Synthesis of cucurbitine derivatives: facile straightforward approach to methyl 3-amino-4-aryl-1-methylpyrrolydine-3-carboxylates

Article abstract of DOI:10.1016/j.tet.2009.04.059

A general three- or four-step synthesis of cis- and trans-substituted cucurbitine (3-aminopyrrolidine-3-carboxylic acid) derivatives from methyl 2-nitroacetate is reported. The first step utilizes a Knoevenagel condensation with five different aromatic imines or their corresponding aldehydes to form (Z/E)-mixtures of α-nitro acrylates. The second step gives rise to the pyrrolidine-core structures of the title compounds by a 1,3-dipolar cycloaddition reaction using an azomethine ylide. The last step consists of reduction of the nitro group to yield both diastereoisomers of the corresponding 4-aryl cucurbitine methyl esters.

Full text of DOI:10.1016/j.tet.2009.04.059

Tetrahedron 65 (2009) 5393–5401
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of cucurbitine derivatives: facile straightforward approach to methyl
3-amino-4-aryl-1-methylpyrrolydine-3-carboxylates
Daniel Blanco-Ania a, Pedro H.H. Hermkens b, Leo A.J.M. Sliedregt c, Hans W. Scheeren a,
,
Floris P.J.T. Rutjes a
*
a Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
b Schering-Plough, P.O. Box 20, 5340 BH Oss, The Netherlands
c Solvay Pharmaceuticals, Sector Discovery Weesp, P.O. Box 900, 1380 DA Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A general three- or four-step synthesis of cis- and trans-substituted cucurbitine (3-aminopyrrolidine-3-
carboxylic acid) derivatives from methyl 2-nitroacetate is reported. The first step utilizes a Knoevenagel
condensation with five different aromatic imines or their corresponding aldehydes to form (Z/E)-mix-
Received 15 January 2009
Received in revised form 1 April 2009
Accepted 17 April 2009
tures of
a-nitro acrylates. The second step gives rise to the pyrrolidine-core structures of the title
Available online 24 April 2009
compounds by a 1,3-dipolar cycloaddition reaction using an azomethine ylide. The last step consists of
reduction of the nitro group to yield both diastereoisomers of the corresponding 4-aryl cucurbitine
methyl esters.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
the 2-arylethyl amine moiety 2 (Fig. 1), which is encountered in
numerous compounds that are active in the central nervous sys-
Cucurbitine 1 (Fig. 1), (ꢀ)-(S)-3-aminopyrrolidine-3-carboxylic
acid, is a natural product found in the pumpkin seed and other
Cucurbitaceae possessing antiparasitic, and more specifically an-
thelmintic, activity against Schistosoma japonicum.1 Cucurbitine is
also known as a hypohistaminaemic agent as it inhibits the for-
mation of histamine, a well-known mediator of allergies. The
hypohistaminaemic activity arises from the ability to block the
usual function of histidine decarboxylase, the enzyme responsible
for the conversion of histidine to histamine. The administration of
cucurbitine contributes to a decreased histamine concentration in
the blood serum and tissues. Cucurbitine is also used in cosmetic
(notably dermatologic) products in order to soothe greatly irritated,
stressed, or allergy affected skin.2
tem. This moiety is present in neurotransmitters such as dopamine,
epinephrine, norepinephrine and serotonin.3 Salmeterol4 and
venlafaxine,5 2 of the 10 best-selling prescription drugs in 2006,6
also contain this moiety. Moreover, this feature is present in many
hallucinogenic drugs, such as LSD, MDMA (ecstasy), mescaline and
psilocybin (magic mushrooms).7
There is only one example in the literature of methyl 4-phe-
nylcucurbitinate8 and a few random and isolated examples of the
synthesis of 4-aryl derivatives,9 but there are no examples of 4-
heteroaryl containing compounds. The idea of combining two
known privileged structures (cucurbitine and 2-arylethyl amine) to
generate a product with the possibility of new biological activity is
interesting from a pharmaceutical point of view (Scheme 1). In this
case, the 2-arylethyl amine moiety is contained twice within the
structure.
Although much is known about cucurbitine itself, information
on 4-aryl derivatives is rather scarce. The latter compounds possess
Herein we present a general procedure for the synthesis of both
diastereoisomers (trans and cis) of 4-aryl substituted cucurbitine
Figure 1. Cucurbitine 1 and the 2-arylethyl amine moiety 2.
* Corresponding author. Tel.: þ31 (0)24 365 3202; fax: þ31 (0)24 365 3393.
E-mail address: f.rutjes@science.ru.nl (F.P.J.T. Rutjes).
Scheme 1. Combination of two privileged structures.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.059

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D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
Table 1
Formation of N-phenyl imines 9a–e
Entry
Substrate
Solvent
T (ꢁC)
Product
Yielda (%)
1
2
3
4
5
10a
10b
10c
10d
10e
THF
d
21
46
37
21
70
9a
9b
9c
9d
9e
99
99
99
90b
99
d
THF
d
a
Isolated yield.
Conversion, not isolated yield.
b
Figure 2. Target compounds.
Table 2
derivatives (3 and 4), possessing different aryl groups such as
phenyl a, alkoxyphenyl b and c, furyl d and indolyl e (Fig. 2).
Knoevenagel condensation to form the a-nitro acrylates 7a–e
2. Results and discussion
We envisioned that a suitable strategy to these compounds may
proceed as shown retrosynthetically in Scheme 2. The amino group
of compounds 3 and 4 could be derived from a masked amino
function, such as a nitro group, by reduction. Compounds 5 and 6
possess two electron-withdrawing groups on carbon three of the
pyrrolidine, rendering it a perfect pattern for a 1,3-cycloaddition
reaction between azomethine ylides and electron-deficient
alkenes. This would leave the 3-aryl-2-nitroacrylates 7 as starting
materials, which could be obtained by a Knoevenagel condensation
Entry
Imine
Product
Ratioa (Z/E)
Yield (%)
1
2
3
4
5
9a
9b
9c
9d
9e
7a
7b
7c
7d
7e
3:1
3:2
3:1
81
88
69
69
74
2:1
40:1b
a
Calculated by integration of the 1H NMR signals of the crude reaction mixture.
The product obtained by precipitation of the reaction mixture.
b
reaction between methyl 2-nitroacetate
aldehyde.
8 and any aromatic
methyl 2-nitroacetate 8 in acetic anhydride to yield the
a-nitro
acrylates 7a–e in generally good yields12,14 and varying (Z/E)-ratios
The synthesis of compound classes 3 and 4 commenced with the
(Table 2).15
condensation of methyl 2-nitroacetate 810 with aromatic N-phenyl
In spite of our best endeavours, it was proven that the yield for
the condensation of 9d dropped dramatically when an attempt was
made to scale up the reaction to 10 g. To solve this inconvenience,
the reaction was repeated using aldehyde 10d instead. Under the
conditions depicted in Scheme 3,16 product 7d was then synthe-
sized in a higher yield, independent of the scale. All other reactions
could be readily scaled up under the stated conditions.
imines 9a–e to obtain the a-nitro acrylates 7a–e. Since the condi-
tions for the Knoevenagel condensation of these strongly activated
methylene compounds with aldehydes are critical and, therefore,
often low yielding,11 the corresponding imines, which had pre-
viously given good results for similar reactions,12 were used. To this
end, we developed a highly practical procedure for the synthesis of
N-phenyl imines 9b,c and 9e starting from the solid aromatic al-
dehydes 10b,c and 10e. Addition of aniline to the neat aromatic
aldehyde, with MgSO4 as dehydrating agent and reaction at the
melting point temperature of the aldehydes for 4–6 h, gave con-
versions of >90%. Addition of dichloromethane, removal of the
solid by filtration and subsequent distillation of dichloromethane
and water provided the corresponding N-phenyl imines in quan-
titative yields. For liquid aldehydes 10a and 10d the reaction was
run in THF at room temperature (Table 1).13
With N-phenyl imines 9a–e in hand, we proceeded with the
Knoevenagel condensations, which were run overnight with
Scheme 3. Knoevenagel condensation of aldehyde 10d.
Scheme 2. Retrosynthetic analysis for the synthesis of compound classes 3 and 4.

D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
5395
Table 3
(Fig. 3) resulting from acid catalyzed fragmentation of nitroso
compound 13, the first product from the reduction of the nitro
group, followed by Pictet–Spengler cyclization of the intermediate
iminium ion 14 (Scheme 4).
1,3-Dipolar cycloaddition reaction to form the pyrrolidine-core structures 5 and 6
Entry
Acrylate
Time (min)
Products
Yielda (%)
1
2
3
4
5
7a
7b
7c
7d
7e
45
60
110
60
5aþ6a
5bþ6b
5cþ6c
5dþ6d
5eþ6e
90
84
85
82
82
105
a
Combined yield.
Although in some cases the separation of the (Z/E)-mixtures
could be achieved by recrystallization,15 this was not investigated
any further as it was apparent from the next step that (Z/E)-isom-
erization proceeds considerably faster than the cycloaddition,
probably due to the push-pull effect.17
Scheme 4. Possible reaction sequence for the formation of 12.
The next step in the synthesis was the formation of the pyrro-
lidine-core structures by a 1,3-dipolar cycloaddition reaction using
an azomethine ylide. The decarboxylative condensation of a-amino
acids with aldehydes, typically heated in toluene or dime-
thylformamide, was chosen to generate the ylide. This reaction has
been previously used in the synthesis of natural products.18 Thus,
the use of sarcosine (N-methylglycine) with paraformaldehyde in
As a result of the above observations, it was decided not to use
dissolving metal conditions for this type of reaction. Instead, the
reduction was performed using catalytic hydrogenation with Raney
nickel in methanol at room temperature. It appeared that addition
of Et3N activated the metal,22 leading to the exclusive formation of
the amine, rather than the anticipated mixture of the amine and the
corresponding hydroxylamine.23 Thus, compounds 5a–e were
reacted under these conditions to complete the synthesis of 4-aryl
cucurbitinates. After elimination of Raney nickel by filtration
through Celite and evaporation of methanol and Et3N, the reaction
gave the compounds 3a–e as the major products (ratio ꢂ90% by
NMR spectroscopy). Compounds 3a–e were isolated in pure form
after column chromatography, completing the synthesis of cucur-
bitinates. The minor side products 15a–e and 16a–e were also
formed along with the cucurbitinates, resulting from reduction of
carbon three of the heterocycle (Table 4) and will be discussed in
detail below.24,25
When compounds 6a–e were reacted under the reduction
conditions used above, the products 4a–e were obtained with
yields similar to those for 3a–e and similar ratios of the side
products (Table 5). To the best of our knowledge, this is the only
general procedure for the synthesis of either diastereomer of 4-aryl
cucurbitinate.
