d, J = 16.5 Hz, 1 H, 3-CHH), 5.02 (d, J = 2.4 Hz, 1 H, 1-H), 6.94–
6.97 (m, 1 H, ArH), 7.13 (d, J = 8.4 Hz, 2 H, ArH), 7.28–7.74 (m,
2 H, ArH), 7.41 (dd, J = 8.1, 8.1 Hz, 1 H, ArH), 7.48–7.51 (m, 5 H,
ArH), 7.66 (d, J = 8.4 Hz, 2 H, ArH), 7.76 (d, J = 8.1 Hz, 1 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 21.4, 26.1, 26.2, 26.5 (2C), 31.2,
43.7, 55.0, 70.5, 119.9, 125.65, 125.70, 125.9, 127.3 (2C), 127.8
(2C), 128.2, 128.6, 129.1, 129.5 (2C), 130.5, 132.0, 133.3, 134.1,
135.1, 135.8, 137.3, 137.6, 143.4.
1.5 h.
Yield: 37.8 mg (48%); colorless oil.
IR (KBr): 1346 (NSO2), 1163 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.81 (t, J = 6.9 Hz, 3 H, CCH3),
1.02–1.10 (m, 1 H), 1.18–1.25 (m, 4 H), 1.39–1.47 (m, 1 H), 1.89–
2.00 (m, 1 H), 2.13–2.25 (m, 1 H), 2.31 (s, 3 H, ArCH3), 4.77 (d,
J = 14.7 Hz, 1 H, 3-CHH), 4.83 (d, J = 14.7 Hz, 1 H, 3-CHH), 5.16
(t, J = 4.5 Hz, 1 H, 1-H), 7.20 (d, J = 8.1 Hz, 2 H, ArH), 7.40–7.46
(m, 2 H, ArH), 7.53 (s, 1 H, ArH), 7.57 (s, 1 H, ArH), 7.72 (d,
J = 8.1 Hz, 2 H, ArH), 7.75–7.79 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.0, 21.4, 22.5, 23.2, 31.8, 37.0,
53.4, 65.5, 120.8, 120.9, 125.88, 125.93, 127.3 (2C), 127.67,
127.68, 127.8, 129.7 (2C), 133.0, 134.9, 135.0, 139.3, 143.4.
MS (FAB): m/z (%) = 482 (6.8) [M + H+], 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C31H32NO2S: 482.2154;
found: 482.2159.
(1R)-1-Isopropyl-2-(4-methylphenylsulfonyl)-2,3-dihydro-1H-
benzo[f]isoindole (12l)
Bromoenyne 11l (52.8 mg, 0.118 mmol) was converted into 12l in
4 h.
Yield: 10.5 mg (24%); colorless oil; [a]D27 –20.8 (c 0.60, CHCl3).
IR (KBr): 1344 (NSO2), 1161 (NSO2) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.80 (d, J = 6.7 Hz, 3 H, CCH3),
0.99 (d, J = 7.3 Hz, 3 H, CCH3), 2.19 (s, 3 H, ArCH3), 2.32–2.36
[m, 1 H, (CH3)2CH], 4.71 (s, 1 H, J = 15.5 Hz, 3-CHH), 4.74 (d,
J = 15.5 Hz, 1 H, 3-CHH), 4.99 (d, J = 4.3 Hz, 1 H, 1-H), 7.06 (d,
J = 7.9 Hz, 2 H, ArH), 7.357 (d, J = 6.1 Hz, 1 H, ArH), 7.365 (d,
J = 6.1 Hz, 1 H, ArH), 7.47 (s, 1 H, ArH), 7.50 (s, 1 H, ArH), 7.59
(d, J = 7.9 Hz, 2 H, ArH), 7.66–7.71 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 17.3, 18.4, 21.4, 35.8, 53.8, 70.9,
120.6, 121.9, 125.8, 125.9, 127.1 (2C), 127.6, 128.0, 129.6 (2C),
132.8, 133.0, 135.3, 135.9, 137.6, 143.3.
( )-1-Cyclohexyl-2-methylsulfonyl-2,3-dihydro-1H-ben-
zo[f]isoindole (12g)
Bromoenyne 11g (36.8 mg, 0.0897 mmol) was converted into 12g
in 6 h.
Yield: 13.7 mg (46%); colorless oil.
IR (KBr): 1346 (NSO2), 1161 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.99–1.33 (m, 6 H), 1.61–1.80 (m,
5 H), 2.60 (s, 3 H, SO2CH3), 4.76 (d, J = 16.2 Hz, 1 H, 3-CHH),
4.86 (d, J = 16.2 Hz, 1 H, 3-CHH), 4.92 (d, J = 4.5 Hz, 1 H, 1-H),
7.48–7.51 (m, 2 H, ArH), 7.71 (s, 2 H, 4-H and 9-H), 7.82–7.87 (m,
2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.1, 26.17, 26.21, 28.5, 28.6, 34.8,
45.3, 53.8, 70.4, 120.9, 122.3, 126.2, 126.3, 127.8, 128.0, 132.9,
133.2, 135.9, 138.2.
MS (FAB): m/z (%) = 330 (34) [M + H+], 246 (100).
HRMS (FAB): m/z [M + H]+ calcd for C19H24NO2S: 330.1528;
MS (FAB): m/z (%) = 366 (22) [M + H+], 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C22H24NO2S: 366.1528;
found: 330.1514.
found: 366.1523.
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

2574
H. Ohno et al.
SPECIAL TOPIC
(1S)-1-{(1S)-1-[tert-Butyl(diphenyl)silyloxy]ethyl}-9-methyl-2-
(4-methylphenylsulfonyl)-2,3-dihydro-1H-benzo[f]isoindole
(12o)
Bromoenyne 11o (57.3 mg, 0.0818 mmol) was converted into 12o
using Pd(OAc)2 (0.8 mg, 0.00327 mmol) for 24 h.
Yield: 20.0 mg (39%); colorless oil; [a]D23 –86.5 (c 0.60, CHCl3).
