Spirobicyclic and Tetracyclic Pyrazolidinones: Syntheses and Properties

Article abstract of DOI:10.1002/ejoc.201900989

The stereoselective syntheses of spirobicyclic and tetracyclic pyrazolidinones are reported based on a (3+2) annulation between hydrazones and α-oxoketenes. Some of these conformationally constrained molecules were resolved as enantiopure materials by HPLC techniques and evaluated as aminocatalysts for iminium activation in a model Diels–Alder cycloaddition.

Full text of DOI:10.1002/ejoc.201900989

A Journal of
Accepted Article
Title: Spirobicyclic and tetracyclic pyrazolidinones: syntheses and
properties
Authors: Fabien Perez, Thibault Leveille, Mathilde Bertolotti, Jean
Rodriguez, and Yoann Coquerel
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900989
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
Spirobicyclic and tetracyclic pyrazolidinones: syntheses and
properties
Fabien Perez[a], Thibault Leveille[a], Mathilde Bertolotti[a], Jean Rodriguez*[a], and Yoann Coquerel*[a]
Dedicated to the memory of Prof. Dr. Dieter Enders
Abstract: The stereoselective syntheses of spirobicyclic and
tetracyclic pyrazolidinones are reported based on a (3+2) annulation
a) The most famous and used catalysts
between hydrazones and a-oxoketenes. Some of these
F3C
CF3
conformationally constraint molecules were resolved as enantiopure
materials by HPLC techniques and evaluated as aminocatalysts for
iminium activation in a model Diels–Alder cycloaddition.
O
O
CF3
N
N
CF3
N
H
N
H
N
H
N
H
OSiMe3
OSiMe3
Ph
Ph
Hayashi-Jørgensen, 2005
MacMillan, 2000 & 2003
b) Alternative hydrazide-based catalysts
Introduction
O
CO2Bn
O
N
The use of small chiral and enantiopure organic molecules
mimicking the activity of enzymes in accelerating enantioselective
organic chemical transformations is now referred to as
enantioselective organocatalysis.[1] For instance, some
organocatalysts embedding a basic nitrogen atom are amenable
to the activation of enals through the temporary catalytic formation
of the corresponding iminium ions to trigger, among others,
Michael additions and/or Diels–Alder cycloadditions.[2] Most often,
the iminium activation of enals has been found efficient with the
so-called Hayashi-Jørgensen and/or MacMillan’s catalysts
(Figure 1a),[2a–d] which usually induced good enantioselectivity.
Despite their broad applicability, these catalysts are not ideal with
somewhat improvable stereoselectivities (typically 90–95% ee,
rarely >98% ee) and kinetics (typically 10 mol% catalyst loading
for hours to days). Some alternative catalysts have been
proposed in order to overcome these limitations, notably based
on the hydrazide moiety (Figure 1b).[3] Herein, we report the
modular stereoselective syntheses of spirobicyclic and tetracyclic
pyrazolidinones of type 1–3 in a few steps from readily available
chemicals (Figure 1c), as well as the evaluation of their properties
as catalysts for the iminium activation of enals in a model Diels–
Alder cycloaddition.
N
NH
NH
NH
N
H
Ph
N
S
N
O
R
Ph
Smith, 2010
O
O
Bn
Bach, 2010
R = Et, Lee, 2008
R = Bn, Langlois, 2008
Ogilvie, 2005
O
MeO2C
H
N
H
iPr
H
N
N
O
H
O
N
N
N
N
Ph
iPr
iPr
N
CBz
F3C
N
H
O
Ph
Ph
Suzuki, 2011
Smith, 2013
Gleason, 2018
c) This work
R1
O
O
R1
O
N
X
R2
R1
N2
N
H
H
NH
4
O
+
O
NH
R2
N
R3
NH2
2: X = O
3: X = H,H
1
5
Figure 1. Aminocatalysts for the enantioselective iminium activation of enals
and highlights of the present work.
