Optically active α-phenylethylamine as efficient organocatalyst in the solvent-free reactions between 2,3-butanedione and conjugated nitroolefins

Article abstract of DOI:10.1002/chir.22088

(R)-(+) and (S)-(-)-1-phenylethylamine have been shown to promote highly diastereoselective and complementary enantioselective formal [3 + 2]carbocyclization reactions between 2,3-butanedione and conjugated nitroalkenes with formation of enantiomerically

Full text of DOI:10.1002/chir.22088

CHIRALITY (2012)
Optically Active a-Phenylethylamine as Efficient Organocatalyst in the
Solvent-free Reactions Between 2,3-Butanedione and Conjugated
Nitroolefins
1
1
1
1
2
1
*
FULVIA FELLUGA, CRISTINA FORZATO, PATRIZIA NITTI, GIULIANA PITACCO, FABIO PRATI, ENNIO VALENTIN, AND
ENNIO ZANGRANDO1
1Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
2Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy
ABSTRACT
(R)-(+) and (S)-(ꢀ)-1-phenylethylamine have been shown to promote highly diaster-
eoselective and complementary enantioselective formal [3 + 2]carbocyclization reactions between 2,
3-butanedione and conjugated nitroalkenes with formation of enantiomerically rich 2-hydroxy-3-
nitrocyclopentanone derivatives. The reactions were carried out both in solvent and under solvent-
free conditions. The absolute configurations of the products were assigned by X-ray and circular di-
chroism spectra analyses. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: primary amine organocatalysis; five-membered ring b-nitro-a-ketols; fully
conjugated nitrocyclopentenone; solvent-free reactions
rotations are quoted in units of 10ꢀ1 degcm2 gꢀ1. High performance liquid
INTRODUCTION
chromatograms (HPLC) were obtained on a Hewlett-Packard series 1100 in-
strument, Knauer UV detector, from a chiral column Lux 5m Cellulose-2
with a Cellulose tris(3-chloro-4-methylphenylcarbammate) chiral stationary
phase, eluent: n-hexane/isopropanol 75:25, detector UV 220 nm. Chiral
High Resolution gas liquid chromatography analyses were run on a
Shimadzu GC-14B instrument, the capillary columns being ChiraldexTM
type G-TA, b-cyclodextrin (40mꢂ 0.25 mm) (carrier gas Helium, 180KPa,
split 1:100) at 150ꢁ isotherm; thin-layer chromatographies were performed
on PolygramW Sil G/UV254 silica gel precoated plastic sheets (eluent: light
petroleum–ethyl acetate). Flash chromatography51 was run on silica gel,
230ꢀ400 mesh ASTM (Kieselgel 60, Merck), using light petroleum
40–70ꢁC/ethyl acetate mixtures as the eluent. Mass spectrometries (MS)
were performed on an ion trap Finnigan GCQ (70eV) spectrometer.
Elemental analyses were determined on a Carlo Erba 1106 instrument at
the Department of Chemical Sciences and Technologies of the University
of Udine, Italy. 2,3-Butanedione, b-nitrostyrene, (S)-(+)-1-(2-pyrrolidinyl-
methyl)pyrrolidine, (S)-(ꢀ)-5-(2-pyrrolidinyl)-1H-tetrazole, (S)-(ꢀ)-a,a-
diphenylprolinol trimethylsilyl ether, and L-proline were purchased from
Sigma Aldrich. 1-Nitrocyclopentene,52 1-nitrocyclohexene,52 2-nitro-1-
phenylpropene,53 and 3-bromo-b-nitrostyrene54 were prepared by literature
procedures.
The interest in asymmetric organocatalysis1–12 has rapidly
increased since the pioneering works of List, Barbas, and their
coworkers in 2001.13,14 The reactions between carbonyl com-
pounds and nitroolefins have been among the most studied
reactions.15–28 Conjugated nitroalkenes are highly reactive
and provide easy access to interesting intermediates due to
the synthetic versatility of the nitro group.29–35 However, while
several examples are reported on organocatalyzed conjugated
addition of 1,3-dicarbonyl compounds to nitroalkenes,36–44 only
a few cases can be found in the literature regarding the same
reaction with 1,2-dicarbonyl compounds,7,45,46 namely with
1,2-cyclohexanedione45,46 and a-ketoanilides.7
Several years ago,47–49 (S)-(ꢀ)-1-phenylethylimine 2 derived
from 2,3-butanedione
1
and (S)-(ꢀ)-1-phenylethylamine
(Scheme 1) has been found to react with cyclic and acyclic
nitroolefins 3a–d, both in solvent and under solvent-free condi-
tions, to give products of carbocyclization reactions (ꢀ)-4a–d.
The imine intermediates (ꢀ)-4b–d were converted into the
corresponding a-ketols (+)-5b–d, either by acid hydrolysis
under mild conditions or by oxidation of the C¼N bond
followed by acidic treatment. This reaction sequence was
highly diastereoselective and enantioselective, as the final
ketols were single isomers.49 Acid-catalyzed hydrolysis of
(ꢀ)-4a did not proceed, and the pentalenone derivative (+)-5a
had to be prepared by a different route.50
Syntheses
General procedure for the organocatalyzed reactions.
