A simple general approach to phenanthridinones via palladium-catalyzed intramolecular direct arene arylation

Article abstract of DOI:10.1055/s-2008-1032169

Phenanthridinone derivatives have been prepared in good to high yields via palladium-catalyzed cyclization of readily available N-benzyl-N-benzoyl-o- iodoanilides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032169

PAPER
729
A Simple General Approach to Phenanthridinones via Palladium-Catalyzed
Intramolecular Direct Arene Arylation
P
henanthridinone
o
s
via Direct
b
Pd-Catalyze
d
e
A
rene
A
ry
r
lation ta Bernini,a Sandro Cacchi,*b Giancarlo Fabrizi,b Alessio Sferrazzaa
a
Dipartimento A.B.A.C., Università della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’, Via S. Camillo De Lellis,
01100 Viterbo, Italy
b
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ‘La Sapienza’,
P.le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 21 November 2007
O
O
Abstract: Phenanthridinone derivatives have been prepared in
good to high yields via palladium-catalyzed cyclization of readily
available N-benzyl-N-benzoyl-o-iodoanilides.
R3
R3
N
N
Pd cat.
R1
R1
I
R2
Key words: phenanthridinones, o-iodoanilides, cyclization, palla-
dium, arene arylation
R2
1 R3 = H
3 R3 = Bn
2 R3 = H
4 R3 = Bn
Direct arylation of arenes through C–H bond cleavage
with arylmetals, usually formed in situ, has recently at-
tracted considerable attention as a mean to achieve clean
and economically convenient preparations of polyaryl
units.1 Palladium, rhodium, and ruthenium catalysis have
been used in this chemistry,1a which has undergone signif-
icant advances of late. Palladium-catalyzed C–H activa-
tion processes have provided some of the most general
arylation methods.2–4
Scheme 1
O
O
N
NH
Ph
5a
6a
Figure 1 By-products obtained in the Pd-catalyzed cyclization of
1a to 2a
In this context, and as part of a program devoted to the
conversion of carboxylic acids present in agricultural by-
products5 into more complex fine chemicals by transition-
metal-catalyzed transformations, we decided to explore a
general palladium-catalyzed synthesis of phenanthridino-
nes, a class of compounds which exhibit interesting bio-
logical activities,6 from o-iodoanilides 1 through a direct
intramolecular arylation at one of the positions ortho to
the electron-withdrawing C=O group (Scheme 1).
tion of the benzoyl fragment on the regiochemistry of the
arene arylation.11 Because of our own current interest in
this type of cyclization process, we have explored the
scope and limitations of this chemistry and wish now to
report the results of this study.
Compounds 1 can be readily prepared from o-iodoanilines
and activated carboxylic acids in excellent yields. The cy-
clization of 1a (R1 = R2 = H) was studied as a model sys-
tem for optimizing the formation of phenanthridinones.
Some of the results of our screening studies are summa-
rized in Table 1.
Using 1 mol% Pd2(dba)3 as the Pd(0) source, CsOAc2e or
Bu4OAc as bases, and monodentate and bidentate phos-
phine ligands such as PPh3, dppm, dppp, and Xanthphos
afforded phenanthridinone 2a in low yields (Table 1, en-
tries 1–6). One common by-product that we identified,
along with variable amounts of the reduction product
5a,12,13 was the benzoxazole 6a (Figure 1), very likely de-
rived from the intramolecular palladium-catalyzed C–O
bond-forming reaction involving the amide oxygen and
the ortho-iodo fragment.14
Known palladium-catalyzed approaches to the construc-
tion of the phenanthridinone frame are based on the in-
tramolecular cyclization of N-(o-halobenzoyl)- or N-(o-
triflyloxybenzoyl)anilides,7 a domino process (including
aryl–aryl coupling between two o-bromobenzamide units
and C–N bond formations concomitant with a deamida-
tion reaction),8 a one-pot consecutive aryl–aryl and N-aryl
coupling from iodoarenes bearing ortho electron-releas-
ing substituents and o-bromobenzamides,9 and an Ull-
mann cross-coupling/reductive cyclization sequence from
1-bromo-2-nitrobenzene and its derivatives with a range
of a-haloenals, -enones or -esters.10 The palladium-cata-
lyzed cyclization of N-(o-iodophenyl)benzanilides was
also reported. However, the study was limited to investi-
gating the effect of oxygen substituents in the meta posi-
Using dppe as ligand and CsOAc or K2CO3 as base gave
2a in 50% and 52% yield, but 6a was still isolated in 22%
and 11% yield, respectively (Table 1, entries 7 and 10).
Similar results were achieved with the Pd(OAc)2/pivalic
acid combination in the presence of K2CO3 and Davephos
SYNTHESIS 2008, No. 5, pp 0729–0738
x
x
.
x
x
.2
0
0
8
Advanced online publication: 08.02.2008
DOI: 10.1055/s-2008-1032169; Art ID: Z27107SS
© Georg Thieme Verlag Stuttgart · New York

730
R. Bernini et al.
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Table 1 Reaction Conditions for the Cyclization of 1a to 2aa
Entry
[Pd]
Phosphine
ligandb
Base
Additive
Solvent
Temp
(°C)
Time Yield of 2a Yield of 6a
(h)
48
48
24
48
48
48
24
48
48
48
16
12
12
24
48
8
(%)c
15
10
38
19
30
11
50
41
–
(%)c
1
2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
CsOAc
CsOAc
Bu4OAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
t-BuONa
K2CO3
–
DMF
DMF
DMF
DMF
NMP
DMF
DMF
NMP
toluene
DMF
NMP
NMP
DMA
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
100
100
120
120
120
100
100
100
100
120
5
dppm
dppm
dppp
–
–
3
–
15
4
4
–
5
dppp
–
12
–
6
Xphos
dppe
–
7
–
22
19
–
8
dppe
–
9
dppe
–
10
11
12
13
14
15
16
17
18
dppe
–
52
51
46
48
50
44
–
11
11
16
17
–
d
Davephos
Davephos
Davephos
dppe
Na2CO3
t-BuCO2H
d
K2CO3
t-BuCO2H
d
K2CO3
t-BuCO2H
Li2CO3
K2CO3
Cs2CO3
K2CO3
–
dppe
–
25
61
–
dppe
–
dppe
LiCl
LiCl
12
7
55
65
d
dppe
K2CO3
–
a Unless otherwise stated, reactions were carried out under argon on a 0.25 mmol scale in 4 mL of solvent using 0.01 equiv Pd2(dba)3 or 0.05
equiv of Pd(OAc)2, 0.02 equiv of bidentate phosphine ligand with Pd2(dba)3 and 0.05 equiv of bidentate phosphine ligand with Pd(OAc)2,
2 equiv of base, 0.3 equiv of pivalic acid (when used), and 2 equiv of LiCl (when used).
b PPh3 (0.04 equiv) was used.
c Yields are given for the isolated products.
d Base (2.5 equiv) was used.
