Reaction of electron-deficient 3-acetyl-1-arylpent-2-ene-1,4-diones as a building block of heterocycles?

Article abstract of DOI:10.3987/COM-17-13736

The BF₃-assisted reaction of 3-acetyl-1-arylpent-2-ene-1,4-diones 1a-c with cyclohexanones and piperidin-4-ones 2a-i gave unique 3a,6a-dihydrospirofuro[2,3-d][1,3]dioxoles 3 in good to high yields. A similar reaction with the 2,3-dihydroquinolin-4(1H)-ones did not occur, but the reaction with 4-hydroxychromenone 5 mainly produced 3-furfuryl-4-hydroxychromenone 6 along with furochromenone 7. The reaction of the electron-deficient pentenedione 1a as a Michael acceptor with indole, pyrrole, furan, and N-methylaniline produced the corresponding 1,4-adducts. Especially, the indole adduct was easily converted by the Paal-Knorr synthesis into the corresponding furanyl-, pyrrolyl-, and thiophenyl-substituted indoles. The reaction details and the structure determination of the products are described.

Full text of DOI:10.3987/COM-17-13736

HETEROCYCLES, Vol. 94, No. 8, 2017
1479
HETEROCYCLES, Vol. 94, No. 8, 2017, pp. 1479 - 1505. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 27th April, 2017, Accepted, 8th June, 2017, Published online, 14th June, 2017
DOI: 10.3987/COM-17-13736
REACTION
OF
ELECTRON-DEFICIENT
3
-ACETYL-1-ARYLPENT-2-ENE-1,4-DIONES AS A BUILDING BLOCK
†
OF HETEROCYCLES
a
a
b
Shun Kawabata, Akihiro Oishi, and Hiroshi Nishino *
a
Department of Chemistry, Graduate School of Science and Technology,
Kumamoto University, Kurokami 2-39-1, Chûou-Ku, Kumamoto 860-8555, Japan
b
Department of Chemistry, Faculty of Science, Kumamoto University, Kurokami
2
-39-1, Chûou-Ku, Kumamoto 860-8555, Japan
Fax: +81-96-342-3374; E-mail: nishino@kumamoto-u.ac.jp
†
Dedicated to Dr. Kazu Kurosawa, Professor Emeritus of Kumamoto University,
on his 80th birthday.
Abstract – The BF
3
-assisted reaction of 3-acetyl-1-arylpent-2-ene-1,4-diones
a-c with cyclohexanones and piperidin-4-ones 2a-i gave unique
a,6a-dihydrospirofuro[2,3-d][1,3]dioxoles 3 in good to high yields. A similar
1
3
reaction with the 2,3-dihydroquinolin-4(1H)-ones did not occur, but the reaction
with 4-hydroxychromenone 5 mainly produced 3-furfuryl-4-hydroxychromenone
6
along with furochromenone 7. The reaction of the electron-deficient
pentenedione 1a as a Michael acceptor with indole, pyrrole, furan, and
N-methylaniline produced the corresponding 1,4-adducts. Especially, the indole
adduct was easily converted by the Paal-Knorr synthesis into the corresponding
furanyl-, pyrrolyl-, and thiophenyl-substituted indoles. The reaction details and
the structure determination of the products are described.
INTRODUCTION
The synthesis of novel heterocyclic compounds is always a hot topic in organic chemistry because it
1
sometimes can provide enormous opportunities for the discovery of new pharmaceuticals and materials.
The cycloaddition reaction is one of the direct and powerful tools for the construction of complex
heterocyclic compounds from structurally simple and readily available electron-deficient alkenes as the
starting material in a one-step process, and many examples of both ionic and radical reactions have been

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HETEROCYCLES, Vol. 94, No. 8, 2017
2
found in the literature. In connection with our previous study, we reported the selective transformation of
3
4
the endoperoxide intermediate obtained by the photosensitized oxygenation of furan I into
3
-acetyl-1-phenylpent-2-ene-1,4-dione (1a) and oxirane II depending on the reaction conditions (Scheme
5
6
1
). The electron-deficient pentenedione 1a is very attractive as a building block in many reactions. For
example, the BF
3
-catalyzed reaction of 1a in the presence of acetylacetone (Hacac) in dry tetrahydrofuran
7
a
(
THF) at rt gave the polyfunctionalized furans III and IV. When the reaction in the absence of Hacac
7
b
was carried out in wet THF at reflux temperature, bis(furyl)methane V was preferentially produced. A
typical Diels-Alder reaction of 1a with cyclopentadiene gave a mixture of the endo/exo VI and bicyclic
7
b
compound VII. In order to determine the potential of the pentenedione 1a as a building block of
heterocyclic compounds, we examined the BF -assisted reaction using cyclic ketones such as
3
cyclohexanones and piperidin-4-ones 2a-i. Surprisingly, the reaction did not produce the furyl-substituted
products, but the 3a,6a-dihydrospirofuro[2,3-d][1,3]dioxoles 3. We now report the results of the unique
3
cyclization reaction and also describe the BF -assisted reaction with 4-hydroxychromenone 5. In addition,
we describe the Michael addition of 1a with pyrrole, furan, and indole as an electron donor, and also the
application using the Paal-Knorr strategy.
Ac
Me
1O2
O
O
Ac
Ph
Me
O
rt
Ph
Ac
Ac
(
63%)
MeCN
Ph
O
O
O
I
II
Ac
H O (68%)
2
Me
Me
O
O
Ac
Ph
H
O
Ac
Ac
Bz
Hacac
BF •Et O
III (66%)
Ph
Ph
Ac
VI
(
98%)
Ac
Me
3
2
Ac
O
1a
VI endo:exo:VII
53:12:35
Me
dry THF
3 °C
Ac
=
H
2
O
H
O
H O
2
Ph
VII
BF •Et O THF
3
2
O
O
Me
reflux
H
IV (24%)
Ac Ac
Ph
Ph
O
O
V (79%)
Scheme 1. Some Reactions Using the Pentenedione 1a

HETEROCYCLES, Vol. 94, No. 8, 2017
1481
RESULTS AND DISCUSSION
Reaction with Cyclohexanones and Piperidin-4-ones
The pentenedione 1a was easily prepared by the Knoevenagel condensation of phenylglyoxal with Hacac
7
b
and was not stable in air. When the reaction of 1a with cyclohexanone (3 equiv.) in the presence of
BF ·Et O (1 equiv.) was carried out in dry THF at room temperature, the spirodioxole 3aa was obtained
3
2
in 36% yield together with tetrahydrobenzofuran 4aa (14% yield) (Scheme 2 and Table 1, Entry 1). A
prolonged reaction time led to a slight increase in 3aa (48% yield) (Entry 2). The use of 4 equivalents of
BF
the use of 1a (5 equiv.) and BF
-tert-butylcyclohexanone (2b) was conducted at room temperature to afford the corresponding
3
·Et
2
O caused the decomposition of 3aa (Entry 4). The best yield of 3aa (58% yield) was realized by
3
·Et O (5 equiv.) at 0 °C for 24 h (Entry 3). A similar reaction with
2
4
spirodioxole 3ab as a 47:53 diastereomixture and tetrahydrobenzofuran 4ab (Entry 5). Interestingly, the
reaction at lower than 0 °C led to an increase in the spirodioxole 3ab even though a longer reaction time
was required (Entries 6 and 7). The reaction of the 4-chlorophenyl-substituted pent-2-ene-1,4-dione 1b
with 2b gave a similar result, but with a much better yield of the corresponding product (Entries 8 and 9).
On the other hand, the use of 3-acetyl-1-(4-methoxyphenyl)pent-2-ene-1,4-dione (1c) led to an intractable
mixture, and tetrahydrobenzofuran 4cb rather than the spirodioxole 3cb was produced in 47% yield for
the reaction at room temperature (Entry 11). The structures of the products 3 and 4 were characterized by
spectroscopic methods and elemental analysis. Fortunately, a single crystal of one of the diastereomers
3
bb was successfully grown from hexane and subjected to an X-ray crystallographic measurement. We
8
then obtained the exact structure of the spirodioxole 3bb (see experimental section).
Ar Me
Ar
Ac
O
O
O
R
O
O
BF •Et O
3
2
+
R
O
R
Me
+
H
Ar
Ac
dry THF
O
O
H
Ac
Me
1a-c
2a,b
3
4
1
1
1
a: Ar = Ph
b: Ar = 4-ClC H4
c: Ar = 4-MeOC H
2a: R = H
2b: R = t-Bu
6
6
4
Scheme 2. Reaction of Pentenediones 1a-c with Cyclohexanones 2a,b
a
Table 1. Reaction of Pentenediones 1a-c with Cyclohexanes 2a,b in the Presence of BF
3
1
b
c
Entry 1/Ar
2/R
2a: H
2a
1:2:BF
1:3:1
3
Temp/°C Time/h
Product Yield/%
d
rec./%
4
aa
1
2
1a: Ph
1a
rt
rt
35
45
3aa (36)
3aa (48)
-
(
14)
aa
9)
4
1:3:1
-
(

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HETEROCYCLES, Vol. 94, No. 8, 2017
4
(
4
(
4ab
(19)
aa
9)
aa
10)
3
4
5
6
7
8
9
1a
2a
2a
1:5:2
1:5:4
1:5:1
1:5:1
1:5:2
1:5:1
1:5:2
1:5:1
1:5:1
0
0
24
17
8
3aa (58)
-
-
1a
-
2
b:
e
e
e
e
1a
rt
0
3ab (36) (dr 47:53)
3ab (55) (dr 40:60)
3ab (49) (dr 39:61)
-
t-Bu
4
ab
16)
ab
13)
bb
13)
4bb
19)
4cb
10)
cb
47)
1a
2b
2b
2b
2b
2b
2b
24
72
38
74
185
24
-
(
4
1a
-20
0
4
12
-
(
4
1b: 4-ClC
6
H
4
3bb (58) (dr 50:50)
(
e
1b
0
3bb (70) (dr 41:59)
(
e
1
0
1
1c: 4-MeOC
6
H
4
0
3cb (8) (dr 38:62)
41
-
(
4
e
1
1c
rt
3cb (2) (dr 50:50)
(
a
b
c
d
e
The reaction of 1 (0.5 mmol) with 2a was carried out in dry THF (0.5 mL).
Molar ratio.
Isolated yield based on 1 used.
Recovery of 1.
Diastereomer ratio based on the H NMR spectrum.
1
In order to apply the reaction to azacyclic ketones, such as the piperidin-4-ones, we next examined the
reaction of pentenedione 1a with 1-methylpiperidin-4-one (2c) (Scheme 3 and Table 2). Although the
reaction was carried out in dry THF at room temperature according to the conditions described above, the
reaction did not proceed at all (Entry 1). The reaction at reflux temperature afforded the corresponding
azaspirodioxole 3ac in a poor yield (Entry 2). When the reaction was carried out in dichloromethane
(DCM) at room temperature, the yield of 3ac increased (Entry 3). The reaction was then optimized and a
synthetically acceptable yield of 3ac was achieved at 0 °C under neat conditions (Entry 6). Since the
viscosity of 2c at -20 °C was much higher than that at 0 °C, a small amount of DCM (0.05 mL) was added
to the mixture and the reaction was then conducted at -20 °C to give almost the same result (Entry 7).
Ph
Ac
Ac
O
O
O
BF •Et O
3
2
+
R N
O
R N
Me
Ph
DCM
or
neat
O
H
Ac
1a
2c-i
3
2c : R = Me
2d: R = Et
2e : R = Pr
2f : R = Bn
2g: R = Ac
2h: R = Bz
2
i : R = Cbz
Scheme 3. Reaction of Pentenedione 1a with Piperidin-4-ones 2c-i