To a
mixture of freshly distilled 2,3-butanedione (1.0 mmol) and the appropri-
ate nitroolefin (1.0 mmol) in isopropanol (10 ml) the catalyst (0.2 mmol)
was added. When an acid was used in conjunction with the organocata-
lyst, they were added to the reactants as a 1:1 preformed mixture. The
reaction mixture was kept under stirring at room temperature. When
the reaction did not go to completion, it was stopped when the NMR anal-
ysis revealed a constant ratio between a signal of the nitroolefin and the
nitromethine signal of the major product whose ratio was evaluated using
an internal standard. The solvent was eliminated and the reaction
MATERIAL AND METHODS
General
Infrared (IR) spectra were recorded on a Jasco FT/IR 200 spectrophotom-
eter. 1H-NMR and 13C-NMR spectra were run on a Jeol EX-400 (400 MHz)
spectrometer (100.1 MHz for carbon) and on a Jeol 270 spectrometer
(67.5 MHz for carbon) by using deuteriochloroform as the solvent and tetra-
methylsilane as an internal standard, unless otherwise stated. Chemical
shifts are expressed in parts per million (d). Coupling constants are given
in Hz. Signal attribution of products was made by heteronuclear single-
quantum COSY (COrrelation SpectroscopY), and the relative configuration
of the same compounds was determined by difference nuclear Overhauser
effect experiments. Optical rotations were determined on a Perkin Elmer
Model 241 polarimeter, at 25ꢁC. circular dichroism (CD) spectra were
recorded on a Jasco J-700A spectropolarimeter (0.1 cm cell) at 20ꢁC. Optical
Contract grant sponsor: Ministero dell’Università e della Ricerca; University of
Trieste; Contract grant number: PRIN 2007.
*Correspondence to: Prof. Fulvia Felluga, Department of Chemical and Phar-
maceutical Sciences, University of Trieste, via Giorgieri 1, 34127 Trieste, Italy.
E-mail: ffelluga@units.it
Received for publication 29 February 2012; Accepted 30 May 2012
DOI: 10.1002/chir.22088
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

FELLUGA ET AL.
Scheme 1. Formation of optically active a-ketols from (S)-(ꢀ)-1-phenylethylimine 2 and nitroolefins 3a–d.
products were separated on column chromatography, using light petro-
leum–ethyl acetate in 5:1 ratio as the eluent.
3.97 (dt, J1 =J2 = 11.3 Hz, J3 =5.7Hz, 1H, C-4), 3.22 (dd, J1 = 19.6 Hz,
J2 = 10.6 Hz, 1H, H-5 cis to Ph), 3.09 (bs, 1H, OH), 2.92 (dd, J1 = 19.6 Hz,
J2 = 10.0 Hz, 1H, H-5 trans to Ph), 1.53 (s, 1H, CH3); 13C NMR (100 MHz,
CDCl3) d, ppm: 212.5 (s, CO), 134.4 (s, Ph), 129.2 (2d, Ph), 128.5 (d, Ph),
127.1 (2d, Ph), 96.0 (d, C-3), 80.5 (s, C-2), 40.7 (d, C-4), 35.2 (t, C-5), 22.6
(1R,3aR,6aR)-(+)-1-Hydroxy-1-methyl-6a-nitrohexahydro-1H-pentalen-2-one
[(+)-5a].50 [a]D25 = +32 (c 0.25, CH3OH), 90% e.e.; CD (0.0082 M, CH3OH),
Δe308 = +0.974; Δe265 = ꢀ0.319; high-resolution gas chromatography
(HRGC) (b-cyclodextrin, 150 ꢁC): (+)-5a, 30.4 min, (ꢀ)-5a, 31.1 min.
(1S,3aR,6aR)-(+)-1-Hydroxy-1-methyl-6a-nitrohexahydro-1H-pentalen-2-
one [(+)-6a].50 [a]D25 = +23.5 (c 0.8, CH3OH), 89% e.e. CD (0.0078 M,
CH3OH), Δe305 = +1.01; Δe252 = ꢀ0.48; HRGC (b-cyclodextrin, 150 ꢁC):
(ꢀ)-6a, 45.4 min, (+)-6a, 46.7 min.
+
•
(q, CH3). MS (70 eV): 235 (M , <1), 187 (5, M–OH–NO), 160 (11), 159
(12, 187–CO), 147 (71), 145 (35), 131 (46), 129 (100), 117 (42), 103 (14), 91
(15), 77 (13); Anal. calc. for C12H13NO4: C, 61.27, H, 5.57, N, 5.95. Found:
C, 60.99, H, 5.52, N, 5.67. [a]2D5 =ꢀ45.0 (c, 0.04 CHCl3), 71% e.e.; HPLC (flow
rate, 1 ml/min, pressure 34 bar): (+)-7c, 19.40 min, (ꢀ)-7c, 20.85 min.
(2R,3R,4R)-(+)-2-Hydroxy-2,3-dimethyl-3-nitro-4-phenylcyclopentanone
[(+)-5d].47 Rf 0.75 (eluent: ethyl acetate-light petroleum gradient from 15:85 to
(1R,3aR,7aR)-(+)-1-Hydroxy-1-methyl-7a-nitrooctahydro-2H-inden-2-one
[(+)-5b].48 [a]D25 = +114 (c 0.33, CH3OH), 92% e.e. CD (0.0155M, CH3OH),
Δe310 = +2.39; Δe274 = ꢀ0.41. HRGC (b-cyclodextrin, 150ꢁC): (+)-5b,
96.7 min, (ꢀ)-5b, 100.7min.
1
20:80): M.p. 172–173 ꢁC. H NMR (400 MHz, CDCl3) d, ppm: 7.35 (m, 3H,
Ph), 7.17 (m, 2H, Ph), 3.88 (dd, J1 =11.0Hz, J2 = 9.9 Hz, 1H, H-4), 3.11, 2.96
(part AB of an ABX system, JAB =19.2Hz, JAX = 11.0 Hz, JBX = 9.9Hz, 2H, 2
H-5), 1.60 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) d,
ppm: 209.4 s, 134.2 (s), 129.0 (2d), 128.6 (d), 128.2 (2d), 99.2 (s), 79.8 (s),
48.6 (d), 38.0 (t), 15.9 (q), 14.0 (q); [a]2D5 = +25 (c 0.1, CHCl3), 71% e.e.; CD
(c 0.004, CHCl3): e304 +1.657; e273 ꢀ0.319; e248 +0.756. HRGC (b-cyclodextrin,
150 ꢁC): (+)-5d, 249.1min, (ꢀ)-5d, 254.8 min.
