Synthesis of 5-Substituted 2-Pyrrolidinones by Coupling of Organozinc Reagents with Cyclic N-Acyliminium Ions

Article abstract of DOI:10.1055/s-0037-1610733

A coupling reaction between cyclic N-acyliminium ions with organozinc reagents is described. The cyclic N-acyliminium ions, generated in situ from N-substituted-5-hydroxy-2-pyrrolidinones by treatment with boron trifluoride-diethyl ether complex or titani

Full text of DOI:10.1055/s-0037-1610733

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
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A
en
I. Zaragoza-Galicia et al.
Paper
Synthesis
Synthesis of 5-Substituted 2-Pyrrolidinones by Coupling of
Organozinc Reagents with Cyclic N-Acyliminium Ions
Ivann Zaragoza-Galicia
R1 = allyl,
benzyl,
propargyl
Zaira A. Santos-Sánchez
one-pot
Yazmín I. Hidalgo-Mercado
Horacio F. Olivo
0
0
0
0-0
0
0
2-
8
0
8
2-5
2
8
5
R
2 = benzyl,
butyl,
Boc,
allyl,
homoallyl,
p-methylbenzyl,
piperonyl
Lewis
acid
Moisés Romero-Ortega*
0
0
0
0-0
0
0
1-
8
8
8
4-3
9
7
4
OH
O
N
O
N
R2
R1
R2
O
N
R2
Br R1
Departamento de Química Orgánica, Facultad de Química,
Universidad Autónoma del Estado de México, Toluca,
C.P. 50180, México
BrZn R1
Zn°
11 examples
25–75% yield
mromeroo@uaemex.mx
Received: 03.07.2019
Accepted after revision: 12.09.2019
Published online: 08.10.2019
OH
H
OAc
H
HO
OH
OH
OH
H
N
N
OH
DOI: 10.1055/s-0037-1610733; Art ID: ss-2019-m0375-op
N
OH
NH2
Abstract A coupling reaction between cyclic N-acyliminium ions with
organozinc reagents is described. The cyclic N-acyliminium ions, gener-
ated in situ from N-substituted-5-hydroxy-2-pyrrolidinones by treat-
ment with boron trifluoride–diethyl ether complex or titanium tetra-
chloride, are trapped by the organozinc reagent, which is formed from
an alkyl bromide in the presence of zinc in the same reaction medium.
The N-substituted-5-allyl-2-pyrrolidinones generated using this method
serve as versatile intermediates for the synthesis of azabicyclic systems
with indolizidine and pyrroloazepinolizidine cores.
castanospermine
slaframine
swainsonine
CH3
HO
CH3
O
H
O
O
N
O
O
N
H
O
H
H
tuberostemospironine
(–)-stemoamide
Figure 1 Indolizidine and pyrroloazepinolizidine cores in biologically
active compounds
Key words N-acyliminium ions, organozinc reagents, coupling reac-
tions, 5-allyl-2-pyrrolidinones, azabicyclic systems
envisaged that a very useful method for carbon–carbon
bond formation would involve coupling reactions of imini-
um ions with organometallic compounds. In particular, in-
tramolecular reactions have received considerable atten-
tion for the preparation of azabicyclic systems.10 We there-
fore became interested in the generation of 5-allyl-2-
pyrrolidinones, because the allyl moiety is a versatile func-
tional group that is amenable to further synthetic transfor-
mations; for instance, via intramolecular reactions toward
the synthesis of azabicyclic compounds by ring-closing me-
tathesis (RCM).11
In view of their limited stability and high reactivity, N-
acyliminium ions are generated in situ by treatment of a
suitable precursor with protic or Lewis acids.12 Typically, N-
substituted-5-hydroxy-2-pyrrolidinones and their deriva-
tives are used as precursors of cyclic N-acyliminium ions
when the pyrrolidine moiety is involved in forming part of
the azabicyclic system.13 General methods to prepare pre-
cursors of cyclic N-acyliminium ions involve partial reduc-
tion of the corresponding N-substituted succinimides, for
example, with LiEt3BH,14 sodium borohydride–Mg(ClO4)2,15
lithium thexylborohydride (LTB) and diisobutylaluminum
Indolizidine and pyrroloazepinolizidine alkaloids are
present widely in Nature and are compounds of great inter-
est due to their biological and pharmaceutical properties.1
Representative examples of these azabicyclic alkaloids are
castanospermine and swainsonine, which are prominent
synthetic targets because of their potent glycosidase inhibi-
tory activities, making them potential candidates for the
treatment of various diseases, including cancer, malaria and
obesity.2 In addition, Stemona alkaloids, such as (–)-stemo-
amide and tuberostemospironine, are used for the treat-
ment of respiratory diseases and as anthelmintics (Figure
1).3
A number of innovative methodologies for the synthesis
of indolizidine and pyrroloazepinolizidine systems have
been described in the literature.4 Examples of these meth-
ods include trans-annular cyclization reactions,5 reactions
of cyclic nitrones,6 reactions of ,-unsaturated diazo-
ketones,7 imino Diels–Alder reactions,8 and others.
