Diastereoselective preparation of (S)-(1,4,4-trimethylpyrrolidin-3-yl) amine, a new chiral 1,2-diamine for thiourea-type organocatalysts

Article abstract of DOI:10.1016/j.tetasy.2011.04.002

The enantioselective synthesis of the title compound, its conversion into a thiourea-type organocatalyst and the behavior of this organocatalyst in several enantioselective Michael reactions are described.

Full text of DOI:10.1016/j.tetasy.2011.04.002

Tetrahedron: Asymmetry 22 (2011) 745–751
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective preparation of (S)-(1,4,4-trimethylpyrrolidin-3-yl)amine,
a new chiral 1,2-diamine for thiourea-type organocatalysts
Pelayo Camps a, , Carles Galdeano a, Diego Muñoz-Torrero a, Jordi Rull a, Teresa Calvet b,
⇑
Mercè Font-Bardia b,c
a Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona,
Av. Diagonal 643, E-08028 Barcelona, Spain
b Cristal.lografia, Mineralogia i Dipòsits Minerals, Universitat de Barcelona, Martí i Franquès s/n. E-08028 Barcelona, Spain
c Unitat de Difracció de RX, Centre Científic i Tecnològic de la Universitat de Barcelona (CCiTUB), Universitat de Barcelona, Solé i Sabarís 1-3. E-08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of the title compound, its conversion into a thiourea-type organocatalyst
and the behavior of this organocatalyst in several enantioselective Michael reactions are described.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 9 March 2011
Accepted 4 April 2011
Available online 4 May 2011
Dedicated to Professor Alfredo Ricci
(Bologna University) on the occasion of his
retirement, after a long and fruitful career
1. Introduction
desymmetrization of meso-cyclic anhydrides, we planned the prep-
aration of the related aminopyrrolidine thiourea (S)-16 (Scheme 2)
(R)-Pantolactone (R)-1 (Fig. 1) is a widely used chiral auxiliary.1
Several years ago, we prepared an improved and easily available
closely related chiral auxiliary, 3-hydroxy-4,4-dimethyl-1-phenyl-
pyrrolidin-2-one (N-phenylpantolactam), 2 (Fig. 1), in both enan-
tiomeric forms.2 Compounds (R)- and (S)-2 were used as chiral
auxiliaries in different diastereoselective reactions, such as the
to study its properties as a novel organocatalyst in different trans-
formations. We selected aminopyrrolidine (S)-10 as a key interme-
diate for the preparation of (S)-16 (Scheme 2).
2. Results and discussion
deracemization of
a-arylpropionic acids, Diels–Alder reactions
At first, we carried out the synthesis of racemic aminopyrrol-
idine rac-10, as shown in Scheme 1. Pantolactam rac-5 was
prepared in 48% yield by reaction of rac-pantolactone rac-1 with
40% aqueous methylamine under p-TsOHꢀH2O catalysis at 250 °C
and 75 atm, as previously described.8 Chromic acid oxidation9 of
rac-5 gave in high yield the corresponding ketolactam 6. The same
transformation was also carried out, albeit in lower yield, by oxida-
tion with RuO4, generated from a catalytic amount of RuCl3ꢀ3H2O
and trichloroisocyanuric acid as the stoichiometric oxidant.10
The reaction of ketolactam 6 with benzylamine in toluene at re-
flux, in the absence of an acidic catalyst, with azeotropic elimina-
tion of water quantitatively afforded imine 7, which was reduced
to benzylaminopantolactam rac-8 with NaBH3CN and then sub-
jected to catalytic hydrogenation to give aminopantolactam rac-9
in high yield. Reduction of rac-9 with the BH3ꢀTHF complex in
THF gave the highly volatile aminopyrrolidine rac-10, which was
isolated as its dihydrochloride salt in 60% yield.
and dynamic kinetic resolutions of a-haloesters, and as resolution
agents.1,3 We also synthesized different aminopantolactams, such
as (S)-3,4 which was used as a chiral auxiliary in Michael reactions,
and (S)-4,5 as a ligand for organometallic catalysis.
6,7
Inspired by the work of Pedrosa et al.
on the use of N-
[3,5-bis(trifluoromethyl)phenyl]-N0-[2-(dimethylamino)alkyl]thio-
ureas as organocatalysts in Michael reactions and in the
Me
Me
Me
Me
Me
Me
NH2
O
OH
OH
O
O
N
R
O
N
(R)-1
(S)-3, R = C6H5
(S)-4, R = H
(R)-2
Next, we synthesized (S)-10 as shown in Scheme 2. The reaction
Figure 1. Structures of pantolactone and several pantolactam derivatives.
of ketolactam
6 with (R)-1-phenylethylamine in toluene at
reflux with azeotropic distillation of water in the absence of any
acidic catalyst quantitatively afforded imine (R)-12. Reduction of
this imine with NaBH3CN afforded a diastereomeric mixture of
⇑
Corresponding author. Tel.: +34 93 4024536; fax: +34 93 4035941.
E-mail address: camps@ub.edu (P. Camps).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.002

746
P. Camps et al. / Tetrahedron: Asymmetry 22 (2011) 745–751
Na2Cr2O7·2H2O,
H2SO4, AcOH
93%
Me
Me
Me
O
OH
Me
Toluene,
Me
Me
N
H
reflux, 20 h
O
or RuCl3·3H2O,
TBAB, NaOAc·3H2O,
trichloroisocyanuric acid,
CH3CN/H2O
O
N
Me
N
Me
6
+
Me
6
H
Dean-Stark
quantitative
NH2
O
N
rac-5
Me
33%
(R)-11
Me
(R)-12
NaBH3CN,
Benzylamine (1 eq),
H
H
Me
Me
Me
N
NaBH3CN,
MeOH, AcOH
Me
Me
toluene, Δ, −H2O
Me
N
HN
H
H
H
MeOH, AcOH
Me
Me
−78 ºC, 4.75 h
rt, 4.75 h
96%
quantitative
O
O
N
Me
7
N
O
+
N
(S)-(+)-mandelic
Me
acid
Me
(3R,1'R)-14
(3S,1'R)-13
ratio 13:14 = 80:20
Isolated as salts of
(S)-(+)-mandelic acid:
66% salt of 13
H2 (1 atm),
H2 (1 atm), 5% Pd/C,
MeOH, concd HCl
24 h
Me
Me
NH2
O
Me
Me
HN
5% Pd/C,
MeOH, concd HCl
and 15% salt of 14
90%
O
N
Me
24 h
96%
N
Me
rac-8
H
Me
Me
H
Me
rac-9
(i) BH3·THF, THF, Δ
Me
NH2
O
NH3
2 Cl
Me
Me
NH3
2 Cl
(ii) Na2CO3, MeOH, Δ
N
(i) BH3·THF, THF, Δ
(iii) HCl/MeOH
N
H
Me
(S)-9
Me
(ii) Na2CO3, MeOH, Δ
N
Me
64%
H
(iii) HCl/MeOH
(S)-10·2HCl
Also characterized as a
mono-O,O-di-p-toluoyl-
(2R,3R)-tartrate
60%
rac-10·2HCl
Scheme 1. Preparation of aminopyrrolidine dihydrochloride rac-10ꢀ2HCl.