Results and Discussion
We have earlier shown that a-oxoketenes, generated in situ by a
microwave-assisted Wolff rearrangement of 2-diazo-1,3-
dicarbonyl compounds,[4] are effective dipolarophiles in their
reactions with azomethine imines in three-component processes,
which allowed the expeditious stereoselective syntheses of some
spirobicyclic pyrazolidinones such as 2.[5] Originally, the required
hydrazone intermediates, which upon heating undergo a 1,2-
proton shift to give the corresponding reactive azomethine imines,
were prepared in situ from carbonyl compounds and hydrazines
in the presence of the required diazo compounds (three-
component reaction). The formation of the hydrazones from the
corresponding carbonyl compounds and hydrazines is
accompanied by the formation of an equimolar amount of water,
and the latter can concurrently react with a-oxoketenes to give the
corresponding unstable b-ketocarboxylic acids. For the
[a]
Dr. F. Perez, T. Leveille, M. Bertolotti, Prof. Dr. J. Rodriguez and Dr.
Y. Coquerel
Aix Marseille Université, CNRS, Centrale Marseille, ISM2
13397 Marseille (France)
E-mails: jean.rodriguez@univ-amu.fr
yoann.coquerel@univ-amu.fr
http://ism2.univ-amu.fr/en-gb/user/2207 (JR)
http://ism2.univ-amu.fr/en-gb/user/2204 (YC)
Supporting information for this article is given via a link at the end of
the document. It contains the complementary experimental
information, details of the DFT calculations and copies of spectra
and chromatograms.
1
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
complementary work herein, and in the interest of efficiency, we
have modified the original multicomponent procedure for a one-
pot protocol allowing for the elimination of undesired water after
the formation of the hydrazone intermediates. In practice, as an
illustrative example, a 1:1 mixture of benzaldehyde (4a) and
phenyl hydrazine (5a) in anhydrous toluene was irradiated with
microwaves at 140 ºC for 5 minutes, cooled down to 55 ºC,
concentrated and dried in vacuo. To the resulting material was
added the 2-diazo-1,3-cyclohexanedione and anhydrous toluene,
and the mixture was irradiated with microwaves at 140 ºC for 10
additional minutes, which afforded after purification 86% yield of
the expected spiro product 2a and a trace amount of the
uncyclized acylhydrazone 6a (Table 1, entry 1). In comparison,
only 57% yield were obtained for 2a using the multicomponent
protocol.[5] Using this method, we attempted the syntheses of the
representative spirobicyclic pyrazolidinones 2b-k. While reactions
with phenyl and tert-butyl hydrazines (5a and 5c, respectively)
proceeded without event (entries 1, 3 and 12), the reactions with
methyl hydrazine (5b) were complicated by the formation of the
uncyclized acylhydrazones 6 in various proportions, formally
resulting from the simple nucleophilic addition of the intermediate
hydrazone to the intermediate a-oxoketene. For instance, only
5% of 2d could be obtained together with 89% of 6d from a
reaction performed at 140 ºC for 10 min (entry 4). However,
increasing the reaction temperature to 200 ºC for 30 min allowed
obtaining 2d as the major product in 56% yield (entry 5). In a
separate experiment, the uncyclized acylhydrazone 6h could be
converted into its spirobicyclic pyrazolidinone isomer 2h in 75%
yield by heating at 190 ºC for 3 hours, showing that 6h is the
kinetic isomer and 2h the thermodynamic one. Calculations of the
free Gibbs energies of 6h and 2h by DFT methods indicated that
2h is indeed stabilized by ca. 37.4 kJ.mol-1 relative to 6h (see the
Supporting Information). The syntheses of derivatives 3 and 1
Table 1. Synthesis of spirobicyclic pyrazolidinones 2.[a]
O
R2
H
4a: R2 = Ph
4b: R2 = 4-NO2-C6H4
4c: R2 = 4-OMe-C6H4
4d: R2 = 2-Me-C6H4
4e: R2 = CO2Et
from
2 were devised through the intermediacy of the
corresponding triflyl enol ethers 8 using catalytic palladium(0)
chemistry. Thus, some selected spirobicyclic pyrazolidinones 2
were protected as the corresponding methyl or benzyl
carbamates 7, which were then converted into the desired triflyl
enol ethers 8 under standard conditions (Scheme 1). The
relatively lower yields observed for the formation of the
corresponding triflyl enol ethers 8hBn and 8iBn from ketones 7hBn
and 7iBn having R2 ester substituents are probably due to the
presence of a competing enolizable position in these substrates.
