Exploiting the Reactivity of 1,2-Ketoamides: Enantioselective Synthesis of Functionalized Pyrrolidines and Pyrrolo-1,4-benzodiazepine-2,5-diones

Article abstract of DOI:10.1055/s-0034-1378711

A new strategy for the synthesis of optically active pyrrolo[1,4]benzodiazepine-2,5-diones has been developed. The approach is based on an initial Michael addition of functionalized 1,2-ketoamides on nitroalkenes, with a reduction-double cyclization seque

Full text of DOI:10.1055/s-0034-1378711

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1591–1595
letter
1591
P. Acosta et al.
Letter
Synlett
Exploiting the Reactivity of 1,2-Ketoamides: Enantioselective Syn-
thesis of Functionalized Pyrrolidines and Pyrrolo-1,4-benzodiaze-
pine-2,5-diones
Paola Acostaa
Diana Becerrab
Sébastien Goudedrancheb
R1
O
O
CO2Me
1. organocatalyst
2. Zn, AcOH
H
R2
NH
R2
Jairo Quirogaa
R1
N
Thierry Constantieuxb
Damien Bonne*b
Jean Rodriguez*b
+
N
O
3. 210 °C MW
NO2
X
O
X
3 reactive sites exploited
optically active
pyrrolo-1,4-benzodiazepine-2,5-diones
a Facultad de Ciencias Naturales y Exactas Universidad del Valle
Cali, Colombia
b Aix Marseille Université, CNRS, Centrale Marseille, iSm2 UMR
7313, 13397 Marseille, France
damien.bonne@univ-amu.fr
jean.rodriguez@univ-amu.fr
Received: 06.03.2015
Accepted after revision: 11.05.2015
Published online: 08.06.2015
sors of pyrrolo-1,4-benzodiazepin2,5-diones 5 (Scheme 1).6
The pyrrolo-1,4-benzodiazepine-2,5-dione structural sub-
unit can be found in several natural products such as aster-
relenin, aszonalenin, and oxotomamycin.7 These com-
pounds as well as their analogues or derivatives have shown
antitumor,8 antibiotic,9 anxiolytic,10 and antithrombic ac-
tivities.11 Moreover, their structural motifs and physico-
chemical properties have led to the benzodiazepine scaffold
being considered as a novel non-peptide peptidomimetic,
acting as a mimic of peptide secondary structures such as
γ- and β-turns.12 Considering these biological properties,
rapid and easy access to this scaffold would be of high inter-
est. The novel strategy we designed constitutes an original
route for the synthesis of this molecular scaffold. We antici-
pated that the reduction of the nitro group could trigger an
original domino reductive amination-lactamization se-
quence giving the desired benzodiazepinone derivative in
only two simple synthetic operations from two simple achi-
ral and acyclic starting materials.
We selected 1,2-ketoamides 1a and 1b, bearing an ester
moiety on the phenyl ring of the amide, as model ketoam-
ides, and β-nitrostyrene (2a) as the electrophilic partner
(Table 1). Takemoto thiourea catalyst 613 was selected to
promote this reaction because it gave us excellent results in
previous studies.4 Preliminary optimization of the reaction
conditions led us to the conclusions that dichloromethane
(CH2Cl2) was a better solvent than ethyl acetate, because the
former solvent allowed a higher enantioselectivity to be
achieved (entries 1 and 3). Moreover, conducting the reac-
tion in CH2Cl2 was possible at room temperature, affording
the desired Michael adduct in good yield and excellent ste-
reoselectivities (entries 3 and 5). The diastereoselectivity,
which favored the trans adduct 3a or 3b, was excellent in all
cases.
DOI: 10.1055/s-0034-1378711; Art ID: st-2015-b0154-l
Abstract A new strategy for the synthesis of optically active pyrro-
lo[1,4]benzodiazepine-2,5-diones has been developed. The approach is
based on an initial Michael addition of functionalized 1,2-ketoamides
on nitroalkenes, with a reduction–double cyclization sequence leading
to the desired substituted benzodiazepine.
