Functionalized Cyclopropanes as Versatile Intermediates for the Diversity-Oriented Synthesis of γ-Lactones, γ-Lactams and δ-Lactams

Article abstract of DOI:10.1055/a-1389-1203

A two-step procedure for the preparation of cyclopropanecarboxaldehyde-1,1-diester from a γ,δ-epoxyester and its synthetic versatility are described herein. The epoxide ring-opening/cyclopropanation process occurs in the presence of Mg(ClO ₄) ₂under heating, resulting in cyclopropanemethanol-1,1-diester in 65% yield. A mild TEMPO-mediated oxidation of this substrate readily generated the corresponding aldehyde in 75% yield, which was applied in the one-pot synthesis of four cyclopropylidene-γ-lactams and three δ-lactams. In addition, vinylcyclopropanes were obtained through the Wittig reaction of the aldehyde with phosphonium salts and used as precursors for tetrahydrofurans.

Full text of DOI:10.1055/a-1389-1203

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2
021, 53, A–N
feature
A
en
Synthesis
A. P. Maximiano et al.
Feature
Functionalized Cyclopropanes as Versatile Intermediates for
the Diversity-Oriented Synthesis of -Lactones, -Lactams and

-Lactams
Adrielle P. Maximianoa
Giovana S. Ramosa
Marcelo V. Marquesb
Marcus M. Sá*a
O
H
CO2Et
H
CO2Et
CO2Et
Mg(ClO4)2 MW
OH
O
O
N
N
one-pot
CO2Et
O
R
RNH , MBH4
2
THF
60 °C
N
a
R
MESOLab (Laboratory of Methodology and Organic Synthesis),
Departamento de Química, Universidade Federal de Santa Catarina,
TCCA
TEMPO
CO2Et
CO2Et
CO2Et
HO
O
2 2
RNH , H /Pd
88040-900 Florianópolis-SC, Brazil
CO2Et
one-pot
H
marcus.sa@ufsc.br
Instituto Federal Catarinense (IFC), Campus Fraiburgo, 89580-000
Fraiburgo-SC, Brazil
b
CO2Et
CO2Et
CO2Et
O
CO2Et
R
O
O
To Professor Albert J. Kascheres, in memoriam
O
O
Ph
O
Ph
O
Ar
Corresponding Author
Received: 30.11.2020
Accepted after revision: 11.02.2021
Published online: 11.02.2021
Cyclopropane-1,1-diesters containing the carboxalde-
hyde group (Ι, Scheme 1) have been known for decades and
are of particular interest due to their distinct uses in syn-
DOI: 10.1055/a-1389-1203; Art ID: ss-2020-z0612-fa
16
thesis. Warner was a pioneer in the synthesis of a substi-
tuted cyclopropane-1,1-diester containing the carboxalde-
hyde group Ι, using acrolein and ethyl bromomalonate as
Abstract A two-step procedure for the preparation of cyclopropane-
carboxaldehyde-1,1-diester from a ,-epoxyester and its synthetic ver-
satility are described herein. The epoxide ring-opening/cyclopropana-
tion process occurs in the presence of Mg(ClO4)2 under heating,
resulting in cyclopropanemethanol-1,1-diester in 65% yield. A mild
TEMPO-mediated oxidation of this substrate readily generated the cor-
responding aldehyde in 75% yield, which was applied in the one-pot
synthesis of four cyclopropylidene--lactams and three -lactams. In
addition, vinylcyclopropanes were obtained through the Wittig reac-
tion of the aldehyde with phosphonium salts and used as precursors for
tetrahydrofurans.
1
7
the precursors in the presence of a strong base (Scheme
1). Later, Le Goffic and co-workers reported a method for
the preparation of an analogue of Ι in 60% yield, from acro-
lein and methyl bromomalonate, by replacing NaOEt with
1
8
K CO as the base. More recently, methodologies involving
2
3
the use of organocatalysis for the enantioselective cyclopro-
panation of ,-unsaturated aldehydes have been de-
19–21
scribed.
Key words ,-epoxyester, cyclopropanecarboxaldehyde, lactoniza-
tion, cyclopropylidene--lactams, -lactams, one-pot process, structur-
al diversity
Previous work:
Warner17
O
O
NaOEt, EtOH, 5 °C
~20 h, 49% (R = Et)
RO
OR
+
CO2R
CO2R
H
Br
O
Functionalized cyclopropanes are widely used in organ-
ic synthesis as versatile building blocks due to their distinct
reactivity modes as a C3 unit in a series of inter- or intra-
molecular transformations.1 Despite its unique reactivity,
the cyclopropyl fragment is commonly found in natural
products and pharmacologically active compounds, making
Le Goffic18
O
H
K2CO3, DMF, r.t.
I
H
2
h, 60% (R = Me)
Our group22,23
O
–7
H
CO2R
H
CO2R
R1
R
2
CO2R
R1
N
Ph
N
R3
CO2R
OH
O
R3
O
O
1
8–10
2
3
this strained ring a highly attractive synthetic target.
This work:
Cyclopropanecarboxaldehydes are among the most
commonly employed functionalized cyclopropanes in syn-
H
CO2Et
O
H
CO2Et
X
CO2Et
LA
[O]
O
X
1
1
2
CO Et
H
thesis. They are interesting synthetic intermediates that
have found application in several transformations such as
HO
O
5
1
a
4
X = OEt, N(CH2)4
1
2
13
ring-opening reactions, rearrangements, and annula-
alkenes, furans, γ-lactams, δ-lactams
tions/cyclizations, among others,15 resulting in a diversity
of products that include functionalized carbocycles, hetero-
cycles and polycyclic structures of molecular complexity.
14
Scheme 1 Synthesis of functionalized cyclopropane-1,1-diesters
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
A. P. Maximiano et al.
Feature
We have recently been conducting research on the
chemistry of functionalized cyclopropanes, developing a
cooperative acid/base catalysis for the stereoselective syn-
thesis of cyclopropanecarboxamides 2 from ,-epoxyesters
1 through a domino cyclopropanation/lactonization/ami-
2
2
nolysis process. These cyclopropanecarboxamides 2 were
further employed in a novel acid-mediated diastereoselec-
tive cyclization reaction as a simple and reliable method to
Biographical Sketches
Adrielle Patricio Maximiano
received her master’s degree in
organic chemistry from the Fed-
eral University of Santa Catarina
tegic Areas - researcher in the
company), she returned to UFSC
and joined MESOLab. In 2020,
she obtained her PhD in organic
chemistry under the guidance of
Prof. Marcus Mandolesi Sá. Her
work was focused on the develop-
ment of efficient methods for the
diastereoselective synthesis of
carbo- and heterocycles employ-
ing functionalized epoxides and
cyclopropanes.
(
UFSC) in 2013. After two years
as a fellow of the RHAE-CNPq pro-
gram (Human Resources in Stra-
Marcelo Volpatto Marques
received his bachelor’s degree in
chemistry from the Universidade
Luterana do Brasil in 2007 and his
master’s degree from the Federal
University of Rio Grande do Sul in
2010. In 2014, he received his
PhD from UFSC under the guid-
ance of Prof. Marcus Mandolesi
Sá. His PhD research focused on
the preparation of ,-epoxy-
malonates and their application
in the synthesis of cyclopropane
carboxamides and -arylmethyl
lactones. He is currently the coor-
dinator of the Postgraduate Pro-
gram at the Instituto Federal
Catarinense (IFC).
Giovana da Silva Ramos
earned her BSc degree in chemis-
try in 2018 at the State University
of Londrina (UEL), Brazil. During
that period, she also studied
chemistry at Purdue University –
Calumet (IN, USA) for a year, as a
Science Without Borders ex-
change student. She obtained her
master’s degree also at UEL in
2020, and is currently a graduate
student under the mentoring of
Prof. Marcus Mandolesi Sá at
UFSC. Her main research interests
include organic synthesis, with
emphasis on the synthesis of bio-
active molecules.
Marcus Mandolesi Sá is a Full
Professor of Organic Chemistry at
the Federal University of Santa
Catarina (UFSC), in Florianópolis,
Brazil. He received his diploma
Prof. Albert Padwa at Emory Uni-
versity (Atlanta, USA) working on
the reactivity of diazo com-
pounds. In 1997, he returned to
Brazil and joined the group of
Prof. José Tércio Ferreira at the
Federal University of São Carlos as
a postdoctoral researcher in me-
dicinal chemistry for one year. He
then moved to UFSC in 1998 to
start his independent academic
career. After being promoted to
Associate Professor, he was
awarded Full Professor of Organic
Chemistry in 2019 at UFSC. He
has been granted research schol-
arships from CNPq (Brazilian Re-
search Council, 2007–2022) and
is currently the Coordinator of
the Chemistry Postgraduate Pro-
gram at UFSC. His research group
focuses on the development of
sustainable synthetic methods,
the synthesis of heterocycles and
bioactive substances, and the re-
activity of three-membered rings
and multifunctionalized com-
pounds.
(
1989) and his doctoral (1995)
degrees in organic chemistry
from the State University of
Campinas (UNICAMP) under the
guidance
of
Prof.
Albert
Kascheres, studying the chemis-
try of vinyl azides and azirines. He
then spent two years as a post-
doctoral fellow in the group of
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

