Mn(III)-catalyzed aerobic oxidation of 3-Alkyl-4-hydroxy-1H-pyrrol-2(5H)- ones in the presence of 1,1-diarylethenes. Synthesis of stable 8-aza-1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-one framework

Article abstract of DOI:10.1002/jhet.1840

Twenty-two 3-alkyl-4-hydroxy-1H-pyrrol-2(5H)-ones were prepared and underwent Mn(III)-catalyzed aerobic oxidation in the presence of 1,1-diarylethenes to produce very stable crystalline 6-alkyl-8-aza-4,4-diaryl-1- hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-on

Full text of DOI:10.1002/jhet.1840

May 2014
Mn(III)-catalyzed Aerobic Oxidation of 3-Alkyl-4-hydroxy-1H-pyrrol-2
(5H)-ones in the Presence of 1,1-Diarylethenes. Synthesis of Stable 8-Aza-
1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-one Framework
579
*
Aminul Haque and Hiroshi Nishino
Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami 2-39-1,
Kumamoto 860-8555, Japan
*
E-mail: nishino@sci.kumamoto-u.ac.jp
Received May 22, 2012
DOI 10.1002/jhet.1840
Published online 25 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Twenty-two 3-alkyl-4-hydroxy-1H-pyrrol-2(5H)-ones were prepared and underwent Mn(III)-catalyzed
aerobic oxidation in the presence of 1,1-diarylethenes to produce very stable crystalline 6-alkyl-8-aza-4,
4-diaryl-1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-ones in high yields.
J. Heterocyclic Chem., 51, 579 (2014).
INTRODUCTION
(5H)-ones, in solution [2,13,17]. With the pyrrolidine-2,
4-diones in hand, we preliminarily examined the reaction
of 1-benzyl-4-hydroxy-3-methyl-3-pyrrolin-2-one (1a) with
1,1-diphenylethene (2a) in the presence of Mn(OAc)3•2H2O
according to Nguyen’s procedure [16]. Surprisingly, the reac-
tion proceeded under catalytic conditions and without a dry air
stream, giving a single product. The best conditions were
achieved at room temperature in air at the molar ratio of
1a:2a:Mn(OAc)3 = 1:0.5:0.1 (Table 1, entry 1). The crude
product was purified by recrystallization from a mixture of
ethyl acetate and hexane, giving stable colorless needles that
melted at 210ꢀC. The IR spectrum showed a broad absorption
band at 3400–3000 cmÀ1 and a strong absorption band at
1656 cmÀ1 assigned to a hydroxyl and an amide carbonyl
group, respectively. The 1H NMR spectrum revealed the char-
acteristic three pairs of geminal AB quartets at d 4.76 and
3.72 ppm (J= 15.2 Hz), d 3.55 and 2.29 ppm (J =14.6Hz),
d 3.30 and 2.92 ppm (J = 11.3 Hz), which were assigned to
benzyl methylenes, dioxane ring methylenes at C-5, and
pyrrolinone ring methylenes at C-9, respectively. These
methylene protons correlated to the methylene carbons at
d 51.8, 45.4, and 36.6 ppm in the HMQC spectrum. The 13C
NMR spectrum revealed three quaternary carbons at
d 102.7 ppm assigned to the C-1 carbon attached to two
oxygens, d 85.7 ppm because of the C-4 carbon bearing one
oxygen, and d 44.7 ppm assigned to the C-6 ring junction.
Their spectral data supported a typical N-benzyl-protected
1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-one core. Because
the combustion analysis was consistent with the formula
C26H25NO4, the product was determined to be 8-aza-8-
benzyl-1-hydroxy-6-methyl-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (Experimental section). Comparing the
Tetramic acids, that is, pyrrolidine-2,4-diones, are well
known as a heterocyclic core of natural products [1–3] that
have various biological activities such as antibacterial [4–6]
and cytotoxic activities [7], endothelin [8] and glycine site
N-methyl-D-aspartate receptor antagonists [9]. On the other
hand, endoperoxides [10–12] and hydroperoxides [13,14]
are an important oxidation intermediate, which also have
various biological activities [15]. Therefore, it would be
expected that 8-aza-2,3-dioxabicyclo[4.3.0]nonanes that
have a fused tetramic acid core and an endoperoxide unit
might be a candidate having stronger biological activities
(Scheme 1). From this point of view, we reported the
synthesis of an 8-aza-2,3-dioxabicyclo[4.3.0]nonane analog
using the Mn(III)-based oxidation of 2,3-pyrrolidinedione-
4-carboxylates [16] and 2,4-pyrrolidinedione-3-carboxylates
[17] with various alkenes. In connection with our study, we
found a very stable 8-aza-2,3-dioxabicyclo[4.3.0]nonan-
7-one core that was obtained by the Mn(III)-catalyzed aerobic
oxidation of 3-alkyl-substituted pyrrolidinediones with 1,1-
diarylethenes [18]. In this article, the reaction details, character-
ization of the products, and reaction mechanism are described.
RESULTS AND DISCUSSION
Twenty-two different pyrrolidine-2,4-diones 1a–v were
synthesized by Dieckmann condensation of the corresponding
alkanoyl-protected alkylaminoacetates that were prepared by
the reaction of alkylaminoacetates with alkanoyl chlorides
[19–25]. The prepared 2,4-pyrrolidinediones 1a–v existed as
an enol form, that is, 1,3-dialkyl-4-hydroxy-1H-pyrrol-2
© 2013 HeteroCorporation

580
A. Haque and H. Nishino
Vol 51
Scheme 1
We were pleased to obtain a good result, so that we next
investigated a similar aerobic oxidation of various 3-alkyl-
2,4-pyrrolidinediones 1b–v with 1,1-disubstituted ethenes
2a–e. The reactions were carried out under the optimized
conditions for the reaction of 1a with 2a. The results are
shown in Table 1. All the reaction gave the corresponding
8-aza-1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-ones
3ba–ve in acceptable yields.
In the case of 1-benzyl-3-propyl- 1c, 1-tert-butyl-3-ethyl-
1o, 1-tert-butyl-3-butyl- 1q, and 1-tert-butyl-3-hexyl-
pyrrolidinedione 1r, 3-hydroperoxypyrrolidinediones 4ca,
4oa, 4qa, and 4ra were also isolated as a by-product (5–7%
yields). In addition, the hydroperoxide 4ca underwent
Baeyer–Villiger rearrangement and recyclization with the
release of carbon monoxide to afford 3-benzyl-5-hydroxy-5-
propyloxazolidin-4-one [26].
reaction using 3-methyl-2,4-pyrrolidinedione (1a) with that
using 2,3-pyrrolidinedione-4-carboxylates [16] and 2,4-
pyrrolidinedione-3-carboxylates [17], 3-alkyl-substituted
2,4-pyrrolidinediones such as 1a must be the best candidate
for the construction of the 8-aza-1-hydroxy-2,3-dioxabicyclo
[4.3.0]nonan-7-one skeleton because the reaction proceeded
in air using a strictly catalytic amount of the Mn(OAc)3,
without a dry air stream during the reaction, and the
reaction time was quite shorter (only 4 h).