(1S,3aR,7aR)-(+)-1-Hydroxy-1-methyl-7a-nitrooctahydro-2H-inden-2-one
[(+)-6b].48 [a]D25 = +60 (c 0.18, CH3OH), >99% e.e. CD (0.0084 M,
CH3OH), Δe306 = +2.30; Δe272 = ꢀ0.40. HRGC (b-cyclodextrin, 150 ꢁC):
(ꢀ)-6b, 50.7 min, (+)-6b, 52.3 min.
(2R,3R,4R)-(+)-2-Hydroxy-2-methyl-3-nitro-4-phenylcyclopentanone [(+)-
5c].47 13C NMR (67.8 MHz, CD3OD) d, ppm: 210.8 (s, CO), 140.5 (s,
Ph), 129.9 (2d, Ph), 128.6 (2d, Ph), 128.5 (d, Ph), 95.8 (d, C-3), 77.9 (s,
C-2), 43.6 (t, C-5), 42.2 (d, C-4), 20.2 (q, CH3); [a]2D5 = +133.6 (c, 0.1
CHCl3), 99% e.e. [lit.49 [a]D25 = +134.0 (c 0.1, CHCl3), 99% e.e.]; UV
(1.45 ꢂ 10ꢀ4 M, CH3OH), nm, 212.0 (e, 8090), 224.0 (e, 2772); CD
(0.006 M, CH3OH), Δe312 = +2.2; Δe276 = ꢀ1.2; Δe232 = +1.8).
(2S,3R,4R)-(+)-2-Hydroxy-2,3-dimethyl-3-nitro-4-phenylcyclopentanone
[(+)-6d]. Rf 0.25 (eluent: ethyl acetate-light petroleum gradient 15:85 to
20:80); M.p. 149ꢁC; 1H NMR d, ppm: 7.35 (m, 3H, Ph), 7.17 (m, 2H, Ph),
3.57 (t, J = 10.4 Hz, 1H, H-4), 3.11 (dd, J1 = 10.4 Hz, J2 = 19.6 Hz, 1H, H-5 cis
to Ph), 2.91 (dd, J1 = 10.4 Hz, J2 = 19.6 Hz, 1H, H-5 trans to Ph), 1.63 (s, 3H,
CH3), 1.41 (s, 3H, CH3); 13C NMR (100MHz, CDCl3): 209.4 s, 134.2 (s),
129.0 (2d), 128.6 (d), 128.2 (2d), 99.2 (s), 79.8 (s), 48.6 (d), 38.0 (t), 15.9
(q), 14.0 (q); [a]2D5 = ꢀ43.4 (c 0.65, CHCl3), [a]2D5 = ꢀ59.4 (c 0.325, CH3OH),
89% e.e.; CD (c 0.013, CHCl3): e297 +2.370; e257 ꢀ2.266; e233 –1.139; HRGC (b-
cyclodextrin, 150 ꢁC): (+)-6d, 181.8 min, (ꢀ)-6d, 185.0 min.
High performance liquid chromatograms (flow rate, 1 ml/min, pres-
sure 34 bar): (+)-5c, 7.31 min, (ꢀ)-5c, 7.68 min.
With the use of (R)-(+)-1-phenylethylamine as the catalyst (20 mol%),
ketol (ꢀ)-5c was isolated, [a]2D5 = ꢀ134.0 (c 0.1, CHCl3), 99% e.e. CD
(0.01 M, CH3OH), Δe312 = ꢀ2.2; Δe276 = +1.2; Δe232 = ꢀ1.8).
With the use of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroa-
cetic acid (2PMP/TFA) as the catalyst (20 mol%), ketol (+)-5c was iso-
lated, [a]2D5 = +91.6 (c, 0.1 CHCl3), 68% e.e.
(2R,3R,4R)-(+)-4-(3-bromophenyl)-2-hydroxy-2-methyl-3-nitrocyclopentanone
[(+)-8)]. Ketol (+)-8 was isolated from the reaction catalyzed by (S)-(ꢀ)-1-
phenylethylamine as a white crystalline solid, m.p. 131–132 ꢁC, from n-hep-
tane–ethyl acetate; Rf: 0.57, eluent: light petroleum–ethyl acetate 6:1; IR
(nujol) 3428 (OH), 1595, 651 (Ar), 1759 (CO), 1557, 1382, 1364, 1356 cmꢀ1
(2S,3R,4R)-(+)-2-Hydroxy-2-methyl-4-phenyl-3-nitrocyclopentanone [(+)-6c].