A speculative explanation of how products 15 and 16 are formed
(reaction sequence shown only for 5) is outlined in Scheme 5. The
regular nitro reduction to give the amine is in competition with
refluxing toluene in the presence of the a-nitro acrylates 7 cleanly
provided a ca. 1:1 mixture of the diastereoisomeric cycloadducts 5
and 6,19 independent of the (Z/E)-ratio of the substrate (Table 3).
The separation of these products using column chromatography
was straightforward as a result of the large Rf difference between
the diastereoisomers in all cases. The cis-isomers 6 present
a chemical shift for the methyl group of the ester 0.38–0.88 ppm
lower than the trans-isomers 5, due to the shielding effect of the
aryl group.
The cycloaddition reaction also gave trace amounts of the trans-
de(methoxycarbonyl)ated products 11a–e via a Krapcho reaction
(Fig. 3).20
The reduction of nitro compounds is perhaps the most versa-
tile reduction of a functional group in organic chemistry, poten-
tially giving rise to a variety of products. Reduction of the nitro
group may lead to nitroso compounds, oximes, hydroxylamines,
amines, hydrocarbons, azoxy compounds, azo compounds and
hydrazo compounds.21 In principle, there are optimal conditions
for obtaining any of these products, but it is fairly common to
form mixtures, especially for aliphatic nitro compounds. In our
case, the reduction of the nitro group to the amine was more
problematic than anticipated. Initially, we tried the conditions
previously optimized in our group (SnCl2$2H2O, THF/H2O) for
nitro groups on molecules with a similar structure,12 but the re-
action provided the desired amines in a low yield (<30%) ac-
companied by a mixture of unidentified side products. Among the
different products obtained, we identified rearranged amine 12
Table 4
Reduction of the nitro groups from the trans-diastereoisomers
Entry
Substrate
Products
Ratioa (3/15/16)
Yield (%)b
1
2
3
4
5
5a
5b
5c
5d
5e
3aþ15aþ16a
3bþ15bþ16b
3cþ15cþ16c
3dþ15dþ16d
3eþ15eþ16e
94:5:1
93:5:2
92:6:2
92:7:1
93:6:1
80
79
80
65
62
Calculated by integration of the 1H NMR signals of the crude reaction mixture.
Isolated yield of the major products 3a–e.
a
b
Figure 3. Side products 11a–e and 12.

5396
D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
Table 5
drying agents prior to use and stored under nitrogen. Reactions
Reduction of the nitro groups from the cis-diastereoisomers
were followed, and Rf values obtained, using thin layer chroma-
tography (TLC) on silica gel-coated plates (Merck 60 F254) with the
indicated solvent mixture. Detection was performed with UV light
and/or by charring at ca. 150 ꢁC after dipping into a solution of
KMnO4. Column or flash chromatography was carried out using
ACROS silica gel (0.035–0.070 mm, pore diameter ca. 6 nm). IR
spectra were recorded on an ATI Mattson Genesis Series FTIR
spectrometer. NMR spectra were recorded at 298 K on a Bruker
DMX 300 (300 MHz) and a Varian 400 (400 MHz) spectrometer in
CDCl3 solutions. Chemical shifts are given in parts per million
(ppm) with respect to tetramethylsilane (0.00 ppm) as internal
standard. Coupling constants are reported as J values in hertz (Hz).
Multiplicity data are denoted by s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad) and app (apparent). Peak as-
signment in 13C spectra is based on 2D gHSQC and gHMBC spectra,
and DEPT 135 when needed. Chain numbering corresponds to
IUPAC nomenclature, so unprimed atoms belong to the principal
chain and primed atoms belong to the substituents.
Entry
Substrate
Products
Ratioa (4/15/16)
Yieldb (%)
1
2
3
4
5
6a
6b
6c
6d
6e
4aþ15aþ16a
4bþ15bþ16b
4cþ15cþ16c
4dþ15dþ16d
4eþ15eþ16e
93:4:3
90:6:4
90:7:3
90:7:3
88:8:4
77
71
76
61
60
a
Calculated by integration of the 1H NMR signals of the crude reaction mixture.
Isolated yield of the major products 4a–e.
b
4.2. General procedure for imine formation
A mixture of the aromatic aldehyde 10, aniline (1.02 equiv for
9b,c and 1.20 equiv for 9e) and MgSO4 (0.28 equiv) was stirred
without solvent and heated at the melting point temperature of the
aldehyde for 4 h for 9b,c and for 6 h for 9e. The reaction was cooled
down to room temperature and the solid residue was dissolved in
dichloromethane (40 mL for 9b,c and 300 mL for 9e). The solid
hydrated MgSO4 was filtered off and the filtrate was concentrated
under reduce pressure. When the solvent was evaporated, the
sample was kept under reduced pressure for 1 h (water bath 40 ꢁC)
for 9b,c and 2 h (water bath 75 ꢁC) for 9e. The sample was left
overnight under high vacuum. The product was recrystallized from
heptane.
Scheme 5. Reaction sequence for the denitration of compounds 5.
a radical reduction of this group.26 Thus, the nitro group is adsorbed
onto the surface of Raney nickel and reduced to the radical anion
19. This intermediate cleaves to form a carbon-centred radical,27
which is reduced to the nickel C-enolate 20. The C-enolate is par-
tially hydrogenated to 15 and partially equilibrated, through the O-
enolate, to the C-enolate 21.28 Finally, both C-enolates 20 and 21 are
hydrogenated to 15 and 16, respectively.
4.2.1. (E)-N-(3,5-Dimethoxybenzylidene)aniline 9b
According to the general procedure, the reaction of aldehyde
10b (10.0 g, 60.2 mmol) with aniline (5.7 g, 61.4 mmol) afforded 9b
(14.5 g, 99%) as a light yellow solid. 1H NMR [400 MHz,
d (ppm),
CDCl3]: 8.37 (s, 1 1H, CHN), 7.43–7.36 (m, 2 1H, 3-CHþ5-CH), 7.27–
7.18 (m, 3 1H, 2-CHþ4-CHþ6-CH), 7.07 (d, J¼2.4 Hz, 2 1H, 20-CHþ60-
CH), 6.59 (t, J¼2.4 Hz, 1 1H, 40-CH), 3.86 (s, 6 1H, 2ꢃOCH3). 13C NMR
[75 MHz,
d
(ppm), CDCl3]: 161.2 (30-Cþ50-C), 160.4 (CHN), 152.1 (1-
C), 138.4 (10-C), 129.3 (3-Cþ5-C), 126.1 (4-C), 121.0 (2-Cþ6-C), 106.6
3. Conclusion
(20-Cþ60-C), 104.4 (40-C), 55.7 (2ꢃOCH3). FTIR [
n
(cmꢀ1), neat]:
In summary, we have developed a general method for the syn-
thesis of 4-aryl substituted cucurbitine derivatives. We have shown
that these aryl groups could be phenyl, electron-rich aryls (3,5-
dimethoxyphenyl, 1,3-benzodioxol-5-yl) and electron-rich hetero-
aryls (2-furyl, 1-methylindol-3-yl). As a result, we anticipate that
this methodology can be successfully applied for a wide range of
aromatic groups. These compounds combine the structure of
cucurbitine (an allergy mediator and an anthelmintic agent) with
the 2-arylethyl amine moiety (core structure with central nervous
system activity), rendering it a potentially interesting motive from
the pharmaceutical point of view. In addition, we have developed
a high yielding method for the synthesis of N-phenyl imines from
solid aromatic aldehydes.
2836, 1633, 1594, 1151, 833, 764, 691. HRMS [EI (m/z)] calcd for
ꢄ
C15H15NO2¼241.1103, found for [Mþ ]¼241.1095 (j
D
j¼3.2 ppm),
peaks at (relative intensity): 241 (100), 240 (89), 211 (26), 104 (16),
77 (55), 51 (15). Rf: 0.53 (AcOEt/heptane, 1:2). Mp¼45–46 ꢁC.
4.2.2. (E)-N-Piperonylideneaniline 9c
According to the general procedure, the reaction of aldehyde 10c
(10.0 g, 66.6 mmol) with aniline (6.3 g, 67.9 mmol) afforded 9c
(15.0 g, 99%) as a light yellow solid. 1H NMR [400 MHz,
d (ppm),
CDCl3]: 8.33 (s, 1 1H, CHN), 7.53 (d, J¼1.6 Hz, 1 1H, 40-CH), 7.41–7.35
(m, 2 1H, 3-CHþ5-CH), 7.27 (dd, J¼8.1, 1.6 Hz, 1 1H, 60-CH), 7.24–7.16
(m, 3 1H, 2-CHþ4-CHþ6-CH), 6.88 (d, J¼8.1 Hz, 1 1H, 70-CH), 6.04 (s,
2 1H, OCH2O). 13C NMR [75 MHz,
d (ppm), CDCl3]: 159.5 (CHN),152.2
(1-C), 150.7 (70a-C), 148.6 (30a-C), 131.4 (50-C), 129.3 (3-Cþ5-C),
125.8 (4-Cþ60-C), 121.0 (2-Cþ6-C), 108.4 (70-C), 107.0 (40-C), 101.8
4. Experimental section
4.1. General
(OCH2O). FTIR [n
(cmꢀ1), neat]: 3059, 2892, 2783, 1624, 1600, 1581,
1453, 1262, 935, 812, 766, 698. HRMS [EI (m/z)] calcd for
ꢄ
C14H11NO2¼225.0790, found for [Mþ ]¼225.0790 (j
D
j¼0.0 ppm),
Reagents were obtained from commercial suppliers and used
without purification. Solvents were distilled from appropriate
peaks at (relative intensity): 225 (100), 224 (78), 77 (34), 51 (10).