HETEROCYCLES, Vol. 94, No. 8, 2017
1483
a
Table 2. Reaction of Pentenedione 1a with Piperidin-4-ones 2c-i in the Presence of BF
3
b
c
Entry
2/R
1:2:BF
1:1:1
1:1:3
1:1:1
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
1:1:5
3
Solvent/mL
THF/5
THF/5
DCM/5
DCM/5
neat
Temp/°C
Time/h
24
6
Product Yield/%
1
2
3
4
5
6
7
8
9
2c: Me
2c
rt
reflux
rt
no reaction
d
3ac (14)
d
2c
12
6
3ac (25)
2c
rt
3ac (61)
3ac (74)
3ac (93)
3ac (94)
3ad (71)
3ad (88)
3ae (68)
3ae (77)
3af (68)
3af (89)
3ag (79)
3ag (quant)
3ah (85)
3ah (94)
3ai (94)
2c
rt
2.5
2.5
2.5
2.5
3
2c
neat
0
2c
DCM/0.05
neat
-20
0
2d: Et
2d
DCM/0.05
neat
-40
0
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
2e: Pr
2e
2.5
2.5
2.5
4
DCM/0.05
neat
-20
0
2f: Bn
2f
DCM/0.05
neat
-40
0
2g: Ac
2g
2.5
2.5
2.5
3
DCM/0.05
neat
-20
0
2h: Bz
2h
DCM/0.05
neat
-20
0
2i: Cbz
3
a
b
c
d
The reaction of 1a (0.5 mmol) with 2 was carried out in dry sovent or under neat conditions.
Molar ratio.
Isolated yield based on 1a used.
A small amount of homocyclization products I and V was isolated.
Having succeeded in the cycloaddition of the pentenedione 1a with the azacyclohexanone 2c, we turned
our attention to the reaction with other piperidin-4-ones (Table 2, Entries 8-18). As a result, both the
N-alkyl- 2d-f and N-acyl-substituted piperidin-4-ones 2g-i were tolerated during the cycloaddition
reaction under neat or low temperature conditions, producing the corresponding azaspirodioxoles 3ad-3ai
in high yields. A similar reaction with the 1-methyl- and 1-tosyl-2,3-dihydroquinolin-4(1H)-ones did not
occur, but the homocyclization product V of 1a was only produced.
3
The NMR spectrum of N-acetylspirodioxole 3ag in CDCl at room temperature deserves comments. In
1
the H NMR spectrum, two signals appeared at δ 2.13 (s) and 2.11 (s) assigned to the N-acetyl group and
1
3
most of the signals in the C NMR spectrum each showed two peaks. When the NMR spectrum was
1
measured in DMSO-d
6
at 80 °C, the N-acetyl group in the H NMR spectrum and the signals that
1
3
appeared for each of the two peaks in the C NMR spectrum collapsed into one peak due to existence of
the conformational isomer in CDCl . Although a similar phenomenon was not observed in other
azaspirodioxoles, the methylene peaks of the N-acylspirodioxoles 3ah and 3ai in the C NMR spectrum
3
1
3

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HETEROCYCLES, Vol. 94, No. 8, 2017
appeared as a weak signal on the NMR time scale, probably depending on the flipping velocity of the
azacyclohexane ring.
Reaction with 4-Hydroxy-2H-chromen-2-one
With the unique spirodioxole formation in hand, the reaction using 4-hydroxy-2H-chromen-2-one (5) was
3
next investigated. When the reaction was carried out at the molar ratio of 1a:5:BF = 1:3:1 in DCM (1.0
mL) at rt, unfortunately, the corresponding dioxole was not isolated, but furfurylchromenone 6 and
furochromenone 7 were obtained together with bis(furyl)methane V as the homocyclization product of 1a
7
b
(
Scheme 4 and Table 3, Entry 1). In order to prevent the production of V, the pentenedione 1a was
dropwise added to the mixture of 5 and BF at reflux temperature. As a result, the yield of 6 was
3
improved (Entry 2), but bis(furyl)methane V was still produced. We then scrutinized the solvent and
reaction temperature, and eventually, the use of chlorobenzene at 130 °C led to the maximum yield of 6
and suppressed the production of V (Entry 6).
O H
Me
O
OH
OH
Ph
Ac
Ac
O
BF •Et O
Me
3
2
O
+
+
Ph
Ph
O
Ac
O
O
O
6
O
O
O
1a
5
7
Scheme 4. Reaction of Pentenedione 1a with 4-Hydroxy-2H-chromene-2-one (5)
a
Table 3. Reaction of Pentenedione 1a with 4-Hydroxychromenone (5) in the Presence of BF
3
b
Product Yield/%
Solvent/m
L
Entry
Temperature/°C
Time/min
c
6
7
V
1
DCM/1
DCM/1
DCE/1
rt
70
50
20
10
5
24
41
51
57
69
77
14
1
16
12
3
d
2
40
d
3
80
17
12
13
13
d
4
C
C
C
6
6
6
H
H
H
5
5
5
Cl/1
100
130
130
14
7
d
5
Cl/1
d
6
Cl/0.5
3
5
a
b
c
d
The reaction of 1a (0.3 mmol) with 5 (0.9 mmol) was carried out in the presence of BF
3 2
•OEt (0.3 mmol).
Isolated yield based on 1a used.
Bis(3-acetyl-5-phenyl-2-furyl)methane (V) as a homocyclization product of 1a.
Pentenedione 1a (0.3 mmol) in solvent (0.3 mL) was dropwise added to the mixture of 5 (0.9 mmol) and
BF •OEt (0.3 mmol) in solvent.
3
2

HETEROCYCLES, Vol. 94, No. 8, 2017
1485
Proposed Mechanism for the Formation of the Products
The BF
3
-assisted cyclization of pentenediones 1 with cyclic ketones 2 could be similarly understood by
7
the previously reported literature as depicted in Scheme 5. The production of two diastereomers in the
reaction using 4-tert-butylcyclohexanone (2b) would be caused by exclusive occupation of the tert-butyl
group at the equatorial position. That is, the carbonyl group of the cyclohexanone equatorial fixed
tert-butyl group might be attacked by the pentenedione 1 from the equatorial or axial direction, affording
the corresponding diasteromeric dioxoles. In the case of 1c (Ar = 4-MeOC
6
H
4
) (Table 1, Entries 10 and
1
1), the production of the spirodioxole 3cb was suppressed because the electron-donating methoxy group
might change the electrostatic potential of 1c.
Ar
F3B
O
Ar
O
O
Me
O
O
BF3
O
R X
O
+
R X
Me
Me
Ar
Me
O
Ac
Ac
BF3
O
2
: X = CH, N
R = H, alkyl, acyl
1a-c
Ar
H O
O
O
2
3
R X
Me
Me
O
F3B
O
Scheme 5. Proposed Mechanism for the Formation of Dioxoles 3
F3B
F3B
Ac
Ar
O Ar Ac
F3B
O
Ar
O
O Ar Me
R
R
R
Me
R
O
O
+
BF3
Ac BF3
Ac
H
O
H+
O
BF3
-
O
H
O
O BF3
Ac
BF3
Me
2
a: R = H
1a-c
H+
2b: R = t-Bu
H
F3B
Ar Me
Ar Me
O Ar Me
R
-H+
R
O
R
O
O
O
O
-BF OH
3 2
H O
2
4
BF3
BF3
O
BF3
O
O
H
O
H
Me
Me
Me
Scheme 6. Proposed Mechanism for the Formation of Tetrahydrobenzofurans 4

1486
HETEROCYCLES, Vol. 94, No. 8, 2017
On the other hand, the production of the by-products 4 would be explained by an aldol-type condensation
briefly shown in Scheme 6. This reaction could not be retarded under all of the conditions. However, the
corresponding by-product, such as tetrahydrobenzofuran 4, was not produced during the reaction using
the azacyclohexanones 2c-i.
The furfurylchromenone 6 would be formed by the reaction of methylenedihydrofuranol A prepared by
7
the enolization of 1a followed by in situ cyclization (Scheme 7). It was considered that the by-product
furochromenone 7 would be obtained by a similar reaction sequence as shown in Scheme 6.
BF3
O
H
O
O
O
H
BF3
O
-BF •OH
3
Ph
+
6
Ph
O
O
Ac
Ac
1a
A
5
Scheme 7. Plausible Mechanism for the Formation of Furfurylchromenone 6
Michael Addition Using Indole, Pyrrole, Furan, and N-Methylaniline
In order to further study the reactivity of the electron-deficient pentenedione 1a as a Michael acceptor, we
9
next investigated the reaction with indole as an electron-donor (Scheme 8). The reaction was examined
in various solvents and the Michael adduct 8 was obtained in all the solvents (see Experimental section).
The best yield of 8 (97% yield) was realized in acetonitrile at reflux temperature for 9.5 h. A similar
reaction with pyrrole gave the 1,4-adduct 9 in 84% yield.
Ac
N
H
Ac
Bz
9
(84%)
MeCN
reflux
pyrrole
Ac
Ac
Bz
Ac
indole
furan
1
a
MeCN
reflux
AcOH
rt
O
Ac
N
Bz
10 (76%)
H
AcOH
reflux
N-methylaniline
8
(97%)
Bz
Ac
MeHN
Ac
11 (75%)
Scheme 8. Michael Addition of 1a with Indole, Pyrrole, Furan, and N-Methylaniline

HETEROCYCLES, Vol. 94, No. 8, 2017
1487
In addition, the use of a one-half equivalent of pyrrole provided the 2,5-disubstituted adduct in 79% yield
see Experimental section). On the other hand, the reaction with furan did not proceed in acetonitrile, but
(
the corresponding adduct 10 (76% yield) was obtained in acetic acid at room temperature.
N-Methylaniline also afforded the 1,4-adduct 11 (75% yield) in boiling acetic acid.
Conversion into Heterocycle-substituted Indole Derivatives via Paal-Knorr Strategy
With the 1,4-dicarbonyl-functionalized indole 8 in hand, we finally embarked on the synthesis of the
1
0
five-membered heterocycle-substituted indoles using the Paal-Knorr strategy (Scheme 9). Since it was
reported that the treatment of 1a with indole in the presence of methanesulfonic acid gave the
1
0c
3
3
-furyl-substituted indole, we initially examined the BF -catalyzed reaction of 1a with indole in DCM
1
1
at reflux temperature. Pleasingly, the reaction finished in only 30 min and the reported product 12 (88%
yield) was obtained during the formation of 8. The Michael adduct 8 underwent the typical Paal-Knorr
reaction with ammonium acetate to produce the desired pyrrole-substituted indole 13a in quantitative
yield without purification. Use of benzylamine and ethanolamine also gave the desired products 13b and
1
3c in high yields. Similarly, the treatment of 8 with Lawesson's reagent in toluene at 50 °C afforded the
1
2
thienyl-substituted indole 14 (49% yield) together with 12 (23% yield).
1a
R
Me
Ac
Me
Ac
O
N
Ph
Ph
NH OAc
or R-NH2
4
BF •Et O
3
2
8
DCM
reflux
AcOH
110 °C
N
H
N
H
12 (88%)
13a: R = H (quant)
Lawesson's toluene
reagent
50 °C
13b: R = Bn (89%)
1
3c: R = CH CH OH (74%)
2
2
Me
S
Ph
Ac
1
2 (23%) +
14 (49%)
N
H
Scheme 9. Synthesis of Heterocycle-substituted Indole Derivatives
CONCLUSION
We have accomplished the unique synthesis of spirodioxoles and azaspirodioxoles 3 by the cycloaddition
of pentenediones 1 with cyclohexanones and piperidin-4-ones 2. The reaction with chromenone 5 did not

