A Catalytic One-Pot Synthesis of Indolyl Cyclobutanones

Article abstract of DOI:10.1055/s-0040-1706087

A general strategy for the synthesis of indolyl cyclobutanones via a tandem Bronsted acid catalyzed 2-hydroxycyclobutanone activation-indole nucleophilic addition has been exploited. The procedure leads to a wide range of 2- and 3-functionalized indole derivatives in good to high yields with broad substrate scope.

Full text of DOI:10.1055/s-0040-1706087

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2
020, 52, A–H
feature
A
en
Synthesis
S. Porcu et al.
Feature
A Catalytic One-Pot Synthesis of Indolyl Cyclobutanones
Stefania Porcu
O
Amberlyst-15
Carla Aira Rodriguez
O
R
(
10 mol%)
R
Angelo Frongia
Francesco Secci*
0
0
0
0
-0
0
0
3
-
4
6
5
2
-
9
5
7
8
+
toluene, 50 °C
N
N
0
0
0
0
-
0
0
0
3
-
0
4
4
3
-
2
8
9
0
OH
H
H
2
3 examples
6
8–96% yield
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi
di Cagliari, Complesso Universitario di Monserrato, D block, S.S. 554,
0
9042 Monserrato, Cagliari, Italy
fsecci@unica.it
eFD rMi ap naa icrCl etofi smr cer oeec csnS pi te@ooc uncd nidi ii Scn cag i. ei At n uz teh Co hr imiche
e Geologiche, Università degli Studi di Cagliari, Complesso Universitario di Monserrato, D block, S.S. 554, 09042 Monserrato, Cagliari, Italy
Received: 14.09.2020
Accepted after revision: 30.10.2020
Published online: 03.12.2020
Despite their biological activity, direct insertion of a
cyclobutane unit on the indole skeleton is limited to a few
multistep approaches, generally requiring the preparation
DOI: 10.1055/s-0040-1706087; Art ID: ss-2020-z0486-fa
9
c,10,14
of prefunctionalized substrates (Scheme 1, b).
Abstract A general strategy for the synthesis of indolyl cyclobuta-
nones via a tandem Brønsted acid catalyzed 2-hydroxycyclobutanone
activation–indole nucleophilic addition has been exploited. The proce-
dure leads to a wide range of 2- and 3-functionalized indole derivatives
in good to high yields with broad substrate scope.
a)
O
O
N
HN
O
NH
N
H
N
O
F
Key words indoles, cyclobutanones, Brønsted acids, tandem reac-
tions, catalysis
N
N
N
H
Me
4
991W93
COOH
b)
N
Due to the extremely high number of natural bioactive
1
compounds containing an indole unit, a wide number of
NHCBz
chemoselective syntheses and functionalizations of this
heterocycle have been exploited. In particular, many inves-
AcOH
+
2
NH
2
N
H
2
CH O
N
H
tigations were focused on the identification of new and
specific therapeutic agents for the treatment of several hu-
man diseases such as glaucoma, hypertension,4 depres-
OHC
ref. 10
I
3
Ph
Ph
S
N O
S
N O
5
6
7
KH/THF
sion, Alzheimer’s disease, cardiovascular diseases, and vi-
8
ral infections. A number of strained cyclobutyl- and cyclo-
N
–78 °C, then rt
N
Me
Me
propylindole derivatives have aroused significant interest,
not only for their pharmacological properties but, above all,
for their usefulness in drug–receptor affinity studies. In-
deed, the affinity of lead compounds can be studied by per-
forming radioligand binding assays using constrained mo-
lecular architectures that, by reducing the rotations around
certain bonds, clarify the way in which these molecules in-
ref. 14a
CN
Ph
CN
(
Me
3
Si)
2
NK
+
+
Br
Br
C
N
THF
N
Me
Me
ref. 9c
Ph
O
9
N
2
L*Me SAuCl
teract with biological targets. Examples include compound
N
O
O
4
991W93, a 5HT1B/1D receptor and partial agonist with
N
H
AgOTf
Cl , –78 °C
N
H
O
CH
2
2
1
0
potential for the treatment and prophylaxis of migraine,
the inhibition of leukotriene production, CRTH2 antago-
nists and estrogen receptor modulators (Scheme 1, a).
ref. 14b
1
1
Scheme 1 (a) Representative bioactive cyclobutyl-indole drugs.
(b) Strategies for the insertion of a cyclobutanone unit on indoles.
12
13
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
S. Porcu et al.
Feature
In this context, a versatile one-pot catalytic and chemo-
selective procedure would represent a significant advance
for drug design and synthesis. We recently reported the
preparation of indole cyclopropylcarbaldehydes 3 through a
tandem acid-catalyzed addition/ring-contraction reaction
of 2-hydroxycyclobutanone (1) and indole (2a) (Scheme 2,
covered that functionalized aldehyde 3a furnished the cor-
responding indolylcyclobutanone derivative 4a on treat-
ment with PTSA at 50 °C (Scheme 2, b).
This observation inspired us to develop a two-step, one-
pot synthesis of cyclobutanone indoles 4 following the gen-
eral procedure shown in Scheme 2, c. To explore the feasi-
bility of this process, a series of experiments was per-
formed to identify the best reaction conditions. A summary
of the results is reported in Table 1 (see also Table S1 in the
15
16
a). Continuing our studies in this research field, we dis-
Biographical Sketches
Angelo Frongia was born in
Cagliari (Italy) in 1973. He grad-
uated and received his Ph.D. in
organic chemistry from the Uni-
versity of Cagliari under the su-
pervision of Prof. P. P. Piras. In
2008), he completed an intern-
ship in the group of Prof. P. P.
Piras at the University of
Cagliari, and following collabo-
rative postdoctoral research
(2009) in the group of Prof. D. J.
Aitken at the ‘Institut de Chimie
Moléculaire et des Matériaux
d’Orsay’, University Paris Sud
(France), he started his indepen-
dent career at the ‘Dipartimen-
to di Scienze Chimiche
Geologiche’ (University
e
of
Cagliari) in 2010. He is currently
Associate Professor of Organic
Chemistry at the Faculty of Sci-
ences. His research interests fo-
cus on the synthesis and
reactivity of strained carbo-
cycles and asymmetric organo-
catalytic reactions.
