Functionalized Dialdehydes as Promising Scaffolds for Access to Heterocycles and β-Amino Acids: Synthesis of Fluorinated Piperidine and Azepane Derivatives

Article abstract of DOI:10.1055/s-0036-1588396

Functionalized dialdehydes are considered important substrates that can be transformed into various substituted heterocyclic, alicyclic, and polysubstituted compounds. Here, we report a robust stereocontrolled procedure for the synthesis of novel functionalized trifluoromethyl-containing piperidine and azepane derivatives, based on oxidative ring cleavage of the C=C bond of diversely substituted cycloalkenes, followed by reductive ring closure of the diformyl intermediates in the presence of fluorine-containing amines.

Full text of DOI:10.1055/s-0036-1588396

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
A
feature
Synthesis
R. A. Ábrahámi et al.
Feature
Functionalized Dialdehydes as Promising Scaffolds for Access to
Heterocycles and β-Amino Acids: Synthesis of Fluorinated Piperi-
dine and Azepane Derivatives
Renáta A. Ábrahámia
CO2H
CO Me CO2H
2
Loránd Kissa
Santos Fusteroc
CO Me
CO2Me
2
CO2Me
Ferenc Fülöp*a,b
X
N
CO2R
MeO C
CO2Me
2
X = CO2Bn, CO2Et, NHCbz
a
Institute of Pharmaceutical Chemistry, University of Szeged,
X
6720 Szeged, Eötvös u. 6, Hungary
N
X
N
CHO
fulop@pharm.u-szeged.hu
b
c
OHC
CHO
OHC
CF3
X
CHF2
CO2R
MTA-SZTE Stereochemistry Research Group, Hungarian
Academy of Sciences, 6720 Szeged, Eötvös u. 6, Hungary
Departamento de Química Orgánica, Facultad de Farmácia,
Universidad de Valencia, Av. Vincente Andrés Estellés, s/n
F3C
CHO
OHC
F3C
CO2Me
CO2Me
CO2Me
CO2Me
N
461000 Valencia, Spain
N
N
OHC
CO2Me
CO2Me
OHC
CF3
CH2F
Received: 19.12.2016
Accepted: 23.12.2016
Published online: 24.01.2017
DOI: 10.1055/s-0036-1588396; Art ID: ss-2016-z0870-fa
Y
oxidative
ring opening
Y
ring closure by
reductive amination
Y
H2C
CH2
N
C
C
C
O
C
O
H
H
H
H
X
Abstract Functionalized dialdehydes are considered important sub-
strates that can be transformed into various substituted heterocyclic,
alicyclic, and polysubstituted compounds. Here, we report a robust ste-
reocontrolled procedure for the synthesis of novel functionalized triflu-
oromethyl-containing piperidine and azepane derivatives, based on oxi-
dative ring cleavage of the C=C bond of diversely substituted
cycloalkenes, followed by reductive ring closure of the diformyl inter-
mediates in the presence of fluorine-containing amines.
Figure 1 General scheme for the transformation of cycloalkenes into
N-heterocycles via dialdehydes
Given the high chemical and biological relevance of β-
3
amino acids, during the last decade we have focused devel-
oping ways to access this type of compound. Based on these
studies, our group has demonstrated that various carbocy-
clic and acyclic dialdehydes, derived from unsaturated
mono- or bicyclic substances are useful intermediates for
the synthesis of various functionalized β-amino derivatives.
A stereocontrolled transformation of unsaturated β-
amino acids involving diformyl cyclopentanes is illustrated
in Scheme 1. Carbocyclic dialdehydes, derived from nor-
bornene β-amino acid stereoisomers by oxidative cleavage,
were converted under Wittig reaction conditions into the
corresponding alkenylated cyclopentane β-amino acid de-
rivatives (Scheme 1).4
Key Words aldehydes, alkylation, amino acids, bioorganic chemistry,
heterocycles, piperidines, expansion
Introduction
Since the classical textbook example of tropinone syn-
thesis, alicyclic and open-chain dialdehydes have been re-
garded as valuable scaffolds. They allow the construction of
various saturated N-heterocyclic systems with different
substituents and can serve as precursors that enable access
to highly functionalized β-amino acid derivatives. Thus, the
oxidative ring cleavage of unsaturated carbocyclic com-
pounds followed by ring closure under reductive amination
conditions serves as a methodology for the preparation of
some heterocyclic systems (Figure 1), such as highly substi-
tuted piperidines, morpholine derivatives, and N-bridged
R
R
OHC
oxidative
CO H ring cleavage
Wittig
olefination
CO2Et
2
NH2
NHCOPh
PhOCHN
CO2Et
OHC
1
bicyclic scaffolds.
R = Ph, CO2Me,
MeCO, H
OHC
The oxidative ring cleavage of unsaturated, substituted
mono- or bicyclic compounds, followed by transformations
of the resulting diformyl intermediates as useful substrates,
is an efficient and convenient tool for the synthesis of func-
R
R
oxidative
ring cleavage
Wittig
olefination
CO2Et
CO2H
NH2
NHCOPh
OHC
PhOCHN
CO2Et
2
tionalized acyclic or monocyclic derivatives.
Scheme 1 Stereocontrolled synthesis of functionalized alkenylated cy-
clopentanes from disubstituted norbornenes via diformyl intermediates
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
Synthesis
R. A. Ábrahámi et al.
Feature
The developed stereocontrolled method described
above was efficiently extended to the synthesis of various
functionalized open-chain β-amino acid derivatives. Start-
ing from cis- or trans-cyclopentene β-amino acids, dialde-
hyde intermediates furnished the corresponding anti- and
syn-dialkenylated acyclic derivatives with conservation of
the configuration of the chiral centers (Scheme 2).5
By applying a similar strategy, the six-membered amino
acid stereoisomers, after oxidative ring opening and Wittig
olefination, provided novel functionalized open-chain β-
amino acid derivatives.6
Biographical Sketches
Renáta A. Ábrahámi graduat-
ed as a pharmacist in 2015 from
the University of Szeged (Hun-
gary). She has been working at
the Institute of Pharmaceutical
Chemistry, University of Szeged
since 2011. In 2015 she started
her Ph.D. under the supervision
of Loránd Kiss and Ferenc Fülöp.
Her recent research topic focus-
es on the synthesis of variously
functionalized six- or seven-mem-
bered N-heterocyclic derivatives
and on the preparation of highly
substituted fluorinated building
elements.
