Double C-H functionalization in sequential order: Direct synthesis of polycyclic compounds by a palladium-catalyzed C-H alkenylation-arylation cascade

Article abstract of DOI:10.1002/chem.201103819

Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)₂] and PCy₃aHBF₄ in the presence of Cs₂CO₃ in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring.

Full text of DOI:10.1002/chem.201103819

DOI: 10.1002/chem.201103819
À
Double C H Functionalization in Sequential Order: Direct Synthesis of
À
Polycyclic Compounds by a Palladium-Catalyzed C H Alkenylation–
Arylation Cascade
Hiroaki Ohno,*[a, b] Mutsumi Iuchi,[a] Naoto Kojima,[a] Takehiko Yoshimitsu,[a]
Nobutaka Fujii,[b] and Tetsuaki Tanaka*[a]
Abstract: Palladium-catalyzed cascade
naphthalene-fused indole derivatives in
good yields. This double cyclization re-
action is also applicable to heterocyclic
substrates, giving fused indoles contain-
ing a heteroaromatic ring such as di-
benzofuran, dibenzothiophene, carba-
zole, indole, or benzofuran through
À
C H alkenylation and arylation pro-
vides convenient access to polycyclic
aromatic compounds. Treatment of 3-
bromoaniline derivatives bearing a bro-
mocinnamyl group on the nitrogen
atom with a catalytic amount of [Pd-
À
heterocyclic C H arylation. When
using a 2,6-unsubstituted aniline deriv-
À
ative, the first C H arylation preferen-
À
Keywords: C H bond activation ·
tially proceeds at the more hindered
position of the aniline ring.
domino reactions · heterocycles ·
palladium · polycycles
ACHTUNGTRENNUNG(OAc)2] and PCy3·HBF4 in the pres-
ence of Cs2CO3 in dioxane affords
Introduction
À
C H bond functionalization constitutes a faster and more
atom-economical synthetic approach to the formation of
target molecules than conventional organic transformations
[1–3]
À
using C X bonds.
À
Today, functionalization of aromatic
Figure 1. Naphthalene-fused five-membered heterocycles.
C H bonds typically provides reliable access to various
types of fused aromatic ring systems using nonfunctionalized
aryl groups. In this regard, considerable attention has been
paid recently to catalytic cascade reactions that include
ACTHNUTRGNEUNG
one[10] or naphtho[1,8-bc]furan[11] (Figure 1) are important
[4,5]
À
a C H bond functionalization step.
Particularly, multiple
scaffolds that are found in numerous biologically active
C H bond functionalization provides a more straightfor-
ward strategy for the construction of complex molecules.[6–8]
As a part of a program directed toward the development
of cascade reactions for the synthesis of biologically active
compounds,[9] we wanted to investigate the direct construc-
tion of naphthalene-fused heterocyclic compounds by
compounds, including naturally-occurring aristolactams.[12]
À
À
We expect that an aromatic C H functionalization cascade
will become a promising approach to the construction of
this class of fused aromatic compounds from readily avail-
able substrates.
À
As shown in Scheme 1, C H alkenylation of the dihalide
1 at carbon A would lead to a monocyclic product 2. If the
À
double C H functionalization. Five-membered heterocycles
fused with a naphthalene ring such as benzo[cd]indol-2-
À
À
second C H functionalization (direct C H arylation) is pro-
moted under the same reaction conditions, naphthalene-
fused five-membered heterocyclic compounds 3 condensed
with another arene ring would be obtained. The introduc-
tion of a heteroarene as an Ar group into the substrate facil-
itates the construction of a variety of tetracyclic naphthalene
derivatives. The key to success of the cascade reaction is the
[a] Prof. Dr. H. Ohno, M. Iuchi, Dr. N. Kojima, Prof. Dr. T. Yoshimitsu,
Prof. Dr. T. Tanaka
Graduate School of Pharmaceutical Sciences
Osaka University
1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-8214
E-mail: t-tanaka@phs.osaka-u.ac.jp
[b] Prof. Dr. H. Ohno, Prof. Dr. N. Fujii
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)75-753-4570
E-mail: hohno@pharm.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103819.
À
Scheme 1. Cascade C H alkenylation and arylation strategy.
5352
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5352 – 5360

FULL PAPER
À
C H functionalization in sequential order: the oxidative ad-
with brominated phosphonium ylide followed by reduction
of the resulting unsaturated esters with diisobutylaluminum
hydride (DIBAL-H) (Scheme 4). The isomeric (E)-unsatu-
À
dition of the C Xa bond in 1 should be precedent to that of
À
the C Xb bond. We envisioned that the heteroatom Y
would increase the electron density of the benzene ring
bearing the Xb group thus decreasing the reactivity of the
À
C Xb bond toward oxidative addition. Otherwise, the reac-
À
À
tivity of the C Xa and C Xb bonds might be controlled by
the introduction of different halogen atoms. Another chal-
lenge for this strategy was to achieve selective alkenylation
at carbon A rather than B in the first cyclization step.
Herein, we demonstrate the synthesis of tetra- or pentacy-
À
clic fused naphthalene derivatives by cascade C H function-
alization of di
A
Results and Discussion
Scheme 4. Preparation of substituted dibromosulfonamides 12.
Preparation of the substrates: To avoid regioselectivity
issues in the first cyclization, aniline derivatives bearing
a methyl group at carbon B were prepared (Scheme 1).
Generally, the dihalide substrates were prepared by coupling
substituted haloanilines with a-halogenated cinnamyl alco-
hol derivatives. For example, pivalamide 7a was synthesized
by coupling 5-bromo-2-methylaniline (4a) with (Z)-(2,3-di-
bromoprop-1-enyl)benzene,[14] followed by N-pivaloylation
(Scheme 2).
rated esters produced in the olefination step were removed
after DIBAL-H mediated reduction. The Mitsunobu reac-
tion of 4b using the bromocinnamyl alcohols 11 gave the
substituted dibromo-type substrates 12. Other substrates in-
cluding esters 12c and 12g, heterocyclic congeners, and
ether-tethered derivatives were prepared in
manner (see the Supporting Information).
a similar
Optimization of reaction conditions and substrate struc-
tures: To confirm that the expected first cyclization proceeds
from (halocinnamyl)aniline derivatives, we initially tested
the reaction of monobromide 13 under typical palladium-
catalyzed reaction conditions (Scheme 5). As expected,
Scheme 2. Preparation of dibromopivalamide 7a.
Sulfonamide derivatives 7b–d were obtained by the Mit-
sunobu condensation of N-arylsufonylaniline derivatives
4b–d with a-bromocinnamyl alcohol 8a (Scheme 3). For op-
timization of the two halo groups in the substrate, dihalides
9a–c were prepared from a-iodocinnamyl alcohol 8b or m-
iodo/chloroaniline derivatives 4e/4 f.
Scheme 5. Monocyclization of bromopivalamide 13.
Substituted a-bromocinnamyl alcohols 11 were obtained
by the Wittig olefination of a series of benzaldehydes 10
treatment of 13 with [PdACTHNGUETRN(NUG PPh3)4] (5 mol%) and Cs2CO3 in
MeCN gave the desired monocyclization product 14 in 94%
yield. The resulting benzylideneindoline derivative 14 was
quantitatively isomerized to the corresponding indole 15 in
CDCl3 within 24 h at room temperature.
À
Next, we tested the palladium-catalyzed double C H
functionalization of dibromides 7 (Table 1). Unfortunately,
the reaction of dibromopivalamide 7a with [PdACHTUNGTRENNUNG(PPh3)4]
(5 mol%) and Cs2CO3 in MeCN only gave the monocycliza-
tion product 17a in low yield (28%; Table 1, entry 1). In
contrast, conducting the reaction with an increased amount
of [PdACHTNUTGRNEUG(N PPh3)4] (10 mol%) in dioxane partially promoted the
À
double C H functionalization to afford the desired product
16a, albeit in low yield (11%). Investigations using other
solvents (N,N-dimethylformamide (DMF), dimethylaceta-
mide (DMA), tetrahydrofuran (THF), toluene, and o-
Scheme 3. Preparation of dihalosulfonamides 7 and 9.
Chem. Eur. J. 2012, 18, 5352 – 5360
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5353

H. Ohno, T. Tanaka et al.
Table 1. Optimization of reaction conditions and the nitrogen protecting group.[a]
the same product was formed by biscyclization of
7b. Considering that the reaction of 7b using re-
duced loading of the catalyst produced the mono-
cyclization product 17b (16%) and lower yield of
16b (Table 1, entry 14), this result strongly supports
the reaction pathway shown in Scheme 1, which
Entry Substrate
R
Pd
[(mol%)]
Ligand
ACHTUNGTRENN[UNG (mol%)]
t
Yield
[h] [%][b]
À
À
occurs through cascade C H alkenylation and C H
arylation in sequential order.[16] The (E)-configura-
tion of 17b was confirmed by NOE analysis
(Scheme 6), which showed that the reaction of 7b
proceeded with retention of geometry.
U
16
17
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7b
7b
7b
7c
7d
Piv [Pd
Piv [Pd(PPh3)4] (10)
Piv [Pd(OAc)2] (20)
Piv [Pd(OAc)2] (20)
Piv [Pd(OAc)2] (20)
[Pd(OAc)2] (10)
[Pd(OAc)2] (20)
[Pd(OAc)2] (10)
[Pd(OAc)2] (20)
[Pd(OAc)2] (10)
[Pd(OAc)2] (10)
[Pd(OAc)2] (20)
[Pd(OAc)2] (20)
[Pd(OAc)2] (10)
[Pd(OAc)2] (20)
[Pd(OAc)2] (20)
G
–
–
24
44
5
7
3
0
11
35
0[d]
55
46
46
0[e]
24
15
0
<81
81
46
63
41
28
>10
0
PPh3 (30)
P
E
0
0
0
0
To explore the effect of different halogen atoms
in the substrate on the reactivity, we tested the re-
action of 9a, 9b, and 9c bearing I/Br, Br/I, or Br/Cl
groups, respectively, as the alkenyl/aryl halide moi-
PCy3 (50)
PPh3 (25)
PPh3 (50)
P
P
dppe (20)
dppf (20)
PCy3 (50)
PCy3·HBF4 (50) 20
PCy3·HBF4 (20) 44
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ms
Ns
12
3
R
24
48
48
24
9
0
A
29
19
44
0
0
16
0
eties with [PdACTHNUTRGNEUNG
(OAc)2]/PCy3·HBF4 (Scheme 7).[17]
Contrary to our expectation, alkenyl iodide 9a was
the least efficient, producing 16b in only 16%
yield. A considerable amount of the monocycliza-
tion product 17b (34%) was produced. This result
can be attributed to the poisoning effect of the li-
berated iodide ion on the palladium catalyst. Ac-
tually, reaction of dibromide 7b in the presence of
Bu4NI led to complete recovery of the starting ma-
terial. Similarly, the iodobenzene derivative 9b was
inert under the standard reaction conditions. Be-
cause the chlorobenzene congener 9c was also
PCy3 (50)
PCy3 (50)
21
12
0
[a] Unless otherwise stated, the reaction was carried out in the presence of a palladium
catalyst and Cs2CO3 (4 equiv) in dioxane at reflux. [b] Yield of isolated product.
