A convenient approach to δ-amino-β-ketoesters by vinylogous Mannich reaction of masked acetoacetates

Article abstract of DOI:10.1016/j.tet.2007.09.073

SiCl₄ is an efficient and selective catalyst for the vinylogous Mannich reaction of linear and cyclic synthetic equivalents of acetoacetate dianion, leading to δ-amino-β-ketoesters in moderate to high yields and complete γ-selectivity; anti-diastereoselectivity was observed by using a γ-methyl-substituted cyclic silyloxydiene.

Full text of DOI:10.1016/j.tet.2007.09.073

Tetrahedron 63 (2007) 12317–12323
A convenient approach to d-amino-b-ketoesters by vinylogous
Mannich reaction of masked acetoacetates
*
Rosaria Villano, Maria Rosaria Acocella, Antonio Massa, Laura Palombi and Arrigo Scettri
*
Dipartimento di Chimica, Universitaꢀ di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
Received 26 June 2007; revised 11 September 2007; accepted 27 September 2007
Available online 29 September 2007
Abstract—SiCl4 is an efficient and selective catalyst for the vinylogous Mannich reaction of linear and cyclic synthetic equivalents of
acetoacetate dianion, leading to d-amino-b-ketoesters in moderate to high yields and complete g-selectivity; anti-diastereoselectivity was
observed by using a g-methyl-substituted cyclic silyloxydiene.
Ó 2007 Elsevier Ltd. All rights reserved.
OR''
1. Introduction
OR'' OSiMe3
L.A.
RCHO + R'NH2
+
OMe
d-Amino-b-ketoesters 1 represent a valuable class of com-
pounds, widely used, as starting materials, in many pro-
cedures for the synthesis of monocyclic and bicyclic
alkaloids, containing substituted piperidine moieties,1 such
as the dendrobate alkaloid (+)-241D,2 (ꢀ)-lasubine I and
II,3,4 pseudodistomin B triacetate,5 (ꢀ)-epimyrtine6 and
4-hydroxypipecolio acids.7
R
N
R'
3
O
2a: R''= alkyl
Scheme 2. Imino-aldol reaction of Brassard diene 2a.
A recent investigation on the vinylogous Mukaiyama aldol
reaction of masked forms of 1,3-dicarbonyl compounds13
has confirmed the notable nucleophilic properties of the
Chan diene 2b (R00¼–SiMe3), structurally very similar to
Brassard diene 2a, so that, in the presence of a very weak
Lewis acid as SiCl4, the formation of the corresponding
aldols took place in high yields and complete g-selectivity.
This finding suggested exploitation of the same protocol
for the achievement of a direct approach to d-amino-b-keto-
esters by a vinylogous Mannich reaction.
The typical approach to racemic and enantioenriched com-
pounds 1 is based on chain-extension processes of b-amino-
acids8 and b-aminoesters2–7,9 (Scheme 1).
NH2
NH2
O
O
COOR'
R'= H, Alkyl
Scheme 1. Chain-extension processes.
R
R
OR'
1
2. Results and discussion
In our opinion the vinylogous Mannich reaction10 of a syn-
thetic equivalent of acetoacetate dianion represents a more
convenient approach for the synthesis of 1. However, previ-
ous reports on the imino-aldol reaction of the Brassard diene
2a, under Lewis acid catalysis (Scheme 2), pointed out the
occurrence of the competing cyclization of the resulting
open-chain vinylogous intermediates, leading to the dihydro-
pyridone derivatives 3.11,12
Preliminary experiments were carried out both on crude iso-
lated and in situ generated imine 5a, chosen as the represen-
tative substrate, under the conditions depicted in Scheme 3
and Table 1 (respectively, entries 1 and 2). Although no re-
action was observed at ꢀ78 ꢁC, reactive Chan diene afforded
at ꢀ20 ꢁC and in the absence of catalyst the targeted product
1a in moderate yield. More interestingly, the employment of
Ph
NH
O
i
ii
RCHO + PhNH2
R-CH=N-Ph
COOMe
R
Keywords: Mannich reaction; Imines; Aldehydes; Silicon tetrachloride;
Nucleophilic addition; Diastereoselectivity.
4
5
1
* Corresponding authors. Tel.: +39 089969583; fax: +39 089969603;
e-mail addresses: rvillano@unisa.it; scettri@unisa.it
Scheme 3. Synthesis of imino-aldols 1. Reagents and conditions: ꢁ(i)
˚
CH2Cl2, 3 A MS, SiO2, 1 h/rt; (ii) CH2Cl2, DIPEA, SiCl4, 2b, 0.5 h/ꢀ78 C.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.073

12318
R. Villano et al. / Tetrahedron 63 (2007) 12317–12323
Table 1. SiCl4-catalyzed vinylogous Mannich reaction of Chan diene 2ba
Ph
i
ii
NH
O
O
Entry
R
Aldehyde
SiCl4
(equiv)
DIPEA
(equiv)
1 Yieldb
(%)
RCHO + PhNH2
4
R-CH=N-Ph
5
R
O
7
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
4a
4a
4a
4a
4b
4c
4d
4e
4f
—
—
—
—
36c,d
37d
75c
87
88
86
77
72
39
53
Scheme 5. Synthesis of imino-aldols 7. Reagents and conditions: (i)
ꢁ
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
˚
CH2Cl2, 3 A MS, 1 h/rt; (ii) CH2Cl2, DIPEA, SiCl4, 2c, ꢀ78 C.
pMeOC6H4
pMeC6H4
PhCH]CH
2-Furyl
pNO2C6H4
pCNC6H4
2-Thiazolyl
Table 2. SiCl4-catalyzed vinylogous Mannich reaction of silyloxydiene 2ca
Entry
R
Aldehyde
Reaction
time (h)
Product
7
Yieldb
(%)
9
10
11
1c
2
3
4
5
6
7
8
9
Ph
Ph
4a
4a
4b
4c
4d
4e
4f
16
7a
7a
7b
7c
7d
7e
7f
Traces
87
56
87
74
80
77
77
53
4g
4h
62
0.5
0.5
0.5
1.0
1.0
1.3
1.0
1.0
a
pMeOC6H4
pMeC6H4
PhCH]CH
2-Furyl
pNO2C6H4
pCNC6H4
2-Thiazolyl
With the exception of entries 1 and 3 2b was reacted with in situ generated
imines 5 through a one-pot procedure by using 1/1/0.2/0.2/1.3 RCHO/
PhNH2/SiCl4/DIPEA/2 ratios.
All the yields refer to isolated chromatographically pure compounds
whose structures were confirmed by analytical and spectroscopic data
(MS, IR, 1H NMR and 13C NMR).
In these entries 2b was reacted with crude isolated imine 5a.
In these entries the reaction was performed at ꢀ20 ꢁC. No reaction was
observed at ꢀ78 ꢁC.
b
4g
4h
7g
7h
c
d
a
In all entries 1–9 2c was reacted with in situ generated imines 5 though
a one-pot procedure by using 1/1/0.2/0.2/1.3 RCHO/PhNH2/SiCl4/
DIPEA/2c ratios.
All the yields refer to isolated chromatographically pure compounds
whose structures were confirmed by analytical and spectroscopic data
(MS, IR, 1H NMR and 13C NMR).