Loránd Kiss completed his
Ph.D. in 2002 in the Depart-
ment of Organic Chemistry at
Debrecen University (Debrecen,
Hungary) under the supervision
of Prof. Sándor Antus. In 2003,
he joined the research group of
Professor Ferenc Fülöp at the In-
started to work in the field of
cyclic β-amino acid chemistry.
He followed postdoctoral stud-
ies in the laboratories of Prof.
Norbert De Kimpe at Ghent Uni-
versity (Ghent, Belgium), and
Prof. Santos Fustero, at the De-
partment of Organic Chemistry,
University of Valencia (Valencia,
Spain). He has published 72 sci-
entific papers in reputed jour-
nals. He is currently a faculty
member at the Institute of Phar-
maceutical Chemistry, Universi-
ty of Szeged. His scientific
interest is directed towards the
selective functionalization cyclic
β-amino acids and on the syn-
thesis of highly functionalized
fluorinated building blocks.
stitute
Chemistry, University of Szeged
Szeged, Hungary), where he
of
Pharmaceutical
(
Santos Fustero was born in
Aínsa, Spain, in 1949. He stud-
ied chemistry at the University
of Zaragoza, where he obtained
his B.Sc. degree in 1972. He re-
ceived his Ph.D. in organic
chemistry in 1975 from the
same University, working in the
field of heterocyclic chemistry
under the supervision of Profes-
sor J. Barluenga and Professor V.
Gotor. He spent two years as a
postdoctoral research associate
at Professor H. Lehmkuhl’s labo-
ratory at Max-Planck-Institut für
Kohlenforschung in Mülheim an
der Ruhr, Germany, researching
organometallic chemistry. In
1983, he became Associate Pro-
fessor at the University of
Oviedo, Spain, and, in 1990, he
was promoted to Full Professor
in Organic Chemistry at the Uni-
versity of Valencia. In 2005, he
became research group leader
at Centro de Investigación ‘Prín-
cipe Felipe’ (CIPF) in Valencia.
His research interests include
organofluorine and medicinal
chemistry, organocatalysis, and
new reaction methodologies.
Ferenc Fülöp was born in
Szank, Hungary in 1952. He re-
ceived his MSc in Chemistry in
pointed as a full professor at the
Institute of Pharmaceutical
Chemistry, University of Szeged,
and since 1998 has been the
head of the Institute. He is a
member of the Hungarian Acad-
emy of Sciences and has a wide
range of research interests in
synthetic organic chemistry. His
recent activities have focused
on the use of amino alcohols
and β-amino acids in enzymatic
1975 and his Ph.D. in 1979 from
transformations,
asymmetric
József Attila University, Szeged,
Hungary. At the beginning of
his carrier he worked in Chinoin
Pharmaceuticals, Budapest for
six years. In 1991, he was ap-
syntheses, foldamer construc-
tion, and flow chemistry, in view
of the development of pharma-
cologically active compounds.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
Synthesis
R. A. Ábrahámi et al.
Feature
CO
2
Et
O
oxidative
ring opening
Wittig
olefination
CHO
R
R
OHC
OHC
OHC
OHC
NH
CO2Et
NHR2
CO2Et
NHCOPh
oxidative
ring opening
O
2
H N
2
CO H
PhOCHN
2
CO Et
anti
cis
OHC
OHC
NHR2
CHO
NH
R = H, Ph, CO
2
Et, COMe, CN
O
CO2Et
CO2Et
NHR2
oxidative
ring opening
Wittig
olefination
2
CO Et
CHO
NH
OHC
NHR2
OHC
R
R
OHC
2
H N
CO
2
H
PhOCHN
2
CO Et
NHCOPh
syn
trans
CO Et
2
CO2Et
NHR2
R1
N
R1
N
Scheme 2 Stereocontrolled synthesis of highly functionalized acyclic
NHR2
dienes from disubstituted cyclopentene stereoisomers via diformyl in-
termediates
2
CO Et
CO2Et
ring closure by
reductive amination
NHR2
NHR2
7
N
N
Fluorinated organic molecules, including fluorine-con-
8
R1
CO2Et
R1
taining amino acid derivatives, have generated increasing
attention among medicinal chemists and such compounds
have had a high impact on drug research over the last de-
cade. Our research group has applied various selective ste-
reocontrolled strategies to gain access to a range of fluori-
nated β-amino acid derivatives. An approach to fluorinat-
ed scaffolds consisted of the transformation of diformyl
cyclopentane β-amino esters derived from norbornene β-
CO2Et
NHR2
NHR2
R1
R1
8
N
N
1
2
R
R
3 2 2
= Ph, CF , CHF , CH F
8c
= Cbz, COPh, Boc
Scheme 4 Stereocontrolled synthesis of piperidine and azepane β-
amino acid derivatives from unsaturated bicyclic β-lactams via diformyl
intermediates
9
amino acid stereoisomers (Scheme 3).
OHC
CO2Et
The reductive amination protocol was efficiently ex-
tended further to enable access to tashiromine and epi-
tashiromine natural alkaloids. Diformyl amino ester stereo-
isomers, accessed from cis- or trans-cyclooctene β-amino
esters, underwent intramolecular cyclization under reduc-
tive amination and led to the corresponding indolizidine al-
kaloids.11
CO2H
oxidative
NH2
ring opening
NHR
OHC
OHC
CO2Et
NHR
CO2H
NH2
OHC
F
H
F
F
H
H
F
CO2Et
CO2Et
fluorination
H
H
by chemo-
discrimination
N
NHR
CO2Et
F
H
F
F
CO Et
CHO
CHO
O
R1
2
OHC
OHC
oxidative
ring opening
R = COPh, Z
R1 = Ph, OBn
NHZ
NHZ
CO2Et
Scheme 3 Chemoselective synthesis of highly functionalized fluorinat-
ed scaffolds from disubstituted norbornenes via diformyl intermediates
CO2Et
NHZ
NHZ
HO
HO
Dialdehyde scaffolds resulting from oxidative ring cleav-
age of unsaturated bicyclic β-lactams were used as excel-
lent precursors for the synthesis of N-heterocyclic β-amino
esters (Scheme 4). Double reductive amination of diformyl
β-amino esters with benzylamine or fluorinated amines af-
forded stereoisomers of piperidine or azepane β-amino es-
H
N
ring closure by
reductive amination
H
N
8
d,10a,b
ters.
