Synthesis of enantiopure pyrrolo[3,4-c]pyrazole derivatives via intramolecular cycloaddition of homochiral nitrilimines

Article abstract of DOI:10.1081/SCC-100108230

Intramolecular cycloaddition of homochiral nitrilimines 8 was exploited to obtain enantiopure pyrrolo[3,4-c]pyrazole derivatives 9 and 10 with high overall yields.

Full text of DOI:10.1081/SCC-100108230

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SYNTHESIS OF ENANTIOPURE PYRROLO[3,4-
cPYRAZOLE DERIVATIVES VIA INTRAMOLECULAR
CYCLOADDITION OF HOMO-CHIRAL NITRILIMINES
Gianluigi Broggini a , Giorgio Molteni b , Tullio Pilati b & Gaetano Zecchi a
a Dipartimento di Scienze Chimiche Fisiche e Matematiche , Università dell'Insubria , via
Lucini 3, Como, 22100, Italy
b Dipartimento di Chimica Organica e Industriale , Università di Milano , via Golgi 19,
Milano, 20133, Italy
Published online: 09 Nov 2006.
To cite this article: Gianluigi Broggini , Giorgio Molteni , Tullio Pilati & Gaetano Zecchi (2001) SYNTHESIS OF
ENANTIOPURE PYRROLO[3,4-cPYRAZOLE DERIVATIVES VIA INTRAMOLECULAR CYCLOADDITION OF HOMO-CHIRAL
NITRILIMINES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:24, 3799-3806, DOI: 10.1081/SCC-100108230
To link to this article: http://dx.doi.org/10.1081/SCC-100108230
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SYNTHETIC COMMUNICATIONS, 31(24), 3799–3806 (2001)
SYNTHESIS OF ENANTIOPURE
PYRROLO[3,4-c]PYRAZOLE
DERIVATIVES VIA INTRAMOLECULAR
CYCLOADDITION OF HOMO-
CHIRAL NITRILIMINES
Gianluigi Broggini,1 Giorgio Molteni,2, Tullio Pilati,3
*
and Gaetano Zecchi1
1Dipartimento di Scienze Chimiche, Fisiche e
Matematiche, Universita dell’Insubria,
via Lucini 3, 22100 Como, Italy
2Dipartimento di Chimica Organica e
3
Industriale and CSRSRC-Centro per lo
Studio delle Relazioni tra Struttura e
Reattivita Chimica, Universita
di Milano, via Golgi 19, 20133 Milano, Italy
ABSTRACT
Intramolecular cycloaddition of homochiral nitrilimines 8 was
exploited to obtain enantiopure pyrrolo[3,4-c]pyrazole deriva-
tives 9 and 10 with high overall yields.
*Corresponding author.
3799
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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BROGGINI ET AL.
Due to their versatility, intramolecular nitrilimine cycloadditions con-
stitute a powerful approach to a wide range of heterocyclic systems.1–5
The construction of the pyrrolo[3,4-c]pyrazole skeleton belongs to the
first success of this synthetic methodology.6 In the context of our recent
framework of research focused to intramolecular cycloadditions of homo-
chiral nitrilimines7 we describe here a version of the above methodology
leading to enantiopure 3,3a,4,5-tetrahydro-6-oxo-pyrrolo[3,4-c]pyrazole
derivatives.
Aiming at this target, we devised the inexpensive (S )-1-phenylethyl-
amine and L-alanine benzylester as the starting chiral unities. The latter were
reacted with allyl bromide to give the corresponding amines 1 and 2 as the
fundamental chiral building blocks (see scheme).
Scheme.

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ENANTIOPURE PYRROLO[3,4-c]PYRAZOLE DERIVATIVES
3801
Our synthetic approach involved, as further stages, the sequence 1 !
3 ! 5 or 2 ! 4 ! 6. Subsequent treatment of the a-chloro acetoacetamides
5 and 6 with the appropriate arenediazonium chloride gave the hydrazonoyl
chlorides 7, whose marked lability precluded full characterization.8 The
desired nitrilimine intermediates 8 were then generated in situ by reacting
crude 7 in dioxane solution with silver carbonate. Cycloaddition products,
isolation yields, reaction times and eluents are collected in the table.
Structures 9 and 10 are supported by elemental analyses and IR and
NMR spectra, and the absolute (S ) configuration to the pyrazolinic C-3a of
minor cycloadducts 10 are substantiated by the X-ray diffractometric analy-
sis of 10a.
Finally, the control of the absolute stereochemistry was modest with
both chiral inductors (see table). The large distance between the starting
stereocentre and the new one is perhaps responsible for the observed
Table. Conversion of 5 and 6 into Cycloadducts 9 and 10
Products and Yields (%)a
Product Ratio
Entry Time (h)
9
10
9 : 10
Eluentb
a
b
c
140
76
140
44
34
38
27
21
54 : 46
56 : 44
AcOEt-LP 1:1
AcOEt-n-hexane 1:1
28
433C57H: 43
57 : 43AcOEt:-1LP 3
2Cl2-n-hexane 3:1
d
71 2
aIsolation yield of pure product; LP ¼ light petroleum, b.p. 40–60ꢀC.
b
Figure. ORTEP projection of 10a with the crystallographic numbering scheme.
Ellipsoids are at 50% probability level. H atoms not to scale.

