Yb(OTf)3-Catalyzed vinylogous Mannichreaction of trialkylsilyloxyfuran

Article abstract of DOI:10.3987/COM-05-10335

The one-pot three-component vinylogous Mannich reaction oftrialkylsilyloxyfurans with anilines and aldehydes in the presence of catalytic amounts of Yb(OTf)₃ gave the substituted aminoalkyl-butenolides in good yields (> 90 %) and diastereoselec

Full text of DOI:10.3987/COM-05-10335

HETEROCYCLES, Vol. 65, No. 4, 2005
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HETEROCYCLES, Vol. 65, No. 4, 2005, pp. 823 - 841
Received, 14th January, 2005, Accepted, 21st February, 2005, Published online, 22nd February, 2005
Yb(OTf)3-CATALYZED
VINYLOGOUS
MANNICH
REACTION OF TRIALKYLSILYLOXYFURAN
Sylvain Oudeyer, Bruno Dudot, and Jacques Royer*
« Synthèse et Structure de Molécules d’Intérêt Pharmacologique » UMR 8638
(CNRS-University Paris5), Faculty of Pharmacy, 4 avenue de l’Observatoire,
75270 Paris cedex 06, France
e-mail: jacques.royer@univ-paris5.fr
Abstract – The one-pot three-component vinylogous Mannich reaction of
trialkylsilyloxyfurans with anilines and aldehydes in the presence of catalytic
amounts of Yb(OTf)3 gave the substituted aminoalkyl-butenolides in good yields
(> 90 %) and diastereoselectivities (d.e. > 60 %). The configuration of the major
product is erythro (anti) and was confirmed by chemical transformation into
1
piperidinone derivatives and H NMR spectral studies of the latter compounds.
The vinylogous Mannich reaction performed with preformed imines proceeded
similarly with a preferred erythro selectivity while the condensation of
3-methyl-2-trialkylsilyloxyfurans was threo selective.
INTRODUCTION
Ytterbium triflate was proposed by Kobayashi1 as a very convenient catalyst for various addition
reactions to imines. It is very efficient, easy to handle and since some years broadly used.1 We showed
that this compound is quite useful to catalyse the reaction of silyloxypyrrole with imines.2 As ytterbium
triflate was known to be much less reactive with aldehydes, we also developed a similar strategy in the
three-component Mannich-type reaction.3 An erythro-selectivity was observed in both cases, the
three-component reaction allowing reactions with aliphatic enolisable aldehydes while the corresponding
imines do not react.
In the present paper we want to present the application of the same three-component strategy to
silyloxyfuran and a careful study of the diastereoselectivity of this reaction.
Indeed, the reaction of silyloxyfurans with imines,4 iminiums or acyliminiums5 and nitrones6 has already

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HETEROCYCLES, Vol. 65, No. 4, 2005
been reported by several groups in racemic and enantioselective forms.7 Such reaction is interesting and
was applied to total syntheses.8 The condensation of silyloxyfuran with imines was found to be catalyzed
with various Lewis acids (mainly BF3.OEt2, Ti(OPr-i)4) giving mixture of threo (syn) and erythro (anti)
isomers (Scheme 1). Despites some contradictory reports,4b-e the erythro adduct was usually observed as
the major product7 with imines while threo adducts predominate in the condensation of cyclic
acyliminiums.5
R1
NH
R1
NH
R3SiO
R2
Lewis acid
O
N
R1
R2
R2
O
+
+
O
O
O
erythro
threo
Scheme 1
RESULTS AND DISCUSSION
1- Three-component Mannich type reaction:
Our investigation was concerned with the condensation of t-butyldimethylsilyloxyfuran with simple
aromatic or aliphatic aldehydes and anilines (Scheme 2). A clean and rapid reaction was observed by just
mixing the three components in CH2Cl2 at -78°C in the presence of 5-10% of Yb(OTf)3. The results are
reported in Table 1.
R1
NH
R1
NH
O
O
Si
Yb(OTf)3
R2CHO
R1NH2
R2
R2
O
O
+
+
+
O
O
1a-6a
1b-6b
Scheme 2
Table 1: Three-component Mannich type reaction of t-butyldimethylsilyloxyfuran with some anilines and
aldehydes
compound
(yield %)
1 (95)
2 *
erythro / threo
a : b
R1
R2
Ph
Ph
Ph
83 : 17
79 : 21
83 : 17
80 : 20
90 : 10
92 : 8
p-MeO-C6H4
Ph
Me
3 (99)
4 (95)
5 (90)
6 (99)
p-MeO-C6H4
Me
Ph
Ph
Et
n-C6H13
*not isolated

HETEROCYCLES, Vol. 65, No. 4, 2005
825
The yields are very high (90 to 99%) in all cases and refer to isolated products. The diastereoselectivities
are good and ranging between 80:20 to 90:10 depending upon the structures. Aware of a possible
equilibration (via a retro-Mannich reaction for example) leading to erratic diastereoselectivities,7 a very
careful protocol was followed and applied to all experiments. As a matter of fact, the crude reaction
mixture was analyzed by 1H NMR spectrum to determine the diastereomeric ratio before any purification
by chromatography on silica gel.
3
Table 2: Comparison of J H5-H6 coupling constants of major and minor Mannich adducts, the
corresponding reduced lactones and the rearranged δ-lactams.
R1
R1
R1
N
NH
6
NH
6
R2
O
6
5
R2
R2
O
O
5
5
O
O
HO
R1
R2
3J H5-H6 (Hz)
3J H5-H6 (Hz)
3J H5-H6 (Hz)
major
4.2
4.0
-
minor
major
3.1
3.1
4.1
4.2
5.2
-
minor
Ph
Ph
Ph
1
2
3
4
5
6
6.8
7.0
3.0
3.4
-
7
8
5.5
6.1
-
12a
2.9
2.4
2.6
3.0
2.4
-
p-MeO-C6H4
13a
14a
15a
16a
-
Ph
Me
9
p-MeO-C6H4
Me
4.7
6.0
5.6
10
11
-
2.8
1.1
-
Ph
Ph
Et
n-C6H13
3.8
The assignement of the relative configuration is a very difficult problem to solve. The examination of 1H
NMR spectra for each diastereoisomers and namely the H5-H6 coupling constants do not seem to be a
valuable proof to assign the relative configuration of the major isomer. We report in Table 2, the observed
H5-H6 coupling constants for both diastereoisomers. The major Mannich adduct exhibits the smaller
coupling constant value for reactions using benzaldehyde (R2=Ph, compounds (1) and (2)). At the
opposite, when R2 is aliphatic (from aliphatic aldehydes) the major adduct exhibits larger coupling
constant or could not be observed due to overlapping. The same trend was observed for the corresponding
reduced products (7-11) (Table 2) obtained by hydrogenation (see Scheme 3).
The reversal of the larger coupling constant from the minor to the major isomer could be explained as an
inversion of the diastereoselectivities between the aliphatic and aromatic aldehydes, but a conformational
change in the same erythro (or threo) adduct arising from the aliphatic or aromatic R2 group could also

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HETEROCYCLES, Vol. 65, No. 4, 2005
1
lead to a change in the coupling constant. Thus, the H NMR spectral analysis of the Mannich adducts
could not provide an unambiguous configuration assignment.
The relative configuration of the major diastereomer was determined after chemical transformation.
Casiraghi,4c first reported the transformation of such furanones to δ−lactam derivatives by DBU treatment
allowing a convenient assignment of the relative configuration. In our hands, the DBU or acidic4g
treatment did not undergo the desired cyclization due to the nature of the secondary amine. The sequence
described in Scheme 3 was applied to compounds (1a,b-5a,b). The double bond was first reduced and the
diastereomeric saturated lactones were then separated permitting the isolation of the major isomers
(7a-11a). The latter were treated with KHMDS in THF at low temperature to furnish in good yield the
δ-lactams (12a-16a) which were subjected to 1H NMR spectral analyses. A pure sample of minor lactam
(15b) was also obtained. The coupling constants between H5 and H6 for 12a-16a are low values around 3
Hz (Table 2) suggesting a trans-diaxal relationship of the two substituents born at the δ-lactam ring and
thus an erythro relative configuration of the major Mannich products. This was confirmed, by the pattern
1
of H5 in the H NMR spectrum of compound (12a-16a) which is characteristic of a pseudo-equatorial
position (two small and a medium coupling constants, see EXPERIMENTAL) and by the observation of a
4J coupling constant between H6 and H4. All these features are consistent with a trans-diequatorial
arrangement of the diagnostic protons H5 and H6. Furthermore, analysis of isomeric δ−lactam (15b)
arising from the minor isomer exhibits a H5-H6 coupling constant value of 4.3 Hz characteristic of a
cis-axial-equatorial configuration. The trans-diaxial arrangement of both substituents at C5 and C6
resulted from the presence of a large group on nitrogen which is sp2 hybridized. An important allylic
interaction exists forcing substituents at C5 and C6 to be both placed in an axial position. The same
behaviour was already reported for similar products.4g, 9
R1
R1
R1
N
NH
NH
R2
O
R2
H2
R2
O
O
1) separation
O
O
Pd/C
HO
2) KHMDS
THF, -78°C
AcOEt
1-5
7-11
12a-16a
Scheme 3
As shown in this study, the Mannich reaction we reported herein is highly erythro selective independently
of the nature of R1 or R2. This is consistent with the usually observed diastereoselectivity of silyloxyfuran
condensation with imines.7
2- Yb(OTf)3 catalyzed condensation of imines:
The threo configuration reported by Martin4f for the condensation of some 2-trimethylsilyloxyfurans with