Key words enantioselective Michael addition, benzodiazepine, 1,2-ke-
toamides
Dicarbonyl compounds are privileged substrates for the
development of new multiple bond-forming transforma-
tions (MBFTs) because of their high number of adjacent re-
active sites that can participate in the successive creation of
several bonds.1 The chemistry associated with 1,3-dicar-
bonyl compounds is now well understood, and many cas-
cade reactions exploiting their reactivity have been de-
scribed.2 Although underexploited in comparison to their
1,3-dicarbonyl isomers, 1,2-dicarbonyl compounds also
possess significant synthetic potential.3 As part of our sus-
tained interest in MBFTs, we reported a few years ago the
use of 1,2-ketoamides and 1,2-ketoesters as pronucleo-
philes in enantioselective Michael addition using hydrogen-
bonding organocatalysis.4 These methodologies may repre-
sent the first step in the design of efficient and original
MBFTs by using 1,2-dicarbonyl compounds as substrates.5
Indeed the Michael adduct obtained in optically active form
can be seen as a synthetic platform for many types of carbo-
and heterocycles.
We reasoned that a suitably functionalized ketoamide 1
could be exploited by using our previous methodology to
provide enantioselective access to pyrrolidines 4 as precur-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1591–1595

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Synlett
R2
O
CO2Me
O
CO2Me
H
N
H
R1
O2N
N
cat.*
R2
+
NO2
O
R1
O
X
X
3
1
2
reduction of
NO2
O
R1
NH
N
N
R
R1
R2
O
H
R2
O
O
X
O
NH
N
N
HN
H
R = OH, asterrelenin
R = H aszonalenin
O
MeO2C
O
X
4
5
H
NH
pyrrolo-[1,4]-benzodiazepine-2,5-dione
OH
OH
N
O
oxotomamycin
Scheme 1 Strategy for the synthesis of optically active benzodiazepine-2,5-diones
Table 1 Reaction Optimizationa
S
Ar
N
N
H
H
NMe2
R2
O
CO2Me
Ar = 3,5-(CF3)2C6H3
O
CO2Me
H
H
6 (10 mol%)
R1
N
Ph
O2N
N
+
NO2
T (°C), solvent
R1
O
2a
O
1a, R1 = Et
1b, R1 = Me
3a, R1 = Et, R2 = Ph
3b, R1 = Me, R2 = Ph
Entry
1
Solvent
Temp. (°C)
3
Yield (%)b
drc
ee (%)d
1
2
3
4
5
1a
EtOAc
EtOAc
CH2Cl2
EtOAc
CH2Cl2
r.t.
0
3a
3a
3a
3b
3b
67
65
61
63
61
>20:1
85
92
95
80
89
1a
1a
1b
1b
>20:1
>20:1
>20:1
>20:1
r.t.
0
r.t.
a 1,2-Ketoamide 1 (0.2 mmol), trans-β-nitrostyrene (2a; 0.24 mmol) and catalyst 6 (0.02 mmol) were successively added in a sealed tube and dissolved in CH2Cl2
(0.5 mL). The reaction was stirred at r.t. until consumption of starting ketoamide 1 (usually 48 h, reaction monitored by TLC).
b Isolated yield after flash chromatography.
c Determined by 1H NMR spectroscopic analysis of the crude reaction product.
d Determined by chiral HPLC analysis.
Having identified the best conditions for this reaction,
we studied its scope (Scheme 2) and found that various aryl
nitroalkenes with electron-donating or electron-withdraw-
ing substituents can be used for this transformation with
yields ranging from 50 to 65% and, in all cases, excellent en-
antioselectivities (91–99% ee). We always observed incom-
plete conversion of the starting nitroalkene. No perceptible
evolution was found after 48 h, possibly due to inhibition of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1591–1595

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P. Acosta et al.
Letter
Synlett
the catalyst by hydrogen bonding with the product of the
reaction. In addition, heteroaryl-substituted nitroolefins
were found to be suitable substrates, affording the desired
Michael adduct with similar efficiency (3g, 3h, 3m, and3n).
Surprisingly, the use of ketoamide 1c (R1 = Ph, Y = CO2Me)
gave the product 3o in moderate yield (32%) and enantiose-
lectivity (58%). In contrast, the reaction was found to be
very efficient for ketoamide 1d (R1 = Et, Y = CN) incorporat-
ing a cyano moiety instead of the ester function (3p; 87%
yield, >20:1 dr, 93% ee). The relative and absolute stereo-
chemistry can be justified by the transition state proposed
in preliminary studies. Hence, the thiourea moiety of the
catalyst activates the (Z)-enolate of ketoamide14 while the
ammonium ion activates the nitroalkene through H-bond-
ing interaction. Therefore, a preferential approach of the Si
face of the enolate on the Re face of 2a could account for the
observed stereochemistry.
