Synthesis of N -arylisoindolin-1-ones via pd-catalyzed intramolecular decarbonylative coupling of N -(2-bromobenzyl)oxanilic acid phenyl esters

Article abstract of DOI:10.1055/s-0029-1219580

Ethyl and phenyl oxanilates were readily prepared from N-(2-bromobenzyl) anilines and oxalyl chloride monoethyl and monophenyl esters, respectively. It was found that the ethyl oxanilate survived in the presence of K ₂CO₃ in DMA at 120°C and underwent an intramolecular direct arylation using Pd(OAc)₂-dppf, furnishing the 5,6-dihydrophenanthridine derivative. In contrast, the corresponding phenyl oxanilates decomposed upon exposure to K²CO³ in DMA at 120 C and were transformed into N-arylisoindolin-1-ones via Pd(OAc) ₂-dppf-catalyzed intramolecular decarbonylative coupling. Except for the 4-methoxy-substituted oxanilic acid phenyl ester, other phenyl oxanilates possessing electron-withdrawing (NO₂, Cl) and weak electron-donating (Me) substituents provided the N-arylisoindolin-1-ones in 43-80% yields.

Full text of DOI:10.1055/s-0029-1219580

LETTER
1075
Synthesis of N-Arylisoindolin-1-ones via Pd-Catalyzed Intramolecular
Decarbonylative Coupling of N-(2-Bromobenzyl)oxanilic Acid Phenyl Esters
Synthesis of
N
-
Ary
u
lisoindolin-1-one
s
Zheng,a Gongli Yu,a Jinlong Wu,a Wei-Min Dai*a,b
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
P. R. of China
Fax +85223581594; E-mail: chdai@ust.hk
Received 23 December 2009
Abstract: Ethyl and phenyl oxanilates were readily prepared from
N-(2-bromobenzyl)anilines and oxalyl chloride monoethyl and
monophenyl esters, respectively. It was found that the ethyl oxa-
nilate survived in the presence of K2CO3 in DMA at 120 °C and un-
derwent an intramolecular direct arylation using Pd(OAc)2–dppf,
furnishing the 5,6-dihydrophenanthridine derivative. In contrast,
the corresponding phenyl oxanilates decomposed upon exposure to
K2CO3 in DMA at 120 °C and were transformed into N-arylisoindo-
lin-1-ones via Pd(OAc)2–dppf-catalyzed intramolecular decarbony-
lative coupling. Except for the 4-methoxy-substituted oxanilic acid
phenyl ester, other phenyl oxanilates possessing electron-withdraw-
ing (NO2, Cl) and weak electron-donating (Me) substituents provid-
ed the N-arylisoindolin-1-ones in 43–80% yields.
N
N
O
O
CuBr, Pd(F6-acac)2
P(o-Tol)3
G
G
O–K+
Ar
+
ArBr
NMP or quinoline
170 °C, 16 h
(1 mol% Pd,
O
1
2
3
15 mol% Cu)
O
O
H
R
Cl
PdCl2(PPh3)2, CuI
Et3N, THF, r.t.
1 h–2 d
(1 mol% Pd,
1 mol% Cu)
O
R
N
N
4
5
G
G
Key words: decarbonylative coupling, direct arylation, isoindolin-
1-ones, oxanilates, palladium
Pd(TFA)2
dppp
O
G
G
G
Br
CO2R
O-K+
+
RO
NMP, 150 °C
16–24 h
(1 mol% Pd)
O
6
7 R = Me, Et
8
In the last few years, decarbonylative cross-coupling reac-
tions under palladium catalysis (or with copper) have be-
come an attractive synthetic methodology which promises
use of carboxylic acids as a new source of nucleophilic
coupling partners.1 As compared to the organometallic re-
agents widely used in conventional cross-coupling reac-
tions, such as Negishi, Suzuki–Miyaura, and Stille
protocols, use of aryl and heteroaryl carboxylic acids in
decarbonylative cross-coupling reactions2,3 is advanta-
geous in the aspects of availability and low cost of diverse
reagents and stability for reagent storage and handling. In
an analogous manner, several groups have reported syn-
theses of diaryl ketones 3,4 3-indolyl ynones 5,5 and aryl
carboxylates 86 via Pd- or Pd–Cu-catalyzed decarbonyla-
tive coupling of 1,2-dicarbonyl derivatives (Scheme 1).
