β-Nitroacrylates and silyl enol ethers as key starting materials for the synthesis of polyfunctionalized β-nitro esters and 1,2-oxazine-2-oxides

Article abstract of DOI:10.1016/j.tet.2009.02.009

The reaction of silyl enol ethers with β-nitroacrylates, in the presence of tetrabutyl ammonium fluoride as catalyst, allows the formation of polyfunctionalized β-nitro esters, or hexahydro-4H-benzoxazine-2-oxides, depending on the nature of the starting

Full text of DOI:10.1016/j.tet.2009.02.009

Tetrahedron 65 (2009) 2916–2920
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b-Nitroacrylates and silyl enol ethers as key starting materials for the synthesis
of polyfunctionalized b-nitro esters and 1,2-oxazine-2-oxides
*
Roberto Ballini , Giovanna Bosica, Serena Gabrielli, Alessandro Palmieri
`
Green Chemistry Group, Dipartimento di Scienze Chimiche dell’Universita di Camerino, Via S. Agostino 1, 62032 Camerino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of silyl enol ethers with
as catalyst, allows the formation of polyfunctionalized
b
-nitroacrylates, in the presence of tetrabutyl ammonium fluoride
-nitro esters, or hexahydro-4H-benzoxazine-2-
oxides, depending on the nature of the starting silyl enol ethers.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 November 2008
Received in revised form 21 January 2009
Accepted 5 February 2009
Available online 11 February 2009
b
1. Introduction
acidic hydrogen in the a-position to the carbonyl and the nitro
group in the vicinal carbon can promote the elimination of nitrous
The conjugate addition of a nucleophilic carbon to an electron-
poor system is one of the most important reactions in organic
synthesis for the formation of new C–C bonds.1 In this context,
nitroolefins are widely used as Michael acceptors due to the highly
electron-withdrawing effect of the nitro group.2
acid.11,12
2. Results and discussion
As a continuation of our studies in the use of b-nitroacrylates as
In the last few years, b-nitroacrylates 1 have been shown to be
strategic starting materials for the synthesis of a variety of fine
chemicals, we wish to report a new method for the preparation of
both the targets 3 and 6, arising from silyl enol ethers. In fact, the
reaction of silyl enol ethers 2 with 1 allows, selectively, the for-
a highly versatile class of nitroalkenes prone to give easy access to
a variety of polyfunctionalizsed molecules as a consequence of the
presence of both nitro and ester groups.3
1,2-Oxazine-2-oxides are important class of key building blocks
for the synthesis of a large number of useful products, such as
mation of the g b-nitro esters 3, or the 1,2-oxazine-2-oxides
0-keto-
6, depending on the nature of 2 (Scheme 1). The regioselectivity of
the conjugate addition can be explained in terms of stronger
electron-withdrawing power of the nitro group with respect to the
ester functionality.
pyrrolizidine, pyrrolidines,
b-lactam-N-oxides, oxazine, g-nitro-
ketones, etc.4 1,2-Oxazine-2-oxides are generally obtained by [4þ2]
cycloaddition of nitroolefins with electron-rich alkenes.4,5 In the
last few years, new approaches via addition of silyl enol ethers to
nitroalkenes have been reported and most of these require the
presence of a Lewis acid.6 In addition, very recently Pizzo et al.
reported7 a new solvent- and metal-free synthesis of 1,2-oxazine-
2-oxides, starting from cyclic silyl enol ethers and a specific class of
nitroalkenes in which the double bond must be conjugated, at the
same time, with the nitro, cyano, and phenyl groups.
OSiMe3
2d-e
2a-c
OSiMe3
R''
NO2
AcO
R''
O
O
R
H
R'
N
R'
O
R
R'''
R
R'''
EtOOC
O
EtO
NO2
3
1
6
COOEt
b
-Nitro esters are another valuable class of compounds, which
Scheme 1.
are used as intermediates for the synthesis of natural products.8
These compounds can be prepared by direct nitration of the
corresponding unsaturated ester,9 by nitration of the correspond-
We first examined the preparation of 3 starting from silyl enol
ethers derived from ketones and, as a sample reaction, we tested
the conjugate addition of 2a to b-nitroacrylate 1a. As shown in
Table 1, we found the best results were obtained at ꢀ45 ꢁC, using
1.3 equiv of silyl enol ethers and 1.95 equiv of tetrabutylammonium
fluoride,13 respectively, and in dichloromethane as solvent.
In order to test the generality of our method we extended the
procedure to a series of starting materials and in all cases we
obtained the product in good to excellent yield (72–94%) in short
reaction times (Table 2).
ing
addition of the appropriate nitroalkane to 2-ene-1,4-dicarbonyl
systems.11 However, the syntheses of
-nitro esters require very
b
-halo carbonyl derivatives,8a,10 or through the conjugate
b
mild reaction conditions since the concomitant presence of an
* Corresponding author. Tel.: þ39 0737 402270; fax: þ39 0737 402297.
E-mail address: roberto.ballini@unicam.it (R. Ballini).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.009

R. Ballini et al. / Tetrahedron 65 (2009) 2916–2920
2917
Table 1
Optimization of the reaction
in situ acetylation of the formed hydroxyl group (5 to 6), directly
afforded the target compounds 6. Although compounds 5 can be
isolated by chromatography, they were unstable and we circum-
vented this problem, by the in situ acetylation of the hydroxyl
group in the presence of DMAP and acetic anhydride. All the
products were obtained in good yields and in good diaster-
eoselectivity, in particular, compound 6c was isolated as single di-
astereoisomer. A different behavior was observed using the silyl
enol ether 2e. In fact, although the reaction seems to work, the
acetylated product 6f resulted unstable in the purification step,
affording 40% yield of a diastereomeric mixture (63:37).
NO2
O
OSiMe3
Bu4NF
CH2Cl2
Ph
+
EtO
NO2
Ph
EtOOC O
3a
1a
2a
equiv of 2a equiv of Bu4NF Temperature (ꢁC) Yielda (%) of 3a Reaction time (h)
1.05
1.3
1.3
1.5
1.95
1.95
0
0
ꢀ45
60
67
94
1.5
1
1
a
Yield of pure isolated product.
3. Conclusion
Table 2
In conclusion, we have found new procedures for the prepara-
tion of both hexahydro-4H-benzoxazine-2-oxides and a new class
of polyfunctionalized b-nitro esters, from common starting mate-
rials, simply by changing the nature of the silyl enol ethers. The
procedure shows good yields and good chemoselectivity and, in
addition, represents an extension of the chemical versatility of an
NO2
O
R
OSiMe3
R'
Bu4NF
CH2Cl2, -45 °C
+
R
R'
EtO
NO2
EtOOC O
1
2
3
R
R0
Yielda (%) of 3 Reaction time (h) Diastereomeric ratiob
emerging class of key building blocks such as b-nitroacrylates.
Et
Ph
Ph
3a 94
3b 87
3c 91
3d 94
1
1
1
1
1.5
1
1.5
1
1
1
50:50
50:50
50:50
50:50
50:50
50:50
60:40
50:50
50:50
50:50
PhCH2CH2
MeOCO(CH2)4 Ph
CH3(CH2)3
Me
PhCH2CH2
MeOCO(CH2)4 Me 3g 87
Me
Et
Ph
4. Experimental
4.1. General
Me 3e 75
Me 3f 93
t-Bu 3h 72
t-Bu 3i 88
t-Bu 3j 89
1H NMR spectra were recorded at 400 MHz on a Varian Mercury
Plus 400 in CDCl3 as solvent. 13C NMR spectra were recorded at
100 MHz in CDCl3 as solvent. Microanalyses were performed with
a CHNS-O analyzer Model EA 1108 from Fisons Instruments. IR
spectra were recorded with a Perkin–Elmer Paragon 500 FT-IR. GLC
analyses were performed with an SE-54 fused silica capillary col-
umn (25 m, 0.32 mm internal diameter), FID detector and nitrogen
as carrier gas. GS-MS analyses were carried out by means of the EI
PhCH2CH2
a
Yield of pure isolated product.
b
Diastereomeric ratio was evaluated by 1H NMR spectroscopy.
The reactions work well with a variety of silyl enol ethers and
b
-nitroacrylates, including hindered precursors (R1¼t-Bu). More-
over, under our reaction conditions, the method shows high
chemoselectivity since products arising from the elimination of
nitrous acid were not observed.
technique (70 eV).
b-Nitroacrylates were prepared by the standard
procedure.3a
Finally, we tested the preparation of the 1,2-oxazine-2-oxides 6,
starting from a silyl enol ether arising from an aldehyde. As
reported in Table 3, the Michael addition of 2d to 1, followed by the
4.2. Typical procedure for the synthesis of compounds 3a–j
-Nitroacrylate 1 (1.0 mmol) was dissolved in 10 mL of dry
b
CH2Cl2 and the solution was cooled, under a nitrogen atmosphere,
to ꢀ45 ꢁC. Then, silyl enol ether 2a–c (1.3 mmol) was added to the
reaction mixture, followed by a solution of 1 M Bu4NF (THF,
1.95 mmol) that was slowly dropped (over 15 min). The reaction
was stirred for the appropriate time (TLC), and then treated with
2 M aq HCl (10 mL), followed by the separation of the two layers.
The aqueous phase was extracted with CH2Cl2 (2ꢂ10 mL) and the
collected organic layers were dried over anhydrous Na2SO4, filtered,
concentrated under reduced pressure and the crude product 3 was
purified by flash column chromatography (cyclohexane–ethyl
acetate).
Table 3
O
R
OSiMe3
R''
O
R''
R'''
Bu4NF
NO2
R
+
CH2Cl2
EtO
NO2
-45 °C, 1 h
R'''
COOEt
2d = R'' = R''' = Me
1
4
2e = R'' = H; R''' = CH3(CH2)5
AcO
R''
R'''
O
O
R
HO
R''
R'''
O
O
R
N
N
DMAP, Ac2O
CH2Cl2
4.2.1. Ethyl 3-nitro-2-(2-oxo-2-phenylethyl)pentanoate, 3a
-45 °C, 1 h
COOEt
COOEt
Yield: 94%. Yellow oil. IR (cmꢀ1, neat): 1736, 1711, 1556, 1362,
6
5
1024. 1H NMR (400 MHz, CDCl3)
d: 0.97–1.05 (m, 3H), 1.20–1.29 (m,
R
R00
R%
Yielda (%) of 6
Diastereomeric ratio
3H), 1.76–1.98 (m, 1H), 2.04–2.21 (m, 1H), 3.02–3.11 (m, 0.5H), 3.30
(dd, 0.5H, J¼4.2, 18.2 Hz), 3.51–3.75 (m, 2H), 4.11–4.27 (m, 2H),
4.78–4.89 (m, 1H), 7.42–7.51 (m, 2H), 7.54–7.63 (m, 1H), 7.91–7.98
Et
Bu
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
6a
6b
6c
6d
6e
6f
80
83
47b
79
76
40
78:22
79:21
100:0
73:27
80:20
63:37
(m, 2H). 13C NMR (100 MHz, CDCl3)
d: 10.6, 10.7, 14.2, 14.3, 24.6,
PhCH2CH2
MeOCO(CH2)4
Bu
25.2, 36.6, 36.7, 43.2, 43.9, 62.0, 62.1, 89.6, 90.0, 128.3, 128.4, 128.9,
129.0, 133.8, 133.9, 136.2, 136.3, 170.8, 171.2, 196.8, 196.9. GC–MS
(70 eV) m/z: 246 (8), 217 (5), 201 (16),173 (10),105 (100), 77 (66), 51
(10), 29 (9). Anal. Calcd for C15H19NO5 (293.32): C, 61.42; H, 6.53; N,
4.78. Found: C, 61.98; H, 6.82; N, 4.56.
CH3(CH2)5
a
Yield of pure isolated product.
b
The addition of Bu4NF was performed at ꢀ45 ꢁC, and then the temperature was
left to increase to 0 ꢁC over 5 h and, finally, DMAP and Ac2O were added.

2918
R. Ballini et al. / Tetrahedron 65 (2009) 2916–2920
4.2.2. Ethyl 3-nitro-2-(2-oxo-2-phenylethyl)-5-phenyl-
pentanoate, 3b
C16H21NO5 (307.34): C, 62.53; H, 6.89; N, 4.56. Found: C, 62.83; H,
7.05; N, 4.32.
Yield: 87%. Yellow oil. IR (cmꢀ1, neat): 1735, 1707, 1557, 1364,
1018. 1H NMR (400 MHz, CDCl3)
d
: 1.16–1.26 (m, 3H), 2.00–2.17 (m,
4.2.7. 1-Ethyl 8-methyl 3-nitro-2-(2-oxopropyl)octanedioate, 3g
1H), 2.41–2.57 (m, 1H), 2.57–2.70 (m, 1H), 2.71–2.82 (m, 1H), 3.06
(d, 0.5H, J¼14.9 Hz), 3.21 (dd, 0.5H, J¼4.3, 18.0 Hz), 3.53–3.66 (m,
1.5H), 3.71–3.78 (m, 0.5H), 4.11–4.21 (m, 2H), 4.83–4.96 (m, 1H),
7.13–7.35 (m, 5H), 7.47 (t, 2H, J¼7.7 Hz), 7.56–7.62 (m, 1H), 7.94 (d,
Yield: 87%. Yellow oil. IR (cmꢀ1, neat): 1735, 1560, 1364, 1020. 1H
NMR (400 MHz, CDCl3) d: 1.20–1.28 (m, 3H), 1.29–1.42 (m, 2H),
1.54–1.77 (m, 3H), 1.98–2.12 (m, 1H), 2.17 (s, 1.2H), 2.18 (s, 1.8H),
2.29 (t, 2H, J¼7.3 Hz), 2.52 (dd, 0.4H, J¼3.0, 18.0 Hz), 2.69 (dd, 0.6H,
J¼4.3, 18.0 Hz), 2.91–3.06 (m, 1H), 3.29–3.37 (m, 0.4H), 3.44–3.54
(m, 0.6H), 3.64 (s, 3H), 4.10–4.22 (m, 2H), 4.72–4.83 (m, 1H). 13C
2H, J¼7.7 Hz). 13C NMR (100 MHz, CDCl3)
d: 14.1, 14.2, 32.2, 32.3,
32.6, 32.7, 36.4, 36.5, 43.5, 43.6, 62.0, 62.1, 87.2, 87.5, 126.8, 126.9,
128.3, 128.4, 128.6, 128.7, 128.9, 129.0, 133.8, 133.9, 136.1, 136.2,
139.6, 139.7, 170.4, 170.5, 196.7, 196.8. GC–MS (70 eV) m/z: 275 (10),
187 (16), 105 (100), 91 (44), 77 (48), 51 (7). Anal. Calcd for
C21H23NO5 (369.16): C, 68.28; H, 6.28; N, 3.79. Found: C, 68.57; H,
6.54; N, 3.45.
NMR (100 MHz, CDCl3) d: 14.1, 14.2, 24.3, 25.5, 25.6, 30.1, 30.2, 30.4,
31.1, 33.6, 40.8, 40.9, 43.1, 43.6, 51.8, 62.0, 87.6, 87.8, 170.4, 170.8,
173.6,173.7, 205.1, 205.2. GC–MS (70 eV) m/z: 225 (21),193 (46),165
(33), 149 (43), 123 (36), 95 (29), 81 (26), 67 (18), 55 (28), 43 (100),
29 (22). Anal. Calcd for C14H23NO7 (317.33): C, 52.99; H, 7.31; N, 4.41.
Found: C, 53.24; H, 7.11; N, 4.18.
4.2.3. 1-Ethyl 8-methyl 3-nitro-2-(2-oxo-2-phenylethyl)-
octanedioate, 3c
4.2.8. Ethyl 5,5-dimethyl-2-(1-nitroethyl)-4-oxohexanoate, 3h
Yield: 91%. Yellow oil. IR (cmꢀ1, neat): 1736, 1709, 1555, 1367,
Yield: 72%. Yellow oil. IR (cmꢀ1, neat): 1738, 1709, 1556, 1367,
1023. 1H NMR (400 MHz, CDCl3)
d
: 1.19–1.28 (m, 3H), 1.33–1.47 (m,
1023. 1H NMR (400 MHz, CDCl3)
d: 1.12 (s, 4.5H), 1.13 (s, 4.5H), 1.19–
2H), 1.56–1.88 (m, 3H), 2.06–2.20 (m, 1H), 2.31 (t, 2H, J¼7.3 Hz),
3.05 (d, 0.5H, J¼14.5 Hz), 3.28 (dd, 0.5H, J¼4.7, 18.0 Hz), 3.51–3.74
(m, 2H), 3.65 (s, 1.5H), 3.66 (s, 1.5H), 4.12–4.24 (m, 2H), 4.84–4.95
(m, 1H), 7.43–7.51 (m, 2H), 7.55–7.62 (m, 1H), 7.91–7.98 (m, 2H). 13C
1.25 (m, 3H), 1.51 (d, 1.5H, J¼6.8 Hz), 1.53 (d, 1.5H, J¼7.3 Hz), 2.51
(dd, 0.5H, J¼3.8, 18.0 Hz), 2.71 (dd, 0.5H, J¼4.3, 18.3 Hz), 3.00–3.15
(m, 1H), 3.38–3.45 (m, 0.5H), 3.53–3.60 (m, 0.5H), 4.06–4.23 (m,
2H), 4.86–4.96 (m,1H). 13C NMR (100 MHz, CDCl3)
d: 14.2,14.3,16.6,
NMR (100 MHz, CDCl3)
d
: 14.2, 14.3, 24.4, 25.6, 30.8, 31.3, 33.7, 36.6,
17.0, 26.6, 26.7, 34.5, 34.6, 43.8, 44.3, 44.4, 61.8, 82.4, 82.9, 170.8,
170.9, 212.8. GC–MS (70 eV) m/z: 214 (5), 202 (50), 167 (17), 155
(25), 127 (46), 99 (27), 57 (100), 41 (32), 29 (25). Anal. Calcd for
C12H21NO5 (259.30): C, 55.58; H, 8.16; N, 5.40. Found: C, 55.83; H,
8.42; N, 5.19.
36.7, 43.4, 44.0, 51.9, 54.0, 62.1, 87.9, 88.3, 128.4, 129.0, 133.9, 136.1,
136.2, 170.6, 171.0, 173.8, 196.8. GC–MS (70 eV) m/z: 379 (1), 333 (3),
287 (15), 255 (17), 105 (100), 91 (6), 77 (70). Anal. Calcd for
C19H25NO7 (379.40): C, 60.15; H, 6.64; N, 3.69. Found: C, 60.47; H,
6.91; N, 3.47.
4.2.9. Ethyl 5,5-dimethyl-2-(1-nitropropyl)-4-oxohexanoate, 3i
4.2.4. Ethyl 3-nitro-2-(2-oxo-2-phenylethyl)heptanoate, 3d
Yield: 88%. Yellow oil. IR (cmꢀ1, neat): 1738, 1708, 1555, 1368,
Yield: 94%. Yellow oil. IR (cmꢀ1, neat): 1738, 1708, 1558, 1365,
1021. 1H NMR (400 MHz, CDCl3)
d: 0.95–1.02 (m, 3H), 1.14 (s, 4.5H),
1021. 1H NMR (400 MHz, CDCl3)
d
: 0.85–0.96 (m, 3H), 1.21–1.28 (m,
1.16 (s, 4.5H), 1.22–1.29 (m, 3H), 1.70–1.87 (m, 1H), 1.98–2.15 (m,
1H), 2.55 (dd, 0.5H, J¼3.4, 18.0 Hz), 2.79 (dd, 0.5H, J¼4.7, 18.3 Hz),
3.02–3.17 (m, 1H), 3.34–3.42 (m, 0.5H), 3.47–3.55 (m, 0.5H), 4.09–
3H), 1.29–1.42 (m, 4H), 1.70–1.86 (m, 1H), 2.04–2.19 (m, 1H), 3.06 (d,
0.5H, J¼14.5 Hz), 3.28 (dd, 0.5H, J¼4.3, 18.2 Hz), 3.51–3.76 (m, 2H),
4.10–4.27 (m, 2H), 4.86–4.94 (m, 1H), 7.43–7.51 (m, 2H), 7.55–7.62
4.25 (m, 2H), 4.68–4.78 (m, 1H). 13C NMR (100 MHz, CDCl3)
d: 10.6,
(m, 1H), 7.92–7.99 (m, 2H). 13C NMR (100 MHz, CDCl3)
d: 13.9, 14.2,
10.7, 14.2, 14.3, 24.5, 25.1, 26.6, 26.7, 34.9, 35.0, 43.0, 43.7, 44.3, 61.9,
89.6, 90.0, 170.8, 171.2, 212.9, 213.0. GC–MS (70 eV) m/z: 216 (46),
181 (12), 169 (22), 141 (31), 113 (27), 57 (100), 41 (26), 29 (13). Anal.
Calcd for C13H23NO5 (273.33): C, 57.13; H, 8.48; N, 5.12. Found: C,
57.44; H, 8.75; N, 4.97.
14.3, 22.2, 22.3, 28.1, 28.2, 30.7, 31.3, 36.5, 36.6, 43.5, 44.1, 62.0, 88.2,
88.5, 128.3, 128.4, 128.9, 129.0, 133.8, 133.9, 136.2, 136.3, 170.8, 171.1,
196.9. GC–MS (70 eV) m/z: 275 (6), 229 (15), 201 (14), 105 (100), 77
(40). Anal. Calcd for C17H23NO5 (321.37): C, 63.54; H, 7.21; N, 4.36.
Found: C, 63.21; H, 7.01; N, 4.61.
4.2.10. Ethyl 5,5-dimethyl-2-(1-nitro-3-phenylpropyl)-4-
oxohexanoate, 3j
4.2.5. Ethyl 2-(1-nitroethyl)-4-oxopentanoate, 3e
Yield: 75%. Yellow oil. IR (cmꢀ1, neat): 1739, 1709, 1555, 1366,
Yield: 89%. Yellow oil. IR (cmꢀ1, neat): 1738, 1709, 1556, 1368,
1025. 1H NMR (400 MHz, CDCl3)
d: 1.21–1.29 (m, 3H), 1.52 (d, 1.5H,
1022. 1H NMR (400 MHz, CDCl3)
d: 1.10–1.27 (m, 12H), 1.92–2.07 (m,
J¼7.3 Hz), 1.55 (d, 1.5H, J¼6.9 Hz), 2.19 (s, 1.5H), 2.20 (s, 1.5H), 2.51
(dd, 0.5H, J¼3.4, 18.0 Hz), 2.66 (dd, 0.5H, J¼4.7, 18.0 Hz), 2.93–3.08
(m, 1H), 3.36–3.47 (m, 0.5H), 3.56–3.63 (m, 0.5H), 4.07–4.27 (m,
1H), 2.28–2.48 (m, 1H), 2.50–2.79 (m, 3H), 3.02–3.17 (m, 1H), 3.38–
3.45 (m, 0.5H), 3.49–3.57 (m, 0.5H), 4.07–4.22 (m, 2H), 4.71–4.87
(m, 1H), 7.11–7.36 (m, 5H). 13C NMR (100 MHz, CDCl3)
d: 14.1, 14.2,
2H), 4.86–4.98 (m, 1H). 13C NMR (100 MHz, CDCl3)
d
: 14.2, 16.4, 16.9,
26.6, 26.7, 32.2, 32.3, 32.6, 33.3, 34.8, 34.9, 43.3, 43.8, 44.3, 61.9,
87.2, 87.5, 126.8, 126.9, 128.6, 128.7, 128.9, 139.5, 139.7, 170.5, 170.9,
212.8. GC–MS (70 eV) m/z: 301 (3), 255 (17), 199 (9), 171 (21), 143
(23),129 (21), 117 (28), 91 (100), 57 (94), 41 (18), 29 (11). Anal. Calcd
for C19H27NO5 (349.42): C, 65.31; H, 7.79; N, 4.01. Found: C, 65.61;
H, 7.96; N, 3.88.
30.1, 30.2, 40.5, 43.7, 44.3, 61.9, 62.0, 82.2, 82.6, 170.7, 170.8, 205.2,
205.3. GC–MS (70 eV) m/z: 172 (5),141 (9),125 (48), 97 (40), 81 (13),
73 (17), 55 (35), 43 (100), 29 (31). Anal. Calcd for C9H15NO5 (217.22):
C, 49.76; H, 6.96; N, 6.45. Found: C, 50.12; H, 7.21; N, 6.19.
4.2.6. Ethyl 3-nitro-2-(2-oxopropyl)-5-phenylpentanoate, 3f
Yield: 93%. Yellow oil. IR (cmꢀ1, neat): 1737, 1712, 1558, 1366,
4.3. Typical procedure for the synthesis of compounds 6a–f
1022. 1H NMR (400 MHz, CDCl3)
d: 1.17–1.27 (m, 3H), 1.19–2.05 (m,
1H), 2.18 (s, 3H), 2.32–2.78 (m, 4H), 2.95–3.07 (m, 1H), 3.36–3.44
(m, 0.5H), 3.50–3.57 (m, 0.5H), 4.08–4.21 (m, 2H), 4.71–4.86 (m,
b-Nitroacrylate 1 (1.0 mmol) was dissolved in dry CH2Cl2
(10 mL) and the solution was cooled, under a nitrogen atmosphere,
to ꢀ45 ꢁC. Then, silyl enol ether 2d or 2e (1.3 mmol) was added to
the reaction mixture, followed by a solution of 1 M Bu4NF (THF,
1.95 mmol) that was slowly dropped (over 15 min). The solution
was stirred for 1 h at the same temperature, and then DMAP
(3 mmol) and dry Ac2O (3 mmol) were added in sequence. The
1H), 7.10–7.42 (m, 5H). 13C NMR (100 MHz, CDCl3)
d: 14.1, 14.2, 30.2,
30.3, 32.2, 32.3, 32.4, 33.1, 40.8, 40.9, 43.3, 43.6, 62.1, 86.9, 87.2,
126.8, 126.9, 128.6, 128.7, 129.0, 139.5, 139.6, 170.4, 170.8, 205.2,
205.3. GC–MS (70 eV) m/z: 213 (23), 171 (30), 143 (25), 129 (46), 117
(27), 91 (100), 79 (11), 65 (25), 43 (96), 29 (18). Anal. Calcd for

R. Ballini et al. / Tetrahedron 65 (2009) 2916–2920
2919
reaction was stirred for 1 h, and then was treated with 2 M aq HCl
(10 mL), followed by the separation of the two layers. The aqueous
phase was extracted with CH2Cl2 (2ꢂ10 mL) and the collected or-
ganic layers were dried over anhydrous Na2SO4, filtered, concen-
trated under vacuum and the crude product 6 was purified by flash
column chromatography (cyclohexane–ethyl acetate).
CDCl3)
d
: 1.04 (s, 3H), 1.13 (s, 3H), 1.31 (t, 3H, J¼7.3 Hz), 2.07 (s, 3H),
2.39–2.49 (m, 1H), 2.83–3.08 (m, 3H), 3.22 (s, 1H), 4.24 (q, 2H,
J¼7.3 Hz), 6.16 (s, 1H), 7.18–7.32 (m, 5H). 13C NMR (100 MHz, CDCl3)
d
: 14.4, 20.9, 22.0, 23.3, 29.6, 33.3, 34.1, 50.9, 62.0, 98.2, 118.9, 126.6,
128.5, 128.8, 140.5, 168.6, 168.7. API-ES (m/z): 749 (2MþþNa). Anal.
Calcd for C19H25NO6 (363.40): C, 62.80; H, 6.93; N, 3.85. Found: C,
63.02; H, 7.06; N, 3.61.
4.3.1. 6-Acetoxy-4-(ethoxycarbonyl)-3-ethyl-5,5-dimethyl-5,6-
dihydro-4H-1,2-oxazine 2-oxide, 6a (dr¼78:22)
Minor diastereomer. Yield: 21%. Yellow solid, mp¼137–139 ꢁC. IR
(cmꢀ1, Nujol): 1750, 1718, 1621, 1449, 1216. 1H NMR (400 MHz,
Major diastereomer. Yield: 62%. Yellow solid, mp¼42–44 ꢁC. IR
CDCl3)
d: 0.96 (s, 3H), 1.03 (s, 3H), 1.29 (t, 3H, J¼7.3 Hz), 2.08 (s, 3H),
(cmꢀ1, Nujol): 1759, 1725, 1616, 1455, 1217. 1H NMR (400 MHz,
2.21–2.33 (m,1H), 2.71 (s,1H), 2.83–2.97 (m,1H), 3.00–3.11 (m, 2H),
4.07–4.17 (m, 1H), 4.21–4.31 (m, 1H), 6.01 (s, 1H), 7.16–7.35 (m, 5H).
CDCl3)
d
: 1.10–1.17 (m, 9H), 1.30 (t, 3H, J¼7.3 Hz), 2.13 (s, 3H), 2.18–
2.30 (m, 1H), 2.48–2.62 (m, 1H), 3.47 (s, 1H), 4.19–4.29 (m, 2H), 6.17
13C NMR (100 MHz, CDCl3)
d: 14.4, 20.8, 21.2, 26.4, 29.4, 33.5, 35.0,
(s, 1H). 13C NMR (100 MHz, CDCl3)
d
: 8.4, 14.4, 20.9, 22.0, 23.4, 26.1,
52.2, 61.9, 98.0, 118.9, 126.8, 128.8, 128.9, 140.2, 168.2, 168.8. API-ES
(m/z): 749 (2MþþNa). Anal. Calcd for C19H25NO6 (363.40): C, 62.80;
H, 6.93; N, 3.85. Found: C, 63.04; H, 7.09; N, 3.63.
33.4, 50.3, 62.0, 98.3,120.5,168.6,168.7. API-ES (m/z): 310 (MþþNa),
326 (MþþK), 333 (Mþþ2Na), 597 (2 MþþNa). Anal. Calcd for
C13H21NO6 (287.31): C, 54.35; H, 7.37; N, 4.88. Found: C, 54.68; H,
7.56; N, 4.95.
4.3.5. 6-Acetoxy-4-(ethoxycarbonyl)-3-(5-methoxy-5-oxopentyl)-
5,5-dimethyl-5,6-dihydro-4H-1,2-oxazine 2-oxide, 6e (dr¼80:20)
Major diastereomer. Yield: 61%. Yellow oil. IR (cmꢀ1, neat): 1749,
Minor diastereomer. Yield: 18%. Yellow solid, mp¼105–107 ꢁC. IR
(cmꢀ1, Nujol): 1756, 1720, 1622, 1451, 1219. 1H NMR (400 MHz,
CDCl3)
3H), 2.11–2.24 (m, 1H), 2.61–2.73 (m, 1H), 3.14 (s, 1H), 4.08–4.18 (m,
1H), 4.23–4.33 (m, 1H), 6.10 (s, 1H). 13C NMR (100 MHz, CDCl3)
d: 1.10–1.16 (m, 6H),1.25 (s, 3H),1.31 (t, 3H, J¼7.3 Hz), 2.08 (s,
1718,1622,1455,1224. 1H NMR (400 MHz, CDCl3)
d: 1.12 (s, 6H),1.29
(t, 3H, J¼7.3 Hz), 1.50–1.76 (m, 4H), 2.08–2.19 (m, 1H), 2.12 (s, 3H),
d:
2.31 (dt, 2H, J¼1.7, 7.3 Hz), 2.58–2.68 (m, 1H), 3.45 (s, 1H), 3.63 (s,
8.4, 14.4, 20.9, 21.4, 26.6, 26.7, 33.4, 50.8, 61.9, 98.0, 120.1, 168.2,
168.9. API-ES (m/z): 310 (MþþNa), 326 (MþþK), 333 (Mþþ2Na),
597 (2MþþNa). Anal. Calcd for C13H21NO6 (287.31): C, 54.35; H,
7.37; N, 4.88. Found: C, 54.53; H, 7.54; N, 4.59.
3H), 4.16–4.29 (m, 2H), 6.15 (s, 1H). 13C NMR (100 MHz, CDCl3)
d:
14.4, 20.9, 22.0, 23.3, 23.4, 24.5, 31.9, 33.4, 33.7, 50.6, 51.7, 62.0, 98.3,
119.2, 168.5, 168.7, 173.8. API-ES (m/z): 396 (MþþNa), 412 (MþþK),
419 (Mþþ2Na), 769 (2MþþNa). Anal. Calcd for C17H27NO8 (373.40):
C, 54.68; H, 7.29; N, 3.75. Found: C, 54.87; H, 7.51; N, 3.56.
4.3.2. 6-Acetoxy-3-butyl-4-(ethoxycarbonyl)-5,5-dimethyl-5,6-
Minor diastereomer. Yield: 19%. Yellow waxy solid. IR (cmꢀ1
,
dihydro-4H-1,2-oxazine 2-oxide, 6b (dr¼79:21)
neat): 1750, 1718, 1621, 1449, 1216. 1H NMR (400 MHz, CDCl3)
d: 1.11
Major diastereomer. Yield: 65%. Yellow waxy solid. IR (cmꢀ1
,
(s, 3H), 1.24 (s, 3H), 1.28 (t, 3H, J¼7.3 Hz), 1.49–1.69 (m, 4H), 2.00–
2.10 (m, 1H), 2.06 (s, 3H), 2.32 (t, 2H, J¼7.3 Hz), 2.60–2.72 (m, 1H),
3.13 (s, 1H), 3.64, (s, 3H), 4.06–4.17 (m, 1H), 4.20–4.31 (m, 1H), 6.07
neat): 1757, 1723, 1620, 1453, 1218. 1H NMR (400 MHz, CDCl3)
d:
0.91 (t, 3H, J¼7.3 Hz), 1.13 (s, 3H), 1.14 (s, 3H), 1.26–1.42 (m, 5H),
1.44–1.69 (m, 2H), 2.05–2.17 (m, 1H), 2.12 (s, 3H), 2.60–2.70 (m, 1H),
3.45 (s, 1H), 4.17–4.31 (m, 2H), 6.17 (s, 1H). 13C NMR (100 MHz,
(s, 1H). 13C NMR (100 MHz, CDCl3)
d: 14.3, 20.8, 21.4, 23.4, 24.7, 26.7,
32.8, 33.4, 33.7, 51.2, 51.7, 61.9, 98.0, 118.9, 168.1, 168.8, 173.8. API-ES
(m/z): 396 (MþþNa), 412 (MþþK), 419 (Mþþ2Na), 769 (2MþþNa).
C17H27NO8 (373.40): C, 54.68; H, 7.29; N, 3.75. Found: C, 54.45; H,
7.08; N, 3.89.
CDCl3) d: 14.0, 14.5, 21.0, 22.1, 22.6, 23.5, 26.0, 32.1, 33.5, 50.8, 62.1,
98.3, 119.8, 168.6, 168.7. API-ES (m/z): 338 (MþþNa), 354 (MþþK),
361 (Mþþ2Na), 653 (2MþþNa). Anal. Calcd for C15H25NO6 (315.36):
C, 57.13; H, 7.99; N, 4.44. Found: C, 56.89; H, 8.21; N, 4.19.
Minor diastereomer. Yield 18%. Yellow solid, mp¼110–113 ꢁC. IR
4.3.6. 6-Acetoxy-3-butyl-4-(ethoxycarbonyl)-5-hexyl-5,6-
dihydro-4H-1,2-oxazine 2-oxide, 6f (dr¼63:37)
(cmꢀ1, Nujol): 1750, 1723, 1619, 1453, 1223. 1H NMR (400 MHz,
CDCl3)
d
: 0.92 (t, 3H, J¼7.3 Hz),1.14 (s, 3H),1.26 (s, 3H),1.27–1.41 (m,
Major diastereomer. Yield: 25%. Yellow oil. IR (cmꢀ1, neat): 1735,
5H),1.42–1.65 (m, 2H),1.99–2.07 (m,1H), 2.08 (s, 3H), 2.65–2.75 (m,
1H), 3.13 (s, 1H), 4.08–4.18 (m, 1H), 4.22–4.34 (m, 1H), 6.10 (s, 1H).
1622, 1551, 1213. 1H NMR (400 MHz, CDCl3)
d: 0.81–0.95 (m, 6H),
1.15–1.51 (m, 16H), 1.59–1.76 (m, 1H), 2.11 (s, 3H), 2.12–2.22 (m, 1H),
13C NMR (100 MHz, CDCl3)
d
: 13.8, 14.2, 20.7, 21.2, 22.6, 25.9, 26.6,
2.47–2.62 (m, 2H), 3.25 (d, 1H, J¼10.7 Hz), 4.13–4.30 (m, 2H), 6.55
32.7, 33.2, 51.0, 61.7, 97.8, 119.2, 168.0, 168.6. API-ES (m/z): 338
(MþþNa), 354 (MþþK), 361 (Mþþ2Na), 653 (2MþþNa). Anal. Calcd
for C15H25NO6 (315.36): C, 57.13; H, 7.99; N, 4.44. Found: C, 57.44; H,
8.12; N, 4.21.
(d, 1H, J¼2.6 Hz). 13C NMR (100 MHz, CDCl3)
d: 13.9, 14.2, 14.3, 20.9,
22.5, 22.6, 26.1, 26.2, 29.2, 29.5, 31.0, 31.6, 36.4, 46.8, 62.4, 93.1,
119.2, 168.7, 169.9. API-ES (m/z): 765 (2MþþNa). Anal. Calcd for
C19H33NO6 (371.47): C, 61.43; H, 8.95; N, 3.77. Found: C, 61.65; H,
9.08; N, 3.58.
4.3.3. 6-Acetoxy-4-(ethoxycarbonyl)-5,5-dimethyl-3-phenyl-5,6-
dihydro-4H-1,2-oxazine 2-oxide, 6c (dr¼100:0)
Minor diastereomer. Yield: 15%. Yellow oil. IR (cmꢀ1, neat): 1738,
1618, 1556, 1217. 1H NMR (400 MHz, CDCl3)
d: 0.79–0.99 (m, 6H),
Yield: 47%. White solid, mp¼147–150 ꢁC. IR (cmꢀ1, Nujol): 1732,
1.15–1.68 (m, 17H), 2.00 (s, 3H), 2.19–2.36 (m, 1H), 2.48–2.58 (m,
1H), 2.70–2.81 (m, 1H), 3.16 (br s, 1H), 4.06–4.19 (m, 1H), 4.21–4.33
1593,1456,1225. 1H NMR (400 MHz, CDCl3)
d
: 0.94 (t, 3H, J¼7.3 Hz),
1.24 (s, 3H), 1.25 (s, 3H), 2.15 (s, 3H), 3.88–4.04 (m, 2H), 4.06 (s, 1H),
(m, 1H), 6.38 (d, 1H, J¼2.1 Hz). 13C NMR (100 MHz, CDCl3)
d: 14.0,
6.29 (s, 1H), 7.30–7.43 (m, 3H), 7.72–7.79 (m, 2H). 13C NMR
14.2, 14.3, 20.9, 22.7, 22.8, 26.1, 26.6, 29.1, 30.5, 31.7, 33.3, 35.2, 44.0,
62.1, 95.7, 119.2, 168.3, 169.6. API-ES (m/z): 765 (2MþþNa). Anal.
Calcd for C19H33NO6 (371.47): C, 61.43; H, 8.95; N, 3.77. Found: C,
61.71; H, 9.14; N, 3.60.
(100 MHz, CDCl3) d: 13.9, 21.0, 22.4, 23.6, 33.6, 50.6, 61.7, 98.4, 117.0,
127.7, 128.5, 129.6, 132.1, 168.6, 168.8. API-ES (m/z): 358 (MþþNa),
374 (MþþK), 381 (Mþþ2Na), 693 (2MþþNa). Anal. Calcd for
C17H21NO6 (335.35): C, 60.89; H, 6.31; N, 4.18. Found: C, 60.69; H,
6.38; N, 4.12.
Acknowledgements
4.3.4. 6-Acetoxy-4-(ethoxycarbonyl)-5,5-dimethyl-3-phenethyl-
5,6-dihydro-4H-1,2-oxazine 2-oxide, 6d (dr¼73:27)
Financial support from the University of Camerino and MUR-
Italy (National Project ‘Sintesi organiche ecosostenibili mediate da
nuovi sistemi catalitici’).
Major diastereomer. Yield: 58%. White solid, mp¼93–95 ꢁC. IR
(cmꢀ1, Nujol): 1755, 1723, 1623, 1457, 1222. 1H NMR (400 MHz,

2920
R. Ballini et al. / Tetrahedron 65 (2009) 2916–2920
M.; Babiano, R.; Cintas, P.; Higes, F. J.; Jime´nez, J. L.; Palacios, J. C.; Silva, M. A. J. Org.
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