F3C
H
N
H
N
C
S
N
aminopantolactams (3S,10R)-13 and (3R,10R)-14 in an 80:20 ratio,
established on the basis of the quartet signal of the CH3CH proton
of each diastereomer [d 3.91 ppm for (3S,10R)-13 and 4.31 ppm for
(3R,10R)-14]. The above mixture was separated by crystallization
as salts of (S)-(+)-mandelic acid; both salts were fully characterized.
The absolute configuration of the (S)-mandelate of the minor
aminolactam (3R,10R)-14 was established by X-ray diffraction
analysis (Fig. 2).11 Consequently, the absolute configuration of the
major aminolactam must be (3S,10R)-13. Aminolactams (3S,10R)-13
and (3R,10R)-14 were liberated from their (S)-mandelate salts and
(3S,10R)-13 was hydrogenated to give aminopantolactam (S)-9 in
high yield as an oil, which was also characterized as its solid
mono-O,O-di-p-toluoyl (2R,3R)-tartrate. The reduction of (S)-9 with
BH3ꢀTHF complex, followed by treatment with an excess of HCl/
MeOH as before for rac-9, gave aminopyrrolidine (S)-10ꢀ2HCl. A
sample of free amine (S)-10 was isolated from its dihydrochloride
for characterization purposes. The reaction of (S)-10ꢀ2HCl with
3,5-bis(trifluoromethyl)phenylisothiocyanate,7 15, in CH2Cl2 in
the presence of K2CO3 gave thiourea (S)-16 in good yield.
F3C
15
Me
C
S
F3C
N
Me
CH2Cl2, K2CO3
rt, 24 h
Me
CF3
81%
(S)-16
Scheme 2. Preparation of aminopyrrolidine dihydrochloride (S)-10ꢀ2HCl and
thiourea (S)-16.
be noted that when using Pedrosa’s catalyst (S)-20 (Fig. 3), we
were able to reproduce the results of Pedrosa et al.6 on these
enantioselective Michael reactions, thus establishing that the main
enantiomers obtained in our case were the same, that is, those of
an (S)-configuration.
The new organocatalyst (S)-16 can be considered as a cyclic
analog of (S)-20, the best catalyst described by Pedrosa et al.6
formally derived from it by dehydrogenation with formation of
the five-membered ring of (S)-16, as shown in Fig. 3. Very recently,
related thioureas derived from (S)-(1,2-dimethyl-3,5-diphenyl-
pyrrolidin-3-yl)amine proved to be completely inefficient as
organocatalysts in the Michael addition of diethyl malonate to
b-nitrostyrene.12 It is usually assumed that the transition-state
complex in thiourea organocatalyzed reactions implies several
hydrogen bonds in which the thiourea N–H groups and the tertiary
amine of the catalyst are involved.7,13 The modest enantioselectiv-
ities obtained with catalyst (S)-16 in the Michael reactions studied
must be related to a reduced ability of this catalyst to form the
required hydrogen bonds due to the restricted conformational
mobility of the cyclic tertiary amine.14
Following the optimized experimental conditions described by
6
Pedrosa et al., we studied the enantioselective Michael reactions
of acetylacetone 18a (R = Me), dimethyl malonate 18b (R = OMe),
and diethyl malonate 18c (R = OEt), with trans-b-nitrostyrene, 17,
catalyzed by (S)-16 (Table 1). Reaction times were similar to those
described. The fastest reaction, which used 18a as the dicarbonyl
compound, took place in about 4 h, while reactions using 18b
and 18c required approximately 24 and 48 h, respectively. Good
isolated yields but modest enantioselectivities were observed in
all cases (19a: 82%, 49% ee; 19b: 94%, 35% ee; 19c: 88%, 18% ee).
To establish the chiral HPLC conditions, racemic products 19a,
19b and 19c were prepared by using the known12 achiral organo-
catalyst 21 (Fig. 3) under similar reaction conditions. The configu-
ration of the main stereoisomers in these reactions was established
as (S) in all cases, by comparison of the specific rotation of the ob-
tained mixtures with the described data (see Section 4). It should
3. Conclusion
In conclusion, we have synthesized (S)-(1,4,4-trimethylpyrroli-
din-3-yl)amine, (S)-10, in
a diastereoselective manner, using

P. Camps et al. / Tetrahedron: Asymmetry 22 (2011) 745–751
747
Figure 2. ORTEP representation of (3R,10R)-14ꢀ(S)-mandelate.
CF3
Table 1
Me
S
C
Enantioselective Michael reactions of 17 with 1,3-dicarbonyl compounds 18 catalyzed
H
Me
by (S)-16a
N
H
N
H
CF3
NO2
RCO
COR
NO2
N
(S)-16 (10 mol%)
toluene, −18 ºC
Me
(S)-16
17
CF3
+
Me
S
C
N
H
RCO
COR
Me
H
Me
(S)-19
18
N
H
CF3
N
H
Entry
R
t (h)
Yield (%)
Product (ee (%))b
(Config.)c
Me
(S)-20
1
2
3
Me 18a
OMe 18b
OEt 18c
4
24
48
82
94
88
19a (49)
19b (35)
19c (18)
(S)
(S)
(S)
CF3
S
C
N
a
The reactions were carried out with one equiv of 17 and 2 equiv of 18 in the
N
H
CF3
Me
presence of 10 mol % of (S)-16 at ꢁ18 °C.
N
Me
H
b
Enantiomeric excess was determined by HPLC analysis of (S)-19 using the
21
Chiralpack IC chiral column.
c
The absolute configuration was established by comparison of the specific
Figure 3. Structures of organocatalysts (S)-16, (S)-20 and 21.
rotation of (S)-19 with the literature data and the chiral HPLC data of (S)-19 with
those obtained using Pedrosa’s catalyst (S)-20.
standard (CHCl3 at dH = 7.26 ppm, dC = 77.0 ppm). Assignments gi-
ven for the NMR spectra are based on DEPT sequence, 1H/1H COSY,
1H/13C HETCOR (HSQC sequence) and 1H/1H NOESY experiments
for selected compounds. Coupling constants J are given in Hertz
(Hz). Mass spectra were recorded on a LC/MSD-TOF (2006, Agilent
technologies), using electrospray (ESI-MS, positive mode, capillary:
3.5 kV, fragmentor: 215 V). Unless otherwise stated, IR spectra
were performed with the attenuated total reflection (ATR) tech-
nique and the absorption values are given as wavenumbers
(cmꢁ1). Elemental analyses were done at the Microanalysis Service
of the IIQAB (CSIC, Barcelona, Spain). Optical rotations were deter-
mined on a polarimeter using a 1-dm cell. Column chromatogra-
phy was performed on silica gel 60 A C.C. (35–70 mesh). For the
thin layer chromatography (TLC), aluminum-backed sheets with
silica gel 60 F254 or aluminum oxide ALOX N/UV254 were used
and spots were visualized with UV light and/or 1% aqueous KMnO4.
Chiral HPLC analysis was performed at 20 °C using Perkin Elmer
Series 200 pump equipped with UV detector and using a DaicelÒ
Chiralpak IC column (250 ꢂ 4.6 mm). UV detection was monitored
(R)-1-phenylethylamine as a chiral auxiliary. The absolute configu-
ration of (S)-10 has been unambiguously established by X-ray dif-
fraction of the (S)-mandelate of (3R,10R)-14, diastereomer of
(3S,10R)-13, precursor (S)-10. Amine (S)-10 has been transformed
into organocatalyst (S)-16 by reaction with 3,5-bis(trifluoro-
methyl)phenylisothiocyanate, which in a preliminary study, has
shown modest enantioselectivities in the Michael addition of 1,3-
dicarbonyl compounds to trans-b-nitrostyrene.