(Table 1, entries 11–13), reported to have a beneficial ef- R1 = m-F; R2 = H; 1d, R1 = m-MeO; R2 = H), the reaction
fect on the direct arylation of simple arenes.4 Switching to mixtures were found to contain mostly very polar com-
Pd(OAc)2 and dppe in the presence of Li2CO3 led to a sig- pounds that we did not investigate further and the corre-
nificant increase of the phenanthridinone/benzoxazole se- sponding phenanthridinones 2b–d were isolated in low to
lectivity, but the same yield of 2a was obtained (Table 1, moderate yields (Figure 2).
entry 14). The utilization of K2CO3 as the base under the
same reaction conditions led to the isolation of 2a in 44%
yield combined with a poorer phenanthridinone/benzox-
O
O
F
azole ratio (Table 1, entry 15). Somewhat surprisingly,
NH
NH
use of Cs2CO3 completely reversed the phenanthridinone/
benzoxazole selectivity, 6a being isolated in 61% yield.
No phenanthridinone product was formed (Table 1, entry
16).
MeO
MeO
2b (41%)
2c (20%)
O
O
A slight increase of the yield of 2a was observed upon ad-
dition of LiCl (Table 1, entry 17). Finally, 2a was isolated
in a satisfactory 65% yield subjecting 1a to Pd(OAc)2,
dppe, K2CO3, and LiCl at 120 °C in DMF for seven hours
(Table 1, entry 18).
NH
NH
OMe
2d'
2d (40%)
However, when we applied these optimized conditions to
other o-iodoanilides (1b, R1 = p-MeO, R2 = H; 1c,
Figure 2 Phenanthridinones 2b–d,d¢
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Phenanthridinones via Direct Pd-Catalyzed Arene Arylation
731
O
O
N
O
L
Me
MeO
N
N
A
B
Pd
Pd
L
O
9
I
Me
O
7
8
N
Pd(0)
Figure 3 Palladium coordination to oxygen and nitrogen
A
B
I
Of note is that with 1d, bearing a methoxy substituent
meta to the carbonyl group, the new C–C bond was
formed regioselectively at the less crowded ortho position
of the benzoyl moiety to give 2d. No evidence of the re-
gioisomeric derivative 2d¢ was attained. This high level of
regioselectivity is interesting in view of the known ten-
dency of meta oxygen substituents to direct the formation
of the C–C bond to the more crowded ortho position in
this type of reaction.11 Such a behavior was suggested to
be due to the oxygen coordination to the palladium atom
of the arylpalladium complex formed in situ via oxidative
addition. The resultant intermediate 7 (Figure 2) would
exert a strong directing effect on the cyclization step.
3
O
N
A
B
4
Scheme 2
O
Pd(OAc)2, dppe
K2CO3
OMe
N
DMF, 100 °C
0.5 h
I
10
A possible explanation to account for the result obtained
with 1d is that in the presence of the NH free amide the
coordination of nitrogen to palladium to afford 8
(Figure 3) is likely to prevail over oxygen coordination.
As a result of the absence of the oxygen directing effect,
the usual trend favoring the cyclization at the less crowd-
ed ortho position is observed and 2d is formed regioselec-
tively.
O
O
OMe
+
OMe
N
N
11 (75%)
12 (14%)
Scheme 3
Though the results obtained with N-benzoyl-o-iodoanil-
ides 1 might provide some useful applications, we thought
that further optimization was needed to develop a gener-
ally applicable synthetically effective reaction protocol.
As we felt that the free NH group could be at the origin of
the unsatisfactory yields obtained with some of the o-io-
doanilides that we had investigated, we turned our atten-
tion to the utilization of N-benzyl derivatives 3 as the
starting material.
arylation might also occur via a Heck-like mechanism in-
volving the carbopalladation of the aromatic ring fol-
lowed by the anti elimination of HPdX (or isomerization
and syn elimination of HPdX).18 However, recent work in-
dicates that this process is rather unlikely.19
After some experimentation, we found that the desired 4a
was smoothly formed and isolated in 85% yield by sub-
jecting 3a (R1 = R2 = H) to Pd(OAc)2, dppe, and K2CO3 in
DMF at 100 °C for 20 minutes. No isomeric phenanthri-
dine 9 was observed.
The benzyl protecting group appeared particularly suited
for the purpose: it can be introduced in excellent yield via
reaction of benzyl bromide with 1 (DMSO, NaH, room
temperature) and can be readily and almost quantitatively
removed in the presence of trifluoroacetic acid to give NH
free phenanthridinones.7
Attempting to gain more insight into the factors influenc-
ing the benzoyl-to-benzyl arylation ratio in this cycliza-
tion process, we decided to explore the reaction of the
N-(m-methoxyphenyl)methyl derivative 10, containing an
electron-donating substituent. Notably, treatment of this
substrate under the above conditions afforded an approxi-
mately 84:16 phenanthridinone/phenanthridine mixture
(Scheme 3).
Nevertheless, utilization of N-benzyl derivatives 3 poses a
selectivity problem between the aromatic rings A and B
(Scheme 2). An electrophilic aromatic substitution – a
mechanism initially proposed by Miura et al.15 which,
since then, has been usually favored in palladium-cata-
lyzed arylations2c,e,3e,16 – is expected to afford the phenan-
thridine derivative 9 because of the higher nucleophilicity
of the ring B. A proton abstraction mechanism, as pro-
posed by Echavarren, Maseras et al.2k,17 for the intramo-
lecular arylation of electron-poor arenes and more
recently shown by Fagnou et al.3k to be operating in inter-
molecular palladium-catalyzed arylation of pefluoroben-
zenes, should give the phenanthridinone product 4. Arene
Though only a speculative discussion is possible at this
stage, the implication that can be drawn from the outcome
of these reactions is that the substitution pattern of the
benzyl protecting group may influence the benzoyl/ben-
zyl selectivities through an electronic bias.
