The first case of diastereoselective cycloadditions of enantiopure nitrilimines in aqueous media

Article abstract of DOI:10.1016/j.tetasy.2004.02.006

The diastereoselective cycloadditions of enantiopure nitrilimines 4 with ethyl acrylate were exploited in dry toluene and in aqueous sodium hydrogencarbonate as reaction media. Shorter reaction times and improved diastereoisomeric ratios of the resulting 5-ethoxycarbonyl-4,5-dihydropyrazoles 5 and 6 were observed in aqueous media.

Full text of DOI:10.1016/j.tetasy.2004.02.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1077–1079
The first case of diastereoselective cycloadditions
of enantiopure nitrilimines in aqueous media
Giorgio Molteni*
Universitꢀa degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, Via Golgi 19, 20133 Milano, Italy
Received 28 January 2004; accepted 5 February 2004
Abstract—The diastereoselective cycloadditions ofenantiopure nitrilimines 4 with ethyl acrylate were exploited in dry toluene and in
aqueous sodium hydrogencarbonate as reaction media. Shorter reaction times and improved diastereoisomeric ratios ofthe resulting
5-ethoxycarbonyl-4,5-dihydropyrazoles 5 and 6 were observed in aqueous media.
Ó 2004 Elsevier Ltd. All rights reserved.
Nitrilimine cycloadditions to ethylenic dipolarophiles
represent the choice method in the synthesis ofvariously
substituted 4,5-dihydropyrazoles.1 Due to the utility of
these compounds in enantiopure forms,2 diastereo-
selective nitrilimine cycloadditions have been developed
in which the stereogenic centre(s) is placed on the
dipolarophilic3 or the 1,3-dipolar4 reactants. In the lat-
ter case, however, the reported stereoselectivities are
invariably low. To gain better insights about this
methodology, it was felt advisable to investigate the
behaviour ofenantiopure nitrilimines 4 towards ethyl
acrylate as a function of the reaction media. First, the
enantiopure hydrazonoyl chlorides 35 were synthesised
through the reaction sequence outlined in the Scheme 1.6
Second, base treatment of 3 in the presence ofethyl
acrylate produced the diastereoisomeric cycloadducts 5
and 6. Two different reaction conditions and media were
exploited: (i) refluxing in dry toluene in the presence ofa
large excess (5 equiv) oftriethylamine (homogeneous
conditions, method A);7 and (ii) aqueous 0.1 M sodium
hydrogencarbonate at room temperature in the presence
oftetrahexylammonium chloride (THAC) as a catalyst
(heterogeneous conditions, method B).8 Reaction times,
product yields and diastereoisomeric ratio data are
shown in Table 1. All reactions were completely regio-
selective giving only the 5-ethoxycarbonyl-4,5-dihydro-
pyrazoles 5 and 6, as expected from the electronic
demands ofnitrilimine cycloadditions onto electron-
poor monosubstituted ethylenes.9 Despite the separa-
tion ofdiastereoisomeric cycloadducts 5 and 6 not being
feasible through standard chromatographic methods,
enantiopure 5 was obtained by crystallisation from the
reaction mixtures. Spectroscopic data ofmajor 510 are in
full agreement with those of similar 5-substituted-4,5-
dihydropyrazoles.11
As can be inferred from Table 1, shorter reaction times
and improved diastereoisomeric ratios were experienced
in aqueous media in comparison to the classic12 trieth-
ylamine–toluene cycloaddition protocol. The observed
rate accelerations, which are abnormal for a typically
concerted cycloaddition, can be accounted for by means
ofthe high local concentration ofthe reactants pro-
moted by hydrophobic effects.13 Close association of
organic reactants may also be responsible for the
enhanced diastereoselectivity. To this point, chemical
correlation experiments allowed us to assign the (5S)-
absolute configuration to all the major cycloadducts 5
(Scheme 2). Basic hydrolysis of 5a–c gave the known
25
D
3,5-dicarboxy-4,5-dihydropyrazole(S)-(+)-7, ½aŠ ¼ þ5:8
25
D
(c 0.40, DMSO) {lit.3c ½aŠ ¼ þ5:5 (c 0.40, DMSO)} while
acidic hydrolysis of 5d gave the 3-carboxy-5-ethoxycar-
bonyl-4,5-dihydropyrazole intermediate 8. The sub-
sequent basic hydrolysis ofthe latter also gave ( S)-(+)-7.
In conclusion, this first case ofa diastereoselective nit-
rilimine cycloaddition in an aqueous media, displays
some valuable features with respect to the usual homo-
geneous conditions: (i) rate acceleration and better dia-
stereoselectivity were experienced; (ii) reaction work-up
was greatly simplified by simple filtration ofthe crude
mixture; and (iii) an environmentally friendly 1,3-dipo-
lar cycloadditive protocol can be successfully elaborated
upon.
* Tel.: +39-02-50314141; fax: +39-02-50314115; e-mail: giorgio.
molteni@unimi.it
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.006