The reaction did not proceed in the absence of Mn(OAc)3
or molecular oxygen but only in the presence of a catalytic
amount of Mn(OAc)3 in air, even though the use of 0.03
Table 1
Reaction of 2,4-pyrrolidinediones 1 with alkenes 2 in the presence of Mn(OAc)3.a
b
Entry
1
2
1:2:Mn(OAc)3
Time (h)
Product (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
: R1 = Bn, R2 = Me
: R1 = Bn, R2 = Et
: R1 = Bn, R2 = Pr
: R1 = Bn, R2 = Bu
: R1 = Et, R2 = Me
: R1 = i-Pr, R2 = Me
: R1 = i-Pr, R2 = Et
: R1 = i-Pr, R2 = Pr
: R1 = i-Pr, R2 = Bu
: R1 = Bu, R2 = Me
: R1 = Bu, R2 = Et
: R1 = Bu, R2 = Pr
: R1 = Bu, R2 = Bu
: R1 = t-Bu, R2 = Me
: R1 = t-Bu, R2 = Et
: R1 = t-Bu, R2 = Pr
: R1 = t-Bu, R2 = Bu
: R1 = t-Bu, R2 = n-C6H13
: R1 = Bn, R2 = Me
: R1 = Bn, R2 = Me
: R1 = Bn, R2 = Me
: R1 = Bn, R2 = Me
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
: Ar = Ph
1:0.5:0.1
1:0.5:0.1
1:0.5:0.2
1:0.5:0.1
1:0.5:0.2
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.2
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
1:0.5:0.1
4
5
7
5
6.5
7
7
7
7.5
5
5
5.5
6
7.5
7
5.5
6.5
6.5
5
3aa (92)
3ba (85)
3ca (89)d
3da (84)
3ea (89)
3fa (78)
3ga (81)
3ha (81)
3ia (77)
3ja (91)
3ka (88)
3la (85)
3ma (79)
3na (93)
3oa (76)d
3pa (85)
3qa (81)d
3ra (78)d
3sb (85)
3tc (82)
3ud (75)
3ve (71)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
: Ar = Ph
: Ar = Ph
: Ar = 4-Me-C6H4
: Ar = 4-MeO-C6H4
: Ar = 4-Cl-C6H4
: Ar = 4-F-C6H4
1t
1u
1v
4
4
6
aThe reaction of pyrrolidinedione 1 (1 mmol) with alkene 2 (0.5 mmol) was carried out in acetic acid (25 mL) at ambient temperature in air.
bMolar ratio.
cIsolated yield based on the alkene 2 used.
dA small amount of the corresponding 3-hydroperoxypyrrolidine-2,4-diones 4 (5–7%) was also isolated.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Stable 8-Aza-1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-one Framework
581
Scheme 3
equivalents of Mn(OAc)3 yielded the dioxabicyclo[4.3.0]
nonan-7-ones 3. Therefore, the mechanism for the formation
of 3 would be explained as follows (Scheme 2); Mn(III)-
enolate complex A produced in situ by the reaction of
pyrrolidinedione 1 with Mn(OAc)3 [27] underwent single-
electron transfer oxidation to give pyrrolidinedione radical
B. Because the pyrrolidinedione radical B is electron-poor,
the radical B should inevitably be attacked by electron-rich
alkene 2 via the electron donor-acceptor-like complex [28–30]
to furnish tertiary radical C, which is easily trapped by
dissolved molecular oxygen, giving peroxy radical D. The
resulting peroxy radical intermediate D is reduced by the
Mn(II) species to yield peroxy-Mn(III) complex E, which
undergoes protonation with acetic acid and regeneration
of the Mn(III) species to conclude the catalytic cycle and
to provide hydroperoxide F. The g-hydroperoxyketone
F is then stabilized by cyclization, producing the final
hemiacetal 3 [17,31].
The reduction of the peroxy radical D with the Mn(II)
species deserves comments [32–35]. Although it might
be possible to consider a radical-chain mechanism when
the peroxy radical D directly abstracts hydrogen from
pyrrolidinedione 1 to yield the final product 3 and regenerate
the pyrrolidinedione radical B as shown in Scheme 3, it is
obvious that the reaction occurs through the Mn(III)/Mn(II)
redox system based on the following experiment. When a
mixture of 2,4-pentanedione and Mn(OAc)2 was stirred in
AcOH at room temperature under oxygen, the solution
turned from colorless to dark brown. This can be interpreted
that Mn(OAc)2 undergoes a ligand-exchange reaction with
2,4-pentanedione to afford the corresponding Mn(II)-enolate
complex followed by oxidation with dissolved triplet
molecular oxygen (biradical), producing the Mn(III) species.
To put it the other way around, molecular oxygen should be
reduced by the Mn(II) species, and the Mn(III) species could
be generated in the solution, that is, the dark-brown color of
the solution must be derived from the Mn(III) species. In
fact, to the dark-brown colored solution, 1,1-diphenylethene
was added, and the mixture was heated under reflux for 1 h to
afford 3-acetyl-2-methyl-5,5-diphenyl-4,5-dihydrofuran. This
is the well-known Mn(III)-based oxidative dihydrofuranation
reaction [36,37]. Therefore, the peroxy radical D must be
reduced by the Mn(II) species, and the Mn(III) species should
be regenerated, and thus, the catalytic cycle is completed as
shown in Scheme 2. In addition, it was also reported that the
formation of 1,2-dioxan-3-ols could be possible using only
Mn(OAc)2 in air [31,38,39].
Isolation of the 3-hydroperoxypyrrolidinediones 4 might
support the catalytic cycle in Scheme 2. Probably, the
pyrrolidinedione radical B was somewhat trapped by
dissolved molecular oxygen to afford 4 via a similar reduction
pathway of the corresponding hydroperoxy radical with
Mn(II) (Table 1, entries 3, 15, 17, and 18) [39,40].
CONCLUSION
Construction of the stable 8-aza-1-hydroxy-2,3-dioxabicyclo
[4.3.0]nonan-7-one framework was achieved by the Mn(III)-
catalyzed aerobic oxidation of alkyl-substituted tetramic
acid derivatives 1 with 1,1-diarylethenes 2. Because a
peroxy bond of the hydroperoxides and endoperoxides
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

582
A. Haque and H. Nishino
Vol 51
Calcd for C26H25NO4: C, 75.16; H, 6.06; N, 3.37. Found: C, 75.18;
H, 6.12; N, 3.46.
tends to undergo homolytic cleavage in vivo, the 8-aza-1-
hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-ones 3 may also have
some biological activities such as antimalarial, insecticidal,
bactericidal and cytotoxic activities, and an inhibitory effect
toward mRNAs in cells [13,41].
