Development of sequential type iron salt-catalyzed Nazarov/Michael reaction in an ionic liquid solvent system

Article abstract of DOI:10.1007/s11426-012-4629-3

Sequential type one pot Nazarov/Michael reaction of pyrrole derivatives has been demonstrated using 5 mol% Fe(ClO₄)₃·Al ₂O as catalyst in an ionic liquid as solvent. We succeeded in obtaining 4,5-dihydrocyclopenta[b]pyrrol

Full text of DOI:10.1007/s11426-012-4629-3

SCIENCE CHINA
Chemistry
August 2012 Vol.55 No.8: 1627–1632
doi: 10.1007/s11426-012-4629-3
• ARTICLES •
· SPECIAL ISSUE · Ionic Liquid and Green Chemistry
Development of sequential type iron salt-catalyzed
Nazarov/Michael reaction in an ionic liquid solvent system
IBARA Chie, FUJIWARA Masamune, HAYASE Shuichi,
KAWATSURA Motoi & ITOH Toshiyuki*
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan
Received January 26, 2012; accepted February 22, 2012; published online June 14, 2012
Sequential type one pot Nazarov/Michael reaction of pyrrole derivatives has been demonstrated using 5 mol% Fe(ClO4)3·Al2O
as catalyst in an ionic liquid as solvent. We succeeded in obtaining 4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one derivative in
good yield for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf2], as sol-
vent system.
Nazarov cyclization, Michael reaction, green synthesis, iron catalyst, ionic liquids
tives is not popular [12, 13], though the pyrrole moiety is
1 Introduction
very common in many biologically active or functional
molecules. The reason that the reaction is not popular is
assumed to be that pyrroles are easily polymerized in the
presence of strong Lewis acid [13f].
We recently reported that the Nazarov cyclization of
pyrrole derivatives 1 took place in the presence of
3–5 mol% of alumina-supported iron(III) perchlorate
Iron is one of the most abundant and environmentally
friendly metals on the earth and various types of iron met-
al-catalyzed organic transformations have been developed
during the past decades [1]. We have also been investigat-
ing the possibility of iron-catalyzed reactions and have de-
veloped several of them, i.e., the intramolecular cyclization
of cyclopropanedithioacetals [2], the [2+2]-cycloaddition of
trans-anethol [3], the [2+3]-type cycloaddition of styrene
derivatives with 1,4-benzoquinone [4], the 1,4-addition of
-ketoesters to vinyl ketones [5], the enantioselective Mi-
chael addition of thiols to -unsaturated carbonyl com-
pounds [6], Friedel-Crafts type alkylation of indoles [7] or
pyrroles [8] with vinyl ketones, and the Nazarov type cy-
clization of several types of compounds [9–11].
Nazarov cyclization is one of the versatile methods for
the synthesis of five-membered carbocycles, and it is known
that several Lewis or Brønsted acids promote this reaction
[12, 13]. However, Nazarov cyclization of pyrrole deriva-
Figure 1 Iron(III) salt-catalyzed sequential type Nazarov cyclization/
Michael reaction of pyrrole derivatives [10].
*Corresponding author (email: titoh@chem.tottori-u.ac.jp)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

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Ibara C, et al. Sci China Chem August (2012) Vol.55 No.8
(Fe(ClO4)3·Al2O3) to give the cyclized product 2, and the
compound further reacted with vinyl ketone to afford the
Michael product, 4,5-dihydrocyclopenta-[b]pyrrol-6(1H)-
one derivative 3 with excellent stereoselectivity. A route to
access 5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one derivative
5 has also been accomplished through the same sequential
reaction pathway from pyrrole derivative 4 (Figure 1) [10].
We succeeded in obtaining desired products 3 and 5 in ex-
cellent yield using dichloromethane (CH2Cl2) as solvent
[10]. However, it has now been recognized that the use of
halogenated alkanes as solvent should be avoided in organic
synthesis. Therefore, development of a more environmen-
tally benign reaction system using economical iron salt cat-
alyst which is free of halogenated alkane solvent is required.