1078
G. Molteni / Tetrahedron: Asymmetry 15 (2004) 1077–1079
O
O
O
+
O
O
R*
-
SO2Cl2
0-5oC
pTolN NCl
A or B
pTolNH
N
R*
R*
0-5oC
Cl
Cl
1
2
3
O
O
COOEt
R*
R*
O
-
N
+
N
pTol
+
N
COOEt
N
COOEt
N
N
R*
pTol
pTol
4
6
5
A; Et3N, toluene,∆; B: aq. NaHCO3, THAC, rt.
d
b
c
a
O
R*
O
N
Ph
O
COOEt
H
Scheme 1.
Table 1. Cycloadditions between enantiopure nitrilimines 4 and ethyl
acrylate
Acknowledgements
Nitrilimine
Method
Time (h)
5 and 6a
5:6b
Thanks are due to MURST and CNR for financial
support.
4a
4a
4b
4b
4c
4c
4d
4d
A
B
A
B
A
B
A
B
9
2.5
8
80
73
81
74
43c
70
40c
75
60:40
68:32
65:35
68:32
57:43
60:40
65:35
72:28
3
14
2
References and notes
8
1.5
€
1. Caramella, P.; Grunanger, P. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York,
1984; Vol. 1, Chapter 3.
2. Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett.
2000, 4265.
3. (a) Garanti, L.; Molteni, G.; Pilati, T. Tetrahedron:
a Isolated yields.
b Determined from 1H NMR analysis ofreaction crudes.
c Some amount oftarry material was formed.
ꢀ
Asymmetry 2002, 13, 1285; (b) Barluenga, J.; Fernandez-
Marı, F.; Aguilar, E.; Viado, A. L.; Olano, B. Tetrahedron
ꢀ
ꢀ
Lett. 1998, 39, 4887; (c) Barluenga, J.; Fernandez-Marı,
F.; Gonzales, R.; Aguilar, E.; Revelli, G. A.; Viado, A. L.;
ꢀ
HOOC
ꢀ
aq. NaOH
~
Fananas, F. J.; Olano, B. Eur. J. Org. Chem. 2000, 1773.
4. (a) Agocs, A.; Benyei, A.; Somogyi, L.; Herczegh, P.
5a-c
N
COOH
THF
N
Tetrahedron: Asymmetry 1998, 9, 3359; (b) Grubert, L.;
€
pTol
Galley, G.; Patzel, M. Tetrahedron: Asymmetry 1996, 7,
1137; (c) Tronchet, J. J. M.; Tronchet, J. F.; Barbalat-Rey,
F. Heterocycles 1993, 36, 833.
(S)-(+)-7
HOOC
5. Hydrazonoyl chlorides, 3a and 3b, were synthesised
according to Ref. 4a.
6. Selected spectral data for hydrazonoyl chlorides 3c and d.
aq. HCl
THF
aq. NaOH
THF
(S)-(+)-7
5d
N
COOEt
1
3c: IR (neat) 3270, 1745, 1730 cmꢀ1; H NMR (CDCl3) d
N
1.28 (3H, t, J 6.8), 1.58 (3H, d, J 6.4), 2.33 (3H, s), 4.25
(2H, q, J 6.8), 5.26 (1H, q, J 6.4), 7.1–7.3 (4H, m), 8.34
(1H, br s). 3d: IR (Nujol) 3260, 3180, 1670 cmꢀ1; 1H NMR
(CDCl3) d 1.61 (3H, d, J 6.5), 2.38 (3H, s), 5.18 (1H, q, J
6.5), 6.90 (1H, br s, J 7.2), 7.0–7.4 (9H, m), 8.18 (1H, br s).
pTol
8
Scheme 2.