C
Synthesis
A. P. Maximiano et al.
Feature
access cyclopropylidene iminolactones 3, which were found
tion of alcohol 4a, although the reaction time was longer
than that observed under microwave-assisted conditions
(compare with entry 2).
to be versatile building blocks for the construction of cyclo-
2
3
propanes decorated with a variety of functional groups
Scheme 1).
Herein, we describe the straightforward isomerization
(
This somewhat unexpected chemoselectivity led us to
investigate other possible conditions for this epoxide-to-cy-
clopropane isomerization. It was found that the addition of
an external base hinders the formation of 4a, as lactone 6
was the sole product detected in the crude mixture (Table 1,
entry 4). Similarly, decreasing the amount of Mg(ClO ) had
of epoxide 1a to give cyclopropanemethanol 4a, mediated
by a Lewis acid, and also address its mild oxidation to cyclo-
propanecarboxaldehyde 5a, which was able to participate
in further synthetic transformations to give a diversity of
O- and N-heterocycles.
4
2
a negative effect on the selective formation of 4a, furnishing
lactone 6 competitively in nonnegligible amounts (entry 5).
Other Lewis acids tested proved to be either inefficient (en-
tries 6, 10–12) or nonselective (entries 7–9) for the forma-
tion of alcohol 4a.
During the studies involved in the Lewis acid mediated
preparation of cyclopropanecarboxamides 2 from ,-ep-
oxyesters 1 and amines through the domino process de-
scribed previously,22 we found that the transformation is
catalyst-dependent. For the particular case of the terminal
epoxide 1a, employing LiCl as the catalyst (as in the original
Having established the appropriate conditions for the
Mg(ClO ) -mediated isomerization of epoxide 1a to cyclo-
4
2
22
method) under microwave conditions, in the absence of
an added amine or any other external base, led to the exclu-
sive formation of the known cyclopropylidenelactone 6 (Ta-
ble 1, entry 1). However, replacing LiCl with Mg(ClO ) fur-
propanemethanol 4a (Table 1, entries 2 and 3), the synthet-
ic application of 4a was investigated. Firstly, the acylation of
the primary hydroxyl group was readily achieved with
functionalized carboxylic acids through the Steglich esteri-
4
2
2
4
nished cyclopropanemethanol 4a in 65% yield, with no de-
tectable presence of lactone 6 (entry 2). Conducting the
Mg(ClO ) -mediated transformation under conventional
fication reaction. This simple strategy generates potential
precursors 7 for the Lewis acid mediated intramolecular
[3+2] cycloaddition attempted in this study (Scheme 2).
However, no bicyclic framework, such as 8, was detected
under the various conditions applied. Instead, cyclopro-
panes 7 underwent ring expansion in the presence of scan-
dium(III) triflate, employed as the catalyst, to give exclu-
sively -lactones 9. The Lewis acid catalyzed unimolecular
formation of -lactones from cyclopropane-1,1-diesters has
some precedents in the literature as an alternative pathway
4
2
heating (oil bath, entry 3) also led to the exclusive forma-
Table 1 Synthesis of Cyclopropanemethanol 4a and Cyclopropylidene-
lactone 6 from ,-Epoxyester 1a
O
O
CO2Et
CO2Et
CO Et
Lewis acid
+
2
HO
OEt
OEt
25
THF, MW
60 °C, 80 W
to other previously designed transformations. For the par-
O
O
O
1
a
4a
6
ticular case of fumaric ester 7a, the corresponding lactone
9
a was isolated in excellent yield as a diastereomeric mix-
Entry Lewis acid (equiv)
Time (h)
Conv. (%)a
Ratio 4a/6
ture (1:1 syn/anti, Scheme 2). The ,-unsaturated ester 7b
was also tested and, as anticipated, led to -lactone 9b in
moderate yield. On the other hand, the isomeric ,-unsat-
urated ester 7c underwent extensive isomerization of the
C=C double bond during the ring expansion, giving rise to a
complex mixture of diastereoisomers 9b and 9c (syn versus
anti as well as ,- versus ,-unsaturation) that could not
be properly separated by chromatography. For the malonyl
derivative 7d, slow consume of the starting material was
observed and the expected lactone was not formed in sig-
nificant amounts after 72 hours.
a
b
(%) [Yield (%)]
1
2
3
4
5
6
7
8
9
LiCl (1.0)
0.75
0.75
2
48
100
100
100
100
0
0:100
100:0 [65]
100:0 [58]
0:100
73:27
–
Mg(ClO
Mg(ClO
Mg(ClO
Mg(ClO
4
4
4
4
)
)
)
)
2
2
2
2
(1.0)
(1.0)c
(1.0)d
(0.2)
0.75
2
MgSO
4
(1.0)
0.75
0.75
24
Yb(OTf)
3
3
(0.2)
(0.2)e
(0.2)
(0.2)
100
100
100
100
0
0:100
50:50
0:100f
–f
Yb(OTf)
It is also important to note that cyclopropanemethanol
a was unable to generate the corresponding -lactone un-
Cu(OTf)
Fe(OTf)
Zn(OAc)
SrCl (0.2)
2
0.75
0.75
0.75
0.75
4
1
0
1
2
3
der reaction conditions similar to those used for esters 7
[Sc(OTf) , CH Cl , r.t.] or even more vigorous conditions
1
2
(0.2)
–
3
2
2
(
heating for prolonged periods), suggesting that the pres-
1
2
0
–
a
1
ence of the free hydroxyl group in 4a hinders the ring ex-
pansion process.
Another interesting application of cyclopropanemetha-
nol 4a was found in the straightforward oxidation to the
corresponding cyclopropanecarboxaldehyde 5a through a
combination of trichloroisocyanuric acid (TCCA) and cata-
Conversion (%) and ratio (%) were determined by H NMR integration of
the crude reaction mixture.
b
Yield of isolated cyclopropanemethanol 4a after column chromatography.
Reaction carried out at 60 °C under conventional heating (oil bath).
Addition of triethylamine (1 equiv).
c
d
e
f
Reaction carried out at r.t.
Presence of unidentified products.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

D
Synthesis
A. P. Maximiano et al.
Feature
O
CO2Et
CO2Et
CO Et
CO2Et
CO2Et
CO2Et
CO2Et
2
CO2Et
CO2Et
O
O
O
O
O
O
O
O
O
HO
R
OH
2
CO Et
DIC or EDC
DMAP, r.t.
OEt
4
a
7a (53%)
r.t. Sc(OTf)3
7b (25%)
7c (78%)
7d (50%)
EtO
O
r.t. Sc(OTf)3
72 h CH2Cl2
r.t. Sc(OTf)3
22 h CH2Cl2
7
2 h CH2Cl2
O
O
O
CO2Et
CO2Et
CO2Et
O
CO2Et
CO2Et
CO2Et
O
O
O
EtO
O
O
O
O
O
O
O
8
O
9a (99%)
:1 diastereoisomers
9b (48%)
1:1 diastereoisomers
9c-(β,γ)
+ 9b-(α,β)
1
Scheme 2 Preparation of -lactones 9 from O-acylated cyclopropanes 7
lytic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), at
room temperature, according to the method described by
De Luca and co-workers26 (Scheme 3).
cyclopropanecarboxamides 4b and 2b (Scheme 3). In the
case of cyclopropanecarboxaldehyde monoamide 5b, it was
obtained from 4b after 30 minutes in 76% yield. The less re-
active secondary alcohol in the phenyl-substituted cyclo-
propanecarboxamide 2b was also conveniently oxidized to
the ketonic derivative 10, although a more prolonged reac-
tion time was required to achieve a reasonable isolated
yield. In contrast, cyclopropanecarboxamide 4c underwent
extensive decomposition under similar oxidation condi-
tions and did not result in the expected aldehyde. This
could be explained by the presence of a free N–H amidic
bond in 4c, which might be competitively oxidized to give
reactive N–O and N–Cl intermediates that decompose un-
der the reaction conditions employed.
CO2Et
CO2Et
CO2Et
[
O]
HO
O
20 min
CO2Et
H
4
a
5a (75%)
H
CO2Et
N
[O]
H
CO2Et
N
HO
HO
30 min
O
O
H
O
4
b
5b (76%)
H
CO2Me
N
H CO2Me
[O]
O
N
O
O
24 h
O
With the straightforward preparation of cyclopropane-
carboxaldehyde 5a in hand, it was attractive to employ this
functionalized building block in a variety of reactions using
different nucleophiles. Firstly, a mild Wittig reaction with
phosphonium salts 11 in the presence of a weak base, such
as K CO , was developed to give vinylcyclopropanes 12 with
2
b
10
47%)
(
H
CO2Et
NH
[
O]
Conditions: [O] =
TCCA (1.05 equiv)
TEMPO (0.02 equiv)
CH2Cl2, 0–25 °C
HO
X
4
c
2
3
Scheme 3 Oxidation of cyclopropanemethanol 4a and carboxamides
varied trans/cis diastereoselectivity depending on the
structure of the starting phosphonium (Scheme 4). Thus,
benzyl-derived semistabilized ylides originating from salts
11a–c gave alkenes 12a–c in trans/cis ratios ranging from
80:20 to 60:40, while the stabilized ylide obtained from -
keto phosphonium 11d furnished exclusively the trans-
alkene 12d in high yield.
4
b and 2b
With these simple reaction conditions, it was possible to
obtain cyclopropanecarboxaldehyde 5a in a short reaction
time of 20 minutes. Aldehyde 5a was obtained in 75% yield
after a workup which consisted of simple filtration through
Celite followed by washing the filtrate with aqueous satu-
rated Na CO and 1 M HCl. No additional purification step
was necessary due to the high purity of the product, as de-
termined by H NMR analysis (see the Supporting Informa-
tion). The fact that the oxidation is carried out at room tem-
perature with readily accessible reagents compares favor-
ably to the existing methods described in the literature for
the oxidation of related cyclopropanemethanols to cyclo-
CO2Et
CO2Et
RCH2PPh3X (11)
CO2Et
2
3
O
K2CO3, THF
r.t., 12–48 h
R
2
CO Et
5
a
12
H
1
NO2
CO2Et
CO2Et
CO2Et
CO2Et
1
2a (77%, 12 h)
12b (77%, 24 h)
trans/cis = 60:40
trans/cis = 80:20
Br
CO2Et
CO2Et
CO2Et
CO2Et
propanecarboxaldehydes, which involve the use of toxic
chromium-based oxidizing agents15c,27 or the Swern oxida-
O
tion under cryogenic conditions (–78 °C).28
12c (51%, 24 h)
trans/cis = 67:33
12d (83%, 48 h)
trans/cis >99:1
Given the facility with which aldehyde 5a could be ob-
tained from alcohol 4a, this oxidation method with TCCA/
TEMPO was also extended to the hydroxy-substituted
Scheme 4 Preparation of vinylcyclopropanes 12 through the Wittig re-
action from aldehyde 5a and phosphonium salts 11 (RPPh X; X = Br, Cl)
3
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

E
Synthesis
A. P. Maximiano et al.
Feature
CO
CO
2
Me
CO
CO Et
2
Et
4
-MeC
6
H
4
CHO
Sc(OTf)
(0.2 equiv)
3
CO Et
2
2
Me
2
Sc(OTf)3 (0.2 equiv)
CO
Et
Et
2
CH Cl , 2 h, 50%
2
2
CO
CH Cl , r.t.
2
2
O
O
Ph
O
2
O
4
8 h, 43%
Ph
(trans/cis = 80:20)
Ph
14'
ref. 29a
Ph
14
(syn/anti = 85:15)
12a
Ph
13
(dr = 55:45)
Scheme 5 Synthesis of O-heterocycles 13 and 14 from vinylcyclopropane 12a
Vinylcyclopropanes, such as 12a, have been applied in
the synthesis of several compounds, serving as a 1,3-dipolar
synthon due to the donor–acceptor substitution pattern at-
clopropylidene--lactams 15 and an iminosugar analogue.
Initially, allylamine was employed as the model amine and
the reaction conditions were evaluated, including the type
and stoichiometry of reducing agent, the solvent and the re-
action time (Table 2). As observed in entry 1, treating 5a
with allylamine for 16–18 hours followed by the addition of
2
9,30
tached to the ring.
We explored the synthetic versatility
of 12a for the preparation of O-heterocycles such as -lac-
tone 13 and tetrahydrofuran 14 (Scheme 5). Vinylcyclopro-
pane 12a was treated with catalytic Sc(OTf) to give the cor-
1.0 equivalent of NaBH to the pre-formed imine 16a pro-
3
4
responding -lactone 13 in 43% yield (55:45 mixture of
anti/syn diastereoisomers) through ring expansion, as ob-
served previously for the O-acylated cyclopropanes 7 (see
Scheme 2). On the other hand, a different reaction outcome
was observed in the presence of tolualdehyde as an external
duced cyclopropylidene--lactam 15a (58% yield), which
was obtained in reasonable purity from the organic extracts
after aqueous workup with NH Cl. The relatively low per-
4
centage of recovered mass for 15a was correlated to the
competitive formation of hydroxylated cyclopropylidene--
lactam 17a, which was recovered from the aqueous layer af-
ter basification of the acidic aqueous phase and subsequent
back-extraction with ethyl acetate. This interesting bicycle
17a possesses a structural motif related to pyrrolidine imi-
2
9
dipolarophile. The spectroscopic data for the cycloaddi-
tion adduct 14 are in agreement with those found for the
analogue 14′ (Scheme 5), which was previously prepared by
2
9a
Pohlhaus and Johnson.
On the basis of these previous
2
9a
31
studies, the relative stereochemistry of the major isomer
was assigned as being syn.
nosugars and may originate from the selective overreduc-
tion of the carboxylate group in the main product 15a or in
the various intermediates postulated for this one-pot pro-
cess. Indeed, a control reaction partially supported the for-
mation of 17a from the direct reduction of 15a with NaBH4,
The synthetic versatility of cyclopropanecarboxalde-
hyde 5a was also addressed through a one-pot imina-
tion/reductive cyclization as a direct strategy to access cy-
Table 2 Reaction Conditions Used in the Preparation of Cyclopropylidene--lactam 15aa
CO2Et
CO2Et
CO2Et
CO2Et
1. MBH4
1.5–36 h
H
CO2Et
O
H
H2N
OH
O
+
solvent, r.t.
overnight
2. NH4Cl(aq)
O
H
N
N
N
5a
16a
(
M = Na, K)
1
5a
17a
Time (h)b
Yield (%) of 15a
c
Yield (%) of 17a
c
Entry
Reducing agent (equiv)
Solvent
1
2
3
4
5
6
7
8
NaBH
NaBH
NaBH
NaBH
NaBH
NaBH
4
4
4
4
4
4
(1.0)
(0.5)
(2.0)
(1.0)
(1.0)
(1.0)d
2-propanol
2-propanol
2-propanol
2-propanol
ethanol
21
26
26
58
40
25
30
15
25
20
0
64c
37
1.5
40
36
24
28
23
24
25
2-propanol
2-propanol
ethanol
32
KBH
4
4
(1.0)
(1.0)
21e
24e
35e
KBH
–f
9
NaBH
3
CN (1.0)
ethanol
–f
a
One-pot reaction conditions: 1. aldehyde 5a, amine (1.0 equiv), solvent, r.t., 16–18 h; 2. reducing agent, r.t.
b
c
d
e
f
Time refers to the reduction step.
Yields after aqueous workup; products were of satisfactory purity, as verified by H NMR analysis of the crude reaction mixtures.
LiCl (1.0 equiv) was added to the reaction medium.
1
Yield of cyclopropylidene--lactam 15a after column chromatography.
The aqueous phase was not recovered.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