Gooben et al.4 used a bimetallic catalyst system consisting
of Pd(F6-acac)2–P(o-Tol)3 and CuBr–1,10-phenanthroline
for promoting decarbonylative coupling of a-oxocarbox-
ylates 1 with aryl bromides 2, affording ketones 3 in 45–
99% yields except for those products possessing a 2,6-
G
O
O
O
Pd
N
Ph
N
this work
O
R
R
Br
9
10
Scheme 1 Pd-catalyzed decarbonylative coupling of a-oxocarboxy-
lates 1, indole-3-glyoxylyl chlorides 4, potassium oxalate monoesters
7, and phenyl oxanilates 9
dimethyl-substituted phenyl group. When bulky (o-biphe-
nyl)P(t-Bu)2 was used as the ligand, aryl chlorides could
replace aryl bromides 2 for the formation of 3. It was sug-
gested that 1 was first converted into an acyl copper spe-
cies, ArC(=O)[Cu], which underwent acyl group transfer
to a Pd species, leading to the formation of ketones 3.3e,4
Müller and co-workers generated indole-3-glyoxylyl chlo-
rides 4 from the indoles and oxalyl chloride via a Friedel–
Crafts acylation and used them, without purification, for
the decarbonylative Sonogashira coupling with terminal
alkynes to form alkynones 5 in 43–85% overall yields.5,7
An acyl palladium species was proposed by direct oxida-
tive addition of the C(=O)Cl bond in 4 followed by decar-
bonylative elimination, indicating no function of copper
in the decarbonylation.5 Furthermore, a copper-free inter-
SYNLETT 2010, No. 7, pp 1075–1080
x
x.
x
x.
2
0
1
0
Advanced online publication: 10.03.2010
DOI: 10.1055/s-0029-1219580; Art ID: W20409ST
© Georg Thieme Verlag Stuttgart · New York

1076
Y. Zheng et al.
LETTER
molecular coupling of potassium oxalate monoesters 7 NaBH(OAc)3 in 1,2-dichloroethane12 gave 14 in 62–94%
with aryl bromides 6 was reported by Fu and Liu’s yields (entries 1, 4, 5, 7, and 8, Table 1). Some of the prod-
groups,6 affording aromatic esters 8 in 52–98% yields. By ucts 14 were contaminated with inseparable byproduct(s)
using 1,3-bis(dicyclohexylphosphino)propane (dCypp) and were used for the next step (entries 2, 3, and 6,
instead of dppp, decarbonylative coupling of aryl chlo- Table 1). Treatment of 13 and 14 with NaH and subse-
rides with 7 was successfully realized. A five-coordinated quently with oxalyl chloride monophenyl13 and mono-
Pd(II) transition state with an energy barrier of ca. 30 kcal/ ethyl esters, respectively, afforded phenyl oxanilates 15a–
mol was obtained for the rate-limiting decarbonylation i (entries 1–9, Table 1) and ethyl oxanilate 15j (entry 10,
from standard density functional theory calculations. We Table 1) in 68–90% yields.14
report here on an intramolecular decarbonylative coupling
of N-(2-bromobenzyl)oxanilic acid phenyl esters 9 under
The thermal stability of phenyl and ethyl oxanilates 15a
and 15j was first examined in the presence of 2 equiva-
palladium catalysis (Scheme 1). It should serve as the first
lents of K2CO3 in DMA15 at 120 °C for 2 hours. It was
example of formation of bioactive heterocycles via Pd-
found that phenyl oxanilate 15a decomposed presumably
via cleavage of the phenyl ester moiety while ethyl oxa-
nilate 15j remained intact with recovery of most materi-
catalyzed decarbonylative coupling of oxalic acid deriva-
tives
Isoindolin-1-ones are not only the core structural motif of als. Upon exposure of 15j to Pd(OAc)2–dppf12c (K2CO3,
alkaloids but also the proven ‘privileged scaffold’.8 A DMA, 120 °C, 2 h), an intramolecular direct arylation
number of synthetic methods has been developed for the took place to furnish the 5,6-dihydrophenanthridine deriv-
synthesis of isoindolin-1-ones.9 Among them, the Pd- ative 16 in 71% yield along with the minor inseparable de-
catalyzed carbonylative heteroannulation enables an effi- bromination byproduct (Scheme 3).16 On the other hand,
cient three-component reaction cascade starting with 2- it was interesting to find that under the identical catalysis
halobenzyl halides, amines, and gaseous carbon monox- conditions phenyl oxanilate 15a underwent a novel in-
ide.10 For investigating our proposed novel synthesis of tramolecular decarbonylative coupling to provide N-phe-
isoindolin-1-ones by intramolecular decarbonylative cou- nylisoindolin-1-one (17a)10b in 80% isolated yield. In a
pling we obtained N-(2-bromobenzyl)oxanilates 15 from similar manner, N-phenyl-3-methylisoindolin-1-one (17i)
substituted anilines 11 and 2-bromobenzaldehyde 12 was formed from 15i in 48% yield (Scheme 3).