Ionic liquids (ILs) are well known to be suitable for use
in organic reactions and to provide potential for improve-
ment in control of product distribution, enhanced reactivity,
ease of product recovery, catalyst immobilization, and recy-
cling [14]. Therefore, we anticipated that recycled use of
our iron catalyst might be possible using an ionic liquid as
reaction medium. We now report that an efficient catalyst
recycled use system of sequential type one pot Nazarov
cyclization/Michael reaction of pyrrole derivative has been
accomplished using an ionic liquid as solvent [15].
Figure 2 Catalyst recycled use system using anionic liquid solvent.
The reaction course was monitored by TLC analysis at one
hour intervals, and the reaction was quenched by addition of
a mixed solvent of hexane and ether (2:1) immediately after
1a had been consumed.
As we had previously established that stereochemistry of
the product 2a did not depend on the E/Z ratio of the start-
ing compound 1a and the Nazarov cyclization product 2a
which had the trans relationship between the -car-
bomethoxy group and the -phenyl group was produced as
a major isomer, while a trace amount of cis isomer was also
produced in the CH2Cl2 solvent system [10]. To our delight,
it was revealed that only the trans 2a was obtained when the
reaction was conducted in an ionic liquid solvent. It was
also found that we needed no tedious argon atmospheric
conditions for conducting the reaction; the reaction mixture
was just stirred under air atmospheric conditions. Since iron
catalyst remained in the ionic liquid layer, it was possible to
use the catalyst repeatedly (Table 1).
2 Results and discussion
Initially, we evaluated eight ILs, 1-butyl-3-methylimidazo-
lium hexafluorophosphate ([bmim][PF6]), 1-butyl-3-methy-
limidazolium bis(trifluoromethanesulfonyl)amide ([bmim]
[NTf2]), 1-butyl-3-methylimidazolium tetrafluoroborate
(pbmim)[BF4]), 1-butyl-3-methylimidazolium trifluoro-
methylsulfonate ([bmim][OTf]), 1-butyl-3-methylimidazo-
lium ethylsulfate ([bmim][EtSO4]), tri(n-butyl)(2-methoxyethyl)
The product 2a was obtained in excellent yield in every
run five consecutive times (Entries 2 and 3) and in accepta-
ble yield nine times (Entry 4), while the reaction speed
dropped with repetition of the reaction process. It took 25 h
to complete the reaction after ten repetitions of the reactions
phosphoniumbis(trifluoromethanesulfonyl)amide ([P444ME
[NTf2]) [16], N,N-diethyl-N-methyl, N-(2-methoxyethyl)
ammonium bis(trifluoromethanesulfonyl)amide ([N221ME
]
]
[NTf2]), and N,N-diethyl-N-methyl, N-(2-metho-xyethyl)
ammonium tetrafluoroborate ([N221ME][BF4]), for Nazarov
cyclization of 1a in the presence of 5 mol% Fe(ClO4)3·
Al2O3 as catalyst.
when the reaction was carried out in [N221ME
][NTf2] (see the
right column in Entry 5). A significant reduction of chemi-
cal yield of 2a was also recorded in [P444ME][NTf2] solvent
The reaction proceeded smoothly in many ILs and cor-
responding cyclized product 2a was obtained with over 90%
yield, while no reaction took place in [bmim][OTf] or
[bmim][EtSO4]. It was thus revealed that the reaction sig-
nificantly depended on the counter anion part of ILs.
Although ILs which have PF6 and BF4 anion gave 2a in
excellent yield, neither salt are recommended as solvent
because these anions are slightly sensitive to moisture and
sometimes causes decomposition which produces hydrogen
Table 1 Nazarov cyclization of 1a in ionic liquid solvent
Solvent
Entry Run
[P444ME][NTf2]
yield of 2a a)
82% (3 h)
[bmim][NTf2]
yield of 2a a)
78% (3 h)
[N221ME][NTf2]
yield of 2a a)
86% (4 h)
1
2
3
4
5
6
1st
2nd
5th
98% (5 h)
94% (5 h)
96% (5 h)
98% (12 h)
76% (24 h)
35% (24 h)
98% (3 h)
94% (14 h)
63% (24 h)
62% (23 h)
90% (3 h)
93% (9 h)
9th
76% (24 h)
78% (25 h)
92% (3 h)
fluoride [17]. Therefore, we chose [bmim][NTf2], [P444ME
]
10th
11thb)
[NTf2] and [N221ME][NTf2] as appropriate solvents for the
present reaction and next attempted to demonstrate a cata-
lyst recycled use system (Figure 2).
a) isolated yield; b) 5 mol% of Fe(ClO4)3·Al2O3 was added.