Starting from di-exo- or di-endo-norbornene β-
amino acids, the ring expansion with reductive amination
Scheme 5 Stereocontrolled synthesis of natural products tashiromine
and epitashiromine alkaloids from unsaturated bicyclic β-lactams via di-
formyl intermediates.
resulted in the formation of N-bridged bicyclic β-amino es-
8d,10c
ters.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
Synthesis
R. A. Ábrahámi et al.
Feature
Notably, the configuration of the chiral centers of the fi-
nal products prepared by using the above methodologies,
based on the cyclization by reductive amination, were pre-
determined by the configurations of the stereocenters of
the starting materials (Scheme 5).
CO2H
CO Bn
OsO4, t-BuOH
NMO, H2O
acetone
CO2Bn
2
BnCl, DBU, THF
h, 65 °C
3
20 °C, 3 h
HO
OH
3 (85%)
1
2 (64%)
NaIO4, THF, H2O
0 °C, 1 h
2
Results and Discussion
CO2Bn
CO Bn
2
CF3CH2NH2HCl
EtOH, NaHCO3
2 2 2
CHF CH NH HCl
EtOH, NaHCO3
CO2Bn
CHO
Our current aim is to offer an insight into the extension
by generalization of the synthetic method summarized
above. The protocol involves oxidative ring opening of vari-
ous cycloalkenes followed by cyclization of the diformyl de-
rivatives under reductive amination conditions, to synthe-
size various N-heterocyclic scaffolds that incorporate fluo-
rinated entities in their structure. Taking into consideration
the high biorelevance of N-heterocycles and organofluorine
scaffolds, we decided to investigate the formation of fluo-
rine-containing N-heterocyclic systems from various sub-
stituted dialdehydes. The latter compounds were derived
from selected mono- or disubstituted cycloalkenes.
OHC
NaBH3CN, AcOH
NaBH3CN, AcOH
20 °C, 3 h
N
N
20 °C, 3 h
4
CF3
CHF2
5
CH FCH NH HCl
2
2
2
6
(
67%,
two
steps)
EtOH, NaHCO3
NaBH CN, AcOH, 20 °C, 3 h
(79%,
two steps)
3
CO2Bn
N
CH2F
55%, two steps)
7
(
Scheme 6 Synthesis of functionalized piperidine derivatives 5–7 from
cyclopentene carboxylate via a diformyl intermediate
First, we explored the behavior of substituted five-
membered cycloalkenes; namely, a cyclopentene carboxyl-
ate and a cyclopenteneamine. Cyclopentene benzyl ester 2
(
prepared from the commercially available cyclopent-3-en-
ecarboxylic acid 1) was submitted to dialdehyde formation
Scheme 6). First, 2 was oxidized with N-methylmorpholine
droxylation of which furnished a 1:1 mixture of diol deriva-
tive 9 (Scheme 7). Again, this mixture was used in the next
step without separation of the components, giving dialde-
hyde 10. Without isolation, this unstable dialdehyde was
transformed in the reaction with 2,2,2-trifluoroethylamine
(
N-oxide (NMO)/OsO to generate the corresponding vicinal
diol derivatives 3 as a mixture of stereoisomers in nearly
4
1:1 ratio, which could not be separated either by crystalli-
in the presence of NaBH CN into trifluoromethylated piper-
3
zation or by chromatography. Given that the stereocenters
are removed in the next oxidative ring cleavage step, the di-
astereoisomeric diol mixture 3 was used further without
idine 11 in good yield.
OsO4, t-BuOH
NMO, H2O
acetone
NHCbz
CO2H
NHCbz
1. DPPA, PhMe, Et3N
separation. Oxidation with NaIO provided the correspond-
2 h, 90 °C
4
ing unstable acyclic dialdehyde 4, which was submitted
without isolation or purification to a reductive ring-closure
step. The latter reaction was initially performed with the
commercially available fluorine-containing amine, 2,2,2-
trifluoroethylamine. Diformyl intermediate 4, upon reac-
tion with the fluorine-containing amine noted above, fol-
2
. BnOH, 12 h, 90 °C
20 °C, 3 h
HO
OH
1
8
(65%)
9
(74%)
NaIO4, THF, H2O
20 °C, 1 h
NHCbz
N
CF3CH2NH2HCl
EtOH, NaHCO3
NHCbz
lowed by treatment with NaBH CN, furnished the corre-
3
OHC
CHO
sponding trifluoromethylated piperidine derivative 5.
The ring-closing protocol based on reductive amination
of dialdehydes could be applied by using other fluorine-
containing building blocks, which allowed access to other
fluorinated piperidines. Illustrative is the treatment of di-
formyl derivative 4 with the commercially available 2,2-di-
fluoromethylamine or 2-fluoroethylamine followed by re-
duction, affording the corresponding mono- or difluorinat-
ed piperidine derivatives 6 and 7 (Scheme 6).
Next, the substituent on the cyclopentene ring was
changed from an ester to a protected amine. Commercially
accessible unsaturated acid 1 was converted under Curtius
reaction conditions into Cbz-protected amine 8, the dihy-
NaBH3CN, AcOH
20 °C, 3 h
10
CF3
1
1
(
64%, two steps)
Scheme 7 Synthesis of functionalized piperidine derivative 11 from
cyclopentene carboxylate via a diformyl intermediate
The transformation of dialdehyde substrates could be
applied not only for the synthesis of piperidines but also for
the construction of seven-membered functionalized N-het-
erocyclic systems. For this synthesis, we selected the six-
membered analogues of the cyclopentene ester and amine
studied above. Thus, commercially available ethyl cyclohex-
3-enecarboxylate (12) was first subjected to dihydroxyl-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
Synthesis
R. A. Ábrahámi et al.
Feature
ation, yielding 13 as a mixture of diol diastereoisomers
1:1) (Scheme 8). Analogous to the five-membered counter-
ination took place, resulting in the corresponding substitut-
ed azepane derivatives 20 containing a trifluoromethyl
group (Scheme 9). Notably, formation of the seven-mem-
bered ring system proceeded with lower yield in compari-
son to those of the six-membered analogues.
As a continuation of the study, our next aim was to syn-
thesize disubstituted trifluoromethylated N-heterocyclic
derivatives. Dihydroxylation of the olefin bond of the com-
mercially available cyclohexene cis-diester 21 afforded vici-
nal diol 22 (Scheme 10). Subsequent oxidative ring opening
(
part, these could not be separated and, therefore, were used
directly for ring opening with NaIO4 affording the corre-
sponding open-chain dialdehyde 14. Unstable diformyl in-
termediate 14 was next converted without isolation on
treatment with trifluorinated ethylamine into azepane de-
rivative 15.
