Cooperative catalysis for the first asymmetric formal [3+2] cycloaddition reaction of isocyanoacetates to α,β-unsaturated ketones

Article abstract of DOI:10.1002/ejoc.201100409

A cooperative multicatalytic cascade sequence involving isocyanoacetates and α,β-unsaturated ketones is described for the enantioselective synthesis of 2,3-dihydropyrroles. The key to promoting the multistep asymmetric reaction is the combination of cinch

Full text of DOI:10.1002/ejoc.201100409

FULL PAPER
DOI: 10.1002/ejoc.201100409
Cooperative Catalysis for the First Asymmetric Formal [3+2] Cycloaddition
Reaction of Isocyanoacetates to α,β-Unsaturated Ketones
Carlos Arróniz,[a] Alberto Gil-González,[a] Vladislav Semak,[a] Carmen Escolano,*[a]
Joan Bosch,[a] and Mercedes Amat[a]
Keywords: Silver / Organocatalysis / Ketones / Domino reactions / Asymmetric synthesis
A cooperative multicatalytic cascade sequence involving iso-
cyanoacetates and α,β-unsaturated ketones is described for
the enantioselective synthesis of 2,3-dihydropyrroles. The
key to promoting the multistep asymmetric reaction is the
combination of cinchona alkaloid derived organocatalysts
with silver nitrate. Merging both organic and metal catalytic
cycles enables the formation of two C–C bonds and the gen-
eration of a stereogenic center in a single process. The study
has also shown that the bifunctional role of the organocata-
lyst is crucial for the asymmetric version of the cycloaddition
reaction.
Introduction
Cooperative catalysis between organic and metal cata-
lysts has evolved rapidly in recent years and has become
a powerful strategy in asymmetric synthesis.[1] The precise
combination of transition metal and organocatalytic acti-
vation modes has led to the discovery of new synthetic
pathways and the generation of previously unattainable
compounds. Remarkably, this strategy not only perfectly
promotes single reactions but also enables multiple trans-
formations in a one-pot process.
Figure 1. Organobifunctional and metal cooperative catalysis strat-
egy (E = electrophile; Nu = nucleophile).
Seeking new applications for this concept, we envisaged
a cooperative catalytic system for the activation of isocy-
anoacetates by chiral organic bifunctional catalysts and in-
organic salts. Accordingly, the bifunctional organocatalyst
would activate both reaction partners and the metal ion
would enhance the reaction rate by additional substrate ac-
tivation (Figure 1). In addition, the polyfunctional reactiv-
ity of isocyanoacetates would allow the consecutive intro-
duction of both electrophiles and nucleophiles through a
catalytic cascade strategy, thereby gaining rapid molecular
complexity without the necessity for isolating and purifying
intermediate products.[2]
Isocyanides have proved to be exceptionally versatile
starting materials for heterocyclic chemistry.[3] Their di-
valent nature makes smooth reactions possible with a myr-
iad of reaction partners with both electrophiles and nucleo-
philes. Furthermore, the isocyanide functional group has
shown remarkable ability to undergo multicomponent and
cascade reactions.[4] In the particular case of isocyanoacet-
ates, the synthetic potential is even higher, as the ester func-
tionality provides an acidic proton in the α-carbonyl posi-
tion. The diversity of the transformations that isocyanoace-
tates can undergo includes asymmetric additions to alde-
hydes, imines, nitroalkenes, and azodicarboxylates.[5] The
work reported by Gong et al.[5e] deserves special attention,
as it was the first enantioselective addition to nitroolefins
promoted by cinchona alkaloid derivatives. However, to the
best of our knowledge, no examples have been described in
the literature regarding the asymmetric addition of isocy-
anoacetates to α,β-unsaturated ketones.
Although the enantioselective version remains unex-
plored, several studies have developed racemic Michael ad-
ditions of isocyanoacetates to α,β-unsaturated ketones.[6] Of
particular interest for our purposes is the work of Grigg
and co-workers, which describes an efficient formal [3+2]
cycloaddition reaction from isocyanoacetates and Michael
acceptors.[7] The racemic examples described so far allow
efficient syntheses of important classes of nitrogen hetero-
cycles such as pyrrolizidines[6d] and pyrrolines.[7] It is there-
fore of significant interest to develop a methodology for
the stereoselective synthesis of these elaborated key building
[a] Laboratory of Organic Chemistry, Faculty of Pharmacy,
and Institute of Biomedicine (IBUB), University of Barcelona,
08028 Barcelona, Spain
Fax: +34-93-402-4539
E-mail: cescolano@ub.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100409.