G. Molteni / Tetrahedron: Asymmetry 15 (2004) 1077–1079
1079
7. For a typical run: a solution of 3 (2.0 mmol) and ethyl
acrylate (0.60 g, 6.0 mmol) in dry toluene (10 mL) was
treated with triethylamine (1.01 g, 10.0 mmol) and refluxed
for the time indicated in the Table 1. The undissolved
material was filtered off and the solvent evaporated under
reduced pressure. The residue was taken up with chloro-
form (20 mL) and the solution slowly concentrated
affording as the major product 5 as an amorphous
powder, while the remaining solution contained diaste-
reoisomeric 6.
8. For a typical run: a mixture of 3 (5.0 mmol), ethyl acrylate
(1.50 g, 15.0 mmol), THAC (0.19 g, 0.5 mmol) and aqueous
5% sodium hydrogencarbonate (20 mL), was stirred at
room temperature for the time indicated in Table 1.
Filtration gave a residue, which was taken up with
chloroform (20 mL) and the solution slowly concentrated
affording pure 5 as an amorphous powder, while the
remaining solution contained diastereoisomeric 6.
(CDCl3) d 0.82 (3H, d, J 7.2), 0.93 (6H, d, J 7.0), 1.22 (3H,
t, J 6.8), 1.5–2.1 (9H, m), 2.32 (3H, s), 3.28 (1H, dd, J 17.7,
7.6), 3.52 (1H, dd, J 17.7, 11.9), 4.20 (2H, q, J 6.8), 4.80–
4.94 (2H, m), 7.0–7.3 (4H, m). 5b: IR (Nujol) 1735,
1
1730 cmꢀ1; H NMR (CDCl3) d 0.96 (3H, t, J 6.8), 0.98
(3H, d, J 7.1), 1.18 (3H, t, J 7.4), 1.30–1.85 (5H, m), 2.30
(3H, s), 3.30 (1H, dd, J 17.9, 7.6), 3.51 (1H, dd, J 17.9,
12.0), 4.18 (2H, q, J 6.8), 4.87 (1H, dd, J 12.0, 7.6), 6.9–7.2
(4H, m). 5c: IR (Nujol) 1745, 1730 cmꢀ1 1H NMR
;
(CDCl3) d 1.22 (3H, t, J 6.8), 1.38 (3H, t, J 6.7), 1.56
(3H, d, J 6.8), 2.28 (3H, s), 3.31 (1H, dd, J 17.8, 7.3), 3.57
(1H, dd, J 17.8, 12.2), 4.22 (2H, q, J 6.7), 4.28 (2H, q,
J 6.8), 4.93 (1H, dd, J 12.2, 7.3), 5.21 (1H, q, J 6.8), 6.9–
7.2 (4H, m). 5d: IR (Nujol) 3180, 1740, 1730, 1665 cmꢀ1
;
1H NMR (CDCl3) d 1.32 (3H, t, J 6.9), 1.62 (3H, d, J 7.4),
2.28 (3H, s), 3.40 (1H, dd, J 18.1, 8.4), 3.51 (1H, dd,
J 18.1, 12.1), 4.23 (2H, q, J 6.9), 4.84 (1H, dd, J 12.1, 8.4),
5.22 (1H, q, J 7.4), 6.88 (1H, br d, J 7.0), 7.0–7.4 (9H, m).
11. Shimizu, T.; Hayashi, Y.; Nishio, T.; Teramura, K. Bull.
Chem. Soc. Jpn. 1984, 57, 787.
9. (a) Houk, K. N.; Sims, J.; Duke, R. E.; Strozier, R. W.;
George, J. K. J. Am. Chem. Soc. 1973, 95, 7287; (b) Houk,
K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301; (c) Caramella, P.; Houk, K. N. J. Am.
Chem. Soc. 1976, 98, 6397.
12. Huisgen, R.; Seidel, M.; Wallbillich, G.; Knupfer, H.
Tetrahedron 1962, 17, 3.
13. (a) Molteni, G.; Ponti, A.; Orlandi, M. New J.Chem. 2002,
26, 1340; (b) Molteni, G.; Ponti, A. New J. Chem. 2002,
26, 1346.
10. Selected spectral data for 5-ethoxycarbonyl-4,5-dihydro-
pyrazoles 5a–d. 5a: IR (Nujol) 1740, 1730 cmꢀ1; 1H NMR