4f: R2 = CO2Bn
4g: R2 = Bn
O
R1
O
O
O
R1
N
1) toluene, 140 ºC, 5 min.
N2
N
N
NH
+
+
R1
H
2)
toluene,
O
conditions
R2
2a-k
O
N
R2
NH2
6a-k
5a: R1 = Ph
5b: R1 = Me
5c: R1 = tBu
Entry Conditions
Product
R1, R2
Yield
Yield
of 2[b] of 6[b]
O
1
140 ºC, 10 min
2a, 6a: R1 = Ph, R2 = Ph
2b, 6b: R1 = Me, R2 = Ph
86%
49%
90%
5%
<3%[c]
45%
O
O
O
TfO
O
O
Cl
OR
Tf2NPh
KHMDS
N
N
N
Na2CO3
OR
OR
2
140 ºC, 10 min
140 ºC, 10 min
140 ºC, 10 min
200 ºC, 30 min
180 ºC, 20 min
170 ºC, 30 min
170 ºC, 45 min
180 ºC, 25 min
180 ºC, 35 min
180 ºC, 35 min
160 ºC, 15 min
NH
N
N
THF
O
O
R2
2a: R2 = Ph
R2
R2
3
2c, 6c: R1 = Ph, R2 = 4-NO2-C6H4
2d, 6d: R1 = Me, R2 = 4-NO2-C6H4
2d, 6d: R1 = Me, R2 = 4-NO2-C6H4
<3%[c]
89%
7aMe: R = Me, 88%
7aBn: R = Bn, 78%
7dMe: R = Me, 99%
7fBn: R = Bn, 82%
7gMe: R = Me, 99%
7hBn: R = Bn, 80%
7iBn: R = Bn, 52%
7jBn: R = Bn, 78%
8aMe: R = Me, 89%
8aBn: R = Bn, 84%
8dMe: R = Me, 71%
8fBn: R = Bn, 73%
8gMe: R = Me, 67%
8hBn: R = Bn, 46%
8iBn: R = Bn, 41%
8jBn: R = Bn, 84%
2d: R2 = 4-NO2-C6H4
2f: R2 = 4-OMe-C6H4
2g: R2 = 2-Me-C6H4
2h: R2 = CO2Et
4
5
56%
19%
2i: R2 = CO2Bn
2j: R2 = Bn
6
2e, 6e: R1 = Ph, R2 = 4-OMe-C6H4 90%
<3%[c]
39%
7
2f, 6f: R1 = Me, R2 = 4-OMe-C6H4
2g, 6g: R1 = Me, R2 = 2-Me-C6H4
2h, 6h: R1 = Me, R2 = CO2Et
2i, 6i: R1 = Me, R2 = CO2Bn
2j, 6j: R1 = Me, R2 = Bn
42%
43%
10%
23%
75%
48%
Scheme 1. Generation of triflyl enol ethers 8.
8
39%[c]
56%
9
The vinyl triflates 8hBn, 8iBn, and 8jBn were then subjected to
palladium-catalyzed reduction conditions using some ammonium
formate as the source of hydride, which afforded the expected
reduced products 9hBn, 9iBn and 9jBn, respectively (Scheme 2).
Treatment of 9hBn and 9jBn with hydrogen gas in the presence of
catalytic Pd/C led to the concomitant hydrogenation of the double
bond and cleavage of the benzyl carbamate to give the
spirobicyclic pyrazolidinones 3h and 3j, respectively. Significantly,
3j slowly oxidized to the corresponding spirobicyclic
acylhydrazone when exposed to air or non-degassed solvents (a
10
11
12
65%
<3%[c]
<3%[c]
2k, 6k: R1 = tBu, R2 = Ph
[a] All reactions were performed under microwave irradiation in sealed vessels.