N-Acyliminium ions, especially cyclic versions, are high-
ly reactive intermediates, which is reflected in an impres-
sive number of synthetic applications.9 In this context, we
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
I. Zaragoza-Galicia et al.
Paper
Synthesis
hydride (DIBAL-H).16 The reduction with sodium borohy-
dride in methanol solution at 0 °C in the presence of hydro-
chloric acid or potassium hydroxide is perhaps the most
important method known for the preparation of these N-
acyliminium ion precursors.17 However, a large excess of so-
dium borohydride and long reaction times are required to
obtain satisfactory yields, and in many cases the ring-open-
ing product is observed due to over-reduction of the alde-
hyde group during the hydroxy–lactam equilibrium.18
Although, the chemistry of N-acyliminium ions has
been widely studied to date, there are few reports on cou-
pling reactions with organometallic compounds. Those re-
ports that do exist are based on the protocols of Pedregal19
and Wistrand,20 in which a cyclic N-acyliminium ion is cou-
pled with an organocopper reagent, generated from the
more readily available Grignard reagents.
In 1994, Kise reported the reactions of N-acyl--me-
thoxyamines with organozinc reagents for the synthesis of
homoallylamines.21 Specifically, the 5-methoxy-NH-2-pyr-
rolidinone derived from NH-succinimide was reacted with
allylzinc bromide to give the corresponding 5-allyl-NH-suc-
cinimide. Although this coupling reaction resulted in an ac-
ceptable yield, only one example has been examined so far.
Additionally, this method has the disadvantage of requiring
N-acyl--methoxyamines, which are very difficult to obtain
in pure form. Mechanistically, an acid–base reaction is in-
volved, resulting in an N-acylimine species during the cou-
pling reaction with the organozinc reagent. However, the
methodology was limited to the use of NH-acylamines to
generate the corresponding N-acylimines. Therefore, it is
reasonable to expect that N-acyliminium ions, generated
from N-substituted-5-hydroxy-2-pyrrolidinones, would be
better intermediates to carry out this coupling reaction
with organozinc reagents, and might represent a useful tool
for the conversion of N-substituted succinimides into 5-
substituted-2-pyrrolidinone derivatives.
Table 1 Partial Reduction of N-Substituted Succinimidesa
NaBH4
O
OH
O
O
O
OH
N
R
N
R
NH
R
solvent
2
3c
1
e: R = homoallyl
f: R = p-methylbenzyl
g: R = piperonyl
a: R = benzyl
b: R = butyl
c: R = Boc
d: R = allyl
Entry
1
NaBH4 Solvent
(equiv)
Time Temp
Yield of 2 Yield of 3
(%) (%)
(h)
(°C)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1cb
1c
1d
1e
1f
3
3
3
2
9c
3
3
3
3
MeOH
MeOH
MeOH
1
3
1
2
3
3
3
1
1
–5 to rt
93
trace
–5 to rt
–5 to rt
–50
94
0
trace
86
MeOH–THF
MeOH
24
86d
93
81
80
85
30
–78
trace
trace
trace
trace
trace
MeOH
–5 to rt
–5 to rt
–5 to rt
–5 to rt
MeOH
MeOH
1g
MeOH
a Reaction conditions: succinimide 1 (1.0 equiv), NaBH4, MeOH (5.0 mL).
b Reaction carried out on gram scale.
c Reaction employing 5 M HCl solution.
d Based on 20% recovered starting material.
These results clearly show the considerable influence of
the N-substituent present on the succinimide ring on the
equilibrium of the oxy-anion A and amide-aldehyde B
(Scheme 1). When the nitrogen atom of the succinimide
ring contains an electron-donating substituent, the equilib-
rium in the reaction medium is displaced toward the oxy-
anion A, which gives the corresponding N-substituted-5-
hydroxy-2-pyrrolidinone 2 as the predominant product,
even when the reduction is carried out at room tempera-
ture and over long reaction times. In contrast, when the ni-
trogen atom carries an electron-withdrawing group such as
Boc, the equilibrium in the reaction medium shifts toward
the amide-aldehyde B, which is reduced to the amide-
alcohol derivative 3 in the presence of sodium borohydride.