Compound (+)-6c was isolated from the reaction catalyzed by (S)-(+)-1-
2PMP/TFA as a white crystalline solid, m.p. 142–143 ꢁC, from n-heptane-
ethyl acetate; Rf: 0.31, eluent: light petroleum–ethyl acetate 3:1; IR (nujol)
3506 (OH), 1755 (CO), 1600, 1590, 698, 675 cmꢀ1 (Ph), 1546, 1365 (NO2);
1H NMR (400MHz, CDCl3) d, ppm: 7.35 (m, 5H, Ph), 5.20 (d, J= 10.1 Hz,
1H, H-3), 4.03 (dt, J1 = J2 = 11.3 Hz, J3 = 10.1 Hz, 1H, H-4), 3.16 (dd,
J1 = 9.9 Hz, J2 = 19.8Hz, 1H, H-5 trans to Ph), 3.05 (1H, bs, OH), 2.67 (dd,
J1 = 11.3Hz, J2 = 19.8 Hz, 1H, H-5 cis to Ph), 1.37 (s, 1H, CH3); 13C NMR
(100 MHz, CDCl3) d, ppm: 210.4 (s, CO), 137.5 (s, Ph), 129.3 (2d, Ph),
128.3 (d, Ph), 127.2 (2d, Ph), 96.3 (d, C-3), 80.4 (s, C-2), 41.4 (t, C-5), 39.8
1
(NO2). H NMR (400 MHz, CDCl3) d, ppm: 7.45 (m, 2H, o- to Br ArH), d
7.25 (m, 2H, ArH), 4.85 (d, J = 9.5 Hz, 1H, H-3), 4.33 (dt, J1 = J2 = 11.4Hz,
J3 = 9.5 Hz, 1H, H-4), 3.17 (dd, J1 = 9.5 Hz, J2 = 19.4 Hz, 1H, H-5 trans to Ph),
2.60 (dd, J1 = 11.4Hz, J2 = 19.4Hz, 1H, H-5 cis to Ph), 2.53 (bs, 1H, OH),
1.57 (s, 3H, CH3); 13C NMR (100MHz, CDCl3) d, ppm: 207.9 (s, CO),
140.1 (s), 131.5 (d, Ar), 130.8 (d, Ar), 130.2 (d, Ar), 126.7 (d, Ar), 123.3 (s,
Ar), 94.3 (d, C-3), 41.5 (d, C-4), 40.5 (t, C-5), 21.2 (q, CH3); 13C NMR
(100 MHz, CD3OD) d, ppm: 210.1 (s, CO), 143.3 (s), 131.9 (d, Ar), 131.7
(d, Ar), 131.6 (d, Ar), 127.7 (d, Ar), 123.7 (s, Ar), 95.3 (d, C-3), 77.8 (s, C-
2), 43.5 (d, C-4), 42.0 (t, C-5), 20.0 (q, CH3); MS (70 eV): 285, 283 (0.5, M
–30), 227, 225 (100), 211, 209 (30), 197, 195 (9), 145 (60), 128 (35). Anal. calc.
for C12H12NO4Br: C, 45.88, H, 3.85, N, 4.46. Found: C, 46.46, H, 3.91, N, 4.33;
[a]2D5 = +103.3 (c, 0.18, CHCl3), 90% e.e.; CD (0.0025 M, CH3OH), e310 = +2.6;
e277 = ꢀ1.8; e232 = +1.6. HPLC (flow rate, 1 ml/min, pressure 29bar): (+)-8,
8.20min, (ꢀ)-8, 8.94 min.
(d, C-4), 19.7 (q, CH3). MS (70 eV): 235 (M+ , <1), 187 (5, M–OH–NO),
•
160 (10), 159 (14, 187–CO), 147 (72), 145 (35), 131 (46), 129 (100), 117
(42), 103 (14), 91 (15), 77 (13); Anal. calc. for C12H13NO4: C, 61.27, H,
5.57, N, 5.95. Found: C, 60.44, H, 5.41, N, 5.53; [a]2D5 = +22.2 (c, 0.22 CHCl3),
81% e.e.; HPLC (flow rate, 1 ml/min, pressure 30bar): (+)-6c, 8.59 min, (ꢀ)-
6c, 9.22 min.
(2S,3S,4R)-(ꢀ)-2-Hydroxy-2-methyl-4-phenyl-3-nitrocyclopentanone [(ꢀ)-7c].
Compound (ꢀ)-7c was isolated from the reaction catalyzed by 2PMP/TFA
as a pale yellow solid, m.p. 127–128 ꢁC, from n-heptane-ethyl acetate; Rf:
0.12, eluent: light petroleum–ethyl acetate 3:1; IR (nujol) 3414 (OH), 1754
(CO), 1601, 1590, 700, 670 (Ph), 1552, 1365 cmꢀ1 (NO2); 1H NMR
(400 MHz, CDCl3) d, ppm: 7.30 (m, 5H, Ph), 5.18 (d, J= 5.7 Hz, 1H, C-3),
(R)-(ꢀ)-2-Methyl-3-nitro-4-phenylcyclopent-2-en-1-one [(ꢀ)-9)] The crude
mixture of ketols obtained from the reaction between diacetyl and b-
nitrostyrene, catalyzed by (S)-(ꢀ)-1-phenylethylamine, was acetylated in
chloroform with acetic anhydride (25 eq.), in the presence of catalytic
amounts of p-toluenesulfonic acid (PTSA), at 0 ꢁC. The mixture was
stirred at room temperature for 24 h. The reaction mixture was washed
Chirality DOI 10.1002/chir

ORGANOCATALYZED REACTIONS BETWEEN 2,3-BUTANEDIONE AND CONJUGATED NITROOLEFINS
five times with a 5% solution of sodium bicarbonate and then with water
CH3OH), e354 = +3.6; e267 = ꢀ11.6; e226 = +3.3). HPLC (flow rate, 1 ml/min,
and dried on anhydrous sodium sulfate. After elimination of the solvent,
the resulting semisolid material was purified on column chromatography
to give (2R,3R,4R)-2-acetoxy-2-methyl-3-nitro-4-phenylcyclopentanone, as an
oil. 1H NMR (270 MHz, CDCl3) d, ppm: 7.36 (m, 3H, Ph), 7.25 (m, 2H,
Ph), 4.97 (d, J = 11.0 Hz, 1H, H-3), 4.56 (ddd, J1 = 11.0 Hz, J2 = 8.8 Hz,
J3 = 12.1 Hz, 1H, H-4), 3.33 (dd, J1 = 8.8 Hz, J2 = 19.0 Hz, 1H, H-5 trans to
Ph), 2.53 (dd, J1 = 12.1 Hz, J2 = 19.0 Hz, 1H, H-5 cis to Ph), 2.08 (s, 3H,
CH3CO), 1.67 (s, 1H, CH3); 13C NMR (67.8 MHz, CDCl3) d, ppm: 205.7
(s, CO), 170.2 (s, COO), 138.2 (s, Ph), 129.2 (2d, Ph), 128.1 (d, Ph),
127.1 (2d, Ph), 95.8 (d, C-3), 78.9 (s), 42.8 (t, C-5), 42.6 (d, C-4), 22.9 (q,
CH3CO), 21.3 (q, CH3). The acetylated ketol thus formed was dissolved
pressure 37 bar): (+)-10, 9.82 min, (ꢀ)-10, 10.73min.