8-Aza-8-benzyl-6-ethyl-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3ba). Yield (182.6 mg, 85%); Rf =0.66
(EtOAc:hexane = 7:3 v/v); colorless needle (from EtOAc/hexane),
mp 215–216ꢀC; ir (KBr): n 3500–3000 (OH), 1662 (C═O); 1H
NMR (DMSO-d6): d 7.58–7.55 (2H, m, arom H), 7.34–7.07 (11H,
m, arom H), 6.43–6.41 (2H, m, arom H), 4.63 (1H, d, J= 15.6 Hz,
PhCHHa), 3.71 (1H, d, J= 15.6 Hz, PhCHHb), 3.44 (1H, d,
J= 14.1 Hz, Ha-5), 3.40 (1H, s, OH), 3.20 (1H, d, J= 11.4 Hz, Ha-9),
2.69 (1H, d, J= 11.4 Hz, Hb-9), 2.12 (1H, d, J= 14.1 Hz, Hb-5),
1.71–1.56 (2H, m, CH2), 0.87 (3H, t, J=7.2Hz, Me); 13C NMR
(DMSO-d6): d 172.9 (C═O), 145.9, 141.4, 135.9 (arom C), 128.4
(2C), 128.3 (2C), 127.6 (2C), 127.2 (1C), 127.1 (2C), 126.9 (1C),
126.9 (1C), 126.7 (1C), 124.8 (3C) (arom CH), 100.6 (C-1), 84.3
(C-4), 53.1, 44.1, 35.3, 29.7 (CH2), 47.4 (C-6), 8.4 (Me). Anal.
Calcd for C27H27NO4: C, 75.50; H, 6.34; N, 3.26. Found: C, 75.50;
H, 6.41; N, 3.24.
EXPERIMENTAL
Measurements. Melting points were taken using a Yanako
MP-J3 micromelting point apparatus and were not corrected. The
NMR spectra were recorded using a JEOL JNM AL300 or ECX
1
500 FT-NMR spectrometer at 300 or 500 MHz for H and 75 or
125 MHz for 13C, with tetramethylsilane as the internal standard.
The chemical shifts are reported in d values (ppm) and the
coupling constants in Hz. The IR spectra were measured in CHCl3
or KBr using a Shimadzu 8400 FTIR spectrometer and expressed
in cmÀ1. The EI MS spectra were obtained by a Shimadzu
QP-5050A gas chromatograph-mass spectrometer at an ionizing
voltage of 70 eV. The high-resolution mass spectra and the
elemental analysis were performed at the Instrumental Analysis
Center, Kumamoto University, Kumamoto, Japan.
8-Aza-8-benzyl-1-hydroxy-6-propyl-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3ca).
Yield (197.4 mg, 89%); Rf =0.59
(EtOAc:hexane = 4:6 v/v); colorless needles (from EtOAc/hexane),
mp 192ꢀC; ir (KBr): n 3392 (OH), 1674 (C═O); 1H NMR (CDCl3):
d 7.67–7.64 (2H, m, arom H), 7.39–7.07 (11H, m, arom H), 6.45–
6.42 (2H, m, arom H), 4.85 (1H, d, J=15.3Hz, PhCHHa), 3.69 (1H,
s, OH), 3.66 (1H, d, J=15.3Hz, PhCHHb), 3.57 (1H, d, J=14.7Hz,
Ha-5), 3.24 (1H, d, J=11.4Hz, Ha-9), 2.88 (1H, d, J=11.4Hz, Hb-9),
2.22 (1H, d, J=14.7Hz, Hb-5), 1.69–1.53 (4H, m, 2 Â CH2), 0.90
(3H, t, J=6.9Hz, Me); 13C NMR (CDCl3): d 172.3 (C═O), 145.4,
140.5, 135.2 (arom C), 128.6, 128.4, 127.9, 127.5, 127.4, 127.2, 127.2,
124.8 (arom CH), 102.5 (C-1), 85.6 (C-4), 52.7, 45.3, 40.1, 36.2, 16.9
(CH2), 47.8 (C-6), 14.6 (Me). Anal. Calcd for C28H29NO4•1/11H2O: C,
75.54; H, 6.61; N, 3.15. Found: C, 75.28; H, 6.59; N, 3.11.
Materials.
Manganese(II) acetate tetrahydrate, Mn(OAc)
•4H2O, was purchased from Wako Pure Chemical Ind., Ltd.
2
Manganese(III) acetate dihydrate, Mn(OAc)3•2H2O, was prepared
according to the method described in the literature [42,43].
3-Alkyl-4-hydroxy-1H-pyrrol-2(5H)-ones 1a–v were prepared by
the reaction of the corresponding (alkylamino)acetates with acyl
chlorides [13]. The prepared 2,4-pyrrolidinediones 1a–v exist as
an enol form (1,3-dialkyl-4-hydroxy-1H-pyrrol-2(5H)-ones) in an
aprotic polar solvent, such as DMSO-d6 [17].
Reaction of 1,3-dialkyl-4-hydroxy-1H-pyrrol-2(5H)-ones with
8-Aza-8-benzyl-6-butyl-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3da). Yield (192.2 mg, 84%); Rf =0.54
(EtOAc:hexane = 4:6 v/v); colorless needles (from Et2O/hexane),
alkenes in the presence of Mn(OAc)3.
To a solution of 1,3-
dialkyl-4-hydroxy-1H-pyrrol-2(5H)-one 1 (1 mmol) and an alkene 2
(0.5 mmol) in glacial acetic acid (25 mL), Mn(OAc)3•2H2O
(0.1 mmol) was added. The mixture was stirred at room temperature
in air until the alkene was completely consumed, and then, the
reaction was quenched by adding water (25 mL) to the mixture.
The resulting aqueous mixture was extracted three times with
dichloromethane (30 mL), and the combined extract was
washed with water, a saturated aqueous solution of sodium
hydrogen carbonate, dried over anhydrous magnesium sulfate,
and then concentrated to dryness. The residue was purified by
silica gel column chromatography using ethyl acetate and
hexane (50:50 v/v), giving 6,8-dialkyl-4,4-diaryl-8-aza-1-
hydroxy-2,3-dioxabicyclo[4.3.0] nonan-7-one 3. The products
3a–v were further purified by recrystallization from an
appropriate solvent to obtain the analytical samples. The
physical properties are listed in the following.
1
mp 163ꢀC; ir (KBr): n 3500–3000 (OH), 1668 (C═O); H NMR
(CDCl3): d 7.67–7.64 (2H, m, arom H), 7.40–7.06 (11H, m, arom
H), 6.44–6.42 (2H, m, arom H), 4.81 (1H, d, J= 15.0 Hz,
PhCHHa), 4.34 (1H, br. s, OH), 3.67 (1H, d, J= 15.0 Hz,
PhCHHb), 3.56 (1H, d, J= 14.7 Hz, Ha-5), 3.24 (1H, d,
J= 10.8 Hz, Ha-9), 2.88 (1H, d, J= 10.8 Hz, Hb-9), 2.23 (1H, d,
J= 14.7 Hz, Hb-5), 1.74–1.50(2H, m, CH2), 1.50–1.18 (4H, m,
2Â CH2), 0.88 (3H, t, J=7.5Hz, Me); 13C NMR (CDCl3): d 1723.6
(C═O), 145.5, 140.6, 135.1 (arom C), 128.6 (2C), 128.3 (4C), 127.9
(2C), 127.5 (1C), 127.4 (1C), 127.2 (1C), 127.1 (1C), 124.9 (3C)
(arom CH), 102.3 (C-1), 85.6 (C-4), 52.9, 45.3, 37.6, 36.2, 25.8, 23.3
(CH2), 47.7 (C-6), 13.9 (Me). Anal. Calcd for C29H31NO4•1/11H2O:
C, 75.85; H, 6.84; N, 3.05. Found: C, 75.76; H, 6.70; N, 2.99.
