Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams

Article abstract of DOI:10.1055/s-0036-1588672

We report the synthesis of racetams, a diverse class of small molecule drugs, by means of the Ugi four-center three-component reaction (U4C-3CR). For the first time, γ-aminobutyric acid is employed as bifunctional input in the Ugi reaction. This protocol is simple, general, and allows one-pot access to a range of drugs and bioactive small molecules.

Full text of DOI:10.1055/s-0036-1588672

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
paper
A
R. C. Cioc et al.
Paper
Synthesis
Ugi Four-Center Three-Component Reaction as a Direct Approach
to Racetams
Răzvan C. Cioc
COOH
O
Lola Schaepkens van Riempst
H
NH2
+
N
28 examples,
yield up to 71%
R2
N
Peter Schuckman
Eelco Ruijter*
TFE (0.1 M)
40 °C, 24 h
O
C
R1
N
O
R1
H
R2
Romano V. A. Orru*
R1 = H, alkyl, (hetero)aryl
R2 = alkyl, (hetero)aryl
Department of Chemistry & Pharmaceutical Sciences and
Amsterdam Institute for Molecules, Medicines & Systems
(AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108,
1081 HZ Amsterdam, The Netherlands
e.ruijter@vu.nl
r.v.a.orru@vu.nl
Received: 17.10.2016
Accepted after revision: 14.11.2016
Published online: 16.12.2016
Structurally, the bioactive 2-oxo-1-pyrrolidino acet-
amides are relatively simple small molecules; their synthe-
sis is straightforward and invariably relies on an SN2 reac-
tion with pyrrolidone to introduce the γ-lactam unit
(Scheme 1). In the context of drug design, this approach, al-
though reliable and robust, has certain drawbacks: it is
time-consuming (linear, multistep synthesis), it is accom-
panied by a reduced variability at the α-position of the
acetamide (due to the limited availability of precursors),
and it features SN2-specific scope limitations (base-sensi-
tive functionalities, additional electrophilic centers, and
bulky substituents are incompatible). Therefore, a chemo-
selective convergent/multicomponent approach would be
more suitable for the combinatorial synthesis of novel race-
tam analogues.
DOI: 10.1055/s-0036-1588672; Art ID: ss-2016-t0732-op
Abstract We report the synthesis of racetams, a diverse class of small
molecule drugs, by means of the Ugi four-center three-component re-
action (U4C-3CR). For the first time, γ-aminobutyric acid is employed as
bifunctional input in the Ugi reaction. This protocol is simple, general,
and allows one-pot access to a range of drugs and bioactive small mole-
cules.
Key words multicomponent reactions, racetams, pyrrolidones, me-
dicinal chemistry, Ugi reaction
Racetams are a broad class of drugs that feature a pyrro-
lidone ring. Of particular importance are the 2-oxo-1-pyr-
rolidino acetamide derivatives (Figure 1), which find wide-
spread use in the treatment of various medical conditions
such as epilepsy, dementia, depression, anxiety, and hypox-
ia.1 Despite more than 50 years of clinical significance, the
2-oxo-1-pyrrolidino acetamide remains an interesting
pharmacophore for medicinal chemistry and novel applica-
tions of racetam derivatives continue to be developed.2
COOH
O
O
H
N
N
NH2
R1
C
R2
N
H
N
R2
R1
Br
OR
O
R1
Racetams
O
H
O
conventional approach
multicomponent approach
HO
single step synthesis
general, combinatorial
mild conditions
multistep synthesis
O
O
O
SN2-specific limitations
N
N
N
NH2
NH2
NH2
harsh conditions
O
O
O
low availability of bromoesters
readily available precursors
Piracetam
Oxiracetam
Etiracetam
Scheme 1 Conventional versus multicomponent synthesis of racetams
O
O
O
H
H
N
N
N
Recognizing the general 2-oxo-1-pyrrolidino acetamide
structure as an Ugi scaffold,3 we envisaged the construction
of racetam derivatives via this multicomponent condensa-
tion. Ugi approaches towards racetam derivatives have
been previously reported, but these methods graft the pyr-
rolidone core indirectly by subsequent manipulation (i.e.,
NH2
N
N
iPr
N
O
O
O
iPr
Brivaracetam
Nefiracetam
Pramiracetam
Figure 1 Commercial drugs of the racetam class
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
R. C. Cioc et al.
Paper
Synthesis
xanthate cyclization,4 olefin metathesis5) of Ugi adducts
with appropriate functionalization handles. In a more di-
rect approach toward the 2-oxo-1-pyrrolidino acetamide
scaffold, we decided to pursue the direct synthesis from γ-
aminobutyric acid, a carbonyl compound, and an isocya-
nide to provide the target scaffold in a single operation.
Amino acids have been intensively applied in Ugi chem-
istry (Scheme 2). In the case of α-amino acids, the typical
Mumm rearrangement is kinetically blocked and the α-ad-
duct undergoes reactions with external nucleophiles (alco-
hols,6 amines7) or internal nucleophiles (e.g., alcohols8) in-
stead. On the other hand, β-amino acids, unless sterically
constrained,9 do follow the complete Ugi pathway, includ-
ing the final rearrangement, leading to β-lactam deriva-
tives.10 Remarkably, the use of γ-amino acids and higher
homologues11 has not been thoroughly investigated in the
Ugi reaction. Extrapolating the behavior of the first mem-
bers of the series, it is expected that γ-amino acids would
react in an Ugi condensation by the contraction of the
eight-membered ring α-adduct to a pyrrolidone derivative
upon Mumm rearrangement. This hypothesis was only re-
cently validated by Darehkordi et al., who showed that 2-(1-
aminomethyl)cyclohexylacetic acid (gabapentin) can be
successfully applied in Ugi type three-component conden-
sations;12 however, this bifunctional input is strongly bi-
ased toward cyclization by the Thorpe–Ingold effect and
one should be cautious when generalizing this reactivity to
linear, unbranched amino acids. Ugi type reactions of glu-
tamic acid derivatives have also been reported.13 Although
deceptively simple, the use of γ-amino acids in the Ugi reac-
tion involves a number of challenges. The formation of the
α-adduct, an eight-membered ring, is plausibly a slow pro-
cess;14 competition with the intermolecular Ugi reaction is
anticipated. Furthermore, the lactamization of γ-aminobu-
tyric acid (possibly isocyanide-mediated15) is also a kineti-
cally relevant transformation, particularly at high tempera-
tures. Finally, the ring contraction transannulation (the
Mumm rearrangement) in this medium-sized ring may also
be problematic and lead to undesired side reactions (sol-
volysis, addition of other, external nucleophiles). Indeed,
when performing the reaction between γ-aminobutyric
acid, tert-butyl isocyanide, and an aldehyde (aliphatic or ar-
omatic) under typical Ugi conditions (MeOH, 1 M, room
temperature) the yield of the desired product was very low
because the anticipated side reactions also occurred. Exten-
sive optimization efforts16 were rewarded with a signifi-
cantly improved selectivity and a satisfactory yield for the
expected 2-oxo-1-pyrrolidino acetamide derivative using
2,2,2-trifluoroethanol (TFE) as solvent at relatively high di-
lution.17
With the optimized protocol in hand, we set out to ex-
plore the scope of this reaction (Scheme 3). The key (and
rate-determining) step in Ugi type reactions is believed to
be the addition of the isocyanide to the iminium ion.18 In-
deed, we observed that the yield of the product in this reac-
tion generally correlates well with the relevant reactivity
parameters of the inputs; namely, aldehyde electrophilicity
and isocyanide nucleophilicity (except in specific cases that
will be outlined below). The aldehyde scope proved to be
broad, including both aliphatic and aromatic inputs, with
the former generally performing better than the latter (i.e.,
giving products 4i vs. 4s); α,β-unsaturated tiglic aldehyde
gave no conversion due to reduced electrophilicity (expect-
ed product 4p). In the series of aliphatic aldehydes, the
yield was slightly higher for branched inputs (products 4d–
f vs. 4a–c), possibly due to side reactions initiated by enam-
ine formation in the case of linear aldehydes; in this re-
spect, pivalic aldehyde appears to perform the best (4i, 4k).
This feature of our method nicely complements the conven-
tional approach toward racetams, for which the introduc-
tion of bulky substituents at this position in the molecule is
challenging (neopentylic halides are generally very poor
SN2 electrophiles). Formaldehyde, on the other hand, did
not follow the general trend: the yield was somewhat lower
than expected (formaldehyde is the most electrophilic alde-
hyde considering both electronic and steric properties, and
does not enolize) but can be improved by performing the
reaction at reflux (as shown for 4n).19 Furthermore, (hete-
R4
R4
H2N
COOH
NuH
R3
N
R2 R1
H
N
R1
R3
N
CONu
Refs. 6,7
R2
O
H
α-amino acid
O
NuH = ROH, R2NH
HN
R4
NuH
O
via
R5
n
O
N
R4
R5
O
COOH
α-adduct
R1
R2
C
NH2
O
N
Ref. 8
β-amino acid
R3
N
R1
Mumm
nucleophilic
addition
R2
H
rearrangement
R3
O
cyclic chain
(lactams)
open-chain
product
NH2 COOH
H
N
this work
R3
N
R2
γ-amino acid
R1
O
Scheme 2 Ugi reactions with amino acids
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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R. C. Cioc et al.