1488
HETEROCYCLES, Vol. 94, No. 8, 2017
give the spirodioxole, but furfurylchromenone 6 along with furochromenone 7. There is no precedent
1
3
for the synthesis of bicyclo-spirodioxoles 3 except for a similar protecting diol of sugars and
1
4
kendomycin analogues which have a cytotoxic property. We also demonstrated the usefulness of
pentenedione 1a as a convenient building block in the Michael addition followed by the Paal-Knorr
heterocycle synthesis using indole.
EXPERIMENTAL
Measurements. Melting points were taken using a Yanagimoto micromelting point apparatus and are
uncorrected. The NMR spectra were recorded using a JNM ECX 500 or AL300 FT-NMR spectrometer at
1
13
5
00 MHz for the H and at 125 MHz for C, with tetramethylsilane as the internal standard. The
chemical shifts are reported as δ values (ppm) and the coupling constants in Hz. The following
abbreviations are used for the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and
1
brs, broad singlet for the H NMR spectrum. The IR spectra were measured in CHCl
3
or KBr using a
−
1
Shimadzu 8400 FT IR spectrometer and expressed in cm . The high-resolution mass spectra and the
elemental analyses were performed at the Instrumental Analysis Center, Kumamoto University,
Kumamoto, Japan. The X-ray analysis was performed by a Rigaku RAXIS RAPID imaging plate area
detector with graphite monochromated Mo-K
α
radiation.
Materials. The 3-acetyl-1-aryl-2-pentene-1,4-diones 1a-c and piperidin-4-ones 2e, 2h, 2i were prepared
1
4
according to the literature method.
Cyclohexanone (2a), 4-tert-butylcyclohexanone (2b),
1-ethylpiperidin-4-one (2d), 1-benzylpiperidin-4-one (2f),
-hydroxy-2H-chromen-4-one (5), indole, pyrrole, furan, and N-methylaniline were purchased from
1
4
-methylpiperidin-4-one
(2c),
Tokyo Kasei Co., Ltd., and 1-acetylpiperidin-4-one (2g) and the boron trifluoride diethyl ether complex
were from Wako Pure Chemical Ind., Ltd., and used as received. Flash column chromatography was
performed on silica gel 60N (40-50 mm), which was purchased from Kanto Chemical Co., Inc., and
preparative thin layer chromatography (TLC) on Wakogel B-5F from Wako Pure Chemical Ind., Ltd. The
solvents were commercially available first grade and used as received.
Reaction of 1 with Cyclohexanones 2a and 2b in the Presence of BF
pentenedione 1a (216.8 mg, 1.0 mmol) and cyclohexanone (2a) (490.6 mg, 2.5 mmol) in dry THF (1.0
mL) was cooled at 0 °C under argon, and BF ·Et O (254 µL, 2.0 mmol) was slowly added using a syringe.
After the reaction was completed, water (10 mL), brine (10 mL), and a saturated aqueous solution of
NaHCO (30 mL) were then added, and the aqueous mixture was extracted with CHCl (3×20 mL). The
3 2
·OEt . A solution of
3
2
3
3
combined extracts were washed with water (20 mL), dried over anhydrous sodium sulfate, and then
concentrated to dryness. The residue was purified by column chromatography on silica gel eluting with

HETEROCYCLES, Vol. 94, No. 8, 2017
1489
EtOAc/hexane (1:5 v/v), giving the desired spirodioxole 3aa (183 mg, 58%) and tetrahydrobenzofuran
4
aa (25.6 mg, 9%) (Table 1, Entry 3).
3
'
Ph
O
O
4
'
Me
3aa
1
'
O
6'
H
Ac
6
’-Acetyl-5'-methyl-3a'-phenyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]dioxole] (3aa):
f 3
Reaction time, 24 h; yield 58%; pale yellow oil; R = 0.44 (EtOAc-hexane 1:4 v/v); IR (CHCl ) ν 2939
1
(
(
(
PhH), 1672 (C=O); H NMR (500 MHz, CDCl
3
) δ 7.46-7.38 (5H, m, arom. H), 5.31 (1H, s, H-6a’), 2.40
1
3
3H, s, Me), 2.29 (3H, s, Ac), 1.86-1.45 (8H, m, 4×CH
125 MHz, CDCl ) δ 194.7 (C=O), 171.1 (C-5’), 137.6 (arom. C), 129.2 (arom. CH), 128.5 (2C) (arom.
), 29.4
Na
2 2
), 1.44 (2H, quin, J = 4.5 Hz, CH ); C NMR
3
CH), 125.0 (2C) (arom. CH), 114.9 (C-3a’), 114.8 (C-6’), 114.2 (C-2’), 88.7 (C-6a’), 37.2 (2×CH
O=CMe), 24.8, (2×CH ), 23.9 (CH ), 15.3 (Me); FAB HRMS (acetone/NBA): calcd for C19
37.1416 (M+Na); Found 337.1395.
2
(
2
2
22 4
H O
3
3
'
Ph
O
O
4
'
t-Bu
4
Me
3ab
1
'
O
6'
H
Ac
6
’-Acetyl-4-(tert-butyl)-5'-methyl-3a'-phenyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]-
f
dioxole] (3ab): Reaction time, 24 h; yield 22%; colorless needles (from hexane); mp 84-87 °C; R = 0.60
1
(
EtOAc-hexane 1:4 v/v); IR (KBr) ν 2957 (PhH), 1672 (C=O); H NMR (500 MHz, CDCl
3
) δ 7.46-7.39
),
), 1.40 (1H, dq, J = 10.0, 3.0 Hz, H-CH), 1.30-1.25 (1H, m, H-CH), 1.06 (1H, tt, J
(
5H, m, arom. H), 5.32 (1H, s, H-6a’), 2.41 (3H, s, Me), 2.30 (3H, s, Ac), 1.96-1.83 (4H, m, 2×CH
.73-1.64 (2H, m, CH
12.5, 3.0 Hz, H-4), 0.87 (3H×3, s, 3×Me); C NMR (125 MHz, CDCl
37.6 (arom. C), 129.3 (arom. CH), 128.6 (2C) (arom. CH), 125.1 (2C) (arom. CH), 115.0 (C-3a’), 114.7
C-6’), 113.9 (C-2’), 88.9 (C-6a’), 46.7 (C-4), 37.2 (CH ), 36.9 (CH ), 32.3 (C(Me) ), 29.5 (O=CMe),
), 15.3 (Me); FAB HRMS (acetone/NBA): calcd for C23 Na
2
1
2
1
3
=
3
) δ 194.9 (C=O), 171.2 (C-5’),
1
(
2
2
3
2
7.6 (3×Me), 24.8 (CH
2
), 24.7 (CH
2
30 4
H O
3
93.2042 (M+Na); Found 393.2014.
3
'
Ph
O
O
4
'
t-Bu
4
Me
1
'
O
6'
H
Ac
3ab'
6
’-Acetyl-4-(tert-butyl)-5'-methyl-3a'-phenyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]-
dioxole] (3ab’): Reaction time, 24 h; yield 33%; colorless oil; R
f
= 0.54 (EtOAc-hexane 1:4 v/v); IR
) δ 7.46-7.39 (5H, m, arom. H), 5.29 (1H,
), 1.58 (1H, dt,
J = 13.0, 4.0 Hz, H-CH), 1.49 (1H, dq, J = 13.0, 4.0 Hz, H-CH), 1.40 (1H, dq, J = 13.0, 4.0 Hz, H-CH),
1
(CHCl
3
) ν 2955 (PhH), 1672 (C=O); H NMR (500 MHz, CDCl
3
s, H-6a’), 2.41 (3H, s, Me), 2.29 (3H, s, Ac), 1.97-1.95, 1.90-1.83, 1.78-1.72 (5H, m, CH
2

1490
HETEROCYCLES, Vol. 94, No. 8, 2017
1
3
1
.06 (1H, tt, J = 13.0, 4.0 Hz, H-4), 0.87 (3H×3, s, 3×Me); C NMR (125 MHz, CDCl
71.2 (C-5’), 137.7 (arom. C), 129.3 (arom. CH), 128.6 (2C) (arom. CH), 125.1 (2C) (arom. CH), 115.1
), 37.4 (CH ), 32.3 (C(Me) ), 29.4
3
) δ 194.7 (C=O),
1
(
C-3a’), 115.0 (C-6’), 114.5 (C-2’), 88.6 (C-6a’), 47.0 (C-4), 37.5 (CH
2
2
3
(O=CMe), 27.6 (3×Me), 24.9 (CH
2
), 24.8 (CH
2
), 15.3 (Me); FAB HRMS (acetone/NBA): calcd for
23 30 4
C H O Na 393.2042 (M+Na); Found 393.2029.
3'
Ar
O
O
4
'
t-Bu
4
Me
1'
O
6'
H
Ac
bb: Ar = 4-ClC H4
3
6
ORTEP Drawing of 3bb
6
’-Acetyl-4-(tert-butyl)-3a'-(4-chlorophenyl)-5'-methyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-
furo[2,3-d][1,3]dioxole] (3bb): Reaction time, 74 h; yield 29%; colorless prisms (from hexane); mp
1
1
40-143 °C; R
CDCl
×CH
H-CH), 1.06 (1H, tt, J = 11.5, 3.0 Hz, H-4), 0.87 (3H×3, s, 3×Me); C NMR (125 MHz, CDCl
f
= 0.67 (EtOAc-hexane 1:4 v/v); IR (KBr) ν 2953 (PhH), 1682 (C=O); H NMR (500 MHz,
3
) δ 7.37 (4H, s, arom. H), 5.28 (1H, s, H-6a’), 2.39 (3H, s, Me), 2.30 (3H, s, Ac), 1.92-1.86 (4H, m,
), 1.73-1.63 (2H, m, CH ), 1.40 (1H, dq, J = 12.3, 3.5 Hz, H-CH), 1.25 (1H, dq, J = 12.3, 3.5 Hz,
2
2
2
1
3
3
) δ 194.7
C=O), 171.0 (C-5’), 136.2, 135.3 (Cl-C, arom. C), 128.8 (2C) (arom. CH), 126.6 (2C) (arom. CH), 115.2
C-3a’), 114.1 (C-6’), 113.9 (C-2’), 88.9 (C-6a’), 46.6 (C-4), 37.2 (CH ), 36.8 (CH ), 32.2 (C(Me) ), 29.5
O=CMe), 27.5 (3×Me), 24.8 (CH ), 24.6 (CH ), 15.3 (Me); Anal Calcd for C23 : C, 67.89; H,
.09. Found C, 68.22; H, 7.22. X-Ray crystallographic data: empirical formula C23 ; formula
(
(
(
2
2
3
2
2
H
29ClO
4
7
H29ClO
4
weight 404.18; colorless prisms; orthorhombic; space group Pbca; cell lengths a = 11.4756(7), b =
3
1
9.2308(12), c = 19.830(1) Å; cell volume 4376.2(4) Å ; formula units per cell Z = 8; total data collected
5
w
352; R = 0.0557; R = 0.1068; GOF = 3.006.
3
'
Ar
H
O
O
4'
t-Bu
4
Me
1
'
O
6'
Ac
3bb': Ar = 4-ClC6H4
6
’-Acetyl-4-(tert-butyl)-3a'-(4-chlorophenyl)-5'-methyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-