(Scheme 2). (2-Bromo-a-methylbenzyl)aniline 13 was
Table 2 summarizes some results obtained after screening
reaction conditions for the decarbonylative coupling of
15i. We found that prolonged reaction time did not im-
prove the product yield (entries 10–12) and in some cases
prepared by condensation of 11a with 12 followed by
reaction of the resultant imine with MeLi11 in 72% yield
(entry 9, Table 1). Alternatively, a reductive alkylation of
anilines 11 with aldehyde 12 in the presence of
lower yields were observed (entry 1 vs. entry 2), indicat-
ing that the product might be unstable under the heating
conditions. The reaction at 100 °C was not beneficial even
after extension of the reaction time (entry 3). The base
CHO
Br
NH
Br
1. MS, PhMe, r.t.
+
Table 1 Structures and Yields of Aniline Derivatives 13 and 14 and
the Corresponding Ethyl/Phenyl Oxanilates 15
Me
2. MeLi, Et2O
–30 to 0 °C, 1 h
NH2
11a
12
Entry R1
R2
R3
R4
R5
Aniline Oxanilate
(%)a (%)a
13
R1
1
2
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
14a 94 15a 81
14b –b 15b 68c
R2
R3
R1
Cl
H
H
R2
R3
CHO
NaBH(OAc)3
NH
Br
+
3
Cl
H
14c –b
15c 76c
DCE
r.t., 30 min
NH2
Br
4
Me
H
14d 92 15d 89
14e 81 15e 87
11
12
5
Me
H
14
14f –b
15f 75c
R1
6
Me
H
O
R2
R3
O
7
OMe
H
14g 68 15g 81
14h 62 15h 90
O
Cl
R5
O
O
8
NO2
H
N
R5
13 or 14
NaH, THF, r.t., 1 h
O
R4
9
H
13 72
15i 81
15j 90
10
H
H
–
Br
15
a Isolated yield.
b Inseparable mixture which was used for next step.
Scheme 2 Synthesis of aniline derivatives 13 and 14, and the corre-
sponding ethyl/phenyl oxanilates 15
c Overall yield of two steps from 11.
Synlett 2010, No. 7, 1075–1080 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Arylisoindolin-1-ones
1077
and found that the bidentate ligands, dppb, BINAP,17 and
dppp6 were equally efficient as dppf (entries 5, 6, 10 vs.
entry 1) but the monodentate ligands, Aphos18 and Ph3P
were much less preferred (entries 8 and 9). Influence of
palladium precursors on the catalysis was not apparent be-
O
O
O
O
Pd(OAc)2 (10 mol%)
dppf (10 mol%)
N
Et
N
Et
O
O
K2CO3 (2 equiv), DMA
120 °C, 2 h
6
71%
Br
cause Pd(OAc)2, PdCl2, and Pd(TFA)2 gave similar re-
16
15j
sults (entries 6, 7, and 15) but reduction in palladium
loading to 5 mol% caused a sharp drop in the product yield
to 25% (entry 14). For the Pd(OAc)2–dppp catalyst sys-
tem, change of the solvent to NMP (entry 13) and the base
to KOt-Bu and Cs2CO3 (entries 16 and 17) did not signif-
icantly alter the results of the intramolecular decarbonyla-
tive coupling. Therefore, the optimized catalytic
conditions using a mild base are: Pd(OAc)2–dppf (10
mol% each) as the precatalyst with K2CO3 as the base in
DMA at 120 °C for 2 hours.