Paper
Synthesis
ro)aromatic aldehydes could also be employed (4q–v), al-
though the yield was slightly lower than for aliphatic ho-
mologues (the decrease was particularly significant for
electron-rich anisaldehyde, product 4r). Finally, (relatively
reactive) ketones were also found to be suitable carbonyl
components in this reaction (4x); again, this is an import-
ant complementary feature to conventional methods based
on SN2 substitution, which would require here a tertiary
halide electrophile.
The reaction was found to be quite flexible regarding
the isocyanide scope, without notable reactivity differences
between various isocyanides (Scheme 3). Aliphatic (linear
or branched, products 4a, 4d, 4h, 4i, 4n, 4p, 4q), aromatic
(4c, 4f), and α-acidic isocyanides (4g, 4k) were all well tol-
erated in the reaction. To our delight, the convertible re-
agent 2-bromo-6-isocyanopyridine,20 which is somewhat
less nucleophilic than most other isocyanides, could also be
employed in this transformation (4f, 4o). On the other
COOH
O
1
H
N
NH2
R2
N
28 examples,
yield up to 71%
1:1:1
ratio
O
R1
TFE (0.1 M)
40 °C, 24 h
CN
R2
H
O
R1
2
3
4
O
O
O
O
O
H
H
H
H
N
N
N
N
H
N
N
N
N
N
N
BnO
O
O
O
O
O
4a
62%
4b
36%
4c
49%
4d
60%
4e
69%
N
N
O
O
H
N
O
O
O
H
N
O
H
H
N
N
N
N
OMe
N
H
N
N
N
N
N
O
O
O
O
O
Br
4f
66%
4g
49%
4h
45%
4i
71%
4j
46%
O
O
O
O
O
Ts
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
O
N
O
O
O
O
O
Br
4k
65%
4o
48%
4l
n.d.
4m
n.d.
4n
58%a
O
O
O
O
O
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
F3C
O
O
O
O
O
4p
0%
4q
42%
4r
34%
4s
41%
4t
46%
MeO
F3C
O
O
O
H
N
O
O
H
H
N
N
N
OMe
H
N
N
N
N
O
O
O
O
N
N
4u
40%
4v
50%
4x
38%
4y
~15%b
HN Boc
HO
HO
O
O
O
H
N
O
N
H
H
N
N
N
N
H
N
N
OMe
O
O
O
O
5a
50% (d.r. ~1:1)
5b
n.d.a
5c
n.d.a
5d
~10%b
Scheme 3 Reagents and conditions: γ-aminobutyric acid (1 mmol), aldehyde (1 mmol) and isocyanide (1 mmol) in TFE (10 mL) at 40 °C for 24 h; isolated
yields; n.d. = not determined, complex reaction mixture. a Performed at reflux. b Based on 1H NMR analysis of the crude mixture, product not isolated.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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R. C. Cioc et al.
Paper
Synthesis
hand, 2-morpholinoethyl isocyanide [and the related 2-(di-
isopropyl-amino)ethyl isocyanide, envisaged for the syn-
thesis of 4m] most likely displayed peptide coupling reac-
tivity rather than Ugi addition;21 in these two examples, the
desired products were formed in low yields at best.22
Although γ-aminobutyric acid is the component rele-
vant to the family of racetams, we also investigated the
amino acid scope of our reaction. Thus, product 5a was ob-
tained in good yield (as a ~1:1 mixture of diastereoiso-
mers23 starting from Nα-Boc-protected α,γ-diaminobutyric
acid [Boc-Dab-OH]). On the other hand, the introduction of
a 3-hydroxyl group on the amino acid proved to be a prob-
lematic variation, as a complex mixture resulted from the
attempted synthesis of oxiracetam derivatives 5b and 5c.24
A similar result was obtained when 5-aminovaleric acid
was employed,25 providing the desired product 5d in only
~10% yield. It thus seems that this protocol is restricted to
the formation of γ-lactam derivatives and we decided not
to further pursue the exploration of the lactam space acces-
sible via this Ugi type reaction.
We then probed the utility of this novel Ugi reaction in
the synthesis of clinically important racetam derivatives
(Scheme 4). Piracetam 4aa and etiracetam 4bb were pre-
pared in good yields by one-pot Ugi condensation using
1,1,3,3-tetramethylbutyl isocyanide and subsequent acid-
mediated dealkylation to the primary amide. Etiracetam
enriched in the bioactive stereoisomer ((S)-levetiracetam,
Keppra) can be obtained by a crystallization-induced dy-
namic resolution of the diastereoisomeric mixture of Ugi
adduct 4cc,26 which was obtained in a relatively low yield
(typical for enolizable linear aldehydes, in this case pro-
pionaldehyde). Another racetam drug, nefiracetam (4dd),
can be obtained directly via the multicomponent condensa-
tion although the yield was moderate, plausibly due to the
utilization of a less nucleophilic isocyanide (2,6-dimethyl-
phenyl isocyanide, see also 4j vs. 4i in Scheme 3).
COOH
O
N
NH2
CN
NH2
1. TFE, reflux, 3 h
2. TFA, reflux, 1 h
R
RCHO
O
4aa (Piracetam, R = H) 58%
4bb (Etiracetam, R = Et) 53%
O
COOH
NH2
CN
EtCHO
H
N
ref. 26
N
TFE, 40 °C, 24 h
O
(S)-Levetiracetam
4cc
20%, d.r. ~1:1
O
COOH
H
N
N
CN
NH2
CH2O
TFE, reflux, 6 h
O
4dd (Nefiracetam)
39%
O
O
H
iPr2NCH2CH2NH2
H
N
N
N
N
N
110 °C, 11 h
N
O
O
Br
4o
4ee (Pramiracetam)
quant. conversion (not isolated)
O
O
AcCl
H
other
racetams
N
N
N
OEt
EtOH, rt, 24 h
N
O
O
Br
4o
6
70%
Scheme 4 Synthesis of clinically important racetams
tion sequences. Typical problems of the conventional route
are avoided, allowing the generation of a broad range of
racetam derivatives, including examples that are challeng-
ing using traditional methods.
Finally, this Ugi type reaction was exploited to synthe-
size racetams in combination with the convertible isocya-
nide 2-bromo-6-isocyanopyridine:20 Pramiracetam 4ee
could be obtained by heating Ugi product 4o with the req-
uisite primary amine,27 whereas ester 6, the general inter-
mediate in the preparation of racetams, was accessed by
acid-mediated solvolysis of 4o.2c Given the high versatility
of the conversion of Ugi products derived from the convert-
ible isocyanide,20 this approach provides rapid access to a
large number of racetam derivatives, allowing extensive
variation at the α-position of the 2-oxo-pyrrolidino acet-
amide as well as the primary amide side (see also 4f,
Scheme 3).
Unless stated otherwise, all solvents and commercially available re-
agents were used as purchased. Cyclohexane was distilled prior to
use. 2,2,2-Trifluoroethanol was flushed with nitrogen upon storing.
Reactions were performed under nitrogen atmosphere. Melting
points were recorded with a Büchi M-565 melting point apparatus
and are uncorrected. NMR spectra were recorded with a Bruker
Avance 500 (125.78 MHz for 13C) or Bruker Avance 400 (100.62 MHz
for 13C) using the residual solvent as internal standard (1H: δ = 7.26
ppm, 13C{1H}: δ = 77.16 ppm for CDCl3, 1H: δ = 2.50 ppm, 13C{1H}: δ =
39.52 ppm for DMSO-d6 and 1H: δ = 3.31 ppm, 13C{1H}: δ = 49.00 ppm
for CD3OD). Chemical shifts (δ) are given in ppm and coupling con-
stants (J) are quoted in hertz (Hz). Resonances are described as s (sin-
glet), d (doublet), t (triplet), q (quartet), quint (quintet), sext (sextet),
sept (septet), br (broad), and m (multiplet) or combinations thereof.
IR spectra were recorded neat with a Shimadzu FTIR-8400s spectro-
photometer and wavelengths are reported in cm–1. Electrospray ion-
ization (ESI) high-resolution mass spectrometry (HRMS) was carried
out with a Bruker microTOF-Q instrument in positive ion mode (cap-
illary potential of 4500 V). Flash chromatography was performed on
In summary, we have developed a novel, direct multi-
component synthesis of racetam derivatives. The Ugi 4C-
3CR condensation with γ-aminobutyric acid is a simple, re-
source-efficient, and general way to access clinically rele-
vant small molecules in a single step or through short reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

E
R. C. Cioc et al.
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Synthesis
Silicycle Silia-P Flash Silica Gel (particle size 40–63 μm, pore diameter
60 Å) using the indicated eluent. Thin-layer chromatography (TLC)
was performed using TLC plates from Merck (SiO2, Kieselgel 60 F254
neutral, on aluminum with fluorescence indicator). N-[2-(Diisopro-
pylamino)ethyl]formamide was synthesized by reacting N,N-diiso-
propylethane-1,2-diamine with ethyl formate; N-(2-isocyanoethyl)-
N-isopropylpropan-2-amine was synthesized by dehydrating the cor-
responding formamide with POCl3/NEt3. 2-Bromo-6-isocyanopyri-
dine was prepared as described previously.20
IR (neat): 3294 (s), 3074 (m), 2958 (s), 2360 (m), 1649 (s), 1550 (s),
1444 (s), 1390 (s), 1357 (s), 1303 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.06 (br, 1 H), 4.25 (dd, J = 8.5, 6.9 Hz,
1 H), 3.44–3.37 (m, 1 H), 3.36–3.29 (m, 1 H), 2.41–2.27 (m, 2 H), 2.01–
1.90 (m, 2 H), 1.89–1.79 (m, 1 H), 1.63–1.52 (m, 1 H), 1.24 (s, 9 H),
0.80 (t, J = 7.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 175.8 (C), 169.3 (C), 57.1 (CH), 51.2
(C), 43.8 (CH2), 31.2 (CH2), 28.7 (CH3), 21.3 (CH2), 18.3 (CH2), 10.6
(CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H22N2NaO2: 249.1573; found:
249.1563.