We then attempted to validate our strategy by convert-
ing Michael adducts 3 into the functionalized diazepinones
5 (Scheme 3). First, the reaction conditions used to convert
nitroalkane 3a into the substituted pyrrolidine 4a were
screened. The use of various reductive conditions such as H2
in combination with Pd on charcoal or Raney-Ni, or sodium
borohydride in the presence of nickel(II) salt, gave the de-
sired product 4a in good yields, but invariably with no dias-
tereoselectivity. However, we observed that the use of acti-
vated zinc and acetic acid in THF led to the formation of the
desired pyrrolidine in moderate yield (4a; 55%) and very
good diastereoselectivity (dr = 15:1). At this stage, subse-
quent formation of the 1,4-benzodiazepin-2,5-dione was
studied. Optimized reaction conditions consisted of heating
4a at 210 °C in ethylene glycol for 10 min under microwave
irradiation, and afforded 5a in 50% yield. The desired benzo-
diazepinone 5a was isolated with 86% ee starting from pyr-
rolidine 4a (91% ee). To increase the synthetic efficiency of
the cyclization, a two-step sequence for conversion of pyr-
rolidine 4a into 5a was then conducted. The ester function
of 4a was first saponified to give the corresponding carbox-
ylic acid in quantitative yield. Unfortunately, intramolecular
amide coupling only afforded the desired benzodiazepino-
ne 5a in poor yields with significant loss of enantiomeric
purity (70% ee).15 With this synthetic procedure in hand,
microwave-assisted lactamization was finally chosen and
applied for two other examples; benzodiazepinones 5c and
5d were both obtained with modest yields (45%).
In conclusion, we have developed a new strategy for the
synthesis of optically active pyrrolo[1,4]benzodiazepine-
2,5-diones.16 The approach is based on an initial Michael
addition of functionalized 1,2-ketoamides on nitroalkenes,
with the adduct then being converted into the desired sub-
stituted benzodiazepine by following a reduction-double
cyclization sequence.
R2
O
Y
S
O
Y
H
R1
N
H
6 (10 mol%)
R2
N
H
O2N
N
N
H
Ar
N
H
+
(R,R)-6
NO2
r.t., CH2Cl2
O
R1
O
O
2
3
1
O
N
O
Me
CONHAr
R2
R2
1b
O
CO2Me
O
CO2Me
H
Ph
H
H
2a
O2N
N
O2N
N
H
Si face of (Z)-enolate
adds on Re face of β-nitrostyrene
Et
O
Me
O
3a, R2 = Ph, 61%, >20:1 dr, 95% ee
3b, R2 = Ph, 61%, >20:1 dr, 89% ee
3c, R2 = 4-MeC6H4, 65%, >20:1 dr, 92% ee
3d, R2 = 4-MeOC6H4, 58%, >20:1 dr, 91% ee
3e, R2 = 3,4,5-(MeO)3C6H2, 53%, >20:1 dr, 91% ee
3f, R2 = 4-NO2C6H4, 50%, >20:1 dr, 93% ee
3g, R2 = 2-thienyl, 58%, >20:1 dr, 91% ee
3h, R2 = 2-furanyl, 52%, >20:1 dr, 89% ee
3i, R2 = 4-MeC6H4, 60%, >20:1 dr, 92% ee
3j, R2 = 4-MeOC6H4, 56%, >20:1 dr, 91% ee
3k, R2 = 3,4,5-(MeO)3C6H2, 50%, >20:1 dr, 91% ee
3l, R2 = 4-NO2C6H4, 60%, >20:1 dr, 99% ee
3m, R2 = 2-thienyl, 54%, >20:1 dr, 69% ee
3n, R2 = 2-furanyl, 52%, >20:1 dr, 91% ee
Ph
O
R2
R2
O
CN
H
O
CO2Me
(R)
H
O2N
N
H
(R)
O2N
N
Ar
O2N
N
O
Me
Et
O
Ph
O
3o, R2 = Ph, 32%, >20:1 dr, 58% ee
3p, R2 = Ph, 87%, >20:1 dr, 93% ee
3b
Scheme 2 Scope of the reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1591–1595