Crystal Structure Determinations
Diffraction data for the structures reported were collected at room tem-
perature on a Nonius DIP-1030H system (Mo-Ka radiation, l = 0.71073 Å).
All the structures were solved by direct methods and refined by the full-
matrix least-squares method based on F2 with all observed reflections.55
The calculations were performed using the WinGX System, Ver 1.80.05.56
Crystal data for compound 5c. C12H13NO4, fw = 235.23 g molꢀ1
orthorhombic, 212121, a = 5.558(2), b = 13.267(4), c = 15.786(4) Å,
,
P
V = 1164.0(6) Å3, Z = 4, Dcalcd = 1.342 g/cm3, m(Mo-Ka) = 0.102 mmꢀ1
,
in chloroform, and
a catalytic amount of 4-dimethylaminopyridine
F(000) = 496, = 23.25ꢁ. Final R1 = 0.0304, wR2 = 0.0629, GOF = 0.859 for
156 parameters and 1606 unique reflections, of which 1075 with I > 2s(I),
(DMAP) was added. After 8 h, the a,b-unsaturated ketone (ꢀ)-9 was
formed in quantitative yield and purified on column chromatography. It
solidified on standing, m.p. 91–92 ꢁC, Rf: 0.67, eluent: light petroleum–
ethyl acetate 3:1; IR (neat) 3065, 3031, 1602, 733, 700 (Ph), 1727 (CO),
1556 (CC), 1525, 1356 cmꢀ1 (NO2); 1H NMR (400 MHz, CDCl3) d, ppm:
7.30 (m, 3H, Ph), 7.15 (bd, 2H, Ph), 4.62 (d quintet, J4,5 = 7.3 Hz, J4,5 = J4,
Me = 2.2 Hz, 1H, H-4), 3.20 (dd, J1 = 19.4 Hz, J2 = 7.3 Hz, 1H, H-5), 2.66
(dd, J1 = 19.4 Hz, J2 = 2.2 Hz, 1H, H-5), 2.20 (d, J = 2.2 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3) d, ppm: 204.7 (s, CO), 169.7 (s, C-3), 140.2 (s,
C-2), 138.1 (s), 129.3 (2d, Ph), 128.0 (d, Ph), 126.9 (2d, Ph), 45.2 (t, C-
residuals in F map 0.112, –0.119 e. Åꢀ3
.
Crystal data for compound 6c.
orthorhombic, 212121, a = 5.380(2), b = 13.220(3), c = 16.388(3) Å,
C ,
12H13NO4, fw = 235.23 g molꢀ1
P
V = 1165.6(6) Å3, Z = 4, Dcalcd = 1.341 g/cm3, m(Mo-Ka) = 0.101 mmꢀ1
,
F(000) = 496, = 25.31ꢁ. Final R1 = 0.0346, wR2 = 0.0670, GOF = 0.775 for
156 parameters and 1923 unique reflections, of which 1016 with I > 2s(I),
residuals in F map 0.097, –0.135 e. Åꢀ3
.
5), 43.2 (d, C-4), 9.4 (q, CH3); MS: 217 (36, M+ ), 187 (100, M–NO), 145
•
Crystal data for compound (+)-8. C12H12BrNO4, fw = 314.14 g molꢀ1
monoclinic, C 2, a = 18.674(4), b = 5.672(2), c = 15.126(3) Å, b = 125.16
,
(18), 141 (25), 128 (62). Anal. calc. for C12H11NO3: C, 66.35, H, 5.10, N,
6.45. Found: C, 66.20, H, 5.27, N, 6.52. [a]2D5 = ꢀ4.64 (c 0.54, CH3OH),
90% e.e.; UV (2.5 ꢂ 10ꢀ4 M, CH3OH) nm, 214.0 (e 7408), 257.0 (e 5608);
CD (2.5 ꢂ 10ꢀ4 M, CH3OH), e354 = +2.3; e261 = ꢀ5.8; e228 = +2.4. HPLC
(flow rate, 1 ml/min, pressure 29 bar): (+)-9, 11.59 min, (ꢀ)-9, 12.55 min.
(R)-(ꢀ)-4-(3-Bromophenyl)-2-methyl-3-nitrocyclopent-2-en-1-one [(ꢀ)-10].