In this entry the reaction was carried out in the absence of SiCl4 for 2 h at
ꢀ78 ꢁC and, then, 14 h at room temperature to give essentially PhCHO.
b
c
catalytic SiCl4 (0.20 equiv) at ꢀ78 ꢁC proved to be success-
ful since 1a was obtained in high yields and reduced reaction
times (entries 3 and 4). From a preparative point of view, it is
to be noted that the one-pot procedure proved to be even
more efficient than the stepwise one.
A control experiment carried out in the absence of SiCl4
(Table 2, entry 1) confirmed the lower nucleophilicity of
2c with respect to the Chan diene,13 so that the correspond-
ing imino-aldol could be isolated only in traces (<1% yield).
Conversely, in spite of its mildness as Lewis acid, SiCl4
again proved to be a very efficient and selective catalyst
promoting the fast formation of the expected 7a in high
yield. Almost comparable efficiency was usually observed
with several aromatic, heteroaromatic and a,b-unsaturated
aldehydes, while moderate yields were obtained only in en-
tries 3 and 9. Aliphatic substrates 5 (R¼alkyl) again showed
a complete unreactivity under the typical conditions.
Consequently, the protocol of entry 4 was used for a set of
aldehydes in order to assess the scope of the reaction.
Although aliphatic aldehydes such as 3-phenyl propionalde-
hyde proved to be completely unreactive under the standard
conditions, the procedure was successful in the case of aro-
matic (entries 5, 6, 9 and 10), heteroaromatic (entries 8 and
11) and a,b-unsaturated aldehydes (entry 7) affording in all
the cases the corresponding vinylogous imino-aldols 1 as the
only products. The type of substituent on the aromatic
nucleus exerted a notable influence on the efficiency of the
process as confirmed by the lower yields for substrates
bearing electron-withdrawing groups, such as NO2- and
CN-substituents (entries 9 and 10).
The stereochemical aspects of the vinylogous Mannich reac-
tion were examined by submitting the Me-substituted cyclic
silyloxydiene 2d (easily available as an inseparablew5/3 Z/E
mixture)15 to the usual treatment. In spite of the presence of
the methyl group on the reaction site, 2d exhibited a compa-
rable reactivity to 2c, affording the imino-aldols 8 (Scheme
6) in moderate to high yields (Table 3).
The cyclic silyloxydiene 2c (R¼H), easily available starting
from the corresponding 2,2-dimethyl-[1,3]-dioxin-4-one de-
rivative of type 6 (Scheme 4) represents a further equivalent
of acetoacetate dianion and its role, as alternative nucleo-
phile to Brassard and Chan dienes, has been widely sup-
ported by its employment in a variety of very efficient
procedures for the vinylogous Mukaiyama aldol condensa-
tion.14
Ph
NH
i
ii
O
O
RCHO + PhNH2
R-CH=N-Ph
R
O
4
5
8
Scheme 6. Synthesis of imino-aldols 8. Reagents and conditions: (i)
ꢁ
O
O
1) LDA, THF
2) Me3SiCl
O
O
˚
CH2Cl2, 3 A MS, 1 h/rt; (ii) CH2Cl2, DIPEA, SiCl4, 2d, ꢀ78 C.
R
OSiMe3
O
R
2c : R = H
2d : R = Me
Furthermore, an anti-diastereoselectivity was always
observed in agreement with related SiCl4-catalyzed
Mukaiyama reactions of masked acetoacetates.13,16
6
Scheme 4. Synthesis of cyclic silyloxydienes 2c,d.
Therefore, an investigation was devoted to verify the possi-
bility to extend the above one-pot protocol for the imino-
aldol reaction to 2c (Scheme 5 and Table 2).
The employment, as starting materials, of aldehydes bearing
electron-donor or electron-withdrawing substituents in
para-position of the aromatic nucleus did not seem to exert

R. Villano et al. / Tetrahedron 63 (2007) 12317–12323
Table 3. SiCl4-catalyzed vinylogous Mannich reaction of silyloxydiene 2da
12319
4.2. General procedure for the preparation
of compounds 1
Entry
R
Aldehyde Reaction Product Yieldb d.r.c
time (h)
8
(%)
˚
In a dry round bottom flask silica gel (240 mg), activated 3 A
molecular sieves (220 mg), CH2Cl2 (0.6 mL), aldehyde
(1 equiv, 0.5 mmol) and aniline (1 equiv, 0.5 mmol) were
added. The resulting mixture was stirred for 1 h at room
temperature, then it was cooled at ꢀ78 ꢁC and after
10 min DIPEA (0.20 equiv, 0.10 mmol), SiCl4 (0.20 equiv,
0.10 mmol) and a solution of Chan’s diene 2 (1.3 equiv,
0.65 mmol) in CH2Cl2 (1.8 mL) were added dropwise.
1
2
3
4
5
6
7
8
9
Ph
4a
4b
4f
4h
4i
4j
4k
4l
1.0
1.5
2.0
2.0
1.0
1.5
2.0
2.0
2.0
8a
8b
8f
8h
8i
8j
8k
8l
88
79
85
50
92
77
81
41
47
72/28
69/31
72/28
63/37
59/41
86/14
79/21
64/36
79/21
pMeOC6H4
pNO2C6H4
2-Thiazolyl
oMeOC6H4
oNO2C6H4
oCNC6H4
oCF3C6H4
1-NO2naphthyl 4m
8m
a
In all entries 1–9 2d was reacted with in situ generated imines 5 through
a one-pot procedure by using 1/1/0.2/0.2/1.3 RCHO/PhNH2/SiCl4/
DIPEA/2d ratios.
All the yields refer to isolated chromatographically pure compounds
whose structures were confirmed by analytical and spectroscopic data
(MS, IR, 1H NMR and 13C NMR).
The resulting mixture was stirred for 30 min at ꢀ78 ꢁC, then
it was neutralized by the addition of saturated aq NaHCO3.
The reaction mixture was extracted with CH2Cl2 and the
combined organic phase was dried (MgSO4) and concen-
trated. The residue was purified by non-flash chromato-
graphy (petroleum ether/AcOEt 9/1) to give the products
1. All new compounds were fully characterized on the basis
of IR, 1H NMR, 13C NMR and mass spectroscopic data.
b
c
The reported values refer to anti/syn diastereoisomeric ratios, determined
by 1H NMR analysis (400 MHz) on the crude mixtures.
a particular influence both on the level of efficiency and
diastereoselectivity. It is noteworthy that ortho-substituted
aromatic aldehydes, characterized by an enhanced steric
crowding in proximity of the formyl group, usually afforded
the corresponding products 8i–m in good yields, although in
some cases a lower anti-diastereoselectivity was observed
(entries 5 and 8).
4.3. General procedure for the preparation
of compounds 7 and 8
˚
In a dry round bottom flask activated 3 A molecular sieves
(220 mg), CH2Cl2 (0.6 mL), aldehyde (1 equiv, 0.5 mmol)
and aniline (1 equiv, 0.5 mmol) were added. The resulting
mixture was stirred for 1 h at room temperature, then it
was cooled at ꢀ78 ꢁC and after 10 min DIPEA (0.20 equiv,
0.10 mmol), SiCl4 (0.20 equiv, 0.10 mmol) and a solution of
diene 2c or 2d (1.3 equiv, 0.65 mmol) in CH2Cl2 (1.8 mL)
were added dropwise.