[c] The reaction was carried out in MeCN. [d] A complex mixture of unidentified
products was formed. [e] No reaction.
xylene) and bases (CsOAc, CsF, tetrabutylammonium fluo-
ride (TBAF), Cy2NMe, and Na2CO3) were not fruitful (see
the Supporting Information). Among the palladium catalysts
a less effective substrate, dibromides of type 7 were estab-
À
lished as the substrate of choice for the present cascade C
H functionalization reaction.
examined (Table 1, entries 3–5), [PdACTHNUTRGENUG(N OAc)2] (20 mol%)/
PCy3 was the most effective (55% yield; Table 1, entry 5). A
similar trend was observed for tosylamide 7b (Table 1, en-
tries 6–12) and, gratifyingly, the yield of 16 was improved to
81% when using [PdACTHNUTRGNEUNG(OAc)2]/PCy3 (Table 1, entry 12). Be-
cause the yield of the reaction using PCy3 was sometimes
lower than 81%, we used a more convenient ligand,
PCy3·HBF4, and obtained a comparable and reproducible
result (81%; Table 1, entry 13). Unfortunately, decreasing
the loading of the catalyst to 10 mol% was not successful
(Table 1, entry 14). The mesylamide 7c and nosylamide 7d
also produced the biscyclization product 16 in somewhat
low yields (63 and 41%, respectively; Table 1, entries 15 and
16).[15]
Scheme 7. Optimization of halogen substitutions.
As shown in Scheme 6, exposure of the monocyclization
product 17b to catalytic [Pd
optimized reaction conditions afforded 16b in 75% yield;
(OAc)2]/PCy3·HBF4 under the
Scope and limitations: The reaction of dibromides 12,
having a substituted benzene ring, was investigated and the
results are summarized in Table 2. Substitution at the para-
position with an electron-donating group such as a methoxy
or methyl group, had a negative effect on the reaction
(Table 2, entries 1 and 2). This can be explained by the de-
creased reactivity of the alkenyl bromide moiety in the oxi-
dative addition step, because of the electron-rich benzene
ring. The relatively low yield of ester 18c (45%) was due to
by-product formation (Table 2, entry 3). When the nitroben-
zene derivatives 12d and 12h were used, a complex mixture
of unidentified products was formed within 6 h and the de-
À
Scheme 6. C H arylation of the intermediate 17b.
5354
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5352 – 5360

À
Double C H Functionalization
FULL PAPER
Table 2. Reaction of substituted dibromides.[a]
Table 3. Reaction of heterocyclic substrates.[a]
Entry
Substrate
t
Products [(Yield [%])][b]
Entry
Substrate
t
Product [(Yield [%])][b]
[h]
[h]
1
24
24
7
1
2
3
4
12a: R=OMe
12b: R=Me
12c: R=CO2Me
12d: R=NO2
30
14
14
6
18a (42)
18b (63)
18c (45)
18d (0)
20
22
21 (44)
23 (52)
2
3
5
6
12e: R=OMe
12 f: R=Me
12g: R=CO2Me
12h: R=NO2
30
14
16
6
18e (51)
18 f (44)[c]
18g (72)
18h (0)
19e (23)
19 f (14)[c]
19g (0)
7[d]
8
24
26
25 (67)
27 (93)
19h (0)
[a] The reaction was carried out with [PdACHTNUGTRNE(UNG OAc)2] (20 mol%), PCy3·HBF4
4
5
2
8
(50 mol%), and Cs2CO3 (4 equiv) in dioxane at reflux. [b] Yield of isolat-
ed product. [c] Based on the combined isolated yield (58%) and product
ratio (3:1) determined by 1H NMR spectroscopic analysis. [d] An in-
creased amount of [PdACHTUNGTRENNUNG(OAc)2] (30 mol%) was used.
sired products could not be isolated (Table 2, entries 4 and
8). The meta-substitution effect of the cinnamyl group was
relatively small, and the biscyclization products were ob-
tained in 58–74% combined yields (Table 2, entries 5–7). It
should be noted that the reaction of meta-substituted sub-
strates 12e and 12 f produced regioisomeric mixtures 18e/
19e (51/23%) and 18 f/19 f (44/14%; Table 2, entries 5 and
28
29 (87)
[a] The reaction was carried out in the presence of [PdACHTUNGTRENNUNG(OAc)2]
(20 mol%), PCy3·HBF4 (50 mol%), and Cs2CO3 (4 equiv) in dioxane at
reflux. [b] Yield of isolated product.
À
6), respectively. In these cases, the second C H functionali-
zation preferentially proceeded at the sterically less hin-
dered carbon. Interestingly, the reaction of the meta-substi-
tuted benzoate derivative 12g furnished 18g as the sole isol-
able isomer in 72% yield (Table 2, entry 7).
À
The utility of the present cascade C H functionalization
can be seen in the construction of various types of heterocy-
clic frameworks by use of heteroaromatic substrates
(Table 3). For example, the pyrrole-derivative 20 was pre-
pared in four steps from pyrrole-2-carboxaldehyde through
Wittig olefination, tosylation, DIBAL-H mediated reduction
and the Mitsunobu reaction (see the Supporting Informa-
tion), and converted into the indole-fused indoline deriva-
tive 21 in 44% yield (Table 3, entry 1). Similarly, the benzo-
furan-fused indoline derivative 23 was obtained in 52%
yield from 22 through direct arylation with furan (Table 3,
entry 2). Pentacyclic indoline derivatives 25, 27, and 29
fused with a carbazole, dibenzofuran, or dibenzothiophene
ring were directly produced in 67–93% yields from easily
prepared dibromides 24, 26, and 28, respectively (Table 3,
entries 3–5). The improved yields of these pentacyclic com-
pounds compared with tetracyclic compounds 21 and 23 can
Scheme 8. Reaction of ether derivatives.
posure of ether 30 to the standard reaction conditions af-
forded furan-fused phenanthrene derivative 31 in 60%
yield. Similarly, the cascade reaction of benzofuran 32 gave
the fused dibenzofuran derivative 33 in 49% yield. The rela-
tively low yields of these reactions compared with those of
the tosylamide derivatives 7 are probably due to a less effi-
cient effect of the ether tether on the stabilization of the
conformation required for the first cyclization step.
Regioselectivity on the first cyclization: Finally, we investi-
gated the synthesis of the 3-unsubstituted naphthoindole
À
À
be attributed to the decreased number of reactive C H
16e (Scheme 9). For this purpose, the first C H functionali-
bonds existing in the five-membered ring of the substrates
and products, which might cause undesired side reactions.[7]
The ether derivatives 30 and 32 can be used as substrates
zation at the more hindered position of the ortho-unsubsti-
tuted aniline derivative 7e was required. Quite interestingly,
reaction of 7e under the standard reaction conditions af-
forded the desired 3-unsubstituted product 16e in 48%
À
for the double C H functionalization (Scheme 8). Thus, ex-
Chem. Eur. J. 2012, 18, 5352 – 5360
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5355

H. Ohno, T. Tanaka et al.
and the corresponding benzofurans in moderate to good
yields. Because direct arylation of heteroarenes can be in-
À
volved in the cascade reaction, the double C H functionali-
zation is a useful strategy for the construction of fused aro-
matic compounds with complex structures.
Experimental Section
Scheme 9. The reaction of ortho-unsubstituted aniline derivative.
General: Melting points are uncorrected. Nominal (LRMS) and exact
(HRMS) mass spectra were recorded with a JEOL JMS-700 or JMS-600
mass spectrometer. 1H NMR spectra were recorded with a JEOL JNM-
EX270 or JEOL JNM-AL300 in CDCl3; chemical shifts are reported in
parts per million (ppm) downfield from internal 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 polar-
imeter. For flash chromatography, silica gel 60 H (silica gel for thin-layer
chromatography, Merck) or silica gel 60 (finer than 230 mesh, Merck)
was employed. Known compounds 4 f,[19] 8a,[20] and 8b[20] were synthe-
sized according to literature procedures. Other reagents are commercially
available and were used without further purification.