Eur. J. Org. Chem. 2011, 3755–3760
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Arróniz, A. Gil-González, V. Semak, C. Escolano, J. Bosch, M. Amat
FULL PAPER
blocks for rapid access to interesting natural products and was no need to add an external base, as the acetate counter-
biologically active enantiopure compounds.[8]
ion could achieve the α-deprotonation to promote the con-
Herein, we present our studies on the formal [3+2] cyclo- jugate addition of methyl isocyanoacetate upon Michael ac-
addition reaction of isocyanoacetates to α,β-unsaturated ceptors.[11]
ketones by a cooperative multicatalytic cascade sequence
for the enantioselective synthesis of 2,3-dihydropyrroles.
Inspired by this study, we thought of using silver salts to
increase the acidity of our pronucleophile so that the chiral
base could successfully trigger a stereoselective process. In
order to avoid a racemic background reaction, the silver
counterion used could not play any role as a base in the α-
deprotonation of the isocyanoester. With this prerequisite
Results and Discussion
In a preliminary screening, we tested naturally available in mind, we examined several AgI salts such as silver fluo-
quinine (QN, 3a; Figure 2) as a chiral base to achieve enan- ride, silver cyanate, and silver nitrate (Table 1, Entries 2–4).
tioselective 1,4-conjugate addition of methyl isocyanoacet- The first two catalysts provided access to racemic 4a. How-
ate (1a) to methyl vinyl ketone (2a). Natural cinchona alka- ever, to our delight, no conversion to the product was ob-
loids and their synthetic derivatives have proven to be privi- served when using silver nitrate, which left the door open
leged Brønsted bases in asymmetric catalysis, particularly for a stereoselective reaction after the addition of a chiral
for the α-deprotonation of pronucleophiles.[9] However, the base. Indeed, the combination of QN (3a) and AgNO3 al-
application of QN (3a, 20 mol-%) to our model reaction in lowed full conversion to 4a with 9%ee (Table 1, Entry 5).
CH2Cl2 at room temperature failed to promote conversion This result prompted us to deal with the challenge of an
to the product, probably due to the insufficient acidity of enantioselective version of the model reaction by coopera-
the α-hydrogen atoms of the isocyanoester (Table 1, En- tive catalysis between a chiral cinchona alkaloid derived
try 1).
base and silver nitrate.
We then turned our attention to screening different cin-
chona alkaloid derivatives for a better asymmetric induc-
tion (Figure 2). The use of quinidine (QD, 3g) resulted in
the formation of the opposite enantiomer with similar selec-
tivity (Table 1, Entry 6). Screening of natural cinchona al-
kaloids such as cinconine (CN, 3h), cinconidine (CD, 3b),
and hydroquinine (HQ, 3c) afforded 4a in high conversion
with poor enantioselectivity (Table 1, Entries 7–9). We also
tested cinchona alkaloid derivatives without the C9-OH
functionality, such as 3f with a C9-benzoyl ester and 3j with
a C9-NH2 group, but the reaction did not work. These re-
sults suggested that the C9-hydroxy group could activate
the substrate through hydrogen-bonding interactions, and
consequently, the chiral base would play a bifunctional role
in the process.[12] With this in mind, we thought of using
cinchona alkaloid derivatives that feature a phenolic OH
group at the C6Ј position for an additional activating func-
tionality.[13]
Table 1. Screening of catalysts and optimization of the reaction
conditions for the cycloaddition reaction of methyl isocyanoacetate
(1a) and MVK (2a).[a]
Entry
3 [mol-%]
MLn
[mol-%]
Solvent
Conv.