3. Conclusion
In conclusion, a convenient synthesis of d-amino-b-keto-
esters has been achieved through a one-pot multicomponent
reaction involving a SiCl4-catalyzed Mannich reaction of
masked acetoacetates with in situ generated imines. Due to
the mild conditions, the competing cyclization of the result-
ing open-chain imino-aldols is inhibited allowing their
attainment in moderate to high yields. In spite of an in-
creased steric crowding on the reaction site, a synthetic
equivalent of propionoacetate dianion showed a comparable
reactivity under the standard conditions, affording the corre-
sponding g-methyl-d-amino-b-ketoesters in a very satisfac-
tory way and anti-diastereoselectivity.
The resulting mixture was stirred for the reported time at
ꢀ78 ꢁC, then it was neutralized by the addition of saturated
aq NaHCO3. The reaction mixture was extracted with CH2Cl2
and the combined organic phase was dried (MgSO4) and con-
centrated. The residue was purified by non-flash chromato-
graphy (petroleum ether/AcOEt 9/1) to give the products 7
or 8. All new compounds were fully characterized on the
1
basis of IR, H NMR, 13C NMR, elemental analysis and
mass spectroscopic data.
4.4. Spectral data of new compounds
4. Experimental section
4.1. General
4.4.1. Methyl 3-oxo-5-phenyl-5-(phenylamino)penta-
noate (1a). Slightly yellowish oil, m/z: 298 [M+H]+, 320
[M+Na]+; IR (KBr, neat) 3400, 3026, 2953, 1745, 1714,
1602, 1503, 1319–1079, 753, 698; 1H NMR (CDCl3,
400 MHz): d 7.39–7.09 (7H, m), 6.68 (1H, m), 6.54 (2H,
br d, J¼8.1 Hz), 4.90 (1H, dd, J¼7.7, 5.4 Hz), 3.70 (3H,
s), 3.42 (1H, d, J¼15.6 Hz), 3.37 (1H, d, J¼15.6 Hz), 3.11
(1H, dd, J¼16.3, 7.7 Hz), 3.02 (1H, dd, J¼16.3, 5.4 Hz);
13C NMR (CDCl3, 400 MHz): d 200.9, 167.4, 146.4,
142.0, 129.1, 128.8, 127.4, 126.2, 118.0, 113.8, 54.2, 52.4,
50.3, 49.4. Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44;
N, 4.71%. Found: C, 72.58; H, 6.39; N, 4.79%.
All reactions were carried out under Ar or N2 atmosphere by
using dried glassware. CH2Cl2 was freshly distilled from
CaH2 under Ar; solvents for extraction and purification
and commercially available reagents were used without
any purification and were purchased from Sigma–Aldrich
and Fluka. TLC was performed on silica gel 60 F254
0.25 mm on glass plates (Merck) and non-flash chromato-
graphy was performed on silica gel 60 (0.063–0.200 mm)
(Merck). All 1H NMR and 13C NMR spectra were recorded
with a DRX 400 MHz Bruker instrument, by using CDCl3
4.4.2. Methyl 5-(4-methoxyphenyl)-3-oxo-5-(phenyl-
amino)pentanoate (1b). Yellow oil, m/z: 350 [M+Na]+; IR
(KBr, neat) 3398, 3004, 2953, 1743, 1715, 1603, 1509,
1
(d¼7.26 ppm in H NMR spectra and d¼77.0 ppm in 13C
NMR spectra) as solvent. IR spectra were recorded on a
Perkin–Elmer FT-IR spectrometer. ESMS spectra were per-
formed on a Quattro MicroTM Waters mass spectrometer.
1
1318–1106, 753, 695; H NMR (CDCl3, 400 MHz): d 7.29
(2H, d, J¼8.4 Hz), 7.11 (2H, m), 6.86 (2H, d, J¼8.4 Hz),

12320
R. Villano et al. / Tetrahedron 63 (2007) 12317–12323
6.69 (1H, br t, J¼7.8 Hz), 6.57 (2H, br d, J¼7.8 Hz), 4.86
(1H, t-like, J¼6.5 Hz), 3.77 (3H, s), 3.70 (3H, s), 3.42
(1H, d, J¼15.6 Hz), 3.37 (1H, d, J¼15.6 Hz), 3.08 (1H,
dd, J¼16.2, 7.6 Hz), 2.99 (1H, dd, J¼16.2, 5.5 Hz); 13C
NMR (CDCl3, 400 MHz): d 201.1, 167.4, 158.8, 146.6,
134.0, 129.1, 127.3, 117.8, 114.1, 113.7, 55.2, 53.5, 52.4,
50.4, 49.4. Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47;
N, 4.28%. Found: C, 69.80; H, 6.42; N, 4.32%.
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18%. Found: C,
63.28; H, 5.26; N, 8.24%.
4.4.7. Methyl 5-(4-cyanophenyl)-3-oxo-5-(phenylamino)-
pentanoate (1g). Yellow oil, m/z: 323 [M+H]+, 345
[M+Na]+; IR (KBr, neat) 3394, 3024, 2954, 2228, 1745,
1715, 1601, 1502, 1319–1078, 753, 699; 1H NMR (CDCl3,
400 MHz): d 7.59 (2H, d, J¼8.1 Hz), 7.51 (2H, d, J¼
8.1 Hz), 7.09 (2H, br t, J¼7.9 Hz), 6.69 (1H, br t, J¼
7.3 Hz), 6.49 (2H, br d, J¼7.9 Hz), 4.94 (1H, dd, J¼8.0,
4.9 Hz), 3.70 (3H, s), 3.48 (1H, d, J¼15.7 Hz), 3.42 (1H,
d, J¼15.7 Hz), 3.12 (1H, dd, J¼16.9, 8.0 Hz), 3.00 (1H,
dd, J¼16.9, 4.9 Hz); 13C NMR (CDCl3, 400 MHz):
d 200.1, 167.4, 148.0, 146.0, 132.6, 129.2, 127.2, 118.4,
113.7, 113.5, 111.1, 55.6, 53.7, 49.8, 49.1. Anal. Calcd for
C19H18N2O3: C, 70.79; H, 5.63; N, 8.69%. Found: C,
70.66; H, 5.70; N, 8.73%.
4.4.3. Methyl 3-oxo-5-(phenylamino)-5-p-tolylpenta-
noate (1c). Yellow oil, m/z: 312 [M+H]+, 334 [M+Na]+;
IR (KBr, neat) 3399, 3022, 2951, 1744, 1716, 1602, 1505,
1
1318–1166, 752, 696; H NMR (CDCl3, 400 MHz): d 7.27
(2H, d, J¼7.7 Hz), 7.12 (4H, m), 6.70 (1H, br t, J¼
7.3 Hz), 6.57 (2H, br d, J¼8.0 Hz), 4.88 (1H, m), 3.70
(3H, s), 3.43 (1H, d, J¼15.6 Hz), 3.38 (1H, d, J¼15.6 Hz),
3.09 (1H, dd, J¼16.1, 7.8 Hz), 3.00 (1H, dd, J¼16.1,
5.4 Hz), 2.33 (3H, s); 13C NMR (CDCl3, 400 MHz):
d 201.1, 167.4, 146.6, 139.0, 137.0, 129.5, 129.1, 126.1,
117.9, 113.7, 53.9, 52.4, 50.4, 49.4, 21.0. Anal. Calcd for
C19H21NO3: C, 73.29; H, 6.80; N, 4.50%. Found: C,
73.43; H, 6.75; N, 4.54%.