Elem. Anal. Calcd for C14H11NO2: C 74.65%, H 4.92%, N 6.22%; found:

D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
5397
C 74.87%, H 4.79%, N 6.06%. Rf: 0.51 (AcOEt/heptane, 1:3). Mp¼67–
3.80 (s, 6 1H, 2ꢃOCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]: 161.8
68 ꢁC (from heptane, white cotton-like solid).
(CO2), 161.4 (30-Cþ50-C), 142.2 (2-C), 137.1 (3-C), 130.61 (10-C), 108.2
(20-Cþ60-C), 104.8 (40-C), 55.64 (2ꢃOCH3), 53.8 (CO2CH3).
4.2.3. (E)-N-[(1-Methyl-1H-indol-3-yl)methylidene]aniline 9e
According to the general procedure, the reaction of aldehyde 10e
(10.0 g, 62.8 mmol) with aniline (7.0 g, 75.4 mmol) afforded 9e
4.3.3. Methyl 3-(1,3-benzodioxol-5-yl)-2-nitroacrylate (Z)-
7c/(E)-7c (3:1)
(14.6 g, 99%) as a light yellow solid. 1H NMR [400 MHz,
d
(ppm),
According to the general procedure, the reaction of methyl 2-
nitroacetate 8 (3.57 g, 30.0 mmol) with imine 9c (7.4 g, 33.0 mmol)
afforded 7c (5.2 g, 69% yield), as a yellow solid, after column
CDCl3]: 8.63 (s, 1 1H, CHN), 8.50–8.45 (m, 1 1H, 40-CH), 7.54 (s, 1 1H,
1
20-CH), 7.42–7.27 (m, 5 H, 3-CHþ5-CHþ50-CHþ60-CHþ70-CH),
7.25–7.21 (m, 2 1H, 2-CHþ6-CH), 7.20–7.14 (m, 1 1H, 4-CH), 3.86 (s, 3
chromatography (AcOEt/heptane, 1:4/1:3). FTIR [n
(cmꢀ1), neat]:
1H, NCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]: 154.3 (CHN), 153.7
3003, 2950, 2846, 2784, 1721, 1630, 1528, 1502, 1244, 827. HRMS [EI
ꢄ
(1-C), 138.0 (70a-C), 134.3 (20-C), 129.2 (3-Cþ5-C), 126.2 (30a-C),
(m/z)] calcd for C11H9NO6¼251.0430, found for [Mþ ]¼251.0420
124.9 (4-C), 123.4 (60-C), 122.4 (40-C), 121.8 (50-C), 121.1 (2-Cþ6-C),
(j j¼3.9 ppm), peaks at (relative intensity): 251 (100), 204 (43), 173
D
115.2 (30-C), 109.6 (70-C), 33.5 (NCH3). FTIR [
n
(cmꢀ1), neat]: 3055,
(31), 146 (48), 59 (31). Elem. Anal. Calcd for C11H9NO6: C 52.60%, H
3.61%, N 5.58%; found: C 52.49%, H 3.66%, N 5.59%. Rf: 0.26 (AcOEt/
heptane, 1:3). Mp¼114–116 ꢁC (from heptane, yellow crystals).
2848, 1612, 1583, 1573, 1463, 1372, 771, 750, 696. HRMS [EI (m/z)]
ꢄ
calcd for C16H14N2¼234.1157, found for [Mþ ]¼234.1157, (j
Dj¼
0.0 ppm), peaks at (relative intensity): 234 (100), 233 (89), 218 (10),
77 (19). Elem. Anal. Calcd for C16H14N2: C 82.02%, H 6.02%, N 11.96%;
found: C 81.90%, H 6.05%, N 11.75%. Rf: 0.36 (AcOEt/heptane, 1:2).
Mp: 132–134 ꢁC (from heptane).
Compound (Z)-7c: 1H NMR [400 MHz, (ppm), CDCl3]: 7.42 (s, 1 1H,
d
3-CH), 7.00 (dd, J¼8.0, 2.0 Hz,11H, 60-CH), 6.87 (d, J¼2.0 Hz, 11H, 40-
CH), 6.84 (d, J¼8.0 Hz, 1 1H, 70-CH), 6.04 (s, 2 1H, OCH2O), 3.90 (s, 3
1H, OCH3). 13C NMR [75 MHz,
d (ppm), CDCl3]: 160.9 (CO2), 151.5
(70a-C), 149.0 (30a-C), 138.2 (2-C), 133.1 (3-C), 127.7 (60-C), 122.92
(50-C), 109.2 (70-C), 108.3 (40-C), 102.3 (OCH2O), 53.5 (OCH3).
4.3. General procedure for Knoevenagel condensation
Compound (E)-7c: 1H NMR [400 MHz, (ppm), CDCl3]: 8.00 (s, 11H,
d
A solution of methyl 2-nitroacetate 8 in Ac2O (1.0 M) was heated
to 50 ꢁC. Compound 9 (1.1 equiv) was added to this solution and
stirred at 50 ꢁC for 17 h. After this time, H2O (100 mL) was added.
The reaction mixture was stirred for 10 min and then extracted
with dichloromethane (3ꢃ100 mL). The combined organic layers
were washed with brine (50 mL), dried (MgSO4), filtered and con-
centrated in vacuo.
3-CH), 7.09 (dd, J¼8.0, 2.0 Hz,11H, 60-CH), 6.94 (d, J¼2.0 Hz, 11H, 40-
CH), 6.88 (d, J¼8.0 Hz, 1 1H, 70-CH), 6.07 (s, 2 1H, OCH2O), 3.98 (s, 3
1H, OCH3). 13C NMR [75 MHz,
d (ppm), CDCl3]: 162.2 (CO2), 151.9
(70a-C),148.9 (30a-C),140.0 (2-C),137.1 (3-C),128.7 (60-C),122.91 (50-
C), 109.3 (70-C), 108.8 (40-C), 102.4 (OCH2O), 53.8 (OCH3).
4.3.4. Methyl (Z)-3-(1-methyl-1H-indol-3-yl)-2-nitro-
acrylate (Z)-7e
4.3.1. Methyl 2-nitro-3-phenylacrylate (Z)-7a/(E)-7a (3:1)
According to the general procedure, the reaction of methyl 2-
nitroacetate 8 (3.57 g, 30.0 mmol) with imine 9e (7.7 g, 33.0 mmol)
afforded 7e (5.8 g, 74% yield), as a bright yellow solid, after washing
the precipitate from the reaction mixture with cold (ꢀ70 ꢁC) AcOEt.
According to the general procedure, the reaction of methyl
2-nitroacetate
33.0 mmol) afforded 7a (5.04 g, 81% yield), as a yellow sticky solid,
after column chromatography (AcOEt/heptane, 1:4). FTIR [
(cmꢀ1),
8 (3.57 g, 30.0 mmol) with imine 9a (5.98 g,
n
1H NMR [400 MHz, (ppm), CDCl3]: 7.98 (s, 1 1H, 3-CH), 7.79–7.76
d
neat]: 3059, 2956, 1735, 1731, 1643, 1536, 1533, 1269, 765, 687. Rf:
(m, 1 1H, 40-CH), 7.69 (s, 1 1H, 20-CH), 7.41–7.30 (m, 3 1H, 50-CHþ60-
0.28 (AcOEt/heptane, 1:4). Compound (Z)-7a: 1H NMR [400 MHz,
CHþ70-CH), 3.92 (s, 3 1H, OCH3), 3.86 (s, 3 1H, NCH3). 13C NMR
d
(ppm), CDCl3]: 7.55 (s, 1 1H, 3-CH), 7.54–7.40 (m, 5 1H, Ph), 3.92 (s,
[75 MHz, d
(ppm), CDCl3]: 161.0 (CO2), 137.0 (70a-C), 134.7 (2-C),
3 1H, OCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]: 159.8 (CO2), 140.0
133.7 (20-C), 128.4 (30a-C), 127.0 (3-C), 123.9 (60-C), 122.5 (50-C),
118.4 (40-C), 110.4 (70-C), 105.8 (30-C), 53.1 (OCH3), 34.0 (NCH3). FTIR
(2-C),133.4 (3-C), 132.4 (40-C), 129.9 (20-Cþ60-C), 129.54 (30-Cþ50-C),
129.00 (10-C), 53.69 (OCH3). Compound (E)-7a: 1H NMR [400 MHz,
[n
(cmꢀ1), neat]: 3119, 3035, 2955, 1710, 1621, 1523, 1261, 747.
d
(ppm), CDCl3]: 8.10 (s, 1 1H, 3-CH), 7.54–7.40 (m, 5 1H, Ph), 3.96 (s,
HRMS [EI (m/z)] calcd for C13H12N2O4¼260.0797, found for
ꢄ
3 1H, OCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]: 161.8 (CO2), 141.9
[Mþ ]¼260.0806 (j
D
j¼3.4 ppm), peaks at (relative intensity): 260
(2-C), 137.1 (3-C), 132.6 (40-C), 130.5 (20-Cþ60-C), 129.51 (30-Cþ50-C),
(100), 213 (27), 158 (20), 155 (40), 149 (62), 121 (41). Elem. Anal.
Calcd for C13H12N2O4: C 60.00%, H 4.65%, N 10.76%; found: C 60.02%,
H 4.84%, N 10.56%. Rf: 0.33 (AcOEt/heptane, 1:2). Mp¼170–171 ꢁC
(from AcOEt, bright yellow needles).
129.02 (10-C), 53.8 (OCH3).
