Efficient synthesis of pyrroles and 4,5,6,7-tetrahydroindoles via palladium-catalyzed oxidation of hydroxy-enamines

Article abstract of DOI:10.1016/j.tet.2006.06.070

Facile and one-pot synthetic route of poly-substituted pyrroles and 4-oxo-4,5,6,7-tetrahydroindoles is established, which consists of three steps: (1) palladium-catalyzed oxidation of hydroxy-enamines by using tetrakis(triphenylphosphine)palladium and mesityl bromide oxidation system, (2) intramolecular cyclization, and (3) dehydration.

Full text of DOI:10.1016/j.tet.2006.06.070

Tetrahedron 62 (2006) 8533–8538
Efficient synthesis of pyrroles and 4,5,6,7-tetrahydroindoles via
palladium-catalyzed oxidation of hydroxy-enamines
Yutaka Aoyagi, Toshihiko Mizusaki, Masahiro Shishikura, Takashi Komine, Tokuji Yoshinaga,
*
Haruko Inaba, Akihiro Ohta and Koichi Takeya
*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 18 May 2006; revised 20 June 2006; accepted 21 June 2006
Available online 18 July 2006
Abstract—Facile and one-pot synthetic route of poly-substituted pyrroles and 4-oxo-4,5,6,7-tetrahydroindoles is established, which consists
of three steps: (1) palladium-catalyzed oxidation of hydroxy-enamines by using tetrakis(triphenylphosphine)palladium and mesityl bromide
oxidation system, (2) intramolecular cyclization, and (3) dehydration.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
acetate or palladium chloride,8 palladium-catalyzed oxida-
tion of secondary alcohols by the use of bromobenzene
as an oxidant,9–11 and palladium-catalyzed oxidation of pri-
mary and secondary alcohols to carbonyl compounds under
phase transfer catalyst conditions.12 In the present paper, we
describe an efficient synthetic procedure of poly-substituted
pyrroles and 4-oxo-4,5,6,7-tetrahydroindoles, by the palla-
dium-catalyzed oxidation of hydroxy-enamines to the corre-
sponding pyrroles and indoles, part of which has been
previously reported in our communication.13
Highly functionalized pyrroles are subunits of considerable
importance in heme, chlorophyll, bile pigments, vitamin
B12, and marine source-derived pyrrole alkaloids.1 Since
Knorr reported the first synthesis of pyrroles,2 a series of
papers have been published on the syntheses of substituted
pyrroles.3 For example, the pyrrole synthesis by the Lewis
acid-mediated reaction of readily available 2-acetoxypropa-
nal N,N-dimethylhydrazone with cyclic and open chain silyl
enol ethers was reported by Enders et al.,1 low valent
titanium-mediated approach to pyrroles by Furstner et al.,
4
€
pyrrole synthesis via [2+3] cycloaddition reactions of
S-methyl N-(benzotriazol-1-ylmethyl)thioamide with a,b-
unsaturated esters, ketones, nitriles, and vinylpyridines by
Pindur and Adam,5 and convenient synthesis of 2-cyanopyr-
roles from isocyanoacetonitrile by Adamczyk and Reddy.6
4-Substituted indole nucleus is also an important subunit in
a wide range of biologically active natural products, whose
construction has been a topic of interest for many years.7
2. Results and discussion
Our synthetic strategy to prepare pyrroles and indoles via
the palladium-catalyzed oxidation is shown in Scheme 1.
Poly-substituted pyrroles and 4-oxo-4,5,6,7-tetrahydro-
indoles are to be synthesized by the oxidation of b-hydroxy-
enamines, which can be obtained by the condensation of
amino alcohols and carbonyl compounds.
There are a few reports on the palladium-catalyzed oxidation
of hydroxyl groups such as efficient oxidation of alcohols
with CCl4 in the presence of bases by using palladium
First, b-hydroxy-enamines 3 were prepared by condensation
of amino alcohol 2 with b-ketoester or b-diketone 1 in the
˚
presence of 4 A molecular sieves, in moderate to good yields.
O
O
O
O
OH
O
R5
R4
R5
R4
R5
R4
R5
R4
OH
R2
R2
R2
R2
+
R1
NHR3
R1
N
R1
N
R1
N
O
R3
R3
R3
Scheme 1.