IR (KBr): 1346 (NSO2), 1161 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.63 [s, 9 H, C(CH3)3], 1.26 (d,
J = 6.0 Hz, 3 H, CCH3), 2.17 (s, 3 H, CCH3), 2.32 (s, 3 H, ArCH3),
4.27 (d, J = 6.0 Hz, 1 H, OCH), 4.81 (d, J = 15.6 Hz, 1 H, 3-CHH),
5.00 (d, J = 15.6 Hz, 1 H, 3-CHH), 5.13 (s, 1 H, 1-H), 6.99–7.02
(m, 6 H, ArH), 7.27–7.58 (m, 11 H, ArH), 7.75 (d, J = 7.5 Hz, 1 H,
ArH), 7.90 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (68 MHz, CDCl3): d = 15.5, 18.8, 21.4, 21.6, 26.6 (3C),
55.0, 70.8, 72.8, 118.7, 123.7, 125.3 (2C), 127.0 (2C), 127.23 (2C),
127.25 (2C), 127.6, 128.2, 129.2 (2C), 129.37, 129.40, 132.1,
132.7, 133.4, 134.1, 135.0, 135.5 (2C), 135.9 (2C), 136.2, 136.8,
143.1.
HRMS (FAB): m/z [M + H]+ calcd for C30H38NO3S: 492.2572;
found: 492.2581.
( )-4-[(Z)-Benzylidene]-2-tert-butyl-1-(4-methylphenylsulfo-
nyl)-3-[(Z)-pentylidene]-1H-pyrrole (13j)
Bromoenyne 11j (61.3 mg, 0.119 mmol) was converted into 13j in
7 h.
Yield: 3.6 mg (7%); colorless oil.
IR (KBr): 1348 (NSO2), 1163 (NSO2) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.93 (t, J = 7.5 Hz, 3 H, CCH3),
0.97 [s, 9 H, C(CH3)3], 1.25–1.37 (m, 4 H), 1.89–2.04 (m, 2 H),
2.37 (s, 3 H, ArCH3), 4.24 (s, 1 H, 2-H), 4.35 (dd, J = 17.1, 1.8 Hz,
1 H, 5-CHH), 4.58 (dd, J = 17.1, 2.4 Hz, 1 H, 5-CHH), 5.60 (dd,
J = 9.2, 5.5 Hz, 1 H, C=CH), 6.48 (s, 1 H, C=CH), 7.19–7.21 (m,
4 H, ArH), 7.23 (d, J = 7.3 Hz, 1 H, ArH), 7.34 (d, J = 7.3 Hz, 1 H,
ArH), 7.36 (d, J = 7.9 Hz, 1 H, ArH), 7.63 (d, J = 7.9 Hz, 2 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 14.1, 21.5, 22.7, 27.3 (3C), 31.0,
31.7, 38.2, 52.8, 69.6, 118.0, 125.5, 126.9, 127.5 (2C), 128.4 (2C),
128.7 (2C), 129.5 (2C), 135.2, 136.8, 137.4, 138.7, 143.2.
MS (FAB): m/z (%) = 438 (15) [M + H+], 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C27H36NO2S: 438.2467;
MS (FAB): m/z (%) = 620 (21) [M + H+], 336 (100).
HRMS (FAB): m/z [M + H]+ calcd for C38H42NO3SSi: 620.2665;
found: 620.2663.
(1R)-9-Butyl-1-cyclohexyl-6-methoxy-2-(4-methylphenylsulfo-
nyl)-2,3-dihydro-1H-benzo[f]isoindole (12p)
Bromoenyne 11p (60.2 mg, 0.105 mmol) was converted into 12p in
5 h.
found: 438.2481.
N-(But-2-ynyl)-N-(3-phenylprop-2-ynyl)-4-methylbenzene-
sulfonamide (14m)
Bromoenyne 11m (43.7 mg, 0.105 mmol) was converted into 14m
in 0.5 h.
Yield: 29.4 mg (57%); colorless oil; [a]D26 –63.9 (c 0.82, CHCl3).
IR (KBr): 1348 (NSO2), 1163 (NSO2) cm–1.
Yield: 19.2 mg (54%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.97 (t, J = 7.2 Hz, 3 H, CCH3),
1.11–1.46 (m, 9 H), 1.60–1.94 (m, 6 H), 2.20 (s, 3 H, ArCH3), 2.82
(dt, J = 11.7, 4.8 Hz, 1 H, 1¢-CHH), 3.40 (dt, J = 11.7, 5.1 Hz, 1 H,
1¢-CHH), 3.91 (s, 3 H, OCH3), 4.70 (d, J = 16.5 Hz, 1 H, NCHH),
4.79 (d, J = 16.5 Hz, 1 H, NCHH), 5.10 (s, 1 H, 1-H), 6.77 (dd,
J = 5.7, 3.3 Hz, 1 H, 7-H), 7.01 (d, J = 8.4 Hz, 2 H, ArH), 7.26–
7.28 (m, 3 H, ArH), 7.57 (d, J = 8.4 Hz, 2 H, ArH).
IR (KBr): 2362 (C≡C), 2330 (C≡C), 1352 (NSO2), 1165 (NSO2)
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.69 (t, J = 2.4 Hz, 3 H, CCH3),
2.35 (s, 3 H, ArCH3), 4.13 (q, J = 2.4 Hz, 2 H, NCH2), 4.38 (s, 2 H,
NCH2), 7.16 (dd, J = 6.6, 1.8 Hz, 2 H, ArH), 7.23–7.30 (m, 5 H,
PhH), 7.75 (dd, J = 6.6, 1.8 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.2, 21.3, 23.5, 26.2, 26.5, 26.6,
26.7, 31.5, 33.3, 34.5, 45.7, 55.0, 55.2, 70.8, 105.2, 118.6, 121.3,
123.9, 125.4, 127.2 (2C), 129.4 (2C), 134.1, 135.2, 136.0, 136.4,
137.7, 143.1, 157.7.
13C NMR (75 MHz, CDCl3): d = 3.46, 21.4, 37.0, 37.1, 71.6, 81.6,
81.9, 85.6, 122.2, 128.0 (2C), 128.1 (2C), 128.4, 129.4 (2C), 131.6
(2C), 135.4, 143.6.