With benzyl derivatives 3 the direct intramolecular arene
arylation process involves selectively one of the ortho po-
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732
R. Bernini et al.
PAPER
sitions of the electron-poor aryl fragment. This appears to Table 2. Phenanthridinones 4, incorporating a wide range
be consistent with a cyclization controlled by the acidity of substituents both in the benzoyl and the aniline moiety,
of the C–H bond rather than by the nucleophilicity of the were usually isolated in good to high yields. Some steric
arene and proceeding through a proton abstraction mech- hindrance is tolerated (Table 2, entry 10). The presence of
anism. When the N-(m-methoxyphenyl)methyl derivative electron-donating groups on the benzoyl fragment, which
10 is used as substrate, a competing cyclization at the less might be expected to weaken the electron-withdrawing ef-
crowded ortho position of the electron-rich aromatic ring fect of the carbonyl group and consequently influence the
can take place to give the phenanthridine derivative 12, benzoyl/benzyl selectivity, does not change the general
the formation of which being compatible with an electro- trend favoring the cyclization to phenanthridinones over
philic aromatic substitution mechanism. The structure of the formation of phenanthridines, at least with the sub-
12 was assigned by NOESY experiments.
strates that we have investigated. For example, the cy-
clization of 3l which gave 4l in 57% isolated yield along
with a mixture of tarry polar material (Table 2, entry 12),
did not provide any evidence of a phenanthridine (or de-
halogenated) product.
Having established the reaction conditions and the basic
substrate requirements for the preparation of phenanthrid-
inones, we next extended the procedure to a variety of
anilides 3. Our preparative results are summarized in
Table 2 Palladium-Catalyzed Synthesis of Phenanthridinones 4 from Anilides 3a
Entry
Anilide 3
Time (min)
Phenanthridinone 4
Yield (%)b
O
O
Bn
Bn
N
N
1
3a
3b
3c
3d
3e
3f
10
4a
4b
4c
4d
4e
4f
85
I
O
O
Bn
Bn
N
N
2
3
4
5
6
7
20
20
10
25
20
20
69
82
71
72
72
83
I
Cl
Cl
O
O
Bn
Bn
N
O
N
I
F
F
O
Bn
Bn
N
N
I
MeO
MeO
Me2N
Ph
O
O
Bn
Bn
N
N
I
Me2N
O
O
Bn
Bn
N
N
I
Ph
F
O
O
Bn
Bn
N
N
3g
4g
I
F
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Phenanthridinones via Direct Pd-Catalyzed Arene Arylation
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Table 2 Palladium-Catalyzed Synthesis of Phenanthridinones 4 from Anilides 3a (continued)
Entry
8
Anilide 3
Time (min)
300
Phenanthridinone 4
Yield (%)b
Cl
O
Cl
O
Bn
Bn
O
N
N
3h
3i
4h
4i
61
I
O
MeO
MeO
Bn
Bn
MeO
MeO
Bn
Bn
N
N
N
9
30
30
87
88
I
OMe
OMe
O
O
N
I
10
3j
Me
4j
Me
OMe
OMe
O
Me
I
Me
Bn
O
Bn
N
N
O
11
12
13
14
15
3k
30
30
30
20
30
4k
73
57
77
75
82
Me
Bn
F
F
Me
Me
Me
O
Bn
N
N
I
3l
4l
Me
MeO
Ph
Cl
MeO
Ph
Cl
Me
Me
Me
O
O
Bn
Bn
N
N
3m
3n
3o
4m
4n
4o
I
Me
N
Me
N
O
O
Bn
Bn
I
Me
Me
O
O
Bn
Bn
N
N
I
F
F
COMe
COMe
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R. Bernini et al.
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Table 2 Palladium-Catalyzed Synthesis of Phenanthridinones 4 from Anilides 3a (continued)
Entry
16
Anilide 3
Time (min)
Phenanthridinone 4
Yield (%)b
O
O
Bn
Bn
N
N
3p
3q
3r
20
4p
4q
4r
66
72
76
I
MeO
MeO
Cl
Cl
O
O
Bn
N
Bn
N
17
18
20
20
I
F
F
Cl
Cl
O
O
Bn
N
Bn
N
I
Cl
Cl
a Reactions were carried out on a 0.25 mmol scale under an argon atmosphere at 100 °C in 3 mL of DMF using 0.05 equiv of Pd(OAc)2, 0.05
equiv of dppe and 2 equiv of K2CO3.
b Yields are given for isolated products.
columns, packed with 25–40 mm silica gel (Macherey Nagel), con-
O
O
nected to a Gilson solvent delivery system and to a Gilson refractive
Bn
1
N
NH
CF3COOH
index detector, and eluting with n-hexane–EtOAc mixtures. H
NMR spectra (400 MHz) and 13C NMR spectra (100.6 MHz) were
recorded with a Bruker Avance 400 spectrometer. IR spectra were
recorded with a Jasco FT/IR-430 spectrometer. Mass spectra were
recorded with a Shimadzu GC-MS QP-2010S spectrometer.
100 °C, 24 h
2a (95%)
4a
Scheme 4
N-Benzylphenanthridinone (4a) from N-Benzyl-N-Benzoyl-o-
iodoanilide (3a); Typical Procedure
NH free phenanthridinones 2 can be readily obtained from
the N-benzyl derivatives 4 by treatment with trifluoroace-
tic acid.7 As an example, 2a was isolated in 95% yield
upon treatment of 4a with trifluoroacetic acid at 100 °C
for 24 hours (Scheme 4).