HETEROCYCLES, Vol. 94, No. 8, 2017
1491
furo[2,3-d][1,3]dioxole] (3bb’): Reaction time, 74 h; yield 41%; colorless oil; R
f
= 0.56 (EtOAc-hexane
1
1
:4 v/v); IR (CHCl
3
) ν 1672 (C=O); H NMR (500 MHz, CDCl
3
) δ 7.39-7.35 (4H, m, arom. H), 5.26 (1H,
), 1.58 (1H, dt, J = 13.0, 3.0
Hz, H-CH), 1.47 (1H, dq, J = 13.0, 3.0 Hz, H-CH), 1.38 (1H, dq, J = 13.0, 3.0 Hz, H-CH), 1.06 (1H, tt, J
s, H-6a’), 2.40 (3H, s, Me), 2.27 (3H, s, Ac), 1.95-1.72 (5H, m, H-CH, 2×CH
2
1
3
=
13.0, 3.0 Hz, H-4), 0.87 (3H×3, s, 3×Me); C NMR (125 MHz, CDCl
36.3, 135.2 (Cl-C, arom. C), 128.7 (2C) (arom. CH), 126.6 (2C) (arom. CH), 115.1 (C-3a’), 114.4 (C-2’,
C-6’), 88.5 (C-6a’), 46.9 (C-4), 37.4 (CH ), 37.3 (CH ), 32.3 (C(Me) ), 29.4 (O=CMe), 27.6 (3×Me), 24.9
CH ), 24.8 (CH ), 15.3 (Me); FAB HRMS (acetone/NBA): calcd for C23 Na 427.1652 (M+Na);
Found 427.1650.
3
) δ 194.5 (C=O), 170.9 (C-5’),
1
2
2
3
(
2
2
H29ClO
4
3
'
Ar
O
O
4
'
t-Bu
4
Me
1
'
O
6'
H
Ac
3cb: Ar = 4-MeOC H
6 4
6
’-Acetyl-4-(tert-butyl)-3a'-(4-methoxyphenyl)-5'-methyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-
furo[2,3-d][1,3]dioxole] (3cb): Reaction time, 185 h; yield 3%; colorless oil; R
f
= 0.45 (EtOAc-hexane
) δ 7.38-7.36
1
1
:4 v/v); IR (CHCl
3
) ν 2961 (PhH), 1709, 1670 (C=C–C=O); H NMR (500 MHz, CDCl
3
(
2H, m, arom. H), 6.92-6.90 (2H, m, arom. H), 5.28 (1H, s, H-6a’), 3.82 (3H, s, OMe), 2.39 (3H, s, Me),
.30 (3H, s, Ac), 1.93-1.81 (4H, m, 2×CH ), 1.72-1.63 (2H, m, CH ), 1.40 (1H, dq, J = 12.0, 3.0 Hz,
H-CH), 1.27-1.24 (1H, m, H-CH), 1.06 (1H, tt, J = 12.0, 3.0 Hz, H-4), 0.87 (3H×3, s, 3×Me); C NMR
125 MHz, CDCl ) δ 194.9 (C=O), 171.2 (C-5’), 160.3 (MeO-C), 129.8 (arom. C), 126.5 (2C) (arom.
CH), 114.8 (C-3a’), 114.7 (C-6’), 113.9 (C-2’), 113.9 (2C) (arom. CH), 88.8 (C-6a’), 55.3 (OMe), 46.7
2
2
2
1
3
(
3
(C-4), 37.3 (CH
2
), 36.9 (CH
2
), 32.3 (C(Me)
3
), 29.5 (O=CMe), 27.6 (3×Me), 24.8 (CH
2 2
), 24.7 (CH ), 15.3
(Me); FAB HRMS (acetone/NBA): calcd for C24
32 5
H O
Na 423.2174 (M+Na); Found 423.2169.
3
'
Ar
H
O
O
4'
t-Bu
4
Me
1
'
O
6'
Ac
3cb': Ar = 4-MeOC H
6 4
6
’-Acetyl-4-(tert-butyl)-3a'-(4-methoxyphenyl)-5'-methyl-3a',6a'-dihydrospiro[cyclohexane-1,2'-
furo[2,3-d][1,3]dioxole] (3cb’): Reaction time, 185 h; yield 5%; colorless oil; R
f
= 0.42 (EtOAc-hexane
) δ 7.38-7.36
1
1
:4 v/v); IR (CHCl
3
) ν 2959 (PhH), 1710, 1670 (C=C–C=O); H NMR (500 MHz, CDCl
3
(
2H, m, arom. H), 6.94-6.91 (2H, m, arom. H), 5.26 (1H, s, H-6a’), 3.82 (3H, s, OMe), 2.39 (3H, s, Me),
.30 (3H, s, Ac), 1.95-1.82 (5H, m, H-CH, 2×CH ), 1.72-1.63 (1H, m, H-CH), 1.48 (1H, dq, J = 12.0, 3.5
Hz, H-CH), 1.40 (1H, dq, J = 12.0, 3.5 Hz, H-CH), 1.06 (1H, tt, J = 12.0, 3.5 Hz, H-4), 0.87 (3H×3, s,
2
2
1
3
3
×Me); C NMR (125 MHz, CDCl
3
) δ 194.8 (C=O), 171.0 (C-5’), 160.3 (MeO-C), 129.9 (arom. C),
1
26.5 (2C) (arom. CH), 115.2 (C-3a’), 114.7 (C-6’), 114.5 (C-2’), 113.9 (2C) (arom. CH), 88.5 (C-6a’),

1492
HETEROCYCLES, Vol. 94, No. 8, 2017
5
5.4 (OMe), 47.0 (C-4), 37.5 (2×CH ), 29.4 (O=CMe), 27.7 (3×Me), 24.9 (2×CH
2
), 32.3 (C(Me)
3
2
), 15.4
(
Me); FAB HRMS (acetone/NBA): calcd for C24H O Na 423.2174 (M+Na); Found 423.2140.
32 5
Ph Me
O
O
H
O
Me
4aa
(Z)-4-Hydroxy-3-(3-phenyl-4,5,6,7-tetrahydrobenzofuran-2-yl)pent-3-en-2-one (4aa): Reaction time,
2
4 h; yield 9%; colorless cubes (from methanol); mp 92-97 °C; R
f
= 0.75 (Et
) δ 16.81 (1H, s, OH), 7.35-7.32 (2H, m,
), 2.51 (2H, t, J = 5.5 Hz, CH ), 1.91
) δ 193.7
C=O), 151.0 (C-7a), 143.1 (C-2), 133.5 (arom. C), 128.6 (2C) (arom. CH), 127.8 (arom. CH), 126.6 (2C)
arom. CH), 124.8 (C-3), 117.1 (C-3a), 105.6 (C-3’), 23.9 (2×Me), 23.3 (CH ), 23.2 (CH ), 22.8 (CH ),
2.1 (CH ); Anal Calcd for C19 : C, 77.00; H, 6.80. Found C, 76.85; H, 6.89.
2
O-hexane 1:1 v/v); IR (KBr)
1
ν 2941 (PhH), 1605 (C=C–C=O); H NMR (500 MHz, CDCl
3
arom. H), 7.25-7.21 (3H, m, arom. H), 2.65 (2H, t, J = 5.5 Hz, CH
2
2
1
3
(
(
(
2 2 3
6H, s, 2×Me), 1.91-1.89 (2H, m, CH ), 1.79-1.76 (2H, m, CH ); C NMR (125 MHz, CDCl
2
2
2
2
2
20 3
H O
Ph Me
t-Bu
O
O
H
O
Me
4ab
(Z)-3-(5-(tert-Butyl)-3-phenyl-4,5,6,7-tetrahydrobenzofuran-2-yl)-4-hydroxypent-3-en-2-one (4ab):
Reaction time, 24 h; yield 16%; colorless oil; R
f
= 0.78 (EtOAc-hexane 1:4 v/v); IR (CHCl
3
) ν 2963
1
(
PhH), 1605 (C=C-C=O); H NMR (500 MHz, CDCl
3
) δ 16.80 (1H, s, OH), 7.37-7.21 (5H, m, arom. H),
2
.74 (1H, dd, J = 16.5, 4.5 Hz, H-CH), 2.61(1H, m, H-CH), 2.49 (1H, m, H-CH), 2.31 (1H, t, J = 13.5, Hz,
), 0.96 (9H, s,
) δ 194.5, 192.9 (C=O), 151.0 (C-7a), 143.4 (C-2), 133.5 (arom. C),
28.6 (2C) (arom. CH), 127.9 (arom. CH), 126.6 (2C) (arom. CH), 125.1 (C-3), 117.3 (C-3a), 105.6
), 27.5 (3×Me), 24.3 (CH ), 24.2 (CH ), 24.0 (CH ), 23.3 (2×Me); FAB
H-5), 2.11 (1H, m, H-CH), 2.05 (3H, s, Me), 1.76 (3H, s, Me), 1.55-1.43 (2H, m, CH
2
1
3
3
×Me); C NMR (125 MHz, CDCl
3
1
(C-3’), 45.3 (C-5), 32.5 (C(Me)
3
2
2
2
HRMS (acetone/NBA): calcd for C23
H
28
O
3
352.2038 (M); Found 352.2052.
Ar Me
t-Bu
O
H
O
O
4
bb: Ar = 4-ClC H
Me
6 4
(Z)-3-(5-(tert-Butyl)-3-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzofuran-2-yl)-4-hydroxypent-3-en-2-
one (4bb): Reaction time, 74 h; yield 19%; colorless prisms (from CH
2
Cl
2
); mp 113-116 °C; R
f
= 0.70
) δ
1
(
EtOAc-hexane 1:4 v/v); IR (CHCl
3
) ν 2963 (PhH), 1607 (C=C–C=O); H NMR (500 MHz, CDCl
3
1
6.82 (1H, s, OH), 7.33-7.32 (2H, m, arom. H), 7.17-7.15 (2H, m, arom. H), 2.73 (1H, dd, J = 16.0, 4.5
Hz, H-CH), 2.60 (1H, t, J = 15.0 Hz, H-CH), 2.45 (1H, d, J = 13.5 Hz, H-CH), 2.28 (1H, t, J = 12.5, Hz,
H-5), 2.11 (1H, m, H-CH), 2.05 (3H, s, Me), 1.76 (3H, s, Me), 1.52-1.46 (2H, m, CH ), 0.96 (9H, s,
2