The partial reduction of succinimide 1c on milligram
scale using NaBH4 (2.0 equiv) in THF–methanol at –50 °C
Our experimental work started with the synthesis of
the N-acyliminium ion precursors. For this purpose, we se-
lected N-benzyl 1a, N-butyl 1b, N-tert-butoxycarbonyl
(Boc) 1c, N-allyl 1d, N-homoallyl 1e, N-p-methylbenzyl 1f
and N-piperonyl 1g succinimides as starting materials. We
evaluated the partial reduction of these N-substituted suc-
cinimides with sodium borohydride in methanol solution.17
When the reduction reaction of succinimides 1a–g was car-
ried out with only 3 equivalents of NaBH4 in methanol (at
–5 °C to rt) under neutral conditions, the corresponding N-
substituted-5-hydroxy-2-pyrrolidinones 2a,b,d–g were ob-
tained in good to very good yields (Table 1, entries 1, 2 and
6–9).
O
O
N
R
1
NaBH4
O
R = EDG
CHO R = EWG
OH
OH
O
O
O
O
N
R
N
R
N
R
B
Interestingly, when the N-Boc-succinimide 1c was re-
duced under these conditions (Table 1, entry 3), the over-
reduced amide-alcohol 3c was obtained as the only product
in 86% yield.
NH
R
2
A
3
Scheme 1 Influence of the N-substituent on the formation of amide-
alcohol 3
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

C
I. Zaragoza-Galicia et al.
Paper
Synthesis
has been previously reported in moderate yield.22 However,
when the reaction was carried out on gram scale, a mixture
of N-Boc-5-hydroxy-2-pyrrolidinone (2c) (24%) along with
the over-reduction product 3c (30%) was obtained (Table 1,
entry 4).
3 equivalents of allyl bromide were added concurrently to a
suspension containing 1 equivalent of N-benzyl-hydroxy-
pyrrolidin-2-one 2a and 3 equivalents of Zn in THF (1.5
mL/1.0 mmol of 2a). This exothermic reaction gave the de-
sired 5-allyl-2-pyrrolidinone 4a in 75% yield (Table 2, entry
1).
Fortunately, we found that when using NaBH4 (9 equiv)
in methanol at –78 °C and employing 5 M HCl solution,
product 2c was obtained as the major product in 86% yield
(based on 20% the recovered starting material; this material
was recycled until total consumption) (Table 1, entry 5).
This result was attributed to the low temperature at which
the reduction is carried out, since under these reaction con-
ditions succinimide 1c becomes partially insoluble offering
a slower and therefore more selective reduction. Addition-
ally, according to the report by D’Ulivo,23 under acidic con-
ditions, NaBH4 is in equilibrium with a hydroboron species,
which could be catalyzing the reduction reaction. This re-
sult was reproducible and significant variations in the yield
were not detected when the reaction was performed on
multigram scale.
Having obtained N-benzyl-hydroxypyrrolidin-2-one 2a
using the optimized methodology, we next evaluated the
conditions for the key coupling reaction of the allyl or-
ganozinc reagent with the corresponding N-acyliminium
ion to obtain the 5-allyl-2-pyrrolidinone derivative 4a
(Scheme 2). Initially, a solution containing equimolar
amounts of N-benzyl-hydroxypyrrolidin-2-one 2a and TiCl4
in anhydrous THF was added to a solution of freshly pre-
pared allyl organozinc reagent, obtained by adding 5 equiv-
alents of allyl bromide to 5 equivalents of Zn in THF. A mix-
ture of 5-allyl-N-benzylpyrrolidin-2-one (4a) and N-ben-
zyl-2-pyrrolinone (5) was obtained in a combined yield of
61%, with the yield of 4a being very poor (11% of 4a and 50%
yield of 5). Compound 5 is suggested to arise as a conse-
quence of a proto-elimination reaction of the correspond-
ing N-acyliminium ion, following a prototopic [1,3] rear-
rangement, an important and common side reaction in cy-
clic N-acyliminium ion chemistry.11a,b This result suggested
that after formation of the iminium ion, the Lewis acid is
possibly faster at promoting the formation of 2-pyrrolinone
5 than in mediating the coupling reaction with the organo-
metallic compound.