4.3.2. Methyl 3-(3,5-dimethoxyphenyl)-2-nitroacrylate (Z)-
7b/(E)-7b (3:2)
According to the general procedure, the reaction of methyl 2-
nitroacetate 8 (3.57 g, 30.0 mmol) with imine 9b (8.0 g, 33.0 mmol)
afforded 7b (7.0 g, 88% yield), as a yellow solid, after column
4.3.4.1. Methyl (E)-3-(1-methyl-1H-indol-3-yl)-2-nitroacrylate (E)-
7e (taken from a 2:1 mixture of (Z)-7e/(E)-7e). 1H NMR [400 MHz,
d
(ppm), CDCl3]: 8.51 (s, 1 1H, 3-CH), 7.99 (s, 1 1H, 20-CH), 7.79–7.75
chromatography (AcOEt/heptane, 1:4/1:3). FTIR [
n
(cmꢀ1), neat]:
(m, 1 1H, 40-CH), 7.41–7.30 (m, 3 1H, 50-CHþ60-CHþ70-CH), 3.98 (s, 3
3003, 2958, 2841, 1736, 1731, 1643, 1536, 1205, 844. HRMS [EI (m/z)]
1H, OCH3), 3.89 (s, 3 1H, NCH3). 13C NMR [75 MHz,
d (ppm), CDCl3]:
ꢄ
calcd for C12H13NO6¼267.0743, found for [Mþ ]¼267.0742
163.5 (CO2), 137.4 (70a-C), 135.8 (20-C), 135.5 (2-C), 131.8 (3-C), 128.9
(30a-C), 124.1 (60-C), 122.8 (50-C), 118.6 (40-C), 110.6 (70-C), 106.1 (30-
C), 53.3 (OCH3), 34.1 (NCH3).
(j j¼0.3 ppm), peaks at (relative intensity): 267 (100), 166 (82), 135
D
(26), 59 (43). Elem. Anal. Calcd for C12H13NO6: C 53.93%, H 4.90%, N
5.24%; found: C 54.15%, H 4.83%, N 5.23%. Rf: 0.41 (AcOEt/heptane,
1:2). Mp¼46–49 ꢁC. Compound (Z)-7b: 1H NMR [400 MHz,
d
(ppm),
4.3.5. Procedure for methyl 3-(2-furyl)-2-nitroacrylate 7d
1
CDCl3]: 7.48 (s, 1 1H, 3-CH), 6.58–6.54 (m, 3 H, 20-CHþ40-CHþ60-
A 0.1 M solution of TiCl4 (133.6 mmol) in THF (1.2 L) was pre-
pared by the addition of a 1.0 M solution of TiCl4 in CH2Cl2 at 0 ꢁC,
followed by the addition of a mixture of methyl 2-nitroacetate 8
(8.00 g, 66.8 mmol) and furfural 10d (9.62 g, 100.2 mmol) in THF
(130 mL) at 0 ꢁC. A 1.0 M solution of 4-methylmorpholine (27.10 g,
267.5 mmol) in THF (235 mL) was then added by syringe over 2 h at
0 ꢁC. The reaction mixture was stirred at room temperature for
CH), 3.92 (s, 3 1H, CO2CH3), 3.78 (s, 6 1H, 2ꢃOCH3). 13C NMR
[75 MHz,
d
(ppm), CDCl3]: 161.4 (30-Cþ50-C), 159.8 (CO2), 140.3 (2-
C), 133.5 (3-C), 130.58 (10-C), 107.5 (20-Cþ60-C), 104.7 (40-C), 55.63
(2ꢃOCH3), 53.7 (CO2CH3). Compound (E)-7b: 1H NMR [400 MHz,
1
d
(ppm), CDCl3]: 8.02 (s, 1 1H, 3-CH), 6.63 (d, J¼2.2 Hz, 2 H, 20-
CHþ60-CH), 6.59 (t, J¼2.2 Hz, 1 1H, 40-CH), 3.96 (s, 3 1H, CO2CH3),

5398
D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
24 h. Water (800 mL) was then added and the solution was
extracted with Et2O (3ꢃ800 mL). The combined organic layers were
dried (MgSO4), filtered and concentrated in vacuo. The brown solid
residue was purified by recrystallization from methanol to afford
pure (Z)-7d (5.23 g, 40% yield) as light brown crystals. The filtrate
was concentrated under reduce pressure and purified by column
chromatography (AcOEt/heptane, 1:3) to afford a 1.7:1 mixture of
(Z)-7d/(E)-7d (6.21 g, 47% yield) as a dark brown solid. Total yield
87%.
164.8 (CO2), 136.2 (10-C), 129.0, 128.2, 127.8 (40-C), 102.9 (3-C), 64.9
(2-C), 61.7 (5-C), 53.0 (CO2CH3), 51.4 (4-C), 41.5 (NCH3). FTIR [
n
(cmꢀ1), neat]: 2950, 2837, 2788, 1750, 1554, 1338, 1243, 789, 754,
699. Rf: 0.54 (AcOEt/heptane, 1:1).
4.4.2. (ꢅ)-Methyl (3R,4R)-4-(3,5-dimethoxyphenyl)-1-methyl-3-
nitropyrrolidine-3-carboxylate 5b and (ꢅ)-methyl (3R,4S)-4-(3,5-
dimethoxyphenyl)-1-methyl-3-nitropyrrolidine-3-carboxylate 6b
According to the general procedure, a-nitro acrylate 7b (9.99 g,
37.4 mmol) afforded 5b (4.85 g, 40%), as a yellow oil, and 6b (5.33 g,
44%), as a yellow solid, after column chromatography (AcOEt/hep-
tane, 1:3/1:2).
4.3.5.1. Methyl (Z)-3-(2-furyl)-2-nitroacrylate (Z)-7d. 1H NMR
[400 MHz,
d
(ppm), CDCl3]: 7.62 (d, J¼1.8 Hz, 1 1H, 50-CH), 7.37 (s, 1
1H, 3-CH), 6.94 (d, J¼3.5 Hz,11H, 30-CH), 6.57 (dd, J¼3.5, 1.8 Hz,11H,
40-CH), 3.90 (s, 3 1H, OCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]:
4.4.2.1. Compound 5b. 1H NMR [400 MHz,
d
(ppm), CDCl3]: 6.51 (d,
1
160.0 (CO2), 148.2 (50-C), 145.5 (20-C), 136.2 (2-C), 121.0 (30-C), 120.0
J¼2.3 Hz, 2 H, 20-CHþ60-CH), 6.36 (t, J¼2.3 Hz, 1 1H, 40-CH), 4.42
(app t, J¼7.4 Hz, 1 1H, 4-CH), 3.85 (s, 3 1H, CO2CH3), 3.77 (d,
J¼11.6 Hz, 1 1H, 2-CHH), 3.75 (s, 6 1H, 2ꢃOCH3), 3.26 (d, J¼11.6 Hz,
1 1H, 2-CHH), 3.08 (dd, J¼9.4, 6.9 Hz, 1 1H, 5-CHH), 3.02 (dd, J¼9.4,
7.9 Hz, 1 1H, 5-CHH), 2.47 (s, 3 1H, NCH3). 13C NMR [75 MHz,
(3-C), 113.4 (40-C), 53.6 (OCH3). FTIR [ (cmꢀ1), neat]: 3131, 3059,
n
2957, 1721, 1642, 1535, 1263, 1210. HRMS [EI (m/z)] calcd for
ꢄ
C8H7NO5¼197.0324, found for [Mþ ]¼197.0324 (j
Dj¼0.0 ppm),
peaks at (relative intensity): 197 (14), 122 (15), 96 (28), 92 (25), 83
(100), 63 (34). Elem. Anal. Calcd for C8H7NO5: C 48.74%, H 3.58%, N
7.10%; found C 48.84%, H 3.58%, N 7.11%. Rf: 0.40 (AcOEt/heptane,
1:2). Mp¼84–85 ꢁC (from methanol).
d
(ppm), CDCl3]: 166.7 (CO2), 160.5 (30-Cþ50-C), 138.4 (10-C), 107.0
(20-Cþ60-C), 100.9 (3-C), 99.9 (40-C), 63.3 (2-C), 61.0 (5-C), 55.2
(2ꢃOCH3), 53.8 (CO2CH3), 51.4 (4-C), 41.4 (NCH3). FTIR [
n
(cmꢀ1),
neat]: 2951, 2838, 2792, 1752, 1594, 1552, 1202, 1154, 845, 693.
4.3.5.2. Methyl (E)-3-(2-furyl)-2-nitroacrylate (E)-7d (from the
HRMS [EI (m/z)] calcd for C15H20N2O6¼324.1321, found for
ꢄ
mixture). 1H NMR [400 MHz,
d
(ppm), CDCl3]: 7.87 (s, 1 1H, 3-CH),
[Mþ ]¼324.1314 (j
D
j¼2.3 ppm), peaks at (relative intensity): 324
7.66 (d, J¼1.8 Hz, 1 1H, 50-CH), 7.07 (d, J¼3.5 Hz, 1 1H, 30-CH), 6.62
(13), 278 (100), 246 (73), 235 (57), 218 (49), 175 (91). Rf: 0.17
(AcOEt/heptane, 1:1).
1
(dd, J¼3.5, 1.8 Hz, 1 H, 40-CH), 4.00 (s, 3 1H, OCH3). 13C NMR
[75 MHz,
d
(ppm), CDCl3]: 161.4 (CO2), 148.7 (50-C), 145.4 (20-C),
138.6 (2-C), 122.9 (3-Cþ30-C), 113.9 (40-C), 53.6 (OCH3).
4.4.2.2. Compound 6b. 1H NMR [400 MHz,
d
(ppm), CDCl3]: 6.49
1
1
(d, J¼2.4 Hz, 2 H, 20-CHþ60-CH), 6.36 (t, J¼2.4 Hz, 1 H, 40-CH),
4.65 (dd, J¼8.6, 7.6 Hz, 1 1H, 4-CH), 3.77 (s, 6 1H, 2ꢃOCH3), 3.66
(d, J¼11.6 Hz, 1 1H, 2-CHH), 3.51 (d, J¼11.6 Hz, 1 1H, 2-CHH), 3.31
(dd, J¼9.2, 7.6 Hz, 1 1H, 5-CHH), 3.30 (s, 3 1H, CO2CH3), 2.75 (app t,
J¼9.1 Hz, 1 1H, 5-CHH), 2.42 (s, 3 1H, NCH3). 13C NMR [75 MHz,
4.4. General procedure for 1,3-dipolar cycloaddition
A round-bottomed flask fitted with a Dean–Stark apparatus,
a reflux condenser, and a drying tube containing calcium chloride
was charged with
a-nitro acrylate 7, MgSO4 (0.5 equiv) and toluene
d
(ppm), CDCl3]: 165.2 (CO2), 160.7 (30-Cþ50-C), 138.7 (10-C), 107.2
(0.20–0.25 M). When the mixture was under reflux, sarcosine (N-
methylglycine; 1.2 equiv) and paraformaldehyde (3.6 equiv) were
added. This addition was repeated every 45 min until the substrate
had completely reacted. Water (20 mL) was then added and the
layers were separated. The aqueous layer was extracted with Et2O
(3ꢃ30 mL) and the combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo.