Ibara C, et al. Sci China Chem August (2012) Vol.55 No.8
1629
(Entry 5, the left column). This drop in reaction rate was
Figure 4 [18].
speculated to be from decomposition of iron catalyst that
might occur due to moisture during the extraction process,
because we carried out the process under ambient condi-
tions. It was possible to recover both chemical yield and
reaction rate by adding 5 mol% of the fresh catalyst as
shown in Table 1 (Entry 6). We thus succeeded in demon-
strating the recyclable use of iron(III)-salt catalyst in the
ionic liquid solvent system.
We next attempted sequential type Nazarov/Michael re-
action and found that the desired reaction proceeded
smoothly in these ionic liquids. The most rapid reaction in
the second step of Michael reaction was accomplished when
the reaction was conducted in [bmim][NTf2], while a poor
reaction rate of the Michael reaction was observed in phos-
Better yield of the Nazarov/Michael reaction product was
recorded when n-pentyl ester 1b was subjected to the present
iron salt-catalyzed reaction compared to when the reaction of
benzyl ester 1c was used as substrate, though it took longer
reaction time to complete the Nazarov reaction process (step
1). We next demonstrated the catalyst recyclable use system
employing n-pentyl ester 1b in [bmim][NTf2] as solvent.
Typically the reaction was carried out as illustrated in
Figure 3. To a solution of 1b (156 mg, 0.50 mmol) in
[bmim][NTf2] (1.0 mL) was added Fe(ClO4)3·Al2O3 (60 mg,
10.7 wt% for Fe3+, 5 mol% vs. 1b) in one portion, and the
mixture was stirred at 80 °C. The reaction course was mon-
itored by silica gel thin layer chromatography (TLC) analy-
sis and 1-buten-2-one (70 mg, 1.0 mmol, 2.0 eq. vs. 1b) was
added after 1b had been consumed.
phonium IL ([P444ME][NTf2]) or ammonium IL ([N221ME
]
[BF4]), though the final products were obtained in accepta-
ble yield in all ILs tested. Therefore, we decided to demon-
strate one pot Nazarov cyclization and Michael reaction
using [bmim][NTf2] as solvent (Figure 3).
The desired reaction indeed took place, however, we en-
countered unexpected difficulty: isolation of the final prod-
uct, 4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one derivative
3a (R = Me), from the reaction mixture was unsuccessful
because 3a was very soluble in [bmim][NTf2].
We anticipated that modification of the ester part of 1 to
more hydrophobic one might solve this problem. Therefore,
we prepared n-pentyl ester 1b and benzyl ester 1c and use
them as substrates for the iron salt-catalyzed Naza-
rov/Michael reaction. To our delight, we succeeded in iso-
lating the desired products, 3b and 3c, from the ionic liquid
reaction mixture in acceptable yields: 78% for 3b and 70%
for 3c, respectively (Figure 3). Stereochemistry of 3b was
determined by X-ray crystallographic analysis as shown in
The reaction mixture was stirred at 60 °C for 2 h until the
spot of 2b disappeared. After being cooled to room temper-
ature (rt), addition of a mixed solvent (hexane and ether =
2:1) to the reaction mixture formed the biphasic layer and
the product 3b (278 mg, 0.73 mmol) was isolated from the
ether layer in 78% yield as a sole stereo isomer. The same
process was repeated, and the results are summarized in
Table 2. We succeeded in obtaining 3b in 78% yield after
five repetitions of the reaction without any addition of the
catalyst in [bmim][NTf2] solvent system, while the reaction
rate for the first step (Nazarov cyclization) had dropped
significantly (Table 2, Entry 3).