O
Pd(OAc)2 (10 mol%)
dppf (10 mol%)
O
O
N
Ph
N
O
K2CO3 (2 equiv), DMA
120 °C, 2 h
(17a 80%; 17i 48%)
R4
R4
Br
17a R4 = H
17i
4 = Me
15a R4 = H
15i
4 = Me
R
R
Scheme 3 Pd-catalyzed intramolecular direct arylation of ethyl
oxanilate 15j and decarbonylative coupling of phenyl oxanilates 15a,i
Table 3 lists other examples of N-arylisoindolin-1-ones
17b–h synthesized via the Pd-catalyzed intramolecular
decarbonylative coupling of phenyl oxanilates 15b–h.
The weak electron-donating methyl group was tolerated
to form the products 17d–f in 43–52% yields (entries 4–6,
Table 3) while the methoxy-substituted substrate 15g
gave a low yield of 27% for 17g (entry 7). In contrast, both
weak and strong electron-withdrawing groups (Cl and
NO2) were compatible for the catalytic reaction, and the
corresponding products 17b,c,h were generated in 50–
75% yields (entries 2, 3, and 8). In particular, the chloro
functionality allows a second cross-coupling reaction for
introducing structural diversity. Some examples are given
in Scheme 4.
Table 2 Screening for Decarbonylative Coupling of 15ia
Entry Pd
Ligand Base
Temp Time 17i
(°C)
120
120
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
(h)
(%)
1
2
Pd(OAc)2
dppf
dppf
dppf
dppf
dppb
K2CO3
2
48
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
K2CO3
K2CO3
5
38
3
7
<40c
<40c
<45c
<50c
47
b
4
K3PO4
2
5
K2CO3
2
Ph
6
BINAP K2CO3
BINAP K2CO3
Aphosd K2CO3
2
PhB(OH)2
cat. (1 mol%)
O
7
7
Cl
K3PO4⋅3H2O (3 equiv)
THF–H2O (10:1)
60 °C, 24 h
N
8
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
20
20
5
23
O
95%
9
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOt-Bu
Cs2CO3
<38c
47
N
18a
Ph
10
11
12
13e
14
15
16
17
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
17b
7
52
trans-PhCH=CHB(OH)2
cat. (2 mol%)
O
20
20
20
50
K3PO4⋅3H2O (3 equiv)
THF–H2O (10:1)
80 °C, 24 h
N
48
f
88%
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
25
18b
3.5
51
Cl
Ph
7
7
54
O
O
PhB(OH)2
cat. (1 mol%)
47
N
N
K3PO4⋅3H2O (3 equiv)
THF–H2O (10:1)
60 °C, 24 h
a Pd and ligand (10 mol% each), base (1.5 equiv), and DMA were used
unless otherwise stated.
b The hydrate form, K3PO4·3H2O, was used.
c Some starting materials remained.
17c
90%
18c
i-Pr
d The structure of Aphos is found in Scheme 4.
e NMP was used as the solvent.
N
O
i-Pr
cat. = Pd(OAc)2-Aphos (1:2); Aphos =
f Pd(OAc)2 and dppp (5 mol% each) were used.
PCy2
K3PO4·3H2O gave somewhat poor result than K2CO3 (en-
try 4 vs. entry 1). We examined several common ligands
Scheme 4 Synthesis of isoindolin-1-ones 18a–c via Suzuki–Miyaura
coupling of 17b,c
Synlett 2010, No. 7, 1075–1080 © Thieme Stuttgart · New York

1078
Y. Zheng et al.
LETTER
Table 3 Synthesis of N-Arylisoindolin-1-ones 17a
References and Notes
R1
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R2
N
R3
O
Entry
R1
R2
H
R3
H
Yield (%)
17a 80 (62)b
17b 68 (53)b
17c 75 (40)b
17d 52 (45)b
17e 46
1
2
3
4
5
6
7
8
H
(3) For selected examples of biaryl coupling reaction using aryl
carboxylic acids, see: (a) Gooben, L. J.; Deng, G.; Levy, L.