( )-N-(1-Cyclohexylhept-2-ynyl)-N-(3-phenylprop-2-
ynyl)amine (14n)
Bromoenyne 11n (59.2 mg, 0.152 mmol) was converted into 14n in
2.5 h.
MS (FAB): m/z (%) = 492 (38) [M + H+], 408 (100).
HRMS (FAB): m/z [M + H]+ calcd for C30H38NO3S: 492.2572;
found: 492.2575.
Yield: 12.0 mg (26%); colorless oil.
IR (KBr): 3317 (NH), 2237 (C≡C) cm–1.
(1R)-9-Butyl-1-cyclohexyl-7-methoxy-2-(4-methylphenylsulfo-
nyl)-2,3-dihydro-1H-benzo[f]isoindole (12q)
Bromoenyne 11q (57.6 mg, 0.101 mmol) was converted into 12q in
8 h.
Yield: 18.5 mg (37%); colorless oil; [a]D28 –88.2 (c 0.40, CHCl3).
IR (KBr): 1344 (NSO2), 1163 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, J = 6.9 Hz, 3 H, CCH3),
1.10–1.92 (m, 15 H), 2.19 (s, 3 H, ArCH3), 2.81–2.95 (m, 2 H, 1¢-
CH2), 3.91 (s, 3 H, OCH3), 4.68 (d, J = 16.2 Hz, 1 H, NCHH), 4.78
(d, J = 16.2 Hz, 1 H, NCHH), 5.11 (s, 1 H, 1-H), 7.01 (d,
J = 8.1 Hz, 2 H, ArH), 7.09 (dd, J = 9.0, 3.0 Hz, 1 H, 6-H), 7.20 (d,
J = 3.0 Hz, 1 H, 8-H), 7.27 (s, 1 H, 4-H), 7.59 (d, J = 8.1 Hz, 2 H,
ArH), 7.61 (d, J = 9.0 Hz, 1 H, 5-H).
13C NMR (75 MHz, CDCl3): d = 14.0, 21.3, 23.3, 26.2, 26.5 (2C),
26.7, 29.5, 31.6, 32.3, 45.5, 54.8, 55.3, 70.5, 103.1, 117.4, 118.4,
127.2 (2C), 129.0, 129.3 (2C), 129.9, 131.1, 132.6, 133.6, 135.2,
137.4, 143.1, 157.4.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.5 Hz, 3 H, CCH3),
1.13–1.55 (m, 10 H), 1.65–1.85 (m, 5 H), 2.22 (td, J = 6.9, 1.8 Hz,
2 H, CH2C≡C), 3.42 (dt, J = 5.1, 1.8 Hz, 1 H, NCH), 3.68 (d,
J = 16.8 Hz, 1 H, NCHH), 3.84 (d, J = 16.8 Hz, 1 H, NCHH), 7.28–
7.30 (m, 3 H, PhH), 7.39–7.44 (m, 2 H, PhH).
13C NMR (75 MHz, CDCl3): d = 13.6, 18.4, 22.0, 26.1, 26.2, 26.5,
28.4, 30.2, 31.1, 37.2, 42.5, 55.0, 79.2, 83.1, 85.1, 87.7, 123.3,
127.9, 128.2 (2C), 131.7 (2C).
(5R)-4-Butyl-5-cyclohexyl-6-(4-methylphenylsulfonyl)-6,7-di-
hydro-5H-furo[2,3-f]isoindole (16a)
Bromoenyne 15a (58.2 mg, 0.109 mmol) was converted into 16a in
2 h.
Yield: 21.3 mg (43%); colorless oil; [a]D29 –67.2 (c 1.02, CHCl3).
IR (KBr): 1344 (NSO2), 1163 (NSO2) cm–1.
MS (FAB): m/z (%) = 492 (30) [M + H+], 408 (100).
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

SPECIAL TOPIC
Palladium-Catalyzed Cascade Cyclization
2575
1H NMR (270 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H, CCH3),
1.00–1.89 (m, 16 H), 2.23 (s, 3 H, ArCH3), 2.71 (t, J = 6.8 Hz, 2 H,
1¢-CH2), 4.63 (d, J = 15.9 Hz, 1 H, 7-CHH), 4.72 (d, J = 15.9 Hz,
1 H, 7-CHH), 5.02 (s, 1 H, 5-H), 6.68 (d, J = 2.2 Hz, 1 H, 2-H), 6.97
(s, 1 H, 8-H), 7.03 (d, J = 8.4 Hz, 2 H, ArH), 7.52 (d, J = 2.2 Hz,
1 H, 3-H), 7.56 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (68 MHz, CDCl3): d = 14.1, 21.4, 23.0, 26.3, 26.5, 26.6,
26.8, 30.5, 31.6, 32.7, 45.6, 55.1, 70.0, 102.4, 105.3, 126.7, 127.1
(2C), 129.2 (2C), 129.5, 132.7, 134.5, 135.1, 143.0, 144.5, 154.7.
(5R)-4-Butyl-5-cyclohexyl-N,N-dimethyl-6-(4-methylphenylsul-
fonyl)-6,7-dihydropyrrolo[3,4-f]indole-1(5H)-sulfonamide
(16d)
Bromoenyne 15d (49.7 mg, 0.0778 mmol) was converted into 16d
using Pd(OAc)2 (1.8 mg, 0.00802 mmol) for 12 h.
25
Yield: 22.7 mg (52%); pale-orange oil; [a]D +37.8 (c 0.740,
CHCl3).
IR (KBr): 1599 (NC=C), 1387 (NSO2), 1344 (NSO2), 1159 (NSO2)
cm–1.
MS (FAB): m/z (%) = 452 (45) [M + H+], 368 (100).
HRMS (FAB): m/z [M + H]+ calcd for C27H34NO3S: 452.2259;
1H NMR (300 MHz, CDCl3): d = 0.96 (t, J = 7.1 Hz, 3 H, CCH3),
1.03–1.54 (m, 9 H), 1.61–1.94 (m, 6 H), 2.23 (s, 3 H, ArCH3), 2.71–
2.79 (m, 2 H, 1¢-CH2), 2.785 (s, 3 H, NCH3), 2.787 (s, 3 H, NCH3),
4.63 (d, J = 16.0 Hz, 1 H, 7-CHH), 4.73 (d, J = 16.0 Hz, 1 H, 7-
CHH), 5.07 (s, 1 H, 5-H), 6.57 (d, J = 3.7 Hz, 1 H, 3-H), 7.04 (d,
J = 8.3 Hz, 2 H, ArH), 7.36 (d, J = 3.7 Hz, 1 H, 2-H), 7.42 (s, 1 H,
8-H), 7.57 (d, J = 8.3 Hz, 2 H, ArH).
found: 452.2258.