2
001, he joined Dr. Jacques
Salaün at the Laboratoire des
Carbocycles (CNRS) Paris
France) as a postdoctoral fel-
(
low. During his studies (2002–
Stefania Porcu obtained her
Master’s degree from the Uni-
versity of Cagliari (Italy) under
the supervision of Prof. Frances-
co Secci. Since 2017, she has
been a Ph.D. student under the
supervision of Prof. Francesco
Secci and Prof. Pier Carlo Ricci
(Italy). Her research interests in-
clude acid-catalyzed synthesis
and functionalization of N-het-
erocycles, their photo-physical
characterization and their use as
photocatalysts.
Carla Aira Rodriguez ob-
tained her Bachelor’s degree in
chemistry from the University
of Vigo (Spain) in 2020. To com-
plete her M.Sc. degree, she
moved to Cagliari and since Oc-
tober 2019 she has worked on
the development of novel eco-
friendly one-pot functionaliza-
tions of indole derivatives under
the supervision of Prof. Frances-
co Secci (Italy).
Francesco Secci was born in
Cagliari (Italy) in 1977. He re-
ceived his Ph.D. in 2006 from
the University of Cagliari and
Université Paris-Sud (Orsay,
France) under the supervision of
Prof. P. P. Piras and Dr. J. Ollivier.
of York (UK) with Prof. P.
O’Brien, he moved back to Ca-
gliari to start his own research
with a grant from the Fund for
Investment in Basic Research
(FIRB) (Italy). Since 2013, he has
served as a lecturer at the same
university, and in 2019 he was
promoted to Associate Profes-
sor. His research interests are
focused on the development of
new synthetic methodologies
involving strained carbo- and
heterocyclic compounds, the
study of novel catalytic transfor-
mations and their synthetic ap-
plications.
After
a
postdoctoral stay
(2007–2010) at the University
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

C
Synthesis
S. Porcu et al.
Feature
CHO
(Nafion resin 50), AR-15 (Amberlyst resin 15) and AR-35
(Amberlyst resin 35) (entries 5, 6 and 7) showed that the
optimum yield of 4a (96%) was obtained when using AR-15
a)
diphenyl phosphate
O
(5 mol%)
+
toluene, rt
N
H
OH
N
H
2a
1
3a
(
10 mol% loading) at 50 °C in toluene.
O
With optimized reaction conditions in hand, we next
b)
c)
CHO
studied the scope of this one-pot, two-step procedure using
substituted indoles 2a–v (Scheme 3). Good functional
group tolerance was observed for indoles 2, allowing access
to a variety of cyclobutanone adducts 4. Indoles 2a–d fur-
nished the corresponding adducts 4a–d in good to high
yields (73–96%). Satisfactory results were achieved by re-
acting 2-hydroxycyclobutanone (1) with N-substituted in-
doles 2e–i, affording the cyclobutanones 4e–i in 89–94%
TsOH (10 mol%)
toluene, 50 °C
N
N
H
H
3a
4a
4a
O
O
acid catalyst
+
N
H
OH reaction conditions
N
H
2a
1
catalytic one-pot procedure
1
7
yields. The 2- and 3-alkyl/aryl indoles 2j–q gave good
Scheme 2 (a) Acid-catalyzed synthesis of indole cyclopropylcarbalde-
hyde 3a. (b) The C3–C4 ring expansion of aldehyde 3a to give cyclobu-
tanone 4a. (c) A catalytic one-pot synthesis of indolyl cyclobutanone
derivative 4a.
conversions and yields of the corresponding indolyl ketones
4
j–p, with 4q being recovered as a 50.50 mixture of diaste-
reoisomers (90% yield), probably due to epimerization at C2
of the cyclobutanone moiety during the chromatographic
purification step. On the other hand, reactions of 1 with in-
doles 2r–v, bearing electron-withdrawing groups at the C4
or C5 positions, did not occur as desired. In these cases, cy-
clopropyl carbaldehydes 3r–v were isolated as unique reac-
tion products in yields of 74–90%.
Supporting Information). We first examined the reaction
between 2-hydroxycyclobutanone (1) and indole (2a) in the
presence of TsOH (10 mol%) under neat conditions and iso-
lated the desired product 4a in only 18% yield after 24 hours
(
entry 1). The reaction carried out in toluene at 40 °C gave
Further experiments carried out with N-benzylpyrrole
afforded the corresponding cyclopropanes 3w/3w′ (as an
80:20 mixture of regioisomers) in 68% overall yield. The re-
action of 1 with 3,5-dimethoxyphenol yielded the cyclobu-
tanone 4x in 86% yield.
The results obtained during this study allowed us to put
forward a plausible mechanism for the acid-catalyzed one-
pot addition of a cyclobutanone to the indole skeleton
the product 4a in an improved 48% yield (entry 2), and this
increased to 58% when the reaction was performed at 50 °C
(
to any further improvement in the yield of 4a (entry 4). Fur-
thermore, no significant benefits were obtained from the
use of 3 Å molecular sieves or other anhydrous reaction
conditions. Finally, a catalyst screen using recyclable NR-50
entry 3). Increasing the temperature to 60 °C did not lead
Table 1 Initial Screening Studiesa
O
O
CHO
1
OH
+
N
H
N
N
H
H
3
a
2a
4a
Entry
Catalyst (mol%)
Solvent
neat
Temp (°C)
Ratio of 3a/4ab
Conv. (%)c
Yield (%)d
1
2
3
4
5
6
TsOH (10)
TsOH (10)
TsOH (10)
TsOH (10)
NR-50 (10)
AR-15 (10)
AR-35 (10)
40
40
50
60
50
50
50
2:1
21
50
63
60
96
97
93
18
48
58
54
94
96
90
toluene
toluene
toluene
toluene
toluene
toluene
1:1
1:3
1:16
1:22
1:28
1:28
7
a
Reaction conditions: 1 (50 mg, 0.58 mmol), 2a (1.0 equiv), acid catalyst [Nafion resin 50 (NR-50), Amberlyst resin 15 (AR-15) or Amberlyst resin 35 (AR-35): 10
mol%], solvent (1.5 mL), 8–24 h, 40–50 °C.
b
c
1
The 3a:4a ratio was determined by H NMR analysis.
1
The conversion into 4a was determined by H NMR analysis.
Yield of isolated product 4a after flash chromatography.
d
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
Synthesis
S. Porcu et al.
Feature
O
However, this process is favored by the presence of elec-
tron-donating groups on the heterocyclic system. On the
other hand, reactions carried out with indoles bearing elec-
tron-withdrawing groups (e.g., 2r–v) destabilize the carbo-
cationic species II and promote the C4–C3 ring contraction
O
CHO
R
1
OH
R
R
or
N
H
AR-15 (10 mol%)
toluene, 50 °C, 16–24 h
N
H
N
H
2
a–u
4a–q
3r–v
O
O
O
19,20
as a preferential stabilization process.