The same procedure applied on compound (+)-8 gave the a,b-unsaturated
ketone (ꢀ)-10, Rf: 0.68, eluent: light petroleum–ethyl acetate 3:1; IR
(neat) 3065, 3031, 1602, 733, 700 (Ph), 1727 (CO), 1556 (CC), 1525,
1356 cmꢀ1 (NO2); 1H NMR (400 MHz, CDCl3) d, ppm: 7.42 (bd,
J = 8.4 Hz, 1H, ArH), 7.30 (t, J = 1.6 Hz, 1H, ArH), 7.20 (t, J = 7.7 Hz, 1H,
ArH), 7.09 (bd, J = 7.7 Hz, 1H, ArH), 4.52 (d quintet, J4,5 = 7.7 Hz, J4,5 = J4,
Me = 2.2 Hz, 1H, H-4), 3.20 (dd, J1 = 19.4 Hz, J2 = 7.7 Hz, 1H, H-5), 2.63
(dd, J1 = 19.4 Hz, J2 = 2.2 Hz, 1H, H-5), 2.20 (d, J = 2.2 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3) d, ppm: 204.0 (s, CO), 168.8 (s, C-3), 141.0 (s,
C-2), 140.5 (s), 131.3 (d, Ar), 130.8 (d, Ar), 130.0 (d, Ar), 125.5 (s, Ar),
123.3 (d, ArH), 44.9 (t, C-5), 42.7 (d, C-4), 9.6 (q, CH3). MS: 297, 295 (48,
(3)ꢁ, V = 1309.9(6) Å3, Z = 4, Dcalcd = 1.593 g/cm3, m(Mo-Ka) = 3.144 mmꢀ1
,
F(000) = 632, = 25.66ꢁ. Final R1 = 0.0397, wR2 = 0.0797, GOF = 0.836 for 165
parameters and 2098 unique reflections, of which 1274 with I > 2s(I),
residuals in F map 0.375, –0.350 e. Åꢀ3. Flack parameter 0.035(17).
RESULTS AND DISCUSSION
In the light of the aforementioned findings, we performed
the reactions between 2,3-butanedione and nitroolefins under
organocatalytic conditions both in solvent and under solvent-
free conditions.
The same nitroolefins were used as electrophiles, namely 1-
nitrocyclopentene 3a, 1-nitrocyclohexene 3b, b-nitrostyrene
3c, and 1-nitro-2-phenylpropene 3d (Scheme 2). (R)-(+)- and
(S)-(ꢀ)-1-phenylethylamine, L-proline, (S)-(ꢀ)-5-(2-pyrrolidinyl)-
1H-tetrazole and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine
M+ ), 267, 265 (92, M–NO), 209, 207 (28), 186 (30), 158 (28), 141 (30),
•
128 (100). [a]2D5 = ꢀ20 (c 0.06, CH3OH), 72% e.e. CD (2.0 ꢂ 10ꢀ4 M,
Scheme 2. Organocatalyzed reactions of 2,3-butanedione 1 with the nitroolefins 3a–d.
Chirality DOI 10.1002/chir

FELLUGA ET AL.
a
in conjunction with an acid. Of the solvents checked, namely
dimethyl sulfoxide, tetrahydrofuran, CHCl3, CH3OH, and
isopropanol, only the alcohols gave satisfactory results, and
among them, isopropanol furnished the products with higher
enantiomeric excess. Organocatalysts and solvents were
first checked for the reaction between 2,3-butanedione and
b-nitrostyrene 3c, and the conditions that gave the best
results were then used for the other nitroolefins. The
1
reactions were monitored with H NMR to determine the
degree of conversion, and they were stopped when they did
not proceed any further.
The reaction of 2,3-butanedione 1 with the nitroolefins 3a–d
in the presence of the organocatalyst (20 mol%), both in
isopropanol and without solvent, produced the corresponding
a-ketols (+)-5a–d, accompanied in most cases by a certain
amount of their diastereomers (+)-6a–c and (ꢀ)-6d. With
b-nitrostyrene 3c and, as a catalyst, (S)-(+)-1-(2-pyrrolidinyl-
methyl)pyrrolidine coupled with an acid, a third diastereomer
(ꢀ)-7c was isolated. The diastereomeric ratios were deter-
b
1
mined by H NMR analysis of the crude reaction mixtures,
and the enantiomeric excesses of the products were
determined either by HPLC or HRGC on chiral columns. The
reactions carried out in the absence of solvent were cleaner
than those performed in solvent with the exception of the
reaction with 1-nitrocyclopentene, which was very sensitive to
basic conditions. On the contrary, the reactions carried out in
isopropanol were characterized by a low catalyst turnover,
probably because of the formation of the relatively stable and
unreactive hemiaminal species.57 When the reaction was
carried out in the absence of solvent, a twofold increase in the
molar amount of 2,3-butanedione did not make significative
changes into yields and diastereoselectivities or enantioselec-
tivities, but it proved helpful in dissolving the nitroolefin when
this latter was solid.
In all cases, the final product was the corresponding enantio-
merically enriched a-ketol, 5 and/or 6. However, in the reaction
with 1-phenyl-1-nitropropene 3d, a small amount of the imine
intermediates was present in the crude reaction mixture, owing
to the fact that they were not completely hydrolyzed under the
conditions used. As a consequence, the catalyst was partially
“sequestered”, resulting in a slightly lower total yield.
Under basic conditions (pH 8), the enantiomerically
enriched compounds 5b–d were partially converted into their
respective diastereomers 6b–d, thus demonstrating that they
were formed under kinetic formation. In the reaction with 1-
nitrocyclopentene, the product of kinetic formation was 6a
that partially was converted into 5a even on standing in solu-
tion at room temperature.
Fig. 1. Oak Ridge Thermal-Ellipsoid Plot Program (ORTEP) P diagrams of
compounds (a) (ꢃ)-5c and (b) (ꢃ)-6c.
The main results relative to the organocatalyzed reactions
are summarized in Tables 1 and 2.