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
QN, 3a [20]
–
–
CH2Cl2
CH2Cl2
nr[d]
100
100
nr[d]
100
100
50
100
100
100
80[f]
100
100
40[g]
–
rac
rac
–
AgF [1]
AgOCN [1] CH2Cl2
–
–
AgNO3 [1]
AgNO3 [1]
AgNO3 [1]
AgNO3 [1]
AgNO3 [1]
AgNO3 [1]
AgNO3 [5]
AgNO3 [2]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
QN, 3a [20]
QD, 3g [20]
CN, 3h [20]
CD, 3b [20]
HQ, 3c [20]
CPD, 3i [20]
CPD, 3i [10]
HCPN, 3d [20] AgNO3 [5]
CPN, 3e [10]
CPN, 3e [10]
9
–7[e]
–4[e]
12
9
10
10
11
12
13
14
–41[e]
–28[e]
46
AgNO3 [5]
AgNO3 [5]
60
72
[a] All the reactions were performed on a 0.4-mmol scale whilst
stirring overnight unless indicated otherwise (see the Experimental
Section). [b] Determined by 1H NMR spectroscopy. [c] Determined
by chiral stationary-phase HPLC. [d] nr = no reaction. [e] Negative
ee values mean that opposite enantiomer was obtained as a major
component. [f] The reaction was performed at 10 °C for 3 d. [g] The
reaction mixture was stirred for 7 d.
The aforementioned work of Grigg and co-workers re-
ported an efficient racemic version of our model reaction
catalyzed by silver acetate.[7] The reaction success was based
on the increased acidity of the α-protons by silver α-met-
alation of the isocyanide.[10] Under these conditions, there Figure 2. Cinchona alkaloid derived catalysts tested in this study.
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Asymmetric Formal [3+2] Cycloaddition Reactions
Notably, when performing the model reaction with cup- Table 2. Scope for the cooperative catalytic synthesis of enantio-
enriched pyrrolines 4 from isocyanoacetates 1 and vinyl ketones
reidine (CPD, 3i), an improvement in selectivity was ob-
served (Table 1, Entry 10). Surprisingly, decreasing the tem-
2.[a]
perature to 10 °C resulted in lower enantioselectivity and
an extended reaction time (Table 1, Entry 11). Very low
conversion occurred when the reaction was conducted at a
lower temperature. No significant enhancement in the
enantioselectivity was achieved when the reaction was car-
ried out in the presence of hydrocupreine (HCPN, 3d;
Table 1, Entry 12). However, using cupreine (CPN, 3e) as a
chiral base led to full conversion of the product with mod-
erate ee (Table 1, Entry 13). Higher enantioselectivity was
observed when the reaction was performed in toluene, al-
though with a very low conversion (Table 1, Entry 14). The
effect of other solvents such as tetrahydrofuran, dichloro-
ethane, and acetonitrile on conversion, enantioselectivity,
and reaction time was also tested, although none of them
appeared more suitable than dichloromethane. Regarding
catalyst loading, the most appropriate ratio to balance reac-
tivity and selectivity was 10 mol-% for the Brønsted base
and 5 mol-% for the Lewis acid.
Entry R1
R2
1
R3
2
4
Yield
ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
tBu
Et
H
H
H
Bn
Bn
H
1a
1a
1a
1b
1b
1c
1d
1d
Me
Et
Et
Me
Et
Me
Me
Et
2a
2b
2b
2a
2b
2a
2a
2b
4a
4b
4b
4c
4d
4e
4f
58 60
49 74
20 89[d]
85 16
66 36
59 58
48 68
43 52
H
H
Et
4g
[a] All the reactions were performed on a 0.4-mmol scale whilst
stirring for 14 h unless indicated otherwise (see the Experimental
Section). [b] Yield of isolated product. [c] Determined by chiral sta-
tionary-phase HPLC. [d] Reaction performed in toluene for 7 d.
Therefore, our best conditions involved a catalytic system
with 10 mol-% of cupreine (3e) and 5 mol-% of AgNO3 in
CH2Cl2 to afford the enantiomerically enriched product
(i.e., 4a) in good yield (Table 2, Entry 1). With proof of
principle established, our efforts were focused on the scope
of the cascade under the aforementioned general reaction
conditions.
To this end, different substitution patterns were explored
in both starting reagents 1 and 2 (R1, R2, and R3). First of
all, a longer alkyl chain was situated in the Michael ac-
ceptor and good enantioselectivity (74%) was obtained
with α,β-unsaturated ketone 2b and isocyanoacetate 1a to
afford product 4b (Table 2, Entry 2). Remarkably, higher
enantiopurity (89%ee) of 4b was achieved when using tolu-
ene as a solvent, although, as mentioned in the initial
screening for the preparation of 4a, the reaction conversion
was low (Table 2, Entry 3). Interestingly, the reaction was
Ethyl vinyl ketone (2b) showed better enantiodifferentiation
with benzyl α-substituted isocyanoacetate 1b (Table 2, En-
try 5). Variations in the ester moiety were also considered.