To a solution of 3a (103 mg, 0.25 mmol) in DMF (3 mL) were add-
ed Pd(OAc)2 (2.8 mg, 0.0125 mmol), dppe (5.1 mg, 0.0125 mmol),
and K2CO3 (69 mg, 0.5 mmol) under argon. The mixture was stirred
at 100 °C for 30 min. After this time, the mixture was cooled, dilut-
ed with Et2O (100 mL), and washed with aq 2 N HCl (2 × 10 mL)
and brine (10 mL). The organic layer was dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified by chro-
matography (silica gel, 90:10 n-hexane–EtOAc); yield: 61 mg
(85%); white solid; mp 112–113 °C.
In conclusion, we have demonstrated that readily avail-
able N-benzyl derivatives of N-benzoyl-o-iodoanilides
can be converted into the corresponding phenanthridino-
nes usually in good to high yields, providing a simple ap-
proach to this class of compounds. The scope of this
transformation seems to be rather broad. The benzyl pro-
tecting group can be almost quantitatively removed by
treatment with trifluoroacetic acid and does not interfere
with the desired cyclization to phenanthridinones. Over-
all, this procedure complements other palladium-based
strategies for phenanthridinone formation which require
N-(o-halobenzoyl)- or N-(o-triflyloxybenzoyl)anilides as
substrates.
IR (KBr): 1650, 1489, 752, 723 cm–1.
1H NMR (CDCl3): d = 8.66 (d, J = 7.4 Hz, 1 H), 8.31 (t, J = 7.9 Hz,
2 H), 7.79 (t, J = 8.2 Hz, 1 H), 7.65 (t, J = 8.4 Hz, 1 H), 7.39 (m, 1
H), 7.34–7.25 (m, 7 H), 5.69 (br s, 2 H).
13C NMR (CDCl3): d = 162.0, 137.4, 136.7, 133.9, 132.8, 129.6,
129.2, 128.9, 128.1, 127.3, 126.6, 125.5, 123.4, 122.6, 121.7, 119.6,
116.1, 46.5.
MS (EI, 70 eV): m/z (%) = 91 (100), 285 (M+, 90), 179 (37), 284
(32).
Anal. Calcd for C20H15NO: C, 84.19; H, 5.30; N, 4.91. Found: C,
83.80; H, 5.69; N, 4.66.
Melting points were determined with a Büchi B-545 apparatus and
are uncorrected. All of the reagents, catalysts and solvents are com-
mercially available and were used as purchased, without further pu-
rification. Reaction products were purified on axially compressed
4b
White solid; mp 184–185 °C.
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Phenanthridinones via Direct Pd-Catalyzed Arene Arylation
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IR (KBr): 1639, 1601, 1439, 1324, 746, 708 cm–1.
13C NMR (CDCl3): d = 161.9, 145.6, 140.5, 137.7, 134.2, 129.9,
129.7, 129.1, 128.9, 128.4, 127.6, 127.3, 127.26, 126.6, 124.4,
123.4, 122.6, 120.3, 119.6, 116.2, 46.5.
1H NMR (CDCl3): d = 8.57 (d, J = 8.5 Hz, 1 H), 8.27 (s, 1 H), 8.21
(d, J = 8.0 Hz, 1 H), 7.58 (d, J = 8.9 Hz, 1 H), 7.43 (m, 1 H), 7.34–
7.26 (m, 7 H), 5.66 (br s, 2 H).
MS (EI, 70 eV): m/z (%) = 91 (100), 361 (M+, 60), 360 (37), 255
(36).
13C NMR (CDCl3): d = 161.3, 139.6, 137.8, 136.4, 123.4, 131.1,
130.3, 128.9, 128.5, 127.4, 126.6, 123.9, 123.5, 122.8, 121.7, 118.5,
116.2, 46.6.
Anal. Calcd for C26H19NO: C, 86.40; H, 5.30; N, 3.88. Found: C,
86.11; H, 5.12; N, 3.89.
MS (EI, 70 eV): m/z (%) = 91 (100), 319 (M+, 30), 213 (18), 65 (17).
4g
Anal. Calcd for C20H14ClNO: C, 75.12; H, 4.41; N, 4.38. Found: C,
74.88; H, 4.66; N, 4.89.
White solid; mp 125–126 °C.
IR (KBr): 1655, 1301, 1232, 752 cm–1.
4c
1H NMR (CDCl3): d = 8.75 (dd, J = 2.7, 8.0 Hz, 1 H), 8.52 (d,
J = 8.8 Hz, 1 H), 7.56 (m, 2 H), 7.42 (m, 2 H), 7.36–7.24 (m, 7 H),
5.69 (br s, 2 H).
13C NMR (CDCl3): d = 160.9 (d, J = 3.0 Hz), 160.0 (d, J = 253.9
Hz), 137.2, 136.4, 129.7 (d, J = 2.2 Hz), 128.9, 128.3 (d, J = 2.8
Hz), 128.2 (d, J = 17.9 Hz), 127.8 (d, J = 3.3 Hz), 127.3, 126.5,
125.3 (d, J = 3.4 Hz), 123.0, 122.7 (d, J = 8.7 Hz), 120.2 (d,
J = 24.4 Hz), 117.3 (d, J = 5.5 Hz), 115.8, 46.9.
White solid; mp 157–158 °C.
IR (KBr): 1644, 1608, 1443, 1185, 745 cm–1.
1H NMR (CDCl3): d = 8.65 (m, 1 H), 8.15 (d, J = 7.6 Hz, 1 H), 7.91
(d, J = 8.8 Hz, 1 H), 7.42 (m, 1 H), 7.35–7.26 (m, 8 H), 5.66 (br s,
2 H).
13C NMR (CDCl3): d = 165.8 (d, J = 252.5 Hz), 161.2, 137.9, 136.6,
136.5, 132.5 (d, J = 9.8 Hz), 130.4, 128.9, 127.3, 126.6, 123.6,
122.7, 122.1, 118.8, 116.5, 116.2, 107.7 (d, J = 23.3 Hz), 46.5.
19F NMR (CDCl3): d = –105.9.
MS (EI, 70 eV): m/z (%) = 91 (100), 303 (M+, 39), 197 (26), 65 (81).
19F NMR (CDCl3): d = –110.8.
MS (EI, 70 eV): m/z (%) = 91 (100), 303 (M+, 43), 197 (24), 65 (16).