Table 2 Synthesis of 5-Substituted-2-pyrrolidinone Derivativesa
Lewis acid
(LA)
Zn
R1
O
O
N
OH
N
R2
R–Br
THF, rt
15 min
R2
4a–k
2
Entry 2 (R2)
LA
BF3
4
Yield (%)
1
2
2a (R2 = Bn)
2a (R2 = Bn)
2a (R2 = Bn)
2b (R2 = n-Bu)
2b (R2 = n-Bu)
2c (R2 = Boc)
2c (R2 = Boc)
2d (R2 = allyl)
4a (R1 = allyl)
4b (R1 = Bn)
75
50
60
72
53
BF3
TiCl4
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
3
4c (R1 = propargyl)
4d (R1 = allyl)
4
5
4e (R1 = Bn)
6
4f (R1 = allyl, R2 = H) 25
7
4g (R1 = Bn, R2 = H)
4h (R1 = allyl)
4i (R1 = allyl)
34
75
75
73
67
8
9
2e (R2 = homoallyl)
2f (R2 = p-MeC6H4CH2)
2g (R2 = piperonyl)
10
11
4j (R1 = allyl)
4k (R1 = allyl)
a Reaction conditions: hydroxypyrrolidin-2-one 2 (1.0 equiv), LA (1.0
equiv), Zn (3.0 equiv), R1–Br (3.0 equiv), THF (1.5 mL/1.0 mmol of 2), rt.
To demonstrate the generality of this methodology we
performed this reaction with different N-substituted deriv-
atives 2b–g, using allyl, benzyl, and propargyl bromides as
precursors of the organozinc reagents (Table 2, entries 2–
11). Under these conditions, the 5-substituted 2-pyrrolidi-
nones 4a,b,d,e,h–k were obtained in acceptable yields (50–
75%) (entries 1, 2, 4, 5 and 8–11). In contrast, the yields
were lower when the N-substituent was Boc (entries 6 and
7). Interestingly, the Boc protecting group was cleaved un-
der these conditions to give directly the NH-5-substituted
pyrrolidinone derivatives 4f and 4g. Unfortunately, the ap-
plication of this coupling process to propargyl bromide was
less successful, affording the propargyl derivative 4c in low
yield. A better yield of 4c (60%) was obtained when titani-
um tetrachloride was used as the Lewis acid to generate the
N-acyliminium ion (entry 3). In stark contrast to allyl, prop-
argyl and benzyl bromides, n-butyl bromide did not pro-
duce the corresponding coupling product. This can possibly
be explained by the lower reactivity of this alkyl halide
compared to the other examples used in this work. It is in-
teresting to note that this methodology is the first report on
the coupling reaction between cyclic N-acyliminium ions
with organozinc reagents, both being generated in situ in
the same reaction medium.
Lewis acid
(LA)
Zn
+
+
O
O
N
O
N
OH
Br
THF, rt
N
2a
4a
5
LA = TiCl4, 4a, 11%; 5, 50%
LA = BF3, 4a, 75%
Scheme 2 Synthesis of 5-allyl-N-benzylpyrrolidin-2-one (4a)
After considering a range of different experimental ap-
proaches, the reaction was optimized when 1 equivalent of
boron trifluoride–diethyl ether complex (BF3-etherate) and
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

D
I. Zaragoza-Galicia et al.
Paper
Synthesis
To show the utility of the 5-allyl pyrrolidinones 4h and
4i, we decided to carry out the synthesis of the indolizidine
6 and pyrroloazepinolizidine 7 cores through RCM (Scheme
3). It should be mentioned that 5-allyl pyrrolidinones 4h
and 4i can also be prepared via N-alkylation of NH-pyrro-
lidinone 4f.
NMR spectra were measured at 300 MHz and 75 MHz, respectively,
on a Bruker Avance 300 spectrometer. 1H NMR chemical shifts () are
reported in parts per million (ppm) relative to Me4Si ( = 0.0), with
coupling constants (J) reported in hertz (Hz). Multiplicities are re-
ported as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
broad singlet (br s). 13C NMR chemical shifts () are reported in parts
per million (ppm) using the signal at  = 77.0 (CDCl3) as an internal
reference.
O
1) NaH, DMF
0 °C, 0.5 h
N
H
1-tert-Butoxycarbonyl-5-hydroxypyrrolidin-2-one (2c)22
Br
To a solution of N-tert-butoxycarbonyl succinimide (1c) (1.0 g, 5.0
mmol) in methanol (40.0 mL) at –78 °C was added sodium borohy-
dride in 9 portions (0.20 g, 5.0 mmol, one portion each 40 min); after
each addition of sodium borohydride a solution of 5 M hydrochloric
acid was added until pH 2–3 was reached (0.4 mL). After 6 hours, the
reaction mixture was quenched by the addition of crushed ice–water
and the product was extracted thoroughly with CH2Cl2 (5 × 50.0 mL).
