Pd(II)-catalyzed synthesis of indoles from α-aryloxime O-pentafluorobenzoates via intramolecular aromatic C-H amination

Article abstract of DOI:10.1016/j.tet.2010.05.029

α-Aryl-a-aminocarbonyloxime O-pentafluorobenzoates are found to be promising precursors for synthesis of 2 3-disubstituted indole derivatives catalyzed by PdCl₂(MeCN)₂ in the presence of MgO as a base. The reaction is supposed to pro

Full text of DOI:10.1016/j.tet.2010.05.029

Tetrahedron 66 (2010) 5692e5700
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(II)-catalyzed synthesis of indoles from
a
-aryloxime O-pentafluorobenzoates
via intramolecular aromatic CeH amination
*
Shunsuke Chiba , Line Zhang, Stephen Sanjaya, Gim Yean Ang
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2010
Received in revised form 22 April 2010
Accepted 10 May 2010
Available online 15 May 2010
a
-Aryl-a-aminocarbonyloxime O-pentafluorobenzoates are found to be promising precursors for syn-
thesis of 2,3-disubstituted indole derivatives catalyzed by PdCl2(MeCN)2 in the presence of MgO as
a base. The reaction is supposed to proceed via intramolecular aromatic CeH amination of a vinyl
nitreneepalladium intermediate.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Oximes
CeH amination
Vinyl nitrene
Palladium catalysts
1. Introduction
base
H
R2
R2
R1
R1
Indole is one of the most ubiquitous heterocyclic compounds,
being present as a basic core in natural products1 and potent
pharmaceutical compounds.2 Despite numerous diverse ap-
proaches toward the synthesis of indoles developed so far,3,4 it is
still challenging to develop synthetic methodologies of indoles
bearing various substituents from readily available starting
materials.
R2
R1
base
N
N
vinyl nitrene
N
OSO2R
OSO2R
O
R1
R2
R1
HCl aq.
insertion
R2
N
2H-azirine
NH2•HCl
Our recent attention has been drawn to the reaction course of
the Neber reaction of O-sulfonyloximes, which has been utilized as
α-amino ketone
Scheme 1.
one of the preparative methods for a-amino ketones via 2H-azir-
ines as an intermediate (Scheme 1).5 One of the plausible reaction
pathways of the formation of 2H-azirines from O-sulfonyloximes
involves initial removal of an
a-proton followed by loss of the
O
O
O
sulfonate to afford vinyl nitrenes, which are converted into 2H-
O
N
N
O
N
O
azirines via insertion onto the CeC double bond.6
Rh2(OCOCF3)4
(5 mol %)
Me
Me
Based on the mechanistic insight of the Neber reaction, we re-
cently disclosed a Rh2(OCOCF3)4-catalyzed isomerization reaction
of 2-aryl-2H-azirines to 2,3-disubstituted indoles (Scheme 2),
where transient vinyl nitrene-rhodium intermediates might un-
dergo intramolecular aromatic CeH amination.7a However, most of
2H-azirines were difficult to prepare and handle due to their
instability.
Me
N
H
N
ClCH2CH2Cl
reflux
N
91%
H
[Rh]
Scheme 2.
Thus we have strived to develop general and efficient methods
to prepare indoles utilizing O-acyloxime derivatives, which are
readily available from the corresponding ketones and rather stable
to utilize. It was expected that coordination of the nitrogen atom of
O-acyloximes I to appropriate transition metal [M] followed by
* Corresponding author. Tel.: þ81 6513 8013; fax: þ81 67911961; e-mail address:
shunsuke@ntu.edu.sg (S. Chiba).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.029

S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
5693
deprotonation would afford metalenitrenoid III.
a
-Elimination of
with MgO in the absence of the catalyst provided only 2H-azirine
5a after 12 h (entry 8). Although the indole formation from both
benzoate 3ab and acetate 3ac was observed using PdCl2(MeCN)2,
the yield of 4a was not satisfactory (entries 9 and 10).
carboxylate from nitrenoid III would give metal-nitrene in-
termediate IV, subsequent aromatic CeH amination4n,7 of which
would provide the corresponding indoles (Scheme 3). Herein, we
wish to report Pd(II)-catalyzed indole formation from
a-aryl-a-
aminocarbonyloxime O-pentafluorobenzoates via aromatic CeH
amination.
Table 1
Optimization of reaction conditions
O
R2
R2
R2
O
O
N
H
R3
R3
[M]
R3
metal cat.
N
O
base
Me
MgO (5 equiv)
N
N
–H+
N
OCOR1
[M]
III
OCOR1
ClCH2CH2Cl
80-85 °C
Me
4a
N
OCOR1
[M]
II
N
H
OCOR1
I
3a
R1
R2
Entry
Metal catalysts
Time/h
Yield/%a
R3
R2
R3
aromatic
1
2
3
4
5
6
7
8
3aaeC6F5
3aaeC6F5
3aaeC6F5
3aaeC6F5
3aaeC6F5
3aaeC6F5
3aaeC6F5
3aaeC6F5
Rh2(OCOCF3)4 (10 mol %)
Rh2(OCOC3F7)4 (10 mol %)
PdCl2(MeCN)2 (15 mol %)
PdCl2(MeCN)2 (25 mol %)
PdBr2 (25 mol %)
PdCl2(MeCN)2 (10 mol %)
PdCl2(MeCN)2 (10 mol %)
d
23
12
9
3
8
23
22
12
15 (34)b
58 (40)b
71
C-H amination
N
–OCOR1
– [M]
[M]
vinyl nitrene
-metal complex IV
N
H
82
V
60
47c
Scheme 3.
55d
0e
2. Results and discussion
9
10
3abeC6H5
3aceMe
PdCl2(MeCN)2 (25 mol %)
PdCl2(MeCN)2 (25 mol %)
9
3
58
47
a
A
synthetic scheme of
rivatives 3 is depicted in Scheme 4. Treatment of
with esters in the presence of NaH provided -acylated product 2,
a
-aryl-
a
-aminocarbonyloxime de-
Isolated yields.
Recovery of starting material 1.
PhI(OAc)2 (0.5 equiv) was added to the reaction.
The reaction was run under an O2 atmosphere.
2H-Azirine 5a was obtained in 78% yield.
O
b
c
a
-arylamide 1
O
N
N
a
d
e
Me
5a
which were converted into O-acyloximes 3 via a reaction with
hydroxylamine followed by acylation.
R1
N
R1
N
With the identification of the optimized conditions in hand, we
next examined the generality of this method for synthesis of
substituted indoles using O-pentafluorobenzoyl oximes
(Table 2). Substrates bearing halogen substituents, such as Cl, Br,
and F atoms on the benzene ring were converted into the corre-
sponding indoles with keeping the Cehalogen bond intact (entries
1e5), although the yield of 5,7-dibromoindole was moderate
(entry 4). In the case of meta-chloro substituted substrate 3f, two
regioisomeric indoles 4f and 4f0 were formed in the ratio of 3:2
(entry 5). Methyl and phenyl groups could be installed on the
O
O
R1
R2
R1
NaH, R2CO2Et
THF, reflux
4
3
O
R3
R3
1
2
R1
N
O
R1
R2
1) NH2OH•HCl, pyridine
2) R3COCl, Et3N
N
OCOR3
R3
3
benzene ring of indoles (entries 6 and 7). The reaction of
a-2-
(22–64% yields for 3 steps)
naphtyl oxime 3h formed CeN bond only with C(1), providing
indole 4h in 87% yield (entry 8). Some alkyl groups on C(2) of
indoles 4 were incorporated in good yields (entries 9e12), while
2-aryl indole 3n was obtained in moderate yield (49%) with for-
mation of the corresponding 2H-azirine 5n (entry 13).9 Along with
a morpholino carbonyl motif, N,N0-dimethylamino-, and piper-
idino carbonyl parts could be introduced at the C(3) position of
indoles (entries 14 and 15).
Scheme 4.
At first, we carried out extensive investigations to identify the
best reaction conditions using 2-aminocarbonyl-2-phenylacetone
oxime O-pentafluorobenzoate 3aa,8 benzoate 3ab, and acetate 3ac
with some transition metal catalysts in the presence of MgO
(5 equiv) as a base in 1,2-dichloroethane, and Table 1 listed repre-
sentative results. Although the reaction of O-pentafluorobenzoate
3aa with Rh2(OCOCF3)4 (10 mol %) afford only 15% yield of desired
indole 4a with 34% recovery of 3aa (entry 1), more electron-de-
ficient Rh2(OCOC3F7)4 provided indole 4a in 58% yield along with
40% recovery of 3a (entry 2). When PdCl2(MeCN)2 (15 mol %) was
used instead of Rh(II) dicarboxylates, the yield of indole 4a was
improved to 71% (entry 3). Higher catalytic loading of
PdCl2(MeCN)2 (25 mol %) accelerated the reaction, providing indole
4a in 82% yield (entry 4). Other Pd(II) catalysts like Pd(OAc)2, Pd
(OTf)2, and PdBr2 (entry 5) were ineffective as well as the other
transition metals, such as Cu(OTf)2, NiBr2, AuCl, and ReCl(CO)5. To
lower catalytic loading, utilization of PhI(OAc)2 and O2 were ex-
amined as an additional oxidant with PdCl2(MeCN)2 (10 mol %),
however, the reactions proceeded slowly, providing indole 4a in 47
and 55% yields, respectively (entries 6 and 7). Treatment of 3aa
Finally, a reaction of deuterium-labeled oxime 3oed was ex-
amined to elucidate the mechanism of the CeH amination process,
namely a concerted s-bond methathesis or a stepwise electrophilic
aromatic substitution (Scheme 5).10,11 The product isotope effect of
obtained indole 4oed was 1.0 (100% conversion, 49% yield), which
would support an electrophilic aromatic substitution for the CeH
amination process, not s
-bond methathesis.4n,12
3. Conclusion
In summary, we have developed
a concise approach to
substituted indoles using readily available and rather stable O-
acyloximes via Pd(II)-catalyzed aromatic CeH amination. Further
application of this method for synthesis of various azaheterocycles
are currently underway.