3 Conclusions
We demonstrated the sequential type Nazarov cyclization/
Figure 3 Sequential type one pot Nazarov cyclization/Michael reaction
of pyrrole derivatives 1 in [bmim][NTf2].
Figure 4 ORTEP view of Nazarov cyclization/Michael reaction product 3b.

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Ibara C, et al. Sci China Chem August (2012) Vol.55 No.8
Table 2 Results of catalyst recycled use system of one-pot Nazarov cy-
clization/Michael reaction of 1b
ion was determined by iodometry titration in aqueous solu-
tion.
Entry
Run
1st
Yield of 3b
1
2
3
78% (6 ha) and 2 hb))
73% (37 ha) and 1 hb))
78% (99 ha) and 1 hb))
4.3 Methyl (E)-2-benzylidene-3-oxo-3-(1H-pyrrol-2-yl)
propanoate (1a) [10]
3rd
5th
KH (8.02 g, 60 mmol, 30% in mineral oil) and NaH (2.60 g,
65 mmol, 60% in mineral oil) were placed in a two necked
flask under argon atmosphere and the mixture was diluted
with THF (100 mL) at 0 °C. To this mixture were added a
THF (50 mL) solution of 1-(1H-pyrrol-2-yl)ethanone (7)
(5.46 g, 50 mmol) and dimethyl carbonate (15.76 g, 175
mmol) at 0 °C, then stirred at 40 °C for 3.5 h. After being
cooled to room temperature (rt), the reaction was quenched
by addition of water and the mixture was extracted with
ethyl acetate. The combined organic layers were dried,
evaporated and chromatographed on a silica gel flash col-
umn to give methyl 3-oxo-3-(1H-pyrrol-2-yl)propanoate (8)
(7.51 g, 44.9 mmol) in 90% yield. Dried molecular sieves
4A (MS 4A) powder (10 g) was placed in a flask under ar-
gon and a CH2Cl2 (40 mL) solution of 8 (2.0 g, 12 mmol)
was added. To this mixture were added piperidine (0.38 mL)
and acetic acid (0.22 mL) at 0 °C and stirred at 0 °C for 5
min, then a CH2Cl2 (10 mL) solution of benzaldehyde (1.48
g, 14 mmol) was added and the resulting mixture was
stirred at rt for 5 h. The reaction mixture was filtered
through a glass sintered filter with a Celite pad and the fil-
trate was evaporated and chromatographed on a silica gel
flash column to give 1a (3.06 g, 12 mmol) in quantitative
yield. 1a: mp 95–97 °C (recrystallized from ethyl acetate);
1H NMR (500 MHz, ppm, CDCl3) δ 3.79 (3H, s), 6.16 (1H,
m), 6.71 (1H, s), 7.08 (1H, m), 7.21–7.28 (3H, m), 7.40
(2H, d, J = 7.0 Hz), 7.94 (1H, s), 10.05–10.11 (1H, brs,
N–H);13CNMR (125 MHz, ppm, CDCl3) δ 52.59, 111.38,
119.71, 126.52, 128.66, 130.17, 130.24, 130.42, 131.70,
133.05, 142.88, 165.72, 183.67; IR (KBr) 3285, 1705(CO),
1624(CO), 1595, 1410, 1259, 1204, 1132, 752, 691 cm–1;
Anal. Calcd. for C15H13NO3: C, 70.58; N, 5.49; H, 5.13
Found: C, 70.43; N, 5.47; H, 5.28.
a) Reaction time for the first step; b) reaction time for the second step
Michael reaction of pyrrole derivatives using an economical
Fe(ClO4)3·Al2O3 catalyst system with an ionic liquid as
reaction medium. A catalyst recycled use system has been
achieved: the product was obtained in good yields after five
repetitions of the reaction without any addition of the cata-
lyst. To the best of our knowledge, this is the first example
of realization of recyclable catalyst in the sequential type
one pot reaction in an ionic liquid solvent system. It should
be emphasized that the reaction can be accomplished under
very mild conditions and requires no tedious argon atmos-
pheric conditions, although we should pay attention to
moisture. Further investigation of the scope and limitations
of this reaction will make it even more valuable.