8-Aza-8-ethyl-1-hydroxy-6-methyl-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3ea).
Yield (157.3 mg, 89%); Rf =0.54
8-Aza-8-benzyl-1-hydroxy-6-methyl-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3aa). Yield (190.9 mg, 92%); Rf =0.68 (EtOAc:
hexane = 7:3 v/v); colorless needles (from EtOAc-hexane), mp
210ꢀC; ir (KBr): n 3400–3100 (OH), 1656 (C═O); 1H NMR
(CDCl3): d 7.67–6.47 (15H, m, arom H), 4.76 (1H, d, J=15.2Hz,
PhCHHa), 3.72 (1H, d, J=15.2Hz, PhCHHb), 3.66 (1H, s, OH),
3.55 (1H, d, J=14.6Hz, Ha-5), 3.30 (1H, d, J=11.3Hz, Ha-9), 2.92
(1H, d, J= 11.3 Hz, Hb-9), 2.29 (1H, d, J= 14.6 Hz, Hb-5), 1.60 (3H,
s, Me); 13C NMR (CDCl3): d 174.4 (C═O), 145.1, 140.5, 135.2
(arom C), 128.6 (2C), 128.4 (2C), 128.0 (2C), 127.6 (1C), 127.4
(2C), 127.3 (2C), 127.2 (1C), 124.8 (3C) (arom CH), 102.7 (C-1),
85.7 (C-4), 51.8, 45.4, 36.6 (CH2), 44.7 (C-6), 22.6 (Me). Anal.
(EtOAc:hexane = 7:3 v/v); colorless needles (from CH2Cl2/hexane),
1
mp 223ꢀC; ir (KBr): n 3500–3000 (OH), 1668 (C═O); H NMR
(CDCl3): d 7.58–7.55 (2H, m, arom H), 7.32–7.14 (8H, m, arom
H), 3.70 (1H, br. s, OH), 3.42 (1H, d, J= 12.0 Hz, Ha-5), 3.37 (1H,
d, J= 12.0 Hz, Ha-9), 3.34–3.20 (1H, m, NCHHa), 3.09 (1H, d,
J= 12.0 Hz, Hb-9), 2.88–2.77 (1H, m, NCHHb), 2.32 (1H, d,
J= 11.0 Hz, Hb-5), 1.24 (3H, s, Me), 0.66 (3H, t, J=9.0Hz, Me);
13C NMR (CDCl3): d 173.7 (C═O), 145.0, 140.7 (arom C), 128.4,
127.7, 127.6, 127.1, 126.9, 124.9 (arom CH), 102.9 (C-1), 85.6
(C-4), 52.3, 36.9, 36.5, (CH2), 44.7 (C-6), 22.0, 11.6 (Me). Anal.
Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.08;
H, 6.69; N, 3.87.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Stable 8-Aza-1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-one Framework
583
8-Aza-1-hydroxy-8-(isopropyl)-6-methyl-2,3-dioxa-4,4-
diphenylbicyclo[4.3.0]nonan-7-one (3fa). Yield (143.3 mg, 78%);
Rf = 0.60 (EtOAc:hexane= 5:5 v/v); colorless needles (from
EtOAc/hexane), mp 222ꢀC; ir (KBr): n 3500–3000 (OH), 1662
hexane), mp 222ꢀC; ir (KBr): n 3500–3000 (OH), 1664 (C═O); 1H
NMR (DMSO-d6): d 7.50–7.46 (2H, m, arom H), 7.34–7.08 (8H,
m, arom H), 3.49 (1H, br. s, OH), 3.30 (1H, d, J=11.0Hz, Ha-9),
3.28 (1H, d, J=14.0Hz, Ha-5), 3.12 (1H, t, J=7.2Hz, NCHHa),
2.98 (1H, d, J=11.0Hz, Hb-9), 2.62 (1H, t, J=7.2Hz, NCHHb),
2.17 (1H, d, J= 14.0 Hz, Hb-5), 1.07 (3H, s, Me), 1.03–0.90 (2H,
1
(C═O); H NMR (CDCl3): d 7.28–7.56 (2H, m, arom H), 7.32–
7.16 (8H, m, arom H), 4.04 (1H, sep, J = 6.9 Hz, CH), 3.41 (1H,
d, J = 14.7Hz, Ha-5), 3.33 (1H, d, J = 11.1Hz, Ha-9), 3.05 (1H, d,
J = 11.1Hz, Hb-9), 2.29 (1H, d, J = 14.7 Hz, Hb-5), 1.72 (1H, s,
OH), 1.24 (3H, s, Me), 0.97 (3H, d, J = 6.9 Hz, Me), 0.53 (3H, d,
J = 6.9 Hz, Me); 13C NMR (CDCl3): d 173.4 (C═O), 144.7, 140.4
(arom C), 128.4, 127.6, 127.5, 127.3, 126.8, 124.9 (arom CH),
102.8 (C-1), 85.6 (C-4), 48.2, 36.7 (CH2), 44.9 (C-6), 42.0 (CH),
22.1, 19.3, 18.8 (Me). Anal. Calcd for C22H25NO4: C, 71.91; H,
6.86; N, 3.81. Found: C, 71.76; H, 6.94; N, 3.75.
m, CH2), 0.68–0.63 (2H, m, CH2), 0.66 (3H, t, J=7.9Hz, Me); 13
C
NMR (DMSO-d6): d 173.7 (C═O), 145.7, 141.4 (arom C), 128.2,
127.3, 127.3, 126.9, 126.4, 124.9 (arom CH), 102.1 (C-1), 84.3 (C-
4), 52.7, 40.3, 35.9, 28.1, 18.6 (CH2), 44.2 (C-6), 21.9, 13.8 (Me).
Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found: C,
72.36; H, 7.18; N, 3.64.
8-Aza-8-butyl-6-ethyl-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3ka).