F
Synthesis
A. P. Maximiano et al.
Feature
although the conversion was not selective and secondary
byproducts were also detected in the NMR analysis of the
crude reaction mixture.
due to the intrinsic conformational constraints. To the best
of our knowledge, there have been only two reports related
to the one-pot imination/reductive cyclization from cyclo-
propanecarboxaldehydes to give cyclopropylidene--lact-
We were unable to improve the formation of alcohol
1
6e,33
1
7a from the one-pot imination/reductive cyclization and
ams.
However, both transformations are very particu-
the protocol described in entry 1 of Table 2 was found to be
the best approach (see the experimental section). On the
other hand, the formation of cyclopropylidene--lactam
lar cases and do not constitute a general method for the
preparation of bicyclic lactams due to the absence of a
broader study to determine the proper reaction conditions
that would be applied to structurally diverse substrates.
Considering these limitations together with our results, we
extended the one-pot imination/reductive cyclization strat-
egy to other representative amines, namely n-butylamine,
benzylamine and p-anisidine (Scheme 6).
1
5a could be slightly improved by decreasing the amount of
NaBH and adding molecular sieves to act as a water scav-
4
enger (entry 2). In this case, 15a was cleanly obtained in
6
4% yield without requiring any further purification. Other
variations in the reaction conditions, such as increasing the
amount of reducing agent (entry 3), decreasing the reaction
time (entry 4), changing the solvent (entry 5) or adding
lithium chloride as an additive (entry 6), all led to inferior
results compared to entries 1 and 2.
The data collected indicate that the one-pot imina-
tion/reductive cyclization process is substrate-dependent
and none of the reducing agents under study were found to
be suitable for general application in terms of furnishing
the expected cyclopropylidene--lactams 15 in acceptable
yield for each amine studied. However, employing either
NaBH or KBH led to satisfactory results depending on the
The replacement of NaBH with a milder hydride, such
4
as KBH (Table 2, entry 7), promoted the expected forma-
4
tion of 15a, but in this case the conversion was not com-
plete and the imine intermediate 16a as well as the starting
4
4
aliphatic amine employed. The use of KBH as the reducing
4
1
aldehyde 5a were both detected in the H NMR analysis of
agent resulted in slightly better yields for -lactams 15b
the crude reaction mixture. The complete consumption of
intermediates and starting materials was achieved when
and 15c when compared with NaBH . Surprisingly, the gen-
4
eration of the elusive hydroxylated cyclopropylidene--lac-
tam 17b or 17c that would arise from the overreduction of
the carboxylate group, as observed previously for allyl-
amine (see the formation of 17a in Table 2), was not detect-
ed in the crude reaction mixture for the other amines under
study. In the case of a less nucleophilic aromatic amine (p-
anisidine), the formation of the expected bicyclic lactam 15
was not observed, possibly due to the low propensity of the
cyclopropylamine intermediate 18d to undergo cyclization,
being isolated as the single product in varying yields de-
pending on the hydride source (Scheme 6).
KBH was used in the presence of ethanol as the solvent
4
(
entry 8) instead of 2-propanol, but the isolated yield ob-
tained for 15a after purification by chromatography (24%)
was not as significant as that observed with the use of
NaBH . Nevertheless, the recovered mass of the crude prod-
4
uct 15a originating from the one-pot imination/reductive
cyclization process with KBH was higher than with NaBH ,
4
4
indicating that the potassium-derived reducing agent could
be employed with other substrates (see below). On the oth-
er hand, the use of a more harmful reducing agent
(
NaBH CN, entry 9) furnished lactam 15a together with un-
Besides the use of metal hydrides in the imination/re-
ductive cyclization from aldehyde 5a and amines, a one-pot
process employing catalytic hydrogenation was also evalu-
ated, and the main results are compiled in Table 3. While
the imination/reductive cyclization mediated by metal
borohydrides furnished cyclopropylidene--lactams 15, the
3
identified byproducts, resulting in a low isolated yield of
5a.
Cyclopropanes fused to pyrrolidine rings represent a
1
privileged class of organic compounds in view of their rec-
ognized pharmacological properties, including antiviral,
antibiotic and anxiolytic activity.32 Nevertheless, accessing
these bicyclic structures represents a synthetic challenge
use of H in the presence of a Pd-supported catalyst pro-
2
moted the lactamization with concomitant ring opening of
i
O
1
. RNH2, PrOH
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
r.t., 18 h
OEt
O
CO2Et 2. NaBH4 or KBH4
O
NH
N
H
N
5
a
r.t., 1.5–26 h
N
16
18
15
R
R
R
H
O
O
O
CO2Et
CO2Et
H
H
H
OEt
OEt
OEt
OH
O
O
N
O
O
N
N
NH
MeO
1
5a
15b
15c
(15%, 1.5 h)
(40%, 24 h)b
17a
(40%, 21 h)a
18d
a
a
a
(29%, 24 h)a
(50%, 24 h)b
(
(
64%, 26 h)
(22%, 1.5 h)
21%, 28 h)b
(25%, 1 h)b
Scheme 6 One-pot synthesis of cyclopropylidene--lactams 15 from aldehyde 5a. a NaBH ; b KBH4.
4
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

G
Synthesis
A. P. Maximiano et al.
Feature
the cyclopropyl moiety to give -lactams (2-piperidinones)
under the catalytic hydrogenation conditions tested did not
lead to the expected -lactam 19d (entries 6 and 7), while
attempts to hydrogenate the intermediate imine 16d gave
mixtures of unidentified products (entry 8).
1
9. The piperidine ring is one of the most prevalent hetero-
3
4
cycles among the US-FDA approved pharmaceuticals.
Therefore, the simple preparation of substituted -lactams
would provide convenient access to advanced building
blocks of synthetic relevance for the chemistry of piperi-
dines.
For the hydrogenation involving aldehyde 5a and n-bu-
tylamine, the corresponding -lactam 19b was obtained us-
In summary, we developed a simple and mild procedure
for the synthesis of diethyl 2-(hydroxymethyl)cyclopro-
pane-1,1-dicarboxylate (4a) from ,-epoxyester 1a pro-
moted by Mg(ClO ) . Acylation of alcohol 4a followed by
4
2
scandium(III)-catalyzed ring expansion gave -lactones 9 in
good yields but poor syn/anti diastereoselectivity. Alcohol
4a was readily oxidized to the corresponding aldehyde 5a in
high yield through a facile protocol based on the combina-
tion of TCCA/catalytic TEMPO. This method was successful-
ly extended to two tertiary cyclopropanecarboxamides 2b
and 4b, although the oxidation of the secondary amide 4c
did not result in the expected carbonyl compound due to
the uncontrolled reactivity of the free N–H amidic bond.
The synthetic versatility of cyclopropanecarboxalde-
hyde-1,1-diester 5a was revealed in a series of transforma-
tions. The preparation of vinylcyclopropanes 12 through
the Wittig reaction with phosphonium salts in a mild alka-
line medium gave access to functionalized O-heterocycles,
either through scandium-catalyzed ring expansion to give
-lactone 13 or a formal [3+2] cycloaddition with tolualde-
hyde to furnish tetrahydrofuran 14. Furthermore, aldehyde
5a was employed in the one-pot synthesis of cyclopro-
pylidene--lactams 15 (as well as the overreduced lactam
17) through an imination/reductive cyclization process in
the presence of a primary amine and a metal borohydride.
Although the yields vary depending on the amine and boro-
hydride used, the conditions are simple and the resulting
bicyclic -lactams 15 and 17 can be considered as advanced
building blocks for the chemistry of iminosugars. Finally,
ing Pd(OH) /C as the catalyst for 1 hour (Table 3, entry 1).
2
Replacing Pd(OH) /C with Pd/C did not lead to the forma-
2
tion of the expected -lactam 19b under the same reaction
conditions and only the intermediate imine 16b was de-
tected in the crude reaction mixture (entry 2). Treating
imine 16b with H –Pd/C for more prolonged periods led to
2
a mixture of unidentified products (entry 3). On the other
hand, when benzylamine was employed in the one-pot pro-
cess, with Pd/C as the catalyst and a reaction time of 1 hour,
the corresponding N-benzyl--lactam 19c was obtained in
1
6
5% yield together with the N-unsubstituted -lactam 20 in
0% yield, which would arise from the hydrogenolysis of
the N-benzyl group (entry 4). The selective formation of de-
benzylated -lactam 20 was achieved through the use of
Pd(OH) /C for an extended time (entry 5). Interestingly, an
2
attempt to convert cyclopropylidene--lactam 15c into -
lactam 19c or 20 under catalytic hydrogenation conditions
[
H , Pd(OH) /C, EtOH, 24 h] was not successful and only the
2 2
starting material was recovered from the reaction medium
after workup (results not shown). This control reaction in-
dicates that -lactam 15 is not involved in the generation of

-lactam 19 or 20 and the ring opening of the cyclopropyl
moiety should occur before the cyclization to the six-mem-
bered ring. Finally, the use of the less reactive p-anisidine
Table 3 Catalytic Hydrogenation in the One-Pot Protocol from Aldehyde 5a and Aminesa
CO2Et
O
CO2Et
O
CO2Et
CO2Et
CO2Et
CO2Et
RNH2
H2, 1 atm
O
EtOH, r.t.
overnight
catalyst, r.t.
N
N
H
N
R
H
5a
R
16
19
20
Entry
R
Catalyst
Time (h)b
Product
Yield (%)c
1
2
3
4
5
6
7
nBu
nBu
nBu
Bn
Pd(OH)
2
/C
1
1
19b
16b
–e
20
Pd/C
–
Pd/Cd
Pd/C
4
–
1
19c/20
20
15/60
Bn
Pd(OH)
2
2
/C
24
0.5
24
12
99
–
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
4
4
4
Pd/C
16d
–e
H
H
Pd/C
–
8
Pd(OH)
/Cd
–e
–
a
2
One-pot reaction conditions: 1. aldehyde 5a, amine (1.0 equiv), EtOH, r.t., 23 h; 2. catalyst (0.1 equiv), H , 1 atm, r.t.
Time refers to the catalytic hydrogenation reaction.
Isolated yield after purification by column chromatography, except for lactam 20 (entry 5), which was obtained in high purity without any further purification step.
The hydrogenation reaction was carried out directly with the imine intermediate 16.
Cyclopropane ring opening and formation of unidentified products.
b
c
d
e
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