5694
S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
Table 2
Synthesis of indolesa
Entry
Oximes 3
Indoles 4
Time, yieldb
O
O
O
N
N
O
CH3
X
CH3
N
H
N
X
OCOC6F5
1
2
3
3b: X¼Cl
3c: X¼Br
3d: X¼F
4b
4c
4d
4 h, 70%
6 h, 75%
4 h, 70%
O
O
Br
O
N
N
O
O
Br
CH3
4
10 h, 33%
CH3
N
N
Br
H
OCOC6F5
4e
Br
3e
O
Cl
N
6 h, 59%
CH3
N
H
O
O
N
N
4f
5
Cl
CH3
O
N
O
OCOC6F5
40%
3f
CH3
N
Cl
H
4f'
O
Me
O
O
Me
N
N
N
O
6
7
6 h, 46%
CH3
CH3
N
H
OCOC6F5
4g
3g
O
N
O
O
N
O
CH3
N
3.5 h, 72%
CH3
N
H
OCOC6F5
4h
3h
O
O
O
N
N
O
CH3
8
9
5 h, 87%
CH3
N
N
H
OCOC6F5
4i
3i
O
O
O
O
N
N
O
12 h, 51%
CH3
OCOC6F5
O
CH3
N
H
N
4j
3j
O
N
N
O
N
N
10
9 h, 91%
N
H
OCOC6F5
O
4k
3k
O
O
O
N
N
11
9 h, 63%
N
H
OCOC6F5
4l
3l

S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
5695
Table 2 (continued)
Entry
Oximes 3
Indoles 4
Time, yieldb
O
N
O
O
N
O
12
9 h, 55%
N
H
N
OCOC6F5
4m
3m
O
O
N
O
N
O
13c
10 h, 49%
N
Br
OCOC6F5
H
N
Br
4n
3n
O
O
NMe2
NMe2
CH3
CH3
14
5 h, 68%
N
N
OCOC6F5
H
4o
3o
O
O
N
N
N
15
5 h, 73%
CH3
CH3
N
H
OCOC6F5
4p
3p
a
The reaction was conducted by treatment of oximes
C
3
with 25 mol % of PdCl2(MeCN)2 and 5 equiv of MgO in 1,2-dichloroethane at
80 ꢀ
O
b
Isolated yields by flash column chromatography
N
O
on silica gel.
c
Yield (32%) of 2H-azirine 5n was isolated from the
Br
reaction.
N
5n
(CH3)4Si (for 1H,
d
¼0.00) as internal standard]. 13C NMR (75 MHz)
O
D
spectra on a Bruker Avance 300 spectrometers and 13C NMR
(100 MHz) spectra on a Bruker Avance 400 spectrometers in CDCl3
NMe2
Me
O
NMe2
Me
D
PdCl2(MeCN)2 (25 mol %)
MgO (5 equiv)
[using CHCl3 (for 13C,
[using DMSO (for 13C,
d¼77.0) as internal standard] or in DMSO-d6
N
H
4o-d
d¼39.5) as internal standard]. The following
+
H
N
ClCH2CH2Cl, 80 °C
O
abbreviations were used to explain the multiplicities: s¼singlet,
d¼doublet, t¼triplet, m¼multiplet, br¼broad. IR spectra were
recorded on a Shimazu IR Prestige-21 FT-IR Spectrometer. High-
resolution mass spectra were obtained with a Finnigan MAT 95 XP
mass spectrometer (Thermo Electron Corporation). Melting points
were uncorrected and were recorded on a Buchi B-54 melting point
apparatus.
Flash column chromatography was performed using Merck
silica gel 60 with distilled solvents. Toluene, tetrahydrofuran
(THF), and dichloromethane (CH2Cl2) were taken from a solvent
purification system (PS-400-5, innovative technology Inc.). N,N-
Dimethylformamide (DMF) was distilled from CaH2 and stored
over MS 4A. 1,2-Dichloroethane (ClCH2CH2Cl) was distilled from
CaH2.
H
OCOC6F5
NMe2
Me
49%
3o-d
k /kD = 1 : 1
H
N
H
4o
an electrophilic aromatic substitution
O
NMe2
Me
O
O
NMe2
Me
NMe2
Me
–[PdII]
N
N
H
N
[PdII]
H
[PdII]
Scheme 5.
4. Experimental section
4.1. General
4.2. Synthesis of amide derivatives 1
4.2.1. 1-Morpholino-2-phenylethanone (1a)13 (method A). To
a solution of 2-phenylacetyl chloride (8.55 mL, 64.5 mmol) in
CH2Cl2 (92 mL) was added morpholine (14.1 mL, 162 mmol), and
the mixture was stirred for 30 min. After that, the mixture was
filtered through Celite and washed with CH2Cl2. The organic ma-
terials were extracted with CH2Cl2 for three times. The combined
extracts were washed with water and brine, dried over MgSO4, and
1H NMR (300 MHz) spectra were recorded on a Bruker Avance
300 spectrometers, 1H NMR (400 MHz) spectra were recorded on
a Bruker Avance 400 spectrometers, and 1H NMR (500 MHz)
spectra were recorded on a Bruker Avance 500 spectrometers in
CDCl3 [using CHCl3 (for 1H,
d
¼7.26) or (CH3)4Si (for 1H,
d
¼0.00) as
internal standard] or in DMSO-d6 [using DMSO (for 1H,
d
¼2.49) or

5696
S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
filtered. The solvents were removed in vacuo. The crude materials
were purified by recrystallization from hexaneeethyl acetate to
give 1a (9.92 g, 48.3 mmol) in 75% yield.
m), d d 39.3,
7.31 (2H, s), 7.54 (1H, s); 13C NMR (100 MHz, CDCl3)
42.1, 46.3, 66.3, 66.6, 122.9, 130.7, 132.6, 138.5, 168.0; ESIMS: found:
m/z 363.9375. Calcd for C12H14NO2Br2: (MþH)þ 363.9371.
1H NMR (300 MHz, CDCl3)
d 3.44e3.64 (8H, m), 3.74 (2H, s),
7.23e7.35 (5H, m); 13C NMR (75 MHz, CDCl3)
d
40.9, 42.2, 46.5, 66.5,
4.2.9. 1-Morpholino-2-o-tolylethanone (1g)13. Yield 88%; 1H NMR
66.8, 126.9, 128.5, 128.8, 134.8, 169.9.
(300 MHz, CDCl3)
d
2.28 (3H, s), 3.39 (2H, t, J¼4.6 Hz), 3.55 (2H, t,
J¼4.4 Hz), 3.67 (2H, s), 3.68 (4H, s), 7.12e7.17 (4H, m); 13C NMR
4.2.2. 2-(4-Chlorophenyl)-1-morpholinoethanone (1b). Yield 89%;
white crystal; mp 107.0e108.0 ꢀC; FTIR (KBr) 2966, 2840, 1650,
(75 MHz, CDCl3) d 19.6, 38.2, 42.0, 46.3, 66.4, 66.8, 126.2, 127.0,
128.5, 130.3, 133.3, 136.1, 169.6.
1499, 1452, 1272, 1112, 1034, 818, 782 cmꢁ1 1H NMR (300 MHz,
;
CDCl3)
d
3.43 (2H, t, J¼4.5 Hz), 3.53 (2H, t, J¼4.4 Hz), 3.65 (4H, s),
4.2.10. 2-(Biphenyl-4-yl)-1-morpholinoethanone (1h)13. Yield 91%;
3.69 (2H, s), 7.18 (2H, d, J¼8.4 Hz), 7.30 (2H, d, J¼8.4 Hz); 13C NMR
1H NMR (300 MHz, CDCl3)
d
3.48 (2H, t, J¼4.2 Hz), 2.51 (2H, t,
J¼4.2 Hz), 3.66 (4H, s), 3.76 (2H, s), 7.30e7.36 (3H, m), 7.41e7.46 (2H,
m), 7.55e7.60 (4H, m); 13C NMR (75 MHz, CDCl3)
40.3, 42.1, 46.5,
(100 MHz, CDCl3)
d 39.8, 42.1, 46.3, 66.3, 66.7, 128.8, 139.9, 132.7,
133.2, 169.0; ESIMS: found: m/z 240.0790. Calcd for C12H15NO2Cl:
d
(MþH)þ 240.0791.
66.5, 66.8, 127.0, 127.3, 127.4, 128.7, 129.0, 133.8, 139.8, 140.6, 169.5.