yield. The monocyclization product 34, derived from cycliza-
tion at the less hindered side, was not isolated. Considering
the possibility that the monocyclization product 34 formed
in the reaction mixture but decomposed during the 24 h re-
action, we repeated the reaction using a shorter reaction
time (5 h). However, only 17g, produced by reaction at the
more hindered position, was obtained in 22% yield as the
monocyclization product, along with the biscyclization prod-
uct 16e (37%). From these observations, it has been con-
cluded that the first cyclization of 7e preferentially proceeds
at the more hindered 2-position of the aniline moiety. The
coordination effect of the meta-bromo group on the palladi-
um atom might play a significant role in the regioselectivity
of the first cyclization. However, we cannot rule out the for-
mation of a small amount of side products generated by the
first cyclization at the less hindered position, because the
yield of 16e is relatively low (48%) and a mixture of many
products were formed that were difficult to analyze.[18]
N-(5-Bromo-2-methylphenyl)-N-[(Z)-2-bromo-3-phenylprop-2-enyl]-
amine (6): 5-Bromo-2-methylaniline 4a (377 mg, 2.03 mmol) and K2CO3
(1.12 g, 8.10 mmol) were successively added to a solution of dibromide 5
(727 mg, 2.63 mmol) in DMF (10 mL), and the mixture was stirred at
608C for 4 h. After addition of water (10 mL) at 08C, the mixture was ex-
tracted with EtOAc. The organic layer was washed with water and brine,
dried over MgSO4, and concentrated under reduced pressure. The residue
was purified by repeated column chromatography over silica gel with n-
hexane/CHCl3 (7:1) and n-hexane/EtOAc (10:1) to give 6 (376 mg, 84%)
1
as a pale-yellow oil. H NMR (300 MHz, CDCl3): d=2.16 (s, 3H; PhMe),
4.21 (s, 3H; NCH2 and NH), 6.74 (d, J=1.8 Hz, 1H; 6-H), 6.81 (dd, J=
8.0, 1.8 Hz, 1H; 4-H), 6.92 (d, J=8.0 Hz, 1H; 3-H), 7.02 (s, 1H; C=CH),
7.27–7.39 (m, 3H; Ph), 7.57 ppm (d, J=7.2 Hz, 2H; Ph); 13C NMR
(75 MHz, CDCl3): d=17.0, 53.3, 112.9, 120.2, 120.5, 120.8, 123.3, 127.9,
128.0 (3C), 128.8 (2C), 131.3, 134.9, 145.9 ppm; IR (KBr): n˜ =3444 cmÀ1
(NH); MS (FAB): m/z (%): 406 (0.69) [M+Na, 81Br/81Br], 404 (1.3)
[M+Na, 81Br/79Br], 402 (0.75) [M+Na, 79Br/79Br], 176 (100); HRMS
(FAB): calcd for C16H15Br2NNa [M+Na, 79Br/79Br]: 401.9469; found:
401.9514.
The synthesis of 3-unsubstituted naphthoindole 16e could
be improved through the use of 5-bromo-2-chloroaniline de-
rivative 7 f (Scheme 10). In this case the cascade cyclization
N-(5-Bromo-2-methylphenyl)-N-[(Z)-2-bromo-3-phenylprop-2-enyl]-2,2-
dimethylpropanamide (7a): PivCl (0.52 mL, 4.28 mmol) was added at
08C to a stirred solution of 6 (408 mg, 1.07 mmol) in pyridine (5 mL),
and the mixture was stirred at 508C for 9 h. After addition of saturated
NH4Cl (5 mL) at 08C, the mixture was extracted with EtOAc. The organ-
ic layer was washed with water and brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by column chro-
matography over silica gel with n-hexane/EtOAc (10:1) to give 7a
Scheme 10. The reaction of ortho-chloroaniline derivatives.
1
(438 mg, 88%) as a colorless oil. H NMR (300 MHz, CDCl3): d=1.08 (s,
gave 3-chloronaphthoindole 16 f in 66% yield. The chlorine
atom was easily removed by catalytic hydrogenation to give
16e in 95% yield. The overall yield of 16e was 63% in two
steps.
9H; CMe3), 2.23 (s, 3H; PhMe), 3.68 (d, J=14.8 Hz, 1H; NCHH), 5.57
(d, J=14.8 Hz, 1H; NCHH), 6.66 (s, 1H; C=CH), 7.16 (d, J=8.2 Hz,
1H; Ph), 7.29–7.52 ppm (m, 7H; Ph); 13C NMR (75 MHz, CDCl3): d=
17.6, 28.7 (3C), 41.2, 59.0, 118.6, 121.4, 127.95, 127.99 (2C), 128.7 (2C),
131.46, 131.50, 132.4, 133.8, 135.1, 135.5, 142.3, 177.4 ppm; IR (KBr): n˜ =
1649 cmÀ1 (C=O); MS (FAB): m/z (%): 468 (39) [M+H, 81Br/81Br], 466
(80) [M+H, 81Br/79Br], 464 (43) [M+H, 79Br/79Br], 384 (100); HRMS
(FAB): calcd for C21H24Br2NO [M+H, 79Br/79Br]: 464.0225; found:
464.0272.
Conclusion
We have developed a novel synthesis of five-membered het-
N-(5-Bromo-2-methylphenyl)-4-methylbenzenesulfonamide (4b): Pyri-
dine (2.36 mL, 29.2 mmol) and TsCl (1.33 g, 7.00 mmol) were successively
added at 08C to a stirred solution of 5-bromo-2-methylaniline 4a (1.09 g,
5.84 mmol) in CH2Cl2 (10 mL). After stirring at this temperature for 1 h,
the mixture was made acidic with 1 N HCl, and the mixture was extract-
ed with EtOAc. The organic layer was washed with H2O and brine, dried
over MgSO4, and concentrated under reduced pressure. The residual
À
erocycles fused with a naphthalene ring through double C
H functionalization, which proceeds in sequential order. The
cascade cyclization of aniline- or phenol-derived dibromides
with [Pd
ACHTUNGTRENNUNG
in dioxane afforded 4,5-naphthoAHCNUTGTRENNUNG
5356
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5352 – 5360

À
Double C H Functionalization
FULL PAPER
solid was recrystallized from n-hexane/EtOAc to give pure 4b (1.48 g,
75%) as colorless crystals. M.p. 125–1268C (n-hexane/EtOAc); 1H NMR
(300 MHz, CDCl3): d=1.96 (s, 3H; PhMe), 2.40 (s, 3H; PhMe), 6.81 (s,
1H; NH), 6.93 (d, J=8.2 Hz, 1H; 3’-H), 7.17 (dd, J=8.2, 1.9 Hz, 1H; 4’-
H), 7.25 (d, J=6.7 Hz, 2H; Ph), 7.52 (d, J=1.9 Hz, 1H; 6’-H), 7.65 ppm
(d, J=6.7 Hz, 2H; Ph); 13C NMR (75 MHz, CDCl3): d=17.2, 21.5, 119.7,
126.5, 127.1 (2C), 128.9, 129.7 (2C), 129.8, 131.9, 135.8, 136.3, 144.1 ppm;
IR (KBr): n˜ =3261 (SO2NH), 1595 (N-Ph), 1574 (N-Ph), 1379 (NSO2),
1161 cmÀ1 (NSO2); elemental analysis calcd (%) for C14H14BrNO2S: C
49.42, H 4.15, N 4.12; found: C 49.23, H 4.15, N 4.14.
(1.4 mL), and the mixture was heated to reflux for 3 h. The mixture was
filtered through a short pad of SiO2 (n-hexane/EtOAc, 1:1) and purified
by column chromatography over silica gel (n-hexane/EtOAc, 15:1) to
give 16a (23.3 mg, 55%) as colorless crystals. M.p. 235–2378C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=1.48 (s, 9H; CMe3), 2.31 (s,
3H; PhMe), 5.35 (s, 2H; 5-CH2), 7.42 (s, 1H; 6-H), 7.46 (d, J=8.2 Hz,
1H; ArH), 7.54 (ddd, J=8.2, 7.2, 1.6 Hz, 1H; ArH), 7.59 (ddd, J=8.2,
7.2, 1.6 Hz, 1H; ArH), 7.84 (d, J=8.2 Hz, 1H; ArH), 8.05 (d, J=8.2 Hz,
1H; ArH), 8.51 ppm (d, J=8.2 Hz, 1H; ArH); 13C NMR (75 MHz,
CDCl3): d=20.7, 28.7 (3C), 40.9, 55.3, 116.0, 116.6, 122.9, 124.3, 125.8,
126.3, 126.5, 128.5, 128.6, 129.4, 132.9, 133.3, 134.6, 143.3, 179.1 ppm; IR
(KBr): n˜ =1664 cmÀ1 (C=O); MS (FAB): m/z (%): 326 (14) [M+Na], 57
(100); HRMS (FAB): calcd for C21H21NNaO [M+Na]: 326.1521; found:
326.1515; elemental analysis calcd (%) for C21H21NO: C 83.13, H 6.98, N
4.62; found: C 83.02, H 7.02, N 4.60.
N-(5-Bromo-2-methylphenyl)-N-[(Z)-2-bromo-3-phenylprop-2-enyl]-4-
methylbenzenesulfonamide (7b): Diethyl azodicarboxylate (DEAD;
2.80 mL, 6.16 mmol) was added dropwise at 08C to a stirred mixture of
aniline 4b (1.40 g, 4.11 mmol), alcohol 8a (1.75 g, 8.22 mmol), and PPh3
(1.62 g, 6.16 mmol) in toluene (30 mL). The mixture was stirred at RT for
2 h and concentrated under reduced pressure. The mixture was filtered
through a short pad of SiO2 (n-hexane/EtOAc, 1:1) and purified by
column chromatography over silica gel (n-hexane/EtOAc, 8:1) to give 7b
(2.07 g, 94%) as colorless needles. M.p. 120–1218C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=2.37 (s, 3H; PhMe), 2.46 (s, 3H; PhMe),
4.32 (d, J=14.2 Hz, 1H; NCHH), 4.66 (d, J=14.2 Hz, 1H; NCHH), 6.67
(s, 1H; C=CH), 6.82 (d, J=2.0 Hz, 1H; Ph), 7.13 (d, J=8.1 Hz, 1H; Ph),
7.25–7.35 (m, 6H; Ph), 7.40 (dd, J=8.1, 2.0 Hz, 2H; Ph), 7.60 ppm (dd,
J=8.1, 2.0 Hz, 2H; Ph); 13C NMR (75 MHz, CDCl3): d=18.4, 21.6, 61.8,
118.5, 119.3, 128.08 (2C), 128.12 (2C), 128.4, 128.8 (2C), 129.6 (2C),
131.6, 131.7, 132.8, 133.0, 134.7, 135.4, 139.0, 139.5, 144.1 ppm; IR (KBr):
n˜ =1597 (N-Ph), 1356 (NSO2), 1165 cmÀ1 (NSO2); elemental analysis
calcd (%) for C23H21Br2NO2S: C 51.61, H 3.95, N 2.62; found: C 51.57, H
3.99, N 2.59.