H
Synthesis
A. P. Maximiano et al.
Feature
the one-pot reduction carried out under catalytic hydroge-
Diethyl 2-(Hydroxymethyl)cyclopropane-1,1-dicarboxylate (4a)
nation [H –Pd/C or Pd(OH) /C] led to -lactams 19 or 20 as
To a stirred solution of ethyl (±)-4,5-epoxy-2-(ethoxycarbonyl)penta-
noate (1a; 0.54 g, 2.5 mmol) in THF (6 mL), at r.t., was added
2
2
a result of the cyclopropane ring opening before lactamiza-
tion. The results described herein demonstrate the poten-
tial of alcohol 4a and aldehyde 5a as versatile intermediates
for the diversity-oriented synthesis of O- and N-hetero-
cycles of biological interest.
Mg(ClO4) (0.56 g, 2.5 mmol). The resulting suspension was submit-
2
ted to microwave irradiation at 60 °C (80 W) for 45 min. Next, H O (50
2
mL) was added to the reaction medium. The reaction mixture was ex-
tracted with EtOAc (6 × 20 mL). The organic extract was dried with
anhydrous Na SO and concentrated under reduced pressure to give a
2
4
crude oil. Purification by column chromatography (silica gel; hex-
ane/EtOAc, 3:2) resulted in 4a as a light yellow oil in 65% yield (0.35
g). The reaction also takes place under conventional heating at 60 °C,
but with a longer time of 2 h.
All chemicals were of reagent grade and used as received. Phosphoni-
um salt 11d (acetonyltriphenylphosphonium chloride) was purchased
from Sigma-Aldrich. Phosphonium salts 11a–c were prepared by re-
acting triphenylphosphine and the corresponding benzyl bromide in
acetonitrile under microwave irradiation at 100 °C (80 W) for 30 min.
IR (KBr): 3523, 2984, 2878, 1728, 1371, 1205, 1132, 1028 cm–1
.
1
H NMR (200 MHz, CDCl ):  = 4.32–4.14 (m, 4 H, OCH ), 3.91 (dd, J =
3
2
1
2
2.4, 5.0 Hz, 1 H, CH OH), 3.31 (dd, J = 12.4, 9.0 Hz, 1 H, CH OH), 2.21–
2
2
Their physical and spectroscopic data were consistent with the ex-
.06 (m, 1 H, CH), 1.52 (dd, J = 9.0, 5.0 Hz, 1 H, CH ), 1.38–1.23 (m, 7 H,
pected structures and the related literature.35 Infrared spectra were
2
CH + CH ).
2
3
acquired with an FT-IR spectrometer (FT Alpha, Bruker) using KBr
pellets. TLC analysis was performed on silica gel plates supported on
aluminum with fluorescent indicator and visualized by irradiation
with UV light. Phosphomolybdic acid in EtOH was used as TLC stain-
ing solution. Column chromatographic purifications were performed
using silica gel (70–230 mesh) as the stationary phase and hex-
1
3
C NMR (50 MHz, CDCl ):  = 170.0 (C), 168.8 (C), 62.4 (CH ), 62.0
3
2
(
(
CH ), 61.9 (CH ), 34.0 (C), 29.9 (CH), 18.2 (CH ), 14.14 (CH ), 14.12
CH3).
2
2
2
3
+
HRMS (ESI+): m/z [M + Na] calcd for C10H16O Na: 239.08899; found:
5
239.08902.
1
13
ane/EtOAc as the eluent. H NMR and C NMR spectra were recorded
on a Bruker AC-200F (200 MHz and 50 MHz, respectively) or Varian
AS-400 (400 MHz and 100 MHz, respectively) spectrometer. Chemical
Esters 7 by O-Acylation of Diethyl 2-(Hydroxymethyl)cyclopro-
pane-1,1-dicarboxylate (4a); General Procedure
shifts were recorded in parts per million (ppm, ), relative to CDCl (
3
To a stirred solution of diethyl 2-(hydroxymethyl)cyclopropane-1,1-
dicarboxylate (4a; 216.2 mg, 1.0 mmol) and the corresponding car-
boxylic acid (1.2 mmol) in CH Cl (2 mL), at 0 °C (in an ice bath), was
1
13
=
7.26 ppm for H NMR and  = 77.16 ppm for C NMR) or TMS (0.00
ppm) as the internal standard. Splitting patterns are designated as s
2
2
(
(
singlet), bs (broad singlet), d (doublet), dd (doublet of doublet), ddd
doublet of doublet of doublet), dt (doublet of triplet), app dt (appar-
added N,N′-diisopropylcarbodiimide (187.8 L, 1.2 mmol) for 7a,c,d
or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
ent douplet of triplet), t (triplet), q (quartet), m (multiplet). Coupling
constants (J) are given in hertz (Hz). The ESI-QTOF mass spectrometer
(
230.0 mg, 1.2 mmol; previously diluted in 1 equiv of 4-(dimethyl-
amino)pyridine and 1 mL of CH Cl ) for 7b. After 5 min, 4-(dimethyl-
2
2
(
micrOTOF Q-II, Bruker Daltonics) was operated in the positive ion
amino)pyridine (146.6 mg, 1.2 mmol) was added and the ice bath was
removed so that the reaction mixture reached r.t. The reaction was
stirred for 2–72 h, then the insoluble solid formed was filtered off un-
der reduced pressure and washed with CH Cl . The filtrate was
mode at 4.5 kV and at a desolvation temperature of 180 °C. A standard
electrospray ion (ESI) source was used to generate the ions. The in-
strument was calibrated in the range of m/z 50–3000 using a calibra-
tion standard (low concentration tuning mix solution) and data were
processed with the aid of computer software. Microwave-assisted re-
actions were performed in 10 mL sealed tubes in a monomode micro-
wave CEM Explorer reactor instrument with infrared temperature
monitoring and a noninvasive pressure transducer.
2
2
washed successively with 1.0 M HCl, satd NaHCO and brine. The or-
3
ganic phase was dried with anhydrous Na SO and concentrated un-
2
4
der reduced pressure, providing the crude product. Purification by
column chromatography (silica gel; hexane/EtOAc, 3:2) gave ester 7.
Diethyl 2-{[(E)-4-Ethoxy-4-oxobutenoyloxy]methyl}cyclopro-
pane-1,1-dicarboxylate (7a)
Ethyl (±)-4,5-Epoxy-2-(ethoxycarbonyl)pentanoate22 (1a)
To a stirred solution of commercially available diethyl 2-allylmalonate
Yield: 53% (181.4 mg); 2 h; yellow oil.
IR (KBr): 2984, 1726, 1646, 1467, 1297, 1026, 775 cm–1
.
(
0.88 mL, 4.5 mmol) in EtOAc (30 mL), acetone (17 mL) and phosphate
–
1
buffer (K HPO /KH PO , 1.0 mol·L , pH 8, 40 mL), at r.t., was added
2
4
2
4
1
dropwise a solution of Oxone (5.53 g, 9.0 mmol) in H O (40 mL). The
H NMR (400 MHz, CDCl ):  = 6.84 (d, J = 16.0 Hz, 1 H, =CH), 6.80 (d,
2
3
reaction was stirred overnight (16–18 h). The insoluble solid was fil-
tered off under reduced pressure and washed with EtOAc. The filtrate
was washed with 1.0 M Na S O and brine, dried with anhydrous
J = 16.0 Hz, 1 H, =CH), 4.34 (dd, J = 12.0, 6.4 Hz, 1 H, OCH ), 4.26–4.11
2
(m, 6 H, OCH ), 4.07 (dd, J = 12.0, 8.4 Hz, 1 H, OCH ), 2.33–2.25 (m, 1
2
2
2
2
3
H, CH), 1.54 (dd, J = 7.6, 5.2 Hz, 1 H, CH ), 1.46 (dd, J = 9.0, 5.2 Hz, 1 H,
2
Na SO and concentrated under reduced pressure to give a crude oil.
CH ), 1.30 (t, J = 7.2 Hz, 3 H, CH ), 1.27–1.23 (m, 6 H, CH ).
2
4
2
3
3
Purification by column chromatography (silica gel; hexane/EtOAc,
13
C NMR (50 MHz, CDCl ):  = 169.3 (C), 167.4 (C), 164.8 (C), 164.5 (C),
3
3:2) provided epoxide 1a as a light yellow oil in 86% yield (0.84 g).
1
34.2 (CH), 132.9 (CH), 63.4 (CH ), 61.8 (2 × CH ), 61.4 (CH ), 33.4 (C),
2 2 2
1
H NMR (200 MHz, CDCl ):  = 4.21–4.09 (m, 4 H, OCH ), 3.47 (dd, J =
25.3 (CH), 18.6 (CH ), 14.1 (CH ), 14.03 (CH ), 13.98 (CH ).
3
2
2 3 3 3
8
.4, 6.3 Hz, 1 H, CH), 3.00–2.91 (m, 1 H, CH), 2.71 (t, J = 4.7 Hz, 1 H,
HRMS (ESI+): m/z [M + H]+ calcd for C16H23O : 343.1387; found:
8
CH ), 2.46 (dd, J = 4.7, 2.5 Hz, 1 H, CH ), 2.20 (ddd, J = 14.2, 8.4, 4.7 Hz,
1
2
2
3
43.1389.
H, CH ), 1.93 (dt, J = 14.2, 6.3 Hz, 1 H, CH ), 1.25–1.17 (m, 6 H, CH ).
2 2 3
Diethyl 2-{[(E)-But-2-enoyloxy]methyl}cyclopropane-1,1-dicar-
boxylate (7b)
Yield: 25% (71.1 mg); 72 h; light yellow oil.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