* Corresponding authors. Tel.: +81 42 676 3007; fax: +81 42 677 1436 (K.T.); e-mail: takeyak@ps.toyaku.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.070

8534
Y. Aoyagi et al. / Tetrahedron 62 (2006) 8533–8538
Table 1. Preparation of b-hydroxy-enamines
O
R6
HO
R5
R1
R5
O
O
R3
R6
R4
Method A or B
R3
N
H
R2
+
N
R2
R1
OH
1
2
R4
3a-s
Entry
Ketones (1)
R2
b-Amino alcohols (2)
R5
Methodsa
Products (3) (yields %)b
R1
R3
R4
R6
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Ph
OEt
OEt
OEt
OEt
OEt
OEt
Me
OEt
OEt
OEt
OEt
OEt
OEt
H
H
H
H
H
H
H
H
Me
Bn
Ph
H
H
H
H
Me
Ph
H
H
H
A
A
A
A
A
A
3a (96)
3b (97)
3c (93)
3d15 (73)
3e (84)
3f (99)
3g (77)
3h (50)
3i (52)
3j (97)
3k (54)
3l (97)
3m (93)
3n (60)
3o16 (80)
3p17 (78)
3q (91)
3r (84)
3s (89)
iPr
H
H
H
Me
Bn
H
A
Bc
B
9
Me
Me
10
11
12
13
14
15
16
17
18
19
–(CH2)3–
H
H
H
A
A
B
A
–(CH2)3–
–(CH2)4–
Me
H
H
H
H
H
H
H
H
H
Bn
Bn
H
H
H
H
H
H
H
–(CH2)4–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
H
Ph
H
Me
H
H
Ph
H
Me
Bd,e
Af
Bd,g
Bd,h
Bd,i
Bd,j
H
–(CH2)4–
a
˚
Method A: a THF solution (20 mL) of ketone (7.9 mmol), b-amino alcohol (9.4 mmol), and 4 A molecular sieves (5.0 g) was stirred at room temperature for
˚
7 days under argon. Method B: a benzene solution (30 mL) of ketone (11.7 mmol), b-amino alcohol (14.9 mmol), and 4 A molecular sieves (15.0 g) was
refluxed for 12 h under argon.
Isolated yields.
p-TsOH$H2O was employed.
THF was used as the solvent instead of benzene.
Reaction time: 6 h.
Reaction time: 144 h.
Reaction time: 6.5 h.
Reaction time: 2 h.
Reaction time: 4 h.
Reaction time: 7 h.
b
c
d
e
f
g
h
i
j
Amino alcohol 2 was obtained commercially or easily syn-
ratio to b-hydroxy-enamine was shown to be above 1:1
(entries 1 vs 19–22 in Table 2). As regards palladium cata-
lyst, palladium(II) acetate and palladium(II) chloride were
also effective (entries 25–28 in Table 2). The Swern, PCC,
and PDC oxidation of b-hydroxy-enamine 3a led to the
decomposition of 3a. In the series of experiments presently
performed, the optimum reaction conditions for the prepara-
tion of 4a are given in entry 17 of Table 2.
thesized by lithium aluminum hydride reduction of amino
acids.14 Preparation of various b-hydroxy-enamines 3a–s
under several different reaction conditions are summarized
in Table 1. Then, 3a was converted to 4a. Different reaction
conditions examined were as summarized in Table 2. Palla-
dium catalyst, aryl halide, and base were all shown to be
indispensable components for the reaction (entries 8, 18,
and 24 in Table 2). Entries 1–3 in Table 2 demonstrated
that better results were to be obtained, when the reaction
temperature was at 150 ꢀC. Entries 5–7 may also support
the conclusion; so all the reactions were performed at about
150 ꢀC. As regards the solvent, DMF was found to be more
efficient (entries 1 vs 4). As regards base component, potas-
sium carbonate at the ratio between the base and b-hydroxy-
enamines of 2:1 was found to give generally better results.
Potassium hydroxide, potassium acetate, triethylamine,
and silver carbonate were found to be less efficient (entries
1 vs 11–14 in Table 2). As regards the aryl halide component,
bromobenzene gave better results than iodobenzene or
chlorobenzene (entries 1 vs 15 and 16 in Table 2). According
to Tamaru et al.,9–11 mesityl bromide is an efficient oxidant
in the reaction of this type. In our experiment, mesityl bro-
mide was also shown to be the aryl halide component giving
the highest yield (entry 17 in Table 2). As regards the amount
of aryl halide to be used, in the case of bromobenzene, its
Then, poly-substituted pyrroles and 4-oxo-4,5,6,7-tetrahydro-
indoles were prepared via palladium-catalyzed oxidation of
various b-hydroxy-enamines as shown in Tables 3 and 4,
and Scheme 2. Palladium-catalyzed oxidation of b-hydroxy-
enamines 3a–h gave the corresponding poly-substituted
pyrroles (4a–h) in moderate to good yields (entries 1–8 in
Table3), exceptinthecase of3i, inwhichR1 isnotahydrogen
but a methyl group and the nucleophilic activity of N-sub-
stituted b-hydroxy-enamine 3i is considered to be lower
(entry 9 in Table 3). As shown in Table 4, these b-hydroxy-
enamines 3n–q gave 4-oxo-4,5,6,7-tetrahydroindoles (4n–q)
in 52–85% yields, which are important intermediates for the
synthesis of 4-substituted indoles such as ergot alkaloids.