General Procedure A
To a solution of γ-aminobutyric acid (1.0 mmol, 1 equiv) in 2,2,2-tri-
fluoroethanol (10 mL) were added the aldehyde (1.0 mmol, 1 equiv)
and the isocyanide (1.0 mmol, 1 equiv). Unless otherwise indicated,
the mixture was stirred and heated at 40 °C for 24 h. The solution was
then concentrated in vacuo and the product was isolated by column
chromatography on silica gel.
3-(Benzyloxy)-N-(naphthalen-2-yl)-2-(2-oxopyrrolidin-1-yl)pro-
panamide (4c)
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), ben-
zyloxyacetaldehyde (150 mg, 1.0 mmol, 1 equiv) and 2-naphthyl iso-
cyanide (156 mg, 1.0 mmol, 1 equiv) according to General Procedure
A. The product was purified by column chromatography on silica gel
(cyclohexane/EtOAc, 10:1 to 100% EtOAc).
General Procedure B
To a solution of γ-aminobutyric acid (1.0 mmol, 1 equiv) in 2,2,2-tri-
fluoroethanol (10 mL) were added the aldehyde (1.0 mmol, 1 equiv)
and the isocyanide (1.0 mmol, 1 equiv). The mixture was heated at
reflux for 3 h, then concentrated and redissolved in trifluoroacetic
acid (3 mL). This solution was heated at reflux for 1 h. The reaction
mixture was then concentrated in vacuo and the product was isolated
by column chromatography on silica gel.
Yield: 191 mg (0.492 mmol, 49%); brown solid; mp 101–111 °C; Rf =
0.30 (cyclohexane/EtOAc, 1:1).
IR (neat): 3263 (m), 2900 (m), 2868 (m), 2358 (s), 1666 (s), 1631 (s),
1585 (s), 1544 (s), 1502 (s), 1433 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.65 (s, 1 H), 8.31 (d, J = 2.0 Hz, 1 H),
7.80–7.71 (m, 3 H), 7.53 (dd, J = 8.8, 1.9 Hz, 1 H), 7.48–7.27 (m, 7 H),
5.25 (dd, J = 8.2, 6.0 Hz, 1 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.52 (d, J =
11.7 Hz, 1 H), 4.03–3.92 (m, 2 H), 3.76–3.68 (m, 1 H), 3.53–3.45 (m,
1 H), 2.52–2.45 (m, 2 H), 2.14–1.96 (m, 2 H).
N-(tert-Butyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)pentanamide
(4a)
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), 3-
methylbutanal (86 mg, 1.0 mmol, 1 equiv) and tert-butyl isocyanide
(83 mg, 1.0 mmol, 1 equiv) according to General Procedure A. The
product was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc, 10:1 to 1:1).
13C NMR (125 MHz, CDCl3): δ = 176.7 (C), 167.1 (C), 137.4 (C), 135.4
(C), 133.7 (C), 130.5 (C), 128.5 (CH), 128.4 (CH), 127.9 (CH), 127.8
(CH), 127.6 (CH), 127.5 (CH), 126.4 (CH), 124.9 (CH), 120.0 (CH), 116.7
(CH), 73.1 (CH2), 66.8 (CH2), 55.2 (CH), 44.8 (CH2), 31.0 (CH2), 18.2
(CH2).
Yield: 167 mg (0.621 mmol, 62%); white solid; mp 148–151 °C; Rf =
0.29 (cyclohexane/EtOAc, 1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C24H24N2NaO3: 411.1679; found:
411.1665.
IR (neat): 3300 (s), 2952 (m), 2871 (m), 2362 (m), 1651 (s), 1552 (s),
1444 (s), 1388 (s), 1290 (s), 1224 (s) cm–1
.
N-Benzyl-3-methyl-2-(2-oxopyrrolidin-1-yl)butanamide (4d)
1H NMR (500 MHz, CDCl3): δ = 6.00 (br, 1 H), 4.45 (dd, J = 9.1, 6.6 Hz,
1 H), 3.43–3.27 (m, 2 H), 2.41–2.26 (m, 2 H), 2.02–1.87 (m, 2 H), 1.66–
1.50 (m, 2 H), 1.43–1.32 (m, 1 H), 1.24 (s, 9 H), 0.87 (d, J = 6.6 Hz, 3 H),
0.84 (d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 175.6 (C), 169.5 (C), 53.7 (CH), 51.2
(C), 43.8 (CH2), 36.6 (CH2), 31.3 (CH2), 28.7 (CH3), 24.8 (CH), 23.0
(CH3), 22.0 (CH3), 18.3 (CH2).
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv),
isobutyraldehyde (72 mg, 1.0 mmol, 1 equiv) and benzyl isocyanide
(117 mg, 1.0 mmol, 1 equiv) according to General Procedure A. The
product was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc, 1:4; Rf = 0.33).
Yield: 165 mg (0.60 mmol, 60%); colorless oil.
IR (neat): 3300 (w), 2968 (w), 1657 (s), 1529 (s), 1229 (m), 698
HRMS (ESI): m/z [M + Na]+ calcd for C14H26N2NaO2: 277.1886; found:
(s) cm–1
.
277.1873.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.10 (m, 6 H), 4.48 (dd, J = 15.0,
6.0 Hz, 1 H), 4.32 (dd, J = 15.0, 6.0 Hz, 1 H), 4.15 (d, J = 11.0 Hz, 1 H),
3.56 (q, J = 7.5 Hz, 1 H), 3.41 (q, J = 7.5 Hz, 1 H), 2.39–2.18 (m, 3 H),
1.98 (quint, J = 7.0 Hz, 2 H), 0.97 (d, J = 7.0 Hz, 3 H), 0.84 (d, J = 7.0 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 175.8 (C), 169.4 (C), 138.3 (C), 128.6
(CH), 127.7 (CH), 127.4 (CH), 62.0 (CH), 44.4 (CH2), 43.3 (CH2), 31.1
(CH2), 26.5 (CH), 19.5 (CH3), 18.9 (CH3), 18.3 (CH2).
N-(tert-Butyl)-2-(2-oxopyrrolidin-1-yl)butanamide (4b)
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), pro-
pionaldehyde (58 mg, 1.0 mmol, 1 equiv) and tert-butyl isocyanide
(83 mg, 1.0 mmol, 1 equiv) according to General Procedure A. The
product was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc, 10:1 to 100% EtOAc).
Yield: 80 mg (0.355 mmol, 36%); white solid; mp 99–104 °C; Rf = 0.19
(cyclohexane/EtOAc, 1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C16H22N2NaO2: 297.1573; found:
297.1565.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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Synthesis
3-Methyl-N-(naphthalen-2-yl)-2-(2-oxopyrrolidin-1-yl)butan-
amide (4e)
1H NMR (500 MHz, CDCl3): δ = 7.02 (t, J = 4.7 Hz, 1 H), 3.99 (dd, J =
18.0, 5.7 Hz, 1 H), 3.88 (dd, J = 18.0, 5.7 Hz, 1 H), 3.75 (d, J = 10.4 Hz,
1 H), 3.66 (s, 3 H), 3.58–3.53 (m, 2 H), 2.36 (t, J = 7.9 Hz, 2 H), 2.08–
1.93 (m, 2 H), 1.36–1.24 (m, 1 H), 0.74–0.66 (m, 1 H), 0.55–0.42 (m,
2 H), 0.26–0.19 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 175.8 (C), 170.2 (C), 190.1 (C), 59.8
(CH3), 52.3 (CH), 44.5 (CH2), 41.0 (CH2), 30.9 (CH2), 18.1 (CH2), 10.2
(CH), 5.3 (CH2), 2.9 (CH2).
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv),
isobutyraldehyde (72 mg, 1.0 mmol, 1 equiv) and 2-naphthyl isocya-
nide (153 mg, 1.0 mmol, 1 equiv) according to General Procedure A.
The product was purified by column chromatography on silica gel
(cyclohexane/EtOAc, 10:1 to 100% EtOAc).
Yield: 213 mg (0.686 mmol, 69%); mp 160–165 °C; brown solid; Rf =
0.36 (cyclohexane/EtOAc, 1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C12H18N2NaO4: 277.1159; found:
277.1150.