I
Synthesis
A. P. Maximiano et al.
Feature
IR (KBr): 3098, 2982, 1726, 1658, 1446, 1371, 1179, 1134, 971 cm–1
.
13
C NMR (50 MHz, CDCl ):  = 171.1 (C), 170.9 (C), 167.5 (C), 167.3 (C),
3
1
164.7 (C), 164.6 (C), 164.5 (C), 164.4 (C), 135.1 (CH), 134.9 (CH), 132.4
H NMR (200 MHz, CDCl ):  = 7.03–6.85 (m, 1 H, =CH), 5.83–5.74 (m,
3
(
(
(
CH), 132.2 (CH), 76.3 (CH), 75.9 (CH), 65.6 (CH ), 65.4 (CH ), 62.6
1
H, =CH), 4.27–4.07 (m, 5 H, OCH ), 4.00 (dd, J = 12.1, 8.1 Hz, 1 H,
2
2
2
CH ), 62.5 (CH ), 61.6 (CH ), 61.5 (CH ), 46.51 (CH), 46.48 (CH), 28.1
OCH ), 2.33–2.17 (m, 1 H, CH), 1.86–1.82 (m, 3 H, CH ), 1.51 (dd, J =
7
Hz, 6 H, CH3).
2
2
2
2
2
3
CH ), 27.8 (CH ), 14.13 (2 × CH ), 14.10 (2 × CH ).
.4, 4.6 Hz, 1 H, CH ), 1.41 (dd, J = 9.1, 4.6 Hz, 1 H, CH ), 1.22 (t, J = 7.3
2
2
3
3
2
2
HRMS (ESI+): m/z [M + Na]+ calcd for C14H18O Na: 337.0894; found:
8
1
3
337.0895.
C NMR (50 MHz, CDCl ):  = 169.6 (C), 167.5 (C), 166.0 (C), 145.2
3
(
CH), 122.3 (CH), 62.2 (CH ), 61.7 (2 × CH ), 33.4 (C), 25.7 (CH), 18.7
2
2
(CH ), 18.0 (CH ), 14.08 (CH ), 14.06 (CH ).
5-{[(E)-But-2-enoyloxy]methyl}-3-(ethoxycarbonyl)--lactone
2
3
3
3
HRMS (ESI+): m/z [M + Na]+ calcd for C14H20O Na: 307.1152; found:
(9b)
6
To a stirred solution of 7b (284.3 mg, 1.0 mmol) in CH Cl (3.5 mL), at
307.1151.
2
2
r.t., was added Sc(OTf) (98.4 mg, 0.2 mmol). After 72 h, the reaction
3
mixture was filtered through a pad of silica gel. The filtrate was con-
centrated under reduced pressure to give a colorless oil.
Diethyl 2-[(But-3-enoyloxy)methyl]cyclopropane-1,1-dicarboxyl-
ate (7c)
Yield: 48% (123.0 mg); mixture of diastereoisomers (1:1).
Yield: 78% (221.8 mg); 19 h; colorless oil.
IR (KBr): 3084, 2984, 1732, 1644, 1467, 1322, 1207, 1134, 997 cm–1
IR (KBr): 2923, 1779, 1724, 1656, 1446, 1261, 1157, 967 cm–1
1H NMR (200 MHz, CDCl
):  = 7.13–6.93 (m, 1 H, =CH), 5.92–5.81 (m,
.
.
1
3
H NMR (200 MHz, CDCl ):  = 5.94–5.73 (m, 1 H, =CH), 5.13–5.03 (m,
3
1
4
1
H, =CH), 4.97–4.85 (m, 0.5 H, CH), 4.79–4.65 (m, 0.5 H, CH), 4.46–
.20 (m, 4 H, OCH ), 3.70–3.60 (m, 1 H, CH), 2.84–2.24 (m, 2 H, CH ),
2
H, =CH ), 4.27–4.04 (m, 5 H, OCH ), 3.95 (dd, J = 11.9, 7.9 Hz, 1 H,
2
2
OCH ), 3.02 (d, J = 6.6 Hz, 2 H, COCH ), 2.28–2.12 (m, 1 H, CH), 1.50–
2
2
2
2
.92–1.87 (m, 3 H, CH ), 1.32 (t, J = 7.0 Hz, 3 H, CH ).
1
.35 (m, 2 H, CH ), 1.21 (t, J = 7.3 Hz, 3 H, CH ), 1.20 (t, J = 7.3 Hz, 3 H,
3
3
2
3
1
3
CH3).
C NMR (50 MHz, CDCl ):  = 171.4 (C), 171.1 (C), 167.7 (C), 167.4 (C),
3
1
3
166.0 (C), 165.9 (C), 146.6 (CH), 146.4 (CH), 121.9 (CH), 121.8 (CH),
C NMR (50 MHz, CDCl ):  = 171.1 (C), 169.5 (C), 167.4 (C), 130.1
3
7
4
1
6.7 (CH), 76.4 (CH), 64.8 (CH ), 64.5 (CH ), 62.6 (CH ), 62.5 (CH ),
(CH), 118.6 (CH ), 62.8 (CH ), 61.72 (CH ), 61.71 (CH ), 38.9 (CH ),
2 2 2 2
2
2
2
2
2
6.7 (CH), 46.6 (CH), 28.3 (CH ), 28.0 (CH ), 18.24 (CH ), 18.21 (CH ),
3
3.4 (C), 25.6 (CH), 18.7 (CH ), 14.10 (CH ), 14.06 (CH ).
2
2
3
3
2
3
3
4.2 (2 × CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C14H21O : 285.1333; found:
6
2
85.1334.
Oxidation of Cyclopropane-1,1-diester 4a and Cyclopropanecar-
boxamides; General Procedure
Diethyl 2-[(3-Ethoxy-3-oxopropanoyloxy)methyl]cyclopropane-
,1-dicarboxylate (7d)
To a stirred solution of cyclopropane-1,1-diester 4a (0.86 g, 4.0
mmol) or cyclopropanecarboxamide 4b or 2b (4.0 mmol) in CH Cl (8
1
2
2
Yield: 50% (165.2 mg); 24 h; yellow oil.
IR (KBr): 3100, 2984, 1752, 1726, 1467, 1132, 1028, 863 cm–1
mL), at 0 °C (in an ice bath), was added TCCA (0.97 g, 4.2 mmol) fol-
lowed by TEMPO (12.5 mg, 0.08 mmol). The ice bath was removed so
that the reaction mixture reached r.t. The reaction was monitored by
TLC until the total consumption of the starting material (20 min to 24
h). Next, the mixture was filtered through Celite and the filtrate was
.
1
H NMR (400 MHz, CDCl ):  = 4.27–4.11 (m, 7 H, OCH ), 4.06 (dd, J =
3
2
12.0, 8.0 Hz, 1 H, OCH ), 3.34 (s, 2 H, CH ), 2.28–2.20 (m, 1 H, CH), 1.51
2
2
(dd, J = 7.4, 5.0 Hz, 1 H, CH ), 1.43 (dd, J = 9.4, 5.0 Hz, 1 H, CH ), 1.27–
2
2
washed with satd Na CO (3 × 20 mL) and 1 M HCl. Then, the organic
1.22 (m, 9 H, CH3).
2
3
extract was dried with anhydrous Na SO and concentrated under re-
1
3
2
4
C NMR (50 MHz, CDCl ):  = 169.3 (C), 167.3 (C), 166.2 (C), 63.4
3
duced pressure to give the expected product in high purity without
any further purification step.
(CH ), 61.7 (CH ), 61.5 (CH ), 41.3 (CH ), 33.4 (C), 25.2 (CH), 18.6
2
2
2
2
(CH ), 13.98 (CH ), 13.96 (2 × CH ).
2
3
3
HRMS (ESI+): m/z [M + Na]+ calcd for C15H22O Na: 353.1207; found:
8
Diethyl 2-Formylcyclopropane-1,1-dicarboxylate17 (5a)
353.1209.
Yield: 75% (0.64 g); 20 min; yellow oil.
IR (KBr): 3104, 2984, 2874, 1783, 1732, 1448, 1373, 1269, 1201, 1022,
8
3

-(Ethoxycarbonyl)-5-{[(E)-4-ethoxy-4-oxobutenoyloxy]methyl}-
-lactone (9a)
65 cm–1
.
1
H NMR (400 MHz, CDCl ):  = 9.31 (d, J = 4.4 Hz, 1 H, CHO), 4.29–4.15
To a stirred solution of 7a (342.3 mg, 1.0 mmol) in CH Cl (3.5 mL), at
r.t., was added Sc(OTf) (98.4 mg, 0.2 mmol). After 72 h, the reaction
mixture was filtered through a pad of silica gel. The filtrate was con-
centrated under reduced pressure to give a yellow oil.
3
2
2
(
m, 4 H, OCH ), 2.73 (ddd, J = 8.8, 7.0, 4.4 Hz, 1 H, CH), 2.06 (dd, J = 7.0,
2
3
5
6
.2 Hz, 1 H, CH ), 1.80 (dd, J = 8.8, 5.2 Hz, 1 H, CH ), 1.27 (t, J = 7.2 Hz,
2 2
H, CH3).
1
3
C NMR (100 MHz, CDCl ):  = 196.4 (CH), 168.0 (C), 166.0 (C), 62.5
Yield: 99% (311.1 mg); mixture of diastereoisomers (1:1).
IR (KBr): 2984, 1781, 1726, 1301, 1263, 1157, 1030, 977 cm–1
3
(
CH ), 62.3 (CH ), 34.9 (CH + C), 19.3 (CH ), 14.1 (2 × CH ).
2
2
2
3
.
HRMS (ESI+): m/z [M + Na]+ calcd for C10H14O Na: 237.0733; found:
1
5
H NMR (200 MHz, CDCl ):  = 6.80 (bs, 2 H, =CH), 4.95–4.83 (m, 0.5 H,
3
2
37.0732.
CH), 4.78–4.64 (m, 0.5 H, CH), 4.45 (dd, J = 4.6, 3.2 Hz, 0.5 H, CH ), 4.39
2
(
3
dd, J = 4.6, 3.2 Hz, 0.5 H, CH ), 4.32–4.14 (m, 5 H, CH + OCH ), 3.68–
2
2
2
Ethyl 2-Formyl-1-(pyrrolidin-1-ylcarbonyl)cyclopropane-1-car-
boxylate (5b)
.58 (m, 1 H, CH), 2.79–2.19 (m, 2 H, CH ), 1.25 (t, J = 7.1 Hz, 6 H, CH ).
2
3
Yield: 76% (0.73 g); 30 min; brown oil.
IR (KBr): 2978, 2878, 1779, 1722, 1636, 1444, 1254, 1146 cm–1
.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