Anal. Calcd for C20H14FNO: C, 79.19; H, 4.65; N, 4.62. Found: C,
78.89; H, 4.55; N, 4.51.
Anal. Calcd for C20H14FNO: C, 79.19; H, 4.65; N, 4.62. Found: C,
78.80; H, 3.99; N, 4.69.
4h
White solid; mp 170–171 °C.
IR (KBr): 1643, 1597, 1306, 745, 734 cm–1.
1H NMR (CDCl3): d = 8.26 (t, J = 7.9 Hz, 2 H), 7.66 (m, 2 H), 7.42
(m, 1 H), 7.32–7.25 (m, 7 H).
13C NMR (CDCl3): d = 160.9, 138.8, 137.6, 136.2, 136.1, 132.7,
130.9, 130.1, 128.9, 127.7, 125.4, 123.9, 123.7, 121.6, 121.4, 118.8,
117.7, 48.2.
MS (EI, 70 eV): m/z (%) = 91 (100), 319 (M+, 43), 213 (35), 318
(15), 321 (15).
4d
White solid; mp 159–160 °C.
IR (KBr): 1639, 1608, 1452, 1439, 750 cm–1.
1H NMR (CDCl3): d = 8.58 (d, J = 8.8 Hz, 1 H), 8.21 (d, J = 7.9 Hz,
1 H), 7.67 (s, 1 H), 7.40–7.18 (m, 9 H), 5.66 (br s, 2 H), 4.01 (s, 3 H).
13C NMR (CDCl3): d = 163.1, 161.6, 137.8, 136.7, 135.7, 131.3,
129.6, 128.7, 127.1, 126.5, 123.3, 122.3, 119.3, 119.1, 116.0, 115.9,
104.5, 55.5, 46.3.
MS (EI, 70 eV): m/z (%) = 91 (100), 315 (M+, 65), 314 (44), 209
(36).
Anal. Calcd for C20H14ClNO: C, 75.12; H, 4.41; N, 4.38. Found: C,
75.01; H, 4.48; N, 4.23.
Anal. Calcd for C21H17NO2: C, 79.98; H, 5.43; N, 4.44. Found: C,
79.80; H, 5.31; N, 4.69.
4i
White solid; mp 162–163 °C.
IR (KBr): 1639, 1606, 1589, 1380, 1345, 1063, 747 cm–1.
4e
Pale yellow solid; mp 231–232 °C.
IR (KBr): 1632, 1609, 1354, 1314, 748 cm–1.
1H NMR (CDCl3): d = 9.21 (d, J = 8.4 Hz, 1 H), 7.82 (s, 1 H), 7.33–
7.23 (m, 7 H), 6.91 (s, 1 H), 5.70 (br s, 2 H), 4.05 (s, 3 H), 3.99 (s,
3 H).
13C NMR (CDCl3): d = 161.5, 159.5, 158.9, 136.6, 135.8, 128.7,
128.4, 127.9, 127.6, 127.1, 126.5, 122.3, 119.6, 117.9, 115.2, 104.7,
101.9, 55.9, 55.6, 47.0.
1H NMR (CDCl3): d = 8.47 (d, J = 8.9 Hz, 1 H), 8.25 (d, J = 7.8 Hz,
1 H), 7.37–7.22 (m, 9 H), 7.03 (d, J = 8.9 Hz, 1 H), 5.66 (br s, 2 H),
3.20 (s, 6 H).
13C NMR (CDCl3): d = 162.1, 153.1, 138.0, 137.3, 135.2, 130.7,
129.2, 128.8, 127.0, 126.6, 123.1, 122.0, 119.9, 116.0, 114.9, 113.5,
102.6, 46.1, 40.4.
MS (EI, 70 eV): m/z (%) = 91 (100), 345 (M+, 78), 226 (22), 344
(21), 239 (20).
MS (EI, 70 eV): m/z (%) = 328 (M+, 100), 327 (73), 91 (60), 222
(32).
Anal. Calcd for C22H19NO3: C, 76.50; H, 5.54; N, 4.06. Found: C,
76.11; H, 5.33; N, 3.99.
Anal. Calcd for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C,
84.11; H, 5.99; N, 8.41.
4j
Pale yellow solid; mp 114–115 °C.
IR (KBr): 1644, 1607, 1376, 1151, 729 cm–1.
4f
White solid; mp 170–171 °C.
1H NMR (CDCl3): d = 8.90 (s, 1 H), 7.69 (s, 1 H), 7.26 (t, J = 6.9
Hz, 2 H), 7.18 (m, 1 H), 7.11 (d, J = 7.2 Hz, 2 H), 7.03 (s, 1 H), 6.89
(s, 1 H), 5.61 (br s, 2 H), 4.06 (s, 3 H), 3.95 (s, 3 H), 2.50 (s, 3 H),
2.42 (s, 3 H).
IR (KBr): 1638, 1612, 1440, 751, 700 cm–1.
1H NMR (CDCl3): d = 8.71 (d, J = 8.3 Hz, 1 H), 8.51 (s, 1 H), 8.40
(d, J = 7.5 Hz, 1 H), 7.87 (d, J = 7.9 Hz, 1 H), 7.78 (m, 2 H), 7.58–
7.26 (m, 11 H), 5.72 (br s, 2 H).
Synthesis 2008, No. 5, 729–738 © Thieme Stuttgart · New York

736
R. Bernini et al.
PAPER
13C NMR (CDCl3): d = 164.02, 159.38, 158.62, 138.7, 135.4, 133.4,
131.9, 129.0, 128.5, 126.6, 126.1, 125.7, 125.1, 122.0, 118.3, 104.9,
101.9, 56.1, 55.7, 52.6, 23.9, 21.2.
13C NMR (CDCl3): d = 161.2, 139.4, 136.5, 135.7, 135,2, 132.3,
131.4, 131.1, 128.9, 128.3, 127.3, 126.5, 123.9, 123.6, 121.6, 118.3,
116.1, 46.4, 20.9.
MS (EI, 70 eV): m/z (%) = 282 (100), 91 (71), 267 (22), 344 (M –
MS (EI, 70 eV): m/z (%) = 91 (100), 333 (M+, 31), 227 (19), 332
29, 4).
(13).