IR (neat): 3265 (s), 2958 (s), 2364 (m), 1658 (s), 1631 (s), 1585 (s),
1552 (s), 1502 (s), 1434 (s), 1350 (s) cm–1
.
N-{(1H-Benzo[d][1,2,3]triazol-1-yl)methyl}-2-cyclohexyl-2-(2-
oxopyrrolidin-1-yl)acetamide (4h)
1H NMR (500 MHz, CDCl3): δ = 9.68 (br, 1 H), 8.37 (s, 1 H), 7.85–7.69
(m, 3 H), 7.58 (d, J = 8.2 Hz, 1 H), 7.44 (t, J = 6.9 Hz, 1 H), 7.38 (t, J =
6.9 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 3.83–3.73 (m, 1 H), 3.59–3.50
(m, 1 H), 2.57–2.40 (m, 3 H), 2.13–1.98 (m, 2 H), 1.09 (d, J = 6.6 Hz,
3 H), 0.94 (d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.0 (C), 168.4 (C), 135.8 (C), 133.8
(C), 130.6 (C), 128.5 (CH), 127.7 (CH), 127.5 (CH), 126.4 (CH), 124.9
(CH), 120.1 (CH), 116.7 (CH), 63.0 (CH), 44.8 (CH2), 31.4 (CH2), 27.1
(CH), 19.5 (CH3), 19.1 (CH3), 18.4 (CH2).
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), cy-
clohexanecarboxaldehyde (112 mg, 1.0 mmol, 1 equiv) and 1H-ben-
zotriazol-1-ylmethyl isocyanide (159 mg, 1.0 mmol, 1 equiv) accord-
ing to General Procedure A. The product was purified by column chro-
matography on silica gel (cyclohexane/EtOAc, 1:2 to EtOAc/MeOH,
9:1).
Yield: 158 mg (0.445 mmol, 45%); yellow solid; mp 88–93 °C; Rf =
0.13 (cyclohexane/EtOAc, 1:2).
HRMS (ESI): m/z [M + Na]+ calcd for C19H22N2NaO2: 333.1573; found:
IR (neat): 3271 (m), 2923 (s), 2850 (s), 2362 (s), 1658 (s), 1546 (s),
333.1573.
1492 (s), 1421 (s), 1286 (s), 1271 (s) cm–1
.
N-(6-Bromopyridin-2-yl)-3-methyl-2-(2-oxopyrrolidin-1-yl)but-
anamide (4f)
1H NMR (500 MHz, CDCl3): δ = 8.99 (t, J = 6.3 Hz, 1 H), 7.97 (d, J =
8.2 Hz, 1 H), 7.82 (d, J = 8.5 Hz, 1 H), 7.45–7.40 (m, 1 H), 7.34–7.29 (m,
1 H), 6.09 (dd, J = 13.9, 6.9 Hz, 1 H), 5.95 (dd, J = 13.9, 6.9 Hz, 1 H),
4.29 (d, J = 11.0 Hz, 1 H), 3.46–3.38 (m, 1 H), 3.35–3.28 (m, 1 H), 2.37–
2.28 (m, 1 H), 2.24–2.15 (m, 1 H), 1.97–1.78 (m, 3 H), 1.63–1.43 (m,
3 H), 1.42–1.32 (m, 2 H), 1.15–1.04 (m, 2 H), 1.03–0.92 (m, 1 H), 0.79–
0.65 (m, 2 H).
Prepared from γ-aminobutyric acid (52 mg, 0.5 mmol, 1 equiv),
isobutyraldehyde (36 mg, 0.5 mmol, 1 equiv) and 2-bromo-6-isocy-
anopyridine (92 mg, 0.5 mmol, 1 equiv) according to General Proce-
dure A. The product was purified by column chromatography on sili-
ca gel (cyclohexane/EtOAc, 2:1; Rf = 0.25).
13C NMR (125 MHz, CDCl3): δ = 176.1 (C), 170.3 (C), 146.0 (C), 132.2
(C), 127.6 (CH), 124.2 (CH), 119.6 (CH), 110.7 (CH), 60.0 (CH), 50.9
(CH2), 44.4 (CH2), 35.3 (CH), 31.0 (CH2), 29.6 (CH2), 29.0 (CH2), 26.1
(CH2), 25.4 (CH2), 25.3 (CH2), 18.2 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C19H25N5NaO2: 378.1900; found:
378.1885.
Yield: 112 mg (0.329 mmol, 66%); green solid; mp 147–152 °C.
IR (neat): 3209 (w), 2964 (w), 1650 (s), 1568 (s), 1529 (s), 1427 (s),
1388 (s), 1124 (s), 784 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.51 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H),
7.42 (t, J = 7.5 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H), 4.51 (d, J = 11.0 Hz,
1 H), 3.71–3.60 (m, 1 H), 3.53–3.39 (m, 1 H), 2.62–2.43 (m, 2 H), 2.42–
2.27 (m, 1 H), 2.14–1.95 (m, 2 H), 1.04 (d, J = 6.0 Hz, 3 H), 0.92 (d, J =
6.0 Hz, 3 H).
3,3-Dimethyl-2-(2-oxopyrrolidin-1-yl)-N-pentylbutanamide (4i)
Prepared from γ-aminobutyric acid (104 mg, 1.0 mmol, 1 equiv), piv-
alaldehyde (86 mg, 1.0 mmol, 1 equiv) and 1-pentyl isocyanide (97
mg, 1.0 mmol, 1 equiv) according to General Procedure A. The prod-
uct was purified by column chromatography on silica gel (cyclohex-
ane/EtOAc, 20:1 to 1:1).
13C NMR (125 MHz, CDCl3): δ = 176.6 (C), 168.9 (C), 151.5 (C), 140.3
(CH), 139.5 (C), 123.6 (CH), 112.5 (CH), 62.6 (CH), 44.5 (CH2), 31.3
(CH2), 26.9 (CH), 19.6 (CH3), 19.0 (CH3), 18.5 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H18BrN3NaO2: 362.0475;
found: 362.0469.
Yield: 189 mg (0.705 mmol, 71%); white solid; mp 42–48 °C; Rf = 0.18
(cyclohexane/EtOAc, 1:1).
Methyl [2-Cyclopropyl-2-(2-oxopyrrolidin-1-yl)acetyl]glycinate
(4g)
IR (neat): 3305 (m), 2956 (s), 2931 (s), 2871 (s), 2360 (m), 1651 (s),
1546 (s), 1421 (s), 1365 (s), 1284 (s) cm–1
.
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), cy-
clopropanecarboxaldehyde (70 mg, 1.0 mmol, 1 equiv) and methyl
isocyanoacetate (99 mg, 1.0 mmol, 1 equiv) according to General Pro-
cedure A. The product was purified by column chromatography on
silica gel (cyclohexane/EtOAc, 1:1 to EtOAc/MeOH 9:1).
1H NMR (500 MHz, CDCl3): δ = 7.22 (t, J = 5.0 Hz, 1 H), 4.40 (s, 1 H),
3.76–3.68 (m, 1 H), 3.66–3.58 (m, 1 H), 3.21–3.12 (m, 1 H), 3.00–2.91
(m, 1 H), 2.31–2.14 (m, 2 H), 1.86 (quint, J = 7.6 Hz, 2 H), 1.37 (quint,
J = 7.3 Hz, 2 H), 1.24–1.12 (m, 4 H), 0.94 (s, 9 H), 0.76 (t, J = 6.9 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 175.8 (C), 168.7 (C), 62.4 (CH), 47.4
(CH2), 39.0 (CH2), 34.7 (C), 30.9 (CH2), 29.0 (CH2), 28.9 (CH2), 27.6
(CH3), 22.2 (CH2), 19.0 (CH2), 13.9 (CH3).
Yield: 126 mg (0.494 mmol, 49%); orange solid; mp 104–115 °C; Rf =
0.38 (EtOAc/MeOH, 9:1).
IR (neat): 3186 (m), 2939 (s), 2362 (s), 1753 (s), 1651 (s), 1546 (s),
1440 (s), 1400 (s), 1359 (s), 1309 (s) cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C15H28N2NaO2: 291.2043; found:
291.2031.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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R. C. Cioc et al.
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Synthesis
N-(2,6-Dimethylphenyl)-3,3-dimethyl-2-(2-oxopyrrolidin-1-yl)bu-
tanamide (4j)
13C NMR (125 MHz, CDCl3): δ = 175.7 (C), 166.9 (C), 55.1 (C), 51.2
(CH2), 48.4 (CH2), 48.0 (CH2), 31.5 (C), 31.3 (CH3), 30.4 (CH2), 29.1
(CH3), 17.9 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H26N2NaO2: 277.1886; found:
277.1893.
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), piv-
alaldehyde (86 mg, 1.0 mmol, 1 equiv) and 2,6-dimethylphenyl isocy-
anide (131 mg, 1.0 mmol, 1 equiv) according to General Procedure A.
The product was purified by column chromatography on silica gel
(cyclohexane/EtOAc, 2:1; Rf = 0.17).
N-(6-Bromopyridin-2-yl)-2-(2-oxopyrrolidin-1-yl)acetamide (4o)
Yield: 139 mg (0.46 mmol, 46%); white solid; mp 147–155 °C.