CO2Et
CO2Et
OsO4, t-BuOH
NMO, H2O, acetone
of 22 mediated by NaIO followed by reductive ring closure
4
with trifluoroethylamine afforded, via dialdehyde 23, aze-
pane diester 24. Again, given that the stereocenters are not
affected during the ring expansion procedure, the configu-
rations of the chiral centers in 24 are predetermined by the
structure of the starting material 21.
20 °C, 3 h
OH
1
2
OH
1
3 (95%)
NaIO4, THF, H2O
0 °C, 1 h
2
CO2Et
CF3CH2NH2HCl
EtOH, NaHCO3
CO2Et
CO Me
OsO , t-BuOH
NMO, H2O, acetone
HO
HO
CO Me
2
4
2
N
CHO
NaBH3CN, AcOH
OHC
CO2Me
20 °C, 3 h
CO2Me
20 °C, 3 h
CF3
14
21
22 (82%)
1
5
(
25%, two steps)
NaIO4, THF, H2O
0 °C, 1 h
2
Scheme 8 Synthesis of functionalized azepane derivative 15 from cy-
clohexene carboxylate via a diformyl intermediate
MeO2C
2
CO Me
CF3CH2NH2HCl
EtOH, NaHCO3
2
CO Me
CHO
OHC
N
NaBH3CN, AcOH
The synthesis of a fluorinated azepane bearing a Cbz-
protected amine substituent could be achieved by starting
from the commercially accessible cyclohex-3-enecarboxylic
acid (16; Scheme 9). Cyclohexeneamine 17, synthesized by
Curtius reaction from 16, led by dihydroxylation to diol
mixture 18, which was subjected to oxidative ring cleavage
in the presence of NaIO4.
CO2Me
20 °C, 3 h
CF3
24
9% (two steps)
23
3
Scheme 10 Synthesis of functionalized azepane derivative 24 from cy-
clohexene dicarboxylate via a diformyl intermediate
In view of the high physiological relevance of N-bridged
bicyclic derivatives (e.g., cocaine, anatoxin-a analogues),
our next aim was to extend the synthetic technique de-
scribed above to the preparation of trifluoromethylated N-
bicyclic systems. Thus, di-endo-norbornene dicarboxylate
3
a,e
CO2H
OsO4, t-BuOH
NMO, H2O
acetone
NHCbz
NHCbz
1
. DPPA, PhMe, Et3N
2
h, 90 °C
2
. BnOH, 12 h, 90 °C
20 °C, 3 h
OH
16
OH
8 (63%)
17 (74%)
1
NaIO4, THF, H2O
HO
20 °C, 1 h
OsO4, t-BuOH
NMO, H2O, acetone
NHCbz
HO
CO2Me
CO Me
CF3CH2NH2HCl
EtOH, NaHCO3
CO Me
2
NHCbz
CHO
20 °C, 3 h
2
CO2Me
N
25
26 (92%)
OHC
NaBH3CN, AcOH
20 °C, 3 h
19
NaIO4, THF, H2O
CF3
20 °C, 1 h
20
20% (two steps)
OHC
OHC
F3C
CF3CH2NH2HCl
EtOH, NaHCO3
N
CO2Me
CO2Me
Scheme 9 Synthesis of functionalized azepane derivative 20 from eth-
yl cyclohexene carboxylate via a diformyl intermediate
CO2Me
CO2Me
NaBH3CN, AcOH
20 °C, 3 h
2
8
27
The formed unstable dialdehyde derivative 19 was fur-
ther used without isolation. On treatment with 2,2,2-tri-
fluroethylamine hydrochloride in EtOH, in the presence of
NaHCO and NaBH CN, ring closure involving reductive am-
(
29%, two steps)
Scheme 11 Synthesis of functionalized bicyclic derivative 28 from nor-
bornene dicarboxylate via a diformyl intermediate
3
3
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F
Synthesis
R. A. Ábrahámi et al.
Feature
2
515 was transformed by dihydroxylation into diol deriva-
tion of the reaction, the mixture was treated with saturated aqueous
Na SO solution and then extracted with CH Cl (3 × 30 mL). The com-
tive 26, then the oxidative ring opening followed by reduc-
tive amination with trifluoroethylamine and NaBH CN,
provided N-bicyclic diester 28 via diformyl derivative 27
2
3
2
2
bined organic layers were dried over Na SO , filtered, and evaporated
2
4
3
under reduced pressure. The crude product was purified by column
chromatography on silica gel (n-hexane/EtOAc).
(Scheme 11).
Fluorine-Containing N-Heterocyclic Derivatives by Ring Closure
with Reductive Amination; General Procedure
Conclusions
To a stirred solution of diol (2 mmol), NaIO (1.5 equiv) was added in
4
THF/H O (25 mL/2 mL). After stirring the mixture for 1 h at 20 °C un-
2
We have demonstrated the high value of substituted
open-chain or alicyclic dialdehyde derivatives for the syn-
thesis by double reductive amination of different types of
N-heterocycles. In the current study we investigated the ap-
plication of this synthetic procedure for the construction of
functionalized fluorine-containing N-heterocyclic systems.
The method includes the reaction of functionalized di-
formyl scaffolds, accessed by oxidative ring opening of vari-
ous substituted cycloalkenes, with simple, commercially
available fluorinated amines. Taking into consideration the
availability of both a wide variety of cycloalkenes and func-
tionalized primary amine building blocks, this convenient
methodology might be further applied towards the synthe-
sis of a series of functionalized saturated N-heterocycles.
der an Ar atmosphere, H O was added until the precipitate dissolved
2
(ca. 40 mL). The mixture was then extracted with CH
Cl (3 × 20 mL),
2
2
the combined extract was dried over Na SO and the resulting dialde-
2
4
hyde solution was evaporated. The crude product was used for the
next reaction without purification. Fluorine-containing ethylamine
hydrochloride (2 mmol), and NaHCO3 (2 equiv) were added to the
solution of the dialdehyde in EtOH (20 mL) and the mixture was
stirred at 20 °C for 10 min. NaBH CN (2 mmol) and AcOH (2 drops)
3
were then added and stirring was continued for another 4 h at 20 °C.
The reaction mixture was diluted with H O (20 mL), extracted with
2
CH Cl (3 × 25 mL), and the combined organic layers were dried over
2
2
Na SO and concentrated under reduced pressure. The residue was
2
4
purified by column chromatography on silica gel (n-hexane/EtOAc).