Palladium-catalyzed oxidation of b-hydroxy-enamines 3j,
3m, and 3s gave 4j (27%), 4m (85%), and 4s (99%), respec-
tively (Scheme 2). Analogous oxidation of 3k–l were shown
to produce a number of products, as demonstrated in TLC.

Y. Aoyagi et al. / Tetrahedron 62 (2006) 8533–8538
8535
Table 2. Preparation of 4a via palladium-catalyzed oxidation under several reaction conditions
COOEt
Me
HO
Bn
COOEt
" Pd "
2 ha
Bn
N
H
N
H
Me
3a
4a
Entry
Pd catalyst (mol %)
ArX (equiv)
Base (equiv)
Solvent
Reaction temperature (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (2.0)
Pd(PPh3)4 (0.8)
None
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhBr (1.0)
PhCl (1.0)
Phl (1.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
None
K2CO3 (1.0)
KHCO3 (2.0)
KOH (2.0)
AcOK (2.0)
Et3N (2.0)
Ag2CO3
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
DMF
DMF
DMF
DMSO
Toluene
150
120
100
150
Reflux
Reflux
Reflux
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
55
46
10
18
38
14
None
None
37
44
8
22
None
None
22
17
82
1,4-Dioxane
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
MesBr (1.0)
None
None
19
28
58
59
PhBr (0.25)
PhBr (0.5)
PhBr (2.0)
PhBr (4.0)
MesBr (1.0)
PhBr (1.0)
MesBr (1.0)
MesBr (1.0)
MesBr (1.0)
MesBr (1.0)
78
None
63
72
74
76
Pd(OAc)2 (3.0)
Pd(OAc)2 (3.0)
Pd(OAc)2 (5.0)
PdCl2 (3.0)
a
The starting material 3a was consumed after 2 h.
Isolated yields.
b
Table 3. Preparation of pyrroles (4a–i)
Table 4. Preparation of 4-oxo-4,5,6,7-tetrahydroindoles
O
O
O
O
Pd(PPh3)4 (2 mol %)
MesBr (1.0 eq.), K2CO3 (2.0 eq.)
DMF, 150 °C
Pd(PPh3)4 (2 mol %)
R5
R4
HO
R2
R5
R2
HO
R4
R3
R3
MesBr (1.0 eq.), K2CO3 (2.0 eq.)
DMF, 150 °C
R2
R1
N
R2
N
H
R1
N
N
H
R1
R1
4a-i
3a-i
3n-r
4n-r
Entry b-Hydroxy- R1 R2 R3
enamine 3
R4 R5 Reaction Pyrroles 4
Entry b-Hydroxy- R1
enamine 3
R2
Reaction 4-Oxo-4,5,6,7-
time (h)
time (h) (yield %)a
tetrahydro-indoles 4
(yield %)a
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
H
Me OEt Bn
Me OEt Ph
Me OEt iPr
Me OEt
Me OEt
Me OEt
H
H
H
H
Me
Ph
H
H
H
2
5
4
1
3
5
3.5
4
2
4a (82)
4b18 (67)
4c (83)
4d19 (74)
4e20 (76)
4f 21 (80)
4g22 (57)
4h (84)
4i23 (36)
1
2
3
4
5
3n
3o
3p
3q
3r
H
Ph
H
Me
H
H
H
Ph
H
Me
4
4n25 (63)
4o26 (65)
4p27 (52)
4q28 (85)
4r29 (60)
2.5
7
H
H
H
2
1
Me OMe Me
Ph OEt Bn
a
Isolated yields.
Me Me OEt
H
a
Isolated yields.
3. Conclusion
A plausible mechanism involved in this series of reaction is
schematically shown in Figure 1. Oxidative addition of pal-
ladium(0) catalyst to aryl bromide produces palladium(II)
adduct, which with b-hydroxy-enamine gives an alkoxy pal-
ladium(II). Finally, b-elimination of the palladium catalyst
proceeded to give a carbonyl compound. Intramolecular
cyclization of the carbonyl compound thus obtained, the
subsequent dehydration, and isomerization of the protons
provide pyrroles and indoles. Palladium(0) catalyst is then
reproduced via reductive elimination of palladium species.
The present study describes an efficient and facile synthesis
of pyrroles and 4,5,6,7-tetrahydroindoles from hydroxy-
enamines. In this procedure, the starting materials, i.e.,
hydroxy-enamines, are prepared easily from commercially
available amino alcohols, and the final products are pro-
duced in a fewer steps in moderate to good yields. Of the
compounds produced in the present method, 4-oxo-4,5,6,7-
tetrahydroindoles are quite useful intermediates for the
synthesis of biologically active natural products such as
ergot alkaloids.