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv),
paraformaldehyde (30 mg, 1.0 mmol, 1 equiv) and 2-bromo-6-isocy-
anopyridine (183 mg, 1.0 mmol, 1 equiv) according to General Proce-
dure A. The product was purified by column chromatography on sili-
ca gel (cyclohexane/EtOAc, 1:1 to 1:3, Rf = 0.13).
IR (neat): 3169 (w), 2957 (w), 1655 (s), 1533 (m), 1161 (m), 770
(s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.10–6.97 (s, 3 H), 4.73 (s,
1 H), 3.86–3.65 (m, 2 H), 2.46–2.23 (m, 2 H), 2.18 (s, 6 H), 2.04–1.85
(m, 2 H), 1.16 (s, 9 H).
Yield: 143 mg (0.48 mmol, 48%); green solid; mp 168–170 °C.
13C NMR (125 MHz, CDCl3): δ = 176.3 (C), 167.6 (C), 135.2 (C), 134.0
(C), 128.2 (CH), 127.1 (CH), 62.6 (CH), 47.3 (C), 35.2 (CH2), 30.9 (CH2),
27.8 (CH3), 19.3 (CH2), 18.7 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C18H26N2NaO2: 325.1886; found:
325.1879.
IR (neat): 3034 (w), 2945 (w), 1672 (s), 1571 (s), 1427 (s), 1288 (s),
1126 (s), 791 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.82 (s, 1 H), 8.09 (d, J = 8.0 Hz, 1 H),
7.52 (t, J = 8.0 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 1 H), 4.16 (s, 2 H), 3.56 (t, J =
7.0 Hz, 2 H), 2.52 (t, J = 8.0 Hz, 2 H), 2.14 (quint, J = 7.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 176.8 (C), 167.1 (C), 151.1 (C), 140.7
(CH), 139.5 (C), 124.0 (CH), 112.6 (CH), 48.6 (CH2), 47.7 (CH2), 30.4
(CH2), 18.1 (CH2).
3,3-Dimethyl-2-(2-oxopyrrolidin-1-yl)-N-(tosylmethyl)butan-
amide (4k)
HRMS (ESI): m/z [M + Na]+ calcd for C11H12BrN3NaO2: 320.0005;
found: 320.0004.
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), piv-
alaldehyde (86 mg, 1.0 mmol, 1 equiv) and tosylmethyl isocyanide
(195 mg, 1.0 mmol, 1 equiv) according to General Procedure A. The
product was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc, 1:2; Rf = 0.36).
N-Isopropyl-2-(2-oxopyrrolidin-1-yl)-2-phenylacetamide (4q)
Prepared from γ-aminobutyric acid (104 mg, 1.0 mmol, 1 equiv),
benzaldehyde (106 mg, 1.0 mmol, 1 equiv) and isopropyl isocyanide
(69 mg, 1.0 mmol, 1 equiv) according to General Procedure A. The
product was purified by column chromatography on silica gel (cyclo-
hexane/EtOAc, 10:1 to 100% EtOAc).
Yield: 238 mg (0.65 mmol, 65%); white solid; mp 182–192 °C.
IR (neat): 3200 (w), 2959 (w), 1655 (s), 1547 (w), 1315 (m), 1140 (s),
567 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.81 (s, 1 H), 7.79 (d, J = 8.0 Hz, 2 H),
7.34 (d, J = 8.0 Hz, 2 H), 4.94 (dd, J = 14.0, 7.0 Hz, 1 H), 4.70 (s, 1 H),
4.43 (dd, J = 14.0, 7.0 Hz, 1 H), 3.53–3.47 (m, 1 H), 3.11–3.05 (m, 1 H),
2.56–2.47 (m, 1 H), 2.44–2.35 (m, 1 H), 2.40 (s, 3 H), 1.95–1.86 (m,
1 H), 1.86–1.77 (m, 1 H), 0.93 (s, 9 H).
Yield: 109 mg (0.417 mmol, 42%); white solid; mp 148–151 °C; Rf =
0.36 (EtOAc).
IR (neat): 3265 (s), 2970 (s), 2360 (m), 1666 (s), 1643 (s), 1556 (s),
1431 (s), 1417 (s), 1365 (s), 1284 (s) cm–1
.
13C NMR (125 MHz, CDCl3): δ = 176.7 (C), 168.6 (C), 145.0 (C), 134.2
(C), 129.9 (CH), 129.2 (CH), 61.9 (CH), 59.9 (CH2), 47.3 (CH2), 35.7 (C),
30.8 (CH2), 27.5 (CH3), 21.8 (CH3), 18.8 (CH2).
1H NMR (500 MHz, CDCl3): δ = 7.35–7.21 (m, 5 H), 6.50 (d, J = 7.3 Hz,
1 H), 5.86 (s, 1 H), 4.08–3.97 (m, 1 H), 3.83–3.74 (m, 1 H), 2.99–2.91
(m, 1 H), 2.40–2.22 (m, 2 H), 2.02–1.91 (m, 1 H), 1.84–1.73 (m, 1 H),
1.07 (d, J = 6.3 Hz, 3 H), 1.05 (d, J = 6.3 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H27N2O4S: 367.1686; found:
13C NMR (125 MHz, CDCl3): δ = 175.3 (C), 168.3 (C), 135.2 (C), 128.8
(CH), 128.7 (CH), 128.3 (CH), 58.4 (CH), 45.0 (CH2), 41.6 (CH), 31.1
(CH2), 22.4 (CH3), 18.1 (CH2).
367.1683.
2-(2-Oxopyrrolidin-1-yl)-N-(2,4,4-trimethylpentan-2-yl)acet-
amide (4n)
HRMS (ESI): m/z [M + Na]+ calcd for C15H20N2NaO2: 283.1417; found:
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv),
paraformaldehyde (30 mg, 1.0 mmol, 1 equiv) and 1,1,3,3-tetrameth-
ylbutyl isocyanide (139 mg, 1.0 mmol, 1 equiv) according to General
Procedure A (reflux, 3 h reaction time). The product was purified by
column chromatography on silica gel (100% EtOAc to EtOAc/MeOH,
19:1).
283.1411.
N-Cyclohexyl-2-(4-methoxyphenyl)-2-(2-oxopyrrolidin-1-yl)acet-
amide (4r)
Prepared from γ-aminobutyric acid (104 mg, 1.0 mmol, 1 equiv), p-
methoxybenzaldehyde (136 mg, 1.0 mmol, 1 equiv) and cyclohexyl
isocyanide (109 mg, 1.0 mmol, 1 equiv) according to General Proce-
dure A. The product was purified by column chromatography on sili-
ca gel (cyclohexane/EtOAc, 10:1 to 100% EtOAc).
Yield: 148 mg (0.582 mmol, 58%); colorless oil; Rf = 0.52 (EtOAc/
MeOH, 19:1).
IR (neat): 3310 (w), 2951 (w), 1659 (s), 1551 (m), 920 (w), 731
(m) cm–1
.
Yield: 111 mg (0.336 mmol, 34%); white solid; mp 139–143 °C; Rf =
1H NMR (500 MHz, CDCl3): δ = 6.14 (s, 1 H), 3.72 (s, 2 H), 3.41 (t, J =
7.0 Hz, 2 H), 2.31 (t, J = 8.0 Hz, 2 H), 1.96 (quint, J = 7.0 Hz, 2 H), 1.62
(s, 2 H), 1.72 (s, 6 H), 0.87 (s, 9 H).
0.12 (cyclohexane/EtOAc, 1:1).
IR (neat): 3255 (s), 2931 (s), 2852 (s), 2358 (m), 1651 (s), 1608 (s),
1546 (s), 1512 (s), 1438 (s), 1365 (s) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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R. C. Cioc et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.21 (d, J = 8.5 Hz, 2 H), 6.83 (d, J =
8.5 Hz, 2 H), 6.22 (d, J = 7.9 Hz, 1 H), 5.77 (s, 1 H), 3.75 (s, 3 H), 3.79–
3.66 (m, 2 H), 2.97 (td, J = 8.8, 5.7 Hz, 1 H), 2.42–2.33 (m, 1 H), 2.32–
2.23 (m, 1 H), 2.03–1.92 (m, 1 H), 1.87–1.74 (m, 3 H), 1.67–1.57 (m,
2 H), 1.53 (dt, J = 12.6, 3.5 Hz, 1 H), 1.34–1.21 (m, 2 H), 1.12–0.96 (m,
3 H).
13C NMR (125 MHz, CDCl3): δ = 175.3 (C), 168.5 (C), 159.5 (C), 130.2
(CH), 127.1 (C), 114.1 (CH), 57.9 (CH), 55.3 (CH3), 48.5 (CH), 44.9
(CH2), 32.7 (CH2), 31.2 (CH2), 25.5 (CH2), 24.8 (CH2), 18.1 (CH2).
Methyl [2-(2-oxopyrrolidin-1-yl)-2-(pyridin-3-yl)acetyl]glycinate
(4u)
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), nic-
otinaldehyde (107 mg, 1.0 mmol, 1 equiv) and methyl isocyanoace-
tate (99 mg, 1.0 mmol, 1 equiv) according to General Procedure A. The
product was purified by column chromatography on silica gel (EtOAc/
MeOH, 9:1; Rf = 0.23).