4.2.3. 2-(4-Fluorophenyl)-1-morpholinoethanone (1d)14. Yield 88%;
4.2.11. 1-Morpholino-2-(naphthalen-2-yl)ethanone (1i). Yield 88%;
white crystal; mp 226.0e227.1 ꢀC; FTIR (KBr) 2919, 2857,1633,1436,
1H NMR (400 MHz, CDCl3)
d
3.43 (2H, t, J¼4.4 Hz), 3.52 (2H, t,
J¼4.6 Hz), 3.63 (4H, s), 3.68 (2H, s), 6.99 (1H, d, J¼8.4 Hz), 7.01 (1H,
1273, 1229, 1111, 1037, 797, 744 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d, J¼8.8 Hz), 7.19 (1H, d, J¼8.4 Hz), 7.20 (1H, d, J¼8.4 Hz); 13C NMR
d
3.46e3.66 (8H, m), 4.00 (2H, s), 7.38 (1H, dd, J¼1.6, 8.4 Hz),
7.48e7.51 (2H, m), 7.68 (1H, s), 7.80e7.85 (3H, m); 13C NMR
(100 MHz, CDCl3) 41.0, 42.1, 46.5, 66.4, 66.8, 125.8, 126.3, 126.7,
(100 MHz, CDCl3)
d
39.7, 42.1, 46.4, 66.4, 66.7, 115.5 (d, J¼21.4 Hz),
130.1 (d, J¼7.9 Hz), 130.4 (d, J¼3.4 Hz), 161.8 (d, J¼243.8 Hz), 169.4.
d
127.0,127.5,127.6,128.5,132.2,132.3,133.5,169.5; ESIMS: found: m/z
4.2.4. N,N-Dimethyl-2-phenylacetamide (1o)15. Yield 85%; 1H NMR
256.1337. Calcd for C16H18NO2: (MþH)þ 256.1338.
(300 MHz, CDCl3) d 2.95 (3H, s), 2.98 (3H, s), 3.71 (2H, s), 7.20e7.33
(5H, m); 13C NMR (75 MHz, CDCl3)
128.6, 135.0, 170.9.
d
35.5, 37.6, 40.9, 126.5, 128.5,
4.3. Synthesis of O-pentafluorobenzoyl oximes 3
4.3.1. 1-morpholino-3-(perfluorobenzoyloxyimino)-2-phenylbutan-
1-one (3aa) (a typical procedure). To an ice cold solution of 1-
morpholino-2-phenylethanone (2.00 g, 9.74 mmol) in THF
(30.0 mL) was added NaH (60% dispersion in paraffin liquid,
896 mg, 22.4 mmol), and the mixture was stirred at room tem-
perature for 30 min. After the mixture was cooled to 0 ꢀC, ethyl
acetate (1.44 mL, 14.6 mmol) was added and the mixture was
stirred at reflux overnight. The mixture was then cooled to 0 ꢀC
and quenched with slow addition of aqueous 1 M HCl. The organic
layer was extracted using ethyl acetate three times and then
washed with brine. The combined extracts were dried over MgSO4
and filtered. The solvents were removed in vacuo, and the
resulting crude mixture was used for next step without
purification.
To an ice cold solution of crude materials in EtOH (12.0 mL) was
added pyridine (2.42 mL, 30.0 mmol) and hydroxylamine hydro-
chloride (1.04 g, 15.0 mmol). The mixture was then stirred at room
temperature for 1 h. The reaction was quenched with water and the
organic layer was extracted with ethyl acetate three times. The
combined extracts were washed with aqueous 1 M HCl then with
brine. The extracts were dried over MgSO4 and filtered. The sol-
vents were removed in vacuo, and the resulting crude mixture was
used for next step without any purification.
4.2.5. 2-Phenyl-1-(piperidin-1-yl)ethanone (1p)16. Yield quant; 1H
NMR (300 MHz, CDCl3) 1.33e1.38 (2H, m), 1.51e1.60 (4H, m), 3.37
d
(2H, t, J¼5.6 Hz), 3.57 (2H, t, J¼5.3 Hz), 3.73 (2H, s), 7.23e7.34 (5H,
m); 13C NMR (75 MHz, CDCl3)
126.6, 128.5, 128.6, 135.4, 169.2.
d 24.4, 25.4, 26.2, 41.1, 42.9, 47.2,
4.2.6. 2-(3-chlorophenyl)-1-morpholinoethanone (1f) (method B).
To a solution of 2-(3-chlorophenyl)acetic acid (2.87 g, 16.8 mmol)
in CH2Cl2 (17 mL) was added (COCl)2 (1.6 mL, 18.5 mmol). A drop
of DMF was added, gas bubbles CO and CO2 started to form. The
solution was stirred until no more gas bubbles were observed.
A solution of morpholine (3.40 mL, 38.6 mmol) was added into
the mixture at 0 ꢀC. After stirring for 1 h, the mixture was
quenched with water and extracted with CH2Cl2. The organic
layer was then washed with saturated NaHCO3 solution and
brine. The extract was dried over MgSO4 and filtered. The sol-
vents were removed in vacuo. The crude materials were purified
by recrystallization from hexaneeethyl acetate to give 1f (3.04 g,
12.6 mmol) in 75% yield.
Yield 75%; white crystal; mp 59.0e60.7 ꢀC; FTIR (KBr) 2976,
2851, 1649, 1609, 1602, 1575, 830, 750 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
3.44 (2H, t, J¼4.6 Hz), 3.54 (2H, t, J¼4.8 Hz), 3.65 (4H, s),
3.70 (2H, s), 7.13 (1H, d, J¼6.4 Hz), 7.23e7.29 (3H, m); 13C NMR
To an ice cold solution of crude oxime obtained above in CH2Cl2
(49.0 mL) was added triethylamine (Et3N) (3.40 mL, 24.4 mmol)
and 2,3,4,5,6-pentafluoro-benzoyl chloride (1.48 mL, 10.7 mmol)
slowly. The mixture was stirred at 0 ꢀC for 30 min and at room
temperature for another 30 min. The reaction was quenched with
water and the organic layer was extracted with ethyl acetate three
times. The extract was dried over MgSO4 and filtered. The solvents
were removed in vacuo. The crude material was purified by flash
column chromatography with hexaneeethyl acetate¼6:4 to give
the 1-morpholino-3-(perfluorobenzoyloxyimino)-2-phenylbutan-
1-one (2.58 g, 5.65 mmol) in 58% yield for three steps. Further
purification was done by recrystallization from a hexaneeethyl
acetate solvent system.
(100 MHz, CDCl3)
d 40.1, 42.2, 46.4, 66.4, 66.8, 126.8, 127.2, 128.8,
129.9, 134.5, 136.7, 168.8; ESIMS: found: m/z 240.0791. Calcd for
C12H15ClNO2: (MþH)þ 240.0791.
4.2.7. 2-(4-Bromophenyl)-1-morpholinoethanone (1c). Yield 92%;
colorless oil; FTIR (KBr) 2966, 2840, 1650, 1499, 1452, 1272, 1112,
1034, 816, 775 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.43 (2H, t,
J¼4.6 Hz), 3.53 (2H, t, J¼4.6 Hz), 3.67 (2H, s), 7.11 (2H, d, J¼8.4 Hz),
7.45 (2H, d, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 40.0, 42.2, 46.4,
66.4, 66.8, 120.9, 130.4, 131.8, 133.7, 169.0; ESIMS: found: m/z
284.0287. Calcd for C12H15NO2Br: (MþH)þ 284.0286.
4.2.8. 2-(3,5-Dibromophenyl)-1-morpholinoethanone
87%; Yellow oil; FTIR (KBr) 2930, 2855, 1628, 1584, 1553, 1458, 1112,
1036, 845, 740 cmꢁ1 1H NMR (400 MHz, CDCl3) 3.42e3.64 (10H,
(1e). Yield
White crystal; mp 113.6e114.7 ꢀC; FTIR (KBr) 3008, 2859, 1761,
1651, 1525, 1497, 1437, 1328, 1194, 1004, 754, 700 cmꢁ1 1H NMR
;
;
(400 MHz, CDCl3) d 2.04 (3H, s), 3.12e3.75 (8H, m), 5.06 (1H, s), 7.31

S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
5697
(2H, d, J¼7.2 Hz), 7.38e7.42 (3H, m); 13C NMR (100 MHz, CDCl3)
145.5 (dm, J¼272 Hz), 156.5, 167.2, 168.8; ESIMS: found: m/z
471.1342. Calcd for C22H20F5N2O4: (MþH)þ 471.1243.
d
15.4, 42.0, 46.2, 54.3, 66.0, 66.6, 106.7 (m), 128.4, 128.5, 129.5,
133.5, 137.7 (dm, J¼243 Hz), 144.4 (dm, J¼267 Hz), 145.5 (dm,
J¼250 Hz), 166.5, 167.8, 168.3; ESIMS: found: m/z 457.1187. Calcd for
C21H18F5N2O4: (MþH)þ 457.1187.