HETEROCYCLES, Vol. 65, No. 4, 2005
827
imines derived from various benzaldehydes and anilines and catalyzed by Ti(OPr-i)4/(S)-BINOL was still
puzzling. Is the discrepancy in the diastereoselectivity due to the presence of a methyl group on the
silyloxyfuran ? to the presence of a substituent on the aromatic group ? or to the use of
Ti(OPr-i)4/(S)-BINOL as
a
catalytic system
?
We studied some condensations of
2-t-butyldimethylsilyloxyfuran and 3-methyl-2-t-butyldimethylsilyloxyfuran with preformed imines
derived from benzaldehyde in the presence of Yb(OTf)3 as a catalyst (Scheme 4).
R1
NH
O
Yb(OTf)3
O
Si
N
Ph
O
Ph
R1
+
O
CH2Cl2, -78°C
R3
R3
1, 2, 17-20
Scheme 4
Table 3: Condensation of t-butyldimethylsilyloxyfuran with preformed imines
compound
(yield %)
1 (99)
3J H5-H6
major minor
6.8 72 / 28
7.0 79 / 21
R1
R3
erythro / threo
Ph
H
H
4.2
4.0
3.6
3.8
5.0
7.0
(83/17)a
(79/21)a
p-MeO-C6H4
o-MeO- C6H4
o-HO- C6H4
o-HO- C6H4
Ph
2 (95)
H
17 (92)
18 (82)
19 (90)
20 (99)
6.4 73 / 27
5.0 70 / 30
3.8 12 / 88
3.8 21 / 79
H
(66/34)b
(09/91)b
Me
Me
a one-pot procedure (cf. Table 2). b values reported by Martin4f
The results are reported in Table 3. A clean and rapid reaction was observed, very similar in all aspects to
the reaction conducted in the three-component method: very similar yields and diastereoselectivities were
observed in the reactions leading to 1 and 2. Two condensations of imines derived from o-aminophenol
and reported by Martin were reproduced in the conditions described by this author or using Yb(OTf)3.
Once again, very similar results were obtained in both conditions (Table 3, 18 and 19).
Looking at the relative configuration of the major isomer, we again examined the coupling constants
between H5 and H6. It appears that the major Mannich adducts all showed smaller 3J values when R3 = H
consistent with the erythro configuration demonstrated for 1 and 2 (see above). At the opposite, for
reactions conducted with 3-methyl-2-t-butyldimethylsilyloxyfuran (R3= CH3, 19 and 20), the major

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HETEROCYCLES, Vol. 65, No. 4, 2005
3
adducts exhibit the larger J constant which could correspond to a threo configuration. The same threo
configuration was obtained and proved in the work of Martin.4f
It thus appears that a reversal of stereoselectivity is occurring by the simple presence or absence of the
methyl group on the silyloxyfuran ring. It is difficult to explain this phenomenon by application of
“Diels-Alder” or “open” form approach mechanism both invoked in vinylogous Mannich reactions.10
In conclusion, we showed along this study, the efficiency of Yb(OTf)3 as a catalyst for the
three-component Mannich-type condensation of silyloxyfuran. This procedure gave very similar yields
and diastereoselectivities compared to the condensation using preformed imines and the same catalyst or
other Lewis acids described in the literature. The diastereoselectivity is mainly in favor of the erythro
adduct except for condensation using 3-methyl-2-trialkylsilyloxyfuran.
EXPERIMENTAL
General conditions
All the solvents were dried according to the common methods and distilled before use. IR spectra were
recorded on a Nicolet 205-FT infrared spectrophotometer. Melting points were determinated with a Leica
VMHB Koffler type apparatus. 1H and 13C NMR spectra were recorded on a Bruker AC 250, AC 300 or
400 Avance. Chemical shifts are reported in δ (ppm). In the case of erythro/threo mixture, NMR spectral
data of the threo isomer were given in square brackets. CIMS spectra were recorded on AEI MS-9, ESMS
on a Micromass ZQ 2000 with an Z-spray source, EIMS on a AEI MS-50 and HRMS on Micromass
Q-Tof 1 with an ESI Z-spray source by the Mass Spectrometry Laboratory at the Faculty of Pharmacy
(Paris). Elementary analyses were performed at the Microanalysis Laboratory (Pierre and Marie Curie
University, Paris). All reactions were carried out under argon atmosphere and were monitored by
thin-layer chromatography with Merck 60F-254 precoated silica (0.2 mm) on aluminium. Flash
chromatographies were performed with SDS Silicagel 60ACC (35-70 µm); preparative layer
chromatographies were performed with Merck 60 HF-254 precoated silica (1 mm) on glass. The solvent
systems were given v/v.
General procedure for the one-pot three-component Yb(OTf)3-catalyzed Mannich-type reaction of
silyloxyfuran with amines and aldehydes:
10% mol of Yb(OTf)3 was added to a 0.16M CH2Cl2 solution of silyloxyfuran (1 equiv.) and of aldehyde
(1.2 to 2 equiv.) containing molecular sieves (4Å) at -78°C, followed by the dropwise addition of amine
(1.2 to 2 equiv.). When the complete consumption of the starting materials was observed (about 45 min),
the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude
mixture was dissolved in CH2Cl2 and washed with water. The layers were separated. The aqueous