J
Synthesis
A. P. Maximiano et al.
Feature
1
H NMR (400 MHz, CDCl ):  = 8.91 (d, J = 6.0 Hz, 1 H, CHO), 4.16 (q,
Diethyl 2-(2-Nitrostyryl)cyclopropane-1,1-dicarboxylate (12b)
3
J = 7.2 Hz, 2 H, OCH ), 3.48–3.21 (m, 4 H, NCH ), 2.61 (ddd, J = 6.4, 6.0,
2
2
Mixture of isomers (60:40 trans/cis).
4
.0 Hz, 1 H, CH), 2.06 (dd, J = 6.4, 4.8 Hz, 1 H, CH ), 1.95–1.80 (m, 5 H,
2
Yield: 77% (256 mg); 24 h; yellow oil.
CH ), 1.20 (t, J = 7.2 Hz, 3 H, CH ).
2
3
IR (KBr): 3070, 2984, 1726, 1526, 1444, 1346, 1203, 1132, 1024, 787
1
3
C NMR (100 MHz, CDCl ):  = 196.5 (CH), 168.3 (C), 162.7 (C), 62.2
3
–1
cm
.
(
CH ), 46.4 (CH ), 46.2 (CH ), 38.1 (C), 35.6 (CH), 25.7 (CH ), 23.9
2
2
2
2
1
H NMR (400 MHz, CDCl ):  (trans isomer) = 7.92 (dd, J = 8.2, 1.0 Hz,
(
CH ), 19.5 (CH ), 13.9 (CH ).
3
2
2
3
1
H, CH ), 7.64–7.36 (m, 3 H, CH ), 7.15 (d, J = 15.6 Hz, 1 H, =CH),
+
A
r
A
r
HRMS (ESI+): m/z [M + Na] calcd for C12H17NO Na: 262.1050; found:
4
5
.84 (dd, J = 15.6, 8.8 Hz, 1 H, =CH), 4.32–4.14 (m, 4 H, OCH ), 2.65–
2
262.1051.
2
.58 (m, 1 H, CH), 1.82 (dd, J = 7.2, 5.2 Hz, 1 H, CH ), 1.72 (dd, J = 9.0,
2
5
.2 Hz, 1 H, CH ), 1.30 (t, J = 7.2 Hz, 3 H, CH ), 1.26 (t, J = 7.2 Hz, 3 H,
2
3
Methyl 2-Benzoyl-1-(pyrrolidin-1-ylcarbonyl)cyclopropane-1-car-
boxylate (10)
CH3).
1
H NMR (400 MHz, CDCl ):  (cis isomer) = 8.08 (dd, J = 8.2, 1.0 Hz, 1
3
Purified by column chromatography (silica gel; hexane/EtOAc, 2:3).
Yield: 47% (0.57 g); 24 h; yellow oil.
H, CH ), 7.64–7.36 (m, 3 H, CH ), 6.92 (d, J = 11.2 Hz, 1 H, =CH), 5.39
(dd, J = 11.2, 10.0 Hz, 1 H, =CH), 4.32–4.14 (m, 4 H, OCH ), 2.82–2.76
Ar
Ar
2
(
m, 1 H, CH), 1.76 (dd, J = 7.4, 4.8 Hz, 1 H, CH ), 1.60 (dd, J = 9.0, 4.8 Hz,
IR (KBr): 3062, 2956, 2878, 1730, 1677, 1646, 1446, 1273, 1148, 702
2
–
1
1 H, CH ), 1.31 (t, J = 7.2 Hz, 3 H, CH ), 1.26 (t, J = 7.2 Hz, 3 H, CH ).
1
cm
.
2
3
3
3
1
C NMR (100 MHz, CDCl ):  = 169.3 (C), 169.2 (C), 167.6 (C), 167.5
3
H NMR (200 MHz, CDCl ):  = 8.01–7.96 (m, 2 H, CHAr), 7.59–7.39 (m,
3
(
(
1
C), 148.1 (C), 147.6 (C), 133.1 (2 × CH), 132.4 (C), 132.2 (C), 132.1
CH), 131.0 (CH), 129.6 (CH), 129.1 (CH), 128.6 (CH), 128.49 (CH),
3
H, CH ), 3.76 (s, 3 H, OCH ), 3.56 (dd, J = 8.6, 7.0 Hz, 1 H, CH), 3.44 (t,
A
r
3
J = 6.8 Hz, 2 H, NCH ), 3.35–3.11 (m, 2 H, NCH ), 2.25 (dd, J = 7.0, 4.0
2
2
28.47 (CH), 128.2 (CH), 124.9 (CH), 124.7 (CH), 61.9 (CH ), 61.83 (2 ×
Hz, 1 H, CH ), 1.82–1.60 (m, 5 H, CH ).
2
2
2
CH ), 61.77 (CH ), 36.7 (C), 36.5 (C), 31.0 (CH), 27.4 (CH), 22.3 (CH ),
2
1
3
2
2
2
C NMR (100 MHz, CDCl ):  = 194.7 (C), 170.4 (C), 163.1 (C), 137.3
3
1.3 (CH ), 14.33 (CH ), 14.29 (CH ), 14.2 (2 × CH ).
2 3 3 3
(
C), 133.4 (CH), 128.7 (2 × CH), 128.4 (2 × CH), 53.3 (CH ), 46.8 (CH ),
3
2
+
HRMS (ESI+): m/z [M + Na] calcd for C17H NO Na: 356.1105; found:
3
4
6.2 (CH ), 40.7 (C), 31.6 (CH), 25.9 (CH ), 24.0 (CH ), 22.0 (CH ).
19
6
2
2
2
2
56.1107.
+
HRMS (ESI+): m/z [M + Na] calcd for C17H19NO Na: 324.1206; found:
4
3
24.1205.
Diethyl 2-(2-Bromostyryl)cyclopropane-1,1-dicarboxylate (12c)
Mixture of isomers (67:33 trans/cis).
Alkenes 12; General Procedure
Yield: 51% (187 mg); 24 h; yellow oil.
To a stirred solution of cyclopropanecarboxaldehyde 5a (214.2 mg,
IR (KBr): 3056, 2982, 1726, 1469, 1371, 1201, 1132, 1024, 753 cm–1
.
1.0 mmol) in THF (4 mL), at r.t., were added the corresponding phos-
phonium salt 11 (1.2 mmol) and K CO (207.3 mg, 1.5 mmol). After
stirring the suspension for 12–48 h, the solvent was evaporated and
the residue was diluted with EtOAc (15 mL). The resulting organic
1
2
3
H NMR (400 MHz, CDCl ):  (trans isomer) = 7.44 (dd, J = 8.0, 1.2 Hz,
3
1
6
(
(
1
H, CH ), 7.30 (dd, J = 8.0, 1.6 Hz, 1 H, CH ), 7.16–7.12 (m, 1 H, CH ),
A
r
A
r
A
r
.99 (dt, J = 8.0, 1.6 Hz, 1 H, CH ), 6.91 (d, J = 15.6 Hz, 1 H, =CH), 5.70
Ar
solution was washed with H O and brine. The organic phase was
2
dd, J = 15.6, 8.8 Hz, 1 H, =CH), 4.22–4.07 (m, 4 H, OCH ), 2.75–2.66
2
dried with anhydrous Na SO and concentrated under reduced pres-
2
4
m, 1 H, CH), 1.75 (dd, J = 7.4, 4.8 Hz, 1 H, CH ), 1.61 (dd, J = 9.0, 4.8 Hz,
2
sure to provide the crude product. Purification by column chromatog-
raphy (silica gel; hexane/EtOAc, 3:2) gave alkene 12.
H, CH ), 1.22 (t, J = 7.2 Hz, 3 H, CH ), 1.17 (t, J = 7.2 Hz, 3 H, CH ).
2
3
3
1
H NMR (400 MHz, CDCl ):  (cis isomer) = 7.51 (dd, J = 7.8, 1.2 Hz, 1
3
H, CH ), 7.41 (dd, J = 7.8, 1.8 Hz, 1 H, CH ), 7.22 (dt, J = 7.8, 1.2 Hz, 1
Diethyl 2-Styrylcyclopropane-1,1-dicarboxylate36 (12a)
Ar
Ar
H, CH ), 7.05 (dt, J = 7.8, 1.8 Hz, 1 H, CH ), 6.58 (d, J = 11.6 Hz, 1 H,
Ar
Ar
Mixture of isomers (80:20 trans/cis).
=
CH), 5.25 (dd, J = 11.6, 9.8 Hz, 1 H, =CH), 4.22–4.07 (m, 4 H, OCH2),
Yield: 77% (222 mg); 12 h; yellow oil.
2.75–2.64 (m, 1 H, CH), 1.67 (dd, J = 7.4, 4.8 Hz, 1 H, CH ), 1.53 (dd, J =
2
IR (KBr): 3082, 2982, 2872, 1724, 1448, 1371, 1201, 1026, 694 cm–1
8.8, 4.8 Hz, 1 H, CH
H, CH3).
), 1.21 (t, J = 7.2 Hz, 3 H, CH ), 1.18 (t, J = 7.2 Hz, 3
2 3
.
1
H NMR (400 MHz, CDCl ):  (trans isomer) = 7.33–7.12 (m, 5 H,
3
1
3
C NMR (100 MHz, CDCl ):  = 169.5 (C), 169.3 (C), 167.7 (C), 167.6
CH ), 6.57 (d, J = 16.0 Hz, 1 H, =CH), 5.74 (dd, J = 16.0, 8.8 Hz, 1 H,
3
Ar
(
(
C), 136.65 (C), 136.62 (C), 133.0 (CH), 132.8 (CH), 132.7 (CH), 132.3
CH), 130.8 (CH), 128.95 (CH), 128.89 (CH), 128.3 (CH), 128.1 (CH),
=
CH), 4.22–4.06 (m, 4 H, OCH ), 2.70–2.64 (m, 1 H, CH), 1.75 (dd, J =
2
7
.6, 4.8 Hz, 1 H, CH ), 1.59 (dd, J = 9.2, 4.8 Hz, 1 H, CH ), 1.22 (t, J = 7.2
2
2
1
6
2
27.5 (CH), 127.1 (CH), 126.8 (CH), 124.1 (C), 123.3 (C), 61.8 (CH2),
Hz, 3 H, CH ), 1.15 (t, J = 7.4 Hz, 3 H, CH ).
3
3
1.70 (CH ), 61.69 (CH ), 61.67 (CH ), 36.6 (C), 36.4 (C), 31.1 (CH),
2
2
2
1
H NMR (400 MHz, CDCl ):  (cis isomer) = 7.33–7.12 (m, 5 H, CH ),
3
Ar
7.6 (CH), 22.3 (CH ), 21.2 (CH ), 14.33 (CH ), 14.30 (CH ), 14.20
2
2
3
3
6.52 (d, J = 11.6 Hz, 1 H, =CH), 5.17 (dd, J = 11.6, 9.6 Hz, 1 H, =CH),
(
CH ), 14.17 (CH ).
3
3
4
.22–4.06 (m, 4 H, OCH ), 2.91–2.85 (m, 1 H, CH), 1.66 (dd, J = 7.6, 4.8
2
+
HRMS (ESI+): m/z [M + Na] calcd for C17H BrO Na: 389.0359; found:
Hz, 1 H, CH ), 1.61–1.55 (m, 1 H, CH ), 1.23–1.13 (m, 6 H, CH ).
19
4
2
2
3
3
89.0360.
1
3
C NMR (50 MHz, CDCl ):  = 169.7 (C), 167.7 (C), 136.9 (C), 136.8 (C),
3
1
1
33.7 (CH), 133.6 (CH), 129.0 (2 × CH), 128.7 (2 × CH), 128.4 (2 × CH),
27.7 (CH), 127.4 (CH), 126.9 (CH), 126.2 (2 × CH), 125.0 (CH), 61.8
Diethyl 2-[(E)-3-Oxobut-1-en-1-yl]cyclopropane-1,1-dicarboxyl-
ate (12d)
(
(
(
CH ), 61.7 (CH ), 61.6 (2 × CH ), 36.8 (C), 36.5 (C), 31.3 (CH), 27.9
CH), 22.6 (CH ), 21.2 (CH ), 14.4 (CH ), 14.34 (CH ), 14.27 (CH ), 14.2
CH3).
2 2 2
Yield: 83% (211 mg); 48 h; yellow oil.
2
2
3
3
3
IR (KBr): 2984, 2876, 1728, 1677, 1626, 1371, 1252, 1205, 1132, 1022,
971 cm–1
.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H20O Na: 311.1254; found:
4
311.1252.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