À
General procedure for the palladium-catalyzed double C H functionali-
zation; Synthesis of 3-methyl-4-tosyl-4,5-dihydronaphtho
(16b; Table 1, entry 13): [Pd
A
(OAc)2] (5.0 mg, 0.0223 mmol), PCy3·HBF4
(20.5 mg, 0.0558 mmol), and Cs2CO3 (145 mg, 0.445 mmol) were succes-
sively added at RT to a stirred solution of 7b (59.5 mg, 0.111 mmol) in di-
oxane (1.1 mL), and the mixture was heated at reflux for 20 h. The mix-
ture was filtered through a short pad of SiO2 (n-hexane/EtOAc, 1:1) and
purified by column chromatography over silica gel (n-hexane/EtOAc,
13:1) to give 16b (33.7 mg, 81%) as colorless crystals. M.p. 119–1208C
(n-hexane/EtOAc); 1H NMR (300 MHz, CDCl3): d=2.17 (s, 3H; PhMe),
2.77 (s, 3H; PhMe), 5.24 (d, J=1.6 Hz, 2H; 5-CH2), 6.96 (d, J=8.2 Hz,
2H; ArH), 7.28 (s, 1H; 6-H), 7.37 (d, J=8.2 Hz, 2H; ArH), 7.50 (d, J=
8.2 Hz, 1H; ArH), 7.53 (ddd, J=7.5, 7.5, 1.5 Hz, 1H; ArH), 7.58 (ddd,
J=7.5, 7.5, 1.5 Hz, 1H; ArH), 7.77 (d, J=7.5 Hz, 1H; ArH), 8.09 (d, J=
8.2 Hz, 1H; ArH), 8.47 ppm (d, J=7.5 Hz, 1H; ArH); 13C NMR
(75 MHz, CDCl3): d=20.3, 21.3, 57.0, 117.0, 118.2, 122.6, 125.9, 126.2,
126.5, 126.8, 127.2 (2C), 128.2, 128.6, 129.3 (2C), 130.9, 133.0, 133.09,
133.14, 133.5, 141.0, 143.8 ppm; IR (KBr): n˜ =1597 (N-Ph), 1354 (NSO2),
1167 cmÀ1 (NSO2); MS (FAB): m/z (%): 396 (28) [M+Na], 218 (100);
HRMS (FAB): calcd for C23H19NNaO2S [M+Na]: 396.1034; found:
396.1034.
1-(3-Benzyl-1H-indol-1-yl)-2,2-dimethylpropan-1-one (15; Scheme 5):
[PdACHTUNGTRENNUNG(PPh3)4] (7.0 mg, 0.00602 mmol) and Cs2CO3 (78.4 mg, 0.240 mmol)
were added at RT to a stirred solution of 13 (44.8 mg, 0.120 mmol) in
CH3CN (1.2 mL), and the mixture was heated at reflux for 4 h. After
cooling, saturated NH4Cl (2 mL) was added at 08C. The mixture was
then extracted with EtOAc and dried over MgSO4. Concentration under
reduced pressure gave an oily residue, which was purified by column
chromatography over silica gel (n-hexane/EtOAc, 10:1) to give 14. Com-
plete conversion into the indole was observed by standing 14 in CDCl3 at
RT for 24 h to give 15 (32.8 mg, 94%) as pale-yellow oil. 1H NMR
(300 MHz, CDCl3): d=1.55 (s, 9H; CMe3), 4.06 (s, 2H; 1’-CH2), 7.20–
7.43 (m, 9H; ArH), 8.50 ppm (dd, J=8.3, 0.6 Hz, 1H; ArH); 13C NMR
(75 MHz, CDCl3): d=28.6 (3C), 31.4, 41.1, 117.4, 118.8, 121.1, 123.3,
123.4, 125.3, 126.3, 128.5 (2C), 128.6 (2C), 129.3, 137.4, 139.3, 176.8 ppm;
IR (KBr): n˜ =1689 cmÀ1 (C=O); MS (FAB): m/z (%): 314 (47) [M+Na],
291 (100); HRMS (FAB): calcd for C20H21NNaO [M+Na]: 314.1521;
found: 314.1497.
3-Methyl-4-(methylsulfonyl)-4,5-dihydronaphtho
G
(16c;
Table 1, entry 15): By using the procedure described for the preparation
of 16b, 7c (78.4 mg, 0.171 mmol) was converted into 16c (31.8 mg, 63%)
as pale-red crystals after 21 h reaction time. M.p. 197–1988C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.66 (s, 3H; PhMe), 2.68 (s,
3H; SO2Me), 5.31 (d, J=1.7 Hz, 2H; 5-CH2), 7.49 (d, J=8.4 Hz, 1H;
ArH), 7.52 (s, 1H; 6-H), 7.59 (ddd, J=7.2, 7.2, 1.7 Hz, 1H; ArH), 7.64
(ddd, J=7.2, 7.2, 1.7 Hz, 1H; ArH), 7.88 (dd, J=7.2, 1.7 Hz, 1H; ArH),
8.15 (d, J=8.4 Hz, 1H; ArH), 8.53 ppm (dd, J=7.2, 1.7 Hz, 1H; ArH);
13C NMR (75 MHz, CDCl3): d=20.0, 35.6, 57.4, 117.8, 118.5, 122.8, 125.9,
126.3, 126.9, 127.3, 128.4, 128.8, 130.5, 133.0, 133.2, 133.5, 140.6 ppm; IR
(KBr): n˜ =1593 (N-Ph), 1335 (NSO2), 1153 cmÀ1 (NSO2); MS (FAB): m/z
(%): 320 (7.1) [M+Na], 154 (100); HRMS (FAB): calcd for
C17H15NNaO2S [M+Na]: 320.0721; found: 320.0732.
4-Bromo-{[1-(1,1-dimethyl)ethyl]carbonyl}-7-methyl-3-[(E)-phenylmeth-
ACHTUNGTRENNUNGylidene]indoline (17a; Table 1, entry 1): [PdCAHTUNGTREN(NNGU PPh3)4] (6.2 mg,
0.00537 mmol) and Cs2CO3 (105 mg, 0.322 mmol) were added at RT to
a stirred solution of 7a (50.0 mg, 0.107 mmol) in CH3CN (1 mL), and the
mixture was heated to reflux for 24 h. After cooling, saturated NH4Cl
(2 mL) was added at 08C. The mixture was then extracted with EtOAc,
washed with water and brine, and dried over MgSO4. Concentration
under reduced pressure gave an oily residue, which was purified by
column chromatography over silica gel (n-hexane/EtOAc, 9:1) to give
17a (10.8 mg, 28%) as colorless crystals. 1H NMR (300 MHz, CDCl3):
d=1.40 (s, 9H; CMe3), 2.07 (s, 3H; PhMe), 4.74 (d, J=1.7 Hz, 2H; 2-
CH2), 6.72 (s, 1H; 1’-H), 6.96 (d, J=8.2 Hz, 1H; ArH), 7.15 (d, J=
8.2 Hz, 1H; ArH), 7.22–7.29 ppm (m, 5H; ArH); 13C NMR (75 MHz,
CDCl3): d=19.7, 28.6 (3C), 40.0, 60.6, 114.5, 123.9, 127.4, 128.1 (2C),
128.8 (2C), 129.1, 130.1, 132.3, 132.7, 134.8, 137.5, 149.3, 177.9 ppm; IR
(KBr): n˜ =1662 cmÀ1 (C=O); MS (FAB): m/z (%): 408 (6.7) [M+Na,
81Br], 406 (6.2) [M+Na, 79Br], 57 (100); HRMS (FAB): calcd for
C21H22BrNNaO [M+Na, 79Br]: 406.0782; found: 406.0800.
3-Methyl-4-(2-nitrophenylsulfonyl)-4,5-dihydronaphthoACTHNUTRGNE[NUG 3,2,1-cd]indole
(16d; Table 1, entry 16): By using the procedure described for the prepa-
ration of 16b, 7d (97.0 mg, 0.171 mmol) was converted into 16d (28.4 mg,
41%) as pale-yellow crystals after 12 h reaction time. M.p. 196–1998C (n-
hexane/EtOAc); 1H NMR (300 MHz, CDCl3): d=2.49 (s, 3H; PhMe),
5.44 (d, J=1.5 Hz, 2H; 5-CH2), 7.34–7.40 (m, 1H; ArH), 7.41 (s, 1H; 6-
H), 7.42 (d, J=8.0 Hz, 1H; ArH), 7.46–7.63 (m, 5H; ArH), 7.83 (d, J=
8.0 Hz, 1H; ArH), 8.12 (d, J=8.0 Hz, 1H; ArH), 8.49 ppm (d, J=8.0 Hz,
1H; ArH); 13C NMR (75 MHz, CDCl3): d=20.2, 57.3, 117.6, 118.5, 122.8,
124.1, 124.6, 126.2, 126.8, 127.1, 128.2, 128.8, 129.8, 130.3, 131.3, 131.5,
132.4 (2C), 133.2, 133.3, 134.0, 140.2 ppm; IR (KBr): n˜ =1545 (N-Ph),
1356 (NSO2), 1171 cmÀ1 (NSO2); MS (FAB): m/z (%): 427 (17) [M+Na],
154 (100); HRMS (FAB): calcd for C22H16N2NaO4S [M+Na]: 427.0728;
found: 427.0737.