(5R)-4-Butyl-5-cyclohexyl-1,6-bis(4-methylphenylsulfonyl)-
1,5,6,7-tetrahydropyrrolo[3,4-f]indole (16b)
Bromoenyne 15b (111 mg, 0.162 mmol) was converted into 16b us-
ing Pd(OAc)2 (7.7 mg, 0.0346 mmol) in DMF at 120 °C for 2 h.
Yield: 73.3 mg (75%); colorless oil; [a]D26 +79.7 (c 0.98, CHCl3).
13C NMR (75 MHz, CDCl3): d = 14.0, 21.3, 22.9, 26.2, 26.4, 26.5,
26.7, 30.1, 31.5, 32.6, 38.4 (2C), 45.4, 55.1, 70.0, 104.6, 105.1,
126.6, 127.2 (2C), 129.2, 129.26 (2C), 129.29, 132.9, 134.6, 135.1,
135.3, 143.0.
MS (FAB): m/z (%) = 558 (37) [M + H+], 474 (100).
HRMS (FAB): m/z [M + H]+ calcd for C29H40N3O4S2: 558.2460;
IR (KBr): 1597 (NC=C), 1360 (NSO2), 1346 (NSO2), 1178 (NSO2),
1161 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.1 Hz, 3 H, CCH3),
1.01–1.37 (m, 8 H), 1.61–1.85 (m, 7 H), 2.20 (s, 3 H, ArCH3), 2.38
(s, 3 H, ArCH3), 2.61–2.67 (m, 2 H, 1¢-CH2), 4.63 (d, J = 15.9 Hz,
1 H, 7-CHH), 4.76 (d, J = 15.9 Hz, 1 H, 7-CHH), 4.97 (s, 1 H, 5-H),
6.57 (dd, J = 3.8, 0.7 Hz, 1 H, 3-H), 6.97 (d, J = 7.9 Hz, 2 H, ArH),
7.25 (d, J = 7.9 Hz, 2 H, ArH), 7.46 (d, J = 3.8 Hz, 1 H, 2-H), 7.48
(s, 1 H, 8-H), 7.53 (ddd, J = 7.9, 1.8, 1.8 Hz, 2 H, ArH), 7.73 (ddd,
J = 7.9, 1.8, 1.8 Hz, 2 H, ArH).
found: 558.2483.
(7R)-8-Butyl-7-cyclohexyl-1,6-bis(4-methylphenylsulfonyl)-
1,5,6,7-tetrahydropyrrolo[3,4-f]indole (16e)
Bromoenyne 15e (53.5 mg, 0.0780 mmol) was converted into 16e
using Pd(OAc)2 (3.5 mg, 0.0156 mmol) in DMF at 120 °C for 4 h.
13C NMR (126 MHz, CDCl3): d = 14.0, 21.3, 21.6, 22.9, 26.2, 26.4,
26.5, 26.7, 30.1, 31.5, 32.6, 45.4, 55.2, 69.9, 104.5, 107.2, 125.8,
126.8 (2C), 127.2 (2C), 129.3 (3C), 129.6, 129.9, 130.0, 133.5,
134.7, 135.1, 135.2, 135.4, 143.0, 145.0.
MS (FAB): m/z (%) = 605 (5.2) [M + H+], 521 (100).
HRMS (FAB): m/z [M + H]+ calcd for C34H41N2O4S2: 605.2508;
Yield: 20.0 mg (42%); colorless oil; [a]D26 –349.8 (c 0.86, CHCl3).
IR (KBr): 1597 (NC=C), 1369 (NSO2), 1344 (NSO2), 1174 (NSO2),
1161 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83–1.47 (m, 11 H), 1.51–1.62
(m, 5 H), 1.79–1.85 (m, 2 H), 2.25 (s, 3 H, ArCH3), 2.30 (s, 3 H,
ArCH3), 2.38–2.53 (m, 1 H, 1¢-CHH), 3.49–3.59 (m, 1 H, 1¢-CHH),
4.54 (d, J = 15.9 Hz, 1 H, 5-CHH), 4.69 (dd, J = 15.9, 0.6 Hz, 1 H,
5-CHH), 4.95 (s, 1 H, 7-H), 6.52 (d, J = 3.8 Hz, 1 H, 3-H), 6.91 (s,
1 H, 4-H), 7.04 (d, J = 8.1 Hz, 2 H, ArH), 7.08 (d, J = 8.1 Hz, 2 H,
ArH), 7.37 (ddd, J = 8.1, 1.9, 1.9 Hz, 2 H, ArH), 7.56 (ddd, J = 8.1,
1.9, 1.9 Hz, 2 H, ArH), 7.59 (d, J = 3.8 Hz, 1 H, 2-H).
found: 605.2493.
(5R)-4-Butyl-5-cyclohexyl-1-(2,4,6-trimethylphenylsulfonyl)-6-
(4-methylphenylsulfonyl)-1,5,6,7-tetrahydropyrrolo[3,4-f]in-
dole (16c)
Bromoenyne 15c (72.0 mg, 0.101 mmol) was converted into 16c us-
ing Pd(OAc)2 (4.5 mg, 0.0202 mmol) in DMF at 120 °C for 2 h.
Yield: 51.4 mg (81%); colorless oil; [a]D26 +52.2 (c 1.645, CHCl3).
IR (KBr): 1603 (NC=C), 1350 (NSO2), 1161 (NSO2) cm–1.