HETEROCYCLES, Vol. 65, No. 4, 2005
829
solution was extracted with CH2Cl2 (2x15 mL). The collected organic fractions were dried over MgSO4,
1
filtered and evaporated under reduced pressure. The crude reaction mixtures were examinated by H
NMR spectrum in order to determine the diastereoisomeric ratios. Products were isolated by flash
chromatography on silica gel using AcOEt-cyclohexane or AcOEt-heptane as solvent.
5-[(Phenylamino)phenylmethyl]furan-2(5H)-one (1).
The general one-pot three-component procedure was applied to t-butyldimethylsilyloxyfuran (63 mg, 0.32
mmol), benzaldehyde (38 µL, 0.38 mmol) and aniline (35 µL, 0.38 mmol) to give 1 (58 mg, 95%) as a
83/17 erythro/threo mixture and as a glassy solid after purification by flash chromatography
1
(AcOEt/heptane 50/50); Rf erythro/threo mixture: 0.25 (AcOEt/heptane 30/70). H-NMR (300 MHz,
CDCl3) δ erythro, [threo]: 7.50-6.60 (m, 11H, H-4, H-Ph, [H-4] and [H-Ph]); [6.20 (dd, J=5.8, 2.0 Hz,
0.17H, H-3)]; 6.10 (dd, J=5.8, 1.8 Hz, 0.83H, H-3); 5.45 (ddd, J=4.2, 2.0, 2.0 Hz, 0.83H, H-5); [5.15 (ddd,
J=6.8, 1.8, 1.8 Hz, 0.17H, H-5)]; 4.70 (d, J=4.2 Hz, 0.83H, H-6); [4.50 (d, J=6.8 Hz, 0.17H, H-6)].
13C-NMR (75 MHz, CDCl3) δ erythro, [threo]: 172.4, [172.4] (CO); [154.0], 153.2 (C-4); [146.6], 146.1
(C-q Ar); [138.3], 136.9 (C-q Ph); 129.3, 129.1, 128.9, 128.5, 128.4, 127.2 (C-Ph and [C-Ph]); 123.2,
[122.8] (C-3); 118.7, [118.7] (C-p Ar); [114.2], 114.0 (C-o Ar); [85.8], 85.3 (C-5); [61.1], 59.4 (C-6).
CIMS (isobutane 180°C) m/z 266 (M+H)+, 182 ((M-furanone)+, base peak).
5-[[(4-Methoxyphenyl)amino]phenylmethyl]furan-2(5H)-one (2).
1
Characterized by H NMR spectrum (erythro/threo mixture: 79/21) but not isolated; Rf erythro/threo
mixture: 0.50 (AcOEt/heptane 50/50). Described below in the imine condensation procedure section.
5-[1-(Phenylamino)ethyl]furan-2(5H)-one (3).
The general one-pot three-component procedure was applied to t-butyldimethylsilyloxyfuran (63 mg, 0.32
mmol), acetaldehyde (66 µL, 0.64 mmol) and aniline (58 µL, 0.64 mmol) to give 3 (66 mg, 99%) as a
83/17 erythro/threo mixture and as a glassy solid after purification by flash chromatography
1
(AcOEt/heptane 30/70); Rf erythro/threo mixture: 0.25 (AcOEt/heptane 30/70). H-NMR (250 MHz,
CDCl3) δ erythro, [threo]: 7.45 (2dd app., J=5.8, 1.2 Hz, 1H, H-4 and [H-4]); 7.20 (2dd app., J=7.4 Hz,
2H, H-m and [H-m]); 6.75 (2t app., J=7.4 Hz, 1H, H-p and [H-p]); 6.60 (2d, J=7.4 Hz, 2H, H-o and
[H-o]); 6.15 (dd, J=5.8, 2.0 Hz, 0.83H, H-3); [6.10 (dd, J=5.8, 2.0 Hz, 0.17H, H-3)]; [5.20 (td app., J=3.0,
1.5 Hz, 0.17H, H-5)]; 5.10-5.00 (m, 0.83H, H-5); [4.00 (qd, J=6.6, 3.0 Hz, 0.17H, H-6)]; 3.80 (m, 1.83H,
13
H-6, NH and [NH]); [1.25 (d, J=6.6 Hz, 0.51H, CH3)]; 1.20 (d, J=6.6 Hz, 2.49H, CH3). C-NMR (50
MHz, CDCl3) δ erythro, [threo]: 173.0, [172.9] (CO); 154.7, [154.3] (C-4); 146.2, [146.2] (C-q); 129.5,
[129.5] (C-m); 122.6, [122.2] (C-p); 118.4, [118.1] (C-3); 113.7, [113.2] (C-o); 85.6, [85.1] (C-5); [50.9],

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HETEROCYCLES, Vol. 65, No. 4, 2005
49.6 (C-6); [17.2], 16.0 (CH3). CIMS (isobutane 180°C) m/z 204 (M+H)+, 120 ((M-furanone)+, base
peak).
5-[1-[(4-Methoxyphenyl)amino]ethyl]furan-2(5H)-one (4).
The general one-pot three-component procedure was applied to t-butyldimethylsilyloxyfuran (531 mg,
2.70 mmol), acetaldehyde (0.30 mL, 5.40 mmol) and p-anisidine (660 mg, 5.40 mmol) to give 4 (593 mg,
95%) as a 80/20 erythro/threo mixture. Separation of diastereoisomers by flash chromatography
(AcOEt/cyclohexane 30/70) furnished pure erythro 4a and threo-enriched 4b.
1
4a (erythro): pale yellow oil; Rf: 0.16 (AcOEt/cyclohexane 30/70). H-NMR (400 MHz, CDCl3) δ: 7.44
(dd, J=5.7, 1.4 Hz, 1H, H-4); 6.75 (d, J=8.9 Hz, 2H, H-m); 6.60 (d, J=8.9 Hz, 2H, H-o); 6.12 (dd, J=5.7,
2.0 Hz, 1H, H-3); 5.05 (ddd, J=4.7, 1.9, 1.4 Hz, 1H, H-5); 3.72 (s, 3H, OCH3); 3.67-3.64 (m, 1H, H-6);
13
3.50 (br s, 1H, NH); 1.10 (d, J=6.6 Hz, 3H, CH3). C-NMR (100 MHz, CDCl3) δ: 173.0 (CO); 154.8
(C-4); 153.0, 140.4 (C-q); 122.2 (C-3); 115.9, 115.2 (C-m and C-o); 85.6 (C-5); 55.8 (OCH3); 52.4 (C-6);
15.9 (CH3). ESMS m/z 272 (M+K)+, 257 (M+H+Na)+, 256 ((M+Na)+, base peak), 234 (M+H)+, 150
(M-furanone)+. IR ν (cm-1) (neat) 3390, 3370, 3089, 3034, 2974, 2934, 2833, 1759, 1620, 1597, 1538,
1514, 1504, 1454. Anal. Calcd for C13H15NO3: C, 66.84; H, 6.48, N, 6.00. Found: C,66.82; H, 6.97; N,
6.07.
4b (threo-enriched): pale yellow oil; Rf: 0.25 (AcOEt/cyclohexane 30/70). 1H-NMR (400 MHz, CDCl )
3
δ (erythro/threo mixture: 14/86): 7.40 (dd, J=5.7, 1.4 Hz, 1H, H-4); 6.75 (d, J=8.9 Hz, 2H, H-m); 6.60 (d,
J=8.9 Hz, 2H, H-o); 6.05 (dd, J=5.7, 2.0 Hz, 1H, H-3); 5.15 (ddd, J=3.4, 1.7, 1.6 Hz, 1H, H-5); 3.70 (s,
13
3H, OCH3); 3.70-3.60 (m, 1H, H-6); 3.5 (br s, 1H, NH); 1.20 (d, J=6.6 Hz, 3H, CH3). C-NMR (100
MHz, CDCl3) δ (erythro/threo mixture: 14/86): 173.0 (CO); 154.5 (C-4); 152.2, 140.3 (C-q); 122.6 (C-3);
116.5, 115.0 (C-m and C-o); 85.5 (C-5); 55.8 (OCH3); 51.0 (C-6); 17.3 (CH3).
5-[1-(Phenylamino)propyl]furan-2(5H)-one (5).
The general one-pot three-component procedure was applied to t-butyldimethylsilyloxyfuran (159 mg,
0.80 mmol), propionaldehyde (0.12 mL, 1.60 mol) and aniline (0.16 mL, 1.60 mmol) to give 5 (156 mg,
90%) as a 90/10 erythro/threo mixture. Separation of diastereoisomers by flash chromatography
(AcOEt/cyclohexane 20/80) furnished pure erythro 5a and threo-enriched 5b.
5a (erythro): mp: 57-60°C (pale yellow solid, AcOEt/cyclohexane); Rf: 0.53 (AcOEt/cyclohexane 30/70).
1H-NMR (400 MHz, CDCl3) δ: 7.48 (dd, J=4.4, 1.3 Hz, 1H, H-4); 7.20 (t app., J=7.4 Hz, 2H, H-m); 6.75
(t app., J=7.6 Hz, 1H, H-p); 6.60 (d app., J=7.8 Hz, 2H, H-o); 6.15 (dd, J=5.7, 2.0 Hz, 1H, H-3); 5.03 (d
app., J=6.0 Hz, 1H, H-5); 3.61 (br s, 1H, NH); 3.51-3.57 (m, 1H, H-6); 1.83 (qdd, J=14.8, 7.5, 3.5 Hz, 1H,