4.4.8. Methyl 3-oxo-5-(phenylamino)-5-(thiazol-2-yl)pen-
tanoate (1h). Yellow oil, m/z: 327 [M+Na]+; IR (KBr, neat)
3393, 2953, 2923, 1745, 1717, 1603, 1503, 1317–1079, 753,
1
696; H NMR (CDCl3, 400 MHz): d 7.17–7.13 (3H, m),
6.97–6.92 (1H, m), 6.74 (1H, br t, J¼7.0 Hz), 6.65 (2H, br
d, J¼7.8 Hz), 5.22 (1H, t-like, J¼6.2 Hz), 3.71 (3H, s),
3.46 (1H, d, J¼15.8 Hz), 3.41 (1H, d, J¼15.8 Hz), 3.23
(1H, dd, J¼16.7, 6.9 Hz), 3.11 (1H, dd, J¼16.7, 5.6 Hz);
13C NMR (CDCl3, 400 MHz): d 200.5, 167.3, 146.8,
146.2, 129.2, 126.9, 124.2, 118.5, 113.9, 52.4, 50.1, 50.0,
49.5. Anal. Calcd for C15H16N2O3S: C, 59.19; H, 5.30; N,
9.20%. Found: C, 59.31; H, 5.36; N, 9.14%.
4.4.4. (E)-Methyl 3-oxo-7-phenyl-5-(phenylamino)hept-
6-enoate (1d). Yellow oil, m/z: 324 [M+H]+, 346
[M+Na]+; IR (KBr, neat) 3397, 3025, 2952, 1745, 1715,
1600, 1507, 1318–1074, 750, 696; 1H NMR (CDCl3,
400 MHz): d 7.36–7.17 (7H, m), 6.76–6.68 (3H, m), 6.62
(1H, d, J¼15.8 Hz), 6.23 (1H, dd, J¼15.8, 6.0 Hz), 4.56
(1H, m), 3.71 (3H, s), 3.52 (1H, d, J¼15.7 Hz), 3.48 (1H,
d, J¼15.7 Hz), 3.01 (1H, dd, J¼16.9, 6.6 Hz), 2.95 (1H,
dd, J¼16.9, 5.9 Hz); 13C NMR (CDCl3, 400 MHz): d 201.1,
167.3, 146.5, 136.4, 131.0, 129.6, 129.2, 128.5, 127.6,
126.4, 118.1, 113.9, 52.4, 51.8, 49.5, 48.0. Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33%. Found: C,
74.46; H, 6.49; N, 4.40%.
4.4.9. 6-(2-Phenylamino-2-phenylethyl)-2,2-dimethyl-
4H-1,3-dioxin-4-one (7a). Yellow oil, m/z: 346 [M+Na]+;
IR (KBr, neat) 3366, 2360, 2340, 1720, 1602, 1499, 1274,
1205, 1013, 772, 669; 1H NMR (CDCl3, 400 MHz):
d 7.37–7.26 (5H, m), 7.11 (2H, m), 6.69 (1H, t-like, J¼
7.3 Hz), 6.54 (2H, br d, J¼7.8 Hz), 5.27 (1H, s), 4.68 (1H,
dd, J¼8.6, 5.8 Hz), 2.76 (1H, dd, J¼14.6, 5.8 Hz), 2.69
(1H, dd, J¼14.6, 8.6 Hz), 1.63 (3H, s), 1.57 (3H, s); 13C
NMR (CDCl3, 400 MHz): d 168.2, 161.1, 146.4, 141.8,
129.5, 129.2, 128.1, 126.4, 118.4, 113.8, 107.1, 95.7, 55.6,
42.4, 25.8, 24.7. Anal. Calcd for C20H21NO3: C, 74.28; H,
6.55; N, 4.33%. Found: C, 74.39; H, 6.59; N, 4.28%.
4.4.5. Methyl 5-(furan-2-yl)-3-oxo-5-(phenylamino)pen-
tanoate (1e). Yellow oil, m/z: 310 [M+Na]+; IR (KBr,
neat) 3392, 3032, 2950, 1744, 1716, 1602, 1503, 1317–
1
1072, 750, 694; H NMR (CDCl3, 400 MHz): d 7.33 (1H,
br s), 7.16 (2H, t-like, J¼7.9 Hz), 6.74 (1H, br t,
J¼7.2 Hz), 6.65 (2H, br d, J¼7.9 Hz), 6.28 (1H, br s),
6.20 (1H, d, J¼2.9 Hz), 5.05 (1H, t, J¼6.3 Hz), 3.70 (3H,
s), 3.44 (2H, s), 3.18 (1H, dd, J¼16.7, 6.3 Hz), 3.10 (1H,
dd, J¼16.7, 6.3 Hz); 13C NMR (CDCl3, 400 MHz):
d 200.6, 167.3, 154.1, 146.2, 141.7, 129.2, 118.5, 113.9,
110.4, 106.5, 52.4, 49.4, 48.1, 46.4. Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.88%. Found: C,
66.98; H, 5.90; N, 4.95%.
4.4.10. 6-(2-(4-Methoxyphenyl)-2-phenylaminoethyl)-
2,2-dimethyl-4H-1,3-dioxin-4-one (7b). Yellow oil, m/z:
376 [M+Na]+; IR (KBr, neat) 3364, 2359, 2339, 1717,
1603, 1273, 1249, 1205, 1014, 772, 693; 1H NMR (CDCl3,
400 MHz): d 7.26 (2H, d, J¼8.6 Hz), 7.11 (2H, m), 6.86
(2H, d, J¼8.6 Hz), 6.71 (1H, m), 6.54 (2H, br d, J¼
7.5 Hz), 5.23 (1H, s), 4.63 (1H, t-like, J¼7.2 Hz), 3.78
(3H, s), 2.71 (2H, m), 1.61 (3H, s), 1.58 (3H, s); 13C NMR
(CDCl3, 400 MHz): d 168.4, 161.1, 159.3, 146.5, 133.7,
129.5, 127.6, 118.4, 114.5, 113.8, 107.1, 95.7, 55.5, 42.4,
25.7, 24.8. Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56;
N, 3.96%. Found: C, 71.47; H, 6.63; N, 3.88%.