(20-Cþ60-C), 102.9 (3-C), 99.8 (40-C), 64.8 (2-C), 61.6 (5-C), 55.4
(2ꢃOCH3), 53.1 (CO2CH3), 51.4 (4-C), 41.3 (NCH3). FTIR [
n
(cmꢀ1),
neat]: 2950, 2839, 2793, 1749, 1594, 1554, 1343, 1203, 1155, 841,
696. HRMS [EI (m/z)] calcd for C15H20N2O6¼324.1321, found for
ꢄ
[Mþ ]¼324.1309 (j
D
j¼3.8 ppm), peaks at (relative intensity): 324
(5), 278 (99), 246 (100), 235 (72), 218 (34), 175 (99). Rf: 0.42
(AcOEt/heptane, 1:1). Mp¼82–85 ꢁC (from hexane, small white
crystals).
4.4.1. (ꢅ)-Methyl (3R,4R)-1-methyl-3-nitro-4-phenylpyrrolidine-3-
carboxylate 5a and (ꢅ)-methyl (3R,4S)-1-methyl-3-nitro-4-
phenylpyrrolidine-3-carboxylate 6a
4.4.3. (ꢅ)-Methyl (3R,4R)-4-(1,3-benzodioxol-5-yl)-1-methyl-3-
nitropyrrolidine-3-carboxylate 5c and (ꢅ)-methyl (3R,4S)-4-(1,3-
benzodioxol-5-yl)-1-methyl-3-nitropyrrolidine-3-carboxylate 6c
According to the general procedure, a-nitro acrylate 7a (2.51 g,
12.1 mmol) afforded 5a (1.38 g, 43%), as a colourless oil, and 6a
(1.50 g, 47%), as a yellow oil, after column chromatography (AcOEt/
heptane, 1:3/1:2).
According to the general procedure, a-nitro acrylate 7c (10.05 g,
40.0 mmol) afforded 5c (4.92 g, 40%), as a colourless oil, and 6c
(5.52 g, 45%), as a yellow oil, after column chromatography (AcOEt/
heptane, 1:3/1:2).
4.4.1.1. Compound 5a. 1H NMR [300 MHz,
d (ppm), CDCl3]: 7.34–
7.21 (m, 5 1H, Ph), 4.49 (app t, J¼7.5 Hz, 1 1H, 4-CH), 3.83 (s, 3 1H,
OCH3), 3.78 (d, J¼11.7 Hz, 1 1H, 2-CHH), 3.26 (d, J¼11.7 Hz, 1 1H, 2-
CHH), 3.10 (dd, J¼9.4, 7.2 Hz, 1 1H, 5-CHH), 3.06 (dd, J¼9.4, 7.8 Hz, 1
4.4.3.1. Compound 5c. 1H NMR [400 MHz,
d (ppm), CDCl3]: 6.88 (d,
J¼1.8 Hz, 1 1H, 40-CH), 6.80 (ddd, J¼8.0, 1.9, 0.4 Hz, 1 1H, 60-CH), 6.69
(d, J¼8.0 Hz,11H, 70-CH), 5.90 (s, 2 1H, OCH2O), 4.42 (app t, J¼7.3 Hz,
1 1H, 4-CH), 3.83 (s, 3 1H, OCH3), 3.77 (d, J¼11.8 Hz, 1 1H, 2-CHH),
3.21 (d, J¼11.8 Hz, 1 1H, 2-CHH), 3.04 (dd, J¼9.4, 6.9 Hz, 1 1H, 5-
1H, 5-CHH), 2.48 (s, 3 1H, NCH3). 13C NMR [75 MHz,
d (ppm), CDCl3]:
164.5 (CO2), 136.0 (10-C), 128.62, 128.35, 128.2 (40-C), 101.1 (3-C),
63.5 (2-C), 61.1 (5-C), 54.0 (OCH3), 51.5 (4-C), 41.8 (NCH3). FTIR [
n
CHH), 2.99 (dd, J¼9.4, 7.6 Hz, 1 1H, 5-CHH), 2.45 (s, 3 1H, NCH3). 13
C
(cmꢀ1), neat]: 2954, 2845, 2792, 1755, 1552, 1342, 1247, 780, 754,
NMR [75 MHz, d
(ppm), CDCl3]: 166.7 (CO2),147.6 (30a-C),147.5 (70a-
698. Rf: 0.23 (AcOEt/heptane, 1:1).
C), 129.7 (50-C), 122.4 (60-C), 109.1 (40-C), 108.1 (70-C), 101.2 (OCH2O),
101.0 (3-C), 63.2 (2-C), 61.1 (5-C), 53.8 (OCH3), 51.1 (4-C), 41.5
4.4.1.2. Compound 6a. 1H NMR [300 MHz,
d
(ppm), CDCl3]: 7.34–
(NCH3). FTIR [n
(cmꢀ1), neat]: 2966, 2878, 2782, 1753, 1552, 1237,
7.19 (m, 5 1H, Ph), 4.72 (app t, J¼8.1 Hz, 1 1H, 4-CH), 3.65 (d,
J¼11.4 Hz, 11H, 2-CHH), 3.52 (d, J¼11.4 Hz, 1 1H, 2-CHH), 3.31 (app t,
J¼8.4 Hz, 1 1H, 5-CHH), 3.16 (s, 3 1H, OCH3), 2.80 (app t, J¼9.0 Hz, 1
730. HRMS [EI (m/z)] calcd for C14H16N2O6¼308.1008, found for
ꢄ
[Mþ ]¼308.1002 (j
D
j¼2.1 ppm), peaks at (relative intensity): 308
(16), 262 (71), 219 (83), 202 (29), 189 (74), 159 (43). Rf: 0.22 (AcOEt/
1H, 5-CHH), 2.43 (s, 3 1H, NCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]:
heptane, 1:1).

D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
5399
4.4.3.2. Compound 6c. 1H NMR [400 MHz,
d
(ppm), CDCl3]: 6.88 (d,
1 1H, 5-CHH), 2.98 (t, J¼9.2 Hz, 1 1H, 5-CHH), 2.49 (s, 3 1H, 1-NCH3).
J¼1.7 Hz, 1 1H, 40-CH), 6.82 (dd, J¼8.0, 1.7 Hz, 1 1H, 60-CH), 6.73 (d,
J¼8.0 Hz, 1 1H, 70-CH), 5.94 (s, 2 1H, OCH2O), 4.64 (app t, J¼8.1 Hz, 1
1H, 4-CH), 3.62 (d, J¼11.4 Hz, 1 1H, 2-CHH), 3.53 (d, J¼11.4 Hz, 1 1H,
2-CHH), 3.33 (s, 3 1H, OCH3), 3.28 (dd, J¼9.3, 7.6 Hz, 1 1H, 5-CHH),
2.74 (app t, J¼9.0 Hz, 1 1H, 5-CHH), 2.42 (s, 3 1H, NCH3). 13C NMR
13C NMR [75 MHz, (ppm), CDCl3]: 167.0 (CO2), 136.6 (70a-C), 128.1
d
(30a-C), 127.5 (20-C), 122.0 (60-C), 119.6 (50-C), 119.5 (40-C), 109.3 (70-
C), 109.0 (30-C), 101.2 (3-C), 63.6 (2-C), 61.9 (5-C), 53.8 (OCH3), 43.9
(4-C), 41.7 (1-NCH3), 32.9 (10-NCH3). FTIR [ (cmꢀ1), neat]: 3049,
n
2948, 2844, 2790, 1752, 1548, 1473, 1251, 740. HRMS [EI (m/z)] calcd
ꢄ
[75 MHz,
d
(ppm), CDCl3]: 165.3 (CO2), 147.7 (30a-C), 147.3 (70a-C),
for C16H19N3O4¼317.1376, found for [Mþ ]¼317.1386 (j
Dj¼3.2 ppm),
130.0 (50-C), 122.7 (60-C), 109.6 (40-C), 108.1 (70-C), 102.8 (3-C), 101.3
(OCH2O), 64.8 (2-C), 61.8 (5-C), 53.2 (OCH3), 51.2 (4-C), 41.4 (NCH3).
peaks at (relative intensity): 317 (16), 271 (18), 228 (100), 168 (22).
Elem. Anal. Calcd for C16H19N3O4: C 60.56%, H 6.03%, N 13.24%;
found C 60.74%, H 6.06%, N 13.30%. Rf: 0.16 (AcOEt/heptane, 1:1).
Mp¼117–119 ꢁC (from methanol, light yellow crystals).
FTIR [n
(cmꢀ1), neat]: 2951, 2844, 2789, 1748, 1555, 1251, 1237, 1038.
HRMS [EI (m/z)] calcd for C14H16N2O6¼308.1008, found for
ꢄ
[Mþ ]¼308.1001 (j
D
j¼2.4 ppm), peaks at (relative intensity): 308
(10), 262 (86), 219 (100), 202 (33), 189 (83), 159 (51). Rf: 0.48
4.4.5.2. Compound 6e. 1H NMR [400 MHz,
d (ppm), CDCl3]: 7.76 (br
(AcOEt/heptane, 1:1).
d, J¼7.9 Hz, 1 1H, 40-CH), 7.25 (br d, J¼8.4 Hz, 1 1H, 70-CH), 7.20 (br t,
J¼7.5 Hz,11H, 60-CH), 7.13–7.09 (m, 11H, 50-CH), 7.00 (s, 11H, 20-CH),
1
4.4.4. (ꢅ)-Methyl (3R,4R)-4-(2-furyl)-1-methyl-3-nitropyrrolidine-
3-carboxylate 5d and (ꢅ)-methyl (3R,4S)-4-(2-furyl)-1-methyl-3-
nitropyrrolidine-3-carboxylate 6d
5.12 (app t, J¼8.0 Hz, 1 1H, 4-CH), 3.73 (s, 3 H, 10-NCH3), 3.67 (d,
J¼11.6 Hz, 11H, 2-CHH), 3.55 (d, J¼11.6 Hz, 11H, 2-CHH), 3.38 (app t,
J¼8.3 Hz, 1 1H, 5-CHH), 2.94 (s, 3 1H, OCH3), 2.77 (app t, J¼8.9 Hz, 1
According to the general procedure,
a-nitro acrylate 7d (8.00 g,
1H, 5-CHH), 2.44 (s, 3 1H, 1-NCH3). 13C NMR [75 MHz,
d (ppm),
40.6 mmol) afforded 5d (4.02 g, 39%), as a yellow oil, and 6d (4.44 g,
43%), as a yellow oil, after column chromatography (AcOEt/heptane,
1:3/1:2).