Anal. Calcd for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C,
77.11; H, 6.33; N, 3.78.
Anal. Calcd for C21H16ClNO: C, 75.56; H, 4.83; N, 4.20. Found: C,
75.69; H, 4.75; N, 4.21.
4k
4o
White solid; mp 170–171 °C.
White solid; mp 179–180 °C.
IR (KBr): 1649, 1614, 1323, 858, 733 cm–1.
IR (KBr): 1679, 1660, 1608, 1247 cm–1.
1H NMR (CDCl3): d = 8.54 (dd, J = 6.2, 8.8 Hz, 1 H), 7.89 (dd,
J = 2.3, 10.7 Hz, 1 H), 7.85 (s, 1 H), 7.31–7.21 (m, 4 H), 7.13–7.11
(m, 3 H), 5.66 (br s, 2 H), 2.52 (s, 3 H), 2.43 (s, 3 H).
1H NMR (CDCl3): d = 8.81 (s, 1 H), 8.76 (dd, J = 1.2, 7.6 Hz, 1 H),
7.99 (dd, J = 3.2, 8.8 Hz, 2 H), 7.39–7.25 (m, 7 H), 5.69 (br s, 2 H),
2.68 (s, 3 H).
13C NMR (CDCl3): d = 163.6 (d, J = 254.1 Hz), 163.5, 136.9, 136.4,
136.1, 133.5 (d, J = 8.9 Hz), 131.6, 129.9 (d, J = 10.1 Hz), 128.3,
126.9, 124.7, 123.1, 122.0, 117.8, 116.1, 113.0 (d, J = 23.3 Hz),
108.1 (d, J = 22.8 Hz), 48.5, 20.1, 24.8.
13C NMR (CDCl3): d = 196.4, 167.3 (d, J = 254.3 Hz), 161.3, 141.2,
136.2 (d, J = 9.7 Hz), 135.9, 132,7 (d, J = 10.1 Hz), 131.5, 130.2,
129.0, 127.6, 126.5, 124.2, 122.1, 118.7, 117.0 (d, J = 22.8 Hz),
116.2, 108.1 (d, J = 23.6 Hz), 46.7, 26.5.
19F NMR (CDCl3): d = –105.8.
MS (EI, 70 eV): m/z (%) = 91 (100), 240 (53), 331 (M+, 33), 225
19F NMR (CDCl3): d = –104.2.
MS (EI, 70 eV): m/z (%) = 91 (100), 345 (M+, 29), 239 (16).
(24).
Anal. Calcd for C22H16FNO2: C, 76.51; H, 4.67; N, 4.06. Found: C,
76.39; H, 4.55; N, 4.12.
Anal. Calcd for C22H18FNO: C, 79.74; H, 5.47; N, 4.23. Found: C,
79.89; H, 5.55; N, 4.11.
4p
4l
Pale yellow solid; mp 195–196 °C.
White solid; mp 180–181 °C.
IR (KBr): 1636, 1609, 1453, 1237 cm–1.
IR (KBr): 1648, 1610, 1239, 1021 cm–1.
1H NMR (CDCl3): d = 8.55 (d, J = 8.8 Hz, 1 H), 8.14 (s, 1 H), 7.57
(s, 1 H), 7.57–7.20 (m, 8 H), 5.63 (br s, 2 H), 4.03 (s, 3 H).
13C NMR (CDCl3): d = 163.3, 161.3, 136.3, 136.28, 134.5, 131.4,
129.4, 128.8, 127.9, 127.3, 126.4, 122.9, 120.7, 119.2, 117.4, 116.7,
104.5, 55.6, 46.3.
1H NMR (CDCl3): d = 8.46 (d, J = 8.8 Hz, 1 H), 7.90 (s, 1 H), 7.66
(s, 1 H), 7.28 (t, J = 5.8 Hz, 2 H), 7.21–7.09 (m, 5 H), 5.65 (br s, 2
H), 4.02 (s, 3 H), 2.51 (s, 3 H), 2.43 (s, 3 H).
13C NMR (CDCl3): d = 163.9, 163.2, 138.9, 137.3, 136.2, 135.7,
132.0, 131.2, 128.5, 126.5, 125.9, 125.8, 121.8, 121.3, 119.3, 115.7,
104.9, 55.6, 51.3, 23.9, 20.7.
MS (EI, 70 eV): m/z (%) = 91 (100), 349 (M+, 33), 243 (20), 65 (16).
Anal. Calcd for C21H16ClNO2: C, 72.10; H, 4.61; N, 4.00. Found: C,
72.01; H, 4.39; N, 4.25.
MS (EI, 70 eV): m/z (%) = 252 (100), 91 (87), 343 (M+, 52), 237
(33), 253 (18).
Anal. Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C,
80.01; H, 6.09; N, 4.21.
4q
White solid; mp 150–151 °C.
IR (KBr): 1656, 1617, 1589, 1431, 1345, 1327, 747 cm–1.
4m
1H NMR (CDCl3): d = 8.64 (dd, J = 2.3, 7.6 Hz, 1 H), 8.08 (s, 1 H),
7.82 (dd, J = 1.1, 7.9 Hz, 1 H), 7.37–7.22 (m, 8 H), 5.63 (br s, 2 H),
4.05 (s, 3 H), 3.99 (s, 3 H).
13C NMR (CDCl3): d = 165.9 (d, J = 253.5 Hz), 160.9, 136.4, 136.1,
135.3 (d, J = 9.5 Hz), 132.6 (d, J = 9.6 Hz), 130.2, 129.0, 128.5,
127.5, 126.5, 123.3, 122.3, 120.1, 117.6, 117.0 (d, J = 22.8 Hz),
107.9 (d, J = 23.5 Hz), 46.5.
White solid; mp 158–159 °C.
IR (KBr): 1650, 1613, 1328, 698 cm–1.
1H NMR (CDCl3): d = 8.70 (d, J = 8.3 Hz, 1 H), 8.48 (s, 1 H), 8.16
(s, 1 H), 7.85 (dd, J = 1.4, 7.3 Hz, 1 H), 7.79 (d, J = 7.2 Hz, 2 H),
7.57 (t, J = 7.3 Hz, 2 H), 7.49 (m, 2 H), 7.33–7.23 (m, 7 H), 5.68
(br s, 2 H), 2.47 (s, 3 H).