HETEROCYCLES, Vol. 65, No. 4, 2005
831
H-7); 1.60-1.45 (m, 1H, H-7’); 1.02 (t, J=7.4 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl ) δ: 173.0 (CO);
3
155.1 (C-4); 147.1 (C-q); 129.6 (C-m); 122.2 (C-p); 118.3 (C-3); 113.6 (C-o); 85.5 (C-5); 57.4 (C-6);
25.0 (C-7); 10.5 (CH3). ESMS m/z 257 (M+H+K)+, 256 (M+K)+, 241 (M+H+Na)+, 240 ((M+Na)+, base
peak), 218 (M+H)+. IR ν (cm-1) (KBr) 3388, 2966, 2931, 2874, 1737, 1601, 1498, 1458. HR-ESMS Calcd
for C13H15NO2Na (M+Na)+ m/z 240.1000, found 240.1000.
5b (threo-enriched): pale yellow oil; Rf: 0.46 (AcOEt/cyclohexane 30/70). 1H-NMR (400 MHz, CDCl )
3
δ (erythro/threo mixture: 83/17): 7.50 (dd, J=4.4, 1.3 Hz, 1H, H-4); 7.20 (t app., J=7.4 Hz, 2H, H-m);
6.75 (t app., J=7.6 Hz, 1H, H-p); 6.60 (d app., J=7.8 Hz, 2H, H-o); 6.05 (dd, J=5.7, 2.0 Hz, 1H, H-3);
5.25-5.20 (m, 1H, H-5); 3.80-3.70 (m, 1H, H-6); 3.60 (br s, 1H, NH); 1.85-1.75 (m, 1H, H-7); 1.05 (t,
13
J=7.6 Hz, 3H, CH3). C-NMR (100 MHz, CDCl3) δ (erythro/threo mixture: 83/17): 173.0 (CO); 154.4
(C-4); 146.7 (C-q); 129.6 (C-m); 122.5 (C-p); 118.1 (C-3); 113.1 (C-o); 84.5 (C-5); 57.7 (C-6); 25.7
(C-7); 11.0 (CH3).
5-[1-(Phenylamino)heptyl]furan-2(5H)-one (6).
The general one-pot three-component procedure was applied to t-butyldimethylsilyloxyfuran (63 mg, 0.32
mmol), heptaldehyde (68 µL, 0.48 mmol) and aniline (46 µL, 0.48 mmol) to give 6 (86 mg, 99%) as a
92/8 erythro/threo mixture and as a glassy solid after purification by flash-chromatography
1
(AcOEt/heptane 30/70); Rf erythro/threo mixture: 0.65 (AcOEt/heptane 50/50). H-NMR (250 MHz,
CDCl3) δ erythro, [threo]: 7.60-7.40 (m, 1H, H-4 and [H-4]); 7.20-6.50 (m, 5H, H-Ph and [H-Ph]); 6.15
(dd, J=6.0, 1.8 Hz, 0.92H, H-3); [6.05 (dd, J=5.6, 1.4 Hz, 0.08H, H-3)]; [5.20 (ddd, J=3.8, 1.6, 1.6 Hz,
0.08H, H-5)]; 5.05 (ddd, J=5.6, 1.8, 1.8 Hz, 0.92H, H-5); [3.85 (m, 0.08H, H-6)]; 3.60 (m, 0.92H, H-6);
13
1.85-1.20 (m, 10H, H-7 to H-11 and [H-7 to H-11]); 0.90 (2t, J=7.0 Hz, 3H, CH3). C-NMR (50 MHz,
CDCl3) δ erythro, [threo]: 172.8, [172.8] (CO); 154.9, [154.3] (C-4); [147.0], 146.8 (C-q); 129.4, [129.4]
(C-m); [122.2], 121.9 (C-3); 118.1, [117.8] (C-p); 113.3, [112.8] (C-o); 85.5, [84.5] (C-5); 55.7, [53.9]
(C-6); 32.2, 32.1, 31.7, 31.5, 29.1, 29.0, 26.2, 25.7, 22.4 (C-7 to C-11); 13.9, [13.9] (CH3). EIMS
(isobutane 180°C) m/z 273 (M+), 190 ((M-furanone)+, base peak).
Hydrogenation of furan-2(5H)-one derivatives:
A solution of pure furan-2(5H)-one derivative (1 equiv.) in AcOEt (10 mL) was hydrogenated for 4 h at
atmospheric pressure in the presence of 10 wt. % palladium on charcoal (Acros, 10% Pd on activated
carbon). The catalyst was removed by filtration through celite, the filter pad was washed with AcOEt (30
mL) then with MeOH (30 mL). The combined filtrate and washings were evaporated under reduced

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pressure to afford the expected product which was used without further purification for the following step
starting from pure erythro or threo-enriched derivatives or purified (and separated) by chromatography on
silica gel starting from crude erythro/threo mixtures.
5-[(Phenylamino)phenylmethyl]dihydrofuran-2(3H)-one (7).
The hydrogenation procedure was applied to a crude 83/17 diastereoisomeric mixture of 1 (1.10 g) to give
7 (427 mg, 70% from 2-t-butyldimethylsilyloxyfuran) as a 82/18 erythro/threo mixture. Separation of
diastereoisomers by flash chromatography (AcOEt/cyclohexane 30/70) furnished pure erythro 7a and
threo-enriched 7b.
7a (erythro): mp: 152-154°C (white solid, AcOEt/cyclohexane); Rf: 0.32 (AcOEt/cyclohexane 30/70).
1H-NMR (400 MHz, CDCl3) δ: 7.39-7.31 (m, 5H, H-Ph); 7.10 (t app., J=7.5 Hz, 2H, H-m Ar); 6.68 (t
app., J=7.3 Hz, 1H, H-p Ar); 6.56 (d app., J=7.7 Hz, 2H, H-o Ar); 5.00 (dddd, J=9.7, 6.1, 3.5, 1.3 Hz, 1H,
H-5); 4.63 (d, J=7.5 Hz, 1H, NH); 4.54 (dd, J=7.5, 3.1 Hz, 1H, H-6); 2.34-2.21 (m, 2H, H-4); 2.12-2.05
(m, 1H, H-3); 1.82-1.73 (m, 1H, H-3’). 13C-NMR (100 MHz, CDCl3) δ: 177.0 (CO); 146.4, 137.1 (C-q);
129.3, 129.0, 128.3, 128.2 (C-Ph and C-m Ar); 118.3, 114.0 (C-Ar); 82.1 (C-5); 60.6 (C-6); 27.8 (C-3);
23.8 (C-4). ESMS m/z 307 (M+H+K)+, 306 (M+K)+, 291 (M+H+Na)+, 290 (M+Na)+, 268 ((M+H)+, base
peak). IR ν (cm-1) (KBr) 3362, 3026, 2989, 2916, 1774, 1602, 1498, 1454. HR-ESMS Calcd for
C17H18NO2 (M+H)+ m/z 268.1338, found 268.1332.
1
7b (threo-enriched): pale yellow solid; Rf: 0.37 (AcOEt/cyclohexane 30/70). H-NMR (400 MHz,
CDCl3) δ (erythro/threo mixture: 45/55): 7.45-7.31 (m, 5H, H-Ph); 7.20 (t app., J=7.5 Hz, 2H, H-m Ar);
6.80 (t app., J=7.4 Hz, 1H, H-p Ar); 6.75-6.65 (m, 2H, H-o Ar); 4.75-4.65 (m, 2H, H-5 and NH); 4.44 (d,
J=5.5 Hz, 1H, H-6); 2.51-2.47 (m, 2H, H-3); 2.35-2.15 (m, 1H, H-4); 2.15-2.00 (m, 1H, H-4’). 13C-NMR
(100 MHz, CDCl3) δ (erythro/threo mixture 45/55): 177.2 (CO); 147.1, 139.2 (C-q); 129.3, 129.1, 128.2,
127.4 (C-Ph and C-m Ar); 118.6, 114.3 (C-Ar); 83.2 (C-5); 61.7 (C-6); 28.7 (C-3); 25.1 (C-4).
5-[[(4-Methoxyphenyl)amino]phenylmethyl]dihydrofuran-2(3H)-one (8).
The hydrogenation procedure was applied to a crude 79/21 diastereoisomeric mixture of 2 (1.72 g, 5.80
mmol) to give 8 (902 mg, 90% from 2-t-butyldimethylsilyloxyfuran) as a 71/29 erythro/threo mixture.
Separation of diastereoisomers by flash chromatography (AcOEt/cyclohexane 30/70) furnished pure
erythro 8a and threo-enriched 8b.
8a (erythro): mp: 148-150°C (pale brown solid, AcOEt/cyclohexane); Rf: 0.54 (AcOEt/cyclohexane
1
50/50). H-NMR (400 MHz, CDCl3) δ: 7.36-7.25 (m, 5H, H-Ph); 6.75 (dd, J=6.5, 2.3 Hz, 2H, H-m Ar);
6.53 (dd, J=6.7, 2.3 Hz, 2H, H-o Ar); 4.97 (ddd, J=9.9, 6.2, 3.4 Hz, 1H, H-5); 4.49 (d, J=3.1 Hz, 1H,