It is evident that the most efficient catalyst was the primary
amine 1-phenylethylamine (Table 1, Entries 1–5), both in the
presence and absence of solvent. The observed diastereoselec-
tivity was good for all nitroolefins with the exception of 1-nitro-
cyclopentene. In that case, the initially formed isomer (+)-6a
rapidly interconverted into (+)-5a to reach the final equilibrium
ratio of 60:40 in favor of 6a. When a preformed mixture of
(S)-(ꢀ)-1-phenylethylamine and TFA was used in the reaction
between diacetyl and b-nitrostyrene 3c, diastereoselectivity
and enantioselectivity was good only when the reaction was
performed in the absence of solvent (Entry 6). On the contrary,
in isopropanol, the conversion was only 3% after 96 h.
L-proline (Table 2, Entries 1–4) was only partially efficient
as an organocatalyst, as yields and enantioselectivities were
low and 3d did not react. The poor reactivity observed for
the other nitroolefins was due to the fact that the reactions
took a different course, yielding mainly pyrrolizidine deriva-
tives.58 When a preformed mixture of L-proline and TFA was
used in the reaction between diacetyl and b-nitrostyrene 3c,
conversion was very poor (4%) after 96 h (Table 2, Entry 5).
With (S)-(ꢀ)-5-(2-pyrrolidinyl)-1H-tetrazole (Entry 11),
conversion and enantioselectivity were very low, while with
(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine, used in conjunc-
tion with different acids (Entries 5–10), conversions were
good only for TFA, as found by Betancort and Barbas,14 but
diastereoselectivities were low.
Diastereoisomers 5, 6, and 7 were assigned the relative
configurations shown in Scheme 2. Stereochemical assign-
ments were made either by means of nuclear Overhauser ef-
fect measurements (whose results are reported in Scheme 2
for 5d, 6d, and 7c) or on the basis of single crystal X-ray
structural determinations that were performed on compounds
5c, 6c (Fig. 1a and b), and 6b.48
The trans configuration between R1 and the nitro group
present in the original nitroolefins was maintained in all pro-
ducts except in those derived from 2-nitro-1-phenylpropene.
In fact, in spite of the fact that the configuration of the nitroo-
lefin 3d is E, in compounds (+)-5d and (ꢀ)-6d, the phenyl
group and NO2 are in cis relationship, evidently for steric
reasons. This constitutes evidence for a two-step reaction
mechanism (Scheme 3).
It is important to underline that in an analogous experiment
performed by D. Ding and coworkers46 with diacetyl and
b-nitrostyrene, in the presence of a quinine-derived thiourea
as the organocatalyst, no product was obtained. This highlights
the importance of a screening for the best organocatalyst.
Chirality DOI 10.1002/chir

ORGANOCATALYZED REACTIONS BETWEEN 2,3-BUTANEDIONE AND CONJUGATED NITROOLEFINS
H
(NO2)
O
R1
H
H
R2
O
H
R1(Ph)
H
(Ph) R1
Me
2(NO2)
O2N
(Me)
R
Me
R2
H
Ph
Me
O2N
H2O
N
H
O
N
H
H
N
O
H
(Me) O2N
Me
Me
13
HO
H
Me Ph
Ph
Me
12
[(S)-11]*
(+)-5a-c, (+)-8
((+)-5d)
(NO2)
R2
R1
H
(Ph)
N
R1
R2
(Ph)
(NO2)
O2N
(Me)
H
Ph
Me
H2O
Me
H
O
O N
(Me)
2
OH
O
Me
H
13'
Me
(+)-6a-c
((-)-6d)
*Enamine tautomer of the imine (S)-(-)-2]
O
H
H
H
H
N
Me Ph
12
Scheme 3. Mechanism proposed for the Michael–Henry tandem reaction.
TABLE 1. Reactions between 2,3-butanedione 1 and conjugated nitroolefins 3a–da catalyzed by (S)-(ꢀ) and (R)-(+)-1-phenylethyl-
amine and L-proline with and without acid
Isopropanol
e.e. %c
No solvent
e.e. %c
Entry
Catalyst
Nitroolefin
Products
5/6b
Yieldd
55
5/6b
Yieldd
85
1
2
3
4
5
6
(S)-1-phenylethylamine
3a
3b
3c
3d
3c
3c
(+)-5a
(+)-6a
(+)-5b
(+)-6b
(+)-5c
(+)-6c
(+)-5d
(ꢀ)-6d
(ꢀ)-5c
(ꢀ)-6c
(+)-5c
(+)-6c
1:9
90
92
92
1:6
85
84
96
4:1
75
65
99:1
99:1
2.3:1
96
98
87
99
15.7:1
13.3:1
13.3:1
99
>99
n.d.e
85
76
89
71
73
(R)-1-phenylethylamine
99
62
n.d.e
(S)-1-phenylethylamine/TFA
4% conv.
24:1
95
35
aIn the experiments performed in isopropanol (5 ml), the reagents were in 1:1 molar ratio and 20 mol% cat. on a 3 mmol scale. The solvent-free experiments were
carried out on a 1 mmol scale. With W-nitrostyrene and 2-nitro-1-phenylpropene, a twofold amount of 2,3-butanedione was used to allow the formation of a homoge-
neous solution.
bDetermined by 1H NMR of the crude mixture.
cDetermined either by chiral high performance liquid chromatograms or by chiral high-resolution gas chromatography of the isolated diastereomer.
dYield of isolated major isomer.
eNot determined.
The absolute configuration of the products was determined
by X-ray analysis performed on compound (+)-8 (Fig. 2), anal-
ogous to (+)-5c, and by analysis of the respective CD curves.