4.3.8. 2-(Biphenyl-4-yl)-1-morpholino-3-(perfluorobenzoyloxyimino)
butan-1-one(3h). Yield 61%; white solid; mp 80.0e81.7 ꢀC; FTIR (KBr)
2919, 2860, 1757, 1653, 1525, 1507, 1496, 1437, 1327, 1192, 1116, 1004,
4.3.2. 2-(4-Chlorophenyl)-1-morpholino-3-(perfluorobenzoyloxyimino)
butan-1-one (3b). Yield 36%; brown viscous oil; FTIR (KBr) 2924,
2859, 1761, 1651, 1524, 1497, 1435, 1327, 1192, 1115, 1092,
750, 699 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.09 (3H, s), 3.18e3.78
(8H, m), 5.10 (1H, s), 7.37e7.40 (3H, m), 7.46 (2H, dd, J¼7.6, 7.2 Hz), 7.59
(2H, d, J¼7.6 Hz), 7.65 (2H, d, J¼7.6 Hz); 13C NMR (75 MHz, CDCl3)
1003,758 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.05 (3H, s), 3.13e3.75
d 15.4, 42.1, 46.3, 54.0, 66.1, 66.6, 106.8 (m), 127.0, 127.8, 128.1, 128.8,
(8H, m), 5.04 (1H, s), 7.26e7.28 (2H, d, J¼8.0 Hz), 7.40 (2H, d,
128.9, 132.4, 139.8, 137.8 (dm, J¼250 Hz), 141.4, 143.5 (dm, J¼259 Hz),
145.5 (dm, J¼252 Hz), 156.5, 167.9,168.3; ESIMS: found: m/z 533.1490.
Calcd for C27H22F5N2O4: (MþH)þ 533.1500.
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 15.4, 42.1, 46.2, 53.6, 66.1,
66.6, 106.6 (m), 129.7, 129.8, 132.0, 134.7, 137.7 (dm, J¼245 Hz),
143.4 (dm, J¼256 Hz), 145.6 (dm, J¼255 Hz), 156.4, 167.5, 167.8;
ESIMS: found: m/z 491.0785. Calcd for C21H17ClF5N2O4: (MþH)þ
491.0797.
4.3.9. 1-Morpholino-2-(naphthalen-2-yl)-3-(perfluorobenzoyloxyimino)-
butan-1-one (3i). Yield 41%; white solid; mp 159.2e160.0 ꢀC; FTIR
(KBr) 3037, 2858, 1761, 1652, 1525, 1506, 1327, 1260, 1192, 1116,
4.3.3. 2-(4-Bromophenyl)-1-morpholino-3-(perfluorobenzoyloxyimino)-
butan-1-one (3c). Yield 35%; white solid; mp 91.3e92.7 ꢀC; FTIR
1092, 1003 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.07 (3H, s),
3.19e3.74 (8H, m), 5.22 (1H, s), 7.40 (1H, dd, J¼1.6, 8.5 Hz),
(KBr) 2851, 1751, 1646, 1525, 1497, 1437, 1327, 1192, 1003, 748 cmꢁ1
;
7.54e7.56 (2H, m), 7.79 (1H, s), 7.83e7.91 (3H, m); 13C NMR
1H NMR (400 MHz, CDCl3)
d
2.04 (3H, s), 3.12e3.74 (8H, m), 5.01
(75 MHz, CDCl3) d 15.5, 42.1, 46.2, 54.4, 66.1, 66.6, 106.8 (m), 125.6,
(1H, s), 7.21 (2H, d, J¼8.4 Hz), 7.55 (2H, d, J¼8.4 Hz); 13C NMR
126.9, 127.0, 127.6, 127.8, 127.9, 129.5, 130.9, 132.9, 133.4, 137.7 (dm,
J¼255 Hz), 143.5 (dm, J¼259 Hz), 145.5 (dm, J¼259 Hz), 156.6,
168.0, 168.3; ESIMS: found: m/z 507.1329. Calcd for C25H20F5N2O4:
(MþH)þ 507.1343.
(100 MHz, CDCl3) d 15.4, 42.1, 46.2, 53.7, 66.1, 66.6, 106.6 (m), 122.8,
130.1, 132.6, 132.7, 137.8 (dm, J¼250 Hz), 143.6 (dm, J¼259 Hz),
145.5 (dm, J¼263 Hz), 156.4, 167.4, 167.8; ESIMS: found: m/z
535.0292. Calcd for C21H17BrF5N2O4: (MþH)þ 535.0292.
4.3.10. 1-Morpholino-3-(perfluorobenzoyloxyimino)-2-phenylhexan-
1-one (3j). Yield 47%; white crystal; mp 108.0e109.0 ꢀC; FTIR (KBr)
2967,2858, 1759, 1651, 1524, 1497, 1435, 1327, 1184, 1115, 1005, 756,
4.3.4. 2-(4-Fluorophenyl)-1-morpholino-3-(perfluorobenzoyloxyimino)-
butan-1-one (3d). Yield 63%; white solid; mp 46.5e51.1 ꢀC; FTIR
(KBr) 2960, 2860, 1764, 1652, 1525, 1506, 1437, 1328, 1228, 1193,
702 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 0.53e0.63 (1H, m), 0.67 (3H,
1116, 1004, 757 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.03 (3H, s),
3.12e3.73 (8H, m), 5.03 (1H, s), 7.08e7.13 (2H, m), 7.26e7.31 (2H,
m); 13C NMR (75 MHz, CDCl3)
15.3, 42.1, 46.2, 53.5, 66.1, 66.6,
t, J¼6.9 Hz), 1.28e1.40 (2H, m), 2.35 (1H, dt, J¼11.9 Hz, 5.0 Hz), 2.68
(1H, dt, J¼11.9, 5.0 Hz), 3.17e3.74 (8H, m), 5.01 (1H, s), 7.32e7.41
d
(5H, m); 13C NMR (100 MHz, CDCl3)
d 14.4, 20.0, 32.4, 42.1, 46.2,
106.7 (m), 116.5 (d, J¼21.6 Hz), 129.3 (d, J¼3.5 Hz), 130.2 (d,
J¼8.2 Hz), 137.7 (dm, J¼247 Hz), 143.5 (dm, J¼264 Hz), 144.5 (dm,
J¼263 Hz), 156.5, 162.6 (d, J¼247 Hz), 167.7, 168.0; ESIMS: found:
m/z 475.1084. Calcd for C21H17F6N2O4: (MþH)þ 475.1093.
54.3, 66.0, 66.6, 106.9 (m), 128.6 (overlapped), 129.4, 133.3, 137.8
(dm, J¼232 Hz), 143.5 (dm, J¼245 Hz), 145.4 (dm, J¼260 Hz), 156.7,
168.1, 171.0; ESIMS: found: m/z 485.1504. Calcd for C23H22F5N2O4:
(MþH)þ 485.1500.
4.3.5. 2-(3,5-Dibromophenyl)-1-morpholino-3-(perfluorobenzoyl-
oxyimino)butan-1-one (3e). Yield 21%; yellow oil; FTIR (KBr) 2870,
4.3.11. 4-Cyclohexyl-1-morpholino-3-(perfluorobenzoyloxyimino)-2-
phenylbutan-1-one (3k). Yield 23%; white powder; mp
135.0e135.5 ꢀC; FTIR (KBr) 2926, 2854, 1762, 1653, 1521, 1496, 1452,
1760, 1652, 1555, 1528, 1332, 1189, 1001, 758 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
2.07 (3H, s), 3.16e3.75 (8H, m), 4.98 (1H, s), 7.43
15.4, 42.3, 46.4,
1434, 1326, 1240, 1201, 1115, 1036, 1003, 702 cmꢁ1 1H NMR
;
(2H, s), 7.69 (1H, s); 13C NMR (75 MHz, CDCl3)
d
(400 MHz, CDCl3)
7.0 Hz), 2.62 (1H, dd, J¼13.2 Hz, 7.0 Hz), 3.15e3.77 (8H, m), 4.97
(1H, s), 7.29e7.39 (5H, m); 13C NMR (100 MHz, CDCl3)
25.8, 26.0,
d
0.45e1.60 (11H, m), 2.47 (1H, dd, J¼13.2 Hz,
53.3, 66.1, 66.6, 106.7 (m), 124.0, 130.2, 134.5, 137.9 (dm, J¼265 Hz),
137.4, 142.4 (dm, J¼244 Hz), 144.6 (dm, J¼383 Hz), 156.4, 166.5,
167.1; ESIMS: found: m/z 612.9358. Calcd for C25H20F5N2O4:
(MþH)þ 612.9397.
d
26.1, 32.9, 33.1, 36.0, 37.5, 42.2, 46.3, 54.6, 66.0, 66.6, 107.2 (m),
128.4, 128.8, 129.2, 133.7, 137.8 (dm, J¼265 Hz), 143.3 (dm,
J¼258 Hz), 145.0 (dm, J¼272 Hz), 157.0, 168.1, 169.5; ESIMS: found:
m/z 539.1959. Calcd for C27H28F5N2O4: (MþH)þ 539.1969.