HETEROCYCLES, Vol. 65, No. 4, 2005
833
H-6); 3.69 (s, 3H, OCH3); 2.34-2.18 (m, 2H, H-3); 2.14-2.05 (m, 1H, H-4); 1.90-1.80 (m, 1H, H-4’).
13C-NMR (100 MHz, CDCl3) δ: 177.0 (CO); 152.9, 147.9, 137.3 (C-q); 128.9, 128.2 (C-Ph); 116.6, 114.9
(C-Ar); 82.2 (C-5); 61.5 (C-6); 55.8 (OCH3); 27.8 (C-3); 23.8 (C-4). ESMS m/z 321 (M+H+Na)+, 320
(M+Na)+, base peak). IR ν (cm-1) (KBr) 3384, 3222, 3004, 2915, 2835, 1775, 1654, 1635, 1514, 1495,
1451. HR-ESMS Calcd for C18H19NO3Na (M+Na)+ m/z 320.1263, found 320.1270.
1
8b (threo-enriched): brown solid; Rf: 0.60 (AcOEt/cyclohexane 50/50). H-NMR (400 MHz, CDCl3)
δ (erythro/threo mixture: 30/70): 7.40-7.20 (m, 5H, H-Ph); 6.70 (dd, J=6.6, 2.1 Hz, 2H, H-m Ar);
6.55-6.51 (m, 2H, H-o Ar); 4.78-4.66 (m, 1H, H-5); 4.34 (d, J=6.1 Hz, 1H, H-6); 3.76 (s, 3H, OCH3);
13
2.53-2.39 (m, 2H, H-3); 2.27-2.19 (m, 1H, H-4); 2.01-1.92 (m, 1H, H-4’). C-NMR (100 MHz, CDCl3)
δ (erythro/threo mixture: 30/70): 177.0 (CO); 152.9, 140.1, 137.3 (C-q); 129.0, 128.3, 127.5 (C-Ph);
116.6, 114.9 (C-Ar); 83.2 (C-5); 62.9 (C-6); 55.8 (OCH3); 28.7 (C-3); 25.1 (C-4).
5-[1-(Phenylamino)ethyl]dihydrofuran-2(3H)-one (9).
The hydrogenation procedure was applied to a crude 83/17 diastereoisomeric mixture of 3 (521 mg) to
give 9 (178 mg, 65% from 2-t-butyldimethylsilyloxyfuran) as a 90/10 erythro/threo mixture. Separation
of distereoisomers by flash chromatography (AcOEt/cyclohexane 30/70) furnished pure erythro 9a and
threo-enriched 9b.
1
9a (erythro): pale yellow oil, Rf: 0.26 (AcOEt/cyclohexane 30/70). H-NMR (400 MHz, CDCl3) δ: 7.19
(dd, J=8.2, 7.5 Hz, 2H, H-m); 6.74 (t, J=7.3 Hz, 1H, H-p); 6.64 (d app., J=7.7 Hz, 2H, H-o); 4.58 (td app.,
J=7.4, 4.1 Hz, 1H, H-5); 3.77-3.66 (m, 2H, H-6 and NH); 2.60-2.53 (m, 2H, H-3); 2.39-2.27 (m, 1H,
H-4); 2.11-2.02 (m, 1H, H-4’); 1.23 (d, J=6.5 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl ) δ: 177.1 (CO);
3
146.8 (C-q); 129.5 (C-m); 118.2 (C-p); 113.8 (C-o); 82.8 (C-5); 51.9 (C-6); 28.5 (C-3); 24.2 (C-4); 15.5
(CH3). ESMS m/z 228 (M+Na)+, 206 ((M+H)+, base peak). IR ν (cm-1) (neat) 3366, 3051, 3021, 2975,
2934, 2875, 1789, 1600, 1514, 1504, 1455. HR-ESMS Calcd for C12H15NO2Na (M+Na)+ m/z 228.1000,
found 228.0990.
1
9b (threo-enriched): pale yellow oil; Rf: 0.33 (AcOEt/cyclohexane 30/70). H-NMR (400 MHz,
CDCl3) δ (erythro/threo mixture: 66/34): 7.19 (t app., J=7.6 Hz, 2H, H-m); 6.74 (t, J=7.3 Hz, 1H, H-p);
6.64 (dd, J=7.7, 2.4 Hz, 2H, H-o); 4.64-4.58 (m, 1H, H-5); 3.80-3.53 (m, 2H, H-6 and NH); 2.60-2.52 (m,
2H, H-3); 2.26-2.21 (m, 2H, H-4); 1.31 (d, J=6.6 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3)
δ (erythro/threo mixture: 66/34): 177.4 (CO); 147.2 (C-q); 129.6 (C-m); 118.3 (C-p); 113.6 (C-o); 83.3
(C-5); 51.2 (C-6); 28.8 (C-3); 24.2 (C-4); 18.0 (CH3).
5-[1-[4-Methoxyphenyl)amino]ethyl]dihydrofuran-2(3H)-one (10).
The hydrogenation procedure was applied to a crude 80/20 diastereoisomeric mixture of 4 (1.58 g) to give

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10 (365 mg, 75% from 2-t-butyldimethylsilyloxyfuran) as a 80/20 erythro/threo mixture. Separation of
diastereoisomers by flash chromatography (AcOEt/cyclohexane 50/50) furnished pure erythro 10a and
threo-enriched 10b. Pure 10a (117 mg, 70%) was also obtained from pure 4a (167 mg, 0.72 mmol).
10a (erythro): pale yellow oil; Rf: 0.49 (AcOEt/cyclohexane 50/50). 1H-NMR (400 MHz, CDCl ) δ: 6.75
3
(dd, J=8.9, 2.1 Hz, 2H, H-m); 6.60 (dd, J=8.9, 2.1 Hz, 2H, H-o); 4.55 (td app., J=7.4, 4.2 Hz, 1H, H-5);
3.75 (s, 3H, OCH3); 3.55 (qd, J=6.7, 4.2 Hz, 1H, H-6); 3.25 (br s, 1H, NH); 2.60-2.45 (m, 2H, H-3);
2.35-2.25 (m, 1H, H-4); 2.10-2.00 (m, 1H, H-4’); 1.20 (d, J=6.7 Hz, 3H, CH3). 13C-NMR (100 MHz,
CDCl3) δ: 176.9 (CO); 152.5, 140.7 (C-q); 115.5, 114.8 (C-m and C-o); 87.5 (C-5); 55.6 (C-6); 53.0
(OCH3); 28.3 (C-3); 23.9 (C-4); 15.3 (CH3). ESMS m/z 275 (M+H+K)+, 275 (M+K)+, 259 (M+H+Na)+,
258 ((M+Na)+, base peak), 174 (M-furanone+Na)+. IR ν (cm-1) (neat) 3520, 3272, 3033, 2935, 2833,
1789, 1620, 1504, 1454. Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28, N, 5.95. Found: C,66.43; H, 7.81;
N, 5.78.
10b (threo-enriched): pale yellow oil; Rf: 0.47 (AcOEt/cyclohexane 50/50). 1H-NMR (400 MHz, CDCl )
3
δ (erythro/threo mixture: 21/79): 6.79 (dd, J=8.9, 2.1 Hz, 2H, H-m); 6.67-6.60 (m, 2H, H-o); 4.59 (td app.,
J=7.5, 2.8 Hz, 1H, H-5); 3.76 (s, 3H, OCH3); 3.55 (qd, J=6.6, 2.8 Hz, 1H, H-6); 3.25 (br s, 1H, NH);
13
2.62-2.48 (m, 2H, H-3); 2.30-2.20 (m, 2H, H-4); 1.27 (d, J=6.6 Hz, 3H, CH3). C-NMR (100 MHz,
CDCl3) δ (erythro/threo mixture: 21/79): 177.5 (CO); 152.7, 141.1 (C-q); 115.8, 115.1 (C-m and C-o);
83.4 (C-5); 55.9 (C-6); 52.6 (OCH3); 28.9 (C-3); 24.3 (C-4); 17.8 (CH3).
5-[1-(Phenylamino)propyl]dihydrofuran-2(3H)-one (11).
The hydrogenation procedure was applied to a crude 90/10 diastereoisomeric mixture of 5 (1.34 g) to give
11 (368 mg, 55% from 2-t-butyldimethylsilyloxyfuran) as a 90/10 erythro/threo mixture. Separation of
diastereoisomers by flash chromatography (AcOEt/cyclohexane 20/80) furnished pure erythro 11a and
threo-enriched 11b.
11a (erythro): mp: 87-89°C (white solid, AcOEt/cyclohexane); Rf: 0.28 (AcOEt/cyclohexane 30/70).
1H-NMR (400 MHz, CDCl3) δ: 7.17 (t app., J=7.5 Hz, 2H, H-m); 6.73 (t, J=7.3 Hz, 1H, H-p); 6.71 (dd,
J=7.7, 0.8 Hz, 2H, H-o); 4.54 (td app., J=7.2, 5.2 Hz, 1H, H-5); 3.55-3.45 (m, 1H, H-6); 3.40 (br s, 1H,
NH); 2.60-2.50 (m, 2H, H-3); 2.35-2.25 (m, 1H, H-4); 2.15-2.05 (m, 1H, H-4’); 1.79 (qdd, J=14.8, 7.7,
3.6 Hz, 1H, H-7); 1.53-1.41 (m, 1H, H-7’); 1.01 (t, J=7.4 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl ) δ:
3
177.0 (CO); 147.9 (C-q); 129.5 (C-m); 118.1 (C-p); 113.6 (C-o); 82.3 (C-5); 58.1 (C-6); 28.6 (C-3); 24.5
(C-7); 24.2 (C-4); 10.6 (CH3). ESMS m/z 258 (M+K)+, 243 (M+H+Na)+, 242 (M+Na)+, base peak), 220
(M+H)+. IR ν (cm-1) (KBr) 3360, 3057, 3021, 2967, 2935, 2877, 1759, 1601, 1518, 1495, 1458.
HR-ESMS Calcd for C13H17NO2Na (M+Na)+ m/z 242.1157, found 242.1158.