O
N
H
N
N
H
OMe
4c 86%
C4–C3 ring
contraction
H
H
4
a 96%
4b 94%
O
O
O
O
F
N
H
O
OH
OH
OH
3
HA
HA
H
H
N
N
N
2
– H O
H
H
Me
1
4d 73%
4e 92%
R = H, 4f 94%
R
OH
R = OMe, 4g 93%
N
N
H
N
H
O
O
2
I
H
II
Cl
–
H+
H
N
N
N
C3–C4 ring
expansion
O
4h 91%
4i 89%
4j 87%
H
Bn
O
HO
H
HA
O
O
N
N
N
H
H
H
III
4
IV
O
N
N
H
N
H
Scheme 4 Proposed reaction mechanism for the synthesis of cyclo-
butanones 4 and cyclopropyl carbaldehydes 3 under acid-catalyzed
conditions
H
4k 84%
4l 91%
4m 95%
OMe
O
Et
Ph
2
O N
O
O
N
Et
O
O
O
In summary, a new one-pot catalytic functionalization
of indoles has been established under mild conditions. This
method provides a straightforward access to diverse indolyl
cyclobutanone compounds in good to excellent yields, un-
derlining a broad substrate scope and some limitations re-
lated to the presence of electron-withdrawing groups. This
two-step, one-pot process has been studied by using a recy-
clable polystyrene-based ion exchange resin. Further stud-
ies aimed toward adapting this reaction to a continuous-
flow process are currently underway in our laboratories.
N
H
N
N
H
H
4
n78%
4o 74%
4p 91%
Ph
NO
2
NC
2
N
O
O
O
N
H
N
H
N
H
4
q 90%
3r 74%
3s 81%
CHO
O
OMe
O
OMe
O
O
O
N
N
H
N
H
H
O
3t 90%
3u 82%
3v 73%
O
Diphenyl phosphate, Amberlyst 15, Amberlyst 35 and indoles
2a,d,i,l,q,r were purchased from Sigma-Aldrich and used without fur-
ther purification. Indoles 2b,c,m,s were purchased from TCI and used
without further purification. Unless noted otherwise, all experiments
were carried out in a 5 mL vial closed with a screw cap and equipped
with a magnetic stir bar. Analytical thin-layer chromatography was
performed using 0.25 mm Aldrich silica gel 60-F plates. Flash chroma-
tography was performed using Merck silica gel (70–200 mesh). Yields
refer to chromatographically and spectroscopically pure materials.
Melting points were determined with a Büchi M-560 apparatus. In-
frared spectra were recorded on FT-IR Bruker Equinox-55 or Thermo
Fisher Scientific Nicolet IS50 FTIR spectrophotometers and are re-
O
OH
+
N
N
MeO
OMe
3
w/3w' (80:20 mix) 68%
4x 86%
Scheme 3 Exploration of the substrate scope
(
Scheme 4). In our hypothesis, the protonation of cyclobu-
tanone 1 promotes indole nucleophilic attack leading to the
formation of the adduct I.15,16a,b At room temperature, this
intermediate undergoes a rapid C4–C3 ring contraction via
carbocationic species II, mainly affording the cyclopropyl
carbaldehydes 3. At higher temperatures (50 °C), the es-
tablishment of an equilibrium between the three-mem-
bered-ring species 3 and the cyclobutane carbocationic in-
–
1
1
13
ported in wavenumbers (cm ). H and C NMR spectra were ob-
1
13
tained on Bruker DRX 600 ( H, 600 MHz; C, 150 MHz) or Varian 500
1
13
(
H, 500 MHz; C, 126 MHz) spectrometers at 27 °C using CDCl (in-
ternal reference = 7.26 ppm) as the solvent. C NMR were recorded at
3
16
13
126 MHz (internal reference = 77.00 ppm) using CDCl as the solvent.
3
Chemical shifts () are given in ppm. Coupling constants (J) are
reported in Hz. Low-resolution mass spectrometry was performed
18,19
termediate II leads to the formation of derivatives 4.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

E
Synthesis
S. Porcu et al.
Feature
1
3
using an Agilent-HP GC-MS (EI, 70 eV). High-resolution mass spec-
trometry (HRMS) was performed in fast atom bombardment (FAB+)
ionization mode (ESI) using Bruker micrOTF-Q II and/or Agilent Q-
TOF 6520 instruments.
C NMR (126 MHz, CDCl ):  = 208.7, 129.7, 122.9, 111.9 (d, J = 1.8
3
Hz), 111.8, 110.9 (d, J = 1.9 Hz), 110.7, 104.1 (d, J = 1.8 Hz), 104.0, 56.8,
45.1, 18.2.
+
HRMS (ESI): m/z [M + Na] calcd for C12H10FNNaO: 226.0644; found:
2
26.0651.
Cyclobutyl Indoles 4; General Procedure
In a 5 mL glass vial, a mixture of 2-hydroxycyclobutanone (1a) (100
mg, 1.1 mmol), indole 2a–v (1.0 mmol), Amberlyst 15 (10 mol%) and
toluene (3.0 mL) was stirred at 50 °C. After completion of the reaction,
the crude product was loaded on a silica gel column and purified by
flash chromatography using hexanes/diethyl ether (10:1 to 3:1) as the
eluent.
2-(1-Methyl-1H-indol-3-yl)cyclobutanone (4e)
Yield: 183 mg (92%); orange oil.
All analytical data were in good accordance with reported data.15
2
-(1-Benzyl-1H-indol-3-yl)cyclobutanone (4f)
Yield: 258 mg (94%); yellow oil.
1
2
-(1H-Indol-3-yl)cyclobutanone (4a)
H NMR (500 MHz, CDCl ):  = 7.49 (d, J = 7.9 Hz, 1 H), 7.22 (dd, J =
3
Yield: 117 mg (96%); colorless oil.
11.7, 4.2 Hz, 3 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.06–7.03 (m, 3 H), 7.00 (s, 1
H), 5.18 (s, 2 H), 4.67 (td, J = 8.4, 2.0 Hz, 1 H), 3.29–3.12 (m, 1 H), 3.04
1
H NMR (500 MHz, CDCl ):  = 7.97 (s, 1 H), 7.50 (d, J = 7.8 Hz, 1 H),
3
(
dddd, J = 17.5, 9.6, 4.9, 2.7 Hz, 1 H), 2.53 (qd, J = 10.6, 4.9 Hz, 1 H),
.22–1.95 (m, 1 H).