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St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F.
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Cl
H
H
H
Cl
H
H
Me
H
H
Me
H
H
Me
H
Me
H
17f 43
OMe
H
17g 27 (50)b
17h 50
NO2
H
a The reaction conditions shown in Scheme 3 for formation of 17a,i
were used.
b The numbers in parentheses were reported in ref. 10b via Pd-cata-
lyzed carbonylative coupling using CO.
By using our Pd(OAc)2–Aphos catalyst system, the aryl
chlorides 17b,c underwent Suzuki–Miyaura cross-
coupling with aryl and vinyl boronic acids under mild
conditions to afford 18a–c in excellent yields.18,19
(6) Shang, R.; Fu, Y.; Li, J.-B.; Zhang, S.-L.; Guo, Q.-X.; Liu,
L. J. Am. Chem. Soc. 2009, 131, 5738.
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Y.; Xi, C. Tetrahedron Lett. 2009, 50, 5434.
Mechanistically, Pd-catalyzed oxidative cleavage of the
C(=O)OPh bond is considered,20 it seems much more ap-
propriate to follow a pathway initiated by cleavage of the
phenyl ester moiety in oxanilates 15a–i on exposure to
K2CO3 in DMA15 at 120 °C. Then, the resultant potassium
oxanilate enters a similar catalytic cycle proposed for the
intermolecular decarbonylative coupling of potassium ox-
alate monoesters 7 (Scheme 1).6 However, a definite
mechanism awaits for further evidences.
(8) For selected recent examples, see: (a) Lee, S.; Shinji, C.;
Ogura, K.; Shimizu, M.; Maeda, S.; Sato, M.; Yoshida, M.;
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In summary, we have established a novel intramolecular
decarbonylative coupling of functionalized phenyl oxa-
nilates by using Pd(OAc)2–dppf as the precatalyst under
mild reaction conditions (K2CO3, DMA, 120 °C). This
protocol enables access to a number of N-arylisoindolin-
1-ones in moderate to good yields. Studies on application
of this methodology to heterocycle synthesis are in
progress in our laboratories.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The Laboratory of Asymmetric Catalysis and Synthesis is esta-
blished under the Cheung Kong Scholars Program of The Ministry
of Education of China. This work is supported in part by the rese-
arch grants from The National Natural Science Foundation of China
(Grant No. 20672092), Zhejiang University, and Zhejiang Univer-
sity Education Foundation.
Synlett 2010, No. 7, 1075–1080 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Arylisoindolin-1-ones
1079
(11) For addition of MeLi with imines, see: Strekowski, L.;
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2007, 2728.
(13) Mao, C. H.; Wang, Q. M.; Huang, R. Q.; Bi, F. C.; Chen, L.;
Liu, Y. X.; Shang, J. J. Agric. Food Chem. 2004, 52, 6737.
(14) Representative Procedure for Synthesis of Oxanilates 15
To a solution of phenol (235.0 mg, 2.0 mmol) and pyridine
(0.31 mL, 3.0 mmol) in dry CH2Cl2 (5 mL) cooled in an ice–
water bath was added oxalyl chloride (0.33 mL, 3.0 mmol)
followed by stirring at r.t. for 30 min. The reaction mixture
was evaporated, and hexane was added to the residue. The
pyridinium salt was removed by quick filtration with
washing by hexane. The combined filtrate was condensed
under reduced pressure in a nitrogen atmosphere, and the
crude oxalyl chloride monophenyl ester was used for next
step without purification.13
DMA. The organic layer was washed with brine, dried over
anhyd Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column
chromatography over silica gel with elution by 20% EtOAc
in PE (60–90 °C) to give N-(p-tolyl)isoindolin-1-one (17e,
61.0 mg, 46%). The results are given in Scheme 3 and
Table 3.
Compound 16 was prepared in 71% yield from 15j
(Scheme 3) under the same conditions as described above
for 17e. The sample of 16 contains two atropisomers along
with a minor inseparable debromination byproduct in the
ratio of 75:15:10. The result was confirmed by independent
synthesis as found in Supporting Information.