The reaction of tert-butyl isocyanoester 1c with methyl vi-
nyl ketone (2a) provided easy access to enantioenriched
product 4e (Table 2, Entry 6). Finally, ethyl isocyanoacetate
1d enabled the formation of 4f and 4g in moderate yield
and ee by reacting with methyl and ethyl vinyl ketone,
respectively (Table 2, Entries 7 and 8).[14]
Mechanistic Considerations
Based on our experimental observations and previous
also able to generate a quaternary stereocenter. Reaction of considerations,[7] a putative mechanism is proposed for the
1b (R2 = Bn) with methyl vinyl ketone (2a) gave 4c in very cooperative Brønsted base/Lewis acid multistep asymmetric
good yield and poor enantioselectivity (Table 2, Entry 4). sequence. Scheme 1 shows the three roles of the catalysts
Scheme 1. Proposed mechanism for the multicatalytic cascade sequence.
Eur. J. Org. Chem. 2011, 3755–3760
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FULL PAPER
pounds 1b,[15] 3d, 3e, 3i,[16] and 3j[17] were prepared according to
literature procedures.
within the reaction, which include (i) activating an α-pro-
ton, (ii) transferring chiral information, and (iii) facilitating
the cyclization step.
General Procedure for the Synthesis of Racemic 2,3-Dihydropyrroles
4a–g: To a solution of silver fluoride or silver cyanate (0.02 mmol)
and isocyanoacetate 1 (0.4 mmol) in CH2Cl2 (4 mL) was added α,β-
unsaturated ketone 2 (0.4 mmol). The reaction mixture was stirred
at room temperature for 14 h. The reaction mixture was concen-
trated, and the residue was purified by column chromatography to
afford pure product 4.
Silver complexation to the terminal carbon would in-
crease the acidity of the α-proton so that the quinuclidine
nitrogen of cupreine (3e) would α-deprotonate isocy-
anoacetate 1. After the α-deprotonation, a rigid chiral ion
pair would be formed by the hydrogen-bonding interaction
between the C9-hydroxy group and the substrate. Then,
vinyl ketone 2 would undergo 1,4-addition by the nucleo-
phile, thereby generating a stereogenic center. To transfer
stereochemical information, the C6Ј-hydroxy group would
play a key role in biasing the approach of the electrophile
through a well-defined hydrogen-bonding interaction. Sub-
sequently, a 5-endo-dig cyclization would take place helped
by the electrophilic silver isocyanide activation. A second
stereocenter is formed after the cyclization step although
this is lost in the final double bond isomerization, leading
to the more stable enantioenriched 2-pyrroline 4.
General Procedure for the Synthesis of Optically Active 2,3-Dihy-
dropyrroles 4a–g: To a solution of catalyst 3e (0.04 mmol), silver
nitrate (0.02 mmol), and isocyanoacetate 1 (0.4 mmol) in CH2Cl2
(4 mL) was added α,β-unsaturated ketone 2 (0.4 mmol). The reac-
tion mixture was stirred at room temperature typically for 14 h. The
reaction mixture was concentrated, and the residue was purified by
column chromatography on silica gel to afford pure product 4. The
enantiomeric excess (ee) was determined by HPLC analysis using
mixtures of methyl tert-butyl ether (MtBE) and EtOH.
Methyl 4-Acetyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4a):[18] Fol-
lowing the general procedure, product 4a (39 mg, 58%) was ob-
tained after chromatography (EtOAc) as a white solid. 1H NMR
(400 MHz, CDCl3, COSY, HSQC): δ = 2.14 (s, 3 H, CH3CO), 3.05
(dd, J = 7.0, 1.0 Hz, 1 H, 3-H), 3.07 (dd, J = 11.5, 1.0 Hz, 1 H, 3-
H), 3.73 (s, 3 H, CH3O), 4.45 (dd, J = 11.5, 6.5 Hz, 1 H, 2-H), 5.24
(br. s, 1 H, NH), 7.25 (m, 1 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.4 (CH3CO), 31.0 (C-3), 52.5 (CH3O), 60.0 (C-2),
115.0 (C-4), 148.7 (C-5), 173.3 (COO), 191.7 (CO) ppm. HPLC
(Chiralpak IA, MtBE/EtOH = 80:10, flow rate = 0.9 mL/min, λ =
300 nm): tR(major) = 12.6 min; tR(minor) = 21.7 min (60%ee).