1H NMR (270 MHz, CDCl3): d = 0.86 (t, J = 6.9 Hz, 3 H, CCH3),
0.91–1.34 (m, 8 H), 1.40–1.86 (m, 7 H), 2.23 (s, 3 H, ArCH3), 2.32
(s, 3 H, ArCH3), 2.46 (s, 6 H, ArCH3), 2.68 (t, J = 6.6 Hz, 2 H, 1¢-
CH2), 4.54 (d, J = 16.0 Hz, 1 H, 7-CHH), 4.66 (d, J = 16.0 Hz, 1 H,
7-CHH), 4.96 (s, 1 H, 5-H), 6.53 (d, J = 3.7 Hz, 1 H, 3-H), 6.94–
6.99 (m, 5 H, ArH), 7.39 (d, J = 3.7 Hz, 1 H, 2-H), 7.50 (d, J =
8.1 Hz, 2 H, ArH).
13C NMR (126 MHz, CDCl3): d = 14.0, 21.0, 21.3, 22.5 (2C), 22.9,
26.2, 26.5, 26.7, 30.1, 31.5, 32.7, 45.3, 55.2, 69.9, 103.7, 105.2
(2C), 125.9, 127.2 (2C), 129.2 (3C), 129.3, 129.6, 132.3 (3C),
132.9, 134.6, 134.7, 135.1, 140.1, 143.0, 144.1.
13C NMR (126 MHz, CDCl3): d = 14.0, 21.4, 21.5, 22.9, 26.2, 26.6
(2C), 26.7, 30.6, 31.0, 32.1, 45.7, 55.0, 70.5, 111.1, 111.9, 126.48,
126.49 (2C), 127.2 (2C), 129.3 (2C), 129.4 (2C), 132.1, 133.9,
134.2, 134.4, 135.1, 135.3, 137.2, 143.2, 144.6.
MS (FAB): m/z (%) = 605 (31) [M + H+], 521 (100).
HRMS (FAB): m/z [M + H]+ calcd for C34H41N2O4S2: 605.2508;
found: 605.2531.
(3R)-4-Butyl-3-cyclohexyl-2,5-bis(4-methylphenylsulfonyl)-
1,2,3,5-tetrahydropyrrolo[3,4-b]carbazole (18a)
Bromoenyne 17a (74.0 mg, 0.101 mmol) was converted into 18a
using Pd(OAc)2 (2.3 mg, 0.0101 mmol) in DMF at 120 °C for 18 h.
Yield: 33.8 mg (51%); colorless oil; [a]D26 –122 (c 0.30, CHCl3).
IR (KBr): 1597 (C=CN), 1367 (NSO2), 1346 (NSO2), 1173 (NSO2),
1163 (NSO2) cm–1.
MS (FAB): m/z (%) = 633 (28) [M + H+], 549 (100).
HRMS (FAB): m/z [M + H]+ calcd for C36H45N2O4S2: 633.2821;
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.2 Hz, 3 H, CCH3),
1.11–1.30 (m, 9 H), 1.53–1.93 (m, 6 H), 2.17 (s, 3 H, ArCH3), 2.22
(s, 3 H, ArCH3), 2.63–2.73 (m, 1 H, 1¢-CHH), 3.84–3.94 (m, 1 H,
1¢-CHH), 4.61 (d, J = 16.5 Hz, 1 H, 1-CHH), 4.76 (d, J = 16.5 Hz,
1 H, 1-CHH), 5.07 (s, 1 H, 3-H), 6.72 (d, J = 8.4 Hz, 2 H, ArH),
6.78 (d, J = 8.4 Hz, 2 H, ArH), 7.06 (d, J = 8.1 Hz, 2 H, ArH), 7.12
(s, 1 H, 10-H), 7.25–7.30 (m, 1 H, ArH), 7.40 (ddd, J = 7.5, 7.5,
found: 633.2795.
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

2576
H. Ohno et al.
SPECIAL TOPIC
1.5 Hz, 1 H, ArH), 7.47 (dd, J = 7.5, 0.6 Hz, 1 H, ArH), 7.61 (d,
J = 8.4 Hz, 2 H, ArH), 8.16 (d, J = 7.5 Hz, 1 H, ArH).
(3R)-4-Butyl-3-cyclohexyl-2-(4-methylphenylsulfonyl)-2,3-di-
hydro-1H-benzo[4,5]thieno[2,3-f]isoindole (18e)
Bromoenyne 17e (70.4 mg, 0.118 mmol) was converted into 18e in
3 h.
Yield: 29.7 mg (49%); colorless oil; [a]D25 +27.8 (c 0.40, CHCl3).
IR (KBr): 1344 (NSO2), 1161 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.2 Hz, 3 H, CCH3),
1.05–1.92 (m, 15 H), 2.20 (s, 3 H, ArCH3), 2.72–2.86 (m, 2 H, 1¢-
CH2), 4.72 (d, J = 15.9 Hz, 1 H, 1-CHH), 4.83 (d, J = 15.9 Hz, 1 H,
1-CHH), 5.09 (s, 1 H, 3-H), 7.03 (d, J = 8.1 Hz, 2 H, ArH), 7.40–
7.43 (m, 2 H, ArH), 7.59 (d, J = 8.1 Hz, 2 H, ArH), 7.65 (s, 1 H,
ArH), 7.79–7.83 (m, 1 H, ArH), 8.00–8.03 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.0, 21.3, 23.0, 26.2, 26.4, 26.5,
26.7, 30.7, 31.6, 32.2, 45.4, 55.1, 70.4, 112.3, 121.4, 122.8, 124.4,
126.7, 127.2 (2C), 129.4 (2C), 131.2, 135.0, 135.3, 135.5, 135.6,
137.3, 139.1, 139.3, 143.3.
13C NMR (75 MHz, CDCl3): d = 14.0, 21.4, 21.5, 22.9, 26.3, 26.5,
26.6, 26.7, 31.0, 31.15, 31.20, 45.9, 55.3, 71.0, 110.4, 119.2, 120.6,
125.8, 127.0 (2C), 127.1, 127.3 (2C), 128.3 (2C), 129.5 (2C), 130.0,
131.08, 131.13, 131.9, 135.0, 135.8, 140.17, 140.24, 142.5, 143.4,
144.3.
MS (FAB): m/z (%) = 655 (10) [M + H+], 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C38H43N2O4S2: 655.2664;
found: 655.2661.