4.4.6. Methyl 5-(4-nitrophenyl)-3-oxo-5-(phenylamino)-
pentanoate (1f). Yellow oil, m/z: 343 [M+H]+, 365
[M+Na]+; IR (KBr, neat) 3401, 3030, 2953, 1744, 1716,
1
1605, 1507, 1319–1107, 856, 753, 697; H NMR (CDCl3,
400 MHz): d 8.16 (2H, d, J¼8.6 Hz), 7.58 (2H, d, J¼
8.6 Hz), 7.09 (2H, br t, J¼7.8 Hz), 6.70 (1H, t-like, J¼
7.4 Hz), 6.50 (2H, br d, J¼8.0 Hz), 5.00 (1H, dd, J¼7.8,
4.8 Hz), 3.71 (3H, s), 3.49 (1H, d, J¼15.9 Hz), 3.43 (1H,
d, J¼15.9 Hz), 3.17 (1H, dd, J¼17.0, 7.8 Hz), 3.04 (1H,
dd, J¼17.0, 4.8 Hz); 13C NMR (CDCl3, 400 MHz):
d 200.1, 167.5, 150.0, 147.1, 145.9, 129.2, 127.3, 124.0,
118.5, 113.8, 55.5, 53.6, 49.8, 49.1. Anal. Calcd for
4.4.11. 6-(2-Phenylamino-2-p-tolylethyl)-2,2-dimethyl-
4H-1,3-dioxin-4-one (7c). Yellow oil, m/z: 360 [M+Na]+;
IR (KBr, neat) 3365, 2999, 2360, 2339, 1718, 1603, 1500,
1
1274, 1204, 1014, 751, 669; H NMR (CDCl3, 400 MHz):
d 7.23 (2H, d, J¼8.0 Hz), 7.14–7.09 (4H, m), 6.71 (1H,
m), 6.54 (2H, br d, J¼7.3 Hz), 5.23 (1H, s), 4.64 (1H,

R. Villano et al. / Tetrahedron 63 (2007) 12317–12323
12321
t-like, J¼7.2 Hz), 2.74 (2H, m), 2.31 (3H, s), 1.61 (3H, s),
1.57 (3H, s); 13C NMR (CDCl3, 400 MHz): d 168.4, 161.1,
146.8, 139.0, 137.6, 129.8, 129.5, 126.3, 118.2, 113.6,
107.1, 95.7, 55.2, 42.5, 25.8, 24.8, 21.3. Anal. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15%. Found: C,
74.61; H, 6.79; N, 4.20%.
[M+Na]+; IR (KBr, neat) 3358, 2997, 2360, 2339, 1719,
1635, 1603, 1392, 1376, 1274, 1203, 1013, 752–669; H
1
NMR (CDCl3, 400 MHz): d 7.76 (1H, br s), 7.26 (1H, br
s), 7.17 (2H, m), 6.77 (1H, m), 6.63 (2H, br d, J¼7.9 Hz),
5.31 (1H, s), 5.10 (1H, dd, J¼8.6, 4.9 Hz), 3.11 (1H, dd,
J¼14.6, 4.9 Hz), 2.84 (1H, dd, J¼14.6, 8.6 Hz), 1.63 (3H,
s), 1.54 (3H, s); 13C NMR (CDCl3, 400 MHz): d 173.6,
167.4, 160.9, 146.1, 143.3, 129.6, 119.6, 119.4, 113.9,
107.3, 96.1, 54.0, 40.7, 25.7, 24.7. Anal. Calcd for
C17H18N2O3S: C, 61.80; H, 5.49; N, 8.48%. Found: C,
61.67; H, 5.41; N, 8.55%.
4.4.12. 6-((E)-2-Phenylamino-4-phenylbut-3-enyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (7d). Yellow oil, m/z: 372
[M+Na]+; IR (KBr, neat) 3366, 3028, 2359, 2339, 1726,
1662, 1601, 1274, 1203, 1014, 750, 669; 1H NMR (CDCl3,
400 MHz): d 7.40–7.08 (7H, m), 6.76–6.60 (4H, m), 6.15
(1H, dd, J¼15.7, 5.9 Hz), 5.35 (1H, s), 4.37 (1H, m), 2.64
(2H, m), 1.67 (3H, s), 1.60 (3H, s); 13C NMR (CDCl3,
400 MHz): d 168.4, 161.1, 146.5, 136.4, 131.8, 129.6,
129.4, 128.9, 128.1, 126.7, 118.7, 114.0, 107.2, 95.7, 53.3,
40.2, 25.7, 24.9. Anal. Calcd for C22H23NO3: C, 75.62; H,
6.63; N, 4.01%. Found: C, 75.50; H, 6.70; N, 4.06%.
4.4.17. 6-(1-Phenylamino-1-phenylpropan-2-yl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (8a). Yellow oil, m/z: 338
[M+H]+, 360 [M+Na]+; IR (KBr, neat) 3400, 2360, 1717,
1630, 1603, 1391, 1317, 1274, 1202, 1030, 808–702. The
compound exists as a mixture of two diasteroisomers. syn:
1H NMR (CDCl3, 400 MHz): d 7.25 (5H, m), 7.10 (2H,
m), 6.65 (1H, m), 6.51 (2H, br d, J¼8.1 Hz), 5.29 (1H, s),
4.68 (1H, d, J¼5.4 Hz), 2.83 (1H, m), 1.62 (3H, s), 1.52
(3H, s), 1.14 (3H, d, J¼7.1 Hz); 13C NMR (CDCl3,
400 MHz): d 172.5, 161.4, 147.0, 140.8, 129.3, 128.9,
127.8, 127.0, 118.1, 113.7, 107.0, 94.3, 59.3, 44.8, 26.0,
24.3, 11.7. anti: 1H NMR (CDCl3, 400 MHz): d 7.32
(5H, m), 7.10 (2H, m), 6.65 (1H, m), 6.51 (2H, br d,
J¼8.1 Hz), 5.34 (1H, s), 4.38 (1H, d, J¼9.2 Hz), 2.62 (1H,
m), 1.70 (3H, s), 1.57 (3H, s), 1.05 (3H, d, J¼7.0 Hz); 13C
NMR (CDCl3, 400 MHz): d 173.0, 161.4, 146.8, 141.1,
129.3, 128.9, 127.9, 127.3, 118.0, 113.7, 107.1, 94.5, 60.3,
46.0, 26.0, 24.5, 15.8. Anal. Calcd for C21H23NO3: C,
74.75; H, 6.87; N, 4.15%. Found: C, 74.70; H, 6.98; N,
4.19%.
4.4.13. 6-(2-(Furan-2-yl)-2-phenylaminoethyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (7e). Yellow oil, m/z: 336
[M+Na]+; IR (KBr, neat) 3366, 2361, 1722, 1635, 1602,
1392, 1376, 1275, 1203, 1013, 750, 693; 1H NMR (CDCl3,
400 MHz): d 7.35 (1H, br s), 7.17 (2H, br t, J¼7.6 Hz),
6.76 (1H, br t, J¼7.3 Hz), 6.65 (2H, br d, J¼7.9 Hz), 6.28
(1H, br s), 6.20 (1H, br s), 5.35 (1H, s), 4.85 (1H, t-like,
J¼7.1 Hz), 2.85 (2H, m), 1.61 (3H, s), 1.58 (3H, s); 13C
NMR (CDCl3, 400 MHz): d 168.0, 161.1, 153.9, 146.2,
142.3, 129.6, 119.0, 114.0, 110.5, 107.1, 95.7, 49.6, 39.0,
25.5, 25.0. Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11;
N, 4.47%. Found: C, 69.13; H, 6.04; N, 4.52%.