2,2-Dimethyl-1-(3-methylnaphtho
[3,2,1-cd]indol-4
N
9-Methoxy-3-methyl-4-tosyl-4,5-dihydronaphtho
N
(18a;
(16a; Table 1, entry 5): [Pd(OAc)2] (6.3 mg, 0.0280 mmol), PCy3 (19.7 mg,
0.0701 mmol) and Cs2CO3 (183 mg, 0.561 mmol) were successively added
at RT to a stirred solution of 7a (65.2 mg, 0.140 mmol) in dioxane
G
Table 2, entry 1): By using the procedure described for the preparation of
16b, 12a (108 mg, 0.191 mmol) was converted into 18a (32.3 mg, 42%)
as a pale-yellow oil after 30 h reaction time. H NMR (300 MHz, CDCl3):
1
Chem. Eur. J. 2012, 18, 5352 – 5360
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5357

H. Ohno, T. Tanaka et al.
d=2.15 (s, 3H; PhMe), 2.75 (s, 3H; PhMe), 3.96 (s, 3H; OMe), 5.19 (s,
2H; 5-CH2), 6.94 (d, J=8.2 Hz, 2H; PhH), 7.15 (dd, J=8.8, 2.5 Hz, 1H;
8-H), 7.19 (s, 1H; 6-H), 7.36 (d, J=8.2 Hz, 2H; PhH), 7.50 (d, J=8.8 Hz,
1H; ArH), 7.65 (d, J=8.8 Hz, 1H; ArH), 7.80 (d, J=2.5 Hz, 1H; 10-H),
8.00 ppm (d, J=8.8 Hz, 1H; ArH); 13C NMR (75 MHz, CDCl3): d=20.3,
21.3, 55.4, 57.0, 103.8, 116.77, 116.84, 118.3, 126.3, 126.4, 127.3 (2C),
127.7, 129.3 (2C), 129.5, 129.9, 130.7, 131.4, 132.7, 133.6, 141.1, 143.8,
158.0 ppm; IR (KBr): n˜ =1597 (N-Ph), 1354 (NSO2), 1227 (PhOMe),
1167 cmÀ1 (NSO2); MS (FAB): m/z (%): 426 (53) [M+Na], 248 (100);
HRMS (FAB): calcd for C24H21NNaO3S [M+Na]: 426.1140; found:
426.1136.
(FAB): m/z (%): 426 (25) [M+Na], 176 (100); HRMS (FAB): calcd for
C24H21NNaO3S [M+Na]: 426.1140; found: 426.1160.
3,8-Dimethyl-4-tosyl-4,5-dihydronaphtho
ACHTUNGTRENNUNG
dimethyl-4-tosyl-4,5-dihydronaphtho[3,2,1-cd]indole
AHCTUNGTRENNUNG
entry 6). By using the procedure described for the preparation of 16b,
12f (70.8 mg, 0.129 mmol) was converted into an inseparable mixture of
18f and 19f (18f/19f=3:1; 29.0 mg, 58%) as a pale-yellow oil after 14 h
1
reaction time. H NMR (300 MHz, CDCl3): d (18f)=2.17 (s, 3H; PhMe),
2.51 (s, 3H; PhMe), 2.75 (s, 3H; PhMe), 5.22 (s, 2H; 5-CH2), 6.95 (d, J=
8.2 Hz, 2H; PhH), 7.20 (s, 1H; ArH), 7.37 (d, J=8.2 Hz, 2H; PhH),
7.38–7.41 (m, 1H; ArH), 7.47 (d, J=8.4 Hz, 1H; ArH), 7.54 (s, 1H;
ArH), 8.04 (d, J=8.4 Hz, 1H; ArH), 8.35 ppm (d, J=8.4 Hz, 1H; ArH);
d (19f)=2.11 (s, 3H; PhMe), 2.78 (s, 3H; PhMe), 3.03 (s, 3H; PhMe),
5.15 (s, 2H; 5-CH2), 6.88–6.93 (m, 2H; PhH), 7.14 (s, 1H; ArH), 7.22–
7.24 (m, 1H; ArH), 7.30–7.49 (m, 4H; ArH), 7.60 (dd, J=7.1 Hz, 1H;
ArH), 8.37 ppm (d, J=8.6 Hz, 1H; ArH); 13C NMR (75 MHz, CDCl3): d
(18f and 19f)=20.1, 20.3, 21.31, 21.32, 21.5, 26.4, 56.3, 57.1, 116.8, 118.1,
118.5, 122.5, 123.3, 125.7, 125.9, 126.1, 126.5, 126.9, 127.2 (4C), 127.3,
127.5, 127.7, 127.8, 128.19, 128.20, 129.3 (4C), 130.0, 130.7, 132.2, 132.4,
133.0, 133.09, 133.11, 133.2, 133.3, 133.6, 134.6, 136.1, 136.32, 136.33,
140.97, 141.01, 143.8, 143.8 ppm; IR (KBr): n˜ =1597 (N-Ph), 1354
(NSO2), 1167 cmÀ1 (NSO2).
3,9-Dimethyl-4-tosyl-4,5-dihydronaphthoACTHUNRGTNEUNG[3,2,1-cd]indole (18b; Table 2,
entry 2): By using the procedure described for the preparation of 16b,
12b (75.6 mg, 0.138 mmol) was converted into 18b (33.7 mg, 63%) as col-
orless crystals after 14 h reaction time. M.p. 129–1308C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.13 (s, 3H; PhMe), 2.55 (s,
3H; PhMe), 2.75 (s, 3H; PhMe), 5.19 (s, 2H; 5-CH2), 6.93 (d, J=8.2 Hz,
2H; PhH), 7.20 (s, 1H; 6-H), 7.32–7.36 (m, 1H; ArH), 7.35 (d, J=
8.2 Hz, 2H; PhH), 7.45 (d, J=8.2 Hz, 1H; ArH), 7.63 (d, J=8.2 Hz, 1H;
ArH), 8.05 (d, J=8.2 Hz, 1H; ArH), 8.23 ppm (s, 1H; 10-H); 13C NMR
(75 MHz, CDCl3): d=20.3, 21.3, 21.8, 57.1, 116.9, 118.3, 122.4, 126.2,
126.6, 127.3 (2C), 128.3 (2C), 128.4, 129.3 (2C), 131.0, 131.2, 132.1, 132.9,
133.6, 135.8, 141.0, 143.8 ppm; IR (KBr): n˜ =1597 (N-Ph), 1356 (NSO2),
1165 cmÀ1 (NSO2); MS (FAB): m/z (%): 410 (27) [M+Na], 232 (100);
HRMS (FAB): calcd for C24H21NNaO2S [M+Na]: 410.1191; found:
410.1187.
Methyl 3-methyl-4-tosyl-4,5-dihydronaphtoACTHUNTGRENNG[U 3,2,1-cd]indole-8-carboxylate
(18g; Table 2, entry 7): By using the procedure described for the prepara-
tion of 16b, 12g (101 mg, 0.171 mmol) was converted into 18g (52.9 mg,
72%) as colorless crystals after 16 h reaction time. M.p. 165–1668C (n-
hexane/EtOAc); 1H NMR (300 MHz, CDCl3): d=2.16 (s, 3H; PhMe),
2.78 (s, 3H; PhMe), 3.98 (s, 3H; OMe), 5.24 (s, 2H; 5-CH2), 6.96 (d, J=
8.2 Hz, 2H; PhH), 7.33 (s, 1H; 6-H), 7.36 (d, J=8.2 Hz, 2H; PhH), 7.53
(d, J=8.4 Hz, 1H; 2-H), 8.10 (d, J=8.4 Hz, 1H; 1-H), 8.16 (dd, J=8.4,
1.6 Hz, 1H; 9-H), 8.47 (m, 1H; 7-H), 8.48 ppm (d, J=8.4 Hz, 1H; 10-H);
13C NMR (75 MHz, CDCl3): d=20.4, 21.4, 52.3, 57.1, 117.5, 118.8, 122.9,
125.9, 126.3, 127.3 (2C), 127.7, 128.0, 129.3 (2C), 130.9, 131.3, 132.0,
132.5, 133.5, 133.6, 134.3, 141.3, 144.0, 167.0 ppm; IR (KBr): n˜ =1720 (C=
O), 1597 (N-Ph), 1360 (NSO2), 1169 cmÀ1 (NSO2); elemental analysis
calcd (%) for C25H21NO4S: C 69.59, H 4.91, N 3.25; found: C 69.35, H
4.99, N 3.21.
Methyl 3-methyl-4-tosyl-4,5-dihydronaphtoACTHUNTGRENNG[U 3,2,1-cd]indole-9-carboxylate
(18c; Table 2, entry 3): By using the procedure described for the prepara-
tion of 16b, 12c (54.5 mg, 0.0919 mmol) was converted into 18c (17.9 mg,
45%) as colorless crystals after 14 h reaction time. M.p. 156–1578C (n-
hexane/EtOAc); 1H NMR (300 MHz, CDCl3): d=2.16 (s, 3H; PhMe),
2.77 (s, 3H; PhMe), 4.00 (s, 3H; OMe), 5.24 (s, 2H; 5-CH2), 6.96 (d, J=
8.2 Hz, 2H; PhH), 7.29 (s, 1H; 6-H), 7.37 (d, J=8.2 Hz, 2H; PhH), 7.55
(d, J=8.3 Hz, 1H; 2-H), 7.78 (d, J=8.4 Hz, 1H; 7-H), 8.12 (d, J=8.4 Hz,
1H; 8-H), 8.17 (d, J=8.3 Hz, 1H; 1-H), 9.17 ppm (s, 1H; 10-H);
13C NMR (75 MHz, CDCl3): d=20.3, 21.4, 52.3, 57.2, 116.6, 118.5, 125.2,
126.5, 127.0, 127.2, 127.3 (2C), 127.8, 128.7, 129.3 (2C), 131.2, 133.5,
134.0, 136.0, 136.2 (2C), 141.4, 144.0, 167.2 ppm; IR (KBr): n˜ =1718 (C=
O), 1358 (NSO2), 1167 cmÀ1 (NSO2); MS (FAB): m/z (%): 454 (25)
[M+Na], 276 (100); HRMS (FAB): calcd for C25H21NNaO4S [M+Na]:
454.1089; found: 454.1086.