Yield: 118 mg (0.404 mmol, 40%); gummy yellow solid.
IR (neat): 3294 (w), 2955 (w), 1749 (m), 1659 (s), 1416 (m), 1204 (s),
HRMS (ESI): m/z [M + Na]+ calcd for C19H26N2NaO3: 353.1836; found:
353.1820.
714 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.56–8.48 (m, 2 H), 7.77 (d, J = 7.5 Hz,
1 H), 7.38 (br, 1 H), 7.30 (t, J = 5.0 Hz, 1 H), 6.0 (s, 1 H), 4.10–3.96 (m,
2 H), 3.80–3.64 (m, 4 H), 3.10–3.00 (m, 1 H), 2.50–2.29 (m, 2 H), 2.14–
2.00 (m, 1 H), 2.00–1.84 (m, 1 H).
2-(2-Oxopyrrolidin-1-yl)-N-pentyl-2-[4-(trifluoromethyl)phe-
nyl]acetamide (4s)
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), p-
trifluoromethylbenzaldehyde (174 mg, 1.0 mmol, 1 equiv) and 1-
pentyl isocyanide (97 mg, 1.0 mmol, 1 equiv) according to General
Procedure A. The product was purified by column chromatography on
silica gel (cyclohexane/EtOAc, 15:1 to 100% EtOAc).
13C NMR (125 MHz, CDCl3): δ = 176.0 (C), 170.1 (C), 168.8 (C), 150.4
(CH), 149.8 (CH), 136.9 (CH), 130.5 (C), 123.7 (CH), 56.3 (CH), 52.5
(CH3), 44.9 (CH2), 41.3 (CH2), 30.9 (CH2), 18.2 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H18N3NaO4: 314.1108; found:
314.1104.
Yield: 145 mg (0.406 mmol, 41%); white solid; mp 84–88 °C; Rf = 0.47
(cyclohexane/EtOAc, 1:1).
2-(2-Oxopyrrolidin-1-yl)-2-(pyridin-4-yl)-N-(2,4,4-trimethyl-
pentan-2-yl)acetamide (4v)
IR (neat): 3253 (m), 2927 (s), 2360 (m), 1679 (s), 1672 (s), 1649 (s),
1552 (s), 1421 (s), 1325 (s), 1286 (s) cm–1
.
Prepared from γ-aminobutyric acid (104 mg, 1.0 mmol, 1 equiv), 4-
pyridinecarboxaldehyde (107 mg, 1.0 mmol, 1 equiv) and 1,1,3,3-te-
tramethylbutyl isocyanide (139 mg, 1.0 mmol, 1 equiv) according to
General Procedure A. The product was purified by column chroma-
tography on silica gel (cyclohexane/EtOAc, 1:2, to EtOAc/MeOH, 9:1).
1H NMR (500 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2 H), 7.43 (d, J =
8.2 Hz, 2 H), 7.08 (t, J = 5.0 Hz, 1 H), 6.00 (s, 1 H), 3.86–3.77 (m, 1 H),
3.29–3.20 (m, 1 H), 3.19–3.11 (m, 1 H), 3.08–3.01 (m, 1 H), 2.44–2.27
(m, 2 H), 2.08–1.97 (m, 1 H), 1.93–1.82 (m, 1 H), 1.44 (quint, J =
7.3 Hz, 2 H), 1.31–1.16 (m, 4 H), 0.83 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 175.7 (C), 168.5 (C), 139.2 (C), 130.5
(q, JC–F = 33 Hz, C ), 129.1 (CH), 125.8 (q, JC–F = 4, CH), 124.0 (q, JC–F
270, C), 58.0 (CH), 45.1 (CH2), 39.7 (CH2), 31.0 (CH2), 29.1 (CH2), 29.0
(CH2), 22.3 (CH2), 18.2 (CH2), 14.0 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C18H23F3N2NaO2: 379.1604;
Yield: 165 mg (0.499 mmol, 50%); white solid; mp 165–173 °C; Rf =
0.45 (EtOAc/MeOH, 9:1).
=
IR (neat): 3276 (s), 2964 (s), 2362 (m), 1654 (s), 1598 (s), 1556 (s),
1436 (s), 1382 (s), 1359 (s), 1259 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.51 (d, J = 6.0 Hz, 2 H), 7.18 (d, J =
6.0 Hz, 2 H), 6.73 (br, 1 H), 5.83 (s, 1 H), 3.79–3.71 (m, 1 H), 3.09–3.02
(m, 1 H), 2.41–2.26 (m, 2 H), 2.05–1.95 (m, 1 H), 1.92–1.83 (m, 1 H),
1.81 (d, J = 14.8 Hz, 1 H), 1.53 (d, J = 14.8 Hz, 1 H), 1.35 (s, 3 H), 1.32 (s,
3 H), 0.87 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 175.5 (C), 166.7 (C), 150.2 (CH), 144.2
(C), 123.4 (CH), 57.9 (CH), 55.8 (C), 51.4 (CH2), 45.1 (CH2), 31.6 (CH2),
31.3 (CH3), 30.8 (C), 29.2 (CH3), 28.7 (CH3), 18.3 (CH2).
found: 379.1588.
N-Cyclohexyl-2-(2-oxopyrrolidin-1-yl)-2-[2-(trifluoromethyl)phe-
nyl]acetamide (4t)
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), 2-
trifluoromethylbenzaldehyde (174 mg, 1.0 mmol, 1 equiv) and cyclo-
hexyl isocyanide (109 mg, 1.0 mmol, 1 equiv) according to General
Procedure A. The product was purified by column chromatography on
silica gel (cyclohexane/EtOAc, 1:1 to 1:2).
HRMS (ESI): m/z [M + Na]+ calcd for C19H29N3NaO2: 354.2152; found:
354.2137.
Yield: 169 mg (0.46 mmol, 46%); white solid; mp 160–165 °C; Rf =
0.26 (cyclohexane/EtOAc, 1:1).
N-Isopropyl-1-(2-oxopyrrolidin-1-yl)cyclohexane-1-carboxamide
(4x)
IR (neat): 3254 (w), 2932 (w), 1664 (s), 1439 (m), 1313 (m), 1124 (s),
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), cy-
clohexanone (98 mg, 1.0 mmol, 1 equiv) and isopropyl isocyanide (69
mg, 1.0 mmol, 1 equiv) according to General Procedure A. The prod-
uct was purified by column chromatography on silica gel (cyclohex-
ane/EtOAc, 1:4; Rf = 0.23).
1040 (m), 779 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.70 (t, J = 8.0 Hz, 2 H), 7.55 (t, J =
7.0 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 5.97 (s, 1 H), 5.74 (d, J = 6.5 Hz,
1 H), 3.80–3.68 (m, 1 H), 3.68–3.57 (m, 1 H), 2.91–2.78 (m, 1 H), 2.48–
2.29 (m, 2 H), 2.08–1.94 (m, 1 H), 1.92–1.76 (m, 3 H), 1.71–1.45 (m,
3 H), 1.36–0.87 (m, 5 H).
Yield: 97 mg (0.385 mmol, 38%); colorless oil.
IR (neat): 3300 (w), 2930 (m), 1668 (s), 1639 (s), 1535 (m), 1256 (m),
13C NMR (125 MHz, CDCl3): δ = 175.1 (C), 168.1 (C), 133.1 (C), 132.1
642 (w) cm–1
.
(CH), 131.2 (CH), 129.8 (q, JC–F = 30 Hz, C), 129.0 (CH), 126.8 (q, JC–F
=
1H NMR (500 MHz, CDCl3): δ = 6.65 (d, J = 8.0 Hz, 1 H), 3.97 (sept, J =
7.5 Hz, 1 H), 3.41 (t, J = 7.0 Hz, 2 H), 2.35 (t, J = 8.0 Hz, 2 H), 2.30–2.17
(m, 2 H), 2.03–1.85 (m, 4 H), 1.62–1.50 (m, 2 H), 1.49–1.30 (m, 4 H),
1.08 (d, J = 6.5 Hz, 6 H).
6 Hz, CH), 124.0 (q, JC–F = 275 Hz, C), 55.5 (CH), 48.9 (C), 45.7 (CH2),
32.8 (CH2), 32.6 (CH2), 31.0 (CH2), 25.5 (CH2), 24.8 (CH2), 24.7 (CH2),
18.3 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C19H24F3N2O2: 369.1784; found:
369.1785.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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R. C. Cioc et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3): δ = 177.7 (C), 172.2 (C), 63.6 (C), 46.3
(CH2), 41.4 (CH), 33.1 (CH2), 32.4 (CH2), 25.3 (CH2), 22.7 (CH3), 22.6
(CH2), 18.1 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H24N2NaO2: 275.1730; found:
275.1724.
cedure A. The product was purified by column chromatography on
silica gel (EtOAc/MeOH, 9:1; Rf = 0.31).
Yield: 90 mg (0.53 mmol, 53%); brown crystals; mp 63–90 °C.