Compound (+)-8 was isolated as a single isomer from
the reaction between the imine (S)-(ꢀ)-2 and m-bromo-
b-nitrostyrene, under solvent-free conditions, followed by
acidic hydrolysis. Its enantiomeric excess was 95%, and
its absolute configuration was (2R,3R,4R) (Flack parameter
0.035(17)) (Fig. 3). The same product (+)-8, with 90% e.e.,
was obtained under organocatalytic conditions from
diacetyl 1 and m-bromo-b-nitrostyrene, in the presence of
(S)-(ꢀ)-1-phenylethylamine.
Chirality DOI 10.1002/chir

FELLUGA ET AL.
TABLE 2. Reactions between 2,3-butanedione 1 and conjugated nitroolefins 3a–da catalyzed by (S)-(+)-1-(2-pyrrolidinylmethyl)
pyrrolidine in conjunction with various acids and (S)-(ꢀ)-5-(2-pyrrolidinyl)-1H-tetrazole
Entry
1
Catalyst
Nitroolefin
Products
5/6/7b
e.e. %c
Yieldd
L-proline
3a
(+)-5a
(+)-6a
(+)-5b
(+)-6b
(+)-5c
No reaction
(+)-5a
(+)-6a
(+)-5b
(+)-6b
(+)-5c
(+)-6c
(ꢀ)-7c
(+)-5d
(ꢀ)-6d
(+)-5c
(+)-6c
(ꢀ)-7c
(+)-5c
(+)-6c
(ꢀ)-7c
(+)-5c
(ꢀ)-7c
9:1:0
30
30
40
24
31
10
n.d.e
15
2
3b
9:1:0
99:1:0
9:1:0
3
4
5
3c
3d
3a
15
65
73
85
(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid
34
73
16
89
68
81
71
61
56
83
83
6
7
3b
3c
1.3:1:0
1.9:1.4:1
8
9
3d
3c
1:2.3:0
87
30
(S)-(+)-1-(2-pyrrolidinylmethyl) pyrrolidine/p-toluenesulfonic acid
(S)-(+)-1-(2-pyrrolidinylmethyl) pyrrolidine/10-camphorsulfonic acid
(S)-(ꢀ)-5-(2-pyrrolidinyl)-1H-tetrazole
5.7:1:7.6
10
11
3c
3c
2.7:1:2.8
5.7:0:1
24
63
45
20
n.d.e
24
n.d.
aIn the experiments performed in isopropanol (5 ml), the reagents were in 1:1 molar ratio and 20 mol% cat. on a 3 mmol scale.
bDetermined by 1H NMR of the crude mixture.
cDetermined either by chiral high performance liquid chromatograms or by chiral high-resolution gas chromatography of the isolated diastereomer.
dYield of isolated major isomer.
eNot determined.
CD curves, and they were also assigned the same absolute
configuration.
As a corollary to these reactions, the dehydration reaction
of the a-ketols (+)-5c and (+)-8 to the respective cyclopente-
nones (ꢀ)-9 and (ꢀ)-10 (Fig. 2) should be mentioned. This
was quantitatively accomplished via acetylation of the
hydroxy group with acetic anhydride in the presence of trace
amounts of PTSA,59 followed by treatment with DMAP at
room temperature for 6 h.60
Fig. 2. a-Ketol (+)-8 and dehydration derivatives (ꢀ)-9 and (ꢀ)-10.
As to the reaction mechanism, three consecutive stereocen-
ters are formed in this reaction. The stereoselectivity of the
reaction is related to the initial Michael reaction, which
creates the stereocentre bearing the R1 residue, and to the
subsequent intramolecular Henry reaction, which generates
the other two stereocentres. The mechanism proposed for
the organocatalyzed reactions described is depicted in
Scheme 3. The reactivity of the imine intermediate (S)-(ꢀ)-
2 is to be ascribed to its cross-conjugated enaminone tauto-
mer form (S)-11. As the configuration of the products is
strictly related to the configuration of the a-phenylethyl
moiety, in the topological approach of the reagents, the
amine component should be opposite to the acetyl group,
as depicted in 12. As a consequence, the firstly formed
stereocentre should be (R). Subsequent collapse of the
carbanion onto the carbonyl carbon atom in the dipolar inter-
mediate 13 (groups in parenthesis for 3d) would generate
the other two stereocentres. The orientation of the acetyl
group, as depicted in Scheme 3, would generate compounds
(+)-5a–d and (+)-8, while its rotation around the OC–CN+
single bond would afford their optically active diastereomers
6a–d, after hydrolysis of the respective cyclic iminium forms
Fig. 3. ORTEP diagram of compound (+)-8.
The CD curve of the a-ketol (+)-5c was essentially superim-
posable on that of (+)-8 [(+)-5c: e312 +2.17, e277 ꢀ1.20, e232
+1.81; (+)-8: e310 +2.60, e277 ꢀ1.77, e232 +1.82], and therefore,
it was assigned the same (2R,3R,4R) absolute configuration.
The bicyclic a-ketols (+)-5a and (+)-5b showed very similar
Chirality DOI 10.1002/chir

ORGANOCATALYZED REACTIONS BETWEEN 2,3-BUTANEDIONE AND CONJUGATED NITROOLEFINS
derived from closure of intermediates 13 and 130. Formation
of (ꢀ)-7c would occur via inversion of the carbanion and its
collapse onto the acetyl carbonyl group, followed by
hydrolysis of the corresponding derivative. The inversion of
diastereoselectivity observed for the products derived from
1-nitrocyclopentene 3a with respect to the other nitroolefins
(Table 1, Entry 1) might be ascribed to a less steric require-
ment of the nitrocyclopentane ring that could favor the dipo-
lar intermediate 130, in which the interaction between the
methyl group of the diacetyl moiety and the iminium group
are reduced.
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