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3802
BROGGINI ET AL.
disappointing outcome. However, the conversions 5 ! 9 þ 10 and 6 !
9 þ 10 seem synthetically valuable in view of the high overall yields as
well of the easy separation of diastereoisomeric cycloadducts 9 and 10 in
enantiopure state.
EXPERIMENTAL
Melting points were determined with a Buchi apparatus and are not
corrected. IR spectra were recorded with a Perkin-Elmer 1725 X spectro-
photometer. Mass spectra were determined with a VG-70EQ apparatus.
1H-NMR spectra (300 MHz) were taken with a Bruker AC 300 or a
Bruker AMX 300 instrument (in CDCl3 solutions). Chemical shifts are
given as ppm from tetramethylsilane and J values are given in Hz. Optical
rotations, ½aŠ2D5, were recorded on a Perkin-Elmer Model 241 polarimeter at
the sodium D line.
Compound 2 was prepared according to literature methods.9
Preparation of benzyl N-(1-prop-2-enyl)-L-alaninate (1). A solution of
L-alanine benzylester (5.00 g, 27.9 mmol) in dry toluene (35 mL) was added
with KI (0.46 g, 2.8 mmol). Allyl bromide (1.58 g, 13.0 mmol) in dry toluene
(5 mL) was slowly added and the mixture was warmed to 65ꢀC for 4 h under
stirring. Toluene (25 mL) was added, the white precipitate was filtered off,
and the solvent was evaporated under reduced pressure affording 1 (2.31 g,
25
81% yield) as undistillable yellow oil; ½aŠ ¼ À26:3 ðCH2Cl2, c ¼ 0:16Þ;
D
1
IR (neat): 3330, 1735 (cmÀ1); H-NMR d: 1.30 (3H, d, J 7.0), 1.85 (1H,
br s), 3.12 (1H, dd, J 13.7, 6.1), 3.25 (1H, dd, J 13.7, 6.1), 3.41 (1H, q, J 7.0),
5.02–5.18 (2H, m), 5.14 (2H, s), 5.83(1H, ddd, J 16.5, 12.9, 6.1), 7.25–7.40
(5H, m); MS: m/z 219 (Mþ).
General procedure for the preparation of benzyl N-(1-prop-2-enyl)-N-
(1,4-dioxobutyl)-L-alaninate (3) and (S )-N-(1-phenyleth-1-yl)-N-(1-prop-2-
enyl)-3-oxobutanamide (4). A solution of 1 or 2 (18.0 mmol) in dry Et2O
(30 mL) was cooled to 0ꢀC, and then added with diketene (1.66 g,
19.8 mmol). The mixture was stirred at 0ꢀC for 2 h, then for 5 h at room
temperature. Evaporation of the solvent gave 3 or 4 as undistillable oils not
analytically pure.
25
D
3 (5.24 g, 96%) as pale yellow oil; ½aŠ ¼ À30:5 ðCH2Cl2, c ¼ 0:26Þ;
IR (neat): 1740, 1655 (cmÀ1); H-NMR d: 1.44 (3H, d, J 7.2), 2.20 (3H, s),
3.46 (2H, s), 3.80 (1H, ddd, J 18.0, 6.0, 3.2), 3.97 (1H, ddd, J 18.0, 6.0, 3.6),
1
4.74 (1H, q, J 7.2), 5.05–5.27 (2H, m), 5.13(2H, s), 5.70–5.87 (1H, m),
7.25–7.40 (5H, m); MS: m/z 303 (Mþ).
25
4 (4.19 g, 95%) as pale yellow oil; ½aŠ ¼ À136 ðCH2Cl2, c ¼ 0:28Þ; IR
D
(neat): 1730, 1640 (cmÀ1); 1H-NMR d: 1.50 (3H, d, J 7.2), 2.26 (3H, s), 3.49