IR (neat): 3379 (w), 2966 (w), 1650 (s), 1421 (m), 1269 (m), 1204 (m),
1130 (m), 611 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.55 (s, 1 H), 5.88 (s, 1 H), 4.45 (q, J =
6.0 Hz, 1 H), 3.50–3.31 (m, 2 H), 2.49–2.32 (m, 2 H), 2.10–2.00 (m,
2 H), 2.00–1.86 (m, 1 H), 1.73–1.59 (m, 1 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.3 (C), 172.7 (C), 56.2 (CH), 44.0
(CH2), 31.2 (CH2), 21.2 (CH2), 18.3 (CH2), 10.7 (CH3).
Racetam Derivative 5a
Prepared from Nα-Boc-L-2,4-diaminobutyric acid (218 mg, 1.0 mmol,
1 equiv), isobutyraldehyde (72 mg, 1.0 mmol, 1 equiv) and cyclohexyl
isocyanide (109 mg, 1.0 mmol, 1 equiv) according to General Proce-
dure A. Diastereoisomers formed in ca. 1:1 ratio. The product was pu-
rified by column chromatography on silica gel (cyclohexane/EtOAc,
2:1 to 1:1). Diastereoisomers were not resolved.
HRMS (ESI): m/z [M + Na]+ calcd for C8H14N2NaO2: 193.0954; found:
193.0954.
Yield: 174 mg (0.46 mmol, 46%); white solid; Rf = 0.29 and 0.14 for
the two diastereoisomers (cyclohexane/EtOAc, 2:1).
2-(2-Oxopyrrolidin-1-yl)-N-[(S)-1-phenylethyl]butanamide (4cc)26
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), pro-
pionaldehyde (58 mg, 1.0 mmol, 1 equiv) and (S)-α-methylbenzyl iso-
cyanide (131 mg, 1.0 mmol, 1 equiv) according to General Procedure
A. Diastereoisomers formed in ca. 1:1 ratio. The product was purified
by column chromatography on silica gel (cyclohexane/EtOAc, 1:2 to
1:4). Diastereoisomers were not resolved.
IR (neat): 3327 (w), 3274 (w), 2927 (m), 1670 (s), 1533 (s), 1435 (m),
1283 (m), 1160 (s), 1047 (w), 707 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.50 (br, 1 H, D1), 6.28 (d, J = 7.0 Hz,
1 H, D2), 5.25 (d, J = 5.0 Hz, 1 H, D1), 5.18 (br, 1 H, D2), 4.23–4.07 (m,
1 H, D1, 1 H, D2), 4.00 (d, J = 10.4 Hz, 1 H, D2), 3.93 (d, J = 11.3 Hz, 1 H,
D1), 3.71–3.59 (m, 2 H, D1, 1 H, D2), 3.42–3.21 (m, 1 H, D1, 2 H, D2),
2.64–2.37 (m, 2 H, D1, 2 H, D2), 2.34–2.19 (m, 1 H, D1, 1 H, D2), 1.90–
1.50 (m, 5 H, D1, 5 H, D2), 1.40 (s, 9 H, D1, 9 H, D2), 1.35–1.03 (m, 4 H,
D1, H, D2), 0.93 (d, J = 7.0 Hz, 3 H, D2), 0.91 (d, J = 7.0 Hz, 3 H, D2),
0.80 (d, J = 7.0 Hz, 3 H, D1), 0.78 (d, J = 7.0 Hz, 3 H, D1).
Yield: 55 mg (0.20 mmol, 20%); pale-yellow oil; Rf = 0.22 and 0.15 for
the two diastereoisomers (cyclohexane/EtOAc, 1:2).
IR (neat): 3299 (w), 2969 (w), 1651 (s), 1533 (m), 1449 (m), 1287 (m),
1213 (w), 700 (s) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.15 (m, 5 H, D1, 5 H, D2), 6.67
(br, 1 H, D2), 6.64 (br, 1 H, D1), 5.05 (quint, J = 7.0 Hz, 1 H, D1, 1 H,
D2), 4.43 (t, J = 7.0 Hz, 1 H, D1), 4.40 (t, J = 7.0 Hz, 1 H, D2), 3.56–3.48
(m, 1 H, D2), 3.45–3.39 (m, 1 H, D2), 3.34–3.27 (m, 1 H, D1), 3.20–3.13
(m, 1 H, D1), 2.48–2.36 (m, 1 H, D1, 2 H, D2), 2.27 (ddd, J = 16.0, 10.0,
6.5 Hz, 1 H, D1), 2.10–1.80 (m, 3 H, D1, 3 H, D2), 1.74–1.60 (m, 1 H,
D1, 1 H, D2), 1.46 (d, J = 7.0 Hz, 3 H, D1), 1.44 (d, J = 7.0 Hz, 3 H, D2),
0.90 (t, J = 7.3 Hz, 3 H, D1), 0.85 (t, J = 7.3 Hz, 3 H, D2).
13C NMR (CDCl3, 125 MHz): δ = 173.2 (C, D2), 173.0 (C, D1), 168.2 (C,
D1), 167.8 (C, D2), 155.7 (C, D1 and D2), 79.9 (C, D1 and D2), 62.8 (CH,
D1), 62.1 (CH, D2), 52.9 (CH, D2), 52.3 (CH, D1), 48.3 (CH, D1 and D2),
41.6 (CH2, D2), 41.4 (CH2, D1), 32.8 (CH2, D1), 32.7 (CH2, D2), 29.7
(CH2, D2), 29.7 (CH2, D1), 28.3 (CH3, D1 and D2), 27.1 (CH, D1), 26.1
(CH, D2), 25.5 (CH2, D1), 25.5 (CH2, D2), 24.9 (CH2, D1), 24.8 (CH2, D2),
19.5 (CH3, D2), 19.3 (CH3, D1), 19.1 (CH3, D1), 18.7 (CH3, D2).
HRMS (ESI): m/z [M + Na]+ calcd for C20H35N3NaO4: 404.2520; found:
13C NMR (125 MHz, CDCl3): δ = 176.2 (C, D2), 176.1 (C, D1), 169.3 (C,
D2), 169.0 (C, D1), 143.7 (C, D1), 143.2 (C, D2), 128.8 (CH, D2), 128.7
(CH, D1), 127.4 (CH, D2), 127.3 (CH, D1), 126.1 (CH, D2), 126.0 (CH,
D1), 56.9 (CH, D2), 56.6 (CH, D1), 49.0 (CH, D2), 49.0 (CH, D1), 44.1
(CH2, D2), 43.8 (CH2, D1), 31.3 (CH2, D2), 31.2 (CH2, D1), 22.2 (CH3,
D1), 22.2 (CH3, D2), 21.4 (CH2, D2), 20.9 (CH2, D1), 18.4 (CH2, D2), 18.2
(CH2, D1), 10.7 (CH3, D2), 10.6 (CH3, D1).
404.2503.
2-(2-Oxopyrrolidin-1-yl)acetamide (4aa)28
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv),
paraformaldehyde (30 mg, 1.0 mmol, 1 equiv) and 1,1,3,3-tetrameth-
ylbutyl isocyanide (139 mg, 1.0 mmol, 1 equiv) according to General
Procedure B. The product was purified by column chromatography on
silica gel (EtOAc to EtOAc/MeOH, 9:1).
HRMS (ESI): m/z [M + Na]+ calcd for C16H22N2NaO2: 297.1573; found:
297.1570.
Yield: 82 mg (0.58 mmol, 58%); off-white solid; mp 136–141 °C; Rf =
0.21 (EtOAc/MeOH, 9:1).
N-(2,6-Dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide
IR (neat): 3333 (m), 3160 (m), 2958 (w), 1688 (s), 1651 (s), 1406 (s),
(4dd)30
1306 (s), 1290 (s), 1163 (m), 1032 (w), 613 (s) cm–1
.
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv),
paraformaldehyde (30 mg, 1.0 mmol, 1 equiv) and 2,6-dimethylphe-
nyl isocyanide (131 mg, 1.0 mmol, 1 equiv) according to General Pro-
cedure A (reflux, 6 h reaction time). The product was purified by col-
umn chromatography on silica gel (EtOAc to EtOAc/MeOH, 19:1).
1H NMR (500 MHz, CDCl3/DMSO-d6): δ = 6.72 (br, 1 H), 6.22 (br, 1 H),
3.27 (s, 2 H), 2.86 (t, J = 7.0 Hz, 2 H), 1.75 (t, J = 8.0 Hz, 2 H), 1.45
(quint, J = 7.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3/DMSO-d6): δ = 174.0 (C), 169.1 (C), 46.6
(CH2), 44.2 (CH2), 29.2 (CH2), 16.4 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C6H10N2NaO2: 165.0634; found:
Yield: 97 mg (0.392 mmol, 39%); white solid; mp 139–142 °C; Rf =
0.14 (EtOAc).
165.0627.
IR (neat): 3258 (s), 2920 (m), 2365 (m), 1697 (s), 1663 (s), 1530 (s),
1468 (s), 1439 (s), 1425 (s), 1406 (s) cm–1
.
2-(2-Oxopyrrolidin-1-yl)butanamide (4bb)29
1H NMR (500 MHz, CDCl3): δ = 8.05 (br, 1 H), 7.10–6.97 (m, 3 H), 4.02
(s, 2 H), 3.51 (t, J = 6.9 Hz, 2 H), 2.34 (t, J = 8.2 Hz, 2 H), 2.14 (s, 6 H),
2.03 (quint, J = 7.6 Hz, 2 H).