4.3.6. 2-(3-Chlorophenyl)-1-morpholino-3-(perfluorobenzoyloxyimino)
butan-1-one (3f). Yield 48%; white solid; mp 53.5e55.5 ꢀC; FTIR
(KBr) 2975, 2859, 1762, 1653, 1525, 1506, 1499, 1437, 1328, 1192,
4.3.12. 1-Morpholino-3-(perfluorobenzoyloxyimino)-2,4-diphenylbu-
tan-1-one (3l). Yield 20%; yellow viscous oil; FTIR (KBr) 3105, 2860,
1762, 1646, 1525, 1496, 1454, 1437, 1327, 1231, 1198, 1116, 1003, 754,
1116, 1004, 701 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
2.06 (3H, s),
3.13e3.78 (8H, m), 5.03 (1H, s), 7.21e7.24 (1H, m), 7.33 (1H, s),
7.35e7.37 (2H, m); 13C NMR (100 MHz, CDCl3)
15.4, 42.2, 46.3,
d
703 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
3.03e3.86 (8H, m), 3.84 (1H,
d, J¼15.3 Hz), 4.12 (1H, d, J¼15.3 Hz), 4.91 (1H, s), 6.83e7.30 (10H,
m); 13C NMR (75 MHz, CDCl3)
36.0, 42.2, 46.0, 53.7, 65.9, 66.5,
53.8, 66.1, 66.6, 106.8 (m), 126.6, 128.6, 128.9, 130.7, 135.5, 135.6,
137.7 (dm, J¼249 Hz), 143.5 (dm, J¼254 Hz), 145.6 (dm, J¼256 Hz),
156.4, 167.2, 167.7; ESIMS: found: m/z 491.0788. Calcd for
C21H17ClF5N2O4: (MþH)þ 491.0797.
d
106.9 (m), 126.6, 128.3, 128.4, 128.6, 129.0, 129.1, 132.8, 134.7, 137.5
(dm, J¼244 Hz), 143.2 (dm, J¼258 Hz), 144.9 (dm, J¼249 Hz), 156.9,
167.7, 168.2; ESIMS: found: m/z 533.1494. Calcd for C27H22F5N2O4:
(MþH)þ 533.1500.
4.3.7. 1-Morpholino-3-(perfluorobenzoyloxyimino)-2-o-tolylbutan-
1-one (3g). Yield 21%; brown oil; FTIR (KBr) 2973, 2859, 1762, 1652,
1525,1506,1496,1437,1328,1259,1228,1193,1116,1004, 757 cmꢁ1
;
4.3.13. 1-Morpholino-3-(perfluorobenzoyloxyimino)-2,5-diphe-
nylpentan-1-one (3m). Yield 44%; white solid; mp 54.0e56.7 ꢀC;
FTIR (KBr) 3040, 2859, 1761, 1647, 1524, 1497, 1456, 1327, 1192, 1115,
1H NMR (300 MHz, CDCl3)
(8H, m), 5.08 (1H, s), 7.23e7.29 (4H, m); 13C NMR (100 MHz, CDCl3)
15.5, 19.5, 42.0, 45.9, 51.9, 65.9, 66.6, 106.9 (m), 126.8, 128.3, 128.7,
131.4, 131.6, 137.6 (dm, J¼255 Hz), 136.8, 143.4 (dm, J¼254 Hz),
d 2.02 (3H, s), 2.38 (3H, s), 2.93e3.81
d
1003, 754, 702 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.79e3.76 (12H,
m), 4.98 (1H, s), 6.84 (2H, d, J¼7.3 Hz), 7.15e7.46 (8H, m); 13C NMR

5698
S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
(100 MHz, CDCl3)
d
32.3, 32.4, 42.1, 46.1, 54.5, 66.0, 66.6, 106.8 (m),
was used to purify to give indole product, (2-Methyl-1H-indol-3-yl)
(morpholino)methanone (45.8 mg, 0.187 mmol) in 82% yield. Further
purification was done by recrystallization method.
126.2, 128.0, 128.4, 128.7 (overlapped), 129.5, 133.2, 137.7 (dm,
J¼251 Hz),140.5,143.5 (dm, J¼265 Hz),145.4 (dm, J¼263 Hz),156.6,
168.0, 169.9; ESIMS: found: m/z 547.1647. Calcd for C28H24F5N2O4:
(MþH)þ 547.1656.
Yield 82%; 1H NMR (300 MHz, CDCl3)
d
2.37 (3H, s), 3.67e3.72
(8H, m), 7.12e7.14 (2H, m), 7.20e7.21 (1H, m), 7.45e7.47 (1H, m),
8.80 (1H, br); 13C NMR (75 MHz, CDCl3)
12.6, 67.3 (overlapped),
d
4 . 3 .14 . 3 - ( 3 - B r o m o p h e n y l ) - 1 - m o r p h o l i n o - 3 - ( p e r -
fluorobenzoyloxyimino)-2-phenylpropan-1-one (3n). Yield 44%;
white solid; mp 134.1e135.9 ꢀC; FTIR (KBr) 2858, 1763, 1651, 1524,
107.9, 110.8, 118.8, 120.7, 121.8, 126.1, 134.7, 137.8, 167.7.
4.4.2. (6-Chloro-2-methyl-1H-indol-3-yl)(morpholino)methanone
1499, 1535, 1327, 1190, 1005, 756, 714 cmꢁ1
;
1H NMR (400 MHz,
(4b). Yield 70%; viscous oil; FTIR (KBr) 3019, 2890,1593,1566,1470,
CDCl3)
d
3.13e3.76 (8H, m), 5.33 (1H, s), 6.96 (1H, d, J¼7.6 Hz),
1427, 1117, 1022, 756 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 2.41
7.07e7.11 (2H, m), 7.16e7.18 (2H, m), 7.32e7.34 (3H, m), 7.39 (1H, d,
(3H, s), 3.46e3.60 (8H, m), 7.05 (1H, dd, J¼1.6, 8.4 Hz), 7.36 (1H, d,
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 42.3, 46.4, 55.8, 65.9, 66.5,
J¼1.6 Hz), 7.40 (1H, d, J¼8.4 Hz), 11.58 (1H, br); 13C NMR (100 MHz,
106.4 (m), 121.4, 126.7, 128.6, 129.0, 129.1, 129.2, 130.6, 132.0, 132.8,
133.3, 137.5 (dm, J¼254 Hz), 143.5 (dm, J¼259 Hz), 145.1 (dm,
J¼262 Hz), 156.6, 166.8, 167.7; ESIMS: found: m/z 597.0438. Calcd
for C26H19BrF5N2O4: (MþH)þ 597.0448.
DMSO-d6) d 12.5, 66.4 (overlapped), 107.2, 110.7, 119.8, 120.1, 124.8,
125.6, 135.1, 138.8, 166.0; ESIMS: found: m/z 279.0905. Calcd for
C14H16ClN2O2: (MþH)þ 279.0900.
4.4.3. (6-Bromo-2-methyl-1H-indol-3-yl)(morpholino)methanone
4.3.15. N,N-Dimethyl-3-(perfluorobenzoyloxyimino)-2-phenyl-
butanamide (3o). Yield 47%; white crystal; mp 104.5e115.8 ꢀC; FTIR
(4c). Yield 75%; brown solid; mp >250 ꢀC; FTIR (KBr) 3020, 2895,
1653, 1590, 1560, 1542, 1474, 1430, 1116, 1023, 753 cmꢁ1 1H NMR
;
(KBr) 3019, 1762, 1657, 1526, 1420, 1332, 1218, 1007, 777 cmꢁ1
;
1H
(300 MHz, DMSO-d6)
J¼1.7, 8.5 Hz), 7.32 (1H, d, J¼8.5 Hz), 7.47 (1H, d, J¼1.7 Hz), 11.56
(1H, br); 13C NMR (75 MHz, DMSO-d6)
12.4, 66.4 (overlapped),
d 2.38 (3H, s), 3.44e3.57 (8H, m), 7.14 (1H, dd,
NMR (400 MHz, CDCl3)
d
2.05 (3H, s), 2.84 (3H, s), 3.02 (3H, s), 5.09
15.3, 35.6,
(1H, s), 7.30e7.40 (5H, m); 13C NMR (100 MHz, CDCl3)
d
d
37.3, 54.4, 106.8 (m), 128.3, 128.4, 129.3, 133.7, 137.7 (dm, J¼251 Hz),
143.4 (dm, J¼259 Hz), 145.5 (dm, J¼251 Hz), 156.5, 168.7, 169.2;
ESIMS: found: m/z 415.1080. Calcd for C19H16F5N2O3: (MþH)þ
415.1081.
107.3, 113.5, 113.6, 120.2, 122.7, 125.0, 135.5, 138.8, 165.9; ESIMS:
found: m/z 323.0393. Calcd for C14H16BrN2O2: (MþH)þ 323.0395.