4 Experimental
4.1 General procedures
Reagents and solvents were purchased from common com-
mercial sources and were used as received or purified by
distillation from appropriate drying agents. Reactions re-
quiring anhydrous conditions were run under an atmosphere
of dry argon. Wako gel C-300 and Wako gel B5F were used
for flash column chromatography and thin-layer chroma-
tography (TLC), respectively. NMR spectra were recorded
1
on JEOL MH-400 (1H) or JEOL MH-500 (500 MHz for H
and 125 MHz for 13C) spectrometers, and chemical shifts
are expressed in ppm downfield from tetramethylsilane
(TMS) in CDCl3 as an internal reference. IR spectra were
obtained on a SHIMADZU FTIR-8000 spectrometer. Ionic
liquids were purchased from Kanto Reagents Co., Ltd. or
Tokyo Chemical Industry Co., Ltd. were used for the reac-
tions without any further purification.
4.4 n-Pentyl(E)-2-benzylidene-3-oxo-3-(1H-pyrrol-2-yl)
propanoate (1b)
4.2 Preparation of Fe(ClO4)3·Al2O3 [3]
Methyl ester 1a (1.73 g, 10.3 mmol) and molecular sieves
4A (5.0 g) were placed in a two necked flask under argon
and the mixture was diluted with 25 mL of dry with toluene.
To the mixture was added pentan-1-ol (1.2 mL, 11.6 mol)
and stirred at 120 °C for 12 h. After being cooled at rt, to
this mixture were added piperidine (0.20 mL, 2.1 mmol),
acetic acid (0.1 mL, 2.1 mmol), and benzaldehyde (1.1 mL,
2.1 mmol) at 0 °C and the mixture was stirred for 5 min at
the same temperature. The reaction mixture was allowed to
warm to rt and stirred for 5 h at the same temperature; it
was then diluted with ethyl acetate and filtered through a
Neutral alumina (714 mg, Aldrich) was added to a solution
of Fe(ClO4)3·nH2O (286 mg) in freshly distilled CH3CN
(0.5 mL) and the solvent was removed at 60 °C under re-
duced pressure using a rotary evaporator. The mixture was
dried under vacuum and the resulting uniformly orange
powder was used for the reaction. The catalyst should be
handled with care because it has been reported that iron(III)
perchlorate salt explodes when subjected to mechanical or
thermal shock. However, our catalyst is believed to be safe
due to the support by neutral alumina. The content of Fe(III)

Ibara C, et al. Sci China Chem August (2012) Vol.55 No.8
1631
glass sintered filter with a Celite pad to remove the piperi-
dinium salt. The filtrate was evaporated and chromato-
graphed on silica gel flash column (hexane:ethyl acetate =
1:1) to afford 1b (2.95 g, 9.48 mol) in 92% overall yield.
1b: mp: 110–114 °C; Rf = 0.52 (hexane/ethyl acetate =
2/1); 1H NMR (500 MHz, CDCl3): δ 0.83 (t, J=7.1 Hz, 3H),
1.17–1.62 (m, 4H), 1.60 (m, 2H), 4.20 (t, J=6.6 Hz, 2H),
6.17 (m, 1H), 6.71 (td, J=2.7 Hz, 1.7, 1H), 7.08 (td, J=2.7
Hz, 1.4, 1H), 7.21–7.28 (m, 3H), 7.41 (t, J=1.8 Hz, 1H)
7.42 (t, J=1.6 Hz, 1H), 7.89 (s,1H), 9.79 (s, 1H); 13C NMR
(125 MHz, CDCl3): δ 13.8, 22.1, 27.8, 28.1, 65.5, 111.2,
119.3, 126.1, 128.11, 128.6, 129.0, 129.3, 130.1, 130.9,
131.8, 133.1, 142.4, 165.3, 183.7; IR (KBr) : 3275, 2935,
2860, 1701(CO), 1612(CO), 1546, 1406, 1255, 740 cm–1;
Hz, 12.7, 5.3, 2H), 4.26 (s, 1H), 6.05 (t, J=1.8 Hz, 1H), 7.08
(dd, J=7.6, 1.6 Hz, 2H), 7.18 (m, 3H), 7.34 (t, J=2.5 Hz,
1H), 10.9 (br, 1H); 13C NMR (125 MHz, CDCl3) : δ13.8,
22.0, 27.5, 27.8, 28.7, 29.9, 38.5, 50.9, 64.9, 71.3, 107, 127,
128.0, 128.6, 129, 134, 134, 138, 153, 170, 189, 208; IR
(KBr): 3292, 2957, 1718(CO), 1676(CO), 1406, 1375, 1271,
1203, 765.7 cm–1; HRMS(ESI): m/z: calcd for [MH]+
+
C23H28NO4 : 382.20194, found: 382.20126.