Prepared from γ-aminobutyric acid (103 mg, 1.0 mmol, 1 equiv), pro-
pionaldehyde (58 mg, 1.0 mmol, 1 equiv) and 1,1,3,3-tetramethylbu-
tyl isocyanide (139 mg, 1.0 mmol, 1 equiv) according to General Pro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

J
R. C. Cioc et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3): δ = 176.2 (C), 167.0 (C), 135.2 (C), 133.5
(C), 128.1 (CH), 127.3 (CH), 48.5 (CH2), 47.2 (CH2), 30.4 (CH2), 18.4
(CH3), 18.1 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H18N2NaO2: 269.1260; found:
269.1256.
References
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G.; Klitgaard, H. V.; Gillard, M. R.; Fuks, B.; Michel, P. J. Med.
Chem. 2004, 47, 530.
N-[2-(Diisopropylamino)ethyl]-2-(2-oxopyrrolidin-1-yl)acet-
amide (4ee)31
To Ugi product 4o (20 mg, 0.065 mmol, 1 equiv) was added N1,N1-
diisopropylethane-1,2-diamine (0.1 mL) and the mixture was stirred
at 110 °C for 11 h (under N2 atmosphere). Crude NMR analysis indi-
cated the complete conversion of 4o into 4ee and 2-amino-6-bro-
mopyridine. The product 4ee was not isolated.
1H NMR (500 MHz, CDCl3): δ = 3.93 (s, 2 H), 3.47 (t, J = 7.0 Hz, 2 H),
3.28 (q, J = 5.5 Hz, 2 H), 3.08 (sept, J = 7.0 Hz, 2 H), 2.65 (t, J = 5.5 Hz,
2 H), 2.43 (t, J = 8.0 Hz, 2 H), 2.08 (quint, J = 7.5 Hz, 2 H), 1.05 (d, J =
7.5 Hz, 12 H).
(3) Ugi, I. K.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem.
1959, 71, 373.
(4) El Kaïm, L.; Grimaud, L.; Miranda, L. D.; Vieu, E. Tetrahedron Lett.
2006, 47, 8259.
(5) Ku, I.-W.; Kang, S.-B.; Keum, G.-C.; Kim, Y.-S. Bull. Korean Chem.
Soc. 2011, 32, 3167.
13C NMR (125 MHz, CDCl3): δ = 175.9 (C), 168.2 (C), 48.4 (CH2), 48.1
(CH), 47.1 (CH2), 37.8 (CH2), 36.5 (CH2), 30.4 (CH2), 20.9 (CH3), 18.1
(CH2).
HRMS (ESI): m/z [M + H]+ calcd for C14H28N3O2: 270.2176; found:
270.2171.
(6) (a) Dawidowski, M.; Sobczak, S.; Wilczek, M.; Kulesza, A.; Turło,
J. Mol. Diversity 2013, 18, 61. (b) Dawidowski, M.; Herold, F.;
Wilczek, M.; Turło, J.; Chodkowski, A.; Gomółka, A.; Kleps, J. Tet-
rahedron 2012, 68, 8222. (c) Kadzimirsz, D.; Hildebrandt, D.;
Merz, K.; Dyker, G. Chem. Commun. 2006, 661. (d) Sollis, S. L.
J. Org. Chem. 2005, 70, 4735. (e) Sung, K.; Chen, F.-L.; Chung, M.-
J. Mol. Diversity 2003, 6, 213. (f) Demharter, A.; Hörl, W.;
Herdtweck, E.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1996, 35, 173.
(g) Ugi, I.; Demharter, A.; Hörl, W.; Schmid, T. Tetrahedron 1996,
52, 11657.
(7) (a) Sinha, M. K.; Khoury, K.; Herdtweck, E.; Dömling, A. Org.
Biomol. Chem. 2013, 11, 4792. (b) Khoury, K.; Sinha, M. K.;
Nagashima, T.; Herdtweck, E.; Dömling, A. Angew. Chem. Int. Ed.
2012, 51, 10280.
(8) (a) Voigt, B.; Linke, M.; Mahrwald, R. Org. Lett. 2015, 17, 2606.
(b) Turner, C. D.; Ciufolini, M. A. Org. Lett. 2012, 14, 4970. (c) Ku,
I. W.; Cho, S.; Doddareddy, M. R.; Jang, M. S.; Keum, G.; Lee, J.-
H.; Chung, B. Y.; Kim, Y.; Rhim, H.; Kang, S. B. Bioorg. Med. Chem.
Lett. 2006, 16, 5244. (d) Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S.
B.; Lee, D. H.; Koh, H. Y.; Kim, Y. Org. Lett. 2001, 3, 4149. (e) Park,
S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.; Lee, D. H. Tetrahe-
dron Lett. 1998, 39, 7109.
Ethyl 2-(2-Oxopyrrolidin-1-yl)acetate (6)31
To a solution of 4o (34 mg, 0.11 mmol, 1 equiv) in EtOH (0.3 mL) was
added acetyl chloride (44 mg, 0.56 mmol, 5 equiv) and the mixture
was stirred at r.t. for 22 h. EtOH was then removed in vacuo and the
crude mixture was redissolved in diethyl ether. A solution of HCl in
cyclopentylmethyl ether (3 M, 0.2 mL) was then added, precipitating
the hydrochloride salt of 2-amino-6-bromopyridine. This byproduct
was filtered off and concentration of the filtrate afforded the product.
Yield: 14 mg (0.08 mmol, 70%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 4.17 (q, J = 7.0 Hz, 2 H), 4.03 (s, 2 H),
3.47 (t, J = 7.0 Hz, 2 H), 2.41 (t, J = 8.0 Hz, 2 H), 2.06 (quint, J = 7.2 Hz,
2 H).
13C NMR (125 MHz, CDCl3): δ = 175.8 (C), 168.8 (C), 61.4 (CH2), 47.8
(CH2), 44.2 (CH2), 30.4 (CH2), 18.0 (CH2), 14.2 (CH3).
Acknowledgment
(9) (a) Banfi, L.; Basso, A.; Chiappe, C.; De Moliner, F.; Riva, R.;
Sonaglia, L. Org. Biomol. Chem. 2012, 10, 3819. (b) Basso, A.;
Banfi, L.; Riva, R.; Guanti, G. Tetrahedron Lett. 2004, 45, 587.
(10) (a) Gedey, S.; Van der Eycken, J.; Fülöp, F. Org. Lett. 2002, 4,
1967. (b) Dömling, A.; Kehagia, K.; Ugi, I. Tetrahedron 1995, 51,
9519. (c) Kehagia, K.; Ugi, I. K. Tetrahedron 1995, 51, 9523.
(d) Hatanaka, M.; Nitta, H.; Ishimaru, T. Tetrahedron Lett. 1984,
25, 2387. (e) Isenring, H. P.; Hofheinz, W. Synthesis 1981, 385.
(11) (a) For Ugi reactions with 6-aminohexanoic acid, see: Rasouli,
M. A.; Mahdavi, M.; Rashidi Ranjbar, P.; Saeedi, M.; Shafiee, A.;
Foroumadi, A. Tetrahedron Lett. 2012, 53, 7088. (b) For Ugi type
reactions of dipeptides leading to diketopiperazines, see: Cho,
S.; Keum, G.; Kang, S. B.; Han, S. Y.; Kim, Y. Mol. Diversity 2003,
6, 283. (c) For a review of the intramolecular Ugi reaction and
its relevance to medicinal chemistry, see: Hulme, C.; Dietrich, J.
Mol. Diversity 2009, 13, 195.
We thank John Braun and Jurriën Collet for HRMS measurements,
Elwin Janssen for technical assistance, and Dr. Andreas W. Ehlers for
NMR maintenance (all Vrije Universiteit Amsterdam). The research
leading to these results has received funding from the Innovative
Medicines
Initiative
Joint
Undertaking
project
CHEM21
(http://www.chem21.eu) under grant agreement no. 115360, re-
sources of which are composed of financial contribution from the Eu-
ropean Union’s Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies’ in-kind contribution.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588672.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(12) Darehkordi, A.; Zand-Vakili, F.; Talebizadeh Rafsanjani, A. Tetra-
hedron Lett. 2016, 57, 498.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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R. C. Cioc et al.
Paper
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(23) Isocyanide additions are notoriously poorly diastereoselective,
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(24) Possibly due to competing N,O-acetal formation.
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(16) See the Supporting Information for details.
(17) TFE is often seen to improve the yield of Ugi type reactions, see
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(19) The need for depolymerization of paraformaldehyde could be
the problem in this case; however, the use of a stabilized mono-
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(26) Forcato, M.; Michieletto, I.; Maragni, P.; Assaccesi, F.; Cotarca, L.
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(27) This reaction occurred with quantitative conversion based on
crude NMR analysis, but the purification of 4ee from the reac-
tion mixture proved troublesome.
(28) Wu, X.-F.; Sharif, M.; Feng, J.-B.; Neumann, H.; Pews-Davtyan,
A.; Langer, P.; Beller, M. Green Chem. 2013, 15, 1956.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K