8536
Y. Aoyagi et al. / Tetrahedron 62 (2006) 8533–8538
Pd(PPh3)4 (2 mol %)
MesBr (1.0 eq.), K2CO3 (2.0 eq.)
DMF, 150 °C, 3 h
4.2. General procedure for the preparation
of b-hydroxy-enamines
COOEt
HO
COOEt
N
Me
27 %
N
Me
˚
Method A: 4 A MS (5 g) and THF solution (10 mL) of b-
3j
4j
dicarbonyl compound (7.9 mmol, 1.0 equiv) were added to
a dry THF solution (20 mL) of b-amino alcohol (9.4 mmol,
1.2 equiv). The reaction mixture was stirred at room temper-
ature for 7 day under an argon atmosphere. After filtration
through a short pad of CeliteÒ 545, the solvent was evapo-
rated in vacuo to give a residue, which was purified by
aluminum oxide flash chromatography (eluting with EtOAc)
to give a b-amino alcohol (3a–g, 3j–k, 3m, and 3o).
Pd(PPh3)4 (2 mol %)
MesBr (1.0 eq.), K2CO3 (2.0 eq.)
DMF, 150 °C, 3 h
COOEt
Me
OH COOEt
85 %
N
N
H
Me
H
24
4m
3m
Pd(PPh3)4 (2 mol %)
MesBr (1.0 eq.), K2CO3 (2.0 eq.)
DMF, 150 °C, 2 h
O
O
HO
99 %
N
N
H
H
30
4s
3s
˚
Method B: 4 A MS (5 g) and THF solution (10 mL) of
b-dicarbonyl compound (11.7 mmol, 1.0 equiv) were added
to a dry benzene solution (30 mL) of b-amino alcohol
(14.9 mmol, 1.2 equiv). The reaction mixture was refluxed
for 12 h under an argon atmosphere. After filtration through
a short pad of CeliteÒ 545, the solvent was evaporated
in vacuo to give a residue, which was purified by aluminum
oxide flash chromatography eluting with EtOAc to give a
b-amino alcohol (3h–i, 3l, 3n, and 3p–s).
Scheme 2.
L
HO
R4
R3
R2
R1
ArPdBr
PdL2
ArBr
N
H
L
2L
ArH
HBr•Base
PdL4
L
L
4.2.1. Compound 3a. Pale yellow oil; IR (film) 3420 (OH),
3290 (NH), 1610 (C]O) cmꢁ1 1H NMR (300 MHz,
;
ArPdO
R3
R2
R1
ArPdH
L
L
R4
N
H
CDCl3) d 8.66 (1H, br d, 9.6), 7.31–7.15 (5H, m), 4.37
(1H, s), 4.08 (2H, q, 7.1), 3.76–3.56 (3H, m), 2.86 (1H, dd,
13.5, 5.2), 2.69 (1H, dd, 13.5, 7.9), 2.24 (1H, br s), 1.62
(3H, s), 1.24 (3H, t, 7.1); MS (EI, m/z) 263 (M+). Anal. Calcd
for C15H21NO3: C, 68.41; H, 8.04; N, 5.32. Found: C, 68.49;
H, 8.09; N, 5.31.
R3
HO
R3
R4
R2
R1
R3
R4
R2
R1
O
R3
R2
R1
R2
R1
4.2.2. Compound 3b. Pale yellow oil; IR (film) 3420 (OH),
3300 (NH), 1650 (C]O) cmꢁ1 1H NMR (300 MHz,
;
-H2O
R4
R4
N
N
N
H
N
H
CDCl3) d 9.20 (1H, br d, 8.4), 7.40–7.25 (5H, m), 4.70–
4.60 (1H, m), 4.55 (1H, s), 4.13 (2H, q, 7.1), 3.86 (1H, dd,
11.3, 4.5), 3.77 (1H, dd, 11.3, 7.0), 1.82 (3H, s), 1.28 (3H, t,
7.1); MS (EI, m/z) 249 (M+). Anal. Calcd for C14H19NO3:
C, 67.44; H, 7.68; N, 5.62. Found: C, 67.40; H, 7.75; N, 5.62.
Figure 1. Plausible reaction mechanism.
4. Experimental
4.1. General methods
4.2.3. Compound 3c. Pale yellow oil; IR (film) 3420 (OH),
3300 (NH), 1650 (C]O) cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 8.62 (1H, br d, 9.4), 4.47 (1H, s), 4.10 (2H, qd,
7 0.9), 3.65–3.76 (1H, m), 3.50–3.60 (1H, m), 3.30–3.42
(1H, m), 1.95 (3H, s), 1.67 (1H, br s), 1.26 (3H, t, 7.1),
0.96 (6H, d, 6.9); HRMS (EI, m/z) Calcd for C11H21NO3
(M+): 215.1521. Found: 215.1532.