Characterization Data for Compound 16
Pale yellow oil; Rf = 0.27 (20% EtOAc in PE). IR (film):
2928, 1742, 1667, 1185 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.83 (d, J = 7.2 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.43–
7.19 (m, 6 H), 4.95 (s, 2 H), 4.16 (q, J = 6.8 Hz, 2 H), 1.12
(t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 162.5,
160.4, 135.6, 133.2, 131.1, 129.0, 128.4, 128.4, 128.1,
127.3, 126.4, 124.7, 123.5, 121.8, 62.1, 44.5, 13.6. MS
(ESI+): m/z (%) = 304 (100) [M + Na+]. HRMS (ESI+): m/z
calcd for C17H15NO3Na [M + Na+]: 304.0944; found:
304.0953.
To a separate dry flask was added NaH (60.0 mg, 1.5 mmol)
and dry THF (5 mL). To the resultant suspension cooled in
an ice–water bath was added a solution of 14e (276.0 mg, 1.0
mmol) in dry THF (5 mL). After stirring at the same
temperature for 1 h, a solution of oxalyl chloride
monophenyl ester prepared above in dry THF (5 mL) was
added. After stirring at r.t. for 1 h, the reaction was quenched
by H2O. The reaction mixture was extracted with EtOAc
(3 × 15 mL), and the combined organic layer was washed
with brine, dried over anhyd Na2SO4, filtered, and
concentrated under reduced pressure. The residue was
purified by column chromatography over silica gel with
elution by 10% EtOAc in PE (60–90 °C) to give the phenyl
oxanilate 15e (367.0 mg, 87%). The results are listed in
Table 1.
Characterization Data for Compound 17e
White crystalline solid; mp 126–128 °C (CH2Cl2–hexane).
Rf = 0.38 (20% EtOAc in PE). IR (KBr): 2921, 1683, 1513,
1447, 1390, 1305, 1159 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.92 (d, J = 7.2 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.60–
7.48 (m, 3 H), 7.23 (d, J = 8.0 Hz, 2 H), 4.83 (s, 2 H), 2.35
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 167.3, 140.1,
136.9, 134.2, 133.3, 131.9, 129.7 (2×), 128.3, 124.1, 122.5,
119.6 (2×), 50.8, 20.8. MS (ESI+): m/z (%) = 246 (35) [M +
Na+], 224 (100) [M + H+]. Anal. Calcd for C15H13NO: C,
80.69; H, 5.87; N, 6.27. Found: C, 80.56; H, 5.79; N, 6.28.
(17) Pd(OAc)2–BINAP were used for catalyzing intramolecular
amidation to form 2-oxindoles, see: Xing, X.; Wu, J.; Luo,
J.; Dai, W.-M. Synlett 2006, 2099.
(18) For Pd–Aphos-catalyzed Suzuki–Miyaura coupling, see:
(a) Dai, W.-M.; Li, Y.; Zhang, Y.; Lai, K. W.; Wu, J.
Tetrahedron Lett. 2004, 45, 1999. (b) Dai, W.-M.; Zhang,
Y. Tetrahedron Lett. 2005, 46, 1377. (c) Jin, J.; Chen, Y.;
Li, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9, 2585.
(d) Dai, W.-M.; Li, Y.; Zhang, Y.; Yue, C.; Wu, J. Chem.
Eur. J. 2008, 14, 5538.
Characterization Data for Compound 15e
White crystalline solid; mp 92–93 °C (CH2Cl2–hexane);
Rf = 0.59 (20% EtOAc in PE). IR (KBr): 1763, 1668, 1511,
1403, 1163 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.52 (d,
J = 8.0 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.31–7.25 (m, 3
H), 7.21–7.12 (m, 6 H), 6.67 (d, J = 7.6 Hz, 2 H), 5.16 (s, 2
H), 2.35 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 161.4,
160.8, 149.4, 139.1, 136.5, 134.8, 132.9, 130.1 (3×), 129.4
(2×), 129.3, 127.8, 127.6 (2×), 126.4, 123.8, 120.9 (2×),
51.7, 21.1. MS (ESI+): m/z (%) = 448 (75) [M + 2 + Na+],
446 (100) [M + Na+]. Anal. Calcd for C22H18BrNO3: C,
62.28; H, 4.28; N, 3.30. Found: C, 62.31; H, 4.31; N, 3.37.