The combined extracts were dried over Na2SO4 and concentrated un-
der reduced pressure. The residue was purified by flash column chro-
matography (silica gel, hexanes–EtOAc, 6:4).
2)
n
4f
Grubbs II
catalyst (10 mol%)
O
O
N
N
n
n
CH2Cl2
Br
6, n = 1, 81%
7, n = 2, 70%
4h, n = 1
4i, n = 2
O
OH
N
Zn/Lewis acid
n
2d, n = 1
2e, n = 2
Scheme 3 RCM of 4h and 4i for the synthesis of indolizidine 6 and pyr-
roloazepinolizidine 7
Yield: 640 mg (86%) based on 270 mg (20%) of recovered starting ma-
terial; white solid; crystallization (hexanes–CH2Cl2); mp 78–79 °C.
To this end, pyrrolidinone 4f was reacted with allyl bro-
mide to give N-allyl pyrrolidinone 4h in 55% yield, and with
homoallyl bromide to give N-homoallyl pyrrolidinone 4i in
63% yield under conditions reported by Boto.24 Finally, 5-al-
lyl pyrrolidinones 4h and 4i were reacted with Grubbs’ cat-
alyst using the RCM conditions reported by Meyers25 to give
the desired azabicyclic systems 6 and 7 in good yields of
81% and 70%, respectively.
In summary, the methodology outlined herein consti-
tutes a convenient and easy means for the synthesis of 5-
substituted-2-pyrrolidinones 4a–k from precursors of N-
acyliminium ions, which were coupled in a satisfactory
manner with organozinc reagents. This is the first example
in which a cyclic N-acyliminium ion and an organozinc re-
agent are generated in situ in the same reaction medium,
followed by their spontaneous coupling to give the desired
products. Although N-Boc-5-hydroxy-2-pyrrolidinone (2c)
is reasonably stable, we found that under the reaction con-
ditions described herein the Boc group was cleaved to give
the coupling products 4f and 4g. Therefore, the use of this
protecting group in 5-hydroxy-2-pyrrolidinones could be
centered on logical N-unsubstituted congeners. Lastly, the
usefulness of the N-alkenyl 5-allyl-2-pyrrolidinones was
demonstrated by their use as precursors for the synthesis of
indolizidine 6 and pyrroloazepinolizidine 7 cores in good
yields.
1H NMR (300 MHz, CDCl3):  = 5.67 (d, J = 6.3 Hz, 1 H), 4.03 (br s, 1 H),
2.76–2.64 (m, 1 H), 2.40–2.31 (m, 1 H), 2.21–2.08 (m, 1 H), 1.97–1.88
(m, 1 H), 1.49 (s, 9 H).
13C NMR (75 MHz, CDCl3):  = 173.0, 150.5, 83.8, 82.0, 30.4, 27.09,
25.4.
2-Pyrrolidinone-5-substituted Derivatives 4a,b,d–k; General Pro-
cedure
To a suspension of the corresponding N-substituted-5-hydroxypyrro-
lidinone 2 (1.0 equiv) and Zn (3.0 equiv) in anhydrous THF (1.5
mL/1.0 mmol of 2) at room temperature was added the Lewis acid
(TiCl4 or BF3·Et2O, 1.0 equiv) and the alkyl bromide (3.0 equiv) at the
same time. Caution! Exothermic reaction. After stirring for 15 min,
the reaction was quenched by the addition of a saturated solution of
NaHCO3. The reaction mixture was filtered over Celite and the filter
cake washed with EtOAc. The product was extracted with EtOAc and
the combined extracts were dried over Na2SO4 and concentrated un-
der reduced pressure. The residue was purified by flash column chro-
matography using hexanes–EtOAc as the eluting solvent.
5-Allyl-1-benzylpyrrolidin-2-one (4a)26
Starting from 2a (191 mg, 1.0 mmol), product 4a was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 6:4).
Yield: 160 mg (75%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.32–7.22 (m, 5 H), 5.65–5.59 (m, 1 H),
5.11–5.08 (m, 2 H), 5.01 (d, J = 15.0 Hz, 1 H), 3.98 (d, J = 15.0 Hz, 1 H),
3.52–3.48 (m, 1 H), 2.51–2.44 (m, 1 H), 2.41–2.34 (m, 2 H), 2.20–2.14
(m, 1 H), 2.08–2.00 (m, 1 H), 1.79–1.74 (m, 1 H).