4. Experimental
4.1. General
Melting points were determined in open capillary tubes. Unless
otherwise stated, NMR spectra were recorded at 25 °C in CDCl3: 1H
NMR (400 MHz), 13C NMR (100.6 MHz). All chemical shifts (dH and
dC) are reported in parts per million (ppm) related to internal

748
P. Camps et al. / Tetrahedron: Asymmetry 22 (2011) 745–751
at different wavelengths. The resolution (Rs) of the two enantio-
5H, Ar–H); 13C NMR (75.4 MHz) 21.5 (CH3) and 26.0 (CH3) [4-
(CH3)2], 29.9 (CH3, N–CH3), 38.6 (C, C4), 53.5 (CH2, N–CH2), 59.9
(CH2, C5), 67.3 (CH, C3), 126.8 (CH), 128.1 (CH) and 128.2 (CH)
(Ar–Cortho, Ar–Cmeta and Ar–Cpara), 140.3 (C, Ar–Cipso), 174.6 (C,
C2). Anal. Calcd for C14H20N2Oꢀ0.25H2O: C, 71.00; H, 8.72; N,
11.83. Found: C, 71.26; H, 8.65; N, 11.80. HRMS (ESI): Calcd for
([M+H]+): 233.1648; found 233.1652.
mers was determined by the equation: Rs = 1.18 (t2 ꢁ t1)ꢀ(W50(1)
+
ꢁ1
W50(2)
)
where t1 and t2 are the retention times of the first and
second eluted peaks, respectively; W50(1) and W50(2) are the corre-
sponding peak widths at the half peak height.
4.2. 1,4,4-Trimethylpyrrolidine-2,3-dione 6
To a cooled (0 °C) solution of rac-5 (330 mg, 2.30 mmol) in
AcOH (18 mL) a solution of Na2Cr2O7ꢀ2H2O (380 mg, 1.28 mmol)
in H2SO4 (20% aqueous solution, 3.5 mL) was added dropwise
and the mixture was stirred for 30 min at room temperature.
Water (30 mL) was added and the mixture was extracted with
CH2Cl2 (3 ꢂ 50 mL). The combined organic phases were washed
with saturated aqueous NaHCO3 (20 mL) and brine (15 mL). The or-
ganic phase was dried (anhydrous MgSO4) and concentrated under
reduced pressure to give 6 (300 mg, 93% yield) as a white solid. An
analytical sample was obtained by crystallization from EtOAc
(3 mL). Mp 116–117 °C (EtOAc); IR 2974, 2935, 2874, 1751 and
1705 (CO), 1492, 1473, 1436, 1406, 1384, 1327, 1269, 1216,
4.5. rac-3-Amino-1,4,4-trimethylpyrrolidin-2-one rac-9
A
mixture of rac-8 (4.51 g, 19.4 mmol), concentrated HCl
(6.20 mL), and 5% Pd/C (16.7 g) in MeOH (150 mL) was hydroge-
nated at 1 atm and room temperature for 24 h. The mixture was fil-
tered through a pad of CeliteÒ, washing the filter with MeOH
(50 mL). The filtrate was basified with aqueous 5 M NaOH
(20 mL) and extracted with CH2Cl2 (3 ꢂ 100 mL). The combined or-
ganic extracts were dried (anhydrous MgSO4) and concentrated
under reduced pressure to give rac-9 (2.65 g, 96% yield) as a color-
less oil. IR 3313 and 3297 (NH), 2957, 2938, 2869, 2830, 2784,
1661 (CO), 1453, 1431, 1313, 1295, 1268, 1208, 1177, 1094,
1076, 1035, 855, 709 cmꢁ1; For the 1H and 13C NMR data, see (S)-
9. Anal. Calcd for C7H14N2Oꢀ2/3H2O: C, 54.52; H, 10.02; N, 18.17.
Found: C, 54.51; H, 9.60; N, 17.85. HRMS (ESI): Calcd for
([M+H]+): 143.1179; found 143.1181.
1101, 1038, 938, 738 cmꢁ1 1H NMR 1.22 [s, 6H, 4-(CH3)2], 3.09
;
(s, 3H, N-CH3), 3.41 (s, 2H, 5-H2); 13C NMR 23.7 [CH3, 4-(CH3)2],
31.7 (CH3, N-CH3), 39.7 (C, C4), 58.4 (CH2, C5), 159.4 (C, C2),
203.5 (C, C3). Anal. Calcd for C7H11NO2: C, 59.56; H, 7.85; N,
9.92. Found: C, 59.72; H, 7.89; N, 9.96. HRMS (ESI): Calcd for
([M+H]+): 142.0863; found 142.0863.
4.6. rac-1,4,4-Trimethylpyrrolidin-3-amine dihydrochloride
rac-10ꢀ2HCl
4.3. 3-(Benzylimino)-1,4,4-trimethylpyrrolidin-2-one 7
To a cold (0 °C) solution of BH3ꢀTHF complex (1 M in THF,
37.0 mL, 37.0 mmol), a solution of rac-9 (1.57, 11.0 mmol) in anhy-
drous THF (50 mL) was added dropwise and the solution was
heated at reflux for 1 h. The solution was cooled to room temper-
ature, was treated with aqueous 5 M HCl (30 mL) and stirred for
30 min, until gas evolution ceased. The solution was concentrated
to dryness under reduced pressure. The residue was taken in MeOH
(100 mL), after which anhydrous Na2CO3 (10 g) was added and the
mixture was heated at reflux for 16 h. The solution was cooled to
room temperature, basified with KOH pellets (85% content) until
pH 12–13 and distilled at atmospheric pressure (63 °C). The distil-
late was treated with 2 M methanolic HCl (6.0 mL) and concen-
trated under reduced pressure to give rac-10ꢀ2HCl (1.56 g) as a
yellow solid, that was crystallized from a mixture of EtOAc/MeOH
5:1 (12 mL) to give rac-10ꢀ2HCl (1.33 g, 60% yield) as a white solid.
Mp 272–274 °C (dec.) (EtOAc/MeOH 5:1); IR 3100–2300 (max. at
2957, 2897, 2624, 2501, 2353) (CH and NH), 1583, 1526, 1462,
1357, 1331, 1230, 1175, 1130, 1099, 1061, 744, 731 cmꢁ1; for the
1H and 13C NMR data, see (S)-10ꢀ2HCl. Anal. Calcd for
C7H16N2ꢀ2.1HClꢀ0.4H2O: C, 39.66; H, 8.99; N, 13.21; Cl, 35.12.
Found: C, 39.65; H, 9.30; N, 13.04; Cl, 35.35.