4.4.4. (6-Fluoro-2-methyl-1H-indol-3-yl)(morpholino)methanone
(4d). Yield 70%; yellow solid; mp >250 ꢀC; FTIR (KBr) 3020, 1653,
4.3.16. 3-(Perfluorobenzoyloxyimino)-2-phenyl-1-(piperidin-1-yl)
butan-1-one (3p). Yield 33%; yellow oil; FTIR (KBr) 2941, 2859,
1559, 1539, 1506, 1465, 1419, 1114, 750 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
2.32 (3H, s), 3.66e3.71 (8H, m), 6.87e6.92 (2H, m),
12.6,
1762, 1642, 1523, 1497, 1444, 1328, 1004, 755, 703 cmꢁ1
;
1H NMR
7.35e7.39 (1H, m), 8.86 (1H, br); 13C NMR (100 MHz, CDCl3)
d
(400 MHz, CDCl3)
m), 5.09 (1H, s), 7.27e7.42 (5H, m); 13C NMR (100 MHz, CDCl3)
15.5, 24.2, 25.4, 25.7, 42.8, 46.9, 54.5, 106.9 (m), 128.2, 128.5, 129.3,
134.1, 136.4 (dm, J¼248 Hz), 142.1 (dm, J¼263 Hz), 144.2 (dm,
J¼257 Hz), 156.6, 167.5, 168.8; ESIMS: found: m/z 455.1395. Calcd
for C22H20F5N2O3: (MþH)þ 455.1394.
d
1.11e1.68 (6H, m), 2.04 (3H, s), 3.13e3.75 (4H,
67.2 (overlapped), 97.4 (d, J¼26 Hz), 107.9, 109.3 (d, J¼23 Hz), 119.5
(d, J¼9.8 Hz), 122.6, 134.7 (d, J¼12.4 Hz), 137.7 (d, J¼3.1 Hz), 159.6
(d, J¼237 Hz), 167.3; ESIMS: found: m/z 263.1195. Calcd for
C14H16FN2O2: (MþH)þ 263.1196.
d
4.4.5. (5,7-Dibromo-2-methyl-1H-indol-3-yl)(morpholino)meth-
anone (4e). Yield 33%; yellow oil; FTIR (KBr) 2960, 2980, 1624, 1567,
4.3.17. 3-(Benzoyloxyimino)-1-morpholino-2-phenylbutan-1-one
1479, 1441, 1429, 1186, 1113, 1019, 752 cmꢁ1 1H NMR (400 MHz,
;
(3ab). Yield 70%; white crystal; mp 133.5e134.5 ꢀC; FTIR (KBr)
DMSO-d6)
d
2.56 (3H, s), 3.64e3.72 (8H, m), 7,45 (1H, s), 7.58 (1H, s),
12.9, 67.2 (overlapped),
3010, 1737, 1643, 1523, 1435, 1215, 1062, 752, 669 cmꢁ1
;
1H NMR
8.42 (1H, br); 13C NMR (100 MHz, DMSO-d6)
d
(300 MHz, CDCl3)
d
2.12 (3H, s), 3.16e3.77 (8H, m), 5.13 (1H, s),
104.6, 109.3, 114.0, 120.9, 126.7, 128.3, 132.3, 139.0, 166.1; ESIMS:
7.33e7.61 (8H, m), 8.07 (2H, d, J¼8.4 Hz); 13C NMR (75 MHz, CDCl3)
found: m/z 402.9481. Calcd for C14H15N2O2Br2: (MþH)þ 402.9480.
d
15.1, 42.0, 46.2, 54.5, 66.1, 66.6, 128.3, 128.4, 128.5, 128.9, 129.4,
129.6, 133.3, 134.1, 163.9, 166.5, 168.3; ESIMS: found: m/z 367.1659.
4.4.6. (5-Chloro-2-methyl-1H-indol-3-yl)(morpholino)methanone
Calcd for C21H23N2O4: (MþH)þ 367.1658.
(4f). Yield 59%; white solid; mp 165.0e166.0 ꢀC; FTIR (KBr) 2900,
2810, 1639, 1461, 1436, 1421, 1263, 1215, 1116, 1022, 758 cmꢁ1 1H
;
4.3.18. 3-(Acetoxyimino)-1-morpholino-2-phenylbutan-1-one
NMR (400 MHz, CDCl3)
d
2.06 (3H, s), 3.65e3.71 (8H, m), 7.01 (2H,
12.2, 67.2
(3ac). Yield 74%; colorless oil; FTIR (KBr) 3018, 1759, 1643, 1435,
s), 7.40 (1H, s), 9.86 (1H, br); 13C NMR (100 MHz, CDCl3)
d
1367, 1215, 1114, 1001, 756, 669 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
(overlapped), 107.0, 112.1, 117.8, 122.0, 126.3, 126.9, 133.2, 139.3,
167.5; ESIMS: found: m/z 279.0880. Calcd for C14H16ClN2O2:
(MþH)þ 279.0900.
d
1.97 (3H, s), 2.16 (3H, s), 3.09e3.77 (8H, m), 5.01 (1H, s), 7.28e7.42
(5H, m); 13C NMR (75 MHz, CDCl3)
d
14.8, 19.4, 41.9, 46.1, 54.3, 65.9,
66.5, 128.1, 128.2,129.3,134.0,165.6,168.2, 168.3; ESIMS: found: m/z
305.1503. Calcd for C16H21N2O4: (MþH)þ 305.1501.
4.4.7. (7-Chloro-2-methyl-1H-indol-3-yl)(morpholino)methanone
(4f). Yield 40%; light yellow viscous oil; FTIR (KBr) 3268, 2900,
4.4. Synthesis of indoles
2854, 1626, 1609, 1468, 1447, 1426, 1119, 1115, 1019, 749 cmꢁ1 1H
;
NMR (400 MHz, CDCl3)
dd, J¼7.6, 7.6 Hz), 7.15 (1H, d, J¼7.6 Hz), 7.38 (1H, d, J¼7.6 Hz), 8.60
(1H, s); 13C NMR (100 MHz, CDCl3)
12.8, 67.2 (overlapped), 109.3,
d 2.55 (3H, s), 3.65e3.71 (8H, br), 7.08 (1H,
4.4.1. (2-Methyl-1H-indol-3-yl)(morpholino)methanone (4a)7a (a
typical procedure). To
a
solution of 1-morpholino-3-(per-
d
fluorobenzoyloxyimino)-2-phenylbutan-1-one (105 mg, 0.230 mmol)
in ClCH2CH2Cl (3.80 mL) were added PdCl2(MeCN)2 (15.0 mg,
0.057 mmol)and MgO (46.3 mg,1.15 mmol). The mixturewas stirred at
reflux for 3 h. After the reaction has finished, most of the solvent was
removed by vacuo. The crude material was then purified by column
chromatography. The silica gel was treated with hexane and Et3N so-
lution (hexaneeEt3N¼99:1). The eluent (Ethyl acetateeEt3N¼99:1)
116.2,117.6,121.3,121.6,127.5,131.9,138.2,166.8; ESIMS: found: m/z
279.0880. Calcd for C14H16ClN2O2: (MþH)þ 279.0900.
4.4.8. (2,4-Dimethyl-1H-indol-3-yl)(morpholino)methanone (4g).
Yield 46%; brown viscous oil; FTIR (KBr) 3249, 2859,1639,1604,1477,
1438, 1420, 1359, 1230, 1116, 1022, 752 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d 2.40 (3H, s), 2.49 (3H, s), 3.38e3.91 (8H, m), 6.88 (1H, d,

S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
5699
J¼7.2 Hz), 7.04 (1H, dd, J¼8.0, 7.2 Hz), 7.12 (1H, d, J¼8.0 Hz), 8.06 (1H,
s); 13C NMR (100 MHz, CDCl3)
11.8,19.1, 42.3, 47.7, 67.0,108.0,108.4,
121.4, 121.9, 125.3, 129.1, 132.7, 135.3, 168.6; ESIMS: found: m/z
259.1443. Calcd for C15H19N2O2: (MþH)þ 259.1447.
J¼8.4 Hz), 7,68 (1H, s), 9.12 (1H, br); 13C NMR (75 MHz, CDCl3)
d
66.7
d
(overlapped), 108.7, 111.4, 119.7, 121.2, 122.9, 123.5, 125.9, 127.2,
130.1, 130.5, 131.5, 133.3, 134.5, 135.8, 168.7; ESIMS: found: m/z
385.0548. Calcd for C19H18BrN2O2: (MþH)þ 385.0552.
4.4.9. (2-Methyl-6-phenyl-1H-indol-3-yl)(morpholino)methanone
4.4.16. (3-(3-Bromophenyl)-2-phenyl-2H-azirin-2-yl)(morpholino)
(4h). Yield 72%; brown solid; mp >250 ꢀC; FTIR (KBr) 2963, 2856,
methanone (5n). Yield 32%; yellow viscous liquid; FTIR (KBr) 2973,
1653, 1601, 1559, 1507, 1467, 1433, 1264, 1115, 1008, 698 cmꢁ1
;
1H
2913, 2857, 1741, 1637, 1564, 1497, 1438, 1114, 749 cmꢁ1 1H NMR
;
NMR (400 MHz, CDCl3)
(1H, d, J¼7.1 Hz), 7.37e7.40 (4H, m), 7.40e7.52 (3H, m), 9.25 (1H, br);
13C NMR (100 MHz, CDCl3)
12.6, 67.3 (overlapped), 107.6, 109.4,
d
2.30 (3H, s), 3.72 (8H, br), 7.26, (1H, s), 7.30
(300 MHz, CDCl3) d 3.55e3.95 (8H, m), 7.19e7.44 (7H, m), 7.72 (1H,
d, J¼8.7 Hz), 7.98 (1H, d, J¼7.8 Hz), 8.17 (1H, br); 13C NMR (75 MHz,
d
CDCl3) d 42.1, 46.7, 66.6, 66.8, 123.2, 124.5, 125.1, 127.8, 128.8, 129.1,
118.9, 120.5, 125.4, 126.7, 127.2, 128.7, 135.3, 135.4, 138.7, 141.8, 167.8;
130.8, 133.1, 136.6, 137.3, 162.3, 168.0; ESIMS: found: m/z 385.0555.
ESIMS:found: m/z321.1603. CalcdforC20H21N2O2:(MþH)þ 321.1603.