CDCl3]: 165.5 (CO2), 136.7 (70a-C), 128.1 (20-C), 127.6 (30a-C), 122.1
(60-C), 119.9 (50-C), 119.5 (40-C), 109.7 (30-C), 109.2 (70-C), 102.9 (3-C),
64.6 (2-C), 62.2 (5-C), 52.5 (OCH3), 43.0 (4-C), 41.4 (1-NCH3), 32.9
(10-NCH3). FTIR [ (cmꢀ1), neat]: 3049, 2947, 2841, 2791, 1749, 1552,
n
4.4.4.1. Compound 5d. 1H NMR [400 MHz,
d
(ppm), CDCl3]: 7.33
1473, 1254, 742. HRMS [EI (m/z)] calcd for C16H19N3O4¼317.1376,
ꢄ
(dd, J¼1.9, 0.9 Hz, 1 1H, 50-CH), 6.29 (dd, J¼3.4, 1.9 Hz, 1 1H, 40-CH),
6.26 (br d, J¼3.2 Hz, 1 1H, 30-CH), 4.61 (dd, J¼8.9, 7.3 Hz, 1 1H, 4-CH),
3.86 (s, 3 1H, OCH3), 3.66 (d, J¼11.4 Hz, 1 1H, 2-CHH), 3.42 (d,
J¼11.4 Hz, 1 1H, 2-CHH), 3.21 (dd, J¼9.2, 7.3 Hz, 1 1H, 5-CHH), 2.98
(app t, J¼9.1 Hz, 1 1H, 5-CHH), 2.47 (s, 3 1H, NCH3). 13C NMR
found for [Mþ ]¼317.1384 (j
D
j¼2.8 ppm), peaks at (relative in-
tensity): 317 (11), 271 (7), 228 (100), 168 (20). Rf: 0.34 (AcOEt/
heptane, 1:1). Mp¼109–112 ꢁC.
4.5. General procedure for reduction
[75 MHz,
d
(ppm), CDCl3]: 166.3 (CO2), 149.2 (20-C), 143.0 (50-C),
110.6 (40-C), 109.2 (30-C), 98.9 (3-C), 62.7 (2-C), 59.1 (5-C), 54.0
An excess (7–8 heaped teaspoons) of freshly washed (with
MeOH) Raney nickel was added to separate solutions of the a-nitro
(OCH3), 45.5 (4-C), 41.6 (NCH3). FTIR [
n
(cmꢀ1), neat]: 2953, 2845,
ꢄ
2796, 1754, 1554, 1254, 743. HRMS [EI (m/z)] not found for [Mþ ],
esters 5 and 6 with Et3N (ca. 1 equiv) in methanol (0.25–0.30 M).
The mixtures were stirred for 8 h at room temperature under
a hydrogen atmosphere (1 atm). The catalyst was separated by fil-
tration with suction through a glass filter with a 0.5 cm layer of
Celite. The catalyst was washed thoroughly with methanol. The
methanolic solutions were concentrated on a rotary evaporator.
calcd for (C11H14NO3)þ¼208.0974, found¼208.0977 (j
j¼1.9 ppm);
D
[CI (m/z)] calcd for (C11H14N2O5þH)þ¼255.0981, found 255.0981
(j j¼0.0 ppm). Rf: 0.19 (AcOEt/heptane, 1:1).
D
4.4.4.2. Compound 6d. 1H NMR [400 MHz,
d (ppm), CDCl3]: 7.36
(dd, J¼1.8, 0.8 Hz, 1 1H, 50-CH), 6.32 (dd, J¼3.2, 1.9 Hz, 1 1H, 40-CH),
6.26 (d, J¼3.2 Hz,11H, 30-CH), 4.84 (app t, J¼8.4 Hz, 11H, 4-CH), 3.74
(d, J¼11.2 Hz, 1 1H, 2-CHH), 3.48 (s, 3 1H, OCH3), 3.39 (d, J¼11.2 Hz, 1
1H, 2-CHH), 3.41–3.35 (m, 1 1H, 5-CHH), 2.73 (app t, J¼9.2 Hz, 1 1H,
4.5.1. (ꢅ)-Methyl (3R,4R)-3-amino-1-methyl-4-phenyl-
pyrrolidine-3-carboxylate 3a
According to the general procedure,
a-nitro ester 5a (1.03 g,
5-CHH), 2.41 (s, 3 1H, NCH3). 13C NMR [75 MHz,
d
(ppm), CDCl3]:
3.9 mmol) afforded 3a (731 mg, 80%), as a light yellow oil, after
164.9 (CO2), 149.9 (20-C), 142.7 (50-C), 110.7 (40-C), 109.0 (30-C), 101.1
(3-C), 64.1 (2-C), 59.4 (5-C), 53.6 (OCH3), 45.3 (4-C), 41.2 (NCH3).
column chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR
[400 MHz,
d
(ppm), CDCl3]: 7.34–7.18 (m, 5 1H, Ph), 3.89 (t, J¼8.3 Hz,
FTIR [
n
(cmꢀ1), neat]: 2953, 2845, 2794,1750,1558, 1258, 741. HRMS
11H, 4-CH), 3.79 (s, 3 1H, OCH3), 3.42 (d, J¼9.8 Hz,11H, 2-CHH), 3.09
(d, J¼8.3 Hz, 2 1H, 5-CH2), 2.57 (d, J¼9.8 Hz, 1 1H, 2-CHH), 2.47 (s, 3
ꢄ
[EI (m/z)] not found for [Mþ ], calcd for (C11H14NO3)þ¼208.0974,
found¼208.0978
(j
Dj¼2.1 ppm);
[CI
(m/z)]
calcd
for
1H, NCH3), 1.75 (br s, 2 1H, NH2). 13C NMR [75 MHz,
d (ppm), CDCl3]:
176.3 (CO2), 136.8 (10-C), 129.1, 128.6, 127.5 (40-C), 68.2 (2-C), 66.5
(C11H14N2O5þH)þ¼255.0981, found 255.0981 (j
Dj¼0.0 ppm). Rf:
0.49 (AcOEt/heptane, 1:1).
(3-C), 59.8 (5-C), 53.3 (4-C), 52.8 (OCH3), 42.5 (NCH3). FTIR [n
(cmꢀ1), neat]: 3372, 3298, 2949, 2842, 2790, 1730, 1453, 1342, 1223,
770, 702.
4.4.5. (ꢅ)-Methyl (3R,4R)-1-methyl-4-(1-methyl-1H-indol-3-yl)-3-
nitropyrrolidine-3-carboxylate 5e and (ꢅ)-methyl (3R,4S)-1-
methyl-4-(1-methyl-1H-indol-3-yl)-3-nitropyrrolidine-3-
carboxylate 6e
4.5.2. (ꢅ)-Methyl (3R,4S)-3-amino-1-methyl-4-phenyl-
pyrrolidine-3-carboxylate 4a
According to the general procedure,
a
-nitro acrylate 7e (9.01 g,
According to the general procedure, a-nitro ester 6a (0.95 g,
34.6 mmol) afforded 5e (4.17 g, 38%), as a yellow solid, and 6e
(4.83 g, 44%), as a light yellow solid, after column chromatography
(AcOEt/heptane, 1:3/1:2).
3.6 mmol) afforded 4a (649 mg, 77%), as a yellow oil, after column
chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR [400 MHz,
d
(ppm), CDCl3]: 7.32–7.15 (m, 5 1H, Ph), 3.36 (dd, J¼9.3, 6.9 Hz, 11H,
4-CH), 3.27 (dd, J¼9.3, 6.9 Hz, 1 1H, 5-CHH), 3.23 (d, J¼9.9 Hz, 1 1H,
2-CHH), 3.19 (s, 3 1H, OCH3), 2.89 (app t, J¼9.2 Hz, 11H, 5-CHH), 2.87
(d, J¼9.9 Hz, 11H, 2-CHH), 2.47 (s, 3 1H, NCH3), 2.07 (br s, 2 1H, NH2).
4.4.5.1. Compound 5e. 1H NMR [400 MHz,
d (ppm), CDCl3]: 7.82
(app dt, J¼7.9, 1.0 Hz, 1 1H, 40-CH), 7.23 (ddd, J¼8.2, 1.5, 0.8 Hz, 1 1H,
70-CH), 7.20 (ddd, J¼8.2, 6.5,1.2 Hz,11H, 60-CH), 7.13 (ddd, J¼7.9, 6.5,
1.5 Hz, 11H, 50-CH), 6.95 (s, 11H, 20-CH), 4.88 (dd, J¼9.2, 6.9 Hz, 11H,
4-CH), 3.82 (s, 3 1H, OCH3), 3.77 (d, J¼11.7 Hz,11H, 2-CHH), 3.68 (s, 3
1H,10-NCH3), 3.44 (d, J¼11.7 Hz,11H, 2-CHH), 3.18 (dd, J¼9.2, 6.9 Hz,
13C NMR [75 MHz, (ppm), CDCl3]: 173.6 (CO2), 138.3 (10-C), 127.89,
d
127.87, 126.9 (40-C), 70.2 (3-C), 67.2 (2-C), 61.1 (5-C), 60.5 (4-C), 51.7
(OCH3), 42.3 (NCH3). FTIR [
(cmꢀ1), neat]: 3369, 3300, 2952, 2842,
2792, 1731, 1450, 1342, 1221, 768, 699.
n

5400
D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
4.5.3. (ꢅ)-Methyl (3R,4R)-3-amino-4-(3,5-dimethoxyphenyl)-1-
methylpyrrolidine-3-carboxylate 3b
(40-C), 108.0 (70-C), 101.0 (OCH2O), 70.0 (3-C), 67.0 (2-C), 61.2 (5-C),
60.1 (4-C), 51.9 (OCH3), 42.2 (NCH3). FTIR [
(cmꢀ1), neat]: 3363, 3293,
n
According to the general procedure,
a
-nitro ester 5b (2.01 g,
2946, 2844, 2786, 1728, 1488, 1249, 1037, 807. HRMS [EI (m/z)] calcd
ꢄ
6.2 mmol) afforded 3b (1.44 g, 79%), as a colourless-whitish oil,
for C14H18N2O4¼278.1267, found for [Mþ ]¼278.1260 (j
Dj¼2.4 ppm),
after column chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR
peaks at (relative intensity): 278 (30), 148 (87), 57 (100), 42 (27). Rf:
0.20 (MeOH/CH2Cl2, 1:8). Mp¼56–59 ꢁC.