Yield (174.0 mg, 88%); Rf = 0.71
8-Aza-6-ethyl-1-hydroxy-8-(isopropyl)-2,3-dioxa-4,4-
(EtOAc:hexane = 6:4 v/v); colorless needles (from EtOAc/
hexane), mp 225ꢀC; ir (KBr): n 3500–3000 (OH), 1663 (C═O);
1H NMR (DMSO-d6): d 7.50–7.09 (10H, m, arom H), 3.40 (1H,
s, OH), 3.31 (1H, d, J = 14.4Hz, Ha-5), 3.22 (1H, d, J = 11.1Hz,
Ha-9), 3.12 (1H, t, J = 6.9Hz, NCHHa), 2.97 (1H, d, J = 11.1Hz,
Hb-9), 2.66 (1H, t, J = 6.9Hz, NCHHb), 2.07 (1H, d, J = 14.4Hz,
Hb-5), 1.66–1.49 (2H, m, CH2), 1.03–0.90 (2H, m, CH2), 0.83
(3H, t, J = 7.5 Hz, Me), 0.65 (3H, br, Me); 13C NMR (DMSO-d6):
d 172.5 (C═O), 145.9, 141.4 (arom C), 128.2, 127.3, 127.2,
126.9, 126.3, 124.8 (arom CH), 101.9 (C-1), 84.2 (C-4), 53.9,
40.2, 35.4, 29.6, 28.1, 18.6 (CH2), 47.4 (C-6), 13.7, 8.4 (Me).
Anal. Calcd for C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found:
C, 72.96; H, 7.53; N, 3.56.
diphenylbicyclo[4.3.0]nonan-7-one (3ga).
Yield (143.1 mg,
75%); Rf = 0.69 (EtOAc:hexane = 5:5 v/v); colorless blocks (from
EtOH/hexane), mp 239ꢀC; ir (KBr): n 3500–3000 (OH), 1666
1
(C═O); H NMR (CDCl3): d 7.58–7.55 (2H, m, arom H), 7.27–
7.15 (8H, m, arom H), 4.09 (1H, sep, J = 6.6 Hz, , CH), 3.91 (1H,
br. s, OH), 3.44 (1H, d, J = 14.4Hz, Ha-5), 3.27 (1H, d,
J = 11.4Hz, Ha-9), 2.99 (1H, d, J = 11.4 Hz, Hb-9), 2.18 (1H, d,
J = 14.4 Hz, Hb-5), 1.71 ( 2H, q, J = 6.0 Hz, CH2), 0.98 (3H, t,
J = 6.0 Hz, Me), 0.94 (3H, d, J = 6.6 Hz, Me), 0.49 (3H, d,
J = 6.6 Hz, Me); 13C NMR (CDCl3): d 172.1 (C═O), 145.1, 140.4
(arom C), 128.4, 127.5, 127.3, 126.8, 124.9 (arom CH), 102.6 (C-
1), 85.6 (C-4), 49.4, 36.3, 30.5 (CH2), 48.1 (C-6), 41.9 (CH),
19.5, 18.7, 8.6 (Me). Anal. Calcd for C23H27NO4: C, 72.42; H,
7.13; N, 3.67. Found: C, 72.29; H, 7.19; N, 3.67.
8-Aza-8-butyl-1-hydroxy-2,3-dioxa-4,4-diphenyl-6-propylbicyclo
[4.3.0]nonan-7-one (3la).
Yield (174.1 mg, 85%); Rf =0.54
8-Aza-1-hydroxy-8-(isopropyl)-2,3-dioxa-4,4-diphenyl-6-
propylbicyclo[4.3.0]nonan-7-one (3ha). Yield (160.2 mg, 81%);
Rf = 0.75 (EtOAc:hexane= 5:5 v/v); colorless blocks (from CHCl3/
hexane), mp 209–210ꢀC; ir (KBr): n 3300–3000 (OH), 1654
(EtOAc:hexane = 4:6 v/v); colorless needles (from CHCl3/hexane),
1
mp 172ꢀC; ir (KBr): n 3550–3150 (OH), 1693 (C═O); H NMR
(CDCl3): d 7.58–7.56 (2H, m, arom H), 7.42–7.16 (8H, m, arom
H), 4.26 (1H, br. s, OH), 3.45 (1H, d, J= 14.7 Hz, Ha-5), 3.34 (1H,
d, J= 11.1 Hz, Ha-9), 3.27 (1H, m, NCHHa), 3.05 (1H, d,
J= 11.1 Hz, Hb-9), 2.71 (1H, m, NCHHb), 2.19 (1H, d, J= 14.7 Hz,
Hb-5), 1.62–0.96 (6H, m, 3 Â CH2), 0.87 (3H, t, J=7.2Hz, Me),
0.79–0.71 (2H, m, CH2), 0.72 (3H, t, J=7.2Hz, Me); 13C NMR
(CDCl3): d 173.1 (C═O), 145.4, 140.5 (arom C), 128.3, 127.6,
127.4, 127.2, 126.9, 124.9 (arom CH), 102.5 (C-1), 85.5 (C-4),
53.7, 40.3, 39.9, 36.2, 28.6, 19.2, 16.9 (CH2), 47.8 (C-6), 14.5,
13.7 (Me). Anal. Calcd for C25H31NO4•1/11H2O: C, 73.03; H,
7.64; N, 3.41. Found: C, 72.84; H, 7.70; N, 3.45.
1
(C═O); H NMR (CDCl3): d 7.58–7.55 (2H, m, arom H), 7.33–
7.13 (8H, m, arom H), 4.17 (1H, br, OH), 4.09 (1H, sep,
J = 6.9 Hz, CH), 3.44 (1H, d, J = 14.7Hz, Ha-5), 3.27 (1H, d,
J = 11.4Hz, Ha-9), 2.99 (1H, d, J = 11.4 Hz, Hb-9), 2.19 (1H, d,
J = 14.7Hz, Hb-5), 1.79–1.23 ( 4H, m, 2 Â CH2), 0.96 (3H, d,
J = 6.9 Hz, Me), 0.89 (3H, t, J = 6.9Hz, Me), 0.48 (3H, d,
J = 6.9 Hz, Me); 13C NMR (CDCl3): d 172.4 (C═O), 145.1, 140.4
(arom C), 128.4, 128.3, 127.5, 127.4, 126.8, 124.9 (arom CH),
102.6 (C-1), 85.6 (C-4), 49.4, 39.9, 36.6, 17.1 (CH2), 48.0 (C-6),
42.0 (CH), 19.4, 18.6, 14.5 (Me). Anal. Calcd for C24H29NO4: C,
72.89; H, 7.39; N, 3.54. Found: C, 72.92; H, 7.46; N, 3.62.
8-Aza-6-butyl-1-hydroxy-8-(isopropyl)-2,3-dioxa-4,4-
8-Aza-6,8-dibutyl-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3ma).
Yield (163.1 mg, 77%); Rf = 0.74
(EtOAc:hexane= 4:6 v/v); colorless microcrystals (from EtOAc/
diphenylbicyclo[4.3.0]nonan-7-one (3ia).