(3R)-4-Butyl-3-cyclohexyl-2-(4-methylphenylsulfonyl)-5-(2,4,6-
trimethylphenylsulfonyl)-1,2,3,5-tetrahydropyrrolo[3,4-b]car-
bazole (18b)
Bromoenyne 17b (53.1 mg, 0.0695 mmol) was converted into 18b
using Pd(OAc)2 (0.8 mg, 0.00356 mmol) in DMF at 120 °C for 3 h.
26
Yield: 14.9 mg (31%); pale-yellow oil; [a]D –107.6 (c 0.690,
MS (FAB): m/z (%) = 518 (23) [M + H+], 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C31H36NO2S2: 518.2187;
CHCl3).
IR (KBr): 1601 (NC=C), 1346 (NSO2), 1162 (NSO2) cm–1.
found: 518.2188.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.1 Hz, 3 H, CCH3),
1.01–1.37 (m, 8 H), 1.61–1.85 (m, 7 H), 2.11 (s, 6 H, ArCH3), 2.20
(s, 3 H, ArCH3), 2.38 (s, 3 H, ArCH3), 2.64 (dt, J = 14.6, 5.0 Hz,
1 H, 1¢-CHH), 3.55 (dt, J = 14.6, 5.0 Hz, 1 H, 1¢-CHH), 4.67 (d, J =
15.6 Hz, 1 H, 1-CHH), 4.80 (d, J = 15.6 Hz, 1 H, 1-CHH), 5.01 (s,
1 H, 3-H), 6.67 (s, 2 H, ArH), 7.03 (d, J = 7.9 Hz, 2 H, ArH), 7.15–
7.20 (m, 2 H, ArH), 7.35 (s, 1 H, 10-H), 7.56–7.59 (m, 1 H, ArH),
7.58 (d, J = 7.9 Hz, 2 H, ArH), 7.66–7.67 (m, 1 H, ArH).
13C NMR (126 MHz, CDCl3): d = 14.0, 20.9, 21.4, 22.5 (2C), 22.9,
26.2, 26.4, 26.6, 26.8, 31.1, 31.2, 31.4, 45.6, 55.3, 71.0, 110.4,
116.7, 119.4 (2C), 124.1, 126.5, 127.1, 127.2 (2C), 128.7, 129.1,
129.5 (2C), 131.8 (2C), 134.1, 134.6, 135.0, 139.9 (2C), 140.1,
141.1, 143.1, 143.3.
(3R)-4-Butyl-3-cyclohexyl-2-(4-methylphenylsulfonyl)-2,3-di-
hydro-1H-benzofuro[2,3-f]isoindole (18f)
Bromoenyne 17f (62.0 mg, 0.106 mmol) was converted into 18f in
1 h.
Yield: 31.4 mg (59%); colorless oil; [a]D26 –119 (c 0.35, CHCl3).
IR (KBr): 1346 (NSO2), 1163 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, J = 6.9 Hz, 3 H, CCH3),
1.15–1.93 (m, 15 H), 2.19 (s, 3 H, ArCH3), 2.89 (dt, J = 14.1,
6.3 Hz, 1 H, 1¢-CHH), 3.04 (dt, J = 9.0, 5.4 Hz, 1 H, 1¢-CHH), 4.69
(d, J = 16.5 Hz, 1 H, 1-CHH), 4.80 (d, J = 16.5 Hz, 1 H, 1-CHH),
5.09 (s, 1 H, 3-H), 7.03 (d, J = 8.1 Hz, 2 H, ArH), 7.06 (s, 1 H,
ArH), 7.33 (ddd, J = 7.5, 7.5, 0.9 Hz, 1 H, ArH), 7.42 (ddd, J = 7.5,
7.5, 0.9 Hz, 1 H, ArH), 7.52 (d, J = 7.5 Hz, 1 H, ArH), 7.59 (d,
J = 8.1 Hz, 2 H, ArH), 7.84 (d, J = 7.5 Hz, 1 H, ArH).
MS (FAB): m/z (%) = 683 (16) [M + H+], 154 (100).
HRMS (FAB): m/z [M + H]+ calcd for C40H47N2O4S2: 638.2977;
found: 638.2974.
13C NMR (75 MHz, CDCl3): d = 14.0, 21.3, 23.2, 26.2, 26.4, 26.5,
26.7, 30.6, 31.6 (2C), 45.7, 55.4, 70.1, 102.7, 111.6, 122.1, 122.2,
122.8, 123.9, 126.5, 127.2 (2C), 129.4 (2C), 132.5, 133.1, 135.1,
137.3, 143.2, 156.3, 156.4.
MS (FAB): m/z (%) = 502 (36) [M + H+], 418 (100).
HRMS (FAB): m/z [M + H]+ calcd for C31H36NO3S: 502.2416;
(3R)-4-Butyl-3-cyclohexyl-5-methyl-2-(4-methylphenylsulfo-
nyl)-1,2,3,5-tetrahydropyrrolo[3,4-b]carbazole (18d)
Bromoenyne 17d (118 mg, 0.20 mmol) was converted into 18d us-
ing Pd(OAc)2 (4.5 mg, 0.0198 mmol) for 36 h.
Yield: 43.7 mg (43%); pale-yellow oil; [a]D27 +10.2 (c 1.28, CHCl3).
found: 502.2409.
IR (KBr): 1601 (NC=C), 1342 (NSO2), 1161 (NSO2), 1092 (NC)
cm–1.
(1R)-11-Butyl-1-cyclohexyl-2-(4-methylphenylsulfonyl)-2,3-di-
hydro-1H-naphtho[2,3-f]isoindole (18g)
Bromoenyne 17g (132 mg, 0.22 mmol) was converted into 18g us-
ing Pd(OAc)2 (1.0 mg, 0.0044 mmol) in DMF at 120 °C for 2 h and
a further 3 h with additional Pd(OAc)2 (1.5 mg, 0.0066 mmol).
Yield: 48.7 mg (43%); colorless oil; [a]D26 –165.5 (c 0.63, CHCl3).