Benzyl Cyclopent-3-enecarboxylate (2)12
Yield: 64% (1.15 g); yellow oil; R = 0.26 (n-hexane/EtOAc, 20:1).
f
1
H NMR (400 MHz, DMSO-d ): δ = 2.54–2.68 (m, 4 H, H-2, H-5), 3.15–
6
3
.26 (m, 1 H, H-1), 5.12 (s, 2 H, OCH ), 5.68 (s, 2 H, CH=CH), 7.31–7.42
2
The chemicals were purchased from Sigma-Aldrich and were used
without further purification. The NMR spectra were recorded at 400
MHz with CDCl or DMSO-d as the solvent and tetramethylsilane as
the internal standard. The solvents were used as received from the
suppliers. Melting points were determined with a Kofler apparatus.
Elemental analyses were recorded on a Perkin-Elmer CHNS-2400 Ser
II elemental analyser. Silica gel 60 F254 was purchased from Merck.
(m, 5 H, Ar-H).
13
C NMR (100 MHz, DMSO-d ): δ = 36.8, 41.5, 66.5, 128.7, 128.9,
6
3
6
129.3, 129.8, 137.2, 179.3.
Anal. Calcd for C13 : C, 77.20; H, 6.98. Found: C, 77.18; H, 6.97.
H O
14 2
Benzyl Cyclopent-3-en-1-ylcarbamate (8)13
Yield: 65% (2.51 g); white solid; mp 31–32 °C; R = 0.33 (n-hex-
ane/EtOAc 8:1).
f
Synthesis of N-Protected Cycloalkeneamines; General Procedure
To a solution of cycloalkencarboxylic acid (12 mmol) in anhydrous
1
H NMR (400 MHz, DMSO-d ): δ = 2.32–2.45 (m, 2 H, H-2, H-5), 2.73–
6
toluene (30 mL), Et N (12 mmol) and diphenylphosphoryl azide
3
2.86 (m, 2 H, H-2, H-5), 4.27–4.39 (m, 1 H, H-1), 5.22 (s, 2 H, OCH2),
5
(
DPPA, 12 mmol) were added and the resulting mixture was stirred
for 2 h at r.t. and then for 1 h at 90 °C. A solution of benzyl alcohol
13.8 mmol) was added to this solution and the mixture was stirred
.87 (s, 2 H, CH=CH), 7.47–7.70 (m, 6 H, Ar-H and N-H).
13
C NMR (100 MHz, DMSO-d ): δ = 40.0, 51.1, 66.0, 120.8, 128.6,
6
(
1
29.2, 129.7, 138.1, 156.6.
overnight at 90 °C. The mixture was then diluted with EtOAc (40 mL)
and washed with NaHCO3 (2 × 20 mL). The organic layer was dried
over Na SO and concentrated under vacuo. The crude material was
Anal. Calcd for C13H14O : C, 71.87; H, 6.96; N, 6.45. Found: C, 71.85; H,
6
2
.95; N, 6.44.
2
4
purified by column chromatography on silica gel (n-hexane/EtOAc).
Benzyl Cyclohex-3-en-1-ylcarbamate (17)14
Esterification of Cycloalkenecarboxylic Acids; General Procedure
Yield: 74% (508 mg); yellow solid; mp 47–49 °C; R = 0.30 (n-hex-
f
ane/EtOAc, 8:1).
To a solution of cycloalkencarboxylic acid (9 mmol) in THF (50 mL),
benzyl chloride (9 mmol) and DBU (22.5 mmol) were added and the
solution was stirred for 3 h at 90 °C. Upon completion of the reaction,
1
H NMR (400 MHz, DMSO-d ): δ = 1.37–1.49 (m, 1 H, H-6), 1.76–1.84
6
(m, 1 H, H-5), 1.86–1.96 (m, 1 H, H-6), 2.04–2.11 (m, 2 H, H-2), 2.16–
2.26 (m, 1 H, H-5), 3.47–3.58 (m, 1 H, H-1), 5.02 (s, 2 H, OCH ), 5.54–
5.66 (m, 2 H, CH=CH), 7.18–7.26 (br s, 1 H, N-H), 7.29–7.43 (m, 5 H,
Ar-H).
the mixture was diluted with EtOAc (40 mL) and washed with H O
2
2
(
3 × 30 mL). The organic layer was dried (Na SO ) and concentrated
2
4
under reduced pressure. The crude product was purified by column
chromatography on silica gel (n-hexane/EtOAc).
13
C NMR (100 MHz, DMSO-d ): δ = 25.4, 29.5, 32.3, 47.6, 66.4, 125.8,
6
1
27.4, 128.6, 129.2, 135.3, 155.5.
Dihydroxylation of Substituted Cycloalkenes; General Procedure
Anal. Calcd for C14H17NO : C, 72.70; H, 7.41; N, 6.06. Found: C, 72.68;
H, 7.39; N, 6.05.
2
To a stirred solution of substituted cycloalkene (10 mmol), OsO (2%
4
in t-BuOH, 0.3 mL), and NMO (1.2 equiv) were added in acetone (30
mL) and the resulting mixture was stirred at r.t. for 3 h. Upon comple-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
Synthesis
R. A. Ábrahámi et al.
Feature
Dimethyl (1R*,2S*,3R*,4S*)-Bicyclo[2.2.1]hept-5-ene-2,3-dicarbox-
ylate (25)
Anal. Calcd for C11H18F NO : C, 52.17; H, 7.16; N, 5.53. Found: C,
52.14; H, 7.15; F, 22.48; N, 5.52.
3
2
15
Yield: 89% (5.70 g); colorless oil; R = 0.42 (n-hexane/EtOAc, 4:1).
f
1
Benzyl [1-(2,2,2-Trifluoroethyl)piperidin-4-yl]carbamate (11)
H NMR (400 MHz, DMSO-d ): δ = 1.23 (d, J = 8.8 Hz, 1 H, H-7), 1.37
6
(d, J = 8.8 Hz, 1 H, H-7), 3.05 (s, 2 H, H-2, H-3), 3.47 (s, 6 H, COOCH3),
Yield: 64% (482 mg); white solid; mp 63–66 °C; R = 0.18 (n-hex-
f
3.51 (s, 2 H, H-1, H-4), 6.12 (s, 2 H, CH=CH).
ane/EtOAc, 4:1).
1
3
1H NMR (400 MHz, DMSO-d
C NMR (100 MHz, DMSO-d ): δ = 46.6, 48.2, 48.9, 51.9, 135.6, 173.1.