3-Methyl-4,7-ditosyl-5,7-dihydro-4H-indoloACTHNUTRGNE[NUG 6,5,4-cd]indole (21; Table 3,
entry 1): By using the procedure described for the preparation of 16b, 20
(81.0 mg, 0.111 mmol) was converted into 21 (27.0 mg, 44%) as colorless
crystals after 24 h reaction time. M.p. 162–1638C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=2.19 (s, 3H; PhMe), 2.33 (s, 3H; PhMe),
2.67 (s, 3H; PhMe), 5.46 (s, 2H; 5-CH2), 7.00 (d, J=8.2 Hz, 2H; PhH),
7.01 (d, J=3.5 Hz, 1H; ArH), 7.20 (d, J=8.2 Hz, 2H; PhH), 7.36 (d, J=
8.2 Hz, 1H; ArH), 7.39 (d, J=8.2 Hz, 2H; PhH), 7.58 (d, J=8.2 Hz, 1H;
ArH), 7.60 (d, J=3.5 Hz, 1H; ArH), 7.70 (d, J=8.2 Hz, 2H; PhH),
7.72 ppm (s, 1H; ArH); 13C NMR (75 MHz, CDCl3): d=20.2, 21.3, 21.5,
57.5, 104.8, 107.1, 118.0, 123.3, 123.7, 123.8, 125.1, 126.6 (2C), 127.1 (2C),
129.3 (2C), 129.5, 129.9 (2C), 132.3, 133.3, 133.7, 133.8, 135.2, 141.0,
143.8, 145.1 ppm; IR (KBr): n˜ =1597 (N-Ph), 1356 (NSO2), 1163 cmÀ1
(NSO2); MS (FAB): m/z (%): 539 (24) [M+Na], 176 (100); HRMS
(FAB): calcd for C28H24N2NaO4S2 [M+Na]: 539.1075; found: 539.1069.
8-Methoxy-3-methyl-4-tosyl-4,5-dihydronaphtho
N
(18e)
and 10-methoxy-3-methyl-4-tosyl-4,5-dihydronaphthoAHCTUNGTRENNUNG
(19e) (Table 2, entry 5): By using the procedure described for the prepa-
ration of 16b, 12e (109 mg, 0.192 mmol) was converted into 18e (39.9 mg,
51%) and 19e (18.0 mg, 23%) after 30 h reaction time.
Compound 18e: Pale-yellow crystals. M.p. 141–1428C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.14 (s, 3H; PhMe), 2.73 (s,
3H; PhMe), 3.89 (s, 3H; OMe), 5.20 (s, 2H; 5-CH2), 6.94 (d, J=8.2 Hz,
2H; PhH), 7.10 (d, J=2.4 Hz, 1H; 7-H), 7.16 (s, 1H; 6-H), 7.16–7.20 (m,
1H; ArH), 7.37 (d, J=8.2 Hz, 2H; PhH), 7.43 (d, J=8.2 Hz, 1H; ArH),
7.95 (d, J=8.2 Hz, 1H; ArH), 8.31 ppm (d, J=8.2 Hz, 1H; ArH);
13C NMR (75 MHz, CDCl3): d=20.2, 21.3, 55.3, 57.1, 108.9, 116.3, 116.5,
117.7, 122.5, 124.1, 125.0, 127.0, 127.2 (2C), 129.3 (2C), 130.0, 133.3,
133.6, 133.8, 134.6, 141.0, 143.8, 158.2 ppm; IR (KBr): n˜ =1597 (N-Ph),
1356 (NSO2), 1221 (PhOMe), 1167 cmÀ1 (NSO2); elemental analysis calcd
(%) for C24H21NO3S: C 71.44, H 5.25, N 3.47; found: C 71.46, H 5.38, N
3.38.
3-Methyl-4-tosyl-4,5-dihydrobenzofuro
[6,5,4-cd]indole
(23;
Table 3,
entry 2): By using the procedure described for the preparation of 16b, 22
(56.5 mg, 0.108 mmol) was converted into 23 (20.4 mg, 52%) as colorless
crystals after 24 h reaction time. M.p. 105–1068C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=2.20 (s, 3H; PhMe), 2.72 (s, 3H; PhMe),
5.25 (s, 2H; 5-CH2), 6.97 (d, J=8.2 Hz, 2H; PhH), 7.10 (d, J=2.0 Hz,
1H; 9-H), 7.21 (s, 1H; 6-H), 7.37 (d, J=8.2 Hz, 2H; PhH), 7.41 (d, J=
8.2 Hz, 1H; ArH), 7.62 (d, J=8.2 Hz, 1H; ArH), 7.68 ppm (d, J=2.0 Hz,
1H; 8-H); 13C NMR (75 MHz, CDCl3): d=20.2, 21.4, 57.2, 104.0, 105.5,
118.4, 120.0, 123.2, 124.0, 127.2 (2C), 129.3 (2C), 132.1 (2C), 133.6, 133.7,
141.2, 143.8, 144.2, 154.2 ppm; IR (KBr): n˜ =1599 (N-Ph), 1360 (NSO2),
1167 cmÀ1 (NSO2); MS (FAB): m/z (%): 386 (17) [M+Na], 208 (100);
HRMS (FAB): calcd for C21H17NNaO3S [M+Na]: 386.0827; found:
386.0831.
Compound 19e: Colorless crystals. M.p. 200–2018C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=2.14 (s, 3H; PhMe), 2.78 (s, 3H; PhMe),
4.11 (s, 3H; OMe), 5.17 (d, J=1.6 Hz, 2H; 5-CH2), 6.92 (d, J=8.2 Hz,
2H; PhH), 7.04 (d, J=7.9 Hz, 1H; ArH), 7.22 (t, J=1.6 Hz, 1H; 6-H),
7.31 (d, J=8.2 Hz, 2H; PhH), 7.37 (d, J=7.9 Hz, 1H; ArH), 7.44 (dd, J=
7.9, 7.9 Hz, 1H; 8-H), 7.48 (d, J=8.6 Hz, 1H; 2-H), 8.87 ppm (d, J=
8.6 Hz, 1H; 1-H); 13C NMR (75 MHz, CDCl3): d=20.2, 21.4, 55.4, 56.5,
106.9, 117.3, 119.0, 121.3, 124.5, 126.45, 126.50, 126.53, 127.4 (2C), 129.2
(2C), 131.5, 132.9, 133.2, 134.0, 135.5, 140.6, 143.8, 158.9 ppm; IR (KBr):
n˜ =1585 (N-Ph), 1354 (NSO2), 1242 (PhOMe), 1165 cmÀ1 (NSO2); MS
3-Methyl-4,11-ditosyl-5,11-dihydro-4H-indolo
G
(25;
Table 3, entry 3): By using the procedure described for the preparation of
5358
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5352 – 5360

À
Double C H Functionalization
FULL PAPER
16b, 24 (91.5 mg, 0.126 mmol) was converted into 25 (48.0 mg, 67%) as
colorless crystals after 7 h reaction time. M.p. 225–2278C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.17 (s, 3H; PhMe), 2.25 (s,
3H; PhMe), 2.74 (s, 3H; PhMe), 5.21 (s, 2H; 5-CH2), 6.76 (d, J=8.2 Hz,
2H; PhH), 6.95 (d, J=8.2 Hz, 2H; PhH), 7.03 (d, J=8.2 Hz, 2H; PhH),
7.26–7.44 (m, 5H; ArH), 7.49 (d, J=8.2 Hz, 1H; ArH), 7.64 (d, J=
8.2 Hz, 1H; ArH), 8.32 (d, J=8.2 Hz, 1H; ArH), 8.59 ppm (d, J=8.2 Hz,
1H; ArH); 13C NMR (75 MHz, CDCl3): d=20.3, 21.56, 21.62, 56.8, 109.3,
118.5, 119.4, 121.7, 122.4, 125.0, 125.3, 126.5 (2C), 127.1, 127.4 (2C),
128.6, 128.7, 128.9 (2C), 129.5 (2C), 132.6, 133.1, 133.5, 133.7, 133.8,
134.1, 140.8, 140.9, 144.0, 144.6 ppm; IR (KBr): n˜ =1597 (N-Ph), 1356
(NSO2), 1169 cmÀ1 (NSO2); MS (FAB): m/z (%): 589 (48) [M+Na], 256
(100); HRMS (FAB): calcd for C32H26N2NaO4S2 [M+Na]: 589.1232;
found: 589.1242.
0.216 mmol) was converted into 16e (37.4 mg, 48%) as a colorless oil
after 24 h reaction time. 1H NMR (300 MHz, CDCl3): d=2.27 (s, 3H;
PhMe), 5.16 (s, 2H; 5-CH2), 7.17 (d, J=8.3 Hz, 2H; PhH), 7.36 (s, 1H; 6-
H), 7.51–7.61 (m, 3H; ArH), 7.70 (d, J=7.5 Hz, 1H; ArH), 7.75–7.80 (m,
1H; ArH), 7.77 (d, J=8.3 Hz, 2H; PhH), 7.99 (d, J=7.5 Hz, 1H; ArH),
8.46 ppm (dd, J=7.5, 2.4 Hz, 1H; ArH); 13C NMR (75 MHz, CDCl3): d=
21.4, 55.3, 109.3, 115.6, 117.2, 123.0, 126.1, 127.0 (3C), 128.1, 128.8 (2C),
129.0, 129.4, 129.8 (2C), 132.7, 133.6, 134.1, 142.8, 144.3 ppm; IR (KBr):
n˜ =1356 (NSO2), 1165 cmÀ1 (NSO2); MS (FAB): m/z (%): 382 (25)
[M+Na], 204 (100); HRMS (FAB): calcd for C22H17NNaO2S [M+Na]:
382.0878; found: 382.0871.
3-Chloro-4-tosyl-4,5-dihydronaphthoACTHNUGTRNEUNG[3,2,1-cd]indole (16 f; Scheme 10):
By using the procedure described for the preparation of 16b, 7 f (228 mg,
0.410 mmol) was converted into 16 f (107 mg, 66%) as pale-yellow crys-
tals after 22 h reaction time. M.p. 197–1988C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=2.30 (s, 3H; PhMe), 5.47 (d, J=1.6 Hz,
2H; 5-CH2), 7.15 (d, J=8.2 Hz, 2H; PhH), 7.44 (s, 1H; 6-H), 7.50 (d, J=
8.6 Hz, 1H; ArH), 7.56–7.64 (m, 2H; ArH), 7.70 (d, J=8.2 Hz, 2H;
PhH), 7.83 (dd, J=6.7, 2.6 Hz, 1H; ArH), 7.99 (d, J=8.6 Hz, 1H; ArH),
8.44 ppm (dd, J=6.7, 2.6 Hz, 1H; ArH); 13C NMR (75 MHz, CDCl3): d=
21.5, 57.9, 117.7, 118.1, 118.6, 122.9, 126.5, 127.2 (2C), 127.3, 127.4, 127.9,
128.8, 129.5 (2C), 131.5, 131.8, 132.5, 133.3, 136.0, 139.4, 144.0 ppm; IR
(KBr): n˜ =1597 (N-Ph), 1356 (NSO2), 1169 (NSO2), 1093 cmÀ1 (Ph-Cl);
elemental analysis calcd (%) for C22H16ClNO2S: C 67.08, H 4.09, N 3.56;
found: C 67.02, H 4.20, N 3.55.