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835
11b (threo-enriched): pale yellow glassy solid; Rf: 0.37(AcOEt/cyclohexane 30/70). 1H-NMR (400 MHz,
CDCl3) δ (erythro/threo mixture: 48/52): 7.20-7.12 (m, 2H, H-m); 6.75-6.70 (m, 1H, H-p); 6.67-6.61 (m,
2H, H-o); 4.72 (td app., J=7.5, 1.1 Hz, 1H, H-5); 3.50-3.45 (m, 1H, H-6); 3.25 (br s, 1H, NH); 2.61-2.51
(m, 2H, H-3); 2.55-2.15 (m, 2H, H-4); 1.80-1.60 (m, 1H, H-7); 1.60-1.40 (m, 1H, H-7’); 0.98 (t, J=7.4 Hz,
3H, CH3). 13C-NMR (100 MHz, CDCl ) δ (erythro/threo mixture: 48/52): 177.7 (CO); 147.9 (C-q); 129.6
3
(C-m); 117.8 (C-p); 113.1 (C-o); 81.8 (C-5); 57.1 (C-6); 28.9 (C-3); 26.2 (C-7); 24.1 (C-4); 11.0 (CH3).
5-Hydroxy-1-arylpiperidin-2-one derivatives formation by base-promoted cyclization of various
dihydrofuran-2(3H)-ones:
A solution of KHMDS (0.5M in toluene, 1.3 equiv.) was slowly added over a 0.07M cooled (-20°C)
solution of the dihydrofuran-2(3H)-one (1 equiv.) in dry THF. The mixture was stirred for 30 min at this
temperature and quenched with a saturated solution of ammonium chloride (10 mL). The mixture was
extracted with CH2Cl2 (3x15 mL), the collected organic fractions were dried over Na2SO4, and the solvent
was removed in vacuo yielding 5-hydroxy-1-arylpiperidin-2-one derivative after flash chromatography.
trans-5-Hydroxy-1,6-diphenylpiperidin-2-one (12a).
The general base-promoted cyclization procedure was applied to 7a (100 mg, 0.37 mmol) to give 12a (62
mg, 62%) as a trans diastereoisomer and as a white solid (mp: 160-162°C, AcOEt) after purification by
1
flash chromatography (AcOEt/cyclohexane 70/30); Rf: 0.12 (AcOEt/cyclohexane 70/30). H-NMR (400
MHz, CDCl3) δ: 7.38-7.12 (m, 10H, H-Ph and H-Ar); 4.90 (d, J=2.9 Hz, 1H, H-6); 4.10 (td, J=4.8, 2.9 Hz,
1H, H-5); 2.86 (ddd, J=18.2, 10.0, 2.3 Hz, 1H, H-3); 2.64 (ddd, J=18.4, 7.4, 3.2 Hz, 1H, H-3’); 2.05-1.95
(m, 1H, H-4), 1.85-1.75 (m, 1H, H-4’). 13C-NMR (100 MHz, CDCl3) δ: 171.0 (CO); 142.6, 139.1 (C-q);
129.1, 128.8, 127.8, 127.5, 127.1 (C-Ph and C-Ar); 72.1 (C-6); 69.7 (C-5); 27.7 (C-3); 23.4 (C-4). ESMS
m/z 332 (M+H+K)+, 331 (M+K)+, 291 (M+H+Na)+, 290 ((M+Na)+, base peak), 268 (M+H)+. IR ν (cm-1)
(KBr) 3345, 3059, 2952, 1636, 1591, 1493, 1457, 1441, 1421. HR-ESMS Calcd for C17H18NO2 (M+H)+
m/z 268.1338, found 268.1350.
trans-5-Hydroxy-1-(4-methoxyphenyl)-6-phenylpiperidin-2-one (13a).
The general base-promoted cyclization procedure was applied to 8a (201 mg, 0.68 mmol) to give 13a (66
mg, 35%) as a trans diastereoisomer and as a pale yellow solid (mp: 172-174°C, AcOEt) after
1
purification by flash chromatography (AcOEt 100); Rf: 0.15 (AcOEt 100). H-NMR (400 MHz, CDCl3)
δ: 7.36-7.26 (m, 5H, H-Ph); 7.05 (dd, J=8.8, 1.8 Hz, 2H, H-m Ar); 6.77 (dd, J=8.8, 1.9 Hz, 2H, H-o Ar);
4.83 (d, J=2.4 Hz, 1H, H-6); 4.20-4.10 (m, 1H, H-5); 3.73 (s, 3H, OCH3); 2.85 (ddd, J=18.2, 9.7, 7.3 Hz,

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1H, H-3); 2.69 (ddd, J=18.3, 7.3, 4.2 Hz, 1H, H-3’); 2.02-1.95 (m, 1H, H-4); 1.81-1.76 (m, 1H, H-4’).
13C-NMR (100 MHz, CDCl3) δ: 171.3 (CO); 158.2, 139.2, 135.4 (C-q); 128.8, 128.6, 127.9, 127.1 (C-Ph
and C-m Ar); 114.3 (C-o Ar); 72.4 (C-6); 69.6 (C-5); 55.4 (OCH3); 27.6 (C-3); 23.3 (C-4). ESMS m/z
337 (M+H+K)+, 336 (M+K)+, 321 (M+H+Na)+, 320 ((M+Na)+, base peak). IR ν (cm-1) (KBr) 3413, 3010,
2961, 2914, 2838, 1631, 1604, 1510, 1458, 1439, 1406, 1348. HR-ESMS Calcd for C18H19NO3Na
(M+Na)+ m/z 320.1263, found 320.1259.
trans-5-Hydroxy-6-methyl-1-phenyllpiperidin-2-one (14a).
The general base-promoted cyclization procedure was applied to 9a (78 mg, 0.38 mmol) to give 14a (42
mg, 54%) as a trans diastereoisomer and as a colorless oil after purification by flash chromatography
1
(AcOEt/MeOH 95/5); Rf: 0.34 (AcOEt/MeOH 95/5). H-NMR (400 MHz, CDCl3) δ: 7.37 (t app., J=7.4
Hz, 2H, H-m); 7.27 (t app., J=7.4 Hz, 1H, H-p); 7.16 (d app., J=7.2 Hz, 2H, H-o); 3.80 (dt, J=5.0, 2.6 Hz,
1H, H-5); 3.72 (qdd, J=6.6, 3.1 (2.6 Hz after homodec. at 1.05 ppm), 0.7 Hz, 1H, H-6); 2.70 (ddd, J=18.0,
10.4, 7.2 Hz, 1H, H-3ax); 2.44 (ddd, J=18.2, 6.8, 3.6 Hz, 1H, H-3eq); 2.03 (dddd, J=16.6, 9.7, 6.9, 2.4 Hz,
13
1H, H-4ax), 1.91-1.83 (m, 1H, H-4eq), 1.05 (d, J=6.7 Hz, 3H, CH3). C-NMR (100 MHz, CDCl3) δ:
170.3 (CO); 141.8 (C-q); 129.3 (C-m); 128.2 (C-o); 127.4 (C-p); 68.0 (C-5); 62.9 (C-6); 27.6 (C-3); 24.3
(C-4); 18.9 (CH3). ESMS m/z 244 (M+K)+, 228 ((M+Na)+, base peak), 206 (M+H)+, 198 (M+H-H2O)+.
IR ν (cm-1) (neat) 3379, 3098, 2940, 2973, 2926, 1633, 1591, 1495, 1470, 1443, 1409. HR-ESMS Calcd
for C12H16NO2 (M+H)+ m/z 206.1181, found 206.1137.
trans-5-Hydroxy-1-(4-methoxyphenyl)-6-methylpiperidin-2-one (15a).
The general base-promoted cyclization procedure was applied to 10a (77 mg, 0.33 mmol) to give 15a (42
mg, 55%) as a trans diastereoisomer and as a pale yellow oil after purification by flash chromatography
1
(AcOEt/MeOH 90/10); Rf: 0.41 (AcOEt/MeOH 90/10). H-NMR (400 MHz, CDCl3) δ: 7.10 (dd, J=8.8,
2.1 Hz, 2H, H-m); 6.90 (dd, J=8.8, 2.1 Hz, 2H, H-o); 3.90 (dt app., J=5.6, 3.0 Hz, 1H, H-5); 3.80 (s, 3H,
OCH3); 3.70 (qdd, J=6.6, 3.4 (2.7 Hz after homodec. at 1.15 ppm), 0.7 Hz, 1H, H-6); 2.70 (ddd, J=17.8,
10.1, 7.1 Hz, 1H, H-3ax); 2.50 (ddd, J=18.1, 6.9, 4.2 Hz, 1H, H-3eq); 2.15 (dddd, J=16.7, 9.8, 6.9, 2.5 Hz,
13
1H, H-4ax), 2.00-1.90 (m, 1H, H-4eq), 1.15 (d, J=6.6 Hz, 3H, CH3). C-NMR (100 MHz, CDCl3) δ:
170.3 (CO); 158.5, 134.5 (C-q); 129.2 (C-m); 114.5 (C-o); 68.4 (C-5); 63.4 (C-6); 55.5 (OCH3); 27.6
(C-3); 24.6 (C-4); 19.0 (CH3). ESMS m/z 274 (M+K)+, 259 (M+H+Na)+, 258 ((M+Na)+, base peak). IR ν
(cm-1) (neat) 3380, 3075, 2940, 2837, 1600, 1530, 1455. HR-ESMS calcd for C13H18NO3 (M+H)+ m/z
236.1287, found 236.1281.
cis-5-Hydroxy-1-(4-methoxyphenyl)-6-methylpiperidin-2-one (15b).