HETEROCYCLES, Vol. 94, No. 8, 2017
1493
1
3
3
×Me); C NMR (125 MHz, CDCl
Cl-C, arom. C), 129.1 (2C) (arom. CH), 128.9 (2C) (arom. CH), 124.0 (C-3), 117.1 (C-3a), 105.3 (C-3’),
5.3 (C-5), 32.6 (C(Me) ), 27.5 (3×Me), 24.2 (CH ), 24.0 (CH ), 23.5 (CH ), 23.2 (2×Me); FAB HRMS
acetone/NBA): calcd for C23
3
) δ 194.5, 192.8 (C=O), 151.3 (C-7a), 143.6 (C-2), 132.5, 132.0
(
4
3
2
2
2
(
H27ClO
3
386.1649 (M); Found 386.1646.
Ar Me
t-Bu
O
H
O
O
Me
4cb: Ar = 4-MeOC H
6 4
(Z)-3-(5-(tert-Butyl)-3-(4-methoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-2-yl)-4-hydroxypent-3-en-
2
-one (4cb): Reaction time, 24 h; yield 47%; pale yellow oil; R
f
= 0.62 (EtOAc-hexane 1:4 v/v); IR
) δ 16.79 (1H, s, OH),
1
(CHCl
3
) ν 2961 (PhH), 1705, 1612 (C=C–C=O); H NMR (500 MHz, CDCl
3
7
.16-7.14 (2H, m, arom. H), 6.90-6.89 (2H, m, arom. H), 3.81 (3H, s, OMe), 2.72 (1H, dd, J = 16.0, 5.0
Hz, H-CH), 2.60 (1H, t, J = 11.5 Hz, H-CH), 2.47 (1H, d, J = 13.5 Hz, H-CH), 2.28 (1H, t, J = 12.5, Hz,
H-5), 2.09 (1H, dd, J = 11.5, 4.0 Hz, H-CH), 2.04 (3H, s, Me), 1.77 (3H, s, Me), 1.52-1.45 (2H, m, CH ),
) δ 194.4, 193.0 (C=O), 158.3 (OMe-C), 150.9 (C-7a),
42.9 (C-2), 129.0 (2C) (arom. CH), 125.9, 124.6 (C-3, arom. C), 117.3 (C-3a), 114.1 (2C) (arom. CH),
05.7 (C-3’), 55.2 (OMe), 45.3 (C-5), 32.5 (C(Me) ), 27.5 (3×Me), 24.3 (CH ), 24.2 (CH ), 24.0 (CH ),
3.3 (2×Me); FAB HRMS (acetone/NBA): calcd for C24 382.2144 (M); Found 382.2154.
·Et O. A solution of pentenedione 1a
106.7 mg, 0.5 mmol) and 1-methylpiperidin-4-one (2c) (57.6 mg, 0.5 mmol) was cooled at 0 °C under
argon, and BF ·Et O (315 mL, 2.5 mmol) was slowly added using a syringe. After the reaction was
completed, a saturated aqueous solution of NaHCO (30 mL) was then added and the aqueous mixture
was extracted with CHCl (3×20 mL). The combined extracts were dried over anhydrous sodium sulfate,
then concentrated to dryness. The residue was purified by column chromatography on silica gel eluting
with CHCl /MeOH (95:5 v/v), giving the desired azaspirodioxole 3ac (149.6 mg, 93%) (Table 2, Entry 6).
2
1
3
0
1
1
2
.95 (9H, s, 3×Me); C NMR (125 MHz, CDCl
3
3
2
2
2
30 4
H O
Reaction of 1a with Piperidin-4-ones 2c-i in the Presence of BF
3
2
(
3
2
3
3
3
O
O
O
Ph
4
Me N
Me
3
O
O 5
1
'
Me N
4'
2
Me
3ac
H
O
O
Me
6
1
H
Ac
HMBC of 3ac
6
-Acetyl-1',5-dimethyl-3a-phenyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]dioxole-2,4'-piperidine] (3ac):
f 3 3
Reaction time, 2.5 h; yield 93%; yellow oil; R = 0.22 (CHCl -MeOH 95:5 v/v); IR (CHCl ) ν 1674
1
(
C=C–C=O); H NMR (500 MHz, CDCl
3
) δ 7.45-7.39 (5H, m, arom. H), 5.34 (1H, s, H-6a), 2.64-2.47
1
3
(4H, m, 2×NCH
2
), 2.40 (3H, s, Me), 2.31 (3H, s, NMe), 2.29 (3H, s, Ac), 2.03-1.86 (4H, m, 2×CH
2
); C
NMR (125 MHz, CDCl
3
) δ 194.4 (C=O), 171.0 (C-5), 137.1 (arom. C), 129.2, 128.5 (2C) (arom. CH),

1494
HETEROCYCLES, Vol. 94, No. 8, 2017
1
24.9 (arom. CH), 114.6 (C-3a), 113.9 (C-6), 112.3 (C-2), 88.7 (C-6a), 53.2 (2×NCH ), 45.6 (NMe), 36.7,
2
3
6.5 (2×CH ), 29.3 (Ac), 15.1 (Me); FAB HRMS (acetone/NBA): calcd for C19H O N 330.1705 (M+H);
2
24 4
Found 330.1712.
3
O
Ph
4
1'
O 5
Et
N
4'
2
Me
O
6
1
H
Ac
3ad
6
-Acetyl-1'-ethyl-5-methyl-3a-phenyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]dioxole-2,4'-piperidine]
3ad): Reaction time, 3.0 h; yield 88%; yellow oil; R = 0.27 (CHCl -MeOH 95:5 v/v); IR (CHCl ) ν 1674
) δ 7.46-7.39 (5H, m, arom. H), 5.34 (1H, s, H-6a), 2.68-2.59
), 2.46 (2H, q, J = 7.3 Hz, NCH CH ), 2.40 (3H, s, Me), 2.30 (3H, s, Ac), 2.03-1.87 (4H,
); C NMR (125 MHz, CDCl ) δ 194.4 (C=O), 170.9 (C-5),
37.2 (arom. C), 129.2, 128.4 (2C) (arom. CH), 124.9 (arom. CH), 114.6 (C-3a), 113.9 (C-6), 112.8 (C-2),
8.6 (C-6a), 51.6, 50.6 (2×NCH , NCH CH ), 36.7, 36.5 (2×CH ), 29.3 (Ac), 15.1 (Me), 12.2
CH ); FAB HRMS (acetone/NBA): calcd for C20 N 344.1862 (M+H); Found 344.1867.
(
(
(
f
3
3
1
C=C–C=O); H NMR (500 MHz, CDCl
4H, m, 2×NCH
), 1.10 (3H, t, J = 7.3 Hz, NCH
3
2
2
3
1
3
m, 2×CH
2
2
CH
3
3
1
8
2
2
3
2
(NCH
2
3
26 4
H O
3
O
Ph
4
O 5
1'
Pr
N
4'
2
Me
3ae
O
6
1
H
Ac
6
-Acetyl-5-methyl-3a-phenyl-1'-propyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]dioxole-2,4'-piperidine]
= 0.38 (CHCl -MeOH 95:5 v/v); IR (CHCl ) ν 1674
) δ 7.45-7.39 (5H, m, arom. H), 5.33 (1H, s, H-6a), 2.67-2.49
4H, m, H-2’, H-6’), 2.40 (3H, s, Me), 2.34 (2H, t, J = 7.6 Hz, NCH Et), 2.29 (3H, s, Ac), 2.02-1.86 (4H,
CH CH ), 0.90 (3H, t, J = 7.6 Hz, NC
) δ 194.6 (C=O), 171.1 (C-5), 137.4 (arom. C), 129.3, 128.6 (2C) (arom. CH),
25.0 (arom. CH), 114.7 (C-3a), 114.0 (C-6), 113.0 (C-2), 88.8 (C-6a), 60.1 (NCH CH ), 51.2 (C-2’,
C-6’), 36.9, 36.7 (C-3’, C-5’), 29.5 (Ac), 20.4 (NCH CH ), 15.3 (Me), 11.9 (NC CH ); FAB HRMS
N 358.2018 (M+H); Found 358.2027.
(
(
(
3ae): Reaction time, 3.0 h; yield 77%; yellow oil; R
f
3
3
1
C=C–C=O); H NMR (500 MHz, CDCl
3
2
1
3
m, H-3’, H-5’), 1.54-1.49 (2H, sex, J = 7.6 Hz, NCH
2
2
3
2 4 3
H CH ); C
NMR (125 MHz, CDCl
3
1
2
2
2
2
2
H
4
3
28 4
(acetone/NBA): calcd for C21H O
3
O
Ph
4
O 5
1'
Bn
N
4'
2
Me
3af
O
6
1
H
Ac
6
-Acetyl-1'-benzyl-5-methyl-3a-phenyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]dioxole-2,4'-piperidine
= 0.34 (CHCl -MeOH 95:5 v/v); IR (CHCl ) ν 1674
) δ 7.45-7.37 (5H, m, arom. H), 7.31-7.28 (4H, m, arom. H),
.25-7.22 (1H, m, arom. H), 5.32 (1H, s, H-6a), 3.50 (2H, s, NBn), 2.64-2.50 (4H, m, 2×NCH ), 2.37 (3H,
) δ 194.5 (C=O), 171.0
(3af): Reaction time, 4.0 h; yield 89%; orange oil; R
f
3
3
1
(C=C–C=O); H NMR (500 MHz, CDCl
3
7
2
1
3
2 3
s, Me), 2.28 (3H, s, Ac), 1.99-1.83 (4H, m, 2×CH ); C NMR (125 MHz, CDCl

HETEROCYCLES, Vol. 94, No. 8, 2017
1495
(
(
(
C-5), 138.4, 137.4 (arom. C), 129.3, 128.6 (2C) (arom. CH), 125.0 (arom. CH), 114.7 (C-3a), 114.0
C-6), 113.0 (C-2), 88.7 (C-6a), 62.4 (NCH Ph), 51.0 (2×NCH ), 36.8, 36.6 (2×CH ), 29.4 (Ac), 15.2
Me); FAB HRMS (acetone/NBA): calcd for C25
2
2
2
H
28
O
4
N 406.2018 (M+H); Found 406.2032.
Ph
O
O
O
O
H
CH2
N
3
O
Ph
4
O 5
H CH2
1'
H
Ac N
4'
2
Me
3ag
CH2
O
O
6
1
H
H
Ac
HMQC of 3ag
1
',6-Diacetyl-5-methyl-3a-phenyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]dioxole-2,4'-piperidine] (3ag):
Reaction time, 2.5 h; yield quant; yellow microcrystals (from Et
2
O/hexane); mp 126 °C; R
f
= 0.28
) δ
),
1
(
CHCl
3
-MeOH 95:5 v/v); IR (KBr) ν 1676 (C=O), 1636 (NC=O); H NMR (500 MHz, CDCl
3
7
.44-7.41 (5H, m, arom. H), 5.38 (1H, s, H-6a), 3.83-3.80 (1H, m, NCH
a
), 3.71 (1H, t, J = 5.9 Hz, NCH
b
3
.65 (1H, t, J = 5.9 Hz, NCHa’), 3.57-3.50 (1H, m, NCHb’), 2.41 (3H, s, Me), 2.29 (3H, s, Ac), 2.13, 2.11
1
(
3H, s, NAc, 1:1.3), 1.98-1.77 (4H, m, 2×CH
2
); H NMR (500 MHz, DMSO-d
6
at 80 °C) δ 7.49-7.43 (5H,
), 2.34 (3H, s, Me), 2.23 (3H, s, Ac), 2.01
); C NMR (125 MHz, CDCl ) δ 194.3, 194.1 (C=O), 171.1 (C-5),
68.8, 168.7 (NC=O), 136.9, 136.8 (arom. C), 129.54, 129.52 (arom. CH), 128.68, 128.66 (2C) (arom.
CH), 124.9 (2C) (arom. CH), 114.9, 114.8 (C-3a), 114.1, 114.0 (C-6), 112.23, 112.20 (C-2), 88.99, 88.95
C-6a), 44.2, 44.1 (NCH ), 39.4, 39.3 (NC’H ), 37.5, 37.2 (CH ), 36.7, 36.4 (C’H ), 29.41, 29.39 (Ac),
1.3 (NAc), 15.28, 15.25 (Me); C NMR (125 MHz, DMSO-d at 80 °C) δ 194.5 (C=O), 171.1 (C-5),
69.4 (NC=O), 138.3 (arom. C), 130.6 (arom. CH), 129.8 (2C) (arom. CH), 126.3 (2C) (arom. CH), 115.6
m, arom. H), 5.51 (1H, s, H-6a), 3.72-3.43 (4H, m, 2×NCH
2
1
3
(
3H, s, NAc), 1.97-1.63 (4H, m, 2×CH
2
3
1
(
2
2
2
2
1
3
2
1
6
(
C-3a), 115.3 (C-6), 113.2 (C-2), 89.4 (C-6a), 30.4 (Ac), 22.2 (NAc), 16.0 (Me); FAB HRMS
acetone/NBA): calcd for C20 N 358.1654 (M+H); Found 358.1665.
(
24 5
H O
3
O
Ph
4
O 5
1'
Bz
N
4'
2
Me
3ah
O
6
1
H
Ac
6
-Acetyl-1'-benzoyl-5-methyl-3a-phenyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]dioxole-2,4'-piperidine
(
3ah): Reaction time, 3.0 h; yield 94%; yellow microcrystals (from Et
2
f
O/hexane); mp 64-65 °C; R = 0.37
1
(CHCl
3
-MeOH 95:5 v/v); IR (KBr) ν 1684 (C=C-C=O), 1653 (NC=O), 1558 (arom); H NMR (500 MHz,
CDCl
3
) δ 7.56-7.35 (10H, m, arom. H), 5.59 (1H, s, H-6a), 4.18-3.77 (2H, m, NCH
), 2.42, 2.36 (3H, s, Me, 1:1.3), 2.28 (3H, s, Ac), 2.14-2.00 (2H, m, CH ), 1.99-1.69 (2H, m, C’H
at 80 °C) δ 7.48-7.43 (10H, m, arom. H), 5.53 (1H, s, H-6a), 3.79-3.42
2
), 3.71-3.37 (2H, m,
NC’H
2
2
2
);
1
H NMR (500 MHz, DMSO-d
4H, m, 2×NCH ), 2.34 (3H, s, Me), 2.25 (3H, s, Ac), 1.97-1.63 (4H, m, 2×CH
CDCl ) δ 194.0 (C=O), 170.9 (C-5), 170.2 (NC=O), 136.7, 135.5 (arom. C), 129.6 (arom. CH), 129.4
arom. CH), 128.5 (2C) (arom. CH), 128.3 (2C) (arom. CH), 126.6 (2C) (arom. CH), 124.8 (2C) (arom.
6
1
3
(
2
2
); C NMR (125 MHz,
3
(