Melting points were measured in Yanagimoto micro melting
point apparatus and are recorded uncorrected. Infrared
spectra (cmꢁ1) were recorded on a Japan Spectroscopic Co.
A-100 and Mass spectra were recorded on a Hitachi M-80B
or Fisons VG Auto Spec instrument. 1H (300 MHz) and 13
C
(75 MHz) NMR spectra were obtained on a Varian Gemini
A-300 and the chemical shifts are given in parts per
million downfield from the internal standard (TMS). Flash
chromatography and MPLC were performed by using Merck
silica gel Kieselgel 60Ò (230–400 mesh) or Merck Alumi-
num oxide 90Ò (70–230 mesh) column and preparative
thin layer chromatography (PTLC) with Merck Kieselgel
60 F254 precoated glass plates (thickness 0.25 or 0.50 mm).
All solvents were of commercial grade, which were distilled
and dried with sodium benzophenone ketyl (tetrahydrofuran
(THF), 1,4-dioxane, toluene, and benzene) or with CaH2
(DMF, DMSO, and CH2Cl2). Lithium bases (nBuLi, sBuLi,
4.2.4. Compound 3e. Colorless prisms, mp 63–65 ꢀC (hex-
ane); IR (KBr) 3420 (OH), 3300 (NH), 1620 (C]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 8.74 (1H, br s), 4.49 (1H, s),
4.09 (2H, q, 7.1), 3.92 (1H, m), 3.27 (1H, ddd, 13.5, 6.2, 4.0),
3.16 (1H, ddd, 13.5, 7.3, 6.4), 1.99 (1H, br d), 1.93 (3H, s),
1.25 (3H, t, 7.1), 1.23 (3H, t, 7.1); MS (EI, m/z) 187 (M+).
Anal. Calcd for C9H17NO3: C, 57.73; H, 9.15; N, 7.48.
Found: C, 57.77; H, 9.15; N, 7.59.
4.2.5. Compound 3f. Colorless needles, mp 91–93 ꢀC (hex-
ane); IR (KBr) 3450 (OH), 3300 (NH), 1640 (C]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 8.88 (1H, br s), 7.40–7.27
(5H, m), 4.85–4.79 (1H, m), 4.48 (1H, s), 4.09 (2H, q,
7.1), 3.43 (1H, dd, 6.4, 4.7), 3.42 (1H, dd, 7.5, 6.2), 2.38
(1H, br d), 1.86 (3H, s), 1.24 (3H, t, 7.1); MS (EI, m/z)
t
and BuLi) were purchased from Aldrich Chemical Co.,
Ltd. All other reagents were of the highest available grade
and used as purchased.

Y. Aoyagi et al. / Tetrahedron 62 (2006) 8533–8538
8537
249 (M+). Anal. Calcd for C14H19NO3: C, 67.44; H, 7.68; N,
5.62. Found: C, 67.34; H, 7.70; N, 5.77.
4.2.13. Compound 3n. Colorless needles, mp 102–106 ꢀC
(MeCN); IR (film) 3260 (OH, NH), 1680 (C]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 5.74 (1H, br s), 5.10 (1H,
s), 3.81 (2H, td, 5.3, 2.4), 3.22 (2H, td, 5.0, 5.0), 2.37 (2H,
t, 6.3), 2.30 (2H, t, 6.5), 1.95 (2H, m); MS (EI, m/z) 155
(M+). Anal. Calcd for C8H13NO2: C, 61.91; H, 8.44; N,
9.03. Found: C, 61.89; H, 8.42; N, 9.09.
4.2.6. Compound 3g. Pale yellow oil; IR (KBr) 3320 (NH),
1
1615 (C]O) cmꢁ1; H NMR (300 MHz, CDCl3) d 10.8
(1H, br s), 4.96 (1H, s), 3.73 (1H, m), 3.66 (1H, m), 3.53
(1H, dd, 11.1, 7.4), 2.42 (1H, br s), 1.99 (3H, s), 1.98 (3H,
s), 1.19 (3H, d, 6.6); MS (EI, m/z) 249 (M+). HRMS (EI,
m/z) Calcd for C8H15NO2 (M+): 157.1103. Found: 157.1095.
4.2.14. Compound 3q. Pale yellow oil; IR (film) 3300 (OH,
NH), 1550 (C]C) cmꢁ1 1H NMR (300 MHz, CDCl3)
;
4.2.7. Compound 3h. Pale yellow oil; IR (KBr) 3450 (OH),
3300 (NH), 1735 (C]O) cmꢁ1 1H NMR (300 MHz,
;
d 5.15 (1H, s), 3.74–3.68 (1H, m), 3.63–3.54 (2H, m),
2.37–2.28 (4H, m), 1.95 (2H, m), 1.20 (3H, d, 6.3); HRMS
(EI, m/z) Calcd for C9H15NO2 (M+): 169.1103. Found:
169.1106.