13C NMR (126 MHz, CDCl
7.29 (d, J = 8.1 Hz, 1 H), 7.17–7.11 (m, 1 H), 7.08 (d, J = 1.4 Hz, 1 H),
7.06 (td, J = 7.6, 1.0 Hz, 1 H), 4.68 (tdd, J = 7.9, 2.5, 1.2 Hz, 1 H), 3.31–
3.14 (m, 1 H), 3.07 (dddd, J = 17.6, 9.7, 4.9, 2.7 Hz, 1 H), 2.55 (qd, J =
10.6, 4.9 Hz, 1 H), 2.14 (ddt, J = 11.0, 9.6, 8.1 Hz, 1 H).
2
):  = 202.1, 137.3, 136.7, 128.7, 127.6,
3
126.8, 125.2, 122.1, 119.7, 119.4, 119.2, 111.0, 109.8, 57.0, 50.0, 45.1,
18.4.
All analytical data were in good accordance with reported data.16
1
3
C NMR (126 MHz, CDCl ):  = 208.8, 136.3, 126.3, 122.4, 121.1,
3
119.7, 119.0, 112.0, 111.2, 57.0, 45.1, 18.3.
All analytical data were in good accordance with reported data.16
2
-[1-(3-Methoxybenzyl)-1H-indol-3-yl]cyclobutanone (4g)
Yield: 283 mg (93%); colorless oil.
FTIR (film): 2984, 1789, 1458, 1227, 1144, 908 cm–1
2
-(5-Methyl-1H-indol-3-yl)cyclobutanone (4b)
Yield: 187 mg (94%); colorless oil.
.
FTIR (film): 2994, 1788, 1612, 1454, 1228, 1129, 1011 cm–1
.
1H NMR (600 MHz, CDCl
7.15–7.08 (m, 2 H), 7.03 (dd, J = 11.0, 3.9 Hz, 1 H), 7.00 (s, 1 H), 6.71
dd, J = 8.2, 2.4 Hz, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 6.59 (s, 1 H), 5.15 (s, 2
H), 4.74–4.57 (m, 1 H), 3.66 (s, 3 H), 3.19 (dddd, J = 18.0, 10.7, 8.3, 2.5
Hz, 1 H), 3.04 (dddd, J = 17.5, 9.6, 4.9, 2.7 Hz, 1 H), 2.53 (qd, J = 10.7,
):  = 7.49 (d, J = 7.9 Hz, 1 H), 7.18 (s, 1 H),
3
1
H NMR (500 MHz, CDCl ):  = 7.94 (s, 1 H), 7.33 (s, 1 H), 7.25 (d, J =
3
(
1
0.0 Hz, 1 H), 7.11 (d, J = 1.4 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 4.80–
.60 (m, 1 H), 3.32–3.23 (m, 1 H), 3.13 (dddd, J = 17.6, 9.6, 4.9, 2.7 Hz,
H), 2.61 (ddd, J = 21.4, 10.6, 4.9 Hz, 1 H), 2.45 (s, 3 H), 2.29–2.13 (m,
H).
4
1
1
4
.9 Hz, 1 H), 2.12 (dtd, J = 10.9, 9.6, 8.2 Hz, 1 H).
13C NMR (151 MHz, CDCl
):  = 208.9, 159.9, 138.9, 136.8, 129.8,
27.0, 125.2, 122.1, 119.4, 119.2, 119.1, 112.7, 112.7, 111.0, 109.8,
7.0, 55.1, 49.9, 45.0, 18.4.
1
3
3
C NMR (126 MHz, CDCl ):  = 208.8, 136.3, 126.3, 122.4, 121.1,
3
1
5
119.7, 119.0, 112.0, 111.2, 57.0, 45.1, 18.3.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO: 222.0895; found:
+
HRMS (ESI): m/z [M + Na] calcd for C20H19NNaO : 328.1313; found:
2
222.0898.
3
28.1314.
2
-(7-Methoxy-1H-indol-3-yl)cyclobutanone (4c)
2
-[1-(Naphthalen-2-ylmethyl)-1H-indol-3-yl]cyclobutanone (4h)
Yield: 185 mg (86%); green oil.
FTIR (film): 2998, 1789, 1614, 1460, 1221, 1129, 1009 cm–1
Yield: 295 mg (91%); brown solid; mp 76 °C.
FTIR (film): 2952, 1790, 1612, 1463, 1352, 1200, 1072 cm–1
.
.
1
H NMR (500 MHz, CDCl ):  = 8.12 (s, 1 H), 7.08 (s, 1 H), 7.00 (d, J =
3
1
H NMR (500 MHz, CDCl ):  = 7.77 (m, 3 H), 7.61–7.55 (m, 2 H), 7.48–
3
7.0 Hz, 1 H), 6.87 (d, J = 7.0 Hz, 1 H), 6.59 (dd, J = 6.5, 3.5 Hz, 1 H), 4.90
7
(
(
.40 (m, 2 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.26–7.21 (m, 1 H), 7.20–7.14
m, 1 H), 7.13–7.08 (m, 2 H), 5.39 (s, 2 H), 4.80–4.67 (m, 1 H), 3.25
dddd, J = 17.8, 10.6, 8.3, 2.5 Hz, 1 H), 3.11 (dddd, J = 17.5, 9.6, 4.9, 2.7
(t, J = 6.5 Hz, 1 H), 3.80 (s, 3 H), 2.72–2.67 (m, 1 H), 2.40–2.37 (m, 1 H),
2.08–2.01 (m, 2 H).
1
3
C NMR (126 MHz, CDCl ):  = 210.9, 154.4, 131.3, 128.3, 124.8,
3
Hz, 1 H), 2.60 (qd, J = 10.6, 4.9 Hz, 1 H), 2.19 (ddt, J = 10.9, 9.6, 8.2 Hz,
1
116.5, 112.6, 112.1, 100.6, 55.9, 40.8, 29.1, 19.0.
H).
+
HRMS (ESI): m/z [M + Na] calcd for C 3H NNaO : 238.0844; found:
13
1
13
2
C NMR (126 MHz, CDCl ):  = 208.8, 136.9, 134.7, 133.3, 132.8,
3
238.0851.