13C NMR (75 MHz, CDCl3):  = 175.2, 136.6, 132.6, 128.6, 127.9, 127.4,
118.7, 56.2, 44.1, 37.1, 30.0, 23.2.
All moisture-sensitive reactions were carried out in oven-dried glass-
ware under a nitrogen atmosphere. Reagents were purchased from
Aldrich and used without any further purification. All solvents were
distilled over appropriate drying reagents (sodium or calcium hy-
dride). All reactions were monitored by TLC on Merck precoated
plates (silica gel 60 F254). Column chromatography was performed
using Merck silica gel 60 (230–400 mesh). Melting points were mea-
1,5-Dibenzylpyrrolidin-2-one (4b)27
Starting from 2a (191 mg, 1.0 mmol), product 4b was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 7:3).
sured using a Mel-Temp II apparatus and are uncorrected. 1H and 13
C
Yield: 132 mg (50%); pale yellow oil.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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I. Zaragoza-Galicia et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3):  = 7.26–6.96 (m, 10 H), 5.04 (d, J = 15.0
Hz, 1 H), 3.95 (d, J = 15.0 Hz, 1 H), 3.62–3.54 (m, 1 H), 2.93 (dd, J1 = 4.2
Hz, J2 = 13.5 Hz, 1 H), 2.49 (dd, J1 = 8.7 Hz, J2 = 13.2 Hz, 1 H), 2.19 (t, J =
8.7 Hz, 2 H), 1.89–1.76 (m, 1 H), 1.72–1.61 (m, 1 H).
13C NMR (75 MHz, CDCl3):  = 175.2, 136.9, 136.6, 129.1, 128.7, 128.5,
128.0, 127.5, 126.7, 58.0, 44.4, 39.1, 29.8, 23.6.
1,5-Diallylpyrrolidin-2-one (4h)31
Starting from 2d (141 mg, 1.0 mmol), product 4h was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 7:3).
Yield: 123 mg (75%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 5.82–5.63 (m, 2 H), 5.21 (qd, J1 = 1.5
Hz, J2 = 7.8 Hz, 1 H), 5.18–5.17 (m, 1 H), 5.16–5.15 (m, 1 H), 5.12–5.11
(m, 1 H), 4.33 (ddt, J1 = 1.5 Hz, J2 = 4.8 Hz, J3 = 15.3 Hz, 1 H), 3.72–3.64
(m, 1 H), 3.52 (ddd, J1 = 0.9 Hz, J2 = 7.8 Hz, J3 = 15.3 Hz, 1 H), 2.48–2.29
(m, 3 H), 2.27–2.06 (m, 2 H), 1.80–1.70 (m, 1 H).
5-Allyl-1-butylpyrrolidin-2-one (4d)28
Starting from 2b (157 mg, 1.0 mmol), product 4d was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 7:3).
13C NMR (75 MHz, CDCl3):  = 174.9, 132.8, 132.7, 118.7, 117.7, 56.6,
Yield: 130 mg (72%); yellow oil.
43.1, 37.3, 30.0, 23.3.
1H NMR (300 MHz, CDCl3):  = 5.75–5.62 (m, 1 H), 5.14 (d, J = 6.3 Hz, 1
H), 5.10 (s, 1 H), 3.70–3.59 (m, 2 H), 2.93–2.86 (m, 1 H), 2.43–2.28 (m,
3 H), 2.22–2.03 (m, 2 H), 1.78–1.67 (m, 1 H), 1.55–1.40 (m, 2 H), 1.29
(sext, J = 7.5 Hz, 2 H), 0.91 (t, J = 7.5 Hz, 3 H).
5-Allyl-1-(but-3-enyl)pyrrolidin-2-one (4i)31
Starting from 2e (310 mg, 2.0 mmol), product 4i was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 7:3).
13C NMR (75 MHz, CDCl3):  = 174.9, 132.8, 118.6, 56.7, 40.0, 37.4,
30.1, 29.3, 23.3, 20.1, 13.7.
Yield: 268 mg (75%); pale yellow oil.
1 H NMR (300 MHz, CDCl3):  = 5.82–5.67 (m, 2 H), 5.18–5.02 (m, 4 H),
3.81–3.65 (m, 2 H), 3.02–2.93 (m, 1 H), 2.47–2.02 (m, 7 H), 1.80–1.69
(m, 1 H).
13C NMR (75 MHz, CDCl3):  = 175.0, 135.1, 132.7, 118.7, 116.8, 56.8,
39.5, 37.4, 31.8, 30.1, 23.3.