A solution of 1,4,4-trimethylpyrrolidine-2,3-dione, 6 (5.00 g,
35.4 mmol), and benzylamine (3.90 mL, 3.82 g, 35.7 mmol) in tolu-
ene (150 mL) was heated at reflux for 24 h in a Dean–Stark equip-
ment. Evaporation of the solvent under reduced pressure gave 7
(8.90 g, quantitative yield) as an orange oil. IR (NaCl) 3062, 3028,
2962, 2927, 2869, 1692 (CO), 1496, 1466, 1453, 1431, 1404,
1322, 1277, 1210, 1108, 753, 733, 698 cmꢁ1; H NMR 1.25 [s, 6H,
4-(CH3)2], 2.97 (s, 3H, N–CH3), 3.28 (s, 2H, 5-H2), 5.48 (s, 2H,
CH2–Ph), 7.22 (t, J = 7.4 Hz, 1H, Ar–Hpara), 7.32 (tm, J = 7.6 Hz, 2H,
Ar–Hmeta), 7.39 (d, J = 7.6 Hz, 2H, Ar–Hortho); 13C NMR 26.5 [CH3,
4-(CH3)2], 30.5 (CH3, N–CH3), 37.7 (C, C4), 53.4 (CH2, CH2–Ph),
59.7 (CH2, C5), 126.3 (CH, Ar–Cpara), 127.7 (CH, Ar–Cortho), 128.2
(CH, Ar–Cmeta), 140.8 (C, Ar–Cipso), 161.0 (C, C2), 166.6 (C, C3). Anal.
Calcd for C14H18N2Oꢀ0.25H2O: C, 71.61; H, 7.94; N, 11.93. Found: C,
71.30; H, 7.87; N, 11.68. HRMS (ESI): Calcd for ([M+H]+): 231.1492;
found 231.1496.
4.4. rac-3-Benzylamino-1,4,4-trimethylpyrrolidin-2-one rac-8
To a solution of 7 (6.00 g, 26.0 mmol) in anhydrous MeOH
(100 mL), a solution of NaBH3CN (95% content, 3.50 g, 52.9 mmol)
and AcOH (1.80 mL, 1.89 g, 31.4 mmol) were added and the reac-
tion mixture was stirred at room temperature for 4 h. Next, more
NaBH3CN (95% content, 1.00 g, 15.1 mmol) was added and stirring
was continued for another 45 min. Water (50 mL) was added and
the organic solvent was evaporated under reduced pressure. The
remaining aqueous phase was treated with aqueous 2 M NaOH un-
til pH 12–13 and extracted with CH2Cl2 (3 ꢂ 50 mL). The combined
organic extracts were dried (anhydrous MgSO4) and concentrated
under reduced pressure to give rac-8 (5.81 g, 96% yield) as a pale
yellow oil. IR (NaCl) 3500 and 3314 (NH), 3061, 3028, 2957,
2925, 2868, 1697 (CO), 1496, 1454, 1438, 1405, 1385, 1368,
1319, 1268, 1149, 1094, 1028, 997, 739, 699 cmꢁ1; H NMR
(300 MHz) 1.02 (s, 3H) and 1.12 (s, 3H) [4-(CH3)2], 1.93 (br s, 1H,
N–H), 2.83 (s, 3H, N–CH3), 2.86 (d, J = 9.6 Hz, 1H) and 3.035 (d,
J = 9.6 Hz, 1H) (5-H2), 3.036 (s, 1H, 3-H), 3.95 (d, J = 13.5 Hz, 1H)
and 4.00 (d, J = 13.5 Hz, 1H) (CH2–Ph), 7.21–7.40 (complex signal,
4.7. (R)-1,4,4-Trimethyl-3-[(1-phenylethyl)imino]pyrrolidin-2-
one (R)-12
A solution of 1,4,4-trimethylpyrrolidine-2,3-dione, 6 (878 mg,
6.22 mmol), and (R)-1-phenylethylamine, (R)-11 (800 lL, 752 mg,
6.22 mmol) in toluene (30 mL) was heated at reflux for 20 h in a
Dean–Stark equipment. Evaporation of the solvent under reduced
pressure gave a crude product (1.63 g) that was crystallized from
EtOAc (6 mL) to give (R)-12 (1.52 g, quantitative yield) as a yellow
solid. Mp 89–90 °C (from EtOAc); ½a D24
¼ þ62 (c 0.81, CH2Cl2); IR
ꢃ
2973, 2958, 2921, 2862, 1687 and 1674 (CO), 1489, 1448, 1397,
1322, 1279, 1204, 1120, 1095, 1068, 907, 763, 698 cmꢁ1 1H
;
NMR 1.21 (s, 3H) and 1.26 (s, 3H) [4-(CH3)2], 1.44 (d, J = 6.8 Hz,
3H, CH3–CH), 2.94 (s, 3H, N–CH3), 3.24 (s, 2H, 5-H2), 6.55 (q,
J = 6.8 Hz, 1H, CH3–CH), 7.19 (tm, J = 7.6 Hz, 1H, Ar–Hpara), 7.30
(tm, J = 7.6 Hz, 2H, Ar–Hmeta), 7.47 (d, J = 7.6 Hz, 2H, Ar–Hortho);

P. Camps et al. / Tetrahedron: Asymmetry 22 (2011) 745–751
749
13C NMR 25.3 (CH3), 26.2 (CH3) and 26.9 (CH3) [4-(CH3)2 and CH3–
CH], 30.5 (CH3, N–CH3), 37.5 (C, C4), 55.9 (CH, CH3–CH), 59.7 (CH2,
C5), 126.3 (CH, Ar–Cpara), 126.6 (CH, Ar–Cortho), 128.1 (CH, Ar–Cme-
ta), 146.5 (C, Ar–Cipso), 160.8 (C, C3), 164.2 (C, C2); Anal. Calcd for
69.25; H, 7.68; N, 6.92. (3R,10R)-14ꢀ(S)-mandelate: mp 121–
122 °C (i-PrOH/Et2O/hexane 2:2:3); ½a D22
¼ þ148 (c 1.04, MeOH);
ꢃ
IR 3600–2100 (max. at 3430, 3036, 2953, 2879; OH, +NH, and
CH), 1709 and 1698 (CO), 1610, 1514, 1456, 1339, 1304, 1267,
C
15H20N2O: C, 73.74; H, 8.25; N, 11.47. Found: C, 73.70; H, 8.38;
1249, 1179, 1126, 1112, 751, 694 cmꢁ1 1H NMR (CD3OD,
;
N, 11.37. HRMS (ESI): Calcd for ([M+H]+) 245.1648; found
245.1646.
300 MHz) 0.87 (s, 3H) and 1.01 (s, 3H) [4-(CH3)2], 1.48 (d,
J = 6.8 Hz, 3H, CH3–CH), 2.80 (s, 3H, N–CH3), 2.92 (d, J = 9.6 Hz,
1H) and 3.04 (d, J = 9.6 Hz, 1H) (5-H2), 3.00 (s, 1H, 3-H), 4.59 (q,
J = 6.8 Hz, 1H, CH3–CH), 4.88 (br s, 4H, mobile H), 5.04 (s, 1H, CH
mandelate), 7.25–7.48 (complex signal, 10H) (Ar–H); 13C NMR
(CD3OD) 21.3 (CH3), 23.3 (CH3) and 24.5 (CH3) [4-(CH3)2 and
CH3–CH], 30.1 (CH3, N–CH3), 38.9 (C, C4), 59.0 (CH, CH3–CH), 60.7
(CH2, C5), 66.3 (CH, C3), 74.8 (CH, CH mandelate), 127.9 (CH),
128.7 (CH), 129.3 (CH) and 129.8 (CH) (Ar–Cortho and Ar–Cmeta man-
delate and Ar–Cortho and Ar–Cmeta phenyl), 128.8 (CH) and 129.1
(CH) (Ar–Cpara mandelate and Ar–Cpara phenyl), 141.8 (C) and
143.6 (C) (Ar–Cipso mandelate and Ar–Cipso phenyl), 175.0 (C, C2),
177.2 (C, COO mandelate). Anal. Calcd for C15H22N2OꢀC8H8O3: C,
69.32; H, 7.59; N, 7.03. Found: C, 68.95; H, 7.51; N, 7.08.