13C NMR (CDCl3): d = 161.7, 145.5, 140.5, 136.8, 135.5, 134.2,
132.1, 130.8, 129.9, 129.1, 128.9, 128.4, 127.7, 127.2, 127.1, 126.6,
124.4, 123.5, 120.2, 119.4, 116.1, 46.5, 21.0.
19F NMR (CDCl3): d = –104.6.
MS (EI, 70 eV): m/z (%) = 91 (100), 337 (M+, 24), 231 (14), 65 (14).
MS (EI, 70 eV): m/z (%) = 91 (100), 375 (M+, 68), 270 (33), 212
(19).
Anal. Calcd for C20H13ClFNO: C, 71.12; H, 3.88; N, 4.15. Found:
C, 71.54; H, 3.75; N, 4.55.
Anal. Calcd for C27H21NO: C, 86.37; H, 5.64; N, 3.73. Found: C,
86.99; H, 5.75; N, 3.66.
4r
White solid; mp 167–168 °C.
IR (KBr): 1639, 1579, 1310, 713 cm–1.
4n
1H NMR (CDCl3): d = 8.63 (d, J = 7.9 Hz, 1 H), 8.22 (s, 2 H), 7.80
(t, J = 7.5 Hz, 1 H), 7.67 (t, J = 7.3 Hz, 1 H) 7.34–7.22 (m, 7 H),
5.64 (br s, 2 H).
13C NMR (CDCl3): d = 161.6, 136.2, 135.9, 133.0, 132.7, 129.4,
129.3, 129.0, 128.8, 128.3, 127.4, 126.5, 125.6, 123.1, 121.8, 120.9,
117.5, 46.6.
White solid; mp 159–160 °C.
IR (KBr): 1645, 1602, 1327, 730 cm–1.
1H NMR (CDCl3): d = 8.56 (d, J = 8.0 Hz, 1 H), 8.27 (s, 1 H), 8.00
(s, 1 H), 7.57 (d, J = 7.2 Hz, 1 H), 7.33–7.20 (m, 7 H), 5.65 (br s, 2
H), 2.46 (s, 3 H).
Synthesis 2008, No. 5, 729–738 © Thieme Stuttgart · New York

PAPER
Phenanthridinones via Direct Pd-Catalyzed Arene Arylation
737
MS (EI, 70 eV): m/z (%) = 91 (100), 319 (M+, 27), 213 (15), 65 (15).
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972.
(p) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (q) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett.
2006, 8, 5097. (r) Stuart, D. R.; Villemure, E.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 12072.
Anal. Calcd for C20H14ClNO: C, 75.12; H, 4.41; N, 4.38. Found: C,
75.25; H, 4.45; N, 4.65.
(4) (a) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 581. (b) For the utilization of
pivalate anions in this type of chemistry, see also ref. 2c–e.
(5) (a) Watanabe, M.; Ohshita, Y.; Tsushida, T. J. Agric. Food
Chem. 1997, 45, 1039. (b) DellaGreca, M.; Fiorentino, A.;
Monaco, P.; Previtera, L.; Temussi, F. Nat. Prod. Lett. 2000,
14, 429. (c) DellaGreca, M.; Monaco, P.; Pinto, G.; Pollio,
A.; Previtera, L.; Temussi, F. Bull. Environ. Contam.
Toxicol. 2001, 67, 352. (d) Llorach, R.; Espiän, J. C.;
Tomaäs-Barberaän, F. A.; Ferreres, F. J. Agric. Food Chem.
2002, 50, 3458. (e) Dey, G.; Sachan, A.; Ghosh, S.; Mitra,
A. Ind. Crop. Prod. 2003, 18, 171. (f) Binaco, A.; Buiarelli,
F.; Cartoni, G.; Coccioli, F.; Jasionowska, R.; Margherita, P.
J. Sep. Sci. 2003, 26, 409. (g) Fiorentino, A.; Gentili, A.;
Isidori, M.; Monaco, P.; Nardelli, A.; Parrella, A.; Temussi,
F. J. Agric. Food Chem. 2003, 51, 1005. (h) DellaGreca,
M.; Previtera, L.; Temussi, F.; Zarrelli, A. Phytochem. Anal.
2004, 15, 184. (i) Balasundram, N.; Sundram, K.; Samman,
S. Food Chem. 2006, 99, 191.
(6) For some recent references, see: (a) Ishida, J.; Hattori, K.;
Yamamoto, H.; Iwashita, A.; Mihara, K.; Matsuoka, N.
Bioorg. Med. Chem. Lett. 2005, 15, 4221. (b) Ishida, J.;
Yamamoto, H.; Kido, Y.; Kamijo, K.; Murano, K.; Miyake,
H.; Ohkubo, M.; Kinoshita, T.; Warizaya, M.; Iwashita, A.;
Mihara, K.; Matsuoka, N.; Hattori, K. Bioorg. Med. Chem.
2006, 14, 1378. (c) Aldinucci, A.; Gerlini, G.; Fossati, S.;
Cipriani, G.; Ballerini, C.; Biagioli, T.; Pimpinelli, N.;
Borgognoni, L.; Massacesi, L.; Moroni, F.; Chiarugi, A. J.
Immunol. 2007, 179, 305. (d) Patil, S.; Kamath, S.; Sanchez,
T.; Neamati, N.; Schinazi, R. F.; Buolamwini, J. K. Bioorg.
Med. Chem. 2007, 15, 1212.
Acknowledgment
Work carried out in the framework of FIRB 2003 supported by the
Ministero dell’Università e della Ricerca Scientifica e Tecnologica
and by the University ‘La Sapienza’.
References
(1) For some recent reviews on the C–H activation processes,
see: (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002,
102, 1731. (b) Kakiuchi, F.; Naoto Chatani, N. Adv. Synth.
Catal. 2003, 345, 1077. (c) See also: Hassan, J.; Sévignon,
M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002,
102, 1359.
(2) For some selected examples of palladium-catalyzed
intramolecular arylations of arenes, see: (a) Hennings, D.
D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2.