5-Benzyl-1-butylpyrrolidin-2-one (4e)
Starting from 2b (157 mg, 1.0 mmol), product 4d was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 7:3).
Yield: 123 mg (53%); yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.26–7.07 (m, 5 H), 3.82–3.74 (m, 1 H),
3.67–3.62 (m, 1 H), 3.34 (t, J = 6.3 Hz, 1 H), 2.95 (dd, J1 = 4.2 Hz, J2 =
13.8 Hz, 1 H), 2.89–2.84 (m, 1 H), 2.51 (dd, J1 = 8.7 Hz, J2 = 13.5 Hz, 1
H), 2.15–2.07 (m, 2 H), 1.94–1.81 (m, 1 H), 1.72–1.61 (m, 1 H), 1.55–
1.40 (m, 1 H), 1.31–1.18 (m, 2 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 174.9, 137.0, 129.2, 128.6, 126.7, 58.5,
40.1, 39.2, 29.9, 29.5, 23.7, 20.1, 13.8.
5-Allyl-1-(p-methylbenzyl)pyrrolidin-2-one (4j)
Starting from 2f (205 mg, 1.0 mmol), product 4j was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 75:25).
Yield: 167 mg (75%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.14 (s, 4 H), 5.71–5.66 (m, 1 H), 5.10
(d, J = 15.0 Hz, 2 H), 4.99 (d, J = 15.0 Hz, 1 H), 3.93 (d, J = 15.0 Hz, 1 H),
3.52–3.46 (m, 1 H), 2.50–2.36 (m, 3 H), 2.32 (s, 3 H), 2.28–2.12 (m, 1
H), 2.08–1.97 (m, 1 H), 1.83–1.69 (m, 1 H).
5-Allylpyrrolidin-2-one (4f)29
Starting from 2c (200 mg, 1.0 mmol), product 4f was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 1:9).
13C NMR (75 MHz, CDCl3):  = 175.1, 137.1, 133.6, 132.7, 129.3, 128.0,
118.7, 56.1, 43.9, 37.2, 30.1, 23.2, 21.1.
Yield: 60 mg (25%); pale yellow oil.
5-Allyl-1-piperonylpyrrolidin-2-one (4k)
1H NMR (300 MHz, CDCl3):  = 7.09 (br s, 1 H), 5.84–5.70 (m, 1 H),
5.15 (d, J = 3.3 Hz, 1 H), 5.11 (s, 1 H), 3.72 (quin, J = 6.6 Hz, 1 H), 2.37–
2.20 (m, 5 H), 1.82–1.69 (m, 1 H).
13C NMR (75 MHz, CDCl3):  = 178.3, 133.5, 118.1, 53.8, 40.7, 30.1,
26.3.
Starting from 2g (235 mg, 1.0 mmol), product 4k was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 75:25).
Yield: 173 mg (67%); as pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 6.76–6.68 (m, 3 H), 5.94 (s, 2 H), 5.72–
5.57 (m, 1 H), 5.10 (d, J = 15.0 Hz, 2 H), 4.90 (d, J = 15.0 Hz, 1 H), 3.89
(d, J = 15.0 Hz, 1 H), 3.57–3.48 (m, 1 H), 2.52–2.41 (m, 3 H), 2.22–2.16
(m, 1 H), 2.10–1.99 (m, 1 H), 1.82–1.72 (m, 1 H).
13C NMR (75 MHz, CDCl3):  = 175.1, 148.0, 147.0, 132.7, 130.6, 121.3,
118.8, 108.4, 108.2, 101.1, 56.1, 44.0, 37.2, 30.1, 23.2.
5-Benzylpyrrolidin-2-one (4g)30
Starting from 2c (200 mg, 1.0 mmol), product 4g was obtained after
purification by flash column chromatography (silica gel, hexanes–
EtOAc, 7:3).
Yield: 59 mg (34%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.27–7.09 (m, 5 H), 6.05 (br s, 1 H),
3.88–3.79 (m, 1 H), 2.71 (qd, J1 = 5.7 Hz, J2 = 13.5 Hz, 2 H), 2.27–2.13
(m, 3 H), 1.82–1.71 (m, 1 H).
13C NMR (75 MHz, CDCl3):  = 178.0, 137.4, 129.0, 128.7, 126.8, 55.7,
42.9, 30.0, 26.8.