4.4.14. 6-(2-(4-Nitrophenyl)-2-phenylaminoethyl)-2,2-di-
methyl-4H-1,3-dioxin-4-one (7f). Yellow oil, m/z: 391
[M+Na]+; IR (KBr, neat) 3366, 2361, 2341, 1720, 1635,
4.4.18. 6-(1-(4-Methoxyphenyl)-1-phenylaminopropan-
2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8b). Yellow oil,
m/z: 368 [M+H]+, 390 [M+Na]+; IR (KBr, neat) 3366,
2999, 2361, 1718, 1630, 1603, 1391, 1317, 1274, 1249,
1203, 1032, 838–668. The compound exists as a mixture of
two diasteroisomers. syn: 1H NMR (CDCl3, 400 MHz):
d 7.24 (2H, m), 7.06 (2H, m), 6.85 (2H, m), 6.64 (1H, m),
6.50 (2H, br d, J¼8.0 Hz), 5.27 (1H, s), 4.62 (1H, d,
J¼5.5 Hz), 3.77 (3H, s), 2.80 (1H, m), 1.61 (3H, s), 1.53
(3H, s), 1.14 (3H, d, J¼7.0 Hz); 13C NMR (CDCl3,
400 MHz): d 172.6, 161.4, 159.2, 147.1, 132.7, 129.4,
128.1, 117.9, 114.3, 113.7, 107.1, 94.3, 58.8, 55.4, 45.0,
1
1602, 1521, 1346, 1275, 1204, 1014, 752, 669; H NMR
(CDCl3, 400 MHz): d 8.19 (2H, d, J¼8.7 Hz), 7.57 (2H, d,
J¼8.7 Hz), 7.09 (2H, m), 6.70 (1H, m), 6.47 (1H, br d,
J¼7.8 Hz), 5.35 (1H, s), 4.79 (1H, dd, J¼9.5, 4.6 Hz),
2.77 (1H, dd, J¼14.7, 4.6 Hz), 2.66 (1H, dd, J¼14.7,
9.5 Hz), 1.67 (3H, s), 1.58 (3H, s); 13C NMR (CDCl3,
400 MHz): d 167.2, 160.8, 149.9, 147.7, 145.9, 129.6,
127.4, 124.5, 118.8, 113.7, 107.4, 96.2, 55.1, 42.3, 26.0,
24.5. Anal. Calcd for C20H20N2O5: C, 65.21; H, 5.47; N,
7.60%. Found: C, 65.35; H, 5.42; N, 7.70%.
1
26.0, 24.4, 11.9. anti: H NMR (CDCl3, 400 MHz): d 7.24
4.4.15. 6-(2-(4-Cyanophenyl)-2-phenylaminoethyl)-2,2-
dimethyl-4H-1,3-dioxin-4-one (7g). Yellow oil, m/z: 371
[M+Na]+; IR (KBr, neat) 3365, 2360, 2341, 2228, 1719,
(2H, m), 7.06 (2H, m), 6.85 (2H, m), 6.64 (1H, m), 6.50
(2H, br d, J¼8.0 Hz), 5.33 (1H, s), 4.33 (1H, d, J¼9.2 Hz),
3.77 (3H, s), 2.59 (1H, m), 1.70 (3H, s), 1.57 (3H, s), 1.04
(3H, d, J¼7.0 Hz); 13C NMR (CDCl3, 400 MHz): d 173.2,
161.4, 159.2, 146.9, 133.1, 129.3, 128.3, 117.9, 114.3,
113.7, 107.1, 94.4, 59.8, 55.4, 46.2, 26.0, 24.5, 15.7. Anal.
Calcd for C22H25NO4: C, 71.91; H, 6.86; N, 3.81%. Found:
C, 72.00; H, 6.79; N, 3.77%.
1
1635, 1603, 1376, 1274, 1204, 1014, 753, 669; H NMR
(CDCl3, 400 MHz): d 7.65 (2H, d, J¼8.2 Hz), 7.51 (2H, d,
J¼8.2 Hz), 7.10 (2H, m), 6.72 (1H, t-like, J¼7.4 Hz), 6.47
(1H, br d, J¼8.0 Hz), 5.32 (1H, s), 4.72 (1H, dd, J¼9.5,
4.9 Hz), 2.76 (1H, dd, J¼14.7, 4.9 Hz), 2.64 (1H, dd,
J¼14.7, 9.5 Hz), 1.66 (3H, s), 1.57 (3H, s); 13C NMR
(CDCl3, 400 MHz): d 167.5, 161.0, 148.0, 146.1, 133.0,
129.6, 127.3, 118.8, 118.7, 113.6, 111.7, 107.4, 96.1,
55.1, 42.3, 26.0, 24.5. Anal. Calcd for C21H20N2O3: C,
72.40; H, 5.79; N, 8.04%. Found: C, 72.29; H, 5.70; N,
8.10%.
4.4.19. 6-(1-(4-Nitrophenyl)-1-phenylaminopropan-
2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8f). Yellow oil,
m/z: 405 [M+Na]+; IR (KBr, neat) 3365, 2938, 2361, 2341,
1719, 1633, 1602, 1521, 1346, 1275, 1031, 752–669. The
compound exists as a mixture of two diasteroisomers. syn:
1H NMR (CDCl3, 400 MHz): d 8.21 (2H, d, J¼8.5 Hz),
7.53 (2H, d, J¼8.5 Hz), 7.09 (2H, m), 6.70 (1H, m), 6.43
(2H, m), 5.33 (1H, s), 4.10 (1H, br d, J¼4.9 Hz), 2.87 (1H,
4.4.16. 6-(2-Phenylamino-2-(thiazol-2-yl)ethyl)-2,2-di-
methyl-4H-1,3-dioxin-4-one (7h). Yellow oil, m/z: 353

12322
R. Villano et al. / Tetrahedron 63 (2007) 12317–12323
m), 1.67 (3H, s), 1.52 (3H, s), 1.12 (3H, d, J¼7.2 Hz); 13C
NMR (CDCl3, 400 MHz): d 171.6, 161.2, 149.0, 147.6,
146.3, 129.5, 128.1, 124.2, 118.6, 113.6, 107.3, 94.7, 58.8,
m/z: 405 [M+Na]+; IR (KBr, neat) 3366, 2360, 1716, 1632,
1603, 1526, 1392, 1366, 1254, 1202, 1031, 751–695. The
compound exists as a mixture of two diasteroisomers. syn:
1H NMR (CDCl3, 400 MHz): d 7.99 (1H, d, J¼7.9 Hz),
7.67–7.54 (2H, m), 7.39 (1H, m), 7.06 (2H, m), 6.64 (1H,
m), 6.50 (2H, br d, J¼7.9 Hz), 5.50 (1H, d, J¼4.3 Hz), 5.38
(1H, s), 3.03 (1H, m), 1.64 (3H, s), 1.52 (3H, s), 1.25 (3H,
d, J¼6.8 Hz); 13C NMR (CDCl3, 400 MHz): d 172.0, 161.2,
149.9, 146.2, 136.4, 133.6, 129.6, 129.1, 128.8, 125.7,
118.7, 113.4, 107.3, 94.4, 55.1, 42.6, 25.9, 24.2, 11.0. anti:
1H NMR (CDCl3, 400 MHz): d 7.89 (1H, d, J¼7.9 Hz),
7.67–7.54 (2H, m), 7.39 (1H, m), 7.06 (2H, m), 6.64 (1H,
m), 6.50 (2H, br d, J¼7.9 Hz), 5.32 (1H, d, J¼7.7 Hz), 5.28
(1H, s), 2.82 (1H, m), 1.67 (3H, s), 1.59 (3H, s), 1.16 (3H,
d, J¼6.8 Hz); 13C NMR (CDCl3, 400 MHz): d 172.0, 161.2,
149.9, 146.2, 136.9, 133.7, 129.6, 129.1, 128.8, 125.1,
118.5, 113.3, 107.3, 95.0, 55.5, 45.5, 25.6, 24.8, 15.5. Anal.