3-Methyl-4-tosyl-4,5-dihydrobenzo
G
G
(27;
Table 3, entry 4): By using the procedure described for the preparation of
16b, 26 (75.2 mg, 0.131 mmol) was converted into 27 (50.3 mg, 93%) as
pale-yellow needles after 2 h reaction time. M.p. 189–1908C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.17 (s, 3H; PhMe), 2.76 (s,
3H; PhMe), 5.29 (s, 2H; 5-CH2), 6.97 (d, J=8.4 Hz, 2H; PhH), 7.28 (s,
1H; 6-H), 7.38 (d, J=8.4 Hz, 2H; PhH), 7.42–7.48 (m, 2H; ArH), 7.53
(d, J=8.4 Hz, 1H; ArH), 7.59–7.62 (m, 1H; ArH), 7.98 (d, J=8.4 Hz,
1H; ArH), 8.18–8.21 ppm (m, 1H; ArH); 13C NMR (75 MHz, CDCl3):
d=20.2, 21.4, 57.4, 104.1, 111.7, 115.3, 118.4, 121.4, 123.2, 123.4, 124.5,
124.8, 125.8, 127.2 (2C), 129.3 (2C), 129.7, 133.5, 134.6, 135.4, 141.6,
144.0, 155.8, 155.9 ppm; IR (KBr): n˜ =1597 (N-Ph), 1358 (NSO2),
1167 cmÀ1 (NSO2); MS (FAB): m/z (%): 436 (23) [M+Na], 258 (100);
HRMS (FAB): calcd for C25H19NNaO3S [M+Na]: 436.0983; found:
436.1000.
Acknowledgements
3-Methyl-4-tosyl-4,5-dihydrobenzoACTHNUGRTENNUG[4’,5’]thieno[2’,3’:4,5]benzoHCATUNGTREN[NNGU 1,2,3-cd]in-
This work was supported in part by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Integrated Organic Synthesis” (H.O.) and
for Scientific Research (B) (T.T.) from the Ministry of Education, Cul-
ture, Sports, Science and Technology of Japan.
dole (29; Table 3, entry 5): By using the procedure described for the
preparation of 16b, 28 (59.8 mg, 0.101 mmol) was converted into 29
(37.6 mg, 87%) as colorless crystals after 8 h reaction time. M.p. 235–
2378C (n-hexane/EtOAc); 1H NMR (300 MHz, CDCl3): d=2.17 (s, 3H;
PhMe), 2.74 (s, 3H; PhMe), 5.30 (s, 2H; 5-CH2), 6.98 (d, J=8.1 Hz, 2H;
PhH), 7.39–7.48 (m, 5H; ArH), 7.60 (d, J=8.2 Hz, 1H; ArH), 7.71 (s,
1H; 6-H), 7.89–7.92 (m, 1H; ArH), 8.05–8.08 ppm (m, 1H; ArH);
13C NMR (75 MHz, CDCl3): d=20.4, 21.4, 57.5, 110.8, 118.7, 121.4, 123.1,
124.5, 124.9, 125.3, 126.2, 127.2 (2C), 129.4 (2C), 131.9, 132.4 (2C), 133.1,
133.7, 133.9, 136.0, 139.2, 141.5, 144.0 ppm; IR (KBr): n˜ =1352 (NSO2),
1167 cmÀ1 (NSO2); MS (FAB): m/z (%): 452 (18) [M+Na], 176 (100);
HRMS (FAB): calcd for C25H19NNaO2S2 [M+Na]: 452.0755; found:
452.0756.
[1] For pioneering works, see: a) D. E. Ames, D. Bull, Tetrahedron
1982, 38, 383–387; b) D. E. Ames, A. Opalko, Tetrahedron 1984, 40,
1919–1925; c) M. Catellani, G. P. Chiusoli, C. Castagnoli, J. Organo-
met. Chem. 1991, 407, C30–33.
[2] For recent reviews, see: a) M. Zhang, Adv. Synth. Catal. 2009, 351,
2243–2270; b) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer,
O. Baudoin, Chem. Eur. J. 2010, 16, 2654–2672; c) P. Thansandote,
M. Lautens, Chem. Eur. J. 2009, 15, 5874–5883; d) T. Newhouse,
P. S. Baran, Angew. Chem. 2011, 123, 3422–3435; Angew. Chem. Int.
Ed. 2011, 50, 3362–3374; e) C. S. Yeung, V. M. Dong, Chem. Rev.
2011, 111, 1215–1292.
[3] For recent reviews on palladium-catalyzed direct arylation of heter-
oarenes, see: a) L. Ackermann, R. Vicente, A. R. Kapdi, Angew.
Chem. 2009, 121, 9976–10011; Angew. Chem. Int. Ed. 2009, 48,
9792–9826; b) F. Bellina, R. Rossi, Tetrahedron 2009, 65, 10269–
10310.
3-Methyl-5H-phenanthroACTHNUTRGNEUG[N 1,10-bc]furan (31; Scheme 8): By using the pro-
cedure described for the preparation of 16b, 30 (65.0 mg, 0.170 mmol)
was converted into 31 (22.5 mg, 60%) as pale-yellow crystals after 8 h re-
action time. M.p. 65–708C (n-hexane/EtOAc); 1H NMR (300 MHz,
CDCl3): d=2.41 (s, 3H; PhMe), 5.74 (s, 2H; 5-CH2), 7.36 (s, 1H; 6-H),
7.36 (d, J=8.0 Hz, 1H; ArH), 7.51 (m, 2H; ArH), 7.79 (d, J=8.0 Hz,
1H; ArH), 7.83 (dd, J=8.0, 1.9 Hz, 1H; 7-H), 8.47 ppm (dd, J=8.0,
1.9 Hz, 1H; ArH); 13C NMR (75 MHz, CDCl3): d=14.6, 75.9, 112.6,
113.9, 115.1, 123.0, 125.7 (2C), 126.4, 127.2, 128.8, 128.9, 132.2, 133.95,
133.99, 136.8 ppm; IR (KBr): n˜ =1630 cmÀ1 (O-Ph); MS (FAB): m/z (%):
220 (53) [M], 154 (100); HRMS (FAB): calcd for C16H12O [M]: 220.0888;
found: 220.0874.
À
[4] For cascade reactions including C H functionalization, see: a) R. C.
Larock, M. J. Doty, Q. Tian, J. M. Zenner, J. Org. Chem. 1997, 62,
7536–7537; b) S. M. A. Rahman, M. Sonoda, K. Itahashi, Y. Tobe,
Org. Lett. 2003, 5, 3411–3414; c) S. M. A. Rahman, M. Sonoda, M.
Ono, K. Miki, Y. Tobe, Org. Lett. 2006, 8, 1197–1200; d) C. Blaszy-
kowski, E. Aktoudianakis, C. Bressy, D. Alberico, M. Lautens, Org.
Lett. 2006, 8, 2043–2045; e) A. Pinto, L. Neuville, P. Retailleau, J.
Zhu, Org. Lett. 2006, 8, 4927–4930; f) I. Alonso, M. Alcamꢁ, P. Mau-
leꢂn, J. C. Carretero, Chem. Eur. J. 2006, 12, 4576–4583; g) L. F.
Tietze, F. Lotz, Eur. J. Org. Chem. 2006, 4676–4684; h) J. Zhao, D.
Yue, M. A. Campo, R. C. Larock, J. Am. Chem. Soc. 2007, 129,
5288–5295; i) C.-G. Dong, P. Yeung, Q.-S. Hu, Org. Lett. 2007, 9,
363–366; j) L.-N. Guo, X.-H. Duan, X.-Y. Liu, J. Hu, H.-P. Bi, Y. M.
Liang, Org. Lett. 2007, 9, 5425–5428; k) A. Pinto, L. Neuville, J.
Zhu, Angew. Chem. 2007, 119, 3355–3359; Angew. Chem. Int. Ed.
2007, 46, 3291–3295; l) R. T. Ruck, M. A. Huffman, M. M. Kim, M.
Shevlin, W. V. Kandur, I. W. Davies, Angew. Chem. 2008, 120, 4789–
3-Methyl-5,7-dihydrobenzoACTHUNRTGENN[GU 4’,5’]furo[2’,3’:6,5]naphthoACHTUTGNREN[NUGN 1,8-bc]furan (33;
Scheme 8): By using the procedure described for the preparation of 16b,
32 (45.4 mg, 0.108 mmol) was converted into 33 (13.8 mg, 49%) as pale-
yellow needles after 8 h reaction time. M.p. 132–1338C (n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=2.40 (s, 3H; PhMe), 5.80 (s,
2H; 5-CH2), 7.38–7.48 (m, 4H; ArH), 7.61–7.64 (m, 1H; ArH), 7.67 (d,
J=8.2 Hz, 1H; ArH), 8.17–8.20 ppm (m, 1H; ArH); 13C NMR (75 MHz,
CDCl3): d=14.4, 76.2, 102.4, 110.8, 111.6, 112.6, 115.4, 121.4, 123.0, 124.8,
124.95, 124.98, 125.4, 133.9, 139.1, 155.9, 156.7, 159.8 ppm; IR (KBr): n˜ =
1606 (O-Ph), 1597 cmÀ1 (O-Ph); MS (FAB): m/z (%): 260 (100) [M];
HRMS (FAB): calcd for C18H12O2 [M]: 260.0837; found: 260.0831.