CDCl3) d 8.50 (1H, br d, 10.2), 7.37–7.20 (6H, m), 7.04–
6.92 (4H, m), 4.57 (1H, s), 4.16 (2H, q, 7.1), 3.64–3.44
(3H, m), 2.79 (1H, dd, 13.5, 5.5), 2.51 (1H, dd, 13.5, 7.8),
2.30 (1H, br s), 1.29 (3H, t, 7.1); MS (EI, m/z) 325 (M+).
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30.
Found: C, 73.53; H, 7.31; N, 4.25.
4.2.15. Compound 3r. Pale yellow amorphous solid, mp
81–82 ꢀC (CHCl3); IR (film) 3300 (OH, NH), 1550
(C]C) cmꢁ1 1H NMR (300 MHz, CDCl3) d 5.44–5.22
;
(1H, br s), 5.10 (1H, s), 4.04–3.98 (1H, s), 3.17 (1H, ddd,
13.1, 6.0, 3.0), 2.96 (1H, ddd, 13.1, 8.5, 4.4), 2.36 (1H, t,
6.2), 2.30 (2H, t, 6.5), 1.95 (2H, m), 1.25 (3H, d, 6.3);
HRMS (EI, m/z) Calcd for C9H15NO2 (M+): 169.1103.
Found: 169.1107.
4.2.8. Compound 3i. Pale yellow oil; IR (KBr) 3430 (OH),
1680, 1660 (C]O) cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 4.63 (1H, s), 4.09 (2H, q, 7.1), 3.77 (2H, q, 5.7), 3.46
(2H, t, 5.7), 2.95 (3H, s), 2.49 (3H, s), 1.51 (1H, br t), 1.25
(3H, t, 7.1); MS (EI, m/z) 187 (M+). Anal. Calcd for
C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C, 57.79;
H, 9.06; N, 7.43.
4.2.16. Compound 3s. Pale yellow needles, mp 198–199 ꢀC
(hexane/AcOEt); IR (film) 3300 (OH, NH), 1580
1
(C]C) cmꢁ1; H NMR (300 MHz, CDCl3) d 6.80 (1H, d,
4.2.9. Compound 3j. Pale yellow oil; IR (KBr) 3450 (OH),
7.1), 4.86 (1H, s), 4.64 (1H, d, 4.9), 3.36–3.20 (1H, m),
3.04–2.93 (1H, m), 2.36–2.26 (2H, m), 2.08–2.02 (2H, m),
1.92–1.80 (2H, m), 1.77 (2H, m), 1.66–1.52 (2H, m),
1.30–0.98 (4H, m); MS (EI, m/z) 209 (M+). Anal. Calcd
for C12H19NO2: C, 68.86; H, 9.15; N, 6.69. Found: C,
68.82; H, 9.07; N, 6.59.
1
3300 (NH), 1740 (C]O), 1660 (C]C) cmꢁ1; H NMR
(300 MHz, CDCl3) d 4.58 (1H, s), 4.08 (2H, td, 7.1, 1.3),
3.98–3.88 (1H, m), 3.66 (1H, dd, 10.9, 3.9), 3.50 (1H, dd,
10.9, 3.5), 3.33–3.21 (2H, m), 2.50 (3H, s), 2.10–1.91 (4H,
m), 1.78 (1H, br s), 1.25 (3H, t, 7.1); MS (EI, m/z) 213
(M+). Anal. Calcd for C11H19NO3: C, 61.94; H, 8.98; N,
6.57. Found: C, 62.15; H, 9.05; N, 6.61.
4.3. General procedure for the preparation of
pyrrole derivatives
4.2.10. Compound 3k. Pale yellow oil; IR (KBr) 3425 (OH),
1
3320 (NH), 1650 (C]O), 1590 (C]C) cmꢁ1; H NMR
A mixture of Pd(PPh3)4 (0.025 g, 0.02 mmol, 2 mol %),
K2CO3 (0.27 g, 2.0 mmol), mesityl bromide (0.20 g,
1.0 mmol), b-hydroxy-enamine (1.0 mmol), and dry DMF
(5 mL) was heated at 150 ꢀC for 2 h under an argon atmo-
sphere. After cooling, H2O (20 mL) was added to the
mixture, which was extracted with Et2O (3ꢂ20 mL). The
extract was then dried over Na2SO4, filtered, and evaporated
in vacuo to give a residue, which was purified by silica gel
flash chromatography (eluting with hexane–EtOAc system)
to give the pyrrole derivatives (4a–j and 4m–r).