1496
HETEROCYCLES, Vol. 94, No. 8, 2017
CH), 114.7 (C-3a), 113.9 (C-6), 112.1 (C-2), 88.9 (C-6a), 45.3 (NCH
2
), 39.9 (NC’H
at 80 °C) δ 193.6 (C=O), 170.3 (C-5),
69.6 (NC=O), 137.4 (arom. C), 136.5 (arom. C), 129.7 (arom. CH), 129.0 (arom. CH), 128.7 (4C) (arom.
CH), 127.1 (2C) (arom. CH), 125.4 (2C) (arom. CH), 114.7 (C-3a), 114.4 (C-6), 112.3 (C-2), 88.6 (C-6a),
2 2
), 37.5 (CH ), 36.3
1
3
(
2 6
C’H ), 29.3 (Ac), 15.1 (Me); C NMR (125 MHz, DMSO-d
1
3
2 2 26 5
7.1 (CH ), 36.7 (C’H ), 29.5 (Ac), 15.1 (Me); FAB HRMS (acetone/NBA): calcd for C25H O N
4
20.1811 (M+H); Found 420.1822.
3
O
Ph
4
O 5
1'
Cbz N
4'
2
Me
3ai
O
6
1
H
Ac
Benzyl 6-Acetyl-5-methyl-3a-phenyl-3a,6a-dihydrospiro[furo[2,3-d][1,3]-dioxole-2,4'-
piperidine]-1'-carboxylate (3ai): Reaction time, 3.0 h; yield 94%; pale yellow oil; R = 0.36
f
1
(
EtOAc-hexane 3:7 v/v); IR (CHCl
m, arom, H), 5.36 (1H, s, H-6a), 5.14 (2H, s, OCH
NC’H ), 2.40 (3H, s, Me), 2.28 (3H, s, Ac), 1.93 (2H, m, CH
CDCl ) δ 194.3 (C=O), 171.1 (C-5), 155.0 (NC=O), 136.9 (arom. C), 136.6 (arom. C), 129.5 (arom. CH),
28.6 (arom. CH), 128.4 (arom. CH), 128.0 (arom. CH), 127.8 (arom. CH), 124.9 (arom. CH), 114.8,
14.0, 112.4 (C-3a, C-2, C-6), 88.9 (C-6a), 67.2 (CH Ph), 41.9 (NCH ), 41.8 (NC’H ), 36.9 (CH ), 36.6
), 29.4 (Ac), 15.2 (Me); FAB HRMS (acetone/NBA): calcd for C26 N 450.1917 (M+H); Found
50.1911.
3
) ν 1682 (C=C–C=O); H NMR (500 MHz, CDCl
3
) δ 7.44-7.32 (10H,
2
Ph), 3.72 (2H, t, J = 5.8 Hz, NCH
2
), 3.63-3.59 (2H, m,
1
3
2
2 2
), 1.82 (2H, m, C’H ); C NMR (125 MHz,
3
1
1
2
2
2
2
(C’H
2
28 6
H O
4
Reaction of 1a with 4-Hydroxy-2H-chromen-2-one (5) in the Presence of BF
3
•Et
2
O. To a 10 mL
two-necked flask, 4-hydroxy-2H-chromen-2-one (5) (145.6 mg, 0.9 mmol), BF •Et
3
2
O (38 µL, 0.3 mmol)
and dry chlorobenzene (0.5 mL) were added under argon and the mixture was heated at 130 °C. After
boiling, a solution of pentenedione 1a (79.0 mg, 0.3 mmol) in dry chlorobenzene (0.3 mL) was dropwise
added over 10 min. The reaction mixture was continued to heat at 130 °C until the reaction was
completed. Water (30 mL) was added to the mixture and the aqueous solution was extracted with CHCl
3
(3×20 mL). The combined extracts were dried over anhydrous sodium sulfate, then concentrated to
dryness. The residue was purified by column chromatography on silica gel eluting with DCM, giving
furfurylchromenone 6 (101.5 mg, 77%) and furochromenone 7 (17.3 mg, 13%) (Table 3, Entry 6).
O
H
Me
H
O
O
H
O
OH
5' Ph
O
'
2
4
O
4
a
3
H
H
4'
3'
2
H
Ac
8
a
O
O
1
6
HMBC of 6

HETEROCYCLES, Vol. 94, No. 8, 2017
1497
3
-((3-Acetyl-5-phenylfuran-2-yl)methyl)-4-hydroxy-2H-chromen-2-one (6): Reaction time, 3.0 min;
yield 77%; colorless needles (from CHCl
3
/hexane); mp 241-242 °C; R
f
= 0.29 (EtOAc-hexane 3:7 v/v); IR
) δ 10.9 (1H, s,
1
(KBr) ν 3482-2720 (OH), 1701 (OC=O), 1653 (C=C–C=O); H NMR (500 MHz, CDCl
3
OH), 7.87 (1H, dd, J = 7.9, 1.8 Hz, H-5), 7.69 (2H, dd, J = 7.5, 2.0 Hz, arom, H), 7.48 (1H, td, J = 7.9,
1
4
.8 Hz, H-7), 7.36 (2H, t, J = 7.5 Hz, arom, H), 7.30-7.22 (3H, m, H-6, H-8, arom, H), 6.79 (1H, s, H-4’),
1
3
2 3
.29 (2H, s, CH ), 2.62 (3H, s, Me); C NMR (125 MHz, CDCl ) δ 200.5 (C=O), 163.6 (OC=O), 162.4
(
C-4), 158.3 (C-2’), 153.6 (C-5’), 152.6 (C-8a), 132.0 (arom. CH), 128.9 (arom. C), 128.8 (arom. CH),
28.5 (arom. CH), 124.1 (arom. CH), 123.8 (arom. CH), 123.7 (arom. CH), 122.8 (C-3’), 116.3 (arom.
CH), 116.2 (C-4a), 103.7 (C-4’), 99.2 (C-3), 28.9 (Me), 22.9 (CH ); Anal. Calcd for C21 N: C,
1
2
19 3
H O
7
3.33; H, 4.48. Found: C, 73.00; H, 4.53.
O H
O H
O
O
H
Me
O
Me
O
Me
O
3
'
2'
1
2
Me
H
H
O
Me
Ph
H
O
Me
O
9
6
9
a
Ph
H
H
H
3
8
7
3
a
H
5a
4
H
O
O
O
O
O
5
7
HMQC of 7
HMBC of 7
(Z)-2-(2-Hydroxy-4-oxopent-2-en-3-yl)-3-phenyl-4H-furo[3,2-c]chromen-4-one (7): Reaction time,
3
3
1
.0 min; yield 13%; colorless microcrystals (from Et
2
O/hexane); mp 174 °C; R
f
= 0.62 (EtOAc-hexane
) δ
1
:7 v/v); IR (KBr) ν 3500-3200 (OH), 1744 (OC=O), 1632 (C=C–C=O); H NMR (500 MHz, CDCl
3
6.99 (1H, s, OH), 7.92 (1H, d, J = 6.5 Hz, H-9), 7.57 (1H, t, J = 7.3 Hz, H-7), 7.49-7.36 (7H, m, H-6,
1
3
H-8, arom, H), 1.96 (6H, s, 2×Me); C NMR (125 MHz, CDCl
3
) δ 193.9 (C=O), 157.8 (C-10), 157.4
OC=O), 152.7 (C-5a), 149.0 (C-2), 131.1 (C-7), 129.4 (arom. C), 129.2 (2C) (arom. CH), 128.5 (2C)
arom. CH), 128.3 (arom. CH), 124.8 (C-3), 124.5 (C-8), 120.9 (C-9), 117.3 (C-6), 112.6 (C-9a), 109.4
C-3a), 103.6 (C-3’), 24.0 (Me); Anal. Calcd for FAB HRMS (acetone/NBA): calcd for C22
61.1076 (M+H); Found 361.1061.
(
(
(
17 5
H O
3
Michael Addition of Pentenedione 1a with Indole. A solution of 1a (214.9 mg, 1.0 mmol) and indole
118.3 mg, 1.0 mmol) in MeCN (1.0 mL) was heated under reflux for 9.5 h. The solvent was then
(
removed under reduced pressure and the residue was purified by column chromatography on silica gel
eluting with EtOAc/hexane (3:7 v/v), giving the desired Michael adduct 8 (136.8 mg, 97%). The reaction
was also carried out in MeCN (3.0 mL) for 19 h to give 8 (98%); DCM for 24 h, 8 (93%); MeOH for 14 h,
8
8
(80%) along with 12 (16%); THF for 48 h, 8 (40%); DMF for 3 h, 8 (83%) and 12 (8%); DCE for 36 h,
(98%); and toluene for 23 h, 8 (97%) (Scheme 8).