HETEROCYCLES, Vol. 65, No. 4, 2005
837
The general base-promoted cyclization procedure was applied to 10b (66 mg, 0.28 mmol) to give 15b (30
mg, 45%) as a cis diastereoisomer and as a pale yellow oil after purification by flash chromatography
(AcOEt/MeOH 100/0 to 90/10); Rf: 0.41 (AcOEt/MeOH 50/50). 1H-NMR (400 MHz, CDCl ) δ: 7.10 (dd,
3
J=8.9, 2.3 Hz, 2H, H-m); 6.90 (dd, J=8.9, 2.2 Hz, 2H, H-o); 4.20 (td app., J=8.4, 4.3 Hz, 1H, H-5); 3.85
(qd, J=6.7, 4.3 Hz, 1H, H-6); 3.80 (s, 3H, OCH3); 2.70 (td app., J=18.1, 6.6 Hz, 1H, H-3); 2.50 (td app.,
13
J=18.1, 7.4 Hz, 1H, H-3’); 2.20-1.90 (m, 2H, H-4), 1.10 (d, J=6.6 Hz, 3H, CH3). C-NMR (100 MHz,
CDCl3) δ: 170.2 (CO); 158.5, 134.0 (C-q); 129.0 (C-m); 114.5 (C-o); 67.3 (C-5); 59.9 (C-6); 55.5
(OCH3); 28.9 (C-3); 25.7 (C-4); 14.9 (CH3). ESMS m/z 258 (M+Na)+, 236 ((M+H)+, base peak), 218
(M+H-H2O)+. IR ν (cm-1) (neat) 3331, 3045, 2970, 1623, 1600, 1522, 1458, 1408. HR-ESMS calcd for
C13H17NO3Na (M+Na)+ m/z 258.1106, found 258.1099.
trans-6-Ethyl-5-hydroxy-1-phenylpiperidin-2-one (16a).
The general base-promoted cyclization procedure was applied to 11a (150 mg, 0.68 mmol) to give 16a
(47 mg, 32%) as a trans diastereoisomer and as a colorless oil after purification by flash chromatography
1
(AcOEt/MeOH 95/5); Rf: 0.37 (AcOEt/MeOH 95/5). H-NMR (400 MHz, CDCl3) δ: 7.41-7.14 (m, 5H,
H-Ph); 4.10 (td app., J=4.5, 2.4 Hz, 1H, H-5); 3.63-3.61 (m, 1H, H-6); 2.68 (ddd, J=18.0, 10.3, 7.5 Hz,
1H, H-3ax); 2.48 (ddd, J=18.2, 7.2, 3.4 Hz, 1H, H-3eq); 2.11-2.03 (m, 1H, H-4); 1.94-1.89 (m, 1H, H-4');
13
1.78-1.63 (m, 1H, H-7); 1.46-1.32 (m, 1H, H-7'), 0.79 (t, J=7.5 Hz, 3H, CH3). C-NMR (100 MHz,
CDCl3) δ: 170.1 (CO); 142.1 (C-q); 129.2, 128.1 (C-m and C-o); 127.2 (C-p); 68.7 (C-6); 65.0 (C-5); 27.4
(C-3); 25.3 (C-7); 24.6 (C-4); 10.3 (CH3). ESMS m/z 259 (M+H+K)+, 258 (M+K)+, 243 (M+H+Na)+, 242
((M+Na)+, base peak). IR ν (cm-1) (neat) 3382, 3063, 2964, 2937, 2878, 1632, 1592, 1495, 1461, 1411,
1355. HR-ESMS calcd for C13H18NO2 (M+H)+ m/z 220.1338, found 220.1333.
General procedure for the Yb(OTf)3-catalyzed Mannich-type reaction of silyloxyfuran with imines
derived from aniline:
10% mol of Yb(OTf)3 was added to a solution of imine (1.5 to 2 equiv.) in CH2Cl2 (2 mL) at -78°C,
followed by the dropwise addition of silyloxyfuran (1 equiv.). When the complete consumption of the
starting materials was observed (about 15 min), the reaction mixture was warmed to rt and washed with
water. The layers were separated. The aqueous solution was extracted with CH2Cl2 (2x15 mL). The
collected organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The
1
crude reaction mixtures were examinated by H NMR spectrum in order to determine the
diastereoisomeric ratios. Products were isolated by preparative layer chromatography using
AcOEt-heptane as solvent.