1
1
28.6, 127.8, 127.6, 127.1, 126.3, 126.0, 125.6, 125.2, 124.8, 122.1,
19.4, 119.3, 111.1, 109.8, 57.0, 50.2, 45.0, 18.4.
2
-(5-Fluoro-1H-indol-3-yl)cyclobutanone (4d)
HRMS (ESI): m/z [M + Na]+ calcd for C23H19NNaO: 348.1364; found:
48.1371.
Yield: 148 mg (73%); yellow oil.
FTIR (film): 2986, 1790, 1463, 1227, 1145, 986 cm–1
3
.
1
2-(1-Benzyl-5-chloro-1H-indol-3-yl)cyclobutanone (4i)
H NMR (500 MHz, CDCl ):  = 7.97 (br s, 1 H), 7.22–7.19 (m, 1 H),
3
7
9
5
.12 (td, J = 9.8, 2.1 Hz, 2 H), 6.88 (td, J = 9.1, 2.3 Hz, 1 H), 4.62 (t, J =
.2 Hz, 1 H), 3.30–3.12 (m, 1 H), 3.14–2.93 (m, 1 H), 2.55 (qd, J = 10.7,
.0 Hz, 1 H), 2.17–2.00 (m, 1 H).
Yield: 275 mg (89%); yellow oil.
FTIR (film): 3073, 1783, 1441, 1224, 1018, 990 cm–1
.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

F
Synthesis
S. Porcu et al.
Feature
1
1
H NMR (500 MHz, CDCl ):  = 7.44 (d, J = 1.3 Hz, 1 H), 7.20 (dd, J =
H NMR (600 MHz, CDCl ):  = 7.49 (dd, J = 7.9, 3.5 Hz, 1 H), 7.13 (dd,
3
3
10.6, 7.1 Hz, 3 H), 7.05 (t, J = 7.8 Hz, 2 H), 7.04–6.99 (m, 3 H), 5.14 (s, 2
J = 7.8, 2.3 Hz, 2 H), 7.05 (ddd, J = 7.9, 5.6, 2.4 Hz, 1 H), 6.83 (d, J = 0.8
H), 4.59 (td, J = 8.1, 2.2 Hz, 1 H), 3.19 (dddd, J = 18.9, 10.6, 8.4, 2.4 Hz,
Hz, 1 H), 5.67–5.45 (m, 1 H), 3.11–3.03 (m, 1 H), 2.99–2.91 (m, 1 H),
1
1
H), 3.09–2.92 (m, 1 H), 2.52 (qd, J = 10.7, 4.9 Hz, 1 H), 2.07 (tt, J =
0.8, 8.3 Hz, 1 H).
2.66 (d, J = 3.0 Hz, 1 H), 2.62 (ddd, J = 21.5, 10.9, 4.4 Hz, 1 H), 2.22 (s, 3
H).
1
3
13
C NMR (126 MHz, CDCl ):  = 208.4, 137.0, 135.3, 129.3, 128.9,
C NMR (151 MHz, CDCl ):  = 203.6, 135.8, 128.9, 122.8, 121.9,
3
3
128.2, 127.9, 127.1, 126.9, 126.7, 125.4, 122.6, 118.9, 111.0, 110.9,
119.4, 119.2, 112.2, 109.1, 68.5, 41.8, 20.2, 9.5.
5
6.8, 50.4, 45.3, 18.5.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO: 222.0895; found:
222.0901.
+
HRMS (ESI): m/z [M + Na] calcd for C19H16ClNNaO: 332.0818; found:
332.0821.
3-[2-(2-Oxocyclobutyl)-1H-indol-3-yl]propionic Acid Methyl Ester
2
-(2-Methyl-1H-indol-3-yl)cyclobutanone (4j)
(4n)
Yield: 173 mg (87%); yellow oil.
Yield: 211 mg (78%); colorless oil.
FTIR (film) : 2989, 1788, 1457, 1231, 1144 cm–1
.
FTIR (film): 3418, 2973, 2881, 1781, 1721, 1622, 1462, 1397, 1087,
912 cm–1
.
1
H NMR (500 MHz, CDCl ):  = 7.83 (br s, 1 H), 7.33 (d, J = 7.8 Hz, 1 H),
3
1
7.25 (d, J = 6.5 Hz, 1 H), 7.10 (t, J = 7.1 Hz, 1 H), 7.08–7.01 (m, 1 H),
H NMR (600 MHz, CDCl ):  = 7.50 (d, J = 7.9 Hz, 1 H), 7.13–7.10 (m, 2
3
4
.67 (ddt, J = 10.7, 8.6, 2.2 Hz, 1 H), 3.28 (dddd, J = 19.3, 10.5, 8.7, 2.0
H), 7.05 (ddd, J = 7.9, 5.9, 2.1 Hz, 1 H), 6.86 (s, 1 H), 5.54 (ddd, J = 10.5,
4.1, 2.1 Hz, 1 H), 3.59 (s, 3 H), 3.11–3.01 (m, 1 H), 2.99 (t, J = 7.8 Hz, 2
H), 2.97–2.90 (m, 1 H), 2.60 (t, J = 7.8 Hz, 2 H), 2.59–2.56 (m, 1 H),
2.26–2.18 (m, 1 H).
Hz, 1 H), 3.23–3.12 (m, 1 H), 2.52 (qd, J = 10.8, 4.8 Hz, 1 H), 2.40–2.34
(m, 1 H), 2.33 (s, 3 H).
1
3
C NMR (126 MHz, CDCl ):  = 210.1, 135.3, 131.9, 127.3, 121.3,
3
1
3
119.5, 118.1, 110.4, 107.2, 57.0, 45.0, 18.3, 12.1.
C NMR (151 MHz, CDCl ):  = 203.2, 173.6, 135.8, 127.8, 122.7,
3
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO: 222.0895; found:
122.0, 119.6, 119.0, 115.2, 109.3, 68.4, 51.5, 41.8, 34.5, 20.4, 20.0.
+
222.0899.
HRMS (ESI): m/z [M + Na] calcd for C16H17NNaO : 294.1106; found:
3
2
94.1112.
2
-(2-Phenyl-1H-indol-3-yl)cyclobutanone (4k)
N,N-Diethyl-3-[2-(2-oxocyclobutyl)-1H-indol-3-yl]propionamide
4o)
Yield: 219 mg (84%); colorless oil.
FTIR (film): 3054, 2989, 1789, 1623, 1456, 1227, 1112, 1024 cm–1
(
.