We succeeded in obtaining 2b in 87% yield when the re-
action was stopped at Nazarov cyclization and isolated from
the reaction mixture.
2b: mp: 99–103 °C; Rf = 0.34 (hexane/ethyl acetate =
2/1); 1H NMR (500 MHz, CDCl3): δ 0.91 (t, J=7.1 Hz, 3H),
1.35 (dt, J=11.5, 4.2 Hz, 4H), 1.71 (dd, J=6.9, 7.3 Hz, 2H),
3.82 (d, J=3.2 Hz, 1H), 4.22 (m, 2H), 4.78 (d, J=3.2 Hz,
1H), 6.13 (t, J=2.1 Hz, 1H), 7.22 (d, J=8.2 Hz, 2H), 7.26
(td, J=6.6, 1.7 Hz, 1H), 7.33 (t, J=7.3 Hz, 2H), 7.39 (t,
J=2.7 Hz, 1H), 11.1 (brs,1H); 13C NMR (125 MHz, CDCl3):
δ 13.9, 22.2, 27.9, 28.2, 44.1, 65.7, 68.3, 106.5, 127.1,
127.2, 128.8, 132.8, 134.4, 141.6, 155.2, 169.4, 184.4; IR
(KBr):3221, 2956, 2872, 1726(CO), 1685(CO), 1450, 1400,
1319, 1161, 777cm–1; HRMS(ESI): m/z: calcd for [MH]+
+
HRMS(ESI): m/z: calcd for [MH]+ C19H22NO3 : 312.15942,
found: 312.15915
Using benzyl alcohol in the first step, benzyl etser 1c was
also prepared in 87% yield (two steps).
4.5 Benzyl (E)-2-benzylidene-3-oxo-3-(1H-pyrrol-2-yl)
propanoate (1c)
mp: 99–104 °C; 1H NMR (400 MHz, CDCl3): δ 4.70 (s, 1H),
5.25 (s, 2H), 6.15–6.18 (brs, 1H), 6.65–6.70 (brs, 1H),
7.00–7.05 (brs, 1H), 7.20–7.30 (brs, 1H), 7.20–7.03 (m,
6H), 7.30–7.45 (m, 4H), 7.90–7.95 (brs, 1H); 13C NMR
(125 MHz, CDCl3): δ 66.89, 111.3, 127.6, 128.0, 128.4,
128.6, 130.2, 130.3, 130.5, 131.8, 133.0, 135.7, 143.0,
165.1, 190.2; IR (KBr): 3269, 1718(CO), 1612(CO), 1545,
1496, 1406, 1251, 1190, 1122, 771 cm–1; HRMS(ESI): m/z:
+
C19H22NO3 : 312.16006, found: 312.15912.
Benzyl ester 3c and 2c were obtained using the same
protocol.