Conclusions
In summary, the cooperative Brønsted base/Lewis acid
cascade catalysis described in this study represents a new
method for the easy and rapid construction of enantioen-
riched 2,3-dihydropyrroles from α,β-unsaturated ketones.
Due to the polyfunctional nature of the isocyanoacetate
(pro)nucleophiles, an essential double catalyst activation
has been possible to trigger the cycloaddition reaction. The
α-deprotonation by the chiral base and the metal electro-
phile activation allowed two bond formations in a cascade
sequence. A bifunctional catalyst such as cupreine (3e) was
required to promote the reaction in a stereoselective man-
ner, which suggests a possible dual activation wherein the
cupreine C6Ј-OH functionality might engage with the vinyl
ketone through hydrogen-bonding interactions. Further ex-
periments are under way and will be reported in due course.
Methyl 4-Propionyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4b): Fol-
lowing the general procedure, product 4b (36 mg, 49%) was ob-
tained after chromatography (EtOAc) as a yellowish solid. 1H
NMR (400 MHz, CDCl3, COSY, HSQC): δ = 1.11 (t, J = 7.5 Hz,
CH3), 2.49 (q, J = 7.5 Hz, CH2CH3), 3.04 (dd, J = 7.5, 1.0 Hz, 1
H, 3-H), 3.07 (dd, J = 11.0, 1.5 Hz, 1 H, 3-H), 4.45 (dd, J = 11.0,
7.5 Hz, 1 H, 2-H), 4.78 (br. s, 1 H, NH), 7.23 (m, 1 H, 5-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 9.67 (CH3CH2), 31.0 and 31.2
(C-3 and CH2CH3), 52.5 (CH3O), 59.8 (C-2), 114.6 (C-4), 147.3
(C-5), 173.6 (COO), 195.6 (CO) ppm. HRMS: calcd. for C9H14NO3
[M + H+] 184.0968; found 184.0966. HPLC (Chiralpak IA, MtBE/
EtOH = 40:10, flow rate = 0.5 mL/min, λ = 300 nm): tR(major)
12.0 min, tR(minor) = 13.1 min (74%ee).
=
Experimental Section
Methyl
4-Acetyl-2-benzyl-2,3-dihydro-1H-pyrrole-2-carboxylate
(4c): Following the general procedure, product 4c (88 mg, 85%) was
obtained after chromatography (EtOAc) as a brown oil. H NMR
General Methods: Unless otherwise indicated, NMR spectra were
recorded in CDCl3 at 400 MHz (1H) and 100.6 MHz (13C), and
chemical shifts are reported in δ values downfield from TMS or
relative to residual chloroform (δ =7.26 ppm, 77.0 ppm) as an in-
ternal standard. Data are reported in the following manner: chemi-
cal shift, multiplicity, coupling constant, integrated intensity. Multi-
plicities are reported using the following abbreviations: s, singlet;
dd, doublet of doublets; m, multiplet; br. s, broad signal. Evapora-
tion of solvents was accomplished with a rotary evaporator. Thin-
layer chromatography was done on SiO2 (silica gel 60 F254), and
the spots were located by UV and 1% aqueous KMnO4.
Chromatography refers to flash column chromatography and was
carried out on SiO2 (silica gel 60, SDS, 230–400 mesh). Mass spec-
tra were recorded with a LTQ spectrometer using electrospray ion-
ization (ESI+) techniques. The enantiomeric excess (ee) of the
products was determined by chiral stationary-phase HPLC (Daicel
Chiralpak IA column). Analytical grade solvents and commercially
available reagents were used without further purification. Com-
1
(400 MHz, CDCl3, COSY, HSQC): δ = 2.15 (s, 3 H, CH3CO), 2.88
and 3.22 (2d, J = 16 Hz, 2 H, CH2Ph), 2.98 and 3.28 (2d, J =
13.5 Hz, 2 H, 3-H), 3.72 (s, 3 H, CH3O), 4.98 (br. s, 1 H, NH),
7.08–7.11 (m, 2 H, PhH), 7.15 (m, 1 H, 5-H), 7.25–7.29 (m, 3 H,
PhH) ppm. 13C NMR (100 MHz): δ = 25.3 (CH3CO), 37.8
(CH2Ph), 45.3 (C-3), 52.5 (CH3O), 72.2 (C-2), 114.8 (C-4), 127.4
(CHPh), 128.6 (2 CHPh), 129.5 (2 CHPh), 135.2 (C-i), 147.2 (C-
5), 174.4 (COO), 191.7 (CO) ppm. HRMS: calcd. for C15H18NO3
[M + H+] 260.1281; found 260.1282. HPLC (Chiralpak IA, MtBE/
EtOH = 50:10, flow rate = 0.6 mL/min, λ = 300 nm): tR(major)
12.5 min, tR(minor) = 14.1 min (16%ee).