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HETEROCYCLES, Vol. 65, No. 4, 2005
5-[(Phenylamino)phenylmethyl]furan-2(5H)-one (1).
The general Yb(OTf)3-catalyzed condensation of preformed imines procedure was applied to
t-butyldimethylsilyloxyfuran (63 mg, 0.32 mmol) and N-benzylideneaniline (89 mg, 0.48 mmol) to give 1
(85 mg, 99%) as a 72/28 erythro/threo mixture and as a glassy solid after purification by preparative layer
chromatography (AcOEt/heptane 50/50); Rf erythro/threo mixture: 0.25 (AcOEt/heptane 30/70).
5-[[(4-Methoxyphenyl)amino]phenylmethyl]furan-2(5H)-one (2).
The general Yb(OTf)3-catalyzed condensation of preformed imines procedure was applied to
t-butyldimethylsilyloxyfuran (63 mg, 0.32 mmol) and N-benzylidene-p-anisidine (96 mg, 0.49 mmol) to
give 2 (91 mg, 95%) as a 79/21 erythro/threo mixture and as a glassy solid after purification by
preparative layer chromatography AcOEt/heptane (50/50); Rf erythro/threo mixture: 0.50
1
(AcOEt/heptane 50/50). H-NMR (300 MHz, CDCl3) δ erythro, [threo]: 7.35-7.25 (m, 5H+0.79H, H-4,
H-Ph and [H-Ph]); [7.20 (dd, J=6.0, 2.0 Hz, 0.21H, H-4)]; 6.60 (2d, J=9.0 Hz, 2H, H-m Ar and [H-m
Ar]); 6.45 (2d, J=9.0 Hz, 2H, H-o Ar and [H-o Ar]); [6.05 (H-3, 0.21H, dd, J=6.0, 2.0 Hz)]; 5.95 (H-3,
0.79H, dd, J=6.0, 2.0 Hz); 5.55 (ddd, J=3.8, 1.6, 1.6 Hz, 0.79H, H-5); [5.15 (ddd, J=7.0, 1.6, 1.6 Hz,
0.21H, H-5)]; 4.70 (d, J=4.0 Hz, 0.79H, H-6); [4.35 (d, J=7.0 Hz, 0.21H, H-6)]; 3.60 (2s, 3H, OCH3 and
13
[OCH3]). C-NMR (75 MHz, CDCl3) δ erythro, [threo]: 172.4, [172.4] (CO); 154.0, [153.4] (C-4);
152.9, [152.9], 140.5, [140.1] (C-q Ar); [138.5], 137.1 (C-q Ph); 129.1, 128.9, 128.5, 128.3, 127.3, 127.2
(C-Ph and [C-Ph]); 123.0, [122.6] (C-3); [115.8], 115.6 (C-m Ar); [114.7], 114.7 (C-o Ar); [85.9], 85.4
(C-5); 62.2, [60.4] (C-6); 60.4 (OCH3 and [OCH3]). ESMS m/z 318 (M+Na)+, 296 ((M+H)+, base peak).
IR ν (cm-1) (KBr) 3368, 1755.
5-[[(2-Methoxyphenyl)amino]phenylmethyl]furan-2(5H)-one (17).
The general Yb(OTf)3-catalyzed condensation of preformed imines procedure was applied to
t-butyldimethylsilyloxyfuran (63 mg, 0.32 mmol) and N-benzylidene-o-anisidine (96 mg, 0.49 mmol) to
give 17 (88 mg, 92%) as a 73/27 erythro/threo mixture and as a glassy solid after purification by
preparative layer chromatography (AcOEt/heptane 50/50); Rf erythro/threo mixture: 0.40
1
(AcOEt/heptane 50/50). H-NMR (300 MHz, CDCl3) δ erythro, [threo]: 7.50-7.20 (m, 6H, H-4, H-Ph,
[H-4] and [H-Ph]); 7.00-6.10 (m, 4H+0.27H, H-Ar, [H-Ar] and [H-3]); 6.05 (dd, J=6.0, 2.0 Hz, 0.73H,
H-3); 5.45 (ddd, J=3.6, 1.8, 1.8 Hz, 0.73H, H-5); [5.20 (ddd, J=6.4, 1.6, 1.6 Hz, 0.27H, H-5)]; 4.80 (d,
J=3.6 Hz, 0.73H, H-6); [4.50 (d, J=6.4 Hz, 0.27H, H-6)]; 3.70 (s, 2.19H, OCH3); [3.60 (s, 0.81H, OCH3)].
13C-NMR (75 MHz, CDCl3) δ erythro, [threo]: 172.3, [172.3] (CO); 160.6, [160.6] (C-q Ar); [153.9],
153.2 (C-4); [147.9], 147.5 (C-q Ar); [138.3], 136.8 (C-q Ph); 130.0, 129.9, 129.1, 128.8, 128.4, 128.3,
127.3 (C-Ph, C-Ar, [C-Ph] and [C-Ar]); 123.1, [122.7] (C-3); [107.1], 106.9, [103.8], 103.6, [100.2],

HETEROCYCLES, Vol. 65, No. 4, 2005
839
100.1 (other C-Ar); [85.7], 85.1 (C-5); [60.9], 59.3 (C-6); 55.0 (OCH3 and [OCH3]). ESMS m/z 318
(M+Na)+, 296 ((M+H)+, base peak). IR ν (cm-1) (KBr) 3377, 1759.
5-[[(2-Hydroxyphenyl)amino]phenylmethyl]furan-2(5H)-one (18). CAS RN threo [258335-89-6].
The general Yb(OTf)3-catalyzed condensation of preformed imines procedure was applied to
t-butyldimethylsilyloxyfuran (52 mg, 0.26 mmol) and o-benzylideneaminophenol (81 mg, 0.42 mmol) to
give 18 (65 mg, 82%) as a 70/30 erythro/threo mixture and as a glassy solid after purification by
preparative layer chromatography (AcOEt/heptane 50/50); Rf erythro/threo mixture: 0.35
(AcOEt/heptane 50/50). 1H-NMR (300 MHz, CD3OD) δ erythro, [threo]: 7.65 (dd, J=5.8, 1.8 Hz, 0.70H,
H-4); [7.55 (dd, J=5.8, 1.8 Hz, 0.30H, H-4)]; 7.50-7.20 (m, 5H, H-Ph and [H-Ph]); 6.70-6.40 (m, 4H,
H-Ar and [H-Ar]); [6.15 (dd, J=5.8, 2.0 Hz, 0.30H, H-3)]; 6.05 (dd, J=5.8, 2.0 Hz, 0.70H, H-3)]; 5.55
(ddd, J=3.6, 1.8, 1.8 Hz, 0.70H, H-5); [5.45 (ddd, J=5.0, 1.8, 1.8 Hz, 0.30H, H-5)]; 4.95 (d, J=3.8 Hz,
13
0.70H, H-6); [4.80 (d, J=5.0 Hz, 0.30H, H-6)]. C-NMR (50 MHz, CD3OD) δ erythro, [threo]: 173.8,
[173.8] (CO); [155.4], 155.0 (C-4); [148.7], 146.2 (C-q NH); [138.8], 137.4 (C-q Ph); [135.6], 135.2 (C-q
OH); 128.6, 128.4, 128.3, 127.7, 127.3, 127.2 (C-Ph and [C-Ph]); 122.0, 121.7 (C-Ar and [C-Ar]); 119.9,
[119.9] (C-3); 118.0, 117.4, 116.3, 113.7, 114.4, 112.5 (other C-Ar); [86.5], 86.1 (C-5); [60.0], 59.3
(C-6).
5-[[(2-Hydroxyphenyl)amino]phenylmethyl]-3-methylfuran-2(5H)-one (19). CAS RN threo
[258335-80-7].
The general Yb(OTf)3-catalyzed condensation of preformed imines procedure was applied to
3-methyl-2-t-butyldimethylsilyloxyfuran (20 mg, 0.09 mmol) and o-benzylideneaminophenol (28 mg,
0.18 mmol) to give 19 (24 mg, 90%) as a 12/88 erythro/threo mixture and as a glassy solid after
purification by preparative layer chromatography (AcOEt/heptane 40/60); Rf erythro/threo mixture: 0.40
1
(AcOEt/heptane 50/50). H-NMR (300 MHz, CD3OD) δ erythro, [threo]: 7.50-7.20 (m, 5H, H-Ph and
[H-Ph]); 7.10-7.00 (m, 1H, H-4 and [H-4]); 6.65-6.40 (m, 4H, H-Ar and [H-Ar]); 5.35 (ddd, J=3.8, 1.8,
1.8 Hz, 0.12H, H-5); [5.25 (ddd, J=5.0, 1.8, 1.8 Hz, 0.88H, H-5)]; 4.75 (d, J=3.8 Hz, 0.12H, H-6); [4.70
(d, J=5.0 Hz, 0.88H, H-6)]; [1.78 (dd, J=1.6, 1.6 Hz, 2.64H, CH3)]; 1.73 (dd, J=1.6, 1.6 Hz, 0.36H, CH3).
13C-NMR (50 MHz, CD3OD) δ threo: 168.2 (CO); 149.0 (C-4); 146.1, 140.7, 137.1, 131.6 (C-q and
C-3); 129.5, 128.8, 128.5 (C-Ph and C-Ar); 121.0 (C-m Ar); 114.7 (C-p Ar); 114.0 (C-o Ar); 85.7 (C-5);
61.5 (C-6); 10.5 (CH3).
5-[(Phenylamino)phenylmethyl]-3-methylfuran-2(5H)-one (20).
The general Yb(OTf)3-catalyzed condensation of preformed imines procedure was applied to

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HETEROCYCLES, Vol. 65, No. 4, 2005
3-methyl-2-t-butyldimethylsilyloxyfuran (20 mg, 0.09 mmol) and N-benzylideneaniline (34 mg, 0.18
mmol) to give 20 (26 mg, 99%) as a 21/79 erythro/threo mixture and as a glassy solid after purification
by preparative layer chromatography (AcOEt/heptane 35/65); Rf erythro/threo mixture: 0.60
1
(AcOEt/heptane 50/50). H-NMR (300 MHz, CD3OD) δ erythro, [threo]: 7.50-7.30 (m, 6H, H-Ph, H-4,
[H-Ph] and [H-4]); 7.10-6.45 (m, 5H, H-Ar and [H-Ar]); [5.35 (ddd, J=3.8, 1.8, 1.8 Hz, 0.79H, H-5)];
5.25 (ddd, J=7.0, 1.8, 1.8 Hz, 0.21H, H-5); [4.75 (d, J=3.8 Hz, 0.79H, H-6)]; 4.35 (d, J=7.0 Hz, 0.21H,
H-6); 1.95 (dd, J=1.6, 1.6 Hz, 0.63H, CH3); [1.90 (dd, J=1.6, 1.6 Hz, 2.37H, CH3)].
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