6
): δ = 1.35–1.48 (m, 2 H, H-3, H-5,), 1.71
d, J = 13.2 Hz, 2 H, H-3, H-5), 2.36 (t, J = 11.6 Hz, 2 H, H-2, H-6), 2.86
6
(
(
Anal. Calcd for C11H14O : C, 62.85; H, 6.71. Found: C, 62.83; H, 6.70.
4
d, J = 12.4 Hz, 2 H, H-2, H-6), 3.06–3.18 (m, 2 H, CH CF ), 5.00 (s, 2 H,
2
3
OCH ), 7.21 (br s, 1 H, N-H), 7.27–7.40 (m, 5 H, Ar-H).
2
Dimethyl (1R*,2S*,4S*,5R*)-4,5-Dihydroxycyclohexane-1,2-dicar-
boxylate (22)
1
3
C NMR (100 MHz, DMSO-d ): δ = 32.5, 48.2, 53.3, 57.3 and 57.5 and
6
2
1
5
7.8 and 58.1 (q, JC–F = 28.0 Hz, CCF ), 66.0, 128.3 (q, JC–F = 260 Hz,
3
Yield: 82% (1.93 g); yellow oil; R = 0.38 (n-hexane/EtOAc 1:3).
f
CF ), 128.6, 129.2, 138.2, 156.2.
3
1
H NMR (400 MHz, DMSO-d ): δ = 1.79–1.88 (m, 2 H, H-3, H-6), 1.89–
6
19
F NMR (100 MHz, DMSO-d ): δ = –68.1.
6
1.97 (m, 2 H, H-3, H-6), 2.99 (s, 2 H, OH), 3.52–3.63 (m, 8 H, COOCH3,
MS (ESI): m/z = 317.3 [M + 1].
H-1, H-2), 4.45 (d, J = 4.4 Hz, 2 H, H-4, H-5).
1
3
Anal. Calcd for C15H19F N O : C, 56.96; H, 6.05; N, 8.86; found: C,
3 2 2
C NMR (100 MHz, DMSO-d ): δ = 30.7, 39.4, 52.3, 68.2, 174.5.
6
56.93; H, 6.04; F, 18.00; N, 8.84.
Anal. Calcd for C10H16O : C, 51.72; H, 6.94. Found: C, 51.70; H, 6.93.
6
Benzyl 1-(2,2,2-Trifluoroethyl)piperidine-4-carboxylate (5)
Dimethyl (1R*,2R*,3S*,4S*,5S*,6R*)-5,6-Dihydroxybicyc-
lo[2.2.1]heptane-2,3-dicarboxylate (26)
16
Yield: 67% (514 mg); brown oil; R = 0.33 (n-hexane/EtOAc, 10:1).
f
1
H NMR (400 MHz, DMSO-d ): δ = 1.53–1.65 (m, 2 H, H-3, H-5), 1.77–
Yield: 92% (1.07 g); colorless oil; R = 0.40 (n-hexane/EtOAc 1:4).
6
f
1.85 (m, 2 H, H-3, H-5 ), 2.34–2.43 (m, 3 H, H-2, H-4, H-6), 2.82–2.90
1
H NMR (400 MHz, DMSO-d ): δ = 1.18 (d, J = 10.0 Hz, 1 H, H-7), 1.83
6
(
m, 2 H, H-2, H-6), 3.08–3.18 (m, 2 H, CH CF ), 5.10 (s, 2 H, OCH ),
2
3
2
(d, J = 10.0 Hz, 1 H, H-7), 2.23 (s, 2 H, OH), 3.05 (t, J = 2.14 Hz, 2 H, H-1,
7.29–7.40 (m, 5 H, Ar-H).
H-4), 3.54 (s, 6 H, COOCH ), 3.88–3.92 (m, 2 H, H-2, H-3), 4.57–4.63
3
1
3
C NMR (100 MHz, DMSO-d ): δ = 28.8, 40.5, 53.4, 57.4 and 57.7 and
(m, 2 H, H-5, H-6).
6
2
1
5
8.0 and 58.3 (q, J = 29.0 Hz, CCF ), 66.3, 125.5 (q, J = 275.6 Hz,
13
C–F 3 C–F
C NMR (100 MHz, DMSO-d ): δ = 33.3, 44.6, 47.2, 52.0, 69.6, 172.8.
6
CF ), 128.6, 128.8, 129.3, 137.2, 174.9.
3
Anal. Calcd for C11H16O : C, 54.09; H, 6.60. Found: C, 54.07; H, 6.59.
6
19
F NMR (100 MHz, DMSO-d ): δ = –69.1.
6
MS (ESI): m/z = 302.3 [M + 1].
Benzyl [1-(2,2,2-Trifluoroethyl)azepan-4-yl]carbamate (20)
Anal. Calcd for C15H18F NO : C, 59.79; H, 6.02; N, 4.65. Found: C,
Yield: 20% (151 mg); yellow oil; R = 0.25 (n-hexane/EtOAc, 3:1).
3
2
f
59.75; H, 6.00; F, 18.90; N, 4.64.
1
H NMR (400 MHz, DMSO-d ): δ = 1.41–1.96 (m, 6 H, H-3, H-5, H-6),
6
2
.68–2.89 (m, 4 H, 2-H, 7-H), 3.17–3.29 (m, 2 H, CH -CF ), 3.48–3.60
2 3
Dimethyl (4R*,5S*)-1-(2,2,2-Trifluoroethyl)azepane-4,5-dicarbox-
ylate (24)
(
(
1
m, 1 H, H-4), 4.99 (s, 2 H, OCH ), 7.16–7.23 (br s, 1 H, N-H), 7.27–7.39
m, 5 H, Ar-H).
2
Yield: 39% (303 mg); colorless oil; R = 0.12 (n-hexane/EtOAc, 10:1).
3
f
C NMR (100 MHz, DMSO-d ): δ = 25.2, 34.1, 35.6, 51.7, 52.0, 56.1,
6
1
2
H NMR (400 MHz, DMSO-d ): δ = 1.84–1.95 (m, 2 H, H-3, H-6), 1.95–
5
7.5 and 57.8 and 58.1 and 58.3 (q, J = 29.05, CCF ), 65.9, 125.9 (q,
6
C–F
3
1
2.09 (m, 2 H, H-3, H-6), 2.71–2.86 (m, 4 H, H-2, H-7), 2.98–3.07 (m,
JC–F = 260.0 Hz, CF ), 128.3, 128.6, 129.2, 138.2, 156.0.