4.8. Mixture of (3S,10R)- and (3R,10R)-1,4,4-trimethyl-3-[(1-
phenylethyl)amino]pyrrolidin-2-one, (3S,10R)-13 and (3R,10R)-
14
To a cold (ꢁ78 °C) solution of (R)-12 (703 g, 2.88 mmol) in
anhydrous MeOH (80 mL), a solution of NaBH3CN (95% content,
600 mg, 9.08 mmol) and AcOH (200 lL, 210 mg, 3.49 mmol) in
anhydrous MeOH (5 mL) was added dropwise and the reaction
mixture was stirred at this temperature for 4 h. Then more
NaBH3CN (95% content, 600 mg, 9.08 mmol) was added and the
mixture was stirred for another 45 min. The mixture was allowed
to warm to room temperature, after which water (100 mL) was
added and the organic solvent was evaporated under reduced pres-
sure. The remaining aqueous phase was treated with aqueous 2 M
NaOH until pH 12–13 and extracted with CH2Cl2 (3 ꢂ 100 mL). The
combined organic extracts were dried (anhydrous MgSO4) and
concentrated under reduced pressure to give a diastereomeric mix-
ture of (3S,10R)-13 and (3R,10R)-14 (610 mg, 87% yield) in a ratio of
80:20 (1H NMR) as a colorless oil.
4.10. Isolation of (3S,10R)-13 from its (S)-mandelate
A solution of (3S,10R)-13ꢀ(S)-mandelate (500 mg, 1.26 mmol) in
CH2Cl2 (30 mL) was washed with aqueous 2 M NaOH (3 ꢂ 10 mL),
dried (anhydrous MgSO4) and concentrated in vacuo to give
(3S,10R)-13 (310 mg, quantitative yield) as
½ ꢃ
a
colorless oil.
¼ þ144 (c 0.74, CH2Cl2); IR 3310 (NH), 2961, 2932, 1686
and 1676 (CO), 1604, 1528, 1511, 1355, 1303, 1252, 1174, 1052,
1031, 842, 763, 733, 700 cmꢁ1 1H NMR (300 MHz) 1.02 (s, 3H)
a 2D2
4.9. Isolation of (3S,10R)-13ꢀ(S)-mandelate and (3R,10R)-14ꢀ(S)-
;
mandelate
and 1.14 (s, 3H) [4-(CH3)2], 1.36 (d, J = 6.6 Hz, 3H, CH3–CH), 2.79
(d, J = 9.6 Hz, 1H) and 2.94 (d, J = 9.6 Hz, 1H) (5-H2), 2.787 (s, 3H,
N–CH3), 2.91 (s, 1H, 3-H), 3.91 (q, J = 6.6 Hz, 1H, CH3–CH), 7.19–
7.25 (complex signal, 3H, Ar–Hpara and Ar–Hmeta), 7.32 (m, 2H,
Ar–Hortho); 13C NMR (75.4 MHz) 21.2 (CH3), 24.6 (CH3) and 25.1
(CH3) [4-(CH3)2 and CH3–CH], 30.0 (CH3, N–CH3), 38.2 (C, C4),
57.5 (CH, CH3–CH), 59.7 (CH2, C5), 66.1 (CH, C3), 126.9 (CH, Ar–
An 80:20 mixture of (3S,10R)-13 and (3R,10R)-14 (5.05 g,
20.5 mmol) was taken in MeOH (10 mL), treated with a solution
of (S)-(+)-mandelic acid (3.12 g, 20.5 mmol) in MeOH (20 mL),
and the mixture was concentrated to dryness in vacuo. The solid
obtained was taken in a mixture of i-PrOH/Et2O/hexane 2:2:3
(17 mL) and was cooled to 5 °C for 24 h. The precipitated solid
was collected by filtration and washed with Et2O (10 mL) to give,
after drying, (3R,10R)-14ꢀ(S)-mandelate (1.21 g, 15% yield) as a
white solid. Hexane (3 mL) was added to the mother liquors and
the solution was kept at ꢁ20 °C for 48 h precipitating an equimolar
mixture of the (S)-mandelate salts of (3S,10R)-13 and (3R,10R)-14
(820 mg, 10% yield). The mother liquors were concentrated to dry-
ness in vacuo obtaining the (S)-mandelate of the major amine
(3S,10R)-13 (5.40 g, 66% yield) as a foamy white solid. An analytical
sample of (3S,10R)-13ꢀ(S)-mandelate was obtained by crystalliza-
tion from a mixture of i-PrOH/Et2O/hexane 2:2:3. (3S,10R)-13ꢀ(S)-
mandelate: mp 110–112 °C (i-PrOH/Et2O/hexane 2:2:3);
Cpara), 127.4 (CH, Ar–Cortho), 128.1 (CH, Ar–Cmeta), 145.8 (C, Ar–Cip-
so), 175.8 (C, C2); Anal. Calcd for C15H22N2O: C, 73.13; H, 9.00; N,
11.37. Found: C, 73.17; H, 9.13; N, 11.34. HRMS (ESI): Calcd for
([M+H]+) 247.1805; found 247.1807.
4.11. Isolation of (3R,10R)-14 from its (S)-mandelate
A solution of (3R,10R)-14ꢀ(S)-mandelate (220 mg, 0.55 mmol) in
CH2Cl2 (20 mL) was washed with aqueous 2 M NaOH (3 ꢂ 10 mL),
dried (anhydrous MgSO4) and concentrated in vacuo to give
(3R,10R)-14 (135 mg, quantitative yield) as
½ ꢃ
a
colorless oil.
¼ þ139 (c 1.10, CH2Cl2); IR (NaCl) 3308 (NH), 2959, 2923,
2865, 1682 (CO), 1493, 1462, 1450, 1403, 1382, 1367, 1314,
1267, 1148, 1092, 862, 762, 701 cmꢁ1 1H NMR 0.77 (s, 3H) and
a 2D2
½
a 2D2
ꢃ
¼ þ171 (c 0.65, MeOH); IR (KBr) 3600–2100 (max. at 3439,
2959, 2875, OH, +NH and CH), 1705 and 1693 (CO), 1619, 1590,
1516, 1499, 1467, 1450, 1442, 1430, 1395, 1377, 1352, 1320,
;
0.89 (s, 3H) [4-(CH3)2], 1.35 (d, J = 6.8 Hz, 3H, CH3–CH), 2.74 (d,
J = 9.6 Hz, 1H) and 2.92 (d, J = 9.6 Hz, 1H) (5-H2), 2.77 (s, 3H, N–
CH3), 2.78 (s, 1H, 3-H), 4.31 (q, J = 6.8 Hz, 1H, CH3–CH), 7.18 (tm,
J = 7.6 Hz, 1H, Ar–Hpara), 7.26 (tm, J = 7.6 Hz, 2H, Ar–Hmeta), 7.36
(dm, 2H, J = 7.6 Hz, Ar–Hortho); 13C NMR 21.1 (CH3), 24.5 (CH3)
and 25.2 (CH3) [4-(CH3)2 and CH3–CH], 29.9 (CH3, N–CH3), 38.1
(C, C4), 57.4 (CH, CH3–CH), 59.6 (CH2, C5), 66.1 (CH, C3), 126.8
(CH, Ar–Cpara), 127.4 (CH, Ar–Cortho), 128.1 (CH, Ar–Cmeta), 146.0
(C, Ar–Cipso), 176.0 (C, C2); HRMS (ESI): Calcd for ([M+H]+)
247.1805; found 247.1809.