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ENANTIOPURE PYRROLO[3,4-c]PYRAZOLE DERIVATIVES
3803
(1H, dd, J 17.3, 3.9), 3.56 (2H, s), 3.62 (1H, dd, J 17.3, 3.6), 4.97–5.62 (3H,
m), 6.06 (1H, q, J 7.2), 7.20–7.40 (5H, m); MS: m/z 245 (Mþ).
General procedure for the preparation of benzyl N-(1-prop-2-enyl)-N-
(1,4-dioxo-3-chlorobutyl)-L-alaninate (5) and (S )-N-(1-phenyleth-1-yl)-N-(1-
prop-2-enyl)-3-oxo-2-chlorobutanamide (6). A solution of 3 or 4 (10.0 mmol)
in dry CHCl3 (20 mL) was cooled to 0ꢀC and then sulfuryl chloride (1.34 g,
10.0 mmol) in dry CDCl3 (3mL) was added dropwise. The mixture was
stirred at 0ꢀC for 1 h and then the solvent was evaporated under reduced
pressure affording 5 or 6 as undistillable oils not analytically pure.
5 (3.27 g, 97%) as yellow oil; IR (neat): 1740, 1655 (cmÀ1); 1H-NMR d:
1.48 (3H, d, J 7.1), 2.30 (3H, s), 3.86–4.20 (2H, m), 4.60 (1H, q, J 7.1), 4.84 (1H,
s), 5.13 (2H, s), 5.22–5.74 (3H, m), 7.30–7.40 (5H, m); MS: m/z 337 (Mþ).
6 (2.68 g, 96%) as yellow oil; IR (neat): 1730, 1650 (cmÀ1); 1H-NMR d:
1.54 (3H, d, J 7.2), 2.41 (3H, s), 3.64 (1H, dd, J 17.2, 3.6), 3.83 (1H, dd, J
17.2, 3.4), 4.90 (1H, s), 5.10–5.75 (3H, m), 5.98 (1H, q, J 7.2), 7.23–7.40 (5H,
m); MS: m/z 279 (Mþ).
General procedure for the conversion of 5,6 into 9,10. A solution of 5 or
6 (4.0 mmol) in MeOH (6.0 mL) was cooled to 0ꢀC, and a cold aqueous
solution of 4-chlorobenzenediazonium chloride or 4-nitrobenzenediazonium
chloride (4.0 mmol) was added dropwise under vigorous stirring by keeping
the temperature between 0 and 5ꢀC. During the addition, the pH was
adjusted to 5 by adding sodium acetate. The mixture was stirred at 0ꢀC
for 2 h, then at room temperature for 5 h, and extracted with Et2O
(50 mL). The organic layer was washed firstly with 5% NaHCO3 (15 mL),
then with water (50 mL), and dried (Na2SO4). The solvent was removed
under reduced pressure to give an oily residue that was dissolved in dry
dioxane (180 mL). Silver carbonate (1.98 g, 7.2 mmol) was added and the
mixture was stirred in the dark at room temperature for the time indicated in
the table. After evaporation of the solvent, the crude was chromatographed
on a silica gel column with the eluents indicated in the table affording
pyrrolo[3,4-c] pyrazole cycloadduts 9 and 10. Major diastereoisomers 9
was eluted first, followed by minor diastereoisomers 10.
25
D
9a (0.70 g, 44%) m.p. 150ꢀC (from diisopropyl ether); ½aŠ
¼
À200:0 ðCH2Cl2, c ¼ 0:14Þ; IR (nujol): 1740, 1690 (cmÀ1); 1H-NMR d:
1.45 (3H, d, J 7.4), 3.28 (1H, dd, J 9.1, 6.9), 3.41 (1H, dd, J 14.0, 9.7), 3.62–3.78
(1H, m), 3.92 (1H, dd, J 9.0, 8.8), 4.37 (1H, dd, J 10.3, 10.1), 5.10 (1H, q, J
7.4), 5.14 (1H, d, J 12.2), 5.20 (1H, d, J 12.2), 7.00–7.40 (9H, m); MS m/z
397 (Mþ) (44%). Anal Cald for C21H20ClN3O3: C, 63.40; H, 5.07; N, 10.56.
Found: C, 63.46; H, 5.11; N, 10.60.
10a (0.61 g, 38%) m.p. 183ꢀC (from diisopropyl ether); ½aŠ
25
D
¼
þ342:0 ðCH2Cl2, c ¼ 0:11Þ; IR (nujol), 1735, 1695 (cmÀ1); dH: 1.50 (3H,
d, J 7.4), 3.27 (1H, dd, J 9.1, 6.9), 3.30 (1H, dd, J 14.0, 9.7), 3.53–3.70