(300 MHz, CDCl3) d 7.46 (1H, br d, 8.7), 7.30–7.10 (5H,
m), 4.14 (2H, q, 7.1), 3.70–3.49 (3H, m), 2.85 (1H, dd,
13.5, 5.2), 2.71 (1H, dd, 13.5, 7.5), 2.50 (1H, br s), 2.49–
2.35 (3H, m), 2.10–1.95 (1H, m), 1.80–1.50 (2H, m), 1.27
(3H, t, 7.1); MS (EI, m/z) 213 (M+). HRMS (EI, m/z) Calcd
for C17H23NO3 (M+): 289.1678. Found: 289.1690.
4.2.11. Compound 3l. Pale yellow oil; IR (film) 3450 (OH),
1
3290 (NH), 1720 (C]O), 1610 (C]C) cmꢁ1; H NMR
(300 MHz, CDCl3) d 9.04 (1H, br d, 10.2), 7.32–7.14 (5H,
m), 4.13 (2H, q, 7.1), 3.82–3.68 (1H, m), 3.65 (1H, dd,
11.0, 4.2), 3.53 (1H, dd, 11.0, 6.8), 2.83 (1H, dd, 13.5,
6.0), 2.70 (1H, dd, 13.5, 7.7), 2.26–2.12 (4H, m), 1.88–
1.78 (2H, m), 1.56–1.32 (3H, m), 1.28 (3H, t, 7.1); MS
(EI, m/z) 303 (M+). Anal. Calcd for C18H25NO3: C, 71.25;
H, 8.31; N, 4.62. Found: C, 71.08; H, 8.47; N, 4.52.
4.3.1. Compound 4a. Colorless prisms, mp 106–107 ꢀC
(hexane); Rf 0.16 (hexane/AcOEt¼4:1); IR (KBr) 3270
(NH), 1660 (C]O) cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 7.77 (1H, s), 7.36–7.16 (5H, m), 6.32 (1H, d, 2.9), 4.25
(2H, q, 7.1), 3.88 (2H, s), 2.45 (3H, s), 1.33 (3H, t, 7.1);
MS (EI, m/z) 243 (M+). Anal. Calcd for C15H17NO2: C,
74.05; H, 7.04; N, 5.76. Found: C, 73.99; H, 6.94; N, 5.72.
4.2.12. Compound 3m. Colorless oil; IR (film) 3450 (OH),
1
3300 (NH), 1740 (C]O), 1610 (C]C) cmꢁ1; H NMR
4.3.2. Compound 4c. Colorless prisms, mp 66–68 ꢀC (hex-
ane); Rf 0.17 (hexane/AcOEt¼4:1); IR (KBr) 3030 (NH),
(300 MHz, CDCl3) d 8.51 (1H, br d, 9.4), 4.48 (1H, s),
4.09 (2H, q, 7.1), 3.42–3.33 (1H, m), 3.23–3.10 (1H, m),
2.30 (1H, br s), 2.10–2.02 (1H, m), 1.98 (3H, s), 1.95–1.87
(1H, m), 1.80–1.67 (2H, m), 1.29 (4H, m), 1.26 (3H, t,
7.1); MS (EI, m/z) 227 (M+). Anal. Calcd for C12H21NO3:
C, 63.41; H, 9.31; N, 6.16. Found: C, 63.43; H, 9.45; N, 6.14.
1
1690 (C]O) cmꢁ1; H NMR (300 MHz, CDCl3) d 7.90
(1H, br s), 6.23 (1H, dd, 3.0, 0.9), 4.25 (2H, q, 7.1), 2.83
(1H, m), 2.50 (3H, s), 1.33 (3H, t, 7.1), 1.24 (6H, d, 6.9);
MS (EI, m/z) 195 (M+). Anal. Calcd for C11H17NO2: C,
67.66; H, 8.78; N, 7.17. Found: C, 67.67; H, 8.72; N, 7.21.

8538
Y. Aoyagi et al. / Tetrahedron 62 (2006) 8533–8538
4.3.3. Compound 4h. Colorless prisms, mp 107–108 ꢀC
(hexane); Rf 0.37 (hexane/AcOEt¼4:1); IR (KBr) 3300
8. Nagashima, H.; Tsuji, J. Chem. Lett. 1981, 1171–1172.
9. Tamaru, Y.; Yamamoto, Y.; Yamada, Y.; Yoshida, Z.
Tetrahedron Lett. 1979, 1401–1404.
(NH), 1660 (C]O) cmꢁ1 1H NMR (300 MHz, CDCl3)
;
10. Tamaru, Y.; Inoue, K.; Yamada, Y.; Yoshida, Z. Tetrahedron
Lett. 1981, 22, 1801–1802.