Yield (157.7 mg,
hexane), mp 185–186ꢀC; ir (KBr): n 3500–3000 (OH), 1663
1
77%); Rf = 0.65 (EtOAc:hexane= 5:5 v/v); colorless needles (from
(C═O); H NMR (CDCl3): d 7.59–7.56 (2H, m, arom H), 7.29–
CH2Cl2/hexane), mp 209ꢀC; ir (KBr): n 3500–3000 (OH), 1659
7.14 (8H, m, arom H), 4.19 (1H, br. s, OH), 3.45 (1H, d,
J = 14.7 Hz, Ha-5), 3.35 (1H, d, J = 11.4Hz, Ha-9), 3.32–3.25 (1H,
m, NCHHa), 3.05 (1H, d, J = 11.4Hz, Hb-9), 2.77–2.68 (1H, m,
NCHHb), 2.19 (1H, d, J = 14.7 Hz, Hb-5), 1.66–0.94 (8H, m,
4 Â CH2), 0.88 (3H, t, J = 6.9 Hz, Me), 1.09–0.68 (2H, m, CH2),
0.71 (3H, t, J = 7.8 Hz, Me); 13C NMR (CDCl3): d (CDCl3): 173.2
(C═O), 145.4, 140.5 (arom C), 128.4, 127.7, 127.5, 127.3, 126.9,
124.9 (arom CH), 102.6 (C-1), 85.6 (C-4), 53.7, 41.3, 37.5, 36.2,
28.6, 25.8, 23.3, 19.2 (CH2), 47.7 (C-6), 13.9, 13.8 (Me). Anal.
Calcd for C27H33NO4•1/2H2O: C, 72.19; H, 7.92; N, 3.24. Found:
C, 72.08; H, 8.20; N, 3.29.
1
(C═O); H NMR (CDCl3): d 7.58–7.12 (10H, m, arom H), 4.08
(1H, sep, J = 6.9Hz, CH), 3.70 (1H, br. s, OH), 3.45 (1H, d,
J = 14.4Hz, Ha-5), 3.28 (1H, d, J = 11.4 Hz, Ha-9), 2.99 (1H, d,
J = 11.4Hz, Hb-9), 2.18 (1H, d, J = 14.4Hz, Hb-5), 1.65–1.61 (2H,
m, CH2), 1.47–1.22 (4H, m, 2 Â CH2), 0.97 (3H, d, J = 6.9 Hz,
Me), 0.89 (3H, t, J = 7.2 Hz, Me), 0.48 (3H, d, J = 6.6 Hz, Me);
13C NMR (CDCl3) d 172.3 (C═O), 145.1, 140.4 (arom C), 128.4,
127.5, 127.4, 126.8, 124.9 (arom CH), 102.7 (C-1), 85.6 (C-4),
49.2, 37.5, 36.5, 25.8, 23.3 (CH2), 47.8 (C-6), 41.9 (CH), 19.5,
18.7, 13.9 (Me). Anal. Calcd for C25H31NO4: C, 73.32; H, 7.63;
N, 3.42. Found: C, 73.42; H, 7.67; N, 3.31.
8-Aza-8-(t-butyl)-1-hydroxy-6-methyl-2,3-dioxa-4,4-
8-Aza-8-butyl-1-hydroxy-6-methyl-2,3-dioxa-4,4-diphenylbicyclo
diphenylbicyclo[4.3.0]nonan-7-one (3na).
Yield (177.4 mg,
[4.3.0]nonan-7-one (3ja).
(EtOAc:hexane = 5:5) v/v; colorless microcrystals (from EtOH/
Yield (173.6 mg, 91%); Rf =0.55
93%); Rf = 0.32 (EtOAc:hexane = 4:6 v/v); colorless needles (from
EtOAc/hexane), mp 222–223ꢀC; ir (KBr): n 3600–3000 (OH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

584
A. Haque and H. Nishino
Vol 51
1668 (C═O); 1H NMR (DMSO-d6): d 7.51–7.50 (2H, m, arom H),
7.48–7.10 (8H, m, arom H), 3.39 (1H, s, OH), 3.37 (1H, d,
J = 10.8Hz, Ha-9), 3.23 (1H, d, J = 14.1 Hz, Ha-5), 3.05 (1H, d,
J = 10.8Hz, Hb-9), 2.14 (1H, d, J = 14.1 Hz, Hb-5), 1.05 (3H, s,
Me), 0.94 (9H, s, 3 Â Me); 13C NMR (DMSO-d6): d 173.5
(C═O), 145.5, 141.3 (arom C), 128.2, 127.2, 127.2, 127.1, 126.2,
124.9 (arom CH), 101.3 (C-1), 84.4 (C-4), 52.7 (quat. C), 51.2,
35.9 (CH2), 44.8 (C-6), 26.7 (3Â Me), 21.8 (Me). Anal. Calcd for
C23H27NO4•1/11H2O: C, 72.11; H, 7.15; N, 3.66. Found: C,
72.05; H, 7.43; N, 3.51.
8-Aza-8-(t-butyl)-6-ethyl-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3oa). Yield (150.0 mg, 76%); Rf =0.43
(EtOAc:hexane = 2:8 v/v); colorless microcrystals (from EtOAc/
hexane), mp 254ꢀC; ir (KBr): n 3300–3050 (OH), 1662 (C═O); 1H
NMR (DMSO-d6): d 7.48–7.09 (10H, m, arom H), 3.44 (1H, s,
OH), 3.29 (1H, d, J=6.9Hz, Ha-9), 3.25 (1H, d, J=8.1Hz, Ha-5),
3.05 (1H, d, J=6.9Hz, Hb-9), 2.03 (1H, d, J=8.1Hz, Hb-5), 1.64–
1.47 (2H, m, CH2), 0.95 (9H, s, 3 Â Me), 0.85 (3H, t, J=4.5Hz,
Me); 13C NMR (DMSO-d6): d 177.5 (C═O), 150.8, 146.5 (arom C),
133.3, 132.4, 132.3, 131.3, 129.9 (arom CH), 106.1 (C-1), 89.4 (C-
4), 58.1 (quat. C), 57.8, 40.9, 34.9 (CH2), 53.1 (C-6), 31.9 (3 Â Me),
13.6 (Me). Anal. Calcd for C24H29NO4: C, 72.89; H, 7.39; N, 3.54.
Found: C, 72.82; H, 7.42; N, 3.47.
8-Aza-8-(t-butyl)-1-hydroxy-2,3-dioxa-4,4-diphenyl-6-
propylbicyclo[4.3.0]nonan-7-one (3pa). Yield (170.0 mg, 85%);
Rf = 0.53 (EtOAc:hexane = 3:7 v/v); colorless needles (from EtOH/
hexane), mp 253ꢀC; ir (KBr): n 3600–3100 (OH), 1655 (C═O);
1H NMR (DMSO-d6): d 7.48–7.07 (10H, m, arom H), 3.40 (1H, s,
OH), 3.29 (1H, d, J=11.0 Hz, Ha-9), 3.26 (1H, d, J=14.0 Hz, Ha-
5), 3.04 (1H, d, J = 11.0 Hz, Hb-9), 2.04 (1H, d, J= 14.0 Hz, Hb-5),
1.56–1.15 (4H, m, 2 Â CH2), 0.94 (9H, s, 3 Â Me), 0.82 (3H, t,
J=7.2Hz, Me); 13C NMR (DMSO-d6): d 172.4 (C═O), 145.7,
141.3 (arom C), 128.2, 127.2, 127.1, 127.1, 126.1, 124.9 (arom
CH), 101.0 (C-1), 84.2 (C-4), 52.9 (quat. C), 52.6, 39.3, 35.9, 16.5
(CH2), 47.8 (C-6), 26.8 (3 Â Me), 14.7 (Me). Anal. Calcd for
C25H31NO4: C, 73.32; H, 7.63; N, 3.42. Found: C, 73.49; H, 7.68;
N, 3.41.