Calcd for C21H22N2O5: C, 65.96; H, 5.80; N, 7.33%. Found:
C, 66.14; H, 5.75; N, 7.26%.
1
44.3, 26.2, 24.1, 11.3. anti: H NMR (CDCl3, 400 MHz):
d 8.21 (2H, d, J¼8.5 Hz), 7.53 (2H, d, J¼8.5 Hz), 7.09
(2H, m), 6.70 (1H, m), 6.43 (2H, m), 5.34 (1H, s), 4.24
(1H, br d, J¼6.2 Hz), 2.63 (1H, m), 1.70 (3H, s), 1.58 (3H,
s), 1.10 (3H, d, J¼7.0 Hz); 13C NMR (CDCl3, 400 MHz):
d 172.2, 161.3, 149.3, 147.7, 146.3, 129.5, 128.5, 124.2,
118.5, 113.6, 107.4, 94.9, 59.8, 45.4, 26.0, 24.4, 15.7.
Anal. Calcd for C21H22N2O5: C, 65.96; H, 5.80; N, 7.33%.
Found: C, 65.78; H, 5.73; N, 7.29%.
4.4.20. 6-(1-Phenylamino-1-(thiazol-2-yl)propan-2-yl)-
2,2-dimethyl-4H-1,3-dioxin-4-one (8h). Yellow oil, m/z:
345 [M+H]+, 367 [M+Na]+; IR (KBr, neat) 3365, 2361,
2341, 1718, 1634, 1602, 1393, 1275, 1203, 772–653. The
1
compound exists as a mixture of two diasteroisomers. H
NMR (CDCl3, 400 MHz): d 7.78 (1H, dd-like, J¼4.6,
3.5 Hz, anti and syn), 7.27 (1H, m, anti and syn), 7.15
(2H, m, anti and syn), 6.75 (1H, m, anti and syn), 6.62
(2H, dd-like, J¼8.3, 2.3 Hz, anti and syn), 5.31 (1H, s,
anti and syn), 5.09 (1H, d, J¼5.0 Hz, syn), 4.91 (1H, d,
J¼7.8 Hz, anti), 3.29 (1H, m, syn), 3.10 (1H, m, anti),
1.69 (3H, s, anti or syn), 1.61 (3H, s, anti or syn), 1.57
(3H, s, anti or syn), 1.49 (3H, s, anti or syn), 1.22 (3H, t-
like, J¼6.7 Hz, anti and syn); 13C NMR (CDCl3,
400 MHz): d 173.3 (anti), 172.6 (syn), 171.5, 161.1, 146.6
(anti or syn), 146.3 (anti or syn), 143.4 (anti or syn), 143.1
(anti or syn), 129.6, 119.6 (anti or syn), 119.5 (anti or
syn), 119.3 (anti or syn), 119.1 (anti or syn), 114.0 (anti),
113.8 (syn), 107.2 (anti), 107.0 (syn), 95.0 (anti), 94.5
(syn), 58.4 (anti), 58.0 (syn), 44.8 (anti), 43.5 (syn), 25.8
(anti or syn), 25.7 (anti or syn), 24.6 (anti or syn), 24.5
(anti or syn), 15.0 (anti), 11.6 (syn). Anal. Calcd for
C18H20N2O3S: C, 62.77; H, 5.85; N, 8.13%. Found: C,
62.89; H, 5.90; N, 8.17%.
4.4.23. 6-(1-(2-Cyanophenyl)-1-phenylaminopropan-2-
yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8k). Yellow oil,
m/z: 385 [M+Na]+; IR (KBr, neat) 3366, 2360, 2340, 1716,
1633, 1603, 1526, 1457, 1394, 1275, 1203, 1030, 771–
652. The compound exists as a mixture of two diastero-
1
isomers. syn: H NMR (CDCl3, 400 MHz): d 7.67 (1H, d,
J¼7.9 Hz), 7.58–7.48 (2H, m), 7.37 (1H, m), 7.09 (2H,
m), 6.69 (1H, m), 6.51 (2H, br d, J¼7.7 Hz), 5.35 (1H, s),
4.99 (1H, d, J¼6.0 Hz), 3.02 (1H, m), 1.64 (3H, s), 1.56
(3H, s), 1.23 (3H, d, J¼6.9 Hz); 13C NMR (CDCl3,
400 MHz): d 172.0, 161.4, 146.2, 145.2, 133.8, 133.3,
129.5, 128.5, 128.2, 118.7, 118.0, 113.7, 112.0, 107.3,
1
94.5, 58.0, 43.8, 25.9, 24.5, 12.2. anti: H NMR (CDCl3,
400 MHz): d 7.67 (1H, d, J¼7.9 Hz), 7.58–7.48 (2H, m),
7.37 (1H, m), 7.09 (2H, m), 6.69 (1H, m), 6.51 (2H, br d,
J¼7.7 Hz), 5.30 (1H, s), 4.80 (1H, d, J¼8.9 Hz), 2.79 (1H,
m), 1.70 (3H, s), 1.58 (3H, s), 1.13 (3H, d, J¼6.8 Hz); 13C
NMR (CDCl3, 400 MHz): d 172.0, 161.4, 146.0, 145.8,
133.6, 133.5, 129.5, 128.5, 128.2, 118.5, 118.2, 113.5,
112.0, 107.5, 94.9, 58.4, 45.5, 25.9, 24.5, 15.5. Anal. Calcd
for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73%. Found: C,
73.10; H, 6.19; N, 7.66%.
4.4.21. 6-(1-(2-Methoxyphenyl)-1-phenylaminopropan-
2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8i). Yellow oil,
m/z: 368 [M+H]+, 390 [M+Na]+; IR (KBr, neat) 3381,
3003, 2360, 2340, 1718, 1632, 1602, 1391, 1317, 1274,
1240, 1203, 1027, 771–669. The compound exists as a mix-
ture of two diasteroisomers. syn: 1H NMR (CDCl3,
400 MHz): d 7.26–7.05 (4H, m), 6.89 (2H, m), 6.66–6.56
(3H, m), 5.29 (1H, s), 4.92 (1H, d, J¼6.0 Hz), 3.87 (3H,
s), 3.09 (1H, m), 1.55 (3H, s), 1.52 (3H, s), 1.18 (3H, d,
J¼6.8 Hz). anti: 1H NMR (CDCl3, 400 MHz): d 7.26–7.05
(4H, m), 6.89 (2H, m), 6.66–6.56 (3H, m), 5.37 (1H, s),
4.77 (1H, d, J¼9.3 Hz), 3.87 (3H, s), 2.92 (1H, m), 1.69
(3H, s), 1.55 (3H, s), 1.04 (3H, d, J¼6.9 Hz); 13C NMR
(CDCl3, 400 MHz): d 174.2 (anti), 173.7 (syn), 161.8, 157.7
(anti), 157.1 (syn), 147.5, 129.3, 128.8, 128.5, 121.0,
120.8, 117.7 (syn), 117.6 (anti), 113.7, 111.1 (anti), 110.9
(syn), 107.0 (anti), 106.8 (syn), 94.3 (anti), 93.7 (syn),
56.2 (syn), 55.9 (anti), 55.6, 44.4 (anti), 42.3 (syn), 26.1
(anti or syn), 25.7 (anti or syn), 24.5 (syn), 24.3 (anti),
15.8 (anti), 12.8 (syn). Anal. Calcd for C22H25NO4: C,
71.91; H, 6.86; N, 3.81%. Found: C, 72.06; H, 6.89; N,
3.89%.