K
Synthesis
A. P. Maximiano et al.
Feature
1
H NMR (400 MHz, CDCl ):  = 6.37–6.29 (m, 2 H, =CH), 4.30–4.15 (m,
Hz, 1 H, OCH), 4.30–4.06 (m, 2 H, OCH ), 3.77–3.31 (m, 2 H, OCH ),
3
2
2
4
H, OCH ), 2.72–2.59 (m, 1 H, CH), 2.21 (s, 3 H, COCH ), 1.81 (dd, J =
3.00 (dd, J = 13.2, 6.5 Hz, 1 H, CH ), 2.23 (s, 3 H, CH ), 2.22–2.14 (m, 1
2
3
2
3
7
.4, 5.2 Hz, 1 H, CH ), 1.74 (dd, J = 8.8, 5.2 Hz, 1 H, CH ), 1.29 (t, J = 7.2
H, CH ), 1.16 (t, J = 7.2 Hz, 3 H, CH ), 0.74 (t, J = 7.2 Hz, 3 H, CH ).
2 3 3
2
2
Hz, 3 H, CH ), 1.28 (t, J = 7.2 Hz, 3 H, CH ).
13
3
3
C NMR (50 MHz, CDCl ):  (major trans isomer) = 170.9 (C), 168.8
3
1
3
C NMR (50 MHz, CDCl ):  = 197.2 (C), 168.9 (C), 167.1 (C), 142.7
(C), 137.8 (C), 136.6 (C), 135.0 (C), 132.8 (CH), 128.7 (2 × CH), 128.58
(CH), 128.55 (2 × CH), 128.0 (CH), 127.2 (2 × CH), 126.8 (2 × CH), 84.2
(CH), 79.0 (CH), 61.9 (CH ), 61.5 (CH ), 40.9 (CH ), 21.2 (CH ), 14.1
3
(
CH), 133.4 (CH), 62.1 (CH ), 62.0 (CH ), 37.1 (C), 29.8 (CH), 27.2 (CH ),
2
2
3
2
1.6 (CH ), 14.3 (CH ), 14.2 (CH ).
2
3
3
2
2
2
3
HRMS (ESI+): m/z [M + Na]+ calcd for C13H18O Na: 277.1046; found:
(CH
3
), 13.5 (CH ).
3
5
277.1047.
HRMS (ESI+): m/z [M + Na]+ calcd for C25H28O Na: 431.1829; found:
5
4
31.1832.
3
-(Ethoxycarbonyl)-5-[(E)-styryl]--lactone37 (13)
Cyclopropylidene--lactams 15; General Procedure
To a stirred solution of 12a (57.6 mg, 0.20 mmol) in CH Cl (1 mL), at
2
2
r.t., was added Sc(OTf) (19.7 mg, 0.04 mmol). After 48 h, the reaction
To a stirred solution of cyclopropanecarboxaldehyde 5a (214.2 mg,
1.0 mmol) in 2-propanol (2 mL), at r.t., was added the corresponding
amine (1.0 mmol). The reaction mixture was stirred overnight (16–18
3
mixture was filtered through a pad of Celite and silica gel. The filtrate
was concentrated under reduced pressure and the residue was puri-
fied by column chromatography (silica gel; hexane/EtOAc, 3:2) to give
lactone 13 as a yellow oil.
h). Next, the corresponding reducing agent (NaBH4 or KBH , 0.5–1.0
4
mmol) was added (for allylamine and benzylamine, 190 mg of 3 Å
molecular sieves were also added to the reaction mixture). After a
certain time (1–26 h), the solvent was removed under reduced pres-
sure and the residue was dissolved in EtOAc (10 mL). The resulting or-
ganic solution was washed with H O and 6 M NH Cl. The organic ex-
Yield: 43% (22.4 mg); mixture of diastereoisomers (55:45).
IR (KBr): 3082, 2990, 1771, 1740, 1452, 1373, 1171, 967, 761, 694 cm–1
.
1
H NMR (400 MHz, CDCl ):  = 7.42–7.26 (m, 5 H, CHAr), 6.72 (d, J =
3
2
4
1
6.0 Hz, 0.55 H, =CH), 6.71 (d, J = 16.0 Hz, 0.45 H, =CH), 6.25 (dd, J =
6.0, 7.2 Hz, 0.55 H, =CH), 6.17 (dd, J = 16.0, 7.2 Hz, 0.45 H, =CH),
.34–5.29 (m, 0.45 H, OCH), 5.09–5.03 (m, 0.55 H, OCH), 4.28 (q, J =
.2 Hz, 2 H, OCH ), 3.71–3.65 (m, 1 H, CH), 2.89–2.83 (m, 0.45 H, CH ),
tract was dried with anhydrous Na SO4 and concentrated under re-
2
1
5
7
2
0
duced pressure to provide a crude residue, which was purified by
column chromatography (silica gel; hexane/EtOAc, 3:2) to give the ex-
pected -lactam.
2
2
.74–2.67 (m, 0.55 H, CH ), 2.62–2.54 (m, 0.55 H, CH ), 2.38–2.30 (m,
.45 H, CH ), 1.33 (t, J = 7.2 Hz, 3 H, CH ).
2
2
2
3
Ethyl 3-Allyl-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylate38
(15a)
1
3
C NMR (100 MHz, CDCl ):  = 171.61 (C), 171.56 (C), 167.8 (C), 167.7
3
(
1
8
C), 135.6 (C), 134.5 (CH), 133.7 (CH), 128.9 (2 × CH), 128.8 (2 × CH),
NaBH (18.9 mg, 0.5 mmol) was used for 26 h.
4
28.7 (2 × CH), 127.0 (2 × CH), 126.9 (2 × CH), 125.7 (CH), 125.6 (CH),
0.1 (CH), 79.8 (CH), 62.5 (CH ), 62.4 (CH ), 47.4 (CH), 46.8 (CH), 33.1
Yield: 64% (134 mg); yellow oil (obtained in high purity without any
further purification step).
2
2
(CH ), 33.0 (CH ), 14.2 (2 × CH ).
2 2 3
IR (KBr): 3082, 2982, 1722, 1695, 1448, 1277, 1179, 1006, 934, 761
HRMS (ESI+): m/z [M + Na]+ calcd for C15H16O Na: 283.0941; found:
2
4
–1
cm
.
83.0938.
1
H NMR (200 MHz, CDCl ):  = 5.71–5.51 (m, 1 H, =CH), 5.14–5.03 (m,
3
2
H, =CH ), 4.17 (q, J = 7.0 Hz, 2 H, OCH ), 3.87–3.63 (m, 2 H, CH ), 3.46
2
2
2
Diethyl 5-Styryl-2-(4-tolyl)tetrahydrofuran-3,3-dicarboxylate (14)
(
(
dd, J = 10.6, 6.0 Hz, 1 H, NCH ), 3.14 (d, J = 10.6 Hz, 1 H, NCH ), 2.27
dt, J = 8.0, 6.0 Hz, 1 H, CH), 1.86 (dd, J = 8.0, 5.0 Hz, 1 H, CH ), 1.23 (t,
2
2
To a stirred solution of 12a (57.6 mg, 0.20 mmol) in CH Cl (2 mL), at
2
2
2
r.t., were added tolualdehyde (70.7 L, 0.6 mmol) and Sc(OTf) (19.7
3
J = 7.0 Hz, 3 H, CH ), 1.02 (t, J = 5.0 Hz, 1 H, CH ).
3
2
mg, 0.04 mmol). After 2 h, the reaction mixture was filtered through a
pad of silica gel. The filtrate was concentrated under reduced pressure
and diluted with EtOH (2 mL). Next, a solution of sodium bisulfite (62
1
3
C NMR (100 MHz, CDCl ):  = 169.2 (C), 168.8 (C), 132.4 (CH), 118.4
3
(
(
CH ), 61.5 (CH ), 46.8 (CH ), 45.2 (CH ), 31.9 (C), 22.9 (CH), 21.0
CH ), 14.3 (CH ).
2 2 2 2
mg) in H O (1 mL) was added to the reaction medium and the result-
2
3
2
+
ing mixture was stirred for 4 h. The reaction mixture was diluted with
H O (10 mL) and extracted with CH Cl (5 × 10 mL). The organic phase
HRMS (ESI+): m/z [M + Na] calcd for C11H15NO Na: 232.0944; found:
232.0944.
3
2
2
2
was dried with anhydrous Na SO and concentrated under reduced
2
4
pressure to furnish 14 as a yellow oil.
Ethyl 3-Butyl-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylate
(15b)
Yield: 50% (40.8 mg); mixture of diastereoisomers (85:15 major
trans/minor trans).
KBH (54.0 mg, 1.0 mmol) was used for 1 h.
4
IR (KBr): 3027, 2982, 1730, 1448, 1369, 1263, 1181, 1048, 694 cm–1
.
Yield: 25% (56.3 mg); yellow oil.
1
IR (KBr): 2960, 2874, 1722, 1693, 1452, 1379, 1279, 1181, 1057 cm–1
H NMR (200 MHz, CDCl ):  (major trans isomer) = 7.39–7.15 (m, 7
.
3
H, CH ), 7.02 (d, J = 7.6 Hz, 2 H, CHAr), 6.64 (d, J = 15.8 Hz, 1 H, =CH),
1
Ar
H NMR (400 MHz, CDCl ):  = 4.16 (q, J = 7.2 Hz, 2 H, OCH ), 3.49 (dd,
3
2
6.36 (dd, J = 15.8, 7.2 Hz, 1 H, =CH), 5.62 (s, 1 H, OCH), 4.49 (app dt, J =
J = 10.4, 6.0 Hz, 1 H, NCH ), 3.22–3.05 (m, 3 H, NCH ), 2.27 (dt, J = 8.0,
6
CH ), 1.26–1.17 (m, 2 H, CH ), 1.23 (t, J = 7.2 Hz, 3 H, CH ), 0.98 (t, J =
4
2
2
1
0.6, 6.5 Hz, 1 H, OCH), 4.30–4.06 (m, 2 H, OCH ), 3.77–3.31 (m, 2 H,
2
.0 Hz, 1 H, CH), 1.84 (dd, J = 8.0, 4.6 Hz, 1 H, CH ), 1.41–1.34 (m, 2 H,
2
OCH ), 2.78 (dd, J = 13.2, 10.6 Hz, 1 H, CH ), 2.46 (dd, J = 13.2, 6.0 Hz, 1
2
2
2
2
3
H, CH ), 2.23 (s, 3 H, CH ), 1.20 (t, J = 7.2 Hz, 3 H, CH ), 0.74 (t, J = 7.2
2
3
3
.6 Hz, 1 H, CH ), 0.84 (t, J = 7.2 Hz, 3 H, CH ).
2
3
Hz, 3 H, CH3).
1
3
C NMR (100 MHz, CDCl ):  = 169.3 (C), 168.9 (C), 61.5 (CH ), 47.1
3
2
1
H NMR (200 MHz, CDCl ):  (minor trans isomer) = 7.39–7.15 (m, 7
3
(
(
CH ), 42.1 (CH ), 31.9 (C), 29.4 (CH ), 22.8 (CH), 20.9 (CH ), 20.0
2
2
2
2
H, CH ), 7.02 (d, J = 7.6 Hz, 2 H, CH ), 6.60 (d, J = 16.2 Hz, 1 H, =CH),
Ar
Ar
CH ), 14.2 (CH ), 13.8 (CH ).
2
3
3
6.18 (dd, J = 16.2, 6.5 Hz, 1 H, =CH), 5.76 (s, 1 H, OCH), 5.16 (q, J = 6.5
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

L
Synthesis
A. P. Maximiano et al.
Feature
+
HRMS (ESI+): m/z [M + Na] calcd for C12H19NO Na: 248.1257; found:
Diethyl 2-{[(4-Methoxyphenyl)amino]methyl}cyclopropane-1,1-
dicarboxylate (18d)
3
248.1260.
To a stirred solution of imine 16d (319.3 mg, 1.0 mmol) in EtOH (2
Ethyl 3-Benzyl-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylate39
15c)
mL), at 0 °C (in an ice bath), was added KBH (53.9 mg, 1.0 mmol). Af-
4
(
ter 5 min, the ice bath was removed so that the reaction mixture
reached r.t. After 23 h, the solvent was evaporated under reduced
pressure and the residue was diluted with EtOAc (10 mL). The result-
ing organic solution was washed with H O and 6 M NH Cl. Next, the
KBH (53.9 mg, 1.0 mmol) was used for 24 h.
4
Yield: 40% (104 mg); yellow oil.
2
4
IR (KBr): 3064, 2982, 1720, 1693, 1448, 1379, 1277, 1185, 702 cm–1
.
organic extract was dried with anhydrous Na SO4 and concentrated
2
1
H NMR (400 MHz, CDCl ):  = 7.27–7.18 (m, 3 H, CH ), 7.13–7.11 (m,
under reduced pressure to give a crude oil. The product was purified
by column chromatography (silica gel; hexane/EtOAc, 7:3) and isolat-
ed as a brown oil in 50% yield (160 mg).
3
Ar
2
H, CH ), 4.43 (d, J = 14.4 Hz, 1 H, CH Ph), 4.20–4.15 (m, 3 H, CH Ph +
A
r
2
2
OCH ), 3.36 (dd, J = 10.4, 5.6 Hz, 1 H, NCH ), 3.02 (d, J = 10.4 Hz, 1 H,
2
2
NCH ), 2.23 (dt, J = 8.0, 5.6 Hz, 1 H, CH), 1.83 (dd, J = 8.0, 4.6 Hz, 1 H,
IR (KBr): 3390, 2982, 2833, 1724, 1514, 1283, 1036, 822 cm–1
2
.
CH ), 1.24 (t, J = 7.0 Hz, 3 H, CH ), 0.98 (t, J = 4.6 Hz, 1 H, CH ).
2
3
2
1
H NMR (400 MHz, CDCl ):  = 6.78 (d, J = 9.0 Hz, 2 H, CH ), 6.60 (d, J =
3
Ar
1
3
C NMR (100 MHz, CDCl ):  = 169.4 (C), 168.8 (C), 136.4 (C), 128.8 (2
3
9.0 Hz, 2 H, CH ), 4.28–4.13 (m, 4 H, OCH ), 3.75 (s, 3 H, OCH ), 3.36
A
r
2
3
×
3
CH), 128.3 (2 × CH), 127.8 (CH), 61.6 (CH ), 46.6 (CH ), 46.5 (CH ),
2 2 2
(dd, J = 13.2, 5.6 Hz, 1 H, NCH ), 2.88 (dd, J = 13.2, 8.0 Hz, 1 H, NCH ),
2 2
1.7 (C), 22.8 (CH), 20.8 (CH ), 14.3 (CH ).
2
3
2.26–2.19 (m, 1 H, CH), 1.51–1.45 (m, 2 H, CH ), 1.28 (t, J = 7.2 Hz, 3 H,
2
+
HRMS (ESI+): m/z [M + Na] calcd for C15H17NO Na: 282.1101; found:
CH ), 1.26 (t, J = 7.2 Hz, 3 H, CH ).
3 3
3
282.1103.
13
C NMR (50 MHz, CDCl ):  = 170.1 (C), 168.1 (C), 152.6 (C), 142.2 (C),
3
1
15.1 (2 × CH), 114.6 (2 × CH), 61.85 (CH ), 61.79 (CH ), 55.9 (CH ),
2
2
3
3
-Allyl-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-one (17a)
44.9 (CH ), 34.0 (C), 27.5 (CH), 19.3 (CH ), 14.3 (CH ), 14.2 (CH ).
2
2
3
3
HRMS (ESI+): m/z [M + H]+ calcd for C17H24NO : 322.1649; found:
To a stirred solution of cyclopropanecarboxaldehyde 5a (214.2 mg,
5
1
1
.0 mmol) in 2-propanol (2 mL), at r.t., was added allylamine (75.0 L,
322.1650.
.0 mmol). After 20 h, NaBH (37.8 mg, 1.0 mmol) was added and the
4
stirring was continued for another 21 h. The solvent was removed un-
der reduced pressure and the residue was dissolved in EtOAc (10 mL).
Ethyl 1-Butyl-2-oxopiperidine-3-carboxylate (19b)
To a stirred solution of cyclopropanecarboxaldehyde 5a (214.2 mg,
The resulting organic solution was washed with H O (10 mL) and 6 M
2
1
1
.0 mmol) in EtOH (2 mL), at r.t., was added n-butylamine (98.8 L,
.0 mmol). After 23 h, palladium(II) hydroxide on carbon 20 wt %
NH Cl (10 mL). The combined aqueous phases were basified with a
4
few drops of 6 M NaOH and extracted with EtOAc (5 × 10 mL) and
CH Cl (10 mL). The combined organic extracts were dried with anhy-
(
70.2 mg, 0.1 mmol) was added to the reaction. Next, a balloon con-
2
2
taining hydrogen gas was connected to the reaction mixture and the
stirring was continued at r.t. for 1 h. The resulting mixture was fil-
tered through a pad of Celite and the filtrate was concentrated under
reduced pressure. The product was purified by column chromatogra-
phy (silica gel; hexane/EtOAc, 3:2) to provide -lactam 19b as a yel-
low oil in 20% yield (45.5 mg).
drous Na SO and concentrated under reduced pressure to give 17a as
2
4
a yellow oil in 40% yield (66.8 mg).
IR (KBr): 3392, 2923, 2872, 1664, 1463, 1254, 1026, 930 cm–1
.
1
H NMR (400 MHz, CDCl ):  = 5.64–5.54 (m, 1 H, =CH), 5.12–5.05 (m,
3
2
H, =CH ), 3.85 (d, J = 12.0 Hz, 1 H, CH O), 3.82–3.76 (m, 1 H, CH ),
2
2
2
3
3
1
.70–3.64 (m, 2 H, CH + CH O), 3.40 (dd, J = 10.4, 6.0 Hz, 1 H, NCH ),
IR (KBr): 2960, 2872, 1736, 1646, 1493, 1371, 1179, 1032, 861 cm–1
2
2
2
.
.16 (d, J = 10.4 Hz, 1 H, NCH ), 1.85 (ddd, J = 8.0, 6.0, 4.4 Hz, 1 H, CH),
2
1
H NMR (400 MHz, CDCl ):  = 4.24–4.14 (m, 2 H, OCH ), 3.47–3.23
3
2
.07 (dd, J = 8.0, 4.4 Hz, 1 H, CH ), 0.68 (t, J = 4.4 Hz, 1 H, CH ).
2
2
(
m, 5 H, CH + NCH ), 2.14–1.87 (m, 3 H, CH ), 1.80–1.71 (m, 1 H, CH ),
2
2
2
1
3
C NMR (50 MHz, CDCl ):  = 175.3 (C), 132.6 (CH), 118.1 (CH ), 62.3
3
2
1.56–1.49 (m, 2 H, CH ), 1.34–1.24 (m, 5 H, CH + CH ), 0.91 (t, J = 7.4
2
2
3
(CH ), 48.2 (CH ), 44.9 (CH ), 32.5 (C), 17.2 (CH ), 16.9 (CH).
2 2 2 2
Hz, 3 H, CH3).
+
HRMS (ESI+): m/z [M + Na] calcd for C H NO Na: 190.0838; found:
13
9
13
2
C NMR (50 MHz, CDCl ):  = 171.4 (C), 165.7 (C), 61.4 (CH ), 49.3
3 2
190.0839.
(
(
CH), 47.7 (CH ), 47.4 (CH ), 29.2 (CH ), 25.3 (CH ), 21.3 (CH ), 20.2
2 2 2 2 2
CH ), 14.2 (CH ), 14.0 (CH ).
2
3
3
Diethyl 2-{[(4-Methoxyphenyl)imino]methyl}cyclopropane-1,1-
dicarboxylate (16d)
+
HRMS (ESI+): m/z [M + Na] calcd for C12H21NO Na: 250.1414; found:
3
2
50.1412.
To a stirred solution of cyclopropanecarboxaldehyde 5a (214.2 mg,
1
.0 mmol) in CH Cl2 (2 mL), at r.t., was added 4-methoxyaniline
Ethyl 1-Benzyl-2-oxopiperidine-3-carboxylate40 (19c)
2
(123.2 mg, 1.0 mmol). After 19 h, the solvent was evaporated to give
To a stirred solution of cyclopropanecarboxaldehyde 5a (214.2 mg,
the crude product as a brown oil.
1
1
.0 mmol) in EtOH (2 mL), at r.t., was added benzylamine (109.2 L,
.0 mmol). After 23 h, palladium on carbon 10 wt % (106 mg, 0.1
Yield: 63% (236 mg, contains ~15% of 4-methoxyaniline).
IR (KBr): 2982, 2837, 1728, 1511, 1246, 1032, 832 cm–1
.
mmol) was added. Next, a balloon containing hydrogen gas was con-
nected to the reaction mixture and the stirring was continued at r.t.
for 1 h. The resulting mixture was filtered through a pad of Celite and
the filtrate was concentrated under reduced pressure. The product
was purified by column chromatography (silica gel; hexane/EtOAc,
1
H NMR (200 MHz, CDCl ):  = 7.52 (d, J = 7.2 Hz, 1 H, CHN), 7.02 (d,
3
J = 9.0 Hz, 2 H, CH ), 6.86 (d, J = 9.0 Hz, 2 H, CH ), 4.28–4.14 (m, 4 H,
OCH ), 3.81 (s, 3 H, OCH ), 2.88 (ddd, J = 9.2, 7.2, 5.0 Hz, 1 H, CH), 2.05
Ar
Ar
2
3
(dd, J = 7.2, 5.0 Hz, 1 H, CH ), 1.83 (dd, J = 9.2, 5.0 Hz, 1 H, CH ), 1.29 (t,
2
2
3
:2) to provide -lactam 19c as a yellow oil in 15% yield (39.2 mg).
J = 7.2 Hz, 3 H, CH ), 1.25 (t, J = 7.2 Hz, 3 H, CH ).
3
3
IR (KBr): 3062, 2939, 1734, 1646, 1493, 1356, 1163, 1030, 700 cm–1
.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