1498
HETEROCYCLES, Vol. 94, No. 8, 2017
H
H
O
H
Ac
Bz
Ac
Ac
3'
H
2'
Ac
3a
3
H
H
2
H
7
a N
N
H
H
H
8
HMQC of 8
3
-Acetyl-2-(1H-indol-3-yl)-1-phenylpentane-1,4-dione (8): Reaction time, 9.5 h; yield 97%; colorless
microcrystals (from benzene); mp 157 °C; R
f
= 0.20 (EtOAc-hexane 2:8 v/v); IR (KBr) ν
) δ 8.34 (1H, br s, NH), 7.95 (2H,
1
3
500−3200 (ΝΗ), 1717, 1705, 1676 (C=O); H NMR (500 MHz, CDCl
3
dd, J = 8.0, 1.3 Hz, arom. H), 7.74-7.72 (1H, m, H-4), 7.39 (1H, t, J = 8.0 Hz, arom. H), 7.30-7.25 (3H, m,
H-7, arom. H), 7.18-7.13 (2H, m, H-5, H-6), 7.03 (1H, d, J = 3.0 Hz, H-2), 5.68 (1H, d, J = 10.5 Hz,
1
3
H-2’), 5.05 (1H, d, J = 10.5 Hz, H-3’), 2.30 (3H, s, Ac), 1.88 (3H, s, Ac); C NMR (125 MHz, CDCl
03.7, 202.0 (MeC=O), 197.7 (PhC=O), 136.3 (arom C), 135.7 (C-7a), 133.0 (arom. CH), 128.7 (2C)
arom. CH), 128.4 (2C) (arom. CH), 125.7 (C-3a), 123.9 (C-2), 122.6 (C-5), 120.4 (C-6), 119.0 (C-4),
3
) δ
2
(
1
19 3
11.5 (C-7), 109.3 (C-3), 70.2 (C-3’), 45.3 (C-2’), 31.4, 30.2 (2×Me); Anal. Calcd for C21H O N: C,
7
5.66; H, 5.74; N, 4.20. Found: C, 75.72; H, 5.79; N, 4.10.
Michael Addition of Pentenedione 1a with Pyrrole. A solution of 1a (108.3 mg, 0.5 mmol) and pyrrole
102.0 mg, 1.5 mmol) in MeCN (0.5 mL) was heated under reflux for 3.5 h. The solvent was then
(
removed in vacuo and the residue was purified by column chromatography on silica gel eluting with
EtOAc/hexane (2:8-4:6 v/v), giving the desired monoalkylpyrrole 9 (122.7 mg, 87%) (Scheme 8).
Ac
3'
2'
2
N
H
Ac
Bz
9
3
-Acetyl-1-phenyl-2-(1H-pyrrol-2-yl)pentane-1,4-dione (9): Reaction time, 3.5 h; yield 84%; colorless
microcrystals (from Et
2
O); mp 115-116 °C; R
f
= 0.43 (EtOAc-hexane 3:7 v/v); IR (KBr) ν 3500-3160
) δ 8.38 (1H, br s, NH), 7.96 (2H, dd, J = 7.4,
1
(NH), 1724, 1701, 1663 (C=O); H NMR (500 MHz, CDCl
3
1
.2 Hz, arom. H), 7.51 (1H, tt, J = 7.4, 1.2 Hz, arom. H), 7.40 (2H, t, J = 7.4 Hz, arom. H), 6.69 (1H, dt, J
5.0, 2.1 Hz, H-5), 6.06 (1H, dd, J = 5.0, 2.1 Hz, H-3), 6.00 (1H, td, J = 5.0, 1.5 Hz, H-4), 5.47 (1H, d, J
=
=
1
3
11 Hz, H-2’), 4.86 (1H, d, J = 11 Hz, H-3’), 2.24 (3H, s, Ac), 2.02 (3H, s, Ac); C NMR (125 MHz,
) δ 204.1, 201.4 (MeC=O), 197.3 (PhC=O), 135.7 (arom. C), 133.4 (arom. CH), 128.8 (arom. CH),
CDCl
3

HETEROCYCLES, Vol. 94, No. 8, 2017
1499
1
28.6 (arom. CH), 123.7 (C-2), 119.1 (C-5), 109.3 (C-4), 108.8 (C-3), 70.1 (C-3’), 46.6 (C-2’), 31.6, 30.1
2×Me); FAB HRMS (acetone/NBA): calcd for C17 N 283.1208 (M+); Found 283.1205.
To a 10-mL round-bottomed flask, 1a (230.6 mg, 1.0 mmol), pyrrole (35.7 mg, 0.5 mmol), and MeCN
0.5 mL) were added, and the mixture was heated under reflux for 1 h. After work-up as previously
described, bis(alkyl)pyrrole was obtained (208.7 mg; 79% yield).
(
17 3
H O
(
Ac
Ac
3'
3'
2
'
2'
Ac
5
2
Ac
N
H
Bz
Bz
2
,2'-(1H-Pyrrole-2,5-diyl)bis(3-acetyl-1-phenylpentane-1,4-dione): Pink microcrystals (from Et
2
O);
mp 240 °C; R = 0.20 (EtOAc-hexane 3:7 v/v); IR (KBr) ν 3400−3200 (NΗ), 1734, 1684, 1653 (C=O),
f
1
1
558 (arom); H NMR (500 MHz, CDCl
3
) δ 8.56 (1H, br s, NH), 7.89 (4H, dd, J = 8.5, 1.0 Hz, arom, H),
7
.46-7.43 (2H, m, arom. H), 7.30 (4H, t, J = 8.0 Hz, arom. H), 5.80 (2H, d, J = 2.5 Hz, H-3, H-4), 5.41
(2H, d, J = 10.8 Hz, 2×H-2’), 4.75 (2H, d, J = 10.8 Hz, 2×H-3’), 2.23 (6H, s, 2×Ac), 1.83 (6H, s, 2×Ac);
1
3
3
C NMR (125 MHz, CDCl ) δ 204.0, 201.2 (MeC=O), 196.4 (PhC=O), 135.5 (arom. C), 133.1 (arom.
CH), 128.8 (arom. CH), 128.4 (arom. CH), 125.8 (C-2, C-5), 109.6 (C-3, C-4), 69.5 (C-3’), 47.1 (C-2’),
2.0, 30.3 (2×Me); FAB HRMS (acetone/NBA): calcd for C30 N 499.1995 (M+); Found 499.2004.
3
29 6
H O
Michael Addition of Pentenedione 1a with Furan. A solution of 1a (108.0 mg, 0.5 mmol) and furan
362 µL, 5.0 mmol) in AcOH (0.5 mL) was stirred at room temperature for 4.0 h. The solvent was then
(
removed under reduced pressure and the residue was purified by column chromatography on silica gel
eluting with EtOAc/hexane (1:3 v/v), giving the desired alkylfuran 10 (107.4 mg, 76%) (Scheme 8).
Ac
3'
2'
2
O
Ac
Bz
10
3
-Acetyl-2-(furan-2-yl)-1-phenylpentane-1,4-dione (10): Reaction time, 4.0 h; yield 76%; colorless
prisms (from Et
2
O); mp 95-96 °C; R
f
= 0.47 (EtOAc-hexane 3:7 v/v); IR (KBr) ν 1734, 1701, 1653 (C=O),
) δ 7.98 (2H, d, J = 7.5 Hz, arom. H), 7.51 (1H, t, J = 7.5 Hz,
1
1
558 (arom); H NMR (500 MHz, CDCl
3
arom. H), 7.40 (2H, t, J = 7.8 Hz, arom. H), 7.30 (1H, d, J = 1.7 Hz, H-5), 6.25 (1H, dd, J =3.2, 1.7 Hz,
H-4), 6.20 (1H, d, J = 3.2 Hz, H-3), 5.56 (1H, d, J = 11.3 Hz, H-2’), 4.92 (1H, d, J = 11.3 Hz, H-3’), 2.29
1
3
(
3H, s, Ac), 2.09 (3H, s, Ac); C NMR (125 MHz, CDCl
48.3 (C-2), 142.9 (C-5), 135.3 (arom. C), 133.4 (arom. CH), 128.8 (arom. CH), 128.5 (arom. CH), 111.1
C-4), 109.3 (C-3), 68.6 (C-3’), 47.0 (C-2’), 30.3, 30.0 (2×Me); FAB HRMS (acetone/NBA): calcd for
285.1127 (M+H); Found 285.1137.
3
) δ 202.5, 201.0 (MeC=O), 194.7 (PhC=O),
1
(
17 17 4
C H O

1500
HETEROCYCLES, Vol. 94, No. 8, 2017
Michael Addition of Pentenedione 1a with N-Methylaniline. A solution of 1a (107.5 mg, 0.5 mmol)
and N-methylaniline (165 µL, 1.5 mmol) in AcOH (0.5 mL) was heated under reflux for 6.0 min. The
solvent was then removed under reduced pressure and the residue was purified by thin layer
3
chromatography on silica gel eluting with CHCl /MeOH (98:2 v/v), giving the desired adduct 11 (120.3
mg, 75%) (Scheme 8).
2
3
Bz
1
4
2'
MeHN
Ac
'
3
Ac
11
3
7
1
-Acetyl-2-(4-(methylamino)phenyl)-1-phenylpentane-1,4-dione (11): Reaction time, 6.0 min; yield
5%; pale yellow amorphous; R
f
3 3
= 0.38 (CHCl -MeOH 98:2 v/v); IR (CH Cl) ν 3474-3360 (NH), 1730,
1
697, 1676 (C=O); H NMR (500 MHz, CDCl
3
) δ 7.93 (2H, dd, J = 7.8, 1.0 Hz, arom. H), 7.43 (1H, tt, J
=
7.8, 1.0 Hz, arom. H), 7.34 (2H, t, J = 7.8 Hz, arom. H), 7.05 (2H, dd, J = 6.6, 1.9 Hz, H-3), 6.49 (2H,
dd, J =6.6, 1.9 Hz, H-2), 5.24 (1H, d, J = 11.5 Hz, H-2’), 4.81 (1H, d, J = 11.5 Hz, H-3’), 3.72 (1H, br s,
1
3
NH), 2.75 (3H, s, NMe), 2.26 (3H, s, Ac), 1.95 (3H, s, Ac); C NMR (125 MHz, CDCl
3
) δ 203.7, 201.7
2×MeC=O), 197.9 (PhC=O), 148.8 (C-1), 135.8 (arom. C), 132.8 (arom. CH), 129.5 (arom. CH), 128.8
arom. CH), 128.3 (arom. C), 122.4 (C-4), 112.9 (C-2), 71.1 (C-3’), 53.0 (C-2’), 31.7 (NMe), 30.3, 30.1
2×Me); FAB HRMS (acetone/NBA): calcd for C20 N 323.1521 (M+); Found 323.1529.
(
(
(
21 3
H O
Synthesis of Furyl-substituted Indole 12. To a 10-mL two-necked flask, pentenedione 1a (108.3 mg,
.5 mmol), indole (70.1 mg, 0.6 mmol), BF ·Et O (32 µg, 0.25 mmol) and DCM (1.5 mL) were added
and the mixture was heated under reflux for 30 min. After the reaction was completed, water (10 mL),
brine (10 mL), and a saturated aqueous solution of NaHCO (30 mL) were then added, and the aqueous
mixture was extracted with CHCl (3×20 mL). The combined extracts were washed with water (20 mL),
0
3
2
3
3
dried over anhydrous sodium sulfate, then concentrated to dryness. The residue was separated by column
chromatography on silica gel eluting with EtOAc/hexane (2:8 v/v), giving the desired furyl-substituted
indole 12 (138.9 mg, 88%) (Scheme 9).
Me
O
2'
5'
Ph
3'
4'
Ac
3a
3
7a
N
H
12
1
0c
3
-(3-Acetyl-2-methyl-5-phenylfuran-4-yl)-1H-indole (12) : Yellow cubes (from DCM); mp 141 °C;
1
R
f
= 0.47 (EtOAc-hexane 3:7 v/v); IR (KBr) ν 3400−3200 (NΗ), 1653 (C=O), 1558 (arom); H NMR
3
(500 MHz, CDCl ) δ 8.63 (1H, br s, NH), 7.43-7.38 (4H, m, arom, H), 7.23 (1H, t, J = 7.0 Hz, arom. H),