27.2 (3 Â Me), 14.0 (Me). Anal. Calcd for C28H37NO4: C, 74.47; H,
8.26; N, 3.10. Found: C, 74.29; H, 8.30; N, 2.93.
8-Aza-8-benzyl-1-hydroxy-4,4-bis(4-methylphenyl)-6-methyl-
2,3-dioxabicyclo[4.3.0]-nonan-7-one (3sb).
Yield (181.9 mg,
82%); Rf = 0.50 (EtOAc:hexane = 5:5 v/v); colorless needles
(from EtOAc/CHCl3), mp 213–214ꢀC; ir (KBr): n 3400–3150
(OH), 1656 (C═O); 1H NMR (CDCl3): d 7.54–7.51 (2H, m,
arom H), 7.20–7.08 (7H, m, arom H), 7.05–7.02 (2H, m, arom
H), 6.48–6.45 (2H, m, arom H), 4.81 (1H, d, J = 15.0 Hz,
PhCHHa), 3.85 (1H, s, OH), 3.68 (1H, d, J = 15.0 Hz, PhCHHb),
3.50 (1H, d, J = 14.4 Hz, Ha-5), 3.30 (1H, d, J = 11.4 Hz, Ha-9),
2.92 (1H, d, J = 11.4 Hz, Hb-9), 2.31 (3H, s, Me), 2.27 (1H, d,
J = 14.4 Hz, Hb-5), 2.25 (3H, s, Me), 1.29 (3H, s, Me); 13C
NMR (CDCl3): d 174.6 (C═O), 142.4, 137.6, 137.3, 136.6,
135.2 (arom C), 129.0 (2C), 128.6 (2C), 128.5 (2C), 127.3
(3C), 127.2 (2C), 124.8 (2C), (arom CH), 102.6 (C-1), 85.6 (C-4),
51.8, 45.3, 36.6 (CH2), 44.7 (C-6), 22.5, 21.0, 20.9 (Me). Anal.
Calcd for C28H29NO4: C, 75.82; H, 6.59; N, 3.16. Found: C,
75.69; H, 6.58; N, 3.25.
8-Aza-8-benzyl-1-hydroxy-4,4-bis(4-methoxyphenyl)-6-methyl-
2,3-dioxabicyclo[4.3.0]-nonan-7-one (3tc).
Yield (194.8 mg,
82%); Rf = 0.55 (EtOAc:hexane = 5:5 v/v); colorless needles (from
CH2Cl2/hexane), mp 199ꢀC; ir (KBr): n 3500–3100 (OH), 1668
1
(C═O); H NMR (CDCl3): d 7.55–7.52 (2H, m, arom H), 7.18–
7.10 (5H, m, arom H), 6.93–6.89 (2H, m, arom H), 6.79–6.76
(2H, m, arom H), 60.53–6.50 (2H, m, arom H), 4.81 (1H, d,
J = 15.0Hz, PhCHHa), 3.77 (3H, s, OMe), 3.74 (3H, s, OMe),
3.72 (1H, d, J = 14.7Hz, Ha-5), 3.61 (1H, s, OH), 3.45 (1H, d,
J = 15.0Hz, PhCHHb), 3.32 (1H, d, J =11.4 Hz, Ha-9), 2.94 (1H,
d, J = 11.4Hz, Hb-9), 2.27 (1H, d, J = 14.7Hz, Hb-5), 1.30 (3H, s,
Me); 13C NMR (CDCl3): d 174.6 (C═O), 158.9, 158.7, 137.5,
135.2, 132.5 (arom C), 128.7 (2C), 128.6 (2C), 127.3 (2C), 127.3
(2C), 126.7 (2C), 113.6 (2C), 113.2 (1C) (arom CH), 102.5 (C-1),
85.5 (C-4), 51.9, 45.5, 36.8 (CH2), 44.7 (C-6), 55.2, 55.2 (OMe),
22.7 (Me). Anal. Calcd for C28H29NO6: C, 70.72; H, 6.15; N,
2.95. Found: C, 70.65; H, 6.14; N, 3.05.
8-Aza-8-benzyl-4,4-bis(4-chlorophenyl)-1-hydroxy-6-methyl-
2,3-dioxabicyclo[4.3.0]-nonan-7-one (3ud). Yield (181.6 mg,
75%); Rf = 0.44 (EtOAc:hexane = 5:5 v/v); colorless needles
(from EtOAc/hexane), mp 217–218ꢀC; ir (KBr): n 3600–3000
(OH), 1657 (C═O); 1H NMR (CDCl3): d 7.57–7.54 (2H, m,
arom H), 7.35–7.31 (2H, m, arom H), 7.26–7.14 (7H, m, arom
H), 6.51–6.49 (2H, m, arom H), 4.78 (1H, d, J = 15.0 Hz,
PhCHHa), 3.82 (1H, s, OH), 3.70 (1H, d, J = 15.0 Hz, PhCHHb),
3.46 (1H, d, J = 14.7 Hz, Ha-5), 3.33 (1H, d, J = 11.4 Hz, Ha-9),
2.95 (1H, d, J = 11.4 Hz, Hb-9), 2.22 (1H, d, J = 14.7 Hz, Hb-5),
1.30 (3H, s, Me); 13C NMR (CDCl3): d 174.2 (C═O), 142.9,
138.5, 134.9, 133.5, (arom C), 128.9 (2C), 128.7 (2C), 128.7
(2C), 128.3 (2C), 127.6 (1C), 127.3 (2C), 126.3 (2C), (arom
CH), 102.6 (C-1), 84.9 (C-4), 51.9, 45.5, 36.3 (CH2), 44.6
(C-6), 22.6 (Me). Anal. Calcd for C26H23Cl2NO4: C, 64.47; H,
4.79; N, 2.89. Found: C, 64.33; H, 4.78; N, 2.96.