1274, 1243, 1183, 1092, 1069, 1060, 769, 736, 706, 698 cmꢁ1 1H
;
NMR (CD3OD) 1.05 (s, 3H) and 1.19 (s, 3H) [4-(CH3)2], 1.43 (d,
J = 6.6 Hz, 3H, CH3–CH), 2.80 (s, 3H, N–CH3), 2.94 (d, J = 10.0 Hz,
1H) and 3.08 (d, J = 10.0 Hz, 1H) (5-H2), 3.22 (s, 1H, 3-H), 4.17 (q,
J = 6.6 Hz, 1H, CH3–CH), 4.87 (br s, 4H, mobile H), 5.06 (s, 1H, CH
mandelate), 7.25–7.41 (complex signal, 8H) and 7.46 (dm,
J = 7.2 Hz, 2H) (Ar–H); 13C NMR (CD3OD) 21.7 (CH3), 23.1 (CH3)
and 26.0 (CH3) [4-(CH3)2 and CH3–CH], 30.1 (CH3, N–CH3), 39.6
(C, C4), 58.4 (CH, CH3–CH), 60.9 (CH2, C5), 66.0 (CH, C3), 74.6
(CH, CH mandelate), 127.9 (CH), 128.1 (CH), 129.3 (CH) and
129.8 (CH) (Ar–Cortho and Ar–Cmeta mandelate and Ar–Cortho and
Ar–Cmeta phenyl), 128.7 (CH) and 128.9 (CH) (Ar–Cpara mandelate
and Ar–Cpara phenyl), 141.5 (C) and 144.0 (C) (Ar–Cipso mandelate
and Ar–Cipso phenyl), 174.7 (C, C2), 176.9 (C, COO mandelate). Anal.
Calcd for C15H22N2OꢀC8H8O3: C, 69.32; H, 7.59; N, 7.03. Found: C,
4.12. (S)-3-Amino-1,4,4-trimethylpyrrolidin-2-one (S)-9
A mixture of (3S,10R)-13 (3.20 g, 13.0 mmol), concentrated HCl
(4.10 mL), and 5% Pd/C (11.0 g) in MeOH (150 mL) was
hydrogenated at 1 atm and room temperature for 24 h. The

750
P. Camps et al. / Tetrahedron: Asymmetry 22 (2011) 745–751
mixture was filtered through a pad of CeliteÒ washing the solid
with MeOH (50 mL). The filtrate was concentrated to dryness un-
der reduced pressure, basified with aqueous 5 M NaOH (25 mL)
and extracted with CH2Cl2 (3 ꢂ 100 mL). The combined organic
extracts were dried (anhydrous MgSO4) and concentrated under
reduced pressure to give (S)-9 (1.66 g, 90% yield) as a colorless
J = 12.0 Hz, 1H) and 3.51 (br d, J = 12.0 Hz, 1H) (5-H2), 3.67 (br s,
1H) and 4.02 (br s, 1H) (2-H2), 3.91 (t, J = 7.8 Hz, 1H, 3-H), 4.78
(broad s, mobile H); 13C NMR (D2O) 22.1 (CH3) and 26.8 (CH3) [4-
(CH3)2], 43.6 (CH3, N–CH3), 45.0 (C, C4), 59.2 (CH, C3), 59.5 (CH2,
C2), 68.5 (CH2, C5). Anal. Calcd for C7H16N2ꢀ2.3HClꢀ0.75H2O: C,
37.27; H, 8.85; N, 12.42; Cl, 36.15. Found: C, 37.14; H, 9.09; N,
12.71; Cl, 36.35.
oil. ½a 2D2
¼ þ41 (c 0.90, CH2Cl2); IR 3364 and 3303 (NH), 2954,
ꢃ
2918, 2867, 1686 (CO), 1495, 1463, 1438, 1403, 1383, 1366,
1318, 1272, 1081, 912, 871, 816, 782, 720 cmꢁ1 1H NMR 0.97 (s,
;
4.15. (S)-(1,4,4-Trimethylpyrrolidin-3-yl)amine (S)-10
3H) and 1.19 (s, 3H) [4-(CH3)2], 1.43 (s, 2H, NH2), 2.86 (s, 3H,
N–CH3), 2.93 (d, J = 9.6 Hz, 1H) and 3.12 (d, J = 9.6 Hz, 1H) (5-H2),
3.13 (s, 1H, 3-H); 13C NMR 20.5 (CH3) and 25.1 (CH3) [4-(CH3)2],
30.0 (CH3, N–CH3), 37.9 (C, C4), 59.9 (CH2, C5), 62.1 (CH, C3),
175.3 (C, C2); Anal. Calcd for C7H14N2Oꢀ0.1H2O: C, 58.39; H, 9.94;
N, 19.45. Found: C, 58.40; H, 9.91; N, 19.37. HRMS (ESI): Calcd
for ([M+H]+) 143.1179; found 143.1180.
A suspension of (S)-10ꢀ2HCl (100 mg, 0.50 mmol) in CH2Cl2
(3 mL) was treated with aqueous 2 M NaOH (4 mL). The organic
phase was dried (anhydrous MgSO4) and carefully concentrated
in vacuo at room temperature to give the volatile amine (S)-10
(24.1 mg, 38% yield) as a colorless oil. ½a D23
¼ ꢁ3 (c 0.73, CH2Cl2);
ꢃ
1H NMR (300 MHz) 0.97 (s, 3H) and 1.05 (s, 3H) [4-(CH3)2], 1.10–
1.40 (br s, 2H, NH2), 2.30 (s, 3H, N–CH3), 2.36 (d, J = 9.3 Hz, 1H)
and 2.47 (d, J = 9.3 Hz, 1H) (5-H2), 2.20–2.29 (m, 1H) and 2.94–
3.04 (m, 2H) (2-Hcis, 2-Htrans and 3-H); 13C NMR (75.4 MHz) 22.1
(CH3) and 28.0 (CH3) [4-(CH3)2], 40.9 (CH3, N–CH3), 43.0 (C, C4),
60.8 (CH, C3), 64.5 (CH2, C2), 70.0 (CH2, C5).