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H2, 10% Pd/C, MeOH
or
R1
NiCl2⋅6H2O, NaBH4, EtOH, 0 °C
or
Ph
R2
O
CO2Me
O
H
O2N
N
H2, Raney-Ni, EtOH, 65 °C
N
HN
H
O
MeO2C
3a
4a
full conversion but dr = 1:1
R1
R1
O
R2
R2
O
CO2Me
O
activated Zn
AcOH
H
NH
R2
MW, 210 °C, 10 min
ethylene glycol
O2N
N
N
N
HN
R1
O
H
THF, r.t., 2 h
O
MeO2C
3a, R1 = Et, R2 = Ph
3c, R1 = Et, R2 = 4-MeC6H4
3d, R1 = Et, R2 = 4-MeOC6H4
4a, R1 = Et, R2 = Ph, 15:1 dr, 55%, 91% ee
4c, R1 = Et, R2 = 4-MeC6H4, 15:1 dr, 50%
4d, R1 = Et, R2 = 4-MeOC6H4, 15:1 dr, 50%, 97% ee
5a, R1 = Et, R2 = Ph, 50%, 86%ee
5c, R1 = Et, R2 = 4-MeC6H4, 45%
5d, R1 = Et, R2 = 4-MeOC6H4, 45%
Scheme 3 Synthesis of pyrrolo[1,4]benzodiazepine-2,5-diones 5
Acknowledgment
(4) (a) Baslé, O.; Raimondi, W.; Sanchez Duque, M. M.; Bonne, D.;
Constantieux, T.; Rodriguez, J. Org. Lett. 2010, 12, 5246.
(b) Raimondi, W.; Baslé, O.; Bonne, D.; Constantieux, T.;
Rodriguez, J. Adv. Synth. Catal. 2012, 354, 563.
(5) For the use of α-ketoamides in organocatalyzed transforma-
tions, see: (a) Goudedranche, S.; Pierrot, D.; Constantieux, T.;
Bonne, D.; Rodriguez, J. Chem. Commun. 2014, 50, 15605.
(b) Sanchez Duque, M. M.; Goudedranche, S.; Quintard, A.;
Constantieux, T.; Bugaut, X.; Bonne, D.; Rodriguez, J. Synthesis
2013, 45, 1659. (c) Joie, C.; Deckers, K.; Enders, D. Synthesis
2014, 46, 799. (d) Joie, C.; Deckers, K.; Raabe, G.; Enders, D. Syn-
thesis 2014, 46, 1539. (e) Lefranc, A.; Guénée, L.; Goncalves-
Contal, S.; Alexakis, A. Synlett 2014, 25, 2947.
Financial support from the Agence Nationale pour la Recherche (ANR-
11-BS07-0014), the Centre National de la Recherche Scientifique
(CNRS), Aix-Marseille Université, Departamento Administrativo de
Ciencia, Tecnología e Innovación (COLCIENCIAS), and Universidad del
Valle is gratefully acknowledged. We also thank Dr. N. Vanthuyne and
M. Jean (ee measurements).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378711.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am.
References and Notes
(1) (a) Stereoselective Multiple Bond-Forming Transformations in
Organic Synthesis; Rodriguez, J.; Bonne, D., Eds.; John Wiley &
Sons, Inc: Hoboken, NJ, 2015. (b) Bonne, D.; Constantieux, T.;
Coquerel, Y.; Rodriguez, J. Chem. Eur. J. 2013, 19, 2218. (c) Green,
N. J.; Sherburn, M. S. Aust. J. Chem. 2013, 66, 267. (d) Menéndez,
J. C. Curr. Org. Chem. 2013, 18, 1919; and reviews included in
this special issue. (e) Coquerel, Y.; Boddaert, T.; Presset, M.;
Mailhol, D.; Rodriguez, J. In Ideas in Chemistry and Molecular
Sciences: Advances in Synthetic Chemistry; Pignataro, B., Ed.;
Wiley-VCH: Weinheim, Germany, 2010, Chap. 9, pp. 187-202.
(2) (a) Bugaut, X.; Constantieux, T.; Coquerel, Y.; Rodriguez, J. In
Multicomponent Reactions in Organic Synthesis; Zhu, J.; Wang,
Q.; Wang, M.-X., Eds.; Wiley-VCH: Weinheim, 2014, Chap. 5, pp
109-158. (b) Bugaut, X.; Bonne, D.; Coquerel, Y.; Rodriguez, J.;
Constantieux, T. Curr. Org. Chem. 2013, 1920. (c) Bonne, D.;
Coquerel, Y.; Constantieux, T.; Rodriguez, J. Tetrahedron: Asym-
metry 2010, 21, 1085.