HETEROCYCLES, Vol. 94, No. 8, 2017
1501
1
3
7
.14-7.08 (5H, m, arom. H), 2.69 (3H, s, Me), 1.85 (3H, s, Ac); C NMR (125 MHz, CDCl
3
) δ 196.9
(
C=O), 157.6 (C-5’), 148.5 (C-2’), 136.1 (C-7a), 130.5 (arom, C), 128.2 (arom, CH), 127.7 (C-3a), 127.2
arom, CH), 125.3 (C-4’), 125.1 (arom. CH), 123.7 (arom. CH), 122.6 (arom. CH), 120.4 (arom. CH),
(
1
19.7 (arom, CH), 113.2 (C-3’), 111.4 (arom, CH), 108.3 (C-3), 29.9 (Ac), 14.7 (Me).
Paal-Knorr Reaction of Alkylindole 8 to Pyrrolylindole 13. To a 10-mL round-bottomed flask,
alkylindole 8 (128.9 mg, 0.4 mmol), ammonium acetate (66.2 mg, 0.8 mmol) and AcOH (0.3 mL) were
added and the mixture was heated at 110 °C for 45 min. After the reaction was completed, water (10 mL)
was added to the reaction mixture. The resulting aqueous mixture was then extracted with CHCl
3
(3×20
mL) and the combined extracts were washed with a saturated aqueous solution of NaHCO (20 mL),
3
water (20 mL), dried over anhydrous sodium sulfate, then concentrated to dryness, giving the desired
pyrrole-substituted indole 13a (125.0 mg, quant) without purification (Scheme 9).
H
H
H
H
N
Me
Ac
Me
Me
N
2'
5'
Ph
3
'
H
4'
4
3a
3
O
2
H
7a
N
H
N
H
7
H
13a
HMBC of 13a
3
-(3-Acetyl-2-methyl-5-phenyl-1H-pyrrol-4-yl)-1H-indole (13a): Reaction time, 45 min; yield quant;
yellow microcrystals (from DCM); mp 96 °C; R
f
= 0.33 (EtOAc-hexane 3:7 v/v); IR (KBr) ν 3500-2500
) δ 9.13 (1H, br s, pyrrole-NH), 8.45 (1H, br s,
1
(
NH), 1636 (C=O); H NMR (500 MHz, CDCl
3
indole-NH), 7.41 (1H, d, J = 7.8 Hz, H-4), 7.36 (1H, d, J = 7.8 Hz, H-7), 7.18 (1H, t, J = 7.8 Hz, H-6),
7
1
.15-7.13 (2H, m, arom. H), 7.07-7.03 (4H, m, arom. H), 6.94 (1H, d, J = 2.5 Hz, H-2), 2.60 (3H, s, Me),
1
3
3
.84 (3H, s, Ac); C NMR (125 MHz, CDCl ) δ 198.0 (C=O), 136.1 (C-7a), 135.9 (C-2’), 132.4 (arom.
C), 128.9 (C-3a), 128.6 (C-5’), 128.3 (2C) (arom. CH), 126.3 (3C) (arom. CH), 123.7 (C-2), 123.6 (C-3’),
22.1 (C-5), 119.97, 119.94 (C-4, C-6), 114.0 (C-4’), 111.2 (C-7), 111.1 (C-3), 29.7 (O=CMe), 14.6
Me); FAB HRMS (acetone/NBA): calcd for C21 314.1419 (M+); Found 314.1427.
1
(
H18ON
2
The alkylindole 8 (99.8 mg, 0.3 mmol) and benzylamine (66 mL, 0.6 mmol) were heated in AcOH (0.3
mL) at 110 °C for 20 min. After the previously described work-up, the residue was purified by column
chromatography on silica gel eluting with EtOAc/hexane (4:6 v/v), giving the desired pyrrole 13b (107.4
mg, 89%) (Scheme 9).

1502
HETEROCYCLES, Vol. 94, No. 8, 2017
H
H
N
H
H
H
H
H
H
Bn
Me
Ac
Me
Me
N
Me
Me
N
'
2'
5
Ph
3
'
H
H
H
4'
4
H
3a
3
O
O
2
H
H
7a
N
H
N
H
N
H
H
7
H
13b
HMQC of 13b
HMBC of 13b
3
-(3-Acetyl-1-benzyl-2-methyl-5-phenyl-1H-pyrrol-4-yl)-1H-indole (13b): Reaction time, 20 min;
yield 89%; colorless microcrystals (from DCM/hexane); mp 264 °C; R
f
= 0.37 (EtOAc-hexane 3:7 v/v);
1
IR (KBr) ν 3500-3100 (NH), 1636 (C=O); H NMR (500 MHz, CDCl
3
) δ 8.02 (1H, br s, NH), 7.47 (1H, d,
J = 8.5 Hz, H-4), 7.32 (3H, m, H-7, arom. H), 7.26 (1H, t, J = 7.3 Hz, arom. H), 7.17 (1H, td, J = 7.4, 1.3
Hz, arom. H), 7.13-7.03 (6H, m, H-5, H-6, arom. H), 6.95 (2H, d, J = 6.5 Hz, arom. H), 6.87 (1H, d, J =
1
3
2
.5 Hz, H-2), 5.08 (2H, s, CH
C=O), 137.7 (arom. C), 135.7 (C-7a), 135.5 (C-2’), 133.1 (C-5’), 132.0 (arom. C), 130.8 (2C) (arom.
CH), 129.2 (C-3a), 128.8 (2C) (arom. CH), 127.8 (2C) (arom. CH), 127.4 (arom. CH), 127.3 (arom. CH),
2 3
), 2.52 (3H, s, Me), 1.92 (3H, s, Ac); C NMR (125 MHz, CDCl ) δ 197.9
(
1
1
25.7 (2C) (arom. CH), 123.5 (C-2), 122.9 (C-3’), 121.9 (C-5), 119.9, 119.8 (C-4, C-6), 115.0 (C-4’),
11.5 (C-3), 110.9 (C-7), 47.8 (CH ), 30.0 (O=CMe), 12.3 (Me); FAB HRMS (acetone/NBA): calcd for
404.1889 (M+); Found 404.1904.
2
28 2
C H24ON
The alkylindole 8 (101.5 mg, 0.3 mmol) and ethanolamine (36.6 µL, 0.6 mmol) were heated in AcOH
0.3 mL) at 110 °C for 1 h. After work-up according to a similar already mentioned precedure, the residue
(
was purified by column chromatography on silica gel eluting with EtOAc/hexane (3:7 v/v), giving the
desired pyrrole 13c (80.9 mg, 74%) (Scheme 9).
HO
Me
Ac
N
2'
5'
Ph
3
'
4'
4
3a
3
2
7a
N
H
13c
3
1
3
-(3-Acetyl-1-(2-hydroxyethyl)-2-methyl-5-phenyl-1H-pyrrol-4-yl)-1H-indole (13c): Reaction time,
.0 h; yield 74%; colorless microcrystals (from DCM/hexane); mp 200-201 °C; R
f
= 0.12 (EtOAc-hexane
) δ 10.9 (1H, br s,
1
:7 v/v); IR (KBr) ν 3600-2500 (NH, OH), 1616 (C=O); H NMR (500 MHz, DMSO-d
6

HETEROCYCLES, Vol. 94, No. 8, 2017
1503
NH), 7.27 (1H, d, J = 7.8 Hz, H-4), 7.24-7.20 (5H, m, arom, H), 7.16 (1H, d, J = 7.8 Hz, H-7), 7.04 (1H,
d, J = 2.5 Hz, H-2), 7.50 (1H, td, J = 7.8, 1.0 Hz, H-6), 6.89 (1H, td, J = 7.8, 1.5 Hz, H-5), 4.90 (1H, t, J =
5
.5 Hz, OH), 3.87 (2H, t, J = 7.4 Hz, CH
2
2
OH), 3.39 (2H, td, J = 7.4, 4.6 Hz, NCH ), 2.57 (3H, s, Me),
1
3
1
.66 (3H, s, Ac); C NMR (125 MHz, DMSO-d ) δ 195.6 (C=O), 135.6 (C-7a), 134.5 (C-2’), 132.2
6
(arom. C), 131.9 (C-5’), 131.2 (2C) (arom. CH), 128.6 (C-3a), 127.8 (2C) (arom. CH), 127.5 (arom. CH),
1
6
24.7 (C-2), 121.8 (C-3’), 120.8 (C-5), 118.8, 118.7 (C-4, C-6), 114.8 (C-4’), 111.4 (C-7), 109.6 (C-3),
0.0 (CH OH), 45.8 (NCH ), 29.5 (O=CMe), 12.0 (Me); FAB HRMS (acetone/NBA): calcd for
358.1681 (M+); Found 358.1689.
2
2
23 22 2 2
C H O N
Paal-Knorr Reaction of 8 to Thienylindole 14. A mixture of 8 (66.3 mg, 0.2 mmol) and Lawesson’s
reagent (123.1 mg, 0.3 mmol) was heated in toluene (3.0 mL) at 50 °C for 30 min under argon. After the
reaction was completed, water (10 mL) was added. The resulting aqueous mixture was extracted with
3
CHCl (3×20 mL) and the combined extracts were dried over anhydrous sodium sulfate, then
concentrated to dryness. The obtained residue was separated by column chromatography on silica gel
eluting with EtOAc/hexane (2:8 v/v), giving the desired thienylindole 14 (32.5 mg, 45%) together with
furylindole 12 (14.2 mg, 23%) (Scheme 9).
H
Me
Ac
S
Me
Me
S
'
2'
5
Ph
3
'
H
H
4'
4
3
a
3
O
2
H
7
a
N
H
N
H
7
14
HMBC of 14
3
-(3-Acetyl-2-methyl-5-phenylthiophen-4-yl)-1H-indole (14): Reaction time, 30 min; yield 45%;
yellow microcrystals (from DCM); mp 159 °C; R
f
= 0.12 (EtOAc-hexane 3:7 v/v); IR (KBr) ν 3500-3120
1
(
NH), 1655 (C=O); H NMR (500 MHz, CDCl
3
) δ 8.29 (1H, br s, NH), 7.35 (1H, d, J = 8.0 Hz, H-4),
7
.30 (1H, d, J = 8.0 Hz, H-7), 7.19-7.11 (6H, m, H-6, arom. H), 7.02 (1H, t, J = 7.0 Hz, H-5), 6.95 (1H, d,
1
3
J = 2.5 Hz, H-2), 2.62 (3H, s, Me), 1.82 (3H, s, Ac); C NMR (125 MHz, CDCl
3
) δ 200.2 (C=O), 142.5
(C-2’), 141.3 (C-3’), 136.9 (C-4’), 135.8 (C-7a), 134.1 (arom. C), 129.4 (C-5’), 128.6 (2C) (arom. CH),
1
28.2 (2C) (arom. CH), 127.4 (C-3a), 127.1 (arom. CH), 123.7 (C-2), 122.5 (C-6), 120.3 (C-5), 119.9
(C-4), 111.8 (C-3), 111.1 (C-7), 30.4 (O=CMe), 15.1 (Me); FAB HRMS (acetone/NBA): calcd for
21
C H17ONS 331.1031 (M+); Found 331.1031.
ACKNOWLEDGEMENTS

1504
HETEROCYCLES, Vol. 94, No. 8, 2017
This research was supported by a Grant-in-Aid for Scientific Research (C), No. 25410049, from the Japan
Society for the Promotion of Science. We also acknowledge Nissan Chemical Industries, Ltd., and
Astellas Foundation for Research on Metabolic Disorders for their financial support.
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6
a) F. Ni, Y. Yang, W.-M. Shu, J.-R. Ma, and A.-X. Wu, Org. Biomol. Chem., 2014, 12, 9466; b) Y.
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7
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HETEROCYCLES, Vol. 94, No. 8, 2017
1505
8
.
.
X-Ray coordinates were deposited with the Cambridge Crystallographic Data Centre
https://www.ccdc.cam.ac.uk), deposition number: CCDC 1546190.
(
9
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1. It took 8 h until the reaction in the presence of methanesulfonic acid was finished in boiling MeCN,
1
0c
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1
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