IR (KBr): 1344 (NSO2), 1161 (NSO2) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95–1.02 (m, 4 H), 1.11–1.61 (m,
10 H), 1.79–1.97 (m, 4 H), 2.16 (s, 3 H, ArCH3), 3.09 (td, J = 12.7,
4.6 Hz, 1 H, 1¢-CHH), 3.58 (td, J = 12.7, 4.6 Hz, 1 H, 1¢-CHH), 4.78
(d, J = 16.2 Hz, 1 H, 3-CHH), 4.90 (d, J = 16.2 Hz, 1 H, 3-CHH),
5.20 (s, 1 H, 1-H), 7.00 (d, J = 8.1 Hz, 2 H, ArH), 7.41 (s, 1 H,
ArH), 7.54–7.64 (m, 6 H, ArH), 7.86 (dd, J = 6.8, 2.2 Hz, 1 H,
ArH), 8.74 (d, J = 7.8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 13.9, 21.3, 23.1, 26.2, 26.5, 26.7
(2C), 31.1, 31.5, 33.9, 45.6, 55.3, 71.4, 120.1, 125.8, 125.9, 126.7,
127.2 (3C), 128.0, 128.9, 129.0, 129.4 (2C), 131.1, 133.3, 134.1,
134.6, 135.1, 135.9, 139.8, 143.2.
1H NMR (300 MHz, CDCl3): d = 0.96–1.00 (m, 4 H), 1.04–1.48 (m,
8 H), 1.60–1.64 (m, 2 H), 1.77–1.92 (m, 4 H), 2.19 (s, 3 H, ArCH3),
2.73–2.82 (m, 1 H, 1¢-CHH), 3.12–3.19 (m, 1 H, 1¢-CHH), 3.98 (s,
3 H, NCH3), 4.74 (d, J = 15.4 Hz, 1 H, 1-CHH), 4.83 (d, J =
15.4 Hz, 1 H, 1-CHH), 5.06 (s, 1 H, 3-H), 7.01 (d, J = 7.9 Hz, 2 H,
ArH), 7.18 (dd, J = 8.0, 8.0 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H,
ArH), 7.43 (dd, J = 8.0, 8.0 Hz, 1 H, ArH), 7.58 (s, 1 H, 10-H), 7.58
(d, J = 7.9 Hz, 2 H, ArH), 7.94 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.8, 22.1, 23.6, 27.0, 27.2, 27.3,
27.5, 29.9, 32.3, 32.8, 34.9, 46.7, 56.0, 71.5, 109.5, 111.6, 119.8,
120.3, 120.8, 123.2, 125.1, 126.5, 127.9 (2C), 129.6, 130.1 (2C),
136.0, 138.4, 139.8, 143.1, 143.8.
MS (FAB): m/z (%) = 515 (21) [M + H+], 431 (100).
HRMS (FAB): m/z [M + H]+ calcd for C32H39N2O2S: 515.2737;
found: 515.2747.
MS (FAB): m/z (%) = 512 (49) [M + H+], 428 (100).
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

SPECIAL TOPIC
Palladium-Catalyzed Cascade Cyclization
2577
HRMS (FAB): m/z [M + H]+ calcd for C33H38NO2S: 512.2623;
found: 512.2661.
References
(1) For recent reviews on cascade reactions, see: (a) Tietze, L.
F. Chem. Rev. 1996, 96, 115. (b) Nicolaou, K. C.;
Diethyl 9-Butyl-1-pentyl-2,3-dihydro-1H-cyclopenta[b]naph-
thalene-2,2-dicarboxylate (20a)
Bromoenyne 19a (48.8 mg, 0.0993 mmol) was converted into 20a
Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(c) Wasilke, J.-C.; Obrey, S. J.; Baker, T.; Bazan, G. C.
Chem. Rev. 2005, 105, 1001. (d) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45, 7134.
(e) Kirsch, S. F. Synthesis 2008, 3183. (f) Nicolaou, K. C.;
Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (g) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
(h) Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth. Catal.
2011, 353, 809.
using Pd(OAc)2 (1.1 mg, 0.0050 mmol) for 2 h.
Yield: 28.1 mg (68%); colorless oil.
IR (KBr): 1733 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 6.7 Hz, 3 H, CCH3),
1.02 (t, J = 7.1 Hz, 3 H, CCH3), 1.13–1.82 (m, 18 H), 2.93–3.02 (m,
1 H, 1¢-CHH), 3.07–3.17 (m, 1 H, 1¢-CHH), 3.45 (d, J = 16.7 Hz,
1 H, 3-CHH), 3.96–4.37 (m, 6 H, 2 × OCH2, 1-H, and 3-CHH), 7.37
(ddd, J = 8.0, 8.0, 1.1 Hz, 1 H, ArH), 7.42 (ddd, J = 8.0, 8.0, 1.1 Hz,
1 H, ArH), 7.47 (s, 1 H, 4-H), 7.73 (d, J = 8.0 Hz, 1 H, ArH), 7.97
(d, J = 8.0 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 13.9, 14.0 (2C), 14.1, 22.5, 23.5,
26.9, 29.5, 31.8, 32.3, 32.8, 38.8, 48.2, 61.45, 61.50, 65.4, 121.1,
123.9, 124.8, 124.9, 128.3, 131.6, 133.6, 133.7, 137.4, 142.3, 170.0,
171.6.
(2) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(3) For recent reviews on C–H activation, see:
(a) Thansandote, P.; Lautens, M. Chem. Eur. J. 2009, 15,
5874. (b) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243.
(c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.
Int. Ed. 2009, 48, 9792. (d) Jazzar, R.; Hitce, J.; Renaudat,
A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010, 16,
2654. (e) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(f) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(4) For reactions including alkene insertion and C–H activation,
see: (a) Blaszykowski, C.; Aktoudianakis, E.; Bressy, C.;
Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043.
(b) Alonso, I.; Alcamí, M.; Mauleón, P.; Carretero, J. C.
Chem. Eur. J. 2006, 12, 4576. (c) Ruck, R. T.; Huffman, M.
A.; Kim, M. M.; Shevlin, M.; Kandur, W. V.; Davies, I. W.
Angew. Chem. Int. Ed. 2008, 48, 4711. (d) Candito, D. A.;
Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 6713.