(b) Tian, Q.; Larock, R. C. Org. Lett. 2000, 2, 3329.
(c) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R.
C. J. Am. Chem. Soc. 2003, 125, 11506. (d) Huang, Q.;
Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 7460. (e) Huang, Q.; Campo, M. A.;
Yao, T.; Tian, Q.; Larock, R. C. J. Org. Chem. 2004, 69,
8251. (f) Harayama, T.; Hori, A.; Serban, G.; Morikami, Y.;
Matsumoto, T.; Abe, H.; Takeuchi, Y. Tetrahedron 2004,
60, 10645. (g) Campeau, L.-C.; Thansandote, P.; Fagnou, K.
Org. Lett. 2005, 7, 1857. (h) Bressy, C.; Alberico, D.;
Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148.
(i) Harayama, T.; Kawata, Y.; Nagura, C.; Sato, T.;
Miyagoe, T.; Abe, H.; Takeuchi, Y. Tetrahedron Lett. 2005,
46, 6091. (j) Abe, H.; Nishioka, K.; Takeda, S.; Arai, M.;
Takeuchi, Y.; Harayama, T. Tetrahedron Lett. 2005, 46,
3197. (k) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras,
F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
(l) Ma, Z.; Xiang, Z.; Luo, T.; Lu, K.; Xu, Z.; Chen, J.; Yang,
Z. J. Comb. Chem. 2006, 8, 696.
(7) (a) Harayama, T.; Akiyama, T.; Nakano, Y.; Nishioka, H.;
Abe, H.; Takeuchi, Y. Chem. Pharm. Bull. 2002, 50, 519.
(b) Nishioka, H.; Shoujiguchi, Y.; Abe, H.; Takeuchi, Y.;
Harayama, T. Heterocycles 2004, 64, 463. (c) Zhibo Ma,
Z.; Xiang, Z.; Luo, T.; Lu, K.; Xu, Z.; Chen, J.; Yang, Z.
J. Comb. Chem. 2006, 8, 696.
(8) Furuta, T.; Kitamura, Y.; Hashimoto, A.; Fujii, S.; Tanaka,
K.; Kan, T. Org. Lett. 2007, 9, 183.
(9) Ferraccioli, R.; Carenzi, D.; Rombolà, O.; Castellani, M.
Org. Lett. 2004, 6, 4759.
(3) For some selected examples of palladium-catalyzed
intermolecular arylations of arenes, see: (a) Satoh, T.;
Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1740. (b) Kawamura, Y.; Satoh, T.;
Miura, M.; Nomura, M. Chem. Lett. 1999, 961.
(10) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes,
(c) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2000, 41, 2655. (d) Okazawa, T.; Satoh,
T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124,
5286. (e) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek,
A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. (f) Lane, B.
L.; Sames, D. Org. Lett. 2004, 6, 2897. (g) Kalyani, D.;
Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (h) Daugulis, O.; Zaitsev, V. G.
Angew. Chem. Int. Ed. 2005, 44, 4046. (i) Shabashov, D.;
Daugulis, O. Org. Lett. 2005, 7, 3657. (j) Zaitsev, V. G.;
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
13154. (k) Campeau, L.-C.; Rousseaux, S.; Fagnou, K.
J. Am. Chem. Soc. 2005, 127, 18020. (l) Lafrance, M.;
Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 8754. (m) Lazareva, A.; Daugulis, O. Org. Lett.
2006, 8, 5211. (n) Shabashov, D.; Daugulis, O. Org. Lett.
2006, 8, 4947. (o) Deprez, N. R.; Kalyani, D.; Krause, A.;
M. O. Org. Lett. 2004, 6, 2741.
(11) (a) Harayama, T.; Kawata, Y.; Nagura, C.; Sato, T.;
Miyagoe, T.; Abe, H.; Takeuchi, Y. Tetrahedron Lett. 2005,
46, 6091. (b) Nishioka, H.; Nagura, C.; Abe, H.; Takeuchi,
Y.; Harayama, T. Heterocycles 2006, 70, 549.
(12) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(13) For the role of DMF as the hydride source in palladium-
catalyzed reduction of aryl halides, see: Zawisza, A. M.;
Muzart, J. Tetrahedron Lett. 2007, 48, 6738.
(14) Previous reports have shown that palladium catalysts do not
promote cyclization of o-bromoanilides to benzoxazoles:
(a) Benedí, C.; Bravo, F.; Uriz, P.; Fernández, E.; Claver, C.;
Castillón, S. Tetrahedron Lett. 2003, 44, 6073.
(b) Altenhoff, G.; Glorius, F. Adv. Synth. Catal. 2004, 346,
1661. (c) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71,
1802.
(15) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
Synthesis 2008, No. 5, 729–738 © Thieme Stuttgart · New York

738
R. Bernini et al.
PAPER
(17) A similar mechanism was proposed for the palladium-
(16) See, for example: (a) Catellani, M.; Chiusoli, G. P.
J. Organomet. Chem. 1992, 425, 151. (b) Martín-Matute,
B.; Mateo, C.; Cárdenas, D. J.; Echavarren, A. M. Chem.
Eur. J. 2001, 7, 2341. (c) Hughes, C. C.; Trauner, D. Angew.
Chem. Int. Ed. 2002, 41, 1569. (d) Sezen, B.; Sames, D. J.
Am. Chem. Soc. 2003, 125, 5274. (e) Li, W.; Nelson, D. P.;
Jensen, M. S.; Hoerrner, S.; Javadi, G. J.; Cai, D.; Larsen, R.
D. Org. Lett. 2003, 5, 4835. (f) Lane, B. S.; Sames, D. Org.
Lett. 2004, 6, 2897. (g) Lane, B. S.; Brown, M. A.; Sames,
D. J. Am. Chem. Soc. 2005, 127, 8050.
catalyzed synthesis of oxindoles via C–H functionalization:
Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 12084.
(18) (a) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.;
Arakawa, M.; Ihara, M. Org. Lett. 2002, 4, 4293.
(b) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. Org. Lett. 2003, 5, 301.
(19) Hughes, C. C.; Trauner, D. Angew. Chem. Int. Ed. 2002, 41,
1569.
Synthesis 2008, No. 5, 729–738 © Thieme Stuttgart · New York