ORDER
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3804
BROGGINI ET AL.
(1H, m), 3.78 (1H, dd, J 9.0, 8.8), 4.33 (1H, dd, J 10.3, 10.0), 5.06 (1H, d, J
12.2), 5.10 (1H, q, J 7.4), 5.17 (1H, d, J 12.2), 7.00–7.30 (9H, m); MS m/z
397 (Mþ) (32%). Anal Calcd for C21H20ClN3O3: C, 63.40; H, 5.07; N, 10.56.
Found: C, 63.44; H, 5.05; N, 10.50.
25
D
9b (0.46 g, 34%) m.p. 159ꢀC (from diisopropyl ether); ½aŠ
¼
À268:9 ðCH2Cl2, c ¼ 0:22Þ; IR (nujol): 1685 (cmÀ1); 1H-NMR d: 1.55
(3H, d, J 7.0), 3.22 (1H, dd, J 9.3, 6.5), 3.35–3.63 (3H, m), 4.33 (1H, dd,
J 9.5, 9.3), 5.67 (1H, q, J 7.0), 7.00–7.40 (9H, m); MS m/z 339 (Mþ) (26%).
Anal Calcd for C19H18ClN3O: C, 67.15; H, 5.34; N, 12.37. Found: C, 67.21;
H, 5.30; N, 12.44.
25
D
10b (0.27 g, 27%) m.p. 209ꢀC (from diisopropyl ether); ½aŠ
¼
þ118:3 ðCH2Cl2, c ¼ 1:6Þ; IR (nujol): 1690 (cmÀ1); H-NMR d: 1.66 (3H,
d, J 7.0), 2.80 (1H, dd, J 9.2, 6.3), 3.30 (1H, dd, J 13.7, 9.7), 3.58–3.77 (3H,
m), 4.30 (1H, dd, J 10.1, 9.8), 5.70 (1H, q, J 7.0), 7.05–7.45 (9H, m); MS m/z
339 (Mþ) (26%). Anal Calcd for C19H18ClN3O: C, 67.15; H, 5.34; N, 12.37.
1
Found: C, 67.17; H, 5.28; N, 12.40.
25
D
9c (0.46 g, 28%) m.p. 168ꢀC (from hexane–benzene); ½aŠ
¼
À30:8 ðCH2Cl2, c ¼ 0:21Þ; IR (nujol): 1740, 1690 (cmÀ1); 1H-NMR d:
1.47 (3H, d, J 7.4), 3.35 (1H, dd, J 9.5, 6.7), 3.59 (1H, dd, J 13.2, 9.5),
3.74–3.88 (1H, m), 3.97 (1H, dd, J 8.9, 8.7), 4.47 (1H, dd, J 10.4, 10.1),
5.10 (1H, q, J 7.4), 5.15 (1H, d, J 12.2), 5.22 (1H, d, J 12.2), 7.10–8.20 (9H,
m); MS m/z 408 (Mþ) (44%). Anal Calcd for C21H20N4O5: C, 61.76; H,
4.94; N, 13.72. Found: C, 61.81; H, 5.01; N, 13.80.
25
D
10c (0.35 g, 21%) m.p. 130ꢀC (from hexane–benzene); ½aŠ
¼
þ225:0 ðCH2Cl2, c ¼ 0:18Þ; IR (nujol); 1740, 1690 (cmÀ1); 1H-NMR d:
1.51 (3H, d, J 7.5), 3.37 (1H, dd, J 8.9, 6.6), 3.49 (1H, dd, J 13.0, 9.9),
3.60–3.80 (1H, m), 3.84 (1H, dd, J 8.7, 8.6), 4.43(1H, dd, J 10.4, 10.0),
5.08 (1H, d, J 12.1), 5.11 (1H, q, J 7.5), 5.19 (1H, d, J 12.1), 7.10–8.30 (9H,
m); MS m/z 408 (Mþ) (40%). Anal Calcd for C21H20N4O5: C, 61.76; H,
4.94; N, 13.72. Found: C, 61.71; H, 5.01; N, 13.77.
25
D
9d (0.60 g, 43%) m.p. 202ꢀC (from diisopropyl ether); ½aŠ
¼
À307:0 ðCH2Cl2, c ¼ 0:20Þ; IR (nujol): 1690 (cmÀ1); 1H-NMR d: 1.57
(3H, d, J 7.0), 3.27 (1H, dd, J 9.6, 6.4), 3.43–3.70 (3H, m), 4.40 (1H, dd,
J 7.7, 7.5), 5.66 (1H, q, J 7.0), 7.10–8.20 (9H, m); MS m/z 350 (Mþ) (16%).
Anal Calcd for C19H18N4O3: C, 65.13; H, 5.18; N, 15.99. Found: C, 65.18;
H, 5.13; N, 16.06.
25
D
10d (0.45 g, 32%) m.p. 267ꢀC (from diisopropyl ether); ½aŠ
¼
þ82:4 ðCH2Cl2, c ¼ 0:20Þ; IR (nujol): 1685 (cmÀ1); H-NMR d: 1.68 (3H,
d, J 7.0), 2.87 (1H, dd, J 8.5, 5.6), 3.49 (1H, dd, J 12.8, 10.1), 3.69–3.84 (2H,
m), 4.43(1H, dd, J 10.5, 10.1), 5.74 (1H, q, J 7.0), 7.10–8.20 (9H, m); MS
m/z 350 (Mþ) (28%). Anal Calcd for C19H18N4O3: C, 65.13; H, 5.18; N,
15.99. Found: C, 65.21; H, 5.19; N, 16.09.
1