(3) (a) Raimondi, W.; Bonne, D.; Rodriguez, J. Angew. Chem. Int. Ed.
2012, 51, 40. (b) Raimondi, W.; Bonne, D.; Rodriguez, J. Chem.
Commun. 2012, 48, 6763.
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Chem. Soc. 1994, 116, 5077. (b) Webb, R. R.; Barker, P. L.; Baier,
M.; Reynolds, M. E.; Robarge, K. D.; Blackbum, B. K.; Tischler, M.
H.; Weese, K. J. Tetrahedron Lett. 1994, 35, 2113.
dried over sodium sulfate, and concentrated to give the crude
product, which was purified by flash chromatography on silica
gel (EtOAc–PE, 40:60).
(12) (a) Verdié, P.; Subra, G.; Feliu, L.; Sanchez, P.; Bergé, G.; Garcin,
G.; Martinez, J. J. Comb. Chem. 2007, 9, 254. (b) Cabedo, N.;
Pannecoucke, X.; Quirion, J.-C. Eur. J. Org. Chem. 2005, 1590.
(13) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
(14) Xu, Y.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2010, 12, 3246.
(15) It is difficult to give a rational answer to this experimental
observation and unfortunately no simple mechanism can be
proposed to account for partial epimerization of the final prod-
ucts.
(16) Synthesis of Michael Adducts 3; General Procedure: 1,2-
Ketoamide 1 (0.20 mmol, 1.0 equiv), nitroalkene 2 (0.24 mmol,
1.2 equiv) and catalyst 6 (0.02 mmol, 0.1 equiv) were succes-
sively added in a sealed tube with a magnetic stir bar and dis-
solved in CH2Cl2 (0.5 mL). The reaction was then stirred at r.t.
until consumption of starting ketoamide 1 was observed (48–
72 h, reaction monitored by TLC). The crude product was puri-
fied directly by flash chromatography on silica gel (EtOAc–
petroleum ether (PE), 20:80).
Methyl 2-[(2S,3R,4R)-3-Ethyl-4-phenylpyrrolidine-2-carbox-
amido]benzoate (4a): Yield: 55%; colorless oil; Rf = 0.5 (PE–
EtOAc, 3:2); HPLC (Lux-Cellulose-2; heptane–EtOH, 80:20; flow
rate = 1.0 mL/min; λ = 254 nm): tR = 6.75 (major), 8.83
(minor) min; ee = 91%. 1H NMR (400 MHz, CDCl3): δ = 12.34
(br s, NH, 1 H), 8.84 (dd, J = 8.5, 1.2 Hz, 1 H), 8.05 (dd, J = 8.0,
1.7 Hz, 1 H), 7.58–7.54 (m, 1 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.25–
7.20 (m, 1 H), 7.18–7.14 (m, 2 H), 7.13–7.08 (m, 1 H), 3.93 (s,
3 H), 3.80 (d, J = 3.7 Hz, 1 H), 3.56 (d, J = 2.4 Hz, 1 H), 3.47 (d, J =
5.1 Hz, 2 H), 2.52–2.43 (m, 1 H), 1.32–1.29 (m, 1 H), 1.20–1.11
(m, 1 H), 0.92 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ =
175.1 (C), 168.1 (C), 141.0 (C), 139.9 (C), 134.5 (CH), 131.2 (CH),
128.4 (CH), 128.4 (CH), 126.5 (CH), 122.7 (CH), 120.6 (CH),
116.2 (C), 66.3 (CH3), 52.4 (CH), 51.1 (CH), 50.0 (CH2), 47.2 (CH),
21.6 (CH2), 12.5 (CH3). HRMS (ESI+): m/z calcd for [C21H24N2O3 +
H+]: 353.1860; found: 353.1862.
Synthesis of Pyrrolo[1,4]benzodiazepine-2,5-dione 5;
General Procedure: A reaction vessel equipped with a mag-
netic stir bar was charged with pyrrolidine 4 (0.2 mmol) and
ethylene glycol (0.6 mL), and the mixture was subjected to
microwave irradiation at 210 °C for 10–20 min. The crude reac-
tion mixture was extracted with CH2Cl2 (2 × 10 mL) and the
combined organic layers were washed with water (10 mL),
dried over sodium sulfate, and concentrated to give the crude
product, which was purified by flash chromatography on silica
gel (EtOAc–PE, 40:60).