3
2
H, H-4, H-5), 3.17–3.28 (m, 2 H, CH CF ), 3.57 (s, 6 H, COOCH ).
19
2
3
3
F NMR (100 MHz, DMSO-d ): δ = –69.4.
6
1
3
C NMR (100 MHz, DMSO-d ): δ = 28.8, 44.5, 52.2, 53.3, 57.6 and 57.9
6
MS (ESI): m/z = 331.3 [M + 1].
2
1
and 58.2 and 58.5 (q, JC–F = 29.2 Hz, CCF ), 125.6, 128.4 (q, JC–F
=
3
Anal. Calcd for C16H21F N O : C, 58.17; H, 6.41; N, 8.48. Found: C,
3
2
2
279.6 Hz, CF ), 174.1.
3
58.15; H, 6.40; F, 17.23; N, 8.45.
19
F NMR (100 MHz, DMSO-d ): δ = –69.7.
6
MS (ESI): m/z = 298.2 [M + 1].
Ethyl 1-(2,2,2-Trifluoroethyl)azepane-4-carboxylate (15)
Anal. Calcd for C12H18F NO : C, 48.48; H, 6.10; F, 19.17; N, 4.71. Found:
C, 48.45; H, 6.09; F, 19.15; N, 4.70.
Yield: 25% (2.045 g); colorless oil; R = 0.30 (n-hexane/EtOAc, 10:1).
3
4
f
1
H NMR (400 MHz, DMSO-d ): δ = 1.17 (t, J = 7.06 Hz, 3 H, CH ), 1.47–
6
3
1
4
4
.77 (m, 4 H, H-5, H-6), 1.80–1.92 (m, 2 H, H-3), 2.51–2.57 (m, 1 H, H-
Dimethyl (1R*,5S*,6R*,7R*)-3-(2,2,2-Trifluoroethyl)-3-azabicyc-
lo[3.2.1]octane-6,7-dicarboxylate (28)
), 2.72–2.93 (m, 4 H, H-2, H-7), 3.24–3.28 (m, 2 H, CF CH ), 4.00–
3
2
.09 (m, 2 H, CH CH ).
2
3
Yield: 29% (254 mg); white solid; mp 52–55 °C; R = 0.35 (n-hex-
13
f
C NMR (100 MHz, DMSO-d ): δ = 15.0, 27.2, 30.1, 31.6, 43.8, 53.7,
6
ane/EtOAc, 8:1).
2
55.9, 57.0 and 57.3 and 57.6 and 57.9 (q, J = 29.2, CCF ), 60.6, 128.6
C–F
3
1
1
H NMR (400 MHz, DMSO-d ): δ = 1.48 (d, J = 12 Hz, 1 H, H-8), 1.60–
6
(q, J = 280 Hz, CF ), 176.6.
C–F
3
1.68 (m, 1 H, H-8), 2.29 (s, 2 H, H-5, H-5), 2.54 (s, 2 H, H-2, H-4), 2.95–
19
F NMR (100 MHz, DMSO-d ): δ = –69.5.
6
3
6
.05 (m, 2 H, CH CF ), 3.13–3.18 (m, 2 H, H-2, H-4), 3.23–3.27 (m, 2 H,
-H, 7-H), 3.54 (s, 6 H, COOCH3).
2
3
MS (ESI): m/z = 254.2 [M + 1].
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
Synthesis
R. A. Ábrahámi et al.
Feature
1
3
C NMR (100 MHz, DMSO-d ): δ = 37.8, 38.2, 46.0, 51.6, 55.5, 57.1
E. M.; van der Marel, G. A.; Overkleeft, H. S.; Overhand, M. J. Org.
Chem. 2004, 69, 8331. (d) Caputo, F.; Cattaneo, C.; Clerici, F.;
Gelmi, M. L.; Pellegrino, S. J. Org. Chem. 2006, 71, 8467.
(e) Gelmi, M. L.; Cattaneo, C.; Pellegrino, S.; Clerici, F.; Montali,
M.; Martini, C. J. Org. Chem. 2007, 72, 9811. (f) Robinson, A.;
Thomas, G. L.; Spandl, R. J.; Welch, M.; Spring, D. R. Org. Biomol.
Chem. 2008, 6, 2978.
6
2
1
and 57.4 and 57.7 and 58.0 (q, JC–F = 29.0 Hz, CCF ), 128.3 (q, JC–F
2
=
3
70 Hz, CF ), 172.2.
3
19
F NMR (100 MHz, DMSO-d ): δ = –66.9.
6
MS (ESI): m/z = 310.3 [M + 1].
Anal. Calcd for C13H18F NO : C, 50.48; H, 5.87; F, 18.43; N, 4.53. Found:
3
4
C, 50.45; H, 5.86; F, 18.40; N, 4.52.
(2) (a) Wrobleski, A.; Sahasrabudhe, K.; Aube, J. J. Am. Chem. Soc.
2004, 126, 5475. (b) Testero, S. A.; Mangione, M. I.; Suárez, A. G.;
Benzyl 1-(2,2-Difluoroethyl)piperidine-4-carboxylate (6)
Spanevello, R. A. Eur. J. Org. Chem. 2013, 5236. (c) Lee, M.; Stahl,
S. S.; Gellman, S. H. Org. Lett. 2008, 10, 5317. (d) Fricke, Y.; Kopp,
N.; Wünsch, B. Synthesis 2010, 791. (e) Perez-Bautista, J. A.;
Sosa-Rivadeneyra, M.; Quintero, L.; Hopfl, H.; Tejeda-Domin-
guez, F. A.; Sartillo-Piscil, F. Tetrahedron Lett. 2009, 50, 5572.
Yield: 79% (566 mg); colorless oil; R = 0.18 (n-hexane/EtOAc, 8:1).
f
1
H NMR (400 MHz, DMSO-d ): δ = 1.41–1.57 (m, 2 H, H-3, H-5), 1.64–
6
1
1
2
.78 (m, 2 H, H-3, H-5), 2.05–2.16 (m, 2 H, H-2, H-6), 2.18–2.32 (m,
H, H-4), 2.49–2.64 (td, J = 15.7, 4.28 Hz, 2 H, CH CHF), 2.66–2.78 (m,
2
(
f) Sousa, C. A. D.; Rizzo-Aguiar, F.; Vale, M. L. C.; García-Mera,
X.; Caamaño, O.; Rodríguez-Borges, J. E. Tetrahedron Lett. 2012,
3, 1029. (g) Kumar, I.; Ramaraju, P.; Mir, N. A.; Singh, A. Org.