11. Tamaru, Y.; Yamada, Y.; Inoue, K.; Yamamoto, Y.; Yoshida, Z.
J. Org. Chem. 1983, 48, 1286–1292.
12. Choudary, B. M.; Reddy, N. P.; Kantam, M. L.; Jamil, Z.
Tetrahedron Lett. 1985, 26, 6257–6258.
d 7.99 (1H, br s), 7.57–7.51 (2H, m), 7.41–7.29 (5H, m),
7.28–7.21 (3H, m), 6.52 (1H, dd, 3.0, 0.9), 4.20 (2H, q,
7.1), 3.98 (2H, s), 1.25 (3H, t, 7.1); MS (EI, m/z) 305
(M+). Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N,
4.59. Found: C, 78.56; H, 6.27; N, 4.70.
13. Aoyagi, Y.; Mizusaki, T.; Ohta, A. Tetrahedron Lett. 1996, 37,
9203–9206.
14. Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem. Soc.
1985, 107, 7974–7978.
15. San Feliciano, A.; Caballero, E.; Pereira, J. A. P.; Puebla, P.
Tetrahedron 1991, 47, 6503–6510.
16. Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-l.;
Gerasyuto, A. I.; Brennessel, W. B. J. Am. Chem. Soc. 2002,
124, 10435–10442.
4.3.4. Compound 4j. Colorless oil; Rf 0.24 (hexane/
;
1H NMR
AcOEt¼4:1); IR (film) 1695 (C]O) cmꢁ1
(300 MHz, CDCl3) d 6.17 (1H, d, 1.1), 4.24 (2H, q, 7.1),
3.82 (2H, t, 7.1), 2.80 (2H, t, 7.4), 2.47 (2H, m), 2.46 (3H,
s), 1.32 (3H, t, 7.1); MS (EI, m/z) 193 (M+). Anal. Calcd
for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C,
68.46; H, 7.78; N, 7.05.
17. Archer, D. A.; Singer, B. W. J. Chem. Soc., Perkin Trans. 1
1976, 2484–2488.
Acknowledgements
18. Padwa, A.; Smolanoff, J.; Tremper, A. J. Org. Chem. 1976, 41,
543–549.
19. Tokuyama, T.; Daly, J. J. Am. Chem. Soc. 1969, 91, 3931–
3938.
20. White, J.; McGillivray, G. J. Org. Chem. 1977, 42, 4248–4251.
21. Houwing, H. A.; Van Leusen, A. M. J. Heterocycl. Chem. 1981,
18, 1127–1132.
This work was supported by the Grant-in-Aids for Scientific
Research (C) from Ministry of Education, science, Sports,
and Culture of Japan. The authors are grateful to Dr. Yoshio
Kodama, Pharmaceutical Research Center, Meiji Seika
Kaisha Ltd, for providing us some information about
compound 4a.15–30
22. Dalton, C. R.; Kane, J. M.; Rampe, D. Tetrahedron Lett. 1992,
33, 5713–5716.
References and notes
23. Wee, A. G. H.; Shu, A. Y. L.; Bunnenberg, E.; Djerassi, C.
J. Org. Chem. 1984, 49, 3327–3336.
1. Enders, D.; Han, S.-H.; Maassen, R. Tetrahedron Lett. 1995,
36, 8007–8010 and references cited therein.
2. Knorr, L. Chem. Ber. 1884, 17, 1635–1642.
3. Patterson, J. M. Synthesis 1976, 281–304 and references cited
therein.
24. Chiu, P. K.; Sammes, M. P. Tetrahedron 1990, 46, 3439–3456.
25. Dianez, M. J.; Galan, J.; Gomez-Sanchez, A.; Lopez-Castro,
A.; Rico, M. J. Chem. Soc., Perkin Trans. 1 1987, 581–588.
26. Oikawa, Y.; Yonemitsu, O. Heterocycles 1977, 8, 307–312.
27. Larson, H. O.; Ooi, T.-C.; Siu, A. K. Q.; Hollenbeak, K. H.;
Cue, F. L. Tetrahedron 1969, 25, 4005–4010.
28. Nitta, M.; Soeda, H.; Iino, Y. Bull. Chem. Soc. Jpn. 1990, 63,
932–934.
€
4. Furstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995,
60, 6637–6641.
5. Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1–8.
6. Adamczyk, M.; Reddy, R. E. Tetrahedron Lett. 1995, 36, 7983–
7986.
7. Sundberg, R. J. Indoles; Katritzky, A. R., Ed.; Academic:
London, 1996 and references cited therein.
29. Clezy, P. S.; Prashar, J. K. Aust. J. Chem. 1990, 43, 825–837.
30. Noguchi, M.; Onimura, K.; Kajigaeshi, S. Heterocycles 1989,
29, 2029–2034.