(15) We used N,N-dimethylacetamide (DMA) as received from
commercial supplies. The anhydrous grade has 99.8% purity
with <0.005% water content. In all of our experiments
described in this work, water was not added. Upon heating
phenyl oxanilate 15a in DMA at 120 °C in the presence of
K2CO3, all materials in the reaction mixture remained on the
base line of the TLC plate while ethyl oxanilate 15j could be
developed up on the TLC plate.
(16) Representative Procedure for Formation of 16 and 17
A 10 mL flask was charged with Pd(OAc)2 (13.5 mg,
6.0×10–2 mmol), dppf (33.0 mg, 6.0×10–2 mmol), and K2CO3
(166.0 mg, 1.2 mmol). The loaded flask was evacuated and
backfilled with N2 (repeated for three times). To the
degassed flask was added a solution of phenyl oxanilate 15e
(255.0 mg, 0.6 mmol) in degassed DMA (3 mL). The
resultant mixture was heated at 120 °C for 2 h under a
nitrogen atmosphere. After cooling to r.t., the reaction was
quenched by adding CH2Cl2 (20 mL), and the resultant
mixture was washing with H2O (3 × 10 mL) to remove
(19) Representative Procedure for Suzuki–Miyaura
Coupling of Aryl Chlorides 17b,c
A 10 mL flask was charged with the aryl chloride 17b (24.4
mg, 0.1 mmol), phenyl boronic acid (19.0 mg, 0.15 mmol),
and K3PO4·3H2O (80.0 mg, 0.3 mmol). The loaded flask was
evacuated and backfilled with N2 (repeated for three times).
To the degassed flask was added degassed H2O (0.1 mL) and
a stock THF (1 mL) solution containing Pd(OAc)2 (0.23 mg,
1.0×10–3 mmol) and Aphos (0.80 mg, 2.0×10–3 mmol). The
resultant mixture was heated at 60 °C for 24 h under a
nitrogen atmosphere. After cooling to r.t., the reaction was
quenched by H2O, and the resultant mixture was extracted
with EtOAc (3 × 5 mL). The combined organic layer was
washed with brine, dried over anhyd Na2SO4, filtrated, and
concentrated under reduced pressure. The residue was
purified by column chromatography over silica gel with
elution by 15% EtOAc in PE (60–90 °C) to give the coupling
product 18a (27.0 mg, 95%). The results are found in
Scheme 4.
Characterization Data for Compound 18a
White crystalline solid; mp 126–128 °C (CH2Cl2–hexane).
Rf = 0.38 (20% EtOAc in PE). IR (KBr): 1691, 1600, 1483,
Synlett 2010, No. 7, 1075–1080 © Thieme Stuttgart · New York

1080
Y. Zheng et al.
LETTER
1429, 1376 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.13 (dd,
J = 2.0, 2.0 Hz, 1 H), 7.93 (d, J = 7.2 Hz, 1 H), 7.85 (dd,
J = 8.4, 2.0 Hz, 1 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.60 (ddd,
J = 6.4, 6.4, 1.2 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 2 H), 7.50 (d,
J = 8.0 Hz, 1 H), 7.48–7.35 (m, 4 H), 4.90 (s, 2 H). 13C NMR
(100 MHz, CDCl3): d = 167.6, 142.2, 140.8, 140.0, 139.9,
133.1, 132.1, 129.5, 128.7 (2×), 128.4, 127.5, 127.2 (2×),
124.1, 123.2, 122.6, 118.2, 118.2, 50.8. MS (ESI+): m/z
(%) = 308 (95) [M + Na+], 286 (100) [M + H+]. Anal. Calcd
for C20H15NO: C, 84.19; H, 5.30; N, 4.91. Found: C, 84.22;
H, 5.32; N, 4.96.
(20) For Pd- and Ni-catalyzed oxidative cleavage of aryl esters,
see: (a) Gooben, L. J.; Paetzold, J. Angew. Chem. Int. Ed.
2002, 41, 1237. (b) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.;
Liu, L. J. Am. Chem. Soc. 2009, 131, 8815.
Synlett 2010, No. 7, 1075–1080 © Thieme Stuttgart · New York

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