(5) For recent examples of palladium-catalyzed cascade
reactions including C–H activation, see: (a) Zhao, J.; Yue,
D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007,
129, 5288. (b) Guo, L.-N.; Duan, X.-H.; Liu, X.-Y.; Hu, J.;
Bi, H.-P.; Liang, Y. M. Org. Lett. 2007, 9, 5425.
MS (FAB): m/z (%) = 461 (8.2) [M + Na+], 438 (100).
HRMS (FAB): m/z [M + Na]+ calcd for C28H38NaO4: 461.2668;
found: 461.2650.
Diethyl 4-Butyl-1-(4-methylphenylsulfonyl)-5-pentyl-5,7-dihy-
drocyclopenta[f]indole-6,6-(1H)-dicarboxylate (20b)
Bromoenyne 19b (104 mg, 0.157 mmol) was converted into 20b us-
ing Pd(OAc)2 (1.8 mg, 0.00786 mmol) in DMF at 120 °C for 24 h.
Yield: 31.9 mg (35%); colorless oil.
IR (KBr): 1732 (C=O), 1597 (NC=C), 1373 (NSO2), 1176 (NSO2)
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80 (t, J = 7.0 Hz, 3 H, CCH3),
0.95 (t, J = 7.0 Hz, 3 H, CCH3), 1.13–1.73 (m, 18 H), 2.36 (s, 3 H,
ArCH3), 2.76 (t, J = 7.9 Hz, 2 H, 1¢-CH2), 3.37 (d, J = 16.7 Hz, 1 H,
7-CHH), 3.91–4.37 (m, 6 H, 2 × OCH2, 5-H, and 7-CHH), 6.61 (d,
J = 3.8 Hz, 1 H, 3-H), 7.24 (d, J = 8.3 Hz, 2 H, ArH), 7.46 (d,
J = 3.8 Hz, 1 H, 2-H), 7.58 (s, 1 H, 8-H), 7.77 (d, J = 8.3 Hz, 2 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 13.9, 13.96, 13.99, 14.1, 21.6, 22.4,
23.3, 26.8, 30.2, 31.8, 32.3, 32.7, 39.0, 47.4, 61.4, 61.5, 65.6, 107.0,
107.4, 125.0, 126.9 (2C), 129.5, 129.9 (2C), 130.9, 134.4, 135.5,
136.3, 138.9, 144.7, 170.0, 171.7.
(c) Candito, D. A.; Lautens, M. Angew. Chem. Int. Ed. 2009,
48, 6713. (d) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. Angew.
Chem. Int. Ed. 2011, 50, 1380.
(6) For reactions including alkyne insertion and C–H activation,
see: (a) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org.
Lett. 2006, 8, 4927. (b) Pinto, A.; Neuville, L.; Zhu, J.
Angew. Chem. Int. Ed. 2007, 46, 3291. (c) Chernyak, N.;
Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636. (d) Liu,
R.; Zhang, J. Adv. Synth. Catal. 2011, 353, 36. For
intermolecular reactions with an alkyne followed by C–H
activation, see: (e) Larock, R. C.; Doty, M. J.; Tian, Q.;
Zenner, J. M. J. Org. Chem. 1997, 62, 7536. (f) Dong, C.-
G.; Yeung, P.; Hu, Q.-S. Org. Lett. 2007, 9, 363.
MS (FAB): m/z (%) = 604 (100) [M + Na+], 604 (100).
HRMS (FAB): m/z [M + Na]+ calcd for C33H43NNaO6S: 604.2709;
(7) For reactions using aryl or alkenyl bromides bearing an
alkyne moiety, see: (a) Rahman, S. M. A.; Sonoda, M.;
Itahashi, K.; Tobe, Y. Org. Lett. 2003, 5, 3411.
found: 604.2724.
(b) Rahman, S. M. A.; Sonoda, M.; Ono, M.; Miki, K.; Tobe,
Y. Org. Lett. 2006, 8, 1197. (c) Tietze, L. F.; Lotz, F. Eur. J.
Org. Chem. 2006, 4676. (d) Tokan, W. M.; Schweizer, S.;
Thies, C.; Meyer, F. E.; Parsons, P. J.; de Meijere, A. Helv.
Chim. Acta 2009, 92, 1729.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are experimental procedures and full characterization of the sub-
strates and synthetic intermediates.
(8) A portion of this study (Table 1, Table 2: entries 2, 3, 6, 11,
12; Table 4: entries 1 and 7) has already been reported in a
preliminary communication, see: Ohno, H.; Yamamoto, M.;
Iuchi, M.; Tanaka, T. Angew. Chem. Int. Ed. 2005, 44, 5103.
(9) (a) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (b) Boyall, D.; López, F.; Sasaki, H.;
Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233.
(10) Oh, C. H.; Lim, Y. M. Tetrahedron Lett. 2003, 44, 267.
(11) For example, the reaction of 11b with Pd(OAc)2 (2 mol%)
using K2CO3 (2 equiv) as the base stereoselectively gave the
monocyclic product 13b in 94% yield (Scheme 4).
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Integrated Organic Synthesis’
(H.O.) and for Scientific Research (B) (T.T.) from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York

2578
H. Ohno et al.
SPECIAL TOPIC
Ph
CO2Me
CO2Me
cat. Pd(OAc)2
Cs2CO3
CO2Me
CO2Me
cat. Pd(OAc)2
K2CO3
H
H
NTs
Br
NTs
DMF
120 ºC, 2 h
Br
EtOH
reflux
c-Hex
NOE
c-Hex
19c
21 (69%)
HO
OH
Scheme 5
11b
13b (94%)
Scheme 4
(13) For recent reviews on palladium-catalyzed direct arylation
of heteroareres, see: (a) Ackermann, L.; Vicente, R.; Kapdi,
A. R. Angew. Chem. Int. Ed. 2009, 48, 9792. (b)Bellina, F.;
Rossi, R. Tetrahedron 2009, 65, 10269.
(12) A similar result was obtained with malonate congener 19c,
which produced diyne 21 in 69% yield (Scheme 5).
(14) (a) Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826. (b) Liégault, B.;
Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010,
75, 1047; and references cited therein.
Synthesis 2011, No. 16, 2567–2578 © Thieme Stuttgart · New York