Calcd for C19H18BrN2O2: (MþH)þ 385.0552.
4.4.10. (2-Methyl-1H-benzo[g]indol-3-yl)(morpholino)methanone
(4i). Yield 87%; yellow solid; mp 205.4e206.5 ꢀC; FTIR (KBr) 3185,
3020, 1589, 1560, 1539, 1507, 1490, 1465, 1437, 1109, 1021, 756,
4.4.17. N,N,2-Trimethyl-1H-indole-3-carboxamide (4o). Yield 68%;
white solid; mp 225.4e226.1 ꢀC; FTIR (KBr) 3019, 1653, 1601, 1576,
1507, 1215, 1064, 668 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.45 (3H,
s), 3.10 (6H, s), 7.11e7.27 (3H, m), 7.45 (1H, m), 8.37 (1H, br); 13C
NMR (100 MHz, CDCl3) 12.7 (overlapped),109.1,110.6,119.4,120.5,
669 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
2.50 (3H, s), 3.53e3.63
(8H, m), 7.39e8.33 (6H, m), 9.28 (1H, br); 13C NMR (100 MHz,
DMSO-d6) 12.5, 66.4 (overlapped), 108.9, 119.0, 120.4, 120.5, 121.4,
d
d
121.6, 126.5, 134.7, 136.8, 168.6; ESIMS: found: m/z 203.07. Calcd for
121.7, 123.6, 125.6, 128.3, 128.9, 129.3, 135.2, 166.5; ESIMS: found:
C12H15N2O: (MþH)þ 203.12.
m/z 295.1440. Calcd for C18H19N2O2: (MþH)þ 295.1447.
4.4.18. (2-Methyl-1H-indol-3-yl)(piperidin-1-yl)methanone (4p). Yield
4.4.11. Morpholino(2-propyl-1H-indol-3-yl)methanone (4j). Yield
73%; brown oil; FTIR (KBr) 3380, 3020, 1653, 1601, 1576, 1507, 1459,
51%; yellow viscous liquid; FTIR (KBr) 3273, 3017, 2862, 1605, 1460,
1426, 1395, 1179, 1065, 749 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
1443, 1115, 1016, 756 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.88 (3H, t,
d 1.58e1.65 (6H, m), 1.98 (3H, s), 3.58 (4H, m), 6.99e7.06 (3H, m),
J¼7.2 Hz), 1.65 (2H, m), 2.74 (2H, br), 3.67e3.72 (8H, br), 7.11e7.12
7.43 (1H, d, J¼7.6 Hz), 10.00 (1H, br); 13C NMR (100 MHz, CDCl3)
(2H, m), 7.24e7.25 (1H, m), 7.43 (1H, dd, J¼5.6, 2.8 Hz), 8.87 (1H,
d
12.0, 24.6 (overlapped), 26.4, 107.9, 111.1, 118.4, 119.9, 121.1, 126.2,
br); 13C NMR (75 MHz, CDCl3)
d
13.7, 22.8, 28.7, 67.3 (overlapped),
134.9, 137.4, 168.0; ESIMS: found: m/z 243.1494. Calcd for
107.7, 111.0, 118.8, 120.6, 121.7, 125.8, 134.5, 142.2, 167.7; ESIMS:
C15H19N2O: (MþH)þ 243.1497.
found: m/z 273.1595. Calcd for C16H21N2O2: (MþH)þ 273.1603.
4.5. A reaction of deuterium-labeled oxime 3oed
4.4.12. (2-(Cyclohexylmethyl)-1H-indol-3-yl)(morpholino)meth-
anone (4k). Yield 91%; white solid; mp >250 ꢀC; FTIR (KBr) 3017,
4.5.1. Synthesis of amide 1oed17. To an ice cold stirred solution of
2-deuteriobenzaldehyde (6)18 (1.28 g, 11.9 mmol) and CBr4 (5.90 g,
18.0 mmol) in dry CH2Cl2 (95 mL) was added PPh3 (9.40 g,
36.0 mmol) in CH2Cl2 (90 mL) with a dropping funnel for 10 min.
After the reaction was completed, the reaction mixture was con-
centrated under reduced pressure and then CHCl3 (20 mL) was
added to the residue. The suspended mixture was filtered to
remove triphenylphosphine oxide that was washed with CHCl3. The
combined filtrates were concentrated under reduced pressure and
the resulting crude mixture of dibromoalkene 7 was used for next
step without any purification.
To a solution of dimethylamine (50.0 mL, 40% in water) was
added dibromoalkene 7 prepared above at room temperature. After
stirring for 3 h, the resulting mixture was concentrated under re-
duced pressure to remove excess amine. Aqueous HCl (3 N, 20 mL)
solution was added to the residue, and the resulting mixture was
extracted with CHCl3. The combined organic layers were washed
with a saturated aqueous NaHCO3 solution and then, dried over
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified with column chromatography
to give the pure product, labeled N,N-dimethyl-2-phenylacetamide
(1oed) (1.06 g, 6.45 mmol) in 54% yield.
2926, 1653, 1558, 1539, 1507, 1457, 1437, 1419, 1112, 1020, 754 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6)
J¼7.2 Hz), 3.49e3.66 (8H, m), 7.01e7.10 (2H, m), 7.32e7.39 (2H, m),
11.37 (1H, br); 13C NMR (100 MHz, DMSO-d6)
25.6, 25.9, 32.5, 33.6,
d 0.89e1.70 (11H, m), 2.72 (2H, d,
d
37.8, 66.4 (overlapped), 107.5, 111.2, 118.3, 119.9, 120.9, 125.3, 134.4,
141.1, 166.5; ESIMS: found: m/z 327.2072. Calcd for C20H27N2O2:
(MþH)þ 327.2073.
4.4.13. (2-Benzyl-1H-indol-3-yl)(morpholino)methanone (4l). Yield
62%; brown solid; mp >250 ꢀC; FTIR (KBr) 3017, 2925, 1605, 1499,
1460, 1443, 1272, 1115, 1016, 1003, 750 cmꢁ1
;
1H NMR (400 MHz,
CDCl3)
d 3.45 (8H, m), 4.16 (2H, s), 7.06e7.29 (7H, m), 7.34 (2H, d,
J¼8.4 Hz), 7.39 (1H, d, J¼7.2 Hz), 11.52 (1H, br); 13C NMR (75 MHz,
CDCl3)
d 32.1, 66.3 (overlapped), 107.4, 111.5, 118.5, 120.1, 121.1,
125.2, 126.2, 128.3, 128.5, 134.5, 139.3, 140.8, 166.3; ESIMS: found:
m/z 321.1606. Calcd for C20H21N2O2: (MþH)þ 321.1603.
4.4.14. Morpholino(2-phenethyl-1H-indol-3-yl)methanone (4m). Yield
55%; Yellow solid; mp >250 ꢀC; FTIR (KBr) 3240, 2922, 1601, 1495,
1462, 1331, 1271, 1115, 1020, 748 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
2.87 (2H, t, J¼7.0 Hz), 2.99 (2H, br), 3.63 (8H, br), 7.02 (2H, d,
J¼6.9 Hz), 7.09e7.11 (2H, m), 7.17e7.22 (4H, m), 7.40 (1H, d,
White viscous liquid; FTIR (KBr) 3018, 1648, 1633, 1477, 1480,
J¼7.1 Hz), 9.16 (1H, br); 13C NMR (100 MHz, CDCl3)
d
28.3, 35.5, 67.2
767 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.94 (6H, s), 3.70 (2H, s),
(overlapped), 107.9, 111.1, 118.7, 120.6, 121.8, 125.5, 126.2, 128.3,
128.4, 134.6, 140.7, 141.5, 167.7; ESIMS: found: m/z 335.1757. Calcd
for C21H23N2O2: (MþH)þ 335.1760.
7.22e7.30 (4H, m); 13C NMR (100 MHz, CDCl3)
d
35.5, 37.4, 40.7,
126.4, 128.2, 128.3, 128.5, 134.8, 170.7; ESIMS: found: m/z 165.1134.
Calcd for C10H13DNO: (MþH)þ 165.1138.
4.4.15. (2-(3-Bromophenyl)-1H-indol-3-yl)(morpholino)methanone
(4n). Yield 49%; white solid; mp 217.6e218.0 ꢀC; FTIR (KBr) 3261,
2973, 2919, 2864, 1606, 1482, 1480, 1359, 1226, 1113, 1002,
4.5.2. Synthesis of oxime 3oed. The same procedures with as in
Section 4.3.1 was applied starting from amide 1oed (0.636 g,
3.87 mmol) to afford 3oed (0.559 g, 1.35 mmol) in 35% yield.
Yield 35%; white crystal; mp 104.6e115.7 ꢀC; FTIR (KBr) 3015,
749 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
3.11e3.90 (8H, m), 7.12e7.28
(4H, m), 7.36 (1H, d, J¼7.6 Hz), 7.42 (1H, d, J¼9.2 Hz), 7.59 (1H, d,
2935, 1747, 1642, 1579, 1540, 1500, 1324, 989, 758, 711 cmꢁ1 1H
;

5700
S. Chiba et al. / Tetrahedron 66 (2010) 5692e5700
3. For recent reviews on the synthesis of indoles, see: (a) Humphrey, G. R.; Kuethe,
NMR (300 MHz, CDCl3)
d
2.04 (3H, s), 2.83 (3H, s), 3.01 (3H, s), 5.08
15.4, 35.6,
J. T. Chem. Rev. 2006, 106, 2875; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873; (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079; (d)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127; (e) Gilchrist, T. L.