=
Methyl 2-Benzyl-4-propionyl-2,3-dihydro-1H-pyrrole-2-carboxylate
(4d): Following the general procedure, product 4d (72 mg, 66%)
was obtained after chromatography (EtOAc/hexanes = 1:1) as a
brown oil. H NMR (400 MHz, CDCl3, COSY, HSQC): δ = 1.09
(t, J = 7.5 Hz, CH3), 2.45 (q, J = 7.5 Hz, CH2CH3), 2.88 and 3.22
1
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Asymmetric Formal [3+2] Cycloaddition Reactions
(2d, J = 16 Hz, 2 H, CH2Ph), 2.98 and 3.28 (2d, J = 13.5 Hz, 2 H,
C. A. thank the Ministry of Education and Science for a predoc-
3-H), 3.72 (s, 3 H, CH3O), 4.94 (br. s, 1 H, NH), 7.08–7.11 (m, 2 toral fellowship.
H, PhH), 7.15 (m, 1 H, 5-H), 7.25–7.29 (m, 3 H, PhH) ppm. 13C
NMR (100 MHz): δ = 9.7 (CH3), 30.9 (CH2CH3), 37.9 (CH2Ph),
[1] For recent reviews on cooperative catalysis, see: a) C. Zhong,
45.2 (C-3), 52.4 (CH3O), 72.0 (C-2), 113.7 (C-4), 127.4 (CHPh),
128.6 (2 CHPh), 129.5 (2 CHPh), 135.2 (C-i), 146.1 (C-5), 174.4
(COO), 195.5 (CO) ppm. HRMS: calcd. for C16H20NO3 [M + H+]
274.1438; found 274.1436. HPLC (Chiralpak IA, MtBE/EtOH =
80:10, flow rate = 0.9 mL/min, λ = 300 nm): tR(major) = 10.7 min,
tR(minor) = 10.0 min (36%ee).
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tert-Butyl 4-Acetyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4e): Fol-
lowing the general procedure, product 4e (50 mg, 59%) was ob-
tained after chromatography (EtOAc) as a brown oil. 1H NMR
(400 MHz, CDCl3, COSY, HSQC): δ = 1.47 [s, 9 H, C(CH3)3], 2.17
(s, 3 H, CH3CO), 2.88 and 3.22 (2d, J = 16 Hz, 2 H, CH2Ph), 2.96
(dd, J = 15.5, 6.5 Hz, 1 H, 3-H), 3.09 (dd, J = 15.5, 12.5 Hz, 1 H,
3-H), 4.36 (dd, J = 12.5, 6.5 Hz, 1 H, 2-H), 5.04 (br. s, 1 H, NH),
7.24 (m, 1 H, 5-H) ppm. 13C NMR (100 MHz): δ = 25.4 (CH3CO),
28.0 [C(CH3)3], 31.3 (C-3), 60.5 (C-2), 82.3 [C(CH3)3], 115.2 (C-
4), 148.8 (C-5), 174.4 (COO), 191.7 (CO) ppm. HRMS: calcd. for
C11H18NO3 [M + H+] 212.1281; found 212.1282. HPLC (Chiralpak
IA, MtBE/EtOH = 80:10, flow rate = 0.9 mL/min, λ = 300 nm):
tR(major) = 11.0 min, tR(minor) = 14.8 min (58%ee).