H, H-2, H-6), 4.99 (s, 2 H, OCH ), 5.78–6.16 (tt, J = 55.7, 4.35 Hz, 1 H,
2
CHF ), 7.16–7.35 (m, 5 H, Ar-H).
2
5
1
3
C NMR (100 MHz, DMSO-d ): δ = 28.8, 40.7, 53.7, 60.0 and 60.2 and
Biomol. Chem. 2015, 13, 1280; and see references cited therein.
(3) (a) Kiss, L.; Fülöp, F. Chem. Rev. 2014, 114, 1116. (b) Grygorenko,
O. O. Tetrahedron 2015, 71, 5169. (c) Risseeuw, M.; Overhand,
M.; Fleet, G. W. J.; Simone, M. I. Amino Acids 2013, 45, 613.
6
2
1
6
0.5 (t, J = 24.1 Hz, CCHF ), 66.2, 114.40 and 116.8 and 119.2 (t, J
=
C–F
2
C–F
2
37.6 Hz, CHF ), 128.6, 128.8, 129.3, 137.2, 174.9.
2
19
F NMR (100 MHz, DMSO-d ): δ = –115.1.
6
(d) Kiss, L.; Cherepanova, M.; Fülöp, F. Tetrahedron 2015, 71,
MS (ESI): m/z = 284.33 [M + 1].
2049. (e) Juaristi, E.; Soloshonok, V. Enantioselective Synthesis of
Anal. Calcd for C15H19F NO : C, 63.59; H, 6.76; F, 13.41; N, 4.94. Found:
2
2
β-Amino Acids, Second Edition; Wiley: Hoboken, 2005.
C, 63.56; H, 6.75; F, 13.39; N, 4.93.
(
4) (a) Kiss, L.; Cherepanova, M.; Forró, E.; Fülöp, F. Chem. Eur. J.
2013, 19, 2102. (b) Cherepanova, M.; Kiss, L.; Sillanpaa, R.;
Benzyl 1-(2-Fluoroethyl)piperidine-4-carboxylate (7)
Fülöp, F. RSC Adv. 2013, 3, 9757.
(
5) Cherepanova, M.; Kiss, L.; Forró, E.; Fülöp, F. Eur. J. Org. Chem.
Yield: 55% (290 mg); colorless oil; R = 0.25 (n-hexane/EtOAc, 1:4).
f
2014, 403.
1
H NMR (400 MHz, DMSO-d ): δ = 1.52–1.68 (m, 2 H, H-3, H-5), 1.76–
6
(
(
6) Cherepanova, M.; Kiss, L.; Fülöp, F. Tetrahedron 2014, 70, 2515.
7) (a) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432. (b) O’Hagan, D. J. Fluorine Chem. 2010, 131,
1
1
2
.89 (m, 2 H, H-3, H-5), 2.01–2.14 (m, 2 H, H-2, H-6), 2.30–2.41 (m,
H, H-4), 2.52–2.66 (dt, J = 28.3, 4.9 Hz, 2 H, CH CH F), 2.77–2.86 (m,
2
2
H, H-2, H-6), 4.41–4.60 (dt, J = 47.8, 4.9 Hz, 2 H, CH F), 5.01 (s, 2 H,
2
OCH ), 7.29–7.41 (m, 5 H, Ar-H).
2
1071. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
1
3
C NMR (100 MHz, DMSO-d ): δ = 28.8, 41.0, 53.4, 58.5 and 58.7 (d,
6
(8) (a) Acena, J. L.; Sorochinsky, A.; Soloshonok, V. A. Synthesis
2012, 1591. (b) Absalom, N.; Yamamoto, I.; O’Hagan, D.; Hunter,
L.; Chebib, M. Aust. J. Chem. 2015, 68, 23. (c) Nonn, M.; Kiss, L.;
Haukka, M.; Fustero, S.; Fülöp, F. Org. Lett. 2015, 17, 1074; and
references therein. (d) Ábrahámi, R. A.; Kiss, L.; Barrio, P.; Fülöp,
F. Tetrahedron 2016, 72, 7526.
2JC–F = 20.0 Hz, CCH F), 66.2, 81.9 and 83.6 (d, J = 163.5 Hz, CH F),
1
2
C–F
2
128.6, 128.8, 129.3, 137.2, 175.0.
19
F NMR (100 MHz, DMSO-d ): δ = –216.8.
6
MS (ESI): m/z = 266.32 [M + 1].
Anal. Calcd for C15H20FNO : C, 67.90; H, 7.60; F, 7.16; N, 5.28. Found:
2
(9) Kiss, L.; Nonn, M.; Sillanpää, R.; Haukka, M.; Fustero, S.; Fülöp, F.
Chem. Asian J. 2016, 23, 3376.
C, 67.88; H, 7.59; F, 7.15; N, 5.27.
(10) (a) Kazi, B.; Kiss, L.; Forró, E.; Fülöp, F. Tetrahedron Lett. 2010,
51, 82. (b) Kiss, L.; Kazi, B.; Forró, E.; Fülöp, F. Tetrahedron Lett.
Acknowledgment
2008, 49, 339. (c) Kazi, B.; Kiss, L.; Forró, E.; Mándity, I.; Fülöp, F.
ARKIVOC 2010, (ix), 31.
11) Kiss, L.; Forró, E.; Fülöp, F. Beilstein J. Org. Chem. 2015, 11, 596.
12) Tamanini, E.; Watkinson, M.; Todd, M. H. Tetrahedron: Asymme-
try 2006, 17, 2235.
13) Barrett, S.; O’Brien, P.; Steffens, H. C.; Towers, T. D.; Voith, M.
Tetrahedron 2000, 56, 9633.
14) Gomez-Sanchez, E.; Marco-Contelles, J. Tetrahedron 2005, 61,
We are grateful to the Hungarian Research Foundation (OTKA Nos. K
(
(
115731 and K 119282) for financial support. This work was support-
ed through the new national excellence program of the Ministry of
Human Capacities (for R.A.Á.).
(
(
(
(
Supporting Information
1207.
15) Pagni, R. M.; Kabalka, G. W.; Hondrogiannis, G.; Bains, S.;
Anosike, P.; Kurt, R. Tetrahedron 1993, 49, 6743.
16) Ishmuratov, G. Y.; Yakovleva, M. P.; Shutova, M. A.; Muslukhov,
R. R.; Vyrypaev, E. M.; Ishmuratova, N. M.; Tolstikov, A. G. Russ. J.
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588396.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H