M
Synthesis
A. P. Maximiano et al.
Feature
1
H NMR (400 MHz, CDCl ):  = 7.35–7.25 (m, 5 H, CHAr), 4.74 (d, J =
Supporting Information
3
1
4.4 Hz, 1 H, CH Ph), 4.51 (d, J = 14.4 Hz, 1 H, CH Ph), 4.28–4.20 (m, 2
2
2
Supporting information for this article is available online at
H, OCH ), 3.50 (t, J = 7.0 Hz, 1 H, CH), 3.31–3.18 (m, 2 H, NCH ), 2.19–
2
2
https://doi.org/10.1055/a-1389-1203. Su
p
p
orting Inform ationS
u
p
p
ortingI
n
form ati
o
n
2
.03 (m, 2 H, CH ), 1.96–1.87 (m, 1 H, CH ), 1.80–1.69 (m, 1 H, CH ),
2
2
2
1.32 (t, J = 7.0 Hz, 3 H, CH3).
1
3
C NMR (50 MHz, CDCl ):  = 171.3 (C), 166.1 (C), 137.0 (C), 128.7 (2
3
References
×
4
CH), 128.1 (2 × CH), 127.5 (CH), 61.5 (CH ), 50.4 (CH ), 49.4 (CH),
2
2
7.1 (CH ), 25.3 (CH ), 21.0 (CH ), 14.2 (CH ).
2
2
2
3
(1) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(2) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4538.
(3) Tang, P.; Qin, Y. Synthesis 2012, 44, 2669.
+
HRMS (ESI+): m/z [M + Na] calcd for C15H19NO Na: 284.1257; found:
3
284.1259.
(
(
4) Green, J. R.; Snieckus, V. Synlett 2014, 25, 2258.
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To a stirred solution of cyclopropanecarboxaldehyde 5a (128.5 mg,
2
014, 53, 5504.
[
(
(
(
(
6) Budynina, E. M.; Ivanov, K. L.; Sorokin, I. D.; Melnikov, M. Y. Syn-
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0.60 mmol). After 23 h, palladium(II) hydroxide on carbon 20 wt %
2
020, 362, 1447.
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taining hydrogen gas was connected to the reaction mixture and the
stirring was continued at r.t. for 24 h. The resulting mixture was fil-
tered through a pad of Celite and the filtrate was concentrated under
reduced pressure to give 20 as a yellow oil in 99% yield (101 mg).
4
(
(
10) Casar, Z. Synthesis 2020, 52, 1315.
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IR (KBr): 3225, 2980, 2874, 1734, 1671, 1493, 1371, 1265, 1173, 1032
(12) (a) Dey, R.; Banerjee, P. Adv. Synth. Catal. 2019, 361, 2849.
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L. K. B.; Jones, P. G.; Werz, D. B. Chem. Eur. J. 2016, 22, 18756.
–
1
cm
.
1
H NMR (400 MHz, CDCl ):  = 6.72 (bs, 1 H, NH), 4.22–4.15 (m, 2 H,
3
OCH ), 3.43–3.24 (m, 3 H, CH + NCH ), 2.14–2.01 (m, 2 H, CH ), 1.95–
2
2
2
(d) Li, L.; Li, Z.; Wang, Q. Synlett 2009, 1830. (e) Sohn, S. S.; Bode,
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.83 (m, 1 H, CH ), 1.76–1.67 (m, 1 H, CH ), 1.26 (t, J = 7.0 Hz, 3 H,
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2
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CH3).
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3
C NMR (50 MHz, CDCl ):  = 170.9 (C), 168.2 (C), 61.5 (CH ), 48.7
3
2
6535. (b) Dey, R.; Rajput, S.; Banerjee, P. Tetrahedron 2020, 76,
(
CH), 42.3 (CH ), 24.9 (CH ), 20.4 (CH ), 14.2 (CH ).
2 2 2 3
131080.
HRMS (ESI+): m/z [M + Na]+ calcd for C H NO Na: 194.0788;
8
13
3
(14) (a) Singh, P.; Kaur, N.; Banerjee, P. J. Org. Chem. 2020, 85, 3393.
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Conflict of Interest
(
15) (a) Han, X.; Fan, J.; Lu, H.; Wan, C.; Li, X.; Li, H.; Yang, D.; Zhang,
The authors declare no conflict of interest.
Funding Information
Y.; Xiao, Y.; Qin, Z. Bioorg. Med. Chem. 2015, 23, 6210.
(
b) Kobayashi, T.; Watanabe, M.; Yoshida, A.; Yamada, S.; Ito, M.;
Abe, H.; Ito, Y.; Arisawa, M.; Shuto, S. Bioorg. Med. Chem. 2010,
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1
The authors are grateful to the Brazilian governmental agencies
CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superi-
or), CNPq (Conselho Nacional de Desenvolvimento Científico e Tec-
nológico) and FAPESC (Fundação de Amparo à Pesquisa do Estado de
Santa Catarina) for fellowships. Support from INCT-Catálise/FAPESC/
CNPq/CAPES (Instituto Nacional de Ciência e Tecnologia Catálise em
Sistemas Moleculares e Nanoestruturados) is also gratefully acknowl-
1
(
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Vicario, J. L. Adv. Synth. Catal. 2017, 359, 1678. (b) Bao, J.; Ren, J.;
Wang, Z. Eur. J. Org. Chem. 2012, 2511. (c) Li, L.; Du, D.; Ren, J.;
Wang, Z. Eur. J. Org. Chem. 2011, 614. (d) Du, D.; Wang, Z. Eur. J.
Org. Chem. 2008, 4949. (e) Dancsó, A.; Kajtár-Peredy, M.;
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Krassny, A. F.; Bélanger, A.; Dionne, G. Can. J. Chem. 1973, 51,
edged.
C
o
ord
e
nação
d
e
A
p
erfeiço
a
me
n
to
d
e
P
esoal
d
e
N
ív
e
l
Superior()C
o
nselh
o
Nacional
d
e
D
ese
n
v
o
lvim ento
C
ientíifco
e
T
e
cn
o
lógico()F
u
n
daçã
o
d
e
A
m
paro
à
P
esq
u
isa
e
In
o
v
açã
o
d
o
Esta
d
o
d
e
Sa
n
taCtarinaInsiut to Nacio
n
al
d
e
C
iência
e
T
e
cn
o
logi
a
Catálise
e
m
S
istemas
M
o
leculares
e
Na
n
o
estruturados()
3
263.
Acknowledgment
(
17) Warner, D. T. J. Org. Chem. 1959, 24, 1536.
(
18) Ariente-Fliche, C.; Braun, J.; Le Goffic, F. Synth. Commun. 1992,
The authors would like to thank the Central de Análises (Departa-
mento de Química, Universidade Federal de Santa Catarina) for the
spectroscopic analysis. Special thanks are due to CEBIME (Laboratório
Central de Biologia Molecular e Estrutural, UFSC) for providing the
mass spectra.
2
2, 1149.
(
(
(
19) Uria, U.; Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E.; Pesquera,
A. Synthesis 2010, 701.
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2
016, 18, 6292.
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(
(
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©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

N
Synthesis
A. P. Maximiano et al.
Feature
(
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