[400 MHz,
d
(ppm), CDCl3]: 6.36 (s, 3 1H, 20-CHþ40-CHþ60-CH), 3.84
(t, J¼8.3 Hz, 1 1H, 4-CH), 3.79 (s, 3 1H, CO2CH3), 3.77 (s, 6 1H,
2ꢃOCH3), 3.37 (d, J¼9.8 Hz, 1 1H, 2-CHH), 3.04 (d, J¼8.3 Hz, 2 1H, 5-
CH2), 2.54 (d, J¼9.8 Hz, 1 1H, 2-CHH), 2.45 (s, 3 1H, NCH3), 1.52 (br s,
4.5.7. (ꢅ)-Methyl (3R,4R)-3-amino-4-(2-furyl)-1-methyl-
pyrrolidine-3-carboxylate 3d
2
1H, NH2). 13C NMR [75 MHz,
d
(ppm), CDCl3]: 176.3 (CO2), 160.9
According to the general procedure, a-nitro ester 5d (3.10 g,
(30-Cþ50-C), 139.5 (10-C), 107.2 (20-Cþ60-C), 99.1 (40-C), 68.4 (2-C),
12.2 mmol) afforded 3d (1.78 g, 65%), as a yellow oil, after column
66.6 (3-C), 59.7 (5-C), 55.4 (2ꢃOCH3), 53.5 (4-C), 52.7 (CO2CH3),
chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR [400 MHz,
42.4 (NCH3). FTIR [
n
(cmꢀ1), neat]: 3375, 2943, 2836, 2787, 1728,
d
(ppm), CDCl3]: 7.36 (dd, J¼2.0, 0.7 Hz, 11H, 50-CH), 6.32 (dd, J¼3.2,
1594, 1203, 1153, 838. HRMS [EI (m/z)] calcd for
2.0 Hz, 1 1H, 40-CH), 6.18 (dt, J¼3.2, 0.7 Hz, 1 1H, 30-CH), 3.95 (dd,
J¼9.3, 7.8 Hz,11H, 4-CH), 3.80 (s, 3 1H, OCH3), 3.39 (d, J¼9.8 Hz,11H,
2-CHH), 3.10 (dd, J¼9.3, 7.8 Hz, 1 1H, 5-CHH), 2.95 (t, J¼9.3 Hz, 1 1H,
5-CHH), 2.48 (d, J¼9.8 Hz, 11H, 2-CHH), 2.43 (s, 3 1H, NCH3), 1.59 (br
ꢄ
C15H22N2O4¼294.1580, found for [Mþ ]¼294.1569 (j
Dj¼3.6 ppm),
peaks at (relative intensity): 294 (53), 206 (24), 164 (62), 57 (100),
42 (65). Rf: 0.29 (MeOH/CH2Cl2, 1:8).
s, 2 1H, NH2). 13C NMR [75 MHz,
d (ppm), CDCl3]: 175.8 (CO2), 151.9
4.5.4. (ꢅ)-Methyl (3R,4S)-3-amino-4-(3,5-dimethoxyphenyl)-1-
methylpyrrolidine-3-carboxylate 4b
(20-C), 142.3 (50-C), 110.3 (40-C), 108.1 (30-C), 68.2 (2-C), 66.4 (3-C),
58.4 (5-C), 52.8 (OCH3), 47.8 (4-C), 42.3 (NCH3). FTIR [
n
(cmꢀ1),
According to the general procedure,
a
-nitro ester 6b (2.01 g,
neat]: 3379, 3314, 2946, 2838, 2786, 1728, 1224, 736. HRMS [EI (m/
ꢄ
6.2 mmol) afforded 4b (1.30 g, 71%), as a whitish oil, after column
z)] calcd for C11H16N2O3¼224.1161, found for [Mþ ]¼224.1150
chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR [400 MHz,
(j j¼4.9 ppm), peaks at (relative intensity): 224 (16), 101 (26), 94
D
1
d
(ppm), CDCl3]: 6.37 (d, J¼2.2 Hz, 2 H, 20-CHþ60-CH), 6.33 (t,
(42), 57 (100), 42 (39). Rf: 0.24 (MeOH/CH2Cl2, 1:8).
J¼2.2 Hz, 11H, 40-CH), 3.77 (s, 6 1H, 2ꢃOCH3), 3.33 (s, 3 1H, CO2CH3),
3.32 (dd, J¼9.3, 6.8 Hz, 1 1H, 4-CH), 3.27 (dd, J¼8.8, 6.8 Hz, 1 1H, 5-
CHH), 3.21 (d, J¼10.0 Hz, 1 1H, 2-CHH), 2.92 (d, J¼10.0 Hz, 1 1H, 2-
CHH), 2.87 (app t, J¼9.0 Hz, 1 1H, 5-CHH), 2.48 (s, 3 1H, NCH3), 2.26
4.5.8. (ꢅ)-Methyl (3R,4S)-3-amino-4-(2-furyl)-1-methyl-
pyrrolidine-3-carboxylate 4d
According to the general procedure,
a-nitro ester 6d (3.16 g,
(br s, 2 1H, NH2). 13C NMR [75 MHz,
d
(ppm), CDCl3]: 174.1 (CO2),
12.4 mmol) afforded 4d (1.70 g, 61%), as a yellow oil, after column
160.6 (30-Cþ50-C), 140.5 (10-C), 106.3 (20-Cþ60-C), 99.1 (40-C), 70.0
chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR [400 MHz,
(3-C), 67.1 (2-C), 61.0 (5-C), 60.4 (4-C), 55.4 (2ꢃOCH3), 51.9
d
(ppm), CDCl3]: 7.30 (dd, J¼1.9, 0.6 Hz, 1 1H, 50-CH), 6.28 (dd, J¼3.2,
(CO2CH3), 42.2 (NCH3). FTIR [
n
(cmꢀ1), neat]: 3373, 3305, 2944,
1.9 Hz, 1 1H, 40-CH), 6.07 (d, J¼3.2 Hz, 1 1H, 30-CH), 3.49 (dd, J¼9.8,
7.0 Hz, 1 1H, 4-CH), 3.44 (s, 3 1H, OCH3), 3.29 (dd, J¼9.2, 7.0 Hz, 1 1H,
5-CHH), 3.11 (d, J¼9.8 Hz, 1 1H, 2-CHH), 2.89 (d, J¼9.8 Hz, 1 1H, 2-
CHH), 2.78 (app t, J¼9.5 Hz, 1 1H, 5-CHH), 2.45 (s, 3 1H, NCH3), 2.12
2837, 2784, 1728, 1594, 1203, 1152, 842. HRMS [EI (m/z)] calcd for
ꢄ
C15H22N2O4¼294.1580, found for [Mþ ]¼294.1586 (j
Dj¼2.1 ppm),
peaks at (relative intensity): 294 (25), 206 (29), 164 (66), 57 (100),
42 (20). Rf: 0.22 (MeOH/CH2Cl2, 1:8).
(br s, 2 1H, NH2). 13C NMR [75 MHz,
d (ppm), CDCl3]: 173.9 (CO2),
152.2 (20-C), 141.6 (50-C), 110.1 (40-C), 106.3 (30-C), 68.7 (3-C), 66.3
4.5.5. (ꢅ)-Methyl (3R,4R)-3-amino-4-(1,3-benzodioxol-5-yl)-1-
methylpyrrolidine-3-carboxylate 3c
(2-C), 59.1 (5-C), 53.4 (4-C), 52.1 (OCH3), 41.9 (NCH3). FTIR [
n
(cmꢀ1),
neat]: 3374, 3297, 2946, 2840, 2785, 1726, 1207, 735. HRMS [EI (m/
ꢄ
According to the general procedure,
a
-nitro ester 5c (3.00 g,
z)] calcd for C11H16N2O3¼224.1161, found for [Mþ ]¼224.1150
9.7 mmol) afforded 3c (2.17 g, 80%), as a light yellow oil, aftercolumn
(j j¼4.9 ppm), peaks at (relative intensity): 224 (16), 101 (26), 94
D
chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR [400 MHz,
(42), 57 (100), 42 (39). Rf: 0.21 (MeOH/CH2Cl2, 1:8).
d
(ppm), CDCl3]: 6.75 (d, J¼8.0 Hz, 1 1H, 70-CH), 6.74 (d, J¼1.5 Hz, 1
1H, 40-CH), 6.66 (dd, J¼8.0,1.5 Hz,11H, 60-CH), 5.94 (d, J¼1.5 Hz,11H,
OCHHO), 5.93 (d, J¼1.5 Hz, 11H, OCHHO), 3.81 (app t, J¼8.3 Hz, 11H,
4-CH), 3.78 (s, 31H, OCH3), 3.44 (d, J¼10.0 Hz,11H, 2-CHH), 3.09 (app
t, J¼8.4 Hz, 11H, 5-CHH), 3.03 (app t, J¼9.2 Hz, 11H, 5-CHH), 2.59 (d,
4.5.9. (ꢅ)-Methyl (3R,4R)-3-amino-1-methyl-4-(1-methyl-1H-
indol-3-yl)pyrrolidine-3-carboxylate 3e
According to the general procedure,
a-nitro ester 5e (2.90 g,
9.1 mmol) afforded3e (1.63 g, 62%), as a light brown stickysolid, after
J¼10.0 Hz,11H, 2-CHH), 2.49 (s, 3 1H, NCH3),1.88 (br s, 21H, NH2).13
C
column chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR
NMR [75 MHz,
d
(ppm), CDCl3]: 176.0 (CO2), 147.9 (30a-C), 147.0 (70a-
[400 MHz,
d
(ppm), CDCl3]: 7.49 (d, J¼8.1 Hz, 1 1H, 40-CH), 7.29 (d,
C),130.2 (50-C), 122.3 (60-C), 109.4 (40-C), 108.3 (70-C), 101.2 (OCH2O),
68.0 (2-C), 66.5 (3-C), 60.0 (5-C), 53.0 (4-C), 52.8 (OCH3), 42.6 (NCH3).