8-Aza-6-butyl-8-(t-butyl)-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3qa). Yield (171.5 mg, 81%); Rf = 0.70 (EtOAc:
hexane = 3:7 v/v); colorless needles (from EtOH/hexane), mp 238ꢀC;
1
ir (KBr): n 3600–3150 (OH), 1655 (C═O); H NMR (DMSO-d6):
d 7.49–7.10 (10H, m, arom H), 3.38 (1H, s, OH), 3.29 (1H, d,
J= 11.0 Hz, Ha-9), 3.26 (1H, d, J=13.8Hz, Ha-5), 3.04 (1H, d,
J= 11.0 Hz, Hb-9), 2.04 (1H, d, J= 13.8 Hz, Hb-5), 1.60–1.15 (6H,
m, 3 Â CH2), 0.94 (9H, s, 3 Â Me), 0.84 (3H, t, J=6.9Hz, Me); 13
C
NMR (DMSO-d6): d 172.5 (C═O), 145.7, 141.4 (arom C), 128.2,
127.1, 127.1, 126.2, 124.9 (arom CH), 101.1 (C-1), 84.3 (C-4), 52.9
(quat. C), 52.5, 36.7, 35.9, 25.2, 22.8 (CH2), 47.8 (C-6), 26.8
(3 Â Me), 14.8 (Me). Anal. Calcd for C26H33NO4•1/2H2O: C, 72.19;
H, 7.92; N, 3.24. Found: C, 72.37; H, 8.01; N, 3.13.
8-Aza-8-(t-butyl)-6-hexyl-1-hydroxy-2,3-dioxa-4,4-diphenylbicyclo
[4.3.0]nonan-7-one (3ra).
Yield (176.2 mg, 78%); Rf =0.67
(EtOAc:hexane = 2:8 v/v); colorless needles (from EtOAc/hexane),
8-Aza-8-benzyl-4,4-bis(4-fluorophenyl)-1-hydroxy-6-methyl-2,3-
dioxabicyclo[4.3.0]-nonan-7-one (3ve). Yield (160.3 mg, 71%);
Rf = 0.50 (EtOAc:hexane = 5:5 v/v); colorless needles (from
CH2Cl2/hexane), mp 213ꢀC; ir (KBr): n 3600–3000 (OH), 1657
(C═O); 1H NMR (DMSO-d6): d 7.62–7.58 (2H, m, arom H), 7.61
(1H, s, OH), 7.40–7.35 (2H, m, arom H), 7.23–7.10 (7H, m, arom
H), 6.51–6.48 (2H, m, arom H), 4.62 (1H, d, J= 15.3 Hz,
PhCHHa), 3.73 (1H, d, J= 15.3 Hz, PhCHHb), 3.41 (1H, d,
J= 14.4 Hz, Ha-5), 3.34 (1H, d, J= 11.7 Hz, Ha-9), 2.75 (1H, d,
J= 11.7 Hz, Hb-9), 2.22 (1H, d, J= 14.4 Hz, Hb-5), 1.17(3H, s,
1
mp 225ꢀC; ir (KBr): n 3400–3100 (OH), 1657 (C═O); H NMR
(CDCl3): d 7.58–7.56 (2H, m, arom H), 7.21–7.14 (8H, m, arom H),
3.60 (1H, s, OH), 3.41 (1H, d, J=8.7Hz, Ha-5), 3.38 (1H, d,
J=6.6Hz, Ha-9), 3.14 (1H, d, J=6.6Hz, Hb-9), 2.12 (1H, d,
J=8.7Hz, Hb-5), 1.59 (2H, t, J=4.8Hz, CH2), 1.5–1.2 (8H, m,
4Â CH2), 1.04 (9H, s, 3 Â Me), 0.86 (3H, t, J=4.8Hz, Me); 13C
NMR (CDCl3): d 172.7 (C═O), 145.1, 140.4 (arom C), 128.4,
127.5, 127.4, 126.7, 124.9 (arom CH), 101.9 (C-1), 85.7 (C-4), 53.9
(quat. C), 52.3, 37.8, 36.3, 31.5, 29.8, 23.4, 22.5 (CH2), 48.1 (C-6),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Stable 8-Aza-1-hydroxy-2,3-dioxabicyclo[4.3.0]nonan-7-one Framework
585
Me); 13C NMR (DMSO-d6): d 173.9 (C═O), 162.8, 159.6, 141.6,
137.1, 135.9, (arom C), 129.3 (1C), 129.2 (1C), 128.2 (2C), 127.3
(1C), 127.2 (1C), 126.9 (1C), 126.8 (2C), 115.2 (1C), 114.9 (1C),
114.5 (1C), 114.2 (1C) (arom CH), 101.9 (C-1), 83.9 (C-4), 51.9,
44.2, 35.9 (CH2), 44.1 (C-6), 22.1 (Me). Anal. Calcd for
C26H23F2NO4•H2O: C, 66.52; H, 5.37; N, 2.98. Found: C, 66.52;
H, 5.10; N, 2.97.
[15] Nishino, H. In Topics in Heterocyclic Chemistry, Eguchi, S.,
Ed.; Springer: Berlin, 2006; Vol 6, pp 39‐76.
[16] Nguyen, V.-H.; Nishino, H.; Kurosawa, K. Heterocycles 1998,
48, 465.
[17] Chowdhury, F. A.; Nishino, H.; Kurosawa, K. Heterocycles
1999, 51, 575.
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Reaction of 2,4-pentanedione with Mn(OAc)2.
To a
solution of 2,4-pentanedione (12 mmol) and AcOH (20 mL), Mn
(OAc)2•4H2O (2 mmol) was added. The mixture was stirred at
room temperature under oxygen (5 atm) using an autoclave, and
the color of the solution turned from colorless to dark brown
within 48 h. To the dark-brown solution, 1,1-diphenylethene
(1 mmol) was added, and then, the mixture was heated under
reflux in air for 1 h. After removal of the solvent, the residue
was treated with 2 M HCl, and the aqueous solution was
extracted with CHCl3. The resulting products were purified by
silica gel TLC, giving 3-acetyl-2-methyl-5,5-diphenyl-4,5-
dihydrofuran (12,4 mg, 4% yield) [36].
[25] Mallinger, A.; Nadal, B.; Chopin, N.; Gall, T. L. Eur. J. Org.
Chem. 2010, 12, 1142.
[26] Haque, M. A.; Ishikawa, H.; Nishino, H. Chem. Lett. 2011, 40,
1349.
[27] We demonstrated the formation of a Mn(III)-enolate complex
in situ using 4,4,4-trifluoro-1-phenylbutane-1,3-dione. The enolate
complex, tris(4,4,4-trifluoro-1-phenylbutane-1,3-dionato)manganese(III),
can be easily isolated from the reaction of the butanedione with Mn
(OAc)3. See Nguyen, V.-H.; Nishino, H.; Kurosawa, K. Synthesis 1997,
899.
Acknowledgments. This research was supported by the Grants-
in-Aid for Scientific Research (C), No. 19550046 and No.
22550041, from the Japan Society for the Promotion of Science.
[28] Ito, Y.; Yoshinaga, T.; Nishino, H. Tetrahedron 2010, 66,
2683.
[29] Ito, Y.; Tomiyasu, Y.; Kawanabe, T.; Uemura, K.; Ushimizu,
Y.; Nishino, H. Org. Biomol. Chem. 2011, 9, 1491.
[30] Ito, Y.; Jogo, S.; Fukuda, N.; Okumura, R.; Nishino,
H. Synthesis 2011, 1365.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet