Synthesis of new aza-bicyclic 2-isoxazolines by 1,3-dipolar cycloaddition of endocyclic enecarbamates and enamides with nitrile oxides

Article abstract of DOI:10.1016/j.tetlet.2008.11.096

Novel aza-bicyclic 2-isoxazolines, 4,5-dihydroisoxazole[5,4-b]pyrrolidines, and 4,5-dihydroisoxazole[5,4-b]piperidines were synthesized in a highly regioselective manner through a 1,3-dipolar cycloaddition reaction of 5- and 6-membered endocyclic enecarba

Full text of DOI:10.1016/j.tetlet.2008.11.096

Tetrahedron Letters 50 (2009) 684–687
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Tetrahedron Letters
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Synthesis of new aza-bicyclic 2-isoxazolines by 1,3-dipolar cycloaddition
of endocyclic enecarbamates and enamides with nitrile oxides
Valderes Moraes de Almeida a, Rosiel José dos Santos a, Alexandre José da Silva Góes b, José Gildo de Lima a,
Carlos Roque Duarte Correia c, Antônio Rodolfo de Faria a,
*
a LASOF-Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco-UFPE,CEP 50470-521, Recife-PE, Brazil
b Departamento de Antibióticos, UFPE, CEP 50560-901, Recife-PE, Brazil
c Instituto de Química, Unicamp, C.P. 6154, CEP 13083-970, Campinas-SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2008
Revised 24 November 2008
Accepted 25 November 2008
Available online 30 November 2008
Novel aza-bicyclic 2-isoxazolines, 4,5-dihydroisoxazole[5,4-b]pyrrolidines, and 4,5-dihydroisoxazole[5,4-
b]piperidines were synthesized in a highly regioselective manner through a 1,3-dipolar cycloaddition
reaction of 5- and 6-membered endocyclic enecarbamates and enamides with several nitrile oxides in
good to excellent yields. Hydrogenolysis of 5- and 6-membered Cbz-cycloadducts led to secondary
amines, which presented distinctive stabilities. 2-Isoxazoline bisamides were obtained in good yields
through a N-benzoylation, followed by ammonolysis of the secondary amine, or directly from ammonol-
ysis of the cycloadducts.
Keywords:
Endocyclic enecarbamates
Enamides
Ó 2008 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition
Nitrile oxides
2-Isoxazolines
Endocyclic enecarbamates and enamides possess a strategically
located enamine functionality which makes these nitrogen con-
taining heterocycles very versatile precursors of other N-heterocy-
cles and alkaloids.1
The 5-membered endocyclic enecarbamates and enamides (8)
were prepared by direct application of the Kraus method,9 whereas
the 6-membered ones (6) were prepared using a modification of
this methodology (Scheme 1).10 Application of the Kraus method
to the synthesis of 6-membered enecarbamates and enamides
led to very low yields of the desired products (<10%).
Five different 1,3-dipoles (p-chlorobenzonitrile oxide, p-
methoxybenzonitrile oxide, p-toluyilformonitrile oxide, (2-furfu-
ryl)-formonitrile oxide, and carboethoxyformonitrile oxide-CEF-
NO) were tested in these 1,3-dipolar cycloaddition reactions with
several endocyclic enecarbamates and enamides. CEFNO was
formed in situ from ethyl chlorooximidoacetate, which was ob-
tained from glycine ethyl ester hydrochloride,11 while benzonitrile
and other formonitrile oxides were formed in situ from the respec-
tive hydroximinoyl chloride precursors,12 which in turn were ob-
tained from the respective oximes (Schemes 1 and 2).13
When the pure ethyl chlorooximidoacetate was used as precur-
sor to generate the CEFNO, the optimum condition for the 1,3-
dipolar cycloaddition reactions, which provided the best output,
such as low formation of CEFNO dimer, was the following: enecar-
bamate/enamide as limiting reagent, dry CHCl3 or THF as solvent,
dry Et3N as base, slow addition of the CEFNO precursor into a solu-
tion of enamide/enecarbamate and Et3N, at room temperature, un-
der vigorous stirring.14
The [2+2] and [4+2] cycloaddition reactions involving enecarba-
mates and enamides have been reported before,2,3 however, the
1,3-dipolar cycloaddition reactions involving these N-heterocycles
have remained unreported in literature in spite of their potential as
dipolarophiles. 1,3-Dipolar cycloaddition of endocyclic enecarba-
mate and enamide with nitrile oxides opens new routes to novel
heterobicyclic compounds by incorporating the 2-isoxazoline nu-
cleus.4 Many compounds bearing the 2-isoxazoline nucleus show
relevant biological activity, for instance, the glutamic acid antago-
nist (1), the antithrombotic (2), the antitumoral (3), the anti-
inflammatory (4), among others (Fig. 1).5–8 New transformations
involving endocyclic enecarbamates and enamides have been the
main focus of our research laboratories and herein we report on
the development of a new synthetic methodology involving the
1,3-dipolar cycloaddition of endocyclic enecarbamates and ena-
mides with nitrile oxides for the construction of new aza-bicyclic
2-isoxazolines: 4,5-dihydroisoxazole[5,4-b]pyrrolidines and 4,5-
dihydroisoxazole[5,4-b]piperidines.
For the other nitrile oxides (benzonitrile oxides and (2-furfu-
ryl)-formonitrile oxide), obtained in situ from their respective
* Corresponding author. Tel./fax: +55 81 21268511.
E-mail address: rodolfo@ufpe.br (A.R. de Faria).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.096

V. M. de Almeida et al. / Tetrahedron Letters 50 (2009) 684–687
685
MeO
H
N
COOH
H
O
O
O
Cl
N
SO2NH2
N
O
H
NH3
OSO2Me
N
O
N
O
O
H
CO2
H2N
COOH
2
3
4
HN
NH2
1
Figure 1. Some bioactive 2-isoxazolines.
crude precursors, excess enecarbamates/enamides in dry CHCl3,
provided the best reaction condition, in which the dimer of the ni-
trile oxide is not observed.14 The use of (2-furfuryl)-hydroximinoyl
chloride, precursor of the (2-furfuryl)-formonitrile oxide, resulted
in very low yields of the cycloadducts (7l) and (9j), probably due
to its instability.
5-Membered endocyclic enecarbamates and enamides (8)
underwent smooth 1,3-cycloaddition when CEFNO was used
(Scheme 2). Complete conversion of the starting enecarbamate/
enamide was observed in all cases evaluated, whereas 6-mem-
bered enecarbamates/enamides led to incomplete conversions
with this reagent.
The chiral 5-membered endocyclic enecarbamates (10) were
prepared as described before15 and were submitted to the 1,3-
dipolar cycloaddition with CEFNO (Scheme 3) applying the same
optimized reaction conditions described for the racemic series.
The diastereoisomeric isoxazolines (11) and (12) were easily
separated by flash chromatography and were identified by estab-
lishment of the relative configuration of the H5 and H6a-protons.
Due to the defined absolute configuration of the C5-carbon from
the starting chiral enecarbamate (10), we assigned the structure
of the diastereoisomer (11) using NOESY and NOEDIF techniques
(Fig. 2). The diastereoisomer (12) does not show correlation be-
tween the H5 and H6a-protons in the NOESY spectrum.
The low diastereoselectivity of the 1,3-dipolar cycloaddition is
probably due to the dipolar mechanism of the reaction and the dis-
tance of the ester group in C5. Similar low selectivity was also ver-
ified in some Heck arylation reactions involving chiral
enecarbamates,16 in contrast with [2+2] cycloadditions of these
enecarbamates with ketenes.17
R2
N
(b)
(a)
N
N
O
N
N
N
R1
O
R1
O
5
7
6
entry enecarbamate /
enamide (yield)
R1
Cycloadducts
(yield)
R1
R2
EtO2C
EtO2C
H
H
1
2
3
4
5
6
7
8
6a (90 %)
6b (94%)
6c (75%)
6d (95%)
6e (96%)
6f (94%)
6g (95%)
6h (95%)
6i (94%)
6a
OEt
OBn
4-NO2C6H4
4-FC6H4
4-OMeC6H4
4-tBuC6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
OEt
7a (70%)
7b (68%)
7c (45%)
7d (61%)
7e (64%)
7f (60%)
7g (60%)
7h (55%)
7i (60%)
7j (54%)
7k (58%)
7l (24%)i
7m (62%)
7n (64%)
OEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
4-OMeC6H4
4-CH3C6H4
2-furfuryl
4-ClC6H4
4-ClC6H4
O
(a)
OBn
4-NO2C6H6
4-FC6H6
4-OMeC6H6
4-tBuC6H6
4-ClC6H6
4-BrC6H6
4-CH3C6H6
OEt
N
O
N
O
O
O
N
+
OR
N
N
Boc
H
H
OR
OR
Boc
Boc
10
11
12
entry
R
Yield of 11
Yield of 12
Ratio of 11 :
12
9
10
11
12
13
14
1
2
a – Me
b – Bn
37 %
34 %
45 %
46 %
45:55
43:57
6b
6f
6f
6e
OBn
OBn
4-tBuC6H4
4-tBuC6H4
4-OMeC6H4
4-tBuC6H4
4-tBuC6H4
4-OMeC6H4
Scheme 3. 1,3-Dipolar cycloaddition of chiral 5-membered endocyclic enecarba-
mates (10). (a) Ethyl chlorooxiimidoacetate, Et3N, THF, rt.
Scheme 1. Synthesis and 1,3-dipolar cycloaddition of 6-membered endocyclic
enecarbamates and enamides (6). (a) Alkyl chloroformates or p-(R1)-benzoyl
chlorides, Et3N, THF, reflux, (b) ethyl chlorooxiimidoacetate or benzohydroximinoyl
chlorides or (2-furfuryl)-hydroximinoyl chloride (i)unstable, Et3N, CHCl3, or THF, rt.
Boc
N
H
H6a
O
N
CO2R2
CO2R2
H5
EtO2C
R2
EtO2C
11
H5
N
(a)
N
N
H6a
O
N
Boc
H
O
3,7 % NOE
12
N
R1
O
O
R1
Figure 2. Assignment of the relative configuration of diastereoisomer 11, by
NOEDIF.
9
8
entry
Cycloadducts
(yield)
R1
R2
1
2
3
4
5
6
7
8
9
9a (80%)
9b (78%)
9c (64%)
9d (70%)
9e (75%)
9f (74%)
9g (65%)
9h (68%)
9i (60%)
9j (29%)i
9k (70%)
9l (72%)
OEt
OBn
4-NO2C6H4
4-FC6H4
4-OMeC6H4
4-tBuC6H4
4-ClC6H4
4-tBuC6H4
4-NO2C6H4
4-tBuC6H4
OBn
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
O
O
O
OEt
OEt
H2, Pd/C
OEt
4-ClC6H4
4-CH3C6H4
2-furfuryl
4-OMeC6H4
4-ClC6H4
H
H
H
H
H
10
11
12
N
N
N
O
O
OEt
N
H
O
N
N
degradation
7b
13
CBz 14
Cbz
Scheme 2. 1,3-Dipolar cycloaddition of 5-membered endocyclic enecarbamates/
enamides (8). (a) Ethyl chlorooxiimidoacetate or benzohydroximinoyl chlorides or
(2-furfuryl)-hydroximinoyl chloride (i)unstable, Et3N, CHCl3, or THF, rt.
Scheme 4. Degradation of unprotected 6-membered isoxazoline amine (13).

686
V. M. de Almeida et al. / Tetrahedron Letters 50 (2009) 684–687
On the other hand, bisamides (17c–g) were obtained in a
O
O
OEt
NH2
straightforward manner. Carbamate (9b) underwent clean hydrog-
enolysis to provide (16), which was acylated with several benzoyl-
chlorides to furnish the corresponding ester-benzamides (9c–g).19
Ammonolysis then converted (9c–g) into the corresponding bisa-
mides (17c–g) in good overall yields (Scheme 6).
N
N
NH4OH, THF, rt
60-71%
O
O
N
N
O
O
In summary, we explored a new 1,3-dipolar cycloaddition reac-
tion of 5- and 6-membered endocyclic enecarbamates/enamides
with nitrile oxides to obtained novel aza-bicyclic 2-isoxazoline
compounds, in good yields and in a highly regioselective manner.
These new bicyclic systems can be used as potential intermediates
in the synthesis of a series of bioactive compounds, such as alka-
loids and amino acids. This study also demonstrates the versatility
of endocyclic enecarbamates/enamides in organic synthesis and
opens up new opportunities for the chemistry of 2-isoxazolines.
Studies regarding the anti-inflammatory activity of compounds
(15) and (17), among other isoxazoline derivatives, are in progress
and will be reported in due course.
R3
R3
15c-f
7c-f
Scheme 5. Ammonolysis of piperidine isoxazoline cycloadducts (7c–f) (R3: c = NO2
(60%), d = F (71%), e = OMe (62%), f = tBu (68%).
O
O
OEt
N
OEt
N
H2, Pd/C
methanol
O
O
N
N
H
100%
Cbz
O
16
9b
Acknowledgments
c- 82%
d- 86%
e- 90%
f- 84%
g- 95%
We thank CNPq (Conselho Nacional de Desenvolvimento Cientí-
fico e Tecnológico), FACEPE (Fundação de Amparo à Ciência e Tecn-
ologia do Estado de Pernambuco) for financial support, Analytical
Center of DQF-UFPE and IQ-UNICAMP for the NMR, FTIR, and MS
spectra.
benzoyl chlorides
Et3N, CHCl3
O
NH2
OEt
N
O
N
O
NH4OH, THF
Supplementary data
N
N
c- 68%
d- 72%
e- 70%
f- 65%
g- 86%
O
O
Representative NMR spectra and experimental procedures for
the hydrogenolysis, the ammonolysis, and the N-benzoylation
reactions. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.11.096.
17
R4
9
R4
Scheme 6. Synthesis of bisamides (17) (R4: c = NO2, d = F, e = OMe, f = t-Bu, g = Cl).
References and notes
The structures of new 6-membered endocyclic enecarbamates
and enamides (6), and aza-bicyclic isoxazolines (7), (9), (11),
(12), (15), and (17) were fully elucidated by 1H and 13C NMR, FTIR,
and HRMS.18 Although NMR spectra at room temperature are com-
plex, due to the presence of rotamers, some diagnostic signals, that
confirm the isoxazoline cycloadduct formation, are present and
clear in 1H NMR spectra, such as a doublet or a broad signal near
6.20 ppm for H6a (for 9, 11, 12, and 17) and H7a (for 7 and 15)
and in 13C NMR spectra, such as a signal near 92 ppm for C6a
and C7a, respectively.
The rotamer signals, due to the high rotational barrier of the
amide and carbamate bonds, underwent total coalescence, when
isoxazoline 1H NMR spectra were obtained at 65 °C.19 Another
peculiarity of the 13C NMR and 1H NMR spectra was the low signal
resolution of the bicyclic ring carbons and exocyclic protons of
isoxazolines, resulting in broad signals.
Another interesting observation uncovered by this study was
the distinctive reactivity of the isoxazoline cycloadducts coming
from the 5- and 6-membered enecarbamates during hydrogenoly-
sis.19 Hydrogenolysis of (7b) led to complex mixtures, whereas
hydrogenolysis of (9b) occurred cleanly to provide the secondary
amine (16) (Schemes 4 and 6).
We hypothesize that the bicyclic piperidine isoxazoline is more
prone to ring opening generating an unstable and very reactive
acyliminium intermediate (14), which decompose to several
unidentified products.
1. (a) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039; (b) De Faria, A. R.;
Salvador, E. L.; Correia, C. R. D. J. Org. Chem. 2002, 67, 3651; (c) Padwa, A.;
Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001, 66, 1716.
2. Correia, C. R. D.; De Faria, A. R.; Matos, C. R. R. Tetrahedron Lett. 1993, 34, 27.
3. (a) Lenz, G. R. Synthesis 1978, 489; (b) Campbell, A.; Lenz, G. R. Synthesis 1987,
421.
4. Excellent reviews: (a) Pellissier, H. Tetrahedron 2007, 63, 3235; (b) 1,3-Dipolar
cycloaddition in ‘Comprehensive Organic Synthesis’ 1991, Vol. 5, pp 247–270.; (c)
Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.
5. Conti, P.; Amici, M. D.; Roda, G.; Vistoli, G.; Stensbol, T. B.; Bräuner-Osborne, H.;
Madsen, U.; Toma, L.; Micheli, C. D. Tetrahedron 2003, 59, 1443.
6. Pruitt, J. R.; Pinto, D. J.; Estrella, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.;
Wright, M. R.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2000, 10, 685.
7. Martin, D. G.; Duchamp, D. J.; Chidester, C. G. Tetrahedron Lett. 1973, 14, 2549.
8. Groutas, W. C.; Venkataramam, R.; Chong, L. S.; Yoder, J. E.; Epp, J. B.; Stanga, M.
A.; Kim, E.-H. Bioorg. Med. Chem. 1995, 3, 125.
9. Kraus, G. A.; Neuenschwander, K. J. Org. Chem. 1981, 46, 4791.
10. The 1-piperideine trimer (5) was prepared according to Claxton, G. P.; Allen, L.;
Grisar, J. M. Org. Synth. 5, 968. The acylation agent is added slowly over a
solution of the trimer and Et3N in dry THF, under reflux. The reaction mixture is
left over reflux for additional 3 h. Next, THF is removed in vacuo and the crude
enamide/enecarbamate purified by flash-chromatography: silica gel, ethyl
acetate/hexane 1:10. Enamides and enecarbamates absorb iodine intensely on
TLC.
11. Kozikowski, A. P.; Adamczy, M. J. Org. Chem. 1983, 48, 366.
12. Mincheva, Z.; Coutois, M.; Creche, J.; Rideau, M. Bioorg. Med. Chem. 2004, 12,
191.
13. Park, K.; Marshall, W. J. Tetrahedron Lett. 2004, 45, 4931. After chlorination of
the oximes with NCS, the reaction mixture was washed with water to remove
the succinimide. The aqueous phase was extracted twice with CH2Cl2. The
organic layers were combined, dried with Na2SO4 and then concentrated in
vacuo. The hydroximinoyl chlorides were used without further purification..
14. Typical experimental procedures for 1,3-dipolar cycloaddition: (a) For CEFNO 1,3-
dipolar cycloadditions: Ethyl chlorooximidoacetate (CEFNO precursor,
5.1 mmol) is added slowly to a solution of the enecarbamate/enamide (6),
(8), or (10) (4.6 mmol) and triethylamine (5.7 mmol) in 15 mL of dry CHCl3 or
THF, using a syringe or an addition funnel with a pressure equalizer, over
approximately an hour. Next, another equiv of triethylamine and ethyl
chlorooximidoacetate is added under the same conditions, if necessary. The
Although cycloadduct (7b) could not be used to obtain amides
(15), they were obtained by direct cycloaddition of the piperideine
N-(benzoyl)-enamides (6c–f), with CEFNO followed by ammonoly-
sis (Scheme 5).19

V. M. de Almeida et al. / Tetrahedron Letters 50 (2009) 684–687
687
reaction mixture is washed with water (50 mL). THF must be removed before,
if used. The aqueous phase is extracted with CHCl3 (2 Â 40 mL). The chloroform
layers are combined and, after removing the solvent, the residue is submitted
to a flash chromatography: silica gel, ethyl acetate/hexane 1:5. Part of the 6-
membered enecarbamate/enamide (6) is recovered. (b) For benzonitrile and (2-
furfuryl)-formonitrile oxides cycloadditions: Crude hydroximinoyl chloride
(1.64 mmol, in 4 mL of dry CHCl3 is added slowly (40–60 min) to a solution
of the enecarbamate/enamide (6) or (8) (2.46 mmol) and Et3N (1.97 mmol) in
4 mL of CHCl3. The reaction mixture is maintained under stirring for two
additional hours. Excess of enamide/enecarbamate is recovered after usual
work up and flash chromatography: silica gel, ethyl acetate/hexane 1:5. The Rf
for the cycloadduct on a TLC plate is smaller than that observed for the
enamide/enecarbamate (UV, phosphomolybdic acid).
cmÀ1) main bands: 3030, 2986, 2860, 1721, 1652, 1600, 1509, 1408, 1270,
1131, 931, 853. HRMS-EI (m/z): M+ calcd for C15H15FN2O4 306.10158, found
306.10147. Compound (9h) 1H NMR (CDCl3, d, 300 MHz, rt): 1.33 (s, 9H); 2.00–
2.35 (m, 2H); 3.20 and 3.65 (br s, 1H, rot.); 4.23 (m, 1H); 4.46 (m, 1H); 6.25 and
6.98 (br s, 1H, rot.); 7.30–7.50 (m, 4H); 7.52–7.76 (m, 4H). 13C NMR (CDCl3, d,
75 MHz, rt): 28.2 (CH2), 31.1 (CH3), 34.8 (CH), 43.1 (CH2), 51.6 (C), 94.7 (CH),
125.3 (CH), 126.6 (C), 128.0 (CH), 128.1 (CH), 129.3 (CH), 132.0 (C), 136,4 (C),
154.1 (C), 156.9 (C@N), 169.7 (C@O). FTIR (KBr, cmÀ1) main bands: 2962, 1635,
1620, 1492, 1411, 1357, 1269, 1176, 1141, 1091, 875, 837. Mp 158–161 °C.
HRMS-EI (m/z): M+ calcd for C22H23ClN2O2 382.14480, found 382.14438.
Compound (11b) 1H NMR (CDCl3, d, 300 MHz, rt): 1.33 (t, J = 7 Hz, 3H), 1.48 and
1.30 (s, rot., 9H), 2.50 (m, 1H), 2.75 (m, 1H), 4.03 (t, J = 8 Hz, 1H), 4.30 (q,
J = 7 Hz, 2H), 4.69 and 4.55 (d, J = 9 Hz, rot., 1H), 5.22–4.90 (m, rot., 2H), 6.48
and 6.35 (d, J = 8 Hz, rot., 1H), 7.33 (br s, 5H). 13C NMR (CDCl3, d, 75 MHz, rt):
13.9 (CH3), 27.9 (CH3), 31.6 and 30.7 (CH2, rot.), 50.3 and 49.3 (CH, rot.), 58.3
and 57.8 (CH, rot.), 62 (CH2, ethyl ester), 67.3 (CH2, benzyl ester), 82 (C, Boc),
94.7 and 94.4 (CH, rot.), 127.8–128.4 (CH, aryl), 135.1 (C, aryl), 151.4 (C@O,
Boc), 152.3 (C@N), 159.8 (C@O, ethyl ester), 170.7 and 170.5 (C@O, benzyl
ester, rot.). FTIR (neat, cmÀ1) main bands: 3090, 2980, 2950, 1720 (bb), 1570,
1455, 1392, 1260, 1165, 1140, 1032, 900. HRMS-EI (m/z): M+ calcd for
C21H26N2O7 418.17400, found 418.17390. Compound (12b) 1H NMR (CDCl3, d,
300 MHz, rt): 1.36 (t, J = 7.2 Hz, 3H), 1.49 and 1.35 (s, rot. 9H), 2.35 (m, 1H),
2.54 (m, 1H), 4.01 (m, 1H), 4.36 (m, 1H), 4.34 (q, J = 7.2 Hz, 2H), 5.16 (m, rot.
2H), 6.53 and 6.37 (d, J = 7.8 Hz, rot.), 7.34 (br s, 5H). 13C NMR (CDCl3, d,
75 MHz, rt): 13.9 (CH3), 27.8 and 28.0 (CH3, rot.), 32.2 and 33.3 (CH2, rot.), 48.2
and 49.3 (CH, rot.), 58.5 and 59.1 (CH, rot.), 62.2 (CH2, ethyl ester), 67.2 (CH2,
benzyl ester), 82.1 (C, Boc), 95.6 and 96.5 (CH, rot.), 128.2-128.6 (CH, aryl),
134.8 and 135.1 (C, aryl), 152.2 and 152.5 (C@O, Boc, rot.), 152.7 (C@N), 159.7
15. Oliveira, D. F.; Miranda, P. C. L.; Correia, C. R. D. J. Org. Chem. 1999, 64, 6646.
16. Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia, C. R. D. Org. Lett. 2003, 5,
305.
17. Ambrósio, J. C. L.; Santos, R. H. deA.; Correia, C. R. D. J. Brazil Chem. Soc. 2003, 14,
27.
18. Representative spectra data for some new compounds: (6d) 1H NMR (CDCl3, d,
300 MHz, rt): 1.95 and 1.81 (m, 2H, rot), 2.13 (m, 2H); 3.81 and 3.57 (m, 2H,
rot), 4.88 and 5.24 (m, 1H, rot), 6.45 and 7.23 (d, J = 8.1 Hz, 1H, rot), 7.10 (m,
2H), 7.51 (m, 2H). 13C NMR (CDCl3, d, 75 MHz, rt): 21.6 (CH2), 21.8 (CH2), 41.2 e
46.7 (CH2, rot), 108.0 e 110.0 (CH, rot), 115.4 (d, 2J = 21.6 Hz, CH), 127.3 e 124.7
(CH, rot), 129.9 (C), 130.6 (d, 3J = 8.4 Hz, CH), 163.7 (d, 1J = 249 Hz, C–F), 168.2
(C@O). FTIR (neat, cmÀ1) main bands: 3110, 2920, 2875, 2800, 1633, 1601,
1507, 1409, 1377, 1227, 993, 848, 757, 723, 577. Compound (7e) 1H NMR
(CDCl3, d, 300 MHz, rt): 1.36 (t, J = 7.2 Hz, 3H), 1.68–1.93 (m, 4H), 3.21 (m, 1H),
3.36 (m, 1H), 3.82 (s, 3H), 4.29 (br s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 6.33 (br s, 1H),
6.92 (d, J = 9 Hz, 2H), 7.52 (d, J = 9 Hz, 2H). 13C NMR (CDCl3, d, 75 MHz, rt): 14
(CH3), 18.9 (CH2), 21.7 (CH2), 39.5 (CH2), 41.3 (CH), 55.3 (CH3), 62.1 (CH2), 91.6
(CH), 113.8 (CH, aryl), 126.4 (C, aryl), 129.7 (CH, aryl), 155.9 (C, aryl), 160
(C=N), 161.4 (C=O, amide), 172.2 (C@O, ester). FTIR (neat, cmÀ1) main bands:
3090, 2985, 2958, 1722, 1651, 1606, 1420, 1344, 1251, 1176, 1129, 1024, 921,
843. HRMS-EI (m/z): M+ calcd for C17H20N2O5 332,13722, found 332.12713.
Compound (9d) 1H NMR (CDCl3, d, 300 MHz, rt): 1.38 (t, J = 7.0 Hz; 3H), 2.22
(m, 1H), 2.40 (dd, J = 6.0 Hz, J = 13.5 Hz, 1H), 3.20 (br m, 1H), 4.12 (t, J = 8.0 Hz,
1H), 4.35 (br m, 1H), 4.36 (q, J = 7.0 Hz, 2H), 6.22 (br s, 1H), 7.12 (m, 2H), 7.69
(br s, 2H). 13C NMR (CDCl3, d, 75 MHz, rt): 14.1 (CH3), 27.9 (CH2), 43.5 (CH2),
51.2 (CH), 62.4 (CH2), 96.2 (CH), 115.6 (d, 2J = 21.5 Hz, CH), 130.4 (CH), 164.1 (d,
1J = 250 Hz, C–F), 131 (C), 152.4 (C), 159.8 (C@O), 168.7 (C@O). FTIR (neat,
(C@O, ethyl ester), 170.8 and 171.3 (C@O, benzyl ester, rot.). FTIR (neat, cmÀ1
)
main bands: 3080, 2980, 2940, 1750, 1725, 1595, 1452, 1380, 1252, 1180,
1039. HRMS-EI (m/z): M+ calcd for C21H26N2O7 418.17400, found 418.17385.
Compound (17g) 1H NMR (DMSO-d6, d, 300 MHz, rt): 2.18 (br m, 2H), 3.15 and
3.48 (br m, 1H, rot.), 4,19 (br m, 2H), 6.17 and 6.66 (d, J = 7.2 Hz, 1H, rot.), 7.58
(br s, 4H); 7.69 (s, 1H), 7.94 (s, 1H). 13C NMR (DMSO-d6, d, 75 MHz, rt): 26.8
(CH2), 43.5 (CH2), 51.9 (CH), 94.5 (CH), 128.5 (CH, aryl), 129.6 (C, aryl), 134.2
(CH, aryl), 135.3 (C, aryl), 152.2 (C@N), 160.5 (C@O, amide), 167.9 (C@O,
amide). FTIR (KBr, cmÀ1) main bands: 3310, 3172, 2990, 2870 1665, 1641,
1410, 841. Mp: 221–223 °C. HRMS-EI (m/z): M+ calcd for C13H12ClN3O3
293.05671, found 293.05628.
19. See the experimental procedures or spectra in the online version.