1-Benzyl-5-propargylpyrrolidin-2-one (4c)32
In a dry round-bottomed flask under nitrogen, N-benzyl-5-hydroxy-
pyrrolidin-2-one (2b) (191 mg, 1.0 mmol) was dissolved in anhydrous
CH2Cl2 (10 mL) at room temperature. Titanium tetrachloride (0.21 mL,
1.1 mmol) was added dropwise and the resulting solution was al-
lowed to stir for 10 min. In a separate round-bottomed flask under ni-
trogen, propargyl bromide (0.35 mL, 80% in toluene, 3.0 mmol) was
dissolved in anhydrous THF (10 mL) at room temperature. Zn powder
(197 mg, 3.0 mmol) was added in one portion and the resulting sus-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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I. Zaragoza-Galicia et al.
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Synthesis
pension was stirred for 10 min and then cooled to 0 °C. The solution
of 2b from the first flask was added dropwise and the resulting mix-
ture stirred overnight and then quenched with saturated NH4Cl solu-
tion. The reaction mixture was filtered over Celite and the filter cake
washed with CH2Cl2. The product was extracted with CH2Cl2 (3 × 50
mL) and the combined extracts were dried over Na2SO4, filtered and
concentrated. The residue was purified by flash column chromatogra-
phy (silica gel, hexanes–EtOAc, 7:3).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610733.
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References
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Yield: 127 mg (60%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 7.40–7.20 (m, 5 H), 5.04 (d, J = 15 Hz, 1
H), 3.98 (d, J = 15 Hz, 1 H), 3.62–3.57 (m, 1 H), 2.68–2.47 (m, 1 H),
2.45–2.35 (m, 3 H), 2.22–2.12 (m, 1 H), 2.08–1.93 (m, 2 H).
13C NMR (75 MHz, CDCl3):  = 175.3, 136.3, 128.7, 128.6, 128.4, 128.0,
127.6, 79.2, 71.2, 55.3, 44.1, 30.1, 23.5, 23.1.
(2) Furneaux, R. H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. C. Tetra-
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1,5,8,8a-Tetrahydroindolizin-3(2H)-one (6)31
To a solution of the bis-alkenylpyrrolidin-2-one 4h (165 mg, 1.0
mmol) in dichloromethane (10 mL) at room temperature was added
dropwise a solution of Grubbs II reagent (40 mg, 10% mol) in di-
chloromethane (5 mL). The reaction was heated at reflux temperature
in a nitrogen atmosphere for 1.5 h. The solvent was removed under
reduced pressure and the residue was purified by flash column chro-
matography with hexanes–EtOAc (1:1) to give 6. Starting from 4h
(165 mg, 1.0 mmol), product 6 was obtained after purification by
flash column chromatography (silica gel, hexanes–EtOAc, 1:1).
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Yield: 115 mg (81%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 5.76–5.62 (m, 2 H), 4.19 (d, J = 18.9 Hz,
1 H), 3.57–3.45 (m, 2 H), 2.36–2.21 (m, 4 H), 2.00–1.90 (m, 1 H), 1.67–
1.55 (m, 1 H).
13C NMR (75 MHz, CDCl3):  = 174.1, 124.1, 123.4, 52.9, 40.3, 32.4,
29.9, 25.4.
1,2,5,6,9,9a-Hexahydro-3H-pyrrolo[1,2-a]azepin-3-one (7)31
Following the typical procedure from 4i (100 mg, 0.55 mmol) in di-
chloromethane (7 mL) and Grubbs II reagent (30 mg) in dichloro-
methane (3 mL), 7 was obtained after purification by flash column
chromatography (hexanes–EtOAc, 1:1). Starting from 4i (100 mg, 0.55
mmol), product 7 was obtained after purification by flash column
chromatography (silica gel, hexanes–EtOAc, 1:1).
Yield: 61 mg (70%); pale yellow oil.
1H NMR (300 MHz, CDCl3):  = 5.93–5.73 (m, 2 H), 3.96–3.88 (m, 1 H),
3.72–3.62 (m, 1 H), 3.09–3.01 (m, 1 H), 2.39–2.17 (m, 7 H), 1.71–1.59
(m, 1 H).
13C NMR (75 MHz, CDCl3):  = 174.2, 131.6, 128.4, 58.5, 41.3, 36.3,
30.4, 27.8, 25.6.
Funding Information
The Consejo Nacional de Ciencia y Tecnología (National Council of Sci-
ence and Technology) is gratefully acknowledged for providing an
M.Sc. fellowship to Zaira A. Santos (CONACyT 642259).
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Acknowledgment
The authors wish to thank Maria de las Nieves Zavala Segovia M.Sc.
(CCIQS UNAM-UAEM) for obtaining NMR spectra and Prof. Joseph M.
Muchowski (UNAM) for helpful discussions and interest in our work.
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Synthesis
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© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G