J. Chem. Soc., Perkin Trans. 1 2001, 2491; (f) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045.
(1H, s), 7.30e7.40 (4H, m); 13C NMR (75 MHz, CDCl3)
d
37.4, 54.4, 109.9 (m), 128.3, 128.4, 129.3, 129.4, 133.6, 137.7 (dm,
J¼248 Hz),143.5 (dm, J¼277 Hz),145.6 (dm, J¼259 Hz),156.6, 168.7,
169.3; ESIMS: found: m/z 416.1132. Calcd for C19H15DN2O3F5:
(MþH)þ 416.1144.
4. For recent selected reports on the synthesis of indoles, see: (a) Nakamura, I.;
Sato, Y.; Terada, M. J. Am. Chem. Soc. 2009, 131, 4198; (b) Barluenga, J.; Jiménez-
Aquino, A.; Aznar, F.; Valdés, C. J. Am. Chem. Soc. 2009, 131, 4031; (c) Nicolaou,
K. C.; Krasovskiy, A.; Majumder, U.; Trépanier, V. È.; Chen, D. Y.-K. J. Am. Chem.
Soc. 2009, 131, 3690; (d) Isono, N.; Lautens, M. Org. Lett. 2009, 11, 1329; (e)
Nakamura, I.; Nemoto, T.; Shiraiwa, N.; Terada, M. Org. Lett. 2009, 11, 1055; (f)
Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11, 221; (g) Stuart,
D. R.; Bertland-Laperle, M.; Burgess, K. M. V.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 16474; (h) Cui, S.-L.; Wang, J.; Wang, Y.-G. J. Am. Chem. Soc. 2008, 130,
4.5.3. Indole formation using oxime 3oed (Scheme 4). The same
procedures with as in Section 4.4.1 was applied starting from oxime
3oed (95.0 mg, 0.228 mmol) to afford 4oed and 4o (22.7 mg,
0.111 mmol) in 49% yield.
Yield 49%; white solid; mp 225.4e226.0 ꢀC; FTIR (KBr) 3019,
€
13526; (i) Würtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew.
1642, 1602, 1504, 1422, 1215, 743, 666 cmꢁ1 1H NMR (300 MHz,
;
Chem., Int. Ed. 2008, 47, 7230; (j) Shen, M.; Leslie, B. E.; Driver, T. G. Angew.
Chem., Int. Ed. 2008, 47, 5056; (k) Pei, T.; Chen, C.-y.; Dormer, P. G.; Davies, I. W.
Angew. Chem., Int. Ed. 2008, 47, 4231; (l) Leogane, O.; Lebel, H. Angew. Chem., Int.
Ed. 2008, 47, 350; (m) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int. Ed. 2008, 47,
346; (n) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am.
Chem. Soc. 2007, 129, 7500.
DMSO-d6)
d
2.37 (3H, s), 2.95 (6H, s), 7.00e7.31 (3.5H, m), 11.3 (1H,
12.5 (overlapped), 110.9, 118.8,
br); 13C NMR (75 MHz, DMSO-d6)
d
119.5, 119.6, 120.7, 134.6, 136.9, 167.2; ESIMS: found: m/z 204.1243.
Calcd for C12H14DN2O: (MþH)þ 204.1247.
5. (a) Neber, P. W.; Friedolsheim, A. Justus Liebigs Ann. Chem. 1926, 449, 109; (b) For
a review, see: O’Brien, C. Chem. Rev. 1964, 64, 81.
Acknowledgements
6. (a) House, H. O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 2271; (b) Ooi, T.;
Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640.
7. (a) Chiba, S.; Hattori, G.; Narasaka, K. Chem. Lett. 2007, 36, 52; (b) Savarin, C. G.;
Grisé, C.; Murry, J. A.; Reamer, R. A.; Hughes, D. L. Org. Lett. 2007, 9, 981.
8. The stereochemistry of oxime 3aa was determined by X-ray crystallographic
analysis. CCDC-767809 contains the supplementary crystallographic data.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/conts/retrieving.html.
9. The stereochemistry of oxime 3n was determined by X-ray crystallographic
analysis. CCDC-767810 contains the supplementary crystallographic data.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/conts/retrieving.html.
This work was supported by funding from Nanyang Techno-
logical University, Singapore Ministry of Education, and Science &
Engineering Research Council (A*STAR grant No. 082 101 0019). We
thank Dr. Yongxin Li (Division of Chemistry and Biological Chem-
istry, School of Physical and Mathematical Sciences, Nanyang
Technological University) for assistance in X-ray crystallographic
analysis.
10. Deuterium-labeled oxime 3oed was prepared by the following scheme.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.029.
D
H
H
D
CBr4 (1.5 equiv)
PPh3 (3 equiv)
Br
O
Br
CH2Cl2, 0 C, 2 h
H
7
References and notes
6
O
NMe2
1. For recent reviews, see: (a) Kawasaki, T.; Higichi, K. Nat. Prod. Rep. 2007, 24, 843;
(b) Kawasaki, T.; Higichi, K. Nat. Prod. Rep. 2005, 22, 761; (c) Somei, M.; Yamada,
F. Nat. Prod. Rep. 2005, 22, 73.
D
Me2NH in water
then aq. HCl
3o-d
2. For recent selected reports, see: (a) Stansfield, I.; Ercolani, C.; Mackay, A.;
Conte, I.; Pompei, M.; Koch, U.; Gennari, N.; Giuliano, C.; Rowley, M.; Narjes,
F. Bioorg. Med. Chem. Lett. 2009, 19, 627; (b) Ambrus, J. I.; Kelso, M. J.;
Bremner, J. B.; Ball, A. R.; Casadei, G.; Lewis, K. Bioorg. Med. Chem. Lett. 2008,
18, 4294; (c) Beevers, R. E.; Buckley, G. M.; Davies, N.; Fraser, J. L.; Galvin, F.
C.; Hannah, D. R.; Haughan, A. F.; Jenkins, K.; Mack, S. R.; Pitt, W. R.; Ratcliffe,
A. J.; Richard, M. D.; Sabin, V.; Sharpe, A.; Williams, S. C. Bioorg. Med. Chem.
Lett. 2006, 16, 2539; (d) Lee, K. L.; Foley, M. A.; Chen, L. R.; Behnke, M. L.;
Lovering, F. E.; Kirincich, S. J.; Wang, W. H.; Shim, J.; Tam, S.; Shen, M. W. H.;
Khor, S. P.; Xu, X.; Goodwin, D. G.; Ramarao, M. K.; Nickerson-Nutter, C.;
Donahue, F.; Ku, M. S.; Clark, J. D.; McKew, J. C. J. Med. Chem. 2007, 50, 1380;
(e) Harper, S.; Avolio, S.; Pacini, B.; Di Filippo, M.; Altamura, S.; Tomei, L.;
Paonessa, G.; Di Marco, S.; Carfi, A.; Giuliano, C.; Padron, J.; Bonelli, F.;
Migliaccio, G.; De Francesco, R.; Laufer, R.; Rowley, M.; Narjes, F. J. Med. Chem.
2005, 48, 4547; (f) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L. S.;
Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.; DiCioccio, A. T.; Petrova, T.;
Mitschler, A.; Podjarny, A. D. J. Med. Chem. 2005, 48, 3141; (g) Sawyer, J. S.;
Beight, D. W.; Smith, E. C. R.; Snyder, D. W.; Chastain, M. K.; Tielking, R. L.;
Hartley, L. W.; Carlson, D. G. J. Med. Chem. 2005, 48, 893.
H
Scheme 3
1o-d
11. Perrin, C. L. J. Org. Chem. 1971, 36, 420.
12. The reaction pathway of aromatic CeH activation by rhodium(II) carbenoid was
proposed as an electrophilic aromatic substitution, see: (a) Padwa, A.; Austin,
D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N.; Winchester,
W. R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669; (b) Doyle, M. P.; Shanklin, M. S.;
Pho, H. Q.; Mahapatro, S. N. J. Org. Chem. 1988, 53, 1017.
13. Cornelia, H.; Ines, Z.; Horst, H. Eur. J. Org. Chem. 2000, 19, 3273.
14. Vanleeuwen, M.; McKillop, A. J. Chem. Soc., Perkin Trans. 1 1993, 20, 2433.
15. Rivierebaudet, M.; Morere, A.; Dias, M. Tetrahedron Lett. 1992, 33, 6453.
16. Song, B. R.; Wang, S. Y.; Sun, C. Y.; Deng, H. I.; Xu, B. Tetrahedron Lett. 2007, 48, 8982.
17. Huh, D. H.; Jeong, J. S.; Lee, H. B.; Ryu, H.; Kim, Y. G. Tetrahedron 2002, 58, 9925.
18. (a) Imhof, W.; Gobel, A.; Ohlmann, D.; Flemming, J.; Fritzsche, H. J. Org. Chem.
1999, 64, 33; (b) Matharu, D. S.; Morris, D. J.; Kawamoto, A. M.; Clarkson, G. J.;
Wills, M. Org. Lett. 2005, 7, 5489.