4.13. (S)-3-Amino-1,4,4-trimethylpyrrolidin-2-one mono-O,O-
di-p-toluoyl-(2R,3R)-tartrate (S)-9ꢀmono-O,O-di-p-toluoyl-
(2R,3R)-tartrate
To a solution of amine (S)-9 (705 mg, 4.96 mmol) in MeOH
(3 mL), a solution of (ꢁ)-O,O-di-p-toluoyl-(2R,3R)-tartaric acid
(97% content, 2.00 g, 5.21 mmol) in MeOH (5 mL) was added. The
resulting solution was concentrated to dryness in vacuo and the
white solid, thus obtained, was crystallized from a mixture of
MeOH/Et2O 2:3 (17 mL) to give (S)-9ꢀmono-O,O-di-p-toluoyl-
(2R,3R)-tartrate (1.94 g, 89% yield). Mp 175–176 °C (MeOH/Et2O
4.16. (S)-N-(1,4,4-Trimethylpyrrolidin-3-yl)- N0-[3,5-
bis(trifluoromethyl)phenyl]thiourea (S)-16
To a mixture of (S)-10ꢀ2HCl (500 mg, 2.49 mmol) and dry
CH2Cl2 (5 mL) in an argon atmosphere, 3,5-bis(trifluoro-
2:3); ½a 2D2
ꢃ
¼ ꢁ106 (c 0.54, MeOH); IR 3200–2500 (max. at 3200,
methyl)phenylisothiocyanate (475 lL, 2.49 mmol) and solid
2924, 2878, 2620, OH, +NH and CH), 1714 and 1667 (CO), 1611,
K2CO3 (1.00 g, 9.43 mmol) were added at 0 °C and the mixture
was stirred overnight at room temperature. The mixture was fil-
tered, the solid was washed with CH2Cl2 (5 mL), the combined fil-
trate and washing was concentrated in vacuo and the residue was
purified by flash column chromatography (CH2Cl2/MeOH mixtures)
to give (S)-16 as a pale yellow solid (807 mg, 81% yield). The ana-
lytical sample of (S)-16 was obtained by crystallization from a mix-
ture of Et2O/pentane 1:1. Mp 115–117 °C (Et2O/pentane 1:1);
1533, 1329, 1265, 1173, 1107, 745, 693 cmꢁ1 1H NMR (CD3OD)
;
1.06 (s, 3H) and 1.25 (s, 3H) [4-(CH3)2], 2.41 (s, 6H, CH3 p-toluoyl),
2.86 (s, 3H, N–CH3), 3.09 (d, J = 10.0 Hz, 1H) and 3.28 (d, J = 10.0 Hz,
1H) (5-H2), 3.76 (s, 1H, 3-H), 4.91 (s, 4H, mobile H), 5.88 [s, 2H,
2(3)-H tartrate], 7.30 [dm, J = 8.0 Hz, 4H, Ar-3(5)-H p-toluoyl],
8.02 [d, J = 8.0 Hz, 4H, Ar-2(6)-H p-toluoyl]; 13C NMR (CD3OD)
21.3 (CH3) and 24.8 (CH3) [4-(CH3)2], 21.7 (CH3, CH3 p-toluoyl),
30.2 (CH3, N–CH3), 37.9 (C, C4), 60.95 (CH, C3), 60.98 (CH2, C5),
74.8 [CH, C2(3) tartrate], 128.4 (C, C1 p-toluoyl), 130.1 [CH, Ar-
C3(5)], 131.1 [CH, Ar-C2(6)], 145.4 (C, C4 p-toluoyl), 167.4 (C, CO
p-toluoyl), 170.2 (C, C2), 171.5 [C, C1(4) tartrate]. Anal. Calcd for
C7H14N2OꢀC20H18O8: C, 61.35; H, 6.10; N, 5.30. Found: C, 61.51;
H, 6.20; N, 5.26.
½
a 2D5
ꢃ
¼ ꢁ23 (c 0.53, CH2Cl2). IR (KBr) 3364, 3314, 3154, 3031,
2965, 2898, and 2794 (NH and CH), 1621, 1559, 1512, 1471,
1384, 1353, 1320, 1279, 1193, 1173, 1137, 1124, 1108, 885, 721,
712, 702, 681 cmꢁ1 1H NMR (CD3OD) 1.09 (s, 3H) and 1.26 (s,
;
3H) [4-(CH3)2], 2.38 (s, 3H, N–CH3), 2.51 (d, J = 9.6 Hz, 1H) and
2.54 (d, J = 9.6 Hz, 1H) (5-H2), superimposed 2.52 (2H, 2-H2), 3.11
(dd, J = 10.2 Hz, 7.4 Hz, 1H, 3-H), 4.86 (s, 2H, mobile H), 7.63 (s,
1H, Ar-4-H), 8.22 [s, 2H, Ar-2(6)-H]; 13C NMR (CD3OD) 21.5 (CH3)
and 27.0 (CH3) [4-(CH3)2], 40.9 (C, C4), 41.2 (CH3, N–CH3), 59.9
(CH2, C2), 61.0 (CH, C3), 69.1 (CH2, C5), 115.8 (CH, Ar-C4), 121.5
[CH, Ar-C2(6)], 122.8 (C, q, J = 271,8 Hz, CF3), 130.7 [C, q,
J = 33.5 Hz, Ar-C3(5)], 141.2 (C, Ar-C1), 181.2 (C, C=S). Anal. Calcd
for C16H19F6N3S: C, 48.12; H, 4.19; N, 10.52; F, 28.54; S, 8.03.
Found: C, 48.84; H, 4.85; N, 10.14; F, 28.91; S, 7.85. HRMS (ESI):
Calcd for ([M+H]+) 400.1277; found 400.1277.
4.14. (S)-(1,4,4-Trimethylpyrrolidin-3-yl)amine dihydrochloride
(S)-10ꢀ2HCl
To a cold (0 °C) solution of BH3ꢀTHF complex (1 M in THF,
74.0 mL, 74.0 mmol), a solution of (S)-9 (3.14 g, 22.0 mmol) in
anhydrous THF (80 mL) was added dropwise and the solution
was heated at reflux for 1 h. The solution was cooled to room tem-
perature, was treated with aqueous 5 M HCl (60 mL) and stirred for
about 30 min, until gas evolution ceased. The solution was concen-
trated to dryness under reduced pressure, the residue was treated
with a suspension of anhydrous Na2CO3 (20 g) in MeOH (200 mL)
and heated at reflux for 15 h. The solution was cooled to room tem-
perature, was basified with KOH pellets (85% content) until pH 12–
13 and was distilled at atmospheric pressure (63 °C). The distillate,
a methanolic solution of (S)-10, was treated with 4 M methanolic
HCl (12 mL) and concentrated under reduced pressure to give a
residue (3.15 g) which was crystallized from EtOAc/MeOH 5:1
(12 mL) to give (S)-10ꢀ2HCl (2.84 g, 64% yield) as a white solid.
4.17. General procedure for the enantioselective Michael
addition of 1,3-dicarbonyl compounds to trans-b-nitrostyrene
The conditions described by Pedrosa and co-workers6 were fol-
lowed. To a stirred solution of trans-b-nitrostyrene, 17 (91 mg,
0.60 mmol) and catalyst (S)-16 (24 mg, 0.06 mmol) in dry toluene
(1.2 mL), 1,3-dicarbonyl compound 18 (1.20 mmol) was added at
ꢁ18 °C under argon. The reaction mixture was stirred until the dis-
appearance of the nitroolefin by TLC (4 h for (S)-19a, 24 h for (S)-
19b, 48 h for (S)-19c). The solvent was removed in vacuo and the
residue was purified by flash column chromatography (hexane/
AcOEt 4:1) to afford the desired product (S)-19. The ee was deter-
mined by chiral HPLC analysis and the main enantiomer was
Mp 275–276 °C (dec.) (EtOAc/MeOH 5:1); ½a D22
¼ ꢁ12 (c 1.03,
ꢃ
H2O); IR 3600–2100 (br band, CH and NH), 1584, 1531, 1471,
1421, 1138, 1096, 1061, 971, 954 cmꢁ1
;
1H NMR (D2O) 1.25 (s,
3H) and 1.29 (s, 3H) [4-(CH3)2], 3.02 (s, 3H, N–CH3), 3.43 (br d,

P. Camps et al. / Tetrahedron: Asymmetry 22 (2011) 745–751
751
deduced from the specific rotation of the enantioenriched mixture
and comparison with the described data.