J¼8.1 Hz, 1 1H, 70-CH), 7.21 (ddd, J¼8.1, 6.5, 1.2 Hz, 1 1H, 60-CH), 7.09
(ddd, J¼8.1, 6.5,1.0 Hz,11H, 50-CH), 7.01(s,11H,20-CH), 4.27(dd, J¼9.8,
7.6 Hz, 1 1H, 4-CH), 3.77 (s, 3 1H, OCH3), 3.76 (s, 31H,10-NCH3), 3.53 (d,
J¼9.8 Hz,11H, 2-CHH), 3.17 (dd, J¼8.9, 7.6 Hz,11H, 5-CHH), 3.06 (app
t, J¼9.5 Hz,11H, 5-CHH), 2.59 (d, J¼9.8 Hz,11H, 2-CHH), 2.50 (s, 3 1H,
FTIR [n
(cmꢀ1), neat]: 3376, 3317, 2946, 2841, 2785, 1727, 1252, 1236,
1036, 929. Rf: 0.21 (MeOH/CH2Cl2, 1:8).
4.5.6. (ꢅ)-Methyl (3R,4S)-3-amino-4-(1,3-benzodioxol-5-yl)-1-
methylpyrrolidine-3-carboxylate 4c
1-NCH3), 1.65 (br s, 2 1H, NH2). 13C NMR [75 MHz,
d (ppm), CDCl3]:
176.3 (CO2), 136.9 (70a-C), 127.89 (30a-C), 127.86 (20-C), 121.9 (60-C),
119.3 (50-C), 119.1 (40-C), 109.3 (70-C), 108.9 (30-C), 68.0 (2-C), 65.4 (3-
C), 60.1 (5-C), 52.6 (OCH3), 45.6 (4-C), 42.6 (1-NCH3), 32.8 (10-NCH3).
According to the general procedure,
a-nitro ester 6c (3.50 g,
11.4 mmol) afforded 4c (2.40 g, 76%), as a off-white solid, after
column chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR
FTIR [n
(cmꢀ1), neat]: 3369, 3299, 3047, 2945, 2836, 2783,1725,1474,
[400 MHz,
d
(ppm), CDCl3]: 6.76 (d, J¼1.7 Hz, 1 1H, 40-CH), 6.71 (d,
1216, 741. HRMS [ESI (m/z)] calcd for (C16H21N3O2þH)þ¼288.17120,
J¼8.1 Hz,11H, 70-CH), 6.68 (dd, J¼8.1,1.7 Hz,11H, 60-CH), 5.91 (s, 2 1H,
OCH2O), 3.34 (s, 3 1H, OCH3), 3.29 (dd, J¼8.6, 6.8 Hz, 11H, 4-CH), 3.23
(d, J¼10.0 Hz, 1 1H, 2-CHH), 3.23 (dd, J¼8.8, 6.8 Hz,11H, 5-CHH), 2.87
(d, J¼10.0 Hz, 1 1H, 2-CHH), 2.84 (app t, J¼8.8 Hz,11H, 5-CHH), 2.47 (s,
found 288.17104 (j j¼0.57 ppm). Rf: 0.16 (MeOH/CH2Cl2, 1:8).
D
4.5.10. (ꢅ)-Methyl (3R,4S)-3-amino-1-methyl-4-(1-methyl-1H-
indol-3-yl)pyrrolidine-3-carboxylate 4e
3 1H, NCH3), 2.15 (br s, 2 1H, NH2). 13C NMR [75 MHz,
174.1 (CO2),147.5 (30a-C),146.7 (70a-C),132.0 (50-C),121.4 (60-C),108.5
d
(ppm), CDCl3]:
According to the general procedure,
a-nitro ester 6e (3.20 g,
10.1 mmol) afforded 4e (1.74 g, 60%), as a light yellow oil, after

D. Blanco-Ania et al. / Tetrahedron 65 (2009) 5393–5401
5401
column chromatography (MeOH/CHCl3, 1:20/1:10). 1H NMR
9. (a) Benhaoua, H.; Danion-Bougot, R.; Carrie, R. Bull. Soc. Chim. Fr. 1989, 409–412;
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atsh. Chem. 1963, 94, 1241–1246.
10. Zen, S.; Koyama, M.; Koto, S. Organic Synthesis; Wiley & Sons: New York, NY,
1988; Collect. Vol. 6; 1976, Vol. 55, 77, 797–799.
11. For a review about Knoevenagel condensation, see: Tietze, L. F.; Beifuss, U. The
Knoevenagel Reaction. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 341–394.
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dron Lett. 2005, 46, 7679–7681; (b) Moonen, K.; Stevens, C. V. Synthesis 2005,
20, 3603–3612.
14. Babievskii, K. K.; Belikov, V. M.; Vinograndova, A. I.; Latov, V. K. J. Org. Chem. U.S.S.R.
1973, 9, 1722–1725.
15. To differentiate the (Z/E)-isomers by X-ray crystallography, see: He, L. W.; Sri-
kanth, G. S. C.; Castle, S. L. J. Org. Chem. 2005, 70, 8140–8147.
16. (a) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 1998, 63, 3528–
3529; (b) These conditions were also used with aldehyde 10e, but the yield was
lower than the one obtained with the imine procedure.
[400 MHz,
d
(ppm), CDCl3]: 7.66 (app dt, J¼8.1, 1.0 Hz, 1 1H, 40-CH),
7.23 (app dt, J¼8.3, 1.0 Hz, 11H, 70-CH), 7.18 (ddd, J¼8.0, 6.8, 1.2 Hz, 1
1H, 60-CH), 7.09 (ddd, J¼8.0, 6.8, 1.2 Hz, 1 1H, 50-CH), 6.89 (s, 1 1H, 20-
CH), 3.77 (dd, J¼10.0, 6.8 Hz,11H, 4-CH), 3.69 (s, 3 1H,10-NCH3), 3.31
(dd, J¼9.3, 6.8 Hz, 1 1H, 5-CHH), 3.29 (d, J¼10.0 Hz, 1 1H, 2-CHH),
3.12 (s, 3 1H, OCH3), 2.96 (d, J¼10.0 Hz, 1 1H, 2-CHH), 2.94 (app t,
J¼9.5 Hz, 1 1H, 5-CHH), 2.55 (br s, 2 1H, NH2), 2.51 (s, 3 1H, 1-NCH3).
13C NMR [75 MHz, (ppm), CDCl3]: 174.4 (CO2), 136.7 (70a-C), 128.0
d
(30a-C), 126.5 (20-C), 121.7 (60-C), 119.2, 119.1, 110.9 (30-C), 109.1 (70-
C), 70.1 (3-C), 66.5 (2-C), 61.5 (5-C), 51.6 (OCH3), 51.5 (4-C), 42.3 (1-
NCH3), 32.7 (10-NCH3). FTIR [ (cmꢀ1), neat]: 3361, 3295, 3049,
n
2944, 2840, 2787, 1727, 1473, 1210, 740. HRMS [EI (m/z)] calcd for
ꢄ
C16H21N3O2¼287.1634, found for [Mþ ]¼287.1636 (j
D
j¼0.8 ppm),
peaks at (relative intensity): 287 (29), 157 (100), 144 (32), 57 (45).
Rf: 0.14 (MeOH/CH2Cl2, 1:8).
17. Kleinpeter, E. J. Serb. Chem. Soc. 2006, 71, 1–17.
18. (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809; (b) Snider, B. B.;
Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217–4220.
Supplementary data
Experimental details and full characterization data, copies of 1H
and 13C NMR spectra for all new compounds, are available free of
charge via the Internet. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2009.04.059.
19. The yields dropped about 20% for a scale larger than 3 mmol because of con-
comitant hydrolysis of the a-nitro acrylates. The addition of MgSO4 to the re-
action mixture solved the problem.
20. For examples of Krapcho reaction with
a-nitro esters, see: (a) Dahnz, A.;
Helmchen, G. Synlett 2006, 697–700; (b) Peel, M. R.; Sternbach, D. D.; Johnson,
M. R. J. Org. Chem. 1991, 56, 4990–4993.
21. Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mecha-
nisms, and Structure, 6th ed.; John Wiley & Sons: Hoboken, NJ, 2007.
22. (a) Avenoza, A.; Cativiela, C.; Paris, M.; Peregrina, J. M. Tetrahedron: Asymmetry
1995, 6, 1409–1418. Here the metal is activated with ammonia. We used Et3N to
prevent amide formation; (b) The reason for this activation is unclear.
23. Yashin, N. V.; Averina, E. B.; Grishin, Y. K.; Kuznetsova, T. S.; Zefirov, N. S.
Synthesis 2006, 279–284.
References and notes
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24. For a reduction of this kind on an
a-nitro ester, see: Krishnamoorthy, P.;
Sivappa, R.; Du, H. W.; Lovely, C. J. Tetrahedron 2006, 62, 10555–10566.
25. The reaction gave also traces of products from elimination of the nitro group
17a–e (<0.5%). Once the nickel enolate is formed (see reaction
sequence below), it eliminates in a Saegusa-type reaction fashion. For a dis-
cussion on the mechanism of the Saegusa reaction, see: Porth, S.; Bats, J. W.;
Trauner, G. G.; Mulzer, J. Angew. Chem., Int. Ed. 1999, 38, 2015–2016. In some
cases, for Ar¼3,5-dimethoxyphenyl and 3,4-methylenedioxyphenyl, products
from subsequent aromatization
18b–c (<0.5%) were also
found.
26. For a radical reduction of a-nitro nitriles, a-nitro esters, and a-nitro ketones,
see: Ono, N.; Tamura, R.; Kaji, A. J. Am. Chem. Soc. 1983, 105, 4017–4022.
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nickel, see: Hauptmann, H.; Walter, W. F. Chem., Rev. 1962, 62, 347–404.
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