Ethyl 4-Acetyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4f): Follow-
ing the general procedure, product 4f (35 mg, 48%) was obtained
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1
after chromatography (EtOAc/hexanes = 1:1) as a colorless oil. H
NMR (400 MHz, CDCl3, COSY, HSQC): δ = 1.11 (t, J = 7.5 Hz,
CH3), 1.46 [s, 9 H, C(CH3)3], 2.48 (q, J = 7.5 Hz, CH2CH3), 2.95
(ddd, J = 15.5, 6.5, 1.0 Hz, 2 H, 3-H), 3.06 (ddd, J = 15.5, 12.5,
1.0 Hz, 2 H, 3-H), 4.32 (dd, J = 12.5, 6.5 Hz, 1 H, 2-H), 4.83 (br.
s, 1 H, NH), 7.24 (m, 1 H, 5-H) ppm. 13C NMR (100 MHz): δ =
9.7 (CH3), 28.0 [C(CH3)3], 31.1 and 31.4 (CH2CH3 and C-3), 60.4
(C-2), 82.3 [C(CH3)3], 115.6 (C-4), 147.5 (C-5), 172.4 (COO), 195.7
(CO) ppm. HRMS: calcd. for C9H14NO3 [M + H+] 184.0968;
found 184.0968. HPLC (Chiralpak IA, MtBE/EtOH = 80:10, flow
[4] a) J. Wu, S. Cao, Curr. Org. Chem. 2009, 13, 1791–1804; b) A.
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rate = 0.9 mL/min, λ = 300 nm): tR(major) = 12.7 min, tR(minor)
18.3 min (68%ee).
=
Ethyl 4-Propionyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4g): Fol-
lowing the general procedure, product 4g (34 mg, 43%) was ob-
tained after chromatography (EtOAc/hexanes = 1:1) as a white so-
[5] For a general review, see: a) A. V. Gulevich, A. G. Zhdanko,
R. V. A. Orru, V. G. Nenajdenko, Chem. Rev. 2010, 110, 5235–
5331; for recent asymmetric additions to aldehydes, see: b) F.
Sladojevich, A. Trabocchi, A. Guarna, D. J. Dixon, J. Am.
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imines, see: d) Z.-W. Zhang, G. Lu, M.-M. Chen, N. Lin, Y.-
B. Li, T. Hayashi, A. S. C. Chan, Tetrahedron: Asymmetry
2010, 21, 1715–1721; for an asymmetric addition to nitroole-
fins, see: e) C. Guo, M.-X. Xue, M.-K. Zhu, L.-Z. Gong, An-
gew. Chem. Int. Ed. 2008, 47, 3414–3417; for racemic and
asymmetric additions to azodicarboxylates, see: f) D. Monge,
K. L. Jensen, I. Marín, K. A. Jørgensen, Org. Lett. 2011, 13,
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1
lid. H NMR (400 MHz, CDCl3, COSY, HSQC): δ = 1.11 (t, J =
7.5 Hz, OCH2CH3), 1.29 (t, J = 7.5 Hz, CH2CH3), 2.48 (q, J =
7.5 Hz, 2 H, CH2CH3), 3.02 (dd, J = 16.0, 6.5 Hz, 1 H, 3-H), 3.10
(ddd, J = 16.0, 12.0, 1.0, Hz, 1 H, 3-H), 4.20 (m, 2 H, OCH2CH3),
4.45 (dd, J = 12.0, 6.5 Hz, 1 H, 2-H), 4.91 (br. s, 1 H, NH), 7.24
(m, 1 H, 5-H) ppm. 13C NMR (100 MHz): δ = 9.7 (OCH2CH3),
14.1 (CH2CH3), 31.1 and 31.3 (CH2CH3 and C-3), 59.9 (C-2), 61.7
(OCH2), 114.6 (C-4), 147.4 (C-5), 173.2 (COO), 195.6 (CO) ppm.
HRMS: calcd. for C10H16NO3 [M + H+] 198.1125; found 198.1124.
HPLC (Chiralpak IA, MtBE/EtOH = 98:2, flow rate = 1.0 mL/
min, λ = 300 nm): tR(major) = 30.7 min, tR(minor) = 28.5 min
(52%ee).
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Supporting Information (see footnote on the first page of this arti-
cle): HPLC chromatograms and NMR spectra for products 4a–g.
[7] R. Grigg, M. I. Lansdell, M. Thornton-Pett, Tetrahedron 1999,
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Financial support from the Ministry of Science and Innovation,
Spain (Project CTQ2009-07021/BQU) and the Agència de Gestió
d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Cata-
lunya (Grant 2009-SGR-111) is gratefully acknowledged. V. S. and
Eur. J. Org. Chem. 2011, 3755–3760
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3759

C. Arróniz, A. Gil-González, V. Semak, C. Escolano, J. Bosch, M. Amat
FULL PAPER
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[18] The racemate was described previously: see ref.[7]
Received: March 24, 2011
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Published Online: May 17, 2011
3760
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3755–3760