3c: mp: 155–160 °C; 1H NMR (500 MHz, CDCl3) δ 2.95
(s, 3H), 2.43–2.48 (m, 1H), 2.56–2.65 (m, 2H), 2.80–2.85
(m, 1H), 4.30 (d, J=15.0 Hz, 1H), 4.37 (s, 1H), 4.49 (d,
J=15.0 Hz, 1H), 6.11 (s, 1H), 7.01–7.03 (m, 2H), 7.15–7.16
(m, 2H), 7.22–7.25 ( m, 6H ), 7.33–7.35 (m, 1H), 11.0 (s,
+
calcd for [M+H]+ C21H18NO3 : 332.12874, found:
3
NH,1H): C NMR (125 MHz, CDCl3): δ 28.7, 30.0, 38.4,
332.12126.
51.0, 66.2, 71.4, 106.5, 127.5, 127.6, 127.8, 127.9, 128.1,
128.3, 128.5, 128.9, 129.2, 134.0, 134.1, 135.2, 138.1,
152.6, 170.1, 188.2, 207.8; IR (KBr): 3244, 3030, 2955,
1734(CO), 1681(CO), 1495, 1456, 1402, 1371, 1259, 1220,
1155, 744 cm–1; HRMS(ESI): m/z: calcd for [MH]+
4.6 Synthesis of 3b through one pot Nazarov cycliza-
tion/Michael reaction
+
To a mixture of Fe(ClO4)3·Al2O3(19 mg, 5.0 mol% for
Fe3+, 0.01 mmol) in [bmim][NTf2] (0.4 mL) was added 1b
(62 mg, 0.20 mmol) at rt and the mixture was stirred at
80 °C for 4 h. The reaction mixture was cooled to rt after
confirmation that the starting 1b had been consumed and 2b
produced, then 2 eq. of 1-buten-3-one (0.03 mL, 0.40 mmol)
was added to the reaction mixture at rt and stirred for 6 h at
60 °C. After being cooled to rt, the reaction was extracted
with a mixed solvent of hexane and ether (2:1). The com-
bined organic layers were evaporated to dryness and silica
gel thin layer chromatography (TLC) (hexane:ethyl acetate
= 3:2) gave 3b (59.5 mg, 0.156 mmol) in 78% yield as a
white solid. Ionic liquid layer was dried under reduced
pressure at 60 °C for 30 min, feeding of substrate 1b (62 mg)
and conducted next reaction.
C25H24NO4 : 402.17062, found: 402.17126.
2c: 155–160 °C; 1H NMR (400 MHz, CDCl3): 3.88 (d,
J=3.25 Hz, 1H), 4.78 (d, J=3.2 Hz, 1H), 5.27 (d, J=3.6 Hz,
2H), 6.20–6.30 (brs, 1H), 7.16 (d, J=7.3 Hz, 1H), 7.23–7.45
(m, 10H), 11.1 (s, NH, 1H); 13C NMR (125 MHz, CDCl3):
44.04, 67.09, 68.09, 106.5, 127.20, 127.23, 127.38,
128.00, 128.05, 128.10, 128.30, 128.40, 128.77, 129.0,
132.7, 134.6, 135.6, 141.4, 155.2, 169.2, 184.1; IR(KBr):
3244, 2955, 1734(CO), 1681(CO), 1495, 1402, 1371, 1259,
1220, 1155, 744 cm–1; HRMS(ESI): m/z: calcd for [MH]+
+
C21H18NO3 : 332.12874, found: 332.12826.
The present work was supported by a Grant-in-Aid for Scientific Research
in a Priority Area, “Science of Ionic Liquids”, from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
3b: mp: 139–142 °C; Rf = 0.11(hexane/ethyl acetate =
2/1); 1H NMR (500 MHz, CDCl3): δ 0.73(t, J=7.3 Hz, 3H),
0.97 (dt, J=15.3, 4.1 Hz, 2H), 1.14 (m, 4H), 2.09 (s, 3H),
2.35 (m, 1H), 2.52 (m, 2H), 2.75 (m, 1H), 3.31 (ddt, J=68.6
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18 Crystallographic data for compound 3b can be obtained free of
charge, on application to CCDC as supplementary publication
number CCDC 864395.Copies of the data can be obtained free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(1223)336033 or e-mail: data_request@ccdc.
cam.ac.uk]