Yield: 230 mg (74%); yellow oil.
1
H NMR (500 MHz, CDCl ):  = 8.06 (br s, 1 H), 7.38–7.34 (m, 5 H),
3
FTIR (film): 3412, 2977, 2889, 1781, 1627, 1460, 1298, 1089, 1086
7.31–7.29 (m, 1 H), 7.17–7.16 (m, 1 H), 7.14–7.13 (m, 1 H), 7.06–7.03
–
1
cm
1H NMR (600 MHz, CDCl
H), 7.04 (ddd, J = 8.0, 4.9, 3.1 Hz, 1 H), 6.87 (s, 1 H), 5.55 (ddd, J = 10.4,
.9, 2.0 Hz, 1 H), 3.30 (dd, J = 14.0, 7.0 Hz, 2 H), 3.12 (dd, J = 14.2, 7.1
.
(m, 1 H), 4.87–4.66 (m, 1 H), 3.31–3.02 (m, 2 H), 2.52–2.30 (m, 2 H).
1
3
3
):  = 7.52 (d, J = 7.9 Hz, 1 H), 7.14–7.07 (m, 2
C NMR (126 MHz, CDCl ):  = 201.8, 136.1, 129.8, 129.1, 129.0,
3
123.0, 122.8, 120.4, 120.2, 119.5, 119.0, 111.2, 111.1, 57.5, 45.1, 18.3.
3
HRMS (ESI): m/z [M + Na]+ calcd for C18H15NNaO: 284.1051; found:
Hz, 2 H), 3.08–3.04 (m, 1 H), 3.02 (dd, J = 9.0, 6.9 Hz, 2 H), 2.93 (dddd,
J = 14.9, 12.3, 7.4, 5.3 Hz, 1 H), 2.63–2.59 (m, 1 H), 2.60–2.57 (m, 2 H),
284.1053.
2
3
.23 (dt, J = 20.0, 9.9 Hz, 1 H), 1.02 (t, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.1 Hz,
H).
2
-[2-(p-Tolyl)-1H-indol-3-yl]cyclobutanone (4l)
Yield: 250 mg (91%); colorless oil.
FTIR (film): 3007, 1790, 1502, 1460, 1134, 1028 cm–1
13
C NMR (151 MHz, CDCl ):  = 203.3, 171.7, 135.7, 127.9, 122.8,
3
.
121.9, 119.5, 119.0, 115.9, 109.3, 68.4, 41.8, 41.7, 40.1, 33.6, 20.8,
19.9, 14.1, 12.9.
1
H NMR (500 MHz, CDCl ):  = 8.07 (br s, 1 H), 7.44 (d, J = 7.9 Hz, 1 H),
3
+
7.39 (d, J = 8.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H),
HRMS (ESI): m/z [M + Na] calcd for C19H24N NaO : 335.1735; found:
2
2
7.21–7.17 (m, 1 H), 7.13–7.09 (m, 1 H), 4.90–4.71 (m, 1 H), 3.35–3.12
335.1737.
(m, 2 H), 2.55–2.45 (m, 2 H), 2.42 (s, 3 H).
1
3
C NMR (126 MHz, CDCl ):  = 209.9, 138.2, 136.2, 135.9, 129.6,
2-[3-(2-Nitro-1-phenylethyl)-1H-indol-2-yl]cyclobutanone (4p)
3
1
1
28.4, 127.7, 127.4, 122.3, 120.0, 119.3, 111.1, 107.6, 57.6, 45.0, 21.2,
8.3.
Yield: 304 mg (91%); colorless oil.
FTIR (film): 2919, 1701, 1456, 1225, 1153, 907, 738 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO: 298.1208; found:
1
H NMR (500 MHz, CDCl ):  = 7.36 (dd, J = 18.2, 8.0 Hz, 1 H), 7.28–
3
298.1211.
7
2
.22 (m, 5 H), 7.14 (t, J = 4.1 Hz, 2 H), 7.06–6.98 (m, 1 H), 6.92 (d, J =
7.1 Hz, 1 H), 5.59 (dt, J = 17.0, 5.3 Hz, 1 H), 5.09 (td, J = 7.9, 4.5 Hz, 1
2
-(3-Methyl-1H-indol-2-yl)cyclobutanone (4m)
H), 4.97 (ddd, J = 12.6, 7.3, 5.3 Hz, 1 H), 4.86 (ddd, J = 17.8, 12.5, 8.6 Hz,
Yield: 189 mg (95%); yellow oil.
1 H), 3.20–3.15 (m, 1 H), 2.98–2.95 (m, 1 H), 2.67–2.65 (m, 1 H), 2.28–
2
13
4 (m, 1 H).
FTIR (film): 3390, 3053, 2919, 1789, 1704, 1612, 1462, 1386, 1238
–
1
cm
.
C NMR (126 MHz, CDCl ):  = 202.7, 138.9, 134.4, 128.9, 127.7,
3
1
2
25.2, 124.3, 123.2, 122.9, 121.1, 118.9, 114.0, 109.4, 84.8, 79.4, 68.6,
7.5, 21.4.
+
HRMS (ESI): m/z [M + Na] calcd for C20H18N NaO : 357.1215; found:
2
3
3
57.1221.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

G
Synthesis
S. Porcu et al.
Feature
2-[5-Methyl-3-(2-nitro-1-phenylethyl)-1H-indol-2-yl]cyclobuta-
FTIR (film): 3348, 2960, 1726, 1665, 1611, 1258, 1094 cm–1
.
none (4q)
1
H NMR (600 MHz, CD OD):  = 9.94 (s, 1 H), 9.17 (s, 1 H), 8.09 (d, J =
3
Obtained as a 55:45 mixture of diastereoisomers.
Yield: 313 mg (90%); colorless oil.
1.0 Hz, 1 H), 7.72 (dd, J = 8.5, 1.5 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.33
(
s, 1 H), 1.70 (q, J = 3.8 Hz, 2 H), 1.48–1.43 (m, 2 H).
1
3
C NMR (151 MHz, CD OD):  = 203.0, 194.6, 141.9, 130.4, 129.2,
FTIR (film): 3013, 2980, 2232, 1789, 1785, 1644, 1470, 1229, 1148,
3
012 cm–1
128.0, 125.7, 122.9, 115.6, 113.3, 30.0, 15.8.
1
.
+
HRMS (ESI): m/z [M + Na] calcd for C13H NNaO : 236.0687; found:
Isomer A
11
2
2
36.0688.