The structure was solved by Direct methods, using SHELXS com-
puter program17 and refined by full-matrix least-squares method
with SHELX97 computer program,18 using 9768 reflections (very
negative intensities were not assumed). The function minimized
4.18. (S)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (S)-19a
was
R
w ||Fo|2 ꢁ |Fc|2|2, where w = [
r ,
2(I) + (0.1058P)2 + 0.5690P]ꢁ1
White solid. Isolated yield: 82%. ½a D25
ꢃ
¼ þ97:5 (c 1.0, CHCl3, 49%
¼ ꢁ147:6}. HPLC (Chiralpak
and P = (|Fo|2 + 2 |Fc|2)/3, f, f0 and f00 were taken from International
Tables of X-ray Crystallography.19 All H atoms were computed and
refined, using a riding model, with an isotropic temperature factor
equal to 1.2 times the equivalent temperature factor of the atom
to which they are linked. The final R(on F) factor was 0.070, wR(on
|F|2) = 0.193 and goodness of fit = 1.132 for all observed reflections.
Number of refined parameters was 263. Max. shift/esd = 0.00, Mean
shift/esd = 0.00. Max. and min. peaks in final difference synthesis
was 0.327 and ꢁ0.290 eÅꢁ3, respectively.
ee) {reported for (R)-19a 95% ee15
½ ꢃ
a 2D5
IC, hexane/i-PrOH = 90:10, 1.0 mL/min, k = 220 nm); tR = 18.66 min
[major, (S)], 30.86 min [minor, (R)]; Rs = 22.54;
a = 1.78.
4.19. Dimethyl (S)-2-(2-nitro-1-phenylethyl)malonate (S)-19b
White solid. Isolated yield: 94%. ½a D25
ꢃ
¼ þ2:2 (c 1.0, CHCl3, 35%
ee) {reported for (R)-19b 89% ee16
½ ꢃ ¼ ꢁ6:15}; (Chiralpak IC,
a 2D5
hexane/i-PrOH = 90:10, 1.0 mL/min, k = 220 nm); tR = 16.79 min
[major, (S)], 23.04 min [minor, (R)]; Rs = 15.69;
a
= 1.46.
Acknowledgments
4.20. Diethyl (S)-2-(2-nitro-1-phenylethyl)malonate (S)-19c
Financial support from Ministerio de Ciencia e Innovación (MIC-
INN) and FEDER (Project CTQ2008-03768/PPQ) and fellowships to
J. Rull (FPU program, MICINN) and C. Galdeano (IBUB, UB) are
gratefully acknowledged. We thank Prof. Rafael Pedrosa and Dr.
R. Manzano for the generous gift of a sample of organocatalyst
(S)-20, Ms. T. Gómez for the determination of several optical rota-
tions, the Centre Científic i Tecnològic of the University of Barcelona
for the NMR and MS facilities and Ms. P. Domènech from the IIQAB
(CSIC, Barcelona, Spain) for carrying out the elemental analyses.
White solid. Isolated yield: 88%. ½a D25
ꢃ
¼ þ2:4 (c 1.0, CHCl3, 18%
¼ ꢁ6:0}; HPLC (Chiralpak
ee); {reported for (R)-19c 93% ee16
½ ꢃ
a 2D5
IC, hexane/i-PrOH = 90:10, 1.0 mL/min, k = 220 nm); tR = 12.88 min
[major, (S)], 17.72 min [minor, (R)]; Rs = 21.07;
a = 1.49.
4.21. X-Ray crystal-structure determination of (3R,10R)-14ꢀ(S)-
mandelate (Table 2)
A prismatic crystal (0.1 ꢂ 0.09 ꢂ 0.09 mm) was selected and
mounted on a MAR345 diffractometer with an image plate detec-
tor. Unit-cell parameters were determined from 177 reflections
(3 < h < 21°) and refined by least-squares method. Intensities were
References
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1995, 6, 985–990; (b) Camps, P.; Pérez, F.; Soldevilla, N. Tetrahedron Lett. 1999,
40, 6853–6856.
collected with graphite monochromatized Mo K
a radiation. 9768
3. (a) Camps, P.; Muñoz-Torrero, D.; Sánchez, L. Tetrahedron: Asymmetry 2004, 15,
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Naessens, L. J. Org. Chem. 2008, 73, 6657–6665.
reflections were measured in the range 2.83 6 h 6 30.37, 5260 of
which were non-equivalent by symmetry (Rint(on I) = 0.034).
4410 reflections were assumed as observed applying the condition
I >2r(I). Lorentz-polarization but no absorption corrections were
made.
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11. Crystallographic data (excluding structure factors) for the structure herein
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 815330 [(3R,10R)-14ꢀ(S)-mandelate].
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Table 2
Experimental data of the X-ray crystal-structure determination of compound (3R,10R)-
14ꢀ(S)-mandelate
Molecular formula
Molecular mass weight
Crystal system
Space group
Cell parameters
a (Å)
C23H30N2O4
398.49
Monoclinic
C2
24.196 (13)
8.924 (4)
10.673 (3)
90
101.04 (2)
90
2261.9 (17)
4
856
b (Å)
c (Å)
a
(°)
ß (°)
c
(°)
V (Å3)
12. Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Lundberg, P. N. P.; Dove, A. P.; Li, H.;
Wade, C. G.; Waymouth, R. M.; Hedrick, J. L. Macromolecules 2006, 39, 7863–
7871.
Z
F (0 0 0)
13. Menguy, L.; Couty, F. Tetrahedron: Asymmetry 2010, 21, 2385–2389.
14. We also studied the methanolysis of two meso-tricyclic anhydrides (endo-5-
norbornene-2,3-dicarboxylic anhydride and exo-7-oxa-5-norbornene-2,3-
dicarboxylic anhydride) catalyzed by (S)-16, under conditions similar to
those described by Pedrosa and co-workers.7 The reactions were completed
in about 36 h, giving essentially racemic methyl hemiesters in high yields, as
established by chiral HPLC of the corresponding methyl 4-bromophenyl ester
derivatives.
dcalcd [Mg mꢁ3
]
1.170
Size of crystal (mm)
Measured reflect
Independent reflect
0.1 ꢂ 0.09 ꢂ 0.09
9768
5260
Observed reflect
4410
0.080
a
l(Mo K
a
) (mmꢁ1
)
R
0.034
15. Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713–4716.
16. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005,
127, 119–125.
17. Sheldrick, G. M. SHELXS: A Computer Program for Automatic Solution of Crystal
Structure Refinement; University of Göttingen: Germany, 1997.
18. Sheldrick, G. M. SHELX-97: A Computer Program for Crystal Structure Refinement;
University of Göttingen: Germany, 1999.
Rw
0.193
0.327
b
D
D
qmax (e Åꢁ3
)
qmin (e Åꢁ3
)
ꢁ0.290
c
Refined parameters
Max. shift/esd
263
0.00
a
b
c
l(Mo K
a) linear absorption coefficient. Radiation Mo K
a
(k = 0.71073 Å).
19. International Tables of X-ray Crystallography; Kinoch Press: Birmingham, 1974;
Vol IV, pp 99–100 and 149.
Maximum peaks in final difference synthesis.
Minimum peaks in final difference synthesis.