4.4.24. 6-(1-(2-Trifluoromethylphenyl)-1-phenylamino-
propan-2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8l). Yel-
low oil, m/z: 406 [M+H]+, 428 [M+Na]+; IR (KBr, neat)
3399, 2360, 1717, 1651, 1456, 873–669. The compound
1
exists as a mixture of two diasteroisomers. syn: H NMR
(CDCl3, 400 MHz): d 7.74–7.35 (4H, m), 7.07 (2H, m),
6.65 (1H, m), 6.48 (2H, br d, J¼8.1 Hz), 5.42 (1H, s), 5.23
(1H, d, J¼3.3 Hz), 2.94 (1H, m), 1.63 (3H, s), 1.53 (3H,
s), 1.12 (3H, d, J¼7.3 Hz); 13C NMR (CDCl3, 400 MHz):
d 172.5, 161.5, 146.4, 139.8, 132.3, 129.5, 128.0, 127.8,
126.7, 123.5, 118.4, 113.5, 107.1, 94.1, 54.6, 42.8, 25.8,
1
25.2, 9.6. anti: H NMR (CDCl3, 400 MHz): d 7.74–7.35
(4H, m), 7.07 (2H, m), 6.65 (1H, m), 6.53 (2H, br d,
J¼8.1 Hz), 5.13 (1H, s), 4.99 (1H, d, J¼6.7 Hz), 2.74 (1H,
m), 1.70 (3H, s), 1.69 (3H, s), 1.18 (3H, d, J¼7.1 Hz); 13C
NMR (CDCl3, 400 MHz): d 171.6, 161.0, 146.4, 140.8,
132.6, 129.5, 128.0, 127.8, 126.7, 123.5, 118.4, 113.7,
107.2, 95.4, 56.5, 46.3, 25.5, 25.0, 15.8. Anal. Calcd for
C22H22F3NO3: C, 65.18; H, 5.47; N, 3.45%. Found: C,
65.00; H, 5.41; N, 3.38%.
4.4.22. 6-(1-(2-Nitrophenyl)-1-phenylaminopropan-2-
yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8j). Yellow oil,

R. Villano et al. / Tetrahedron 63 (2007) 12317–12323
12323
2. Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169–3171.
3. Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855–
3858.
4. Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623–2625.
5. Davis, F. A.; Zhang, J.; Li, Y.; Xu, H.; De Brosse, C. J. Org.
Chem. 2005, 70, 5413–5419.
6. Davis, F. A.; Zhang, J.; Anilkumar, G. J. Org. Chem. 2003, 68,
8061–8064.
7. Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000,
2106–2112.
8. Marin, J.; Didierjean, C.; Aubry, A.; Casimir, J. R.; Briand,
J.-P.; Guichard, G. J. Org. Chem. 2004, 69, 130–141.
9. Leflemme, N.; Dallemagne, P.; Rault, S. Tetrahedron Lett.
2001, 42, 8997–8999.
10. For recent reviews containing selected accounts on vinylogous
Mannich reactions, see: (a) Casiraghi, G.; Zanardi, F.;
Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929–1972;
(b) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–
3242; (c) Martin, S. F. Acc. Chem. Res. 2002, 35, 895–904.
11. Midland, M. M.; Mc Loughlin, J. I. Tetrahedron Lett. 1988, 29,
4653–4656.
4.4.25. 6-(1-(2-Nitronaphthalen-3-yl)-1-phenylamino-
propan-2-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one (8m).
Yellow oil, m/z: 455 [M+Na]+; IR (KBr, neat) 3365, 2361,
2342, 1717, 1635, 1524, 1457, 872, 772. The compound exists
1
as a mixture of two diasteroisomers. syn: H NMR (CDCl3,
400 MHz): d 7.93–7.54 (6H, m), 7.06 (2H, m), 6.65 (1H, m),
6.54 (2H, br d, J¼7.9 Hz), 5.41 (1H, s), 5.01 (1H, d,
J¼4.6 Hz), 3.05 (1H, m), 1.66 (3H, s), 1.53 (3H, s), 1.20
(3H, d, J¼7.0 Hz); 13C NMR (CDCl3, 400 MHz): d 172.0,
161.4, 147.5, 146.1, 133.5, 131.6, 130.8, 129.6, 129.5,
129.1, 128.2, 127.9, 123.7, 118.9, 113.6, 107.3, 94.6, 55.1,
1
43.4, 26.0, 24.2, 10.9. anti: H NMR (CDCl3, 400 MHz):
d 7.93–7.54 (6H, m), 7.06 (2H, m), 6.65 (1H, m), 6.59 (2H,
br d, J¼8.1 Hz), 5.39 (1H, s), 4.75 (1H, d, J¼9.0 Hz), 2.86
(1H, m), 1.71 (3H, s), 1.61 (3H, s), 1.13 (3H, d, J¼7.1 Hz);
13C NMR (CDCl3, 400 MHz): d 172.0, 161.4, 148.1, 146.0,
133.5, 131.6, 130.8, 129.6, 129.5, 129.1, 128.2, 127.9,
123.7, 118.8, 113.6, 107.5, 95.1, 56.1, 45.7, 25.6, 24.8, 15.6.
Anal. Calcd for C25H24N2O5: C, 69.43; H, 5.59; N, 6.48%.
Found: C, 69.62; H, 5.51; N, 6.54%.
12. Kawxcki, R. Tetrahedron 2001, 57, 8385–8390.
13. Acocella, M. R.; De Rosa, M.; Massa, A.; Palombi, L.; Villano,
R.; Scettri, A. Tetrahedron 2005, 61, 4091–4097.
14. For a recent review containing selected accounts on the vinyl-
ogous Mukaiyama aldol reaction of silyloxydienes of type 2,
see: Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A. Curr.
Org. Chem. 2004, 8, 993–1007.
Acknowledgements
We are grateful to MIUR (Ministero dell’Istruzione, Uni-
ꢀ
versita e della Ricerca Scientifica) for financial support.
References and notes
15. Sato, M.; Sunami, T.; Sugita, Y.; Kaneka, C. Heterocycles
1995, 41, 1435–1444.
1. For a review see: Bailey, P. D.; Millwood, P. A.; Smith, P. D.
Chem. Commun. 1998, 633–640.
16. Scettri, A.; Acocella, M. R.; Palombi, L.; Scalera, C.; Villano,
R.; Massa, A. Adv. Synth. Catal. 2006, 348, 2229–2236.