1
H NMR (500 MHz, CDCl ):  = 7.25–7.24 (m, 4 H), 7.20–7.17 (m, 3 H),
3
7
1
2
.00 (m, 1 H), 6.97–6.95 (s, 1 H), 5.53 (d, J = 8.2 Hz, 1 H), 5.07–5.03 (m,
H), 4.99–4.91 (m, 1 H), 4.90–4.80 (m, 1 H), 3.17–3.04 (m, 1 H), 3.03–
.91 (m, 1 H), 2.67–2.55 (m, 1 H), 2.31 (s, 3 H), 2.27–2.21 (m, 1 H).
1
-(1-Benzyl-1H-pyrrol-2-yl)cyclopropanecarbaldehyde (3w)
Obtained as an 80:20 mixture of regioisomers.
1
3
C NMR (126 MHz, CDCl ):  = 202.6, 138.9, 134.4, 129.7, 129.0,
Yield: 153 mg (68%); colorless oil.
3
1
28.9, 127.7, 127.5, 124.3, 122.9, 118.8, 114.0, 109.4, 79.4, 68.6, 28.5,
FTIR (film): 2998, 2982, 1728, 1660, 1224, 1048, 1002, 980 cm–1
.
27.5, 21.3, 20.0.
1
H NMR (600 MHz, CDCl ):  (major regioisomer) = 8.97 (s, 1 H), 7.23
3
+
HRMS (ESI): m/z [M + Na] calcd for C 1H N NaO : 371.1372; found:
2
20
2
3
(dt, J = 12.1, 2.9 Hz, 2 H), 7.19-7.18 (m, 2H), 6.88 (d, J = 1.8 Hz, 1 H),
371.1379.
6
.67–6.59 (m, 1 H), 6.11–6.07 (m, 1 H), 6.03 (dt, J = 12.9, 6.4 Hz, 1 H),
4.98 (s, 2 H), 1.39 (q, J =3.9 Hz, 2 H), 1.17 (q, J = 4.0 Hz, 2 H).
13C NMR (151 MHz, CDCl
):  (major regioisomer) = 200.2, 137.9,
Isomer B)
1
H NMR (500 MHz, CDCl ):  = 7.25–7.23 (m, 4 H), 7.19–7.17 (m, 2 H),
3
3
7
.13–7.12 (m, 1 H), 7.02 (d, J = 4.5 Hz, 1 H), 6.82 (s, 1 H), 6.66–6.23 (m,
H), 5.07–5.04 (m, 1 H), 4.99–4.90 (m, 1 H), 4.89–4.80 (m, 1 H), 3.07–
.06 (m, 1 H), 2.98–2.95 (m, 1 H), 2.76–2.74 (m, 1 H), 2.32 (s, 3 H),
.27–2.19 (m, 1 H).
129.4, 128.7, 127.6, 126.9, 122.9, 110.5, 107.3, 50.9, 29.5, 16.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H15NNaO: 248.1051; found:
1
3
2
2
48.1063.
1
3
C NMR (126 MHz, CDCl ):  = 202.7, 138.9, 134.4, 129.7, 129.0,
2-(2-Hydroxy-4,6-dimethoxyphenyl)cyclobutanone (4x)
3
1
28.9, 127.7, 125.2, 122.9, 121.1, 118.9, 114.0, 109.4, 84.9, 68.7, 41.9,
Yield: 190 mg (86%); colorless oil.
FTIR (film): 3412, 3023, 2988, 1787, 1462, 1228, 1144, 1021 cm–1
28.4, 21.4, 20.1.
.
+
HRMS (ESI): m/z [M + Na] calcd for C21H20N NaO : 371.1372; found:
2
3
1
H NMR (500 MHz, CDCl ):  = 6.31 (s, 1 H), 6.07–5.96 (m, 1 H), 5.92
3
371.1377.
(
d, J = 2.3 Hz, 1 H), 4.74 (dd, J = 10.7, 8.3 Hz, 1 H), 3.74 (s, 3 H), 3.71 (s,
3
1
H), 3.16–3.02 (m, 2 H), 2.47–2.31 (m, 1 H), 2.20 (dq, J = 10.5, 8.5 Hz,
H).
1
-(5-Nitro-1H-indol-3-yl)cyclopropanecarbaldehyde (3r)
Yield: 170 mg (74%); yellow solid.
All analytical data were in good accordance with reported data.16
1
3
C NMR (126 MHz, CDCl ):  = 213.2, 160.2, 159.1, 155.2, 105.2, 94.1,
3
9
1.3, 55.5, 55.2, 55.1, 44.1, 18.0.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14NaO : 245.0790; found:
4
3
-(1-Formylcyclopropyl)-1H-indole-4-carbonitrile (3s)
2
45.0799.
Yield: 170 mg (81%); colorless oil.
All analytical data were in good accordance with reported data.16
Funding Information
3
-(1-Formylcyclopropyl)-1H-indole-5-carboxylic Acid Methyl Es-
We gratefully acknowledge funding from the Fondazione di Sardegna
ter (3t)
(
CUP F71I17000180002).Fo
n
dazio
n
e
di Sard
e
g
na (C
U
P
F
7
1
I1
7
0
0
0
1
8
0
0
0
2)
Yield: 218 mg (90%); colorless oil.
FTIR (film): 3472, 2961, 1785, 1711, 1620, 1437, 1261, 1096 cm–1
.
1
Supporting Information
H NMR (600 MHz, CDCl ):  = 9.25 (s, 1 H), 8.30 (s, 1 H), 8.25 (s, 1 H),
3
7
1
.86 (dd, J = 8.6, 1.6 Hz, 1 H), 7.30 (d, J = 8.6 Hz, 1 H), 7.10 (d, J = 2.1 Hz,
H), 3.86 (s, 3 H), 1.61 (q, J = 4.0 Hz, 2 H), 1.35 (q, J = 4.1 Hz, 2 H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706087. Su
p
p
ortingI
n
form atio
n
S
u
p
p
ortingInform ati
o
n
1
3
C NMR (151 MHz, CDCl ):  = 201.1, 168.0, 138.8, 127.4, 125.4,
3
123.9, 122.1, 121.9, 114.8, 111.1, 51.8, 28.7, 15.8.
+
HRMS (ESI): m/z [M + Na] calcd for C14H13NNaO : 266.0793; found:
References
3
266.0798.