4-Tosyl-4,5-dihydronaphthoACTHUNGTRENUN[NG 3,2,1-cd]indole (16e; Scheme 9): By using
the procedure described for the preparation of 16b, 7e (112.8 mg,
Chem. Eur. J. 2012, 18, 5352 – 5360
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5359

H. Ohno, T. Tanaka et al.
4792; Angew. Chem. Int. Ed. 2008, 47, 4711–4714; m) N. Chernyak,
V. Gevorgyan, J. Am. Chem. Soc. 2008, 130, 5636–5637; n) D. A.
Candito, M. Lautens, Angew. Chem. 2009, 121, 6841–6844; Angew.
Chem. Int. Ed. 2009, 48, 6713–6716; o) G. Satyanarayana, C.
Maichle-Mçssmer, M. E. Maier, Chem. Commun. 2009, 1571–1573;
p) T. K. Hyster, T. Rovis, J. Am. Chem. Soc. 2010, 132, 10565–
10569; q) C. Zhu, J. R. Falck, Org. Lett. 2011, 13, 1214–1217.
[5] For our recent work, see: a) H. Ohno, K. Miyamura, Y. Takeoka, T.
Tanaka, Angew. Chem. 2003, 115, 2751–2754; Angew. Chem. Int.
Ed. 2003, 42, 2647–2650; b) H. Ohno, M. Yamamoto, M. Iuchi, T.
Tanaka, Angew. Chem. 2005, 117, 5233–5236; Angew. Chem. Int.
Ed. 2005, 44, 5103–5106; c) H. Ohno, K. Miyamura, T. Mizutani, Y.
Kadoh, Y. Takeoka, H. Hamaguchi, T. Tanaka, Chem. Eur. J. 2005,
11, 3728–3741; d) H. Ohno, M. Yamamoto, M. Iuchi, N. Fujii, T.
Tanaka, Synthesis 2011, 2567–2578; for other works on C-H aryla-
tion, see: e) T. Watanabe, S. Oishi, N. Fujii, H. Ohno, Org. Lett.
2007, 9, 4821–4824; f) T. Watanabe, S. Oishi, N. Fujii, H. Ohno,
Org. Lett. 2008, 10, 1759–1762.
[6] a) Q. Huang, A. Fazio, G. Dai, M. A. Campo, R. C. Larock, J. Am.
Chem. Soc. 2004, 126, 7460–7461; b) N. Della Ca’, G. Maestri, M,
Catellani, Chem. Eur. J. 2009, 15, 7850–7853; c) V. S. Thirunavuk-
karasu, K. Parthasarathy, C.-H. Cheng, Chem. Eur. J. 2010, 16,
1436–1440; d) C. Pierre, O. Baudoin, Org. Lett. 2011, 13, 1816–
1819; e) G.-W. Wang, T.-T. Yuan, D.-D. Li, Angew. Chem. 2011, 123,
1416–1419; Angew. Chem. Int. Ed. 2011, 50, 1380–1383; f) J. Karthi-
keyan, C.-H. Cheng, Angew. Chem. 2011, 123, 10054–10057; Angew.
Chem. Int. Ed. 2011, 50, 9880–9883.
[11] a) L. M. Deck, D. L. Vander Jagt, R. E. Royer, J. Med. Chem. 1991,
34, 3301–3305; b) Z. Bouaziz, J. Riondel, A. Mey, M. Berlion, J. Vil-
lard, H. Fillion, Eur. J. Med. Chem. 1991, 26, 469–472; c) L. S. Puck-
haber, R. D. Stipanovic, J. Nat. Prod. 2001, 64, 260–261; d) X.
Zhang, H. Zhu, S. Zhang, Q. Yu, L. Xuan, J. Nat. Prod. 2007, 70,
1526–1528; e) L. S. Puckhaber, M. K. Dowd, R. D. Stipanovic, C. R.
Howell, J. Agric. Food Chem. 2002, 50, 7017–7021.
[12] a) S. M. Kupchan, J. J. Merianos, J. Org. Chem. 1968, 33, 3735–3738;
b) M. Akasu, H. Itokawa, M. Fujita, Tetrahedron Lett. 1974, 15,
3609–3612; c) H. A. Priestap, Phytochemistry 1985, 24, 849–852;
d) A. Couture, E. Deniau, P. Grandclaudon, H. Rybalko-Rosen, S.
Lꢃonce, B. Pfeiffer, P. Renard, Bioorg. Med. Chem. Lett. 2002, 12,
3557–3559; e) P.-L. Wu, G.-C. Su, T.-S. Wu, J. Nat. Prod. 2003, 66,
996–998; f) Y.-N. Zhang, X.-G. Zhong, Z.-P. Zheng, X.-D. Hu, J.-P.
Zuo, L.-H. Hu, Bioorg. Med. Chem. 2007, 15, 988–996; g) Y. L.
Choi, J. K. Kim, S.-U. Choi, Y.-K. Min, M.-A. Bae, B. T. Kim, J.-N.
Heo, Bioorg. Med. Chem. Lett. 2009, 19, 3036–3040.
[13] A portion of this study has already been reported in a preliminary
communication, see: H. Ohno, M. Iuchi, N. Fujii, T. Tanaka, Org.
Lett. 2007, 9, 4813–4815.
[14] M. Mori, K. Chiba, M. Okita, I. Kayo, Y. Ban, Tetrahedron 1985, 41,
375–385.
À
[15] We have not tested the domino reaction involving C N bond forma-
À
tion and double C H functionalization using bromoaniline deriva-
tives 4 and dibromide 5. For a related reaction, see: L. Ackermann,
A. Althammer, P. Mayer, Synthesis 2009, 3493–3503.
[16] We cannot completely rule out the alternative mechanism for the
second cyclization: electrocyclization of the bromohexatriene to cy-
clohexadienes followed by elimination of bromide to form an arene
(reviewerꢄs suggestion). However, the results shown in Table 1 sup-
À
[7] For reactions involving several reactive C H bonds of single elec-
tron-rich arenes, see: a) J. Zhao, R. C. Larock, Org. Lett. 2005, 7,
701–704; b) B. Join, T. Yamamoto, K. Itami, Angew. Chem. 2009,
121, 3698–3701; Angew. Chem. Int. Ed. 2009, 48, 3644–3647; c) F.
Shibahara, E. Yamaguchi, T. Murai, Chem. Commun. 2010, 46,
2471–2473; d) R. Liu, J. Zhang, Adv. Synth. Catal. 2011, 353, 36–40;
e) L. Jiao, T. Bach, J. Am. Chem. Soc. 2011, 133, 12990–12993.
À
port the oxidative addition/C H arylation pathway: the second cyc-
lization of the intermediate 17 requires an appropriate palladium
À
catalyst. For palladium-catalyzed C H arylation of cis-halostilbenes
and related compounds under similar reaction conditions, see:
a) A. K. Yadav, H. Ila, H. Junjappa, Eur. J. Org. Chem. 2010, 338–
344; b) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am.
Chem. Soc. 2006, 128, 581–590. See also Kamikawa et al.[8a]
À
[8] For reactions of dihalides in which C H functionalization in sequen-
tial order is not necessary, see: a) K. Kamikawa, I. Takemoto, S.
Takemoto, H. Matsuzaka, J. Org. Chem. 2007, 72, 7406–7408;
b) K. C. Majumdar, S. Chakravorty, Tetrahedron Lett. 2008, 49,
3419–3422.
[17] The reaction with other palladium catalysts was not tested.
[18] The intermediacy of 17g in the cascade reaction was also confirmed
by treatment with the palladium catalyst under the standard condi-
tions to produce 16e in 64%. The relatively low yield of this step
[9] a) S. Inuki, S. Oishi, N. Fujii, H. Ohno, Org. Lett. 2008, 10, 5239–
5242; b) Y. Suzuki, J. Cluzeau, T. Hara, A. Hirasawa, G. Tsujimoto,
S. Oishi, H. Ohno, N. Fujii, Arch. Pharm. 2008, 349, 554–561; c) S.
Inuki, Y. Yoshimitsu, S. Oishi, N. Fujii, H. Ohno, Org. Lett. 2009, 11,
4478–4481; d) S. Inuki, Y. Yoshimitsu, S. Oishi, N. Fujii, H. Ohno, J.
Org. Chem. 2010, 75, 3831–3842; e) K. Hirano, Y. Inaba, N. Takaha-
shi, M. Shimano, S. Oishi, N. Fujii, H. Ohno, J. Org. Chem. 2011, 76,
1212–1227; f) S. Inuki, A. Iwata, S. Oishi, N. Fujii, H. Ohno, J. Org.
Chem. 2011, 76, 2072–2084; g) A. Iwata, S. Inuki, S. Oishi, N. Fujii,
H. Ohno, J. Org. Chem. 2011, 76, 5506–5512.
[10] a) M. L. Lꢃpez-Rodrꢁguez, E. Porras, B. Benhamffl, J. A. Ramos,
M. J. Morcillo, J. L. Lavandera, Bioorg. Med. Chem. Lett. 2000, 10,
1097–1100; b) M. L. Lꢂpez-Rodrꢁguez, E. Porras, M. J. Morcillo, B.
Benhamffl, L. J. Soto, J. L. Lavandera, J. A. Ramos, M. Olivella, M.
Campillo, L. Pardo, J. Med. Chem. 2003, 46, 5638–5650; c) J.-J. Liu,
A. Dermatakis, C. Lukacs, F. Konzelmann, Y. Chen, U. Kammlott,
W. Depinto, H. Yang, X. Yin, Y. Chen, A. Schutt, M. E. Simcox, K.-
C. Luk, Bioorg. Med. Chem. Lett. 2003, 13, 2465–2468; d) H. Yin,
Y. Xu, X. Qian, Bioorg. Med. Chem. 2007, 15, 1356–1362.
would be the major reason for the moderate yield in the reaction of
7e (48% yield, Scheme 9).
[19] K. Konishi, A. Nishiura, J. Synth. Org. Chem. Jpn. 1952, 10, 542–
544.
[20] a) W. R. Bowman, C. F. Bridge, P. Brookes, M. O. Cloonan, D. C.
Leach, J. Chem. Soc. Perkin Trans. 1 2002, 1, 58–68; b) A. S. K.
Hashmi, T. Häffner, M. Rudolph, F. Rominger, Eur. J. Org. Chem.
2011, 667–671.
Received: December 5, 2011
Published online: March 15, 2012
5360
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 5352 – 5360