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ENANTIOPURE PYRROLO[3,4-c]PYRAZOLE DERIVATIVES
3805
X-ray structure determination of 10a. Crystal data were collected with
graphite monochromated Mo-Ka radiation ꢀ ¼ 0.71073A . The structure
was solved by SIR92,10 and refined on F 2 by full-matrix least-squares
using SHELX97;11 heavy atoms anisotropic; H atoms isotropic; H of
metyl and benzyl groups calculated. Absolute configuration was based on
the reactants knowledge and confirmed by refinement [Flack parameter
À0.01(7)]. Data of 10a. C21H20ClN3O3, Mr ¼ 397.85, monoclinic, space
group P21, a ¼ 12.6252(11), b ¼ 5.6152(7), c ¼ 14.4206(15) A, b ¼ 98.644(7),
g ¼ 82.907(6)ꢀ, V ¼ 1010.71(19) A,3 T ¼ 291(1) K, Z ¼ 2, dcalc ¼ 1.307 g cmÀ1
,
m(Mo–Ka) ¼ 0.215 mmÀ1; o/2y scans, 4 < 2y < 60ꢀ; 4646 unique reflections
collected used for all calculations. Final R ¼ 0.0594 and wR ¼ 0.1014, g.o.f.
1.019, À0.12 < Ár < 0.18 e AÀ3. Detailed crystallographic data were depo-
sited (as CCDC 147230) with the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK.
ACKNOWLEDGMENTS
We are grateful to CNR and MURST for financial support.
REFERENCES
1. Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley-Interscience: New York, 1984; vol. 2, pp. 277–406.
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3. Claus, P.K. In Methoden der organischen Chemie (Houben-Weil );
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1990, Band E14b, Teil 1, pp. 33–73.
4. Wade, P.A. In Comprehensive Organic Synthesis; Trost, B., Ed.;
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6. Garanti, L.; Sala, A.; Zecchi, G. Synth. Commun. 1976, 6, 269.
7. (a) Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron:
Asymmetry 1999, 10, 487. (b) Broggini, G.; Garanti, L.; Molteni, G.;
Pilati, T.; Point, A.; Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 2203.
(c) Molteni, G.; Pilati, T. Tetrahedron: Asymmetry 1999, 10, 3873. (d)
Broggini, G.; Casalone, G.; Garanti, L.; Molteni, G.; Pilati, T.; Zecchi,
G. Tetrahedron: Asymmetry 1999, 10, 4447. (e) Broggini, G.; Molteni,
G.; Pilati, T. Tetrahedron: Asymmetry 2000, 11, 1975.

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BROGGINI ET AL.
8. The IR spectra of crude 7 exhibited the typical N–H strech band of
hydrazonoyl chlorides at 3240–3250 cmÀ1
.
9. Galeazzi, R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 3573.
10. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla,
M.C.; Polidori, G.; Camalli, G. J. Appl. Crystallogr. 1994, 27, 435.
11. Sheldrick, G.M. SHELX97. Program for the Refinement of Crystal
Structures, 1997, University of Gottingen, Germany.
Received in the UK November 7, 2000

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