(
1) (a) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442. (b) Klein-
Júnior, L. C.; Cretton, S.; Vander Heyden, Y.; Gasper, A. L.; Nejad-
Ebrahimi, S.; Christen, P.; Henriques, A. T. J. Nat. Prod. 2020, 83,
3
-(1-Formylcyclopropyl)-1H-indole-4-carboxylic Acid Methyl Es-
ter (3u)
8
52. (c) Tanifuji, R.; Minami, A.; Oguri, H.; Oikawa, H. Nat. Prod.
Rep. 2020, 37, 109.
(2) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
b) Youn, S. W.; Ko, T. Y. Asian J. Org. Chem. 2018, 7, 1467.
(c) Kumar, I.; Kumar, R.; Sharma, U. Synthesis 2018, 50, 2655.
d) Santos Neto, J. S.; Zeni, G. Org. Chem. Front. 2020, 7, 155.
3) Triggle, D. J.; Mitchell, J. M.; Filler, R. CNS Drug Rev. 1998, 4, 87.
Yield: 199 mg (82%); colorless oil.
All analytical data were in good accordance with reported data.16
(
3
-(1-Formylcyclopropyl)-1H-indole-5-carbaldehyde (3v)
(
Yield: 155 mg (73%); colorless oil.
(
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

H
Synthesis
S. Porcu et al.
Feature
(
4) Zhu, W.; Bao, X.; Ren, H.; Da, Y.; Wu, D.; Li, F.; Yan, Y.; Wang, L.;
(13) Goodacre, S. C.; Labadie, S.; Li, J.; Liang, J.; Liao, J.; Ortwine, D. F.;
Ray, N. C.; Wang, X.; Zbieg, J.; Zhang, B. WO2017216279A1,
2017.
(14) (a) Harmata, M.; Ying, W.; Hong, X.; Barnes, C. L. Synthesis 2008,
4, 594. (b) Hu, H.; Wang, Y.; Qian, D.; Zhang, Z.-M.; Liu, L.;
Zhang, J. Org. Chem. Front. 2016, 3, 759.
Chen, Z. Eur. J. Med. Chem. 2016, 115, 161.
(
5) Anthes, R.; Benoit, S.; Chen, C.-K.; Corbett, E. A.; Corbett, R. M.;
DelMonte, A. J.; Gingras, S.; Livingston, R. C.; Pendri, Y.; Sausker,
J.; Soumeillant, M. Org. Process Res. Dev. 2008, 12, 178.
(6) Denya, I.; Malan, S. F.; Enogieru, A. B.; Omoruyi, S. I.; Ekpo, O. E.;
Kapp, E.; Zindo, F. T.; Joubert, J. Med. Chem. Commun. 2018, 9,
(15) Turnu, F.; Luridiana, A.; Cocco, A.; Porcu, S.; Frongia, A.; Sarais,
G.; Secci, F. Org. Lett. 2019, 21, 7329.
357.
(
7) Bogus, S. K.; Kuzmin, V. S.; Abramochkin, D. V.; Suzdalev, K. F.;
Galenko-Yaroshevsky, P. A. J. Pharmacol. Sci. 2017, 133, 122.
8) Fink, S. L.; Vojtech, L.; Wagoner, J.; Slivinski, N. S. J.; Jackson, K.
J.; Wang, R.; Khadka, S.; Luthra, P.; Basler, C. F.; Polyak, S. J. Sci.
Rep. 2018, 8, 8989.
9) (a) Papahatjis, D. P.; Nikas, S.; Tsotinis, A.; Vlachou, M.;
Makriyannis, A. Chem. Lett. 2001, 192. (b) Teng, X.; Degterev, A.;
Jagtap, P.; Xing, X.; Choi, C.; Denu, R.; Yuan, J.; Cuny, G. D.
Bioorg. Med. Chem. Lett. 2005, 15, 5039. (c) Piccio, P.; Vonhoff,
S.; Davidson, K.; Teh, M.-T.; Sugden, D. J. Med. Chem. 2006, 49,
(16) (a) Martis, A.; Luridiana, A.; Frongia, A.; Arca, M.; Sarais, G.;
Aitken, D. J.; Guillot, R.; Secci, F. Org. Biomol. Chem. 2017, 15,
10053. (b) Porcu, S.; Luridiana, A.; Martis, A.; Frongia, A.; Sarais,
G.; Aitken, D. J.; Boddaert, T.; Guillot, R.; Secci, F. Chem.
Commun. 2018, 54, 13547. (c) Porcu, S.; Demuro, S.; Luridiana,
A.; Cocco, A.; Frongia, A.; Aitken, D. J.; Charnay-Pouget, F.;
Guillot, R.; Sarais, G.; Secci, F. Org. Lett. 2018, 20, 7699. (d) Secci,
F.; Porcu, S.; Luridiana, A.; Frongia, A.; Ricci, P. C. Org. Biomol.
Chem. 2020, 18, 3684.
(
(
(17) N-Debenzylation of compound 4f was accomplished in a mod-
3509.
erate yield (44%) by using NH /Li in THF at –78 °C, as reported in
3
(
10) Jandu, K. S.; Barrett, V.; Brockwell, M.; Cambridge, D.; Farrant, D.
R.; Foster, C.; Giles, H.; Glen, R. C.; Hill, A. P.; Hobbs, H.; Honey,
A.; Martin, G. R.; Salmon, J.; Smith, D.; Woollard, P.; Selwood, D.
L. J. Med. Chem. 2001, 44, 681.
the Supporting Information.
(18) (a) Conia, J. M.; Salaun, J. Acc. Chem. Res. 1972, 5, 33. (b) Barnier,
J. P.; Denis, J. M.; Salaun, J.; Conia, J. M. Tetrahedron 1974, 30,
1397. (c) Gembus, V.; Karmazin, L.; Pira, S.; Uguen, D. Bull.
Chem. Soc. Jpn. 2018, 91, 319.
(19) Brown, H. C.; Morgan, K. J.; Chloupek, F. J. J. Am. Chem. Soc. 1965,
87, 2137.
(11) Bartolozzi, A.; Chen, Z.; Dines, J. A.; Lo, H. Y.; Loke, P. L.; Olague,
A.; Riether, D.; Tye, H.; Wu, L.; Zindell, R. M. US20130196967A1,
2
013.
(12) Zhang, Y.; Yu, T.; Liu, B.; Zhang, X.; Zhang, S.; Cheng, C.; Zhang, J.
(20) Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477.
WO2016037591A1, 2016.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H