Methyl 2-[(3R,4R)-3-Ethyl-5-nitro-2-oxo-4-phenylpentana-
mido]benzoate (3a): By following the general procedure, the
reaction between 1a (49.8 mg, 0.20 mmol), β-nitrostyrene 2a
(35.8 mg, 0.24 mmol) and catalyst 6 (8.3 mg, 0.02 mmol)
afforded 3a (61%) as a white solid; mp 155–156 °C; Rf = 0.3 (PE–
EtOAc, 8:2); HPLC (Chiralpak IA; hexane–EtOH, 90:10; flow
rate = 1.0 mL/min; λ = 220nm): tR = 10.12 (major), 10.91
(minor) min; ee = 95%. 1H NMR (400 MHz, CDCl3): δ = 12.21
(br s, NH, 1 H), 8.75 (dd, J = 8.4, 0.9 Hz, 1 H), 8.15–8.13 (m, 1 H),
7.68–7.64 (m, 1 H), 7.34 (d, J = 4.3 Hz, 4 H), 7.28–7.23 (m, 2 H),
4.89–4.81 (m, 2 H), 4.29 (td, J = 9.1, 3.9 Hz, 1 H), 4.10–4.06 (m,
(1R,2R,11aS)-1-Ethyl-2-phenyl-2,3-dihydro-1H-benzo[e]pyr-
rolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (5a): Yield:
50%; white solid; mp 234 °C; Rf = 0.2 (PE–EtOAc, 6:4); HPLC
(Chiralpak AD-H; heptane–EtOH, 80:20; flow rate
= 1.0
1 H), 4.03 (s, 3 H), 1.99–1.86 (m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H). 13
C
mL/min; λ = 254 nm): tR = 15.47 (major), 19.39 (minor) min;
ee = 86%. 1H NMR (400 MHz, CDCl3): δ = 8.10–8.06 (m, 2 H),
7.56–7.50 (m, 1 H), 7.28–7.26 (m, 1 H), 7.36–7.31 (m, 3 H),
7.24–7.19 (m, 2 H), 7.03 (dd, J = 8.0, 1.1 Hz, 1 H), 4.08 (dd, J =
8.7, 1.4 Hz, 2 H), 3.94 (d, J = 2.4 Hz, 1 H), 3.81–3.73 (m, 1 H),
3.16–3.09 (m, 1 H), 1.23–1.07 (m, 2 H), 0.77 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.0 (C), 165.7 (C), 138.0 (C),
135.1 (C), 132.7 (CH), 131.4 (CH), 128.6 (CH), 127.9 (CH), 126.9
(CH), 126.8 (C), 125.3 (CH), 121.0 (CH), 60.7 (CH), 49.2 (CH2),
45.3 (CH), 44.6 (CH), 20.1 (CH2), 12.3 (CH3). HRMS (ESI+): m/z
calcd for [C20H20N2O2 + H+]: 321.1598; found: 321.1596.
NMR (100 MHz, CDCl3): δ = 199.6 (C), 168.1 (C), 158.3 (C), 139.5
(C), 137.5 (C), 134.6 (CH), 131.4 (CH), 129.0 (CH), 128.2 (CH),
128.1 (CH), 124.1 (CH), 120.4 (C), 116.7 (C), 77.8 (CH2), 52.8
(CH3), 48.0 (CH), 44.5 (CH), 22.2 (CH2), 11.3 (CH3). HRMS (ESI+):
m/z calcd for [C21H22N2O6 + H+]: 399.1551; found: 399.1548.
Synthesis of Pyrrolidines 4; General Procedure: Michael
adduct 3 (0.3 mmol, 1.0 equiv) was dissolved in anhydrous THF
(15 mL) and activated zinc powder (2.77 g, 42 mmol, 70.0 equiv)
was added followed by acetic acid (15 mL). The mixture was
stirred for 2 h at r.t., then the mixture was concentrated and
saturated aqueous NaHCO3 solution (15 mL) was added. The
aqueous phase was extracted with CH2Cl2 (2 × 20 mL) and the
combined organic layers were washed with water (20 mL),
1
Other examples of compounds 3, 4 and 5 as well as H and 13C
NMR spectra and chiral HPLC analyses are available in the Sup-
porting Information.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1591–1595