[b] Yields for the isolated product after purification unless otherwise noted. [c]
Estimated by 1H NMR analysis of the crude reaction mixture.
reaction similar to 3b
®
12 in Scheme 3). The scenario was found
2
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
O
O
Pd(OAc)2 (cat.)
PPh3, nBu3N
HCOOH
acylhydrazone 12, the hydrogenation of which afforded
pyrazolidinone 3b. Like its analog 3j, pyrazolidinone 3b was found
somewhat unstable in the presence of oxygen and slowly oxidized
back to the acylhydrazone 12.
8hBn
or
N
N
OBn
H2, Pd/C
MeOH
N
NH
8iBn
or
O
R2
R2
DMF
8jBn
9hBn: R2 = CO2Et, 57%
9iBn: R2 = CO2Bn, 77%
9jBn: R2 = Bn, 89%
3h: R2 = CO2Et, 73%
3j: R2 = Bn, 67%
O
N
NH
NH2
O
O
O
O
N
N
NH
H2, Pd/C
MeOH
N
NH
EtO
(3 equiv)
neat
8aMe
or
O
N
LiOH
11
H
O
Pd(OAc)2 (cat.)
PPh3, nBu3N
O2, neat or
in solution
OR
Me
8dMe
or
10a, 39%
N
12, 99%
3b, 59%
O
O
N
slow
2
8fBn
or
H2
DMF
,
Pd
6
/
C
R3
Me
NH
O
8gMe
H
4
Scheme 3. Synthesis of the spirobicyclic pyrazolidinone 3b.
10aMe: R = Me, R3 = H, 99%
10dMe: R =Me, R3 = 4-NO2, 98%
10fBn: R = Bn, R3 = 4-OMe, 98%
10gMe: R = Me, R3 = 6-Me, 93%
MeO
1f, 85%
A motivation for this synthetic work was the identification of a
competent catalyst for iminium activation in this series. Our efforts
in this direction are summarized below. It was rapidly found that
b-ketopyrazolidinones 2 were not suitable. For instance, 2d did
Scheme 2. Syntheses of the spirobicyclic pyrazolidinones 3h,j and the
tetracyclic pyrazolidinones 10a, 1f.
not
promote
the
Diels–Alder
cycloaddition
between
cinnamaldehyde (13) and cyclopentadiene (14) in the absence of
an acidic co-catalyst, while it was rapidly converted into the ring-
opened acylhydrazone 6d in the presence of trifluoroacetic acid.
We focused our efforts on pyrazolidinones 3h, 3j, 3b and 1f. The
stoichiometric formation of the iminium ion derived from hydrazide
3h and cinnamaldehyde (13) was quantitatively evaluated in the
presence of weak to super acids (Figure 3). In all cases
equilibrium was reached after a few hours at 25 ºC. Benzoic acid,
different with the vinyl triflates 8 having an aromatic R2 group.
Indeed, the triflate and the aryl R2 groups are in the same region
of space for stereochemical reasons, and some competing
palladium-catalyzed cyclization may occur through activation of
the aromatic C–H bond at C2.[6] In practice, only C–H activation
products were observed, even in the presence of formic acid, and
excellent yields of the tetracyclic compounds 10 were achieved
(Scheme 2). Hydrolysis of the methyl carbamate 10aMe with LiOH
was found slow and moderately selective, affording a modest 39%
yield of the tetracyclic hydrazide 10a. The concomitant
diastereoselective hydrogenation / benzyl carbamate cleavage of
10fBn afforded the tetracyclic pyrazolidinone 1f. The structures of
10a and the trifluoromethylsulfonate salt 1f•CF3SO3H were
elucidated by monocrystal X-ray diffraction techniques,
confirming the syntheses outcomes (Figure 2).[7]
the
weakest,
left
the
substrates
unchanged,
and
trifluoromethanesulfonic acid, the strongest, promoted a nearly
quantitative formation of the (E)-configured iminium ion
exclusively, as determined by NMR (the iminium ion derived from
hydrazide 3j and 13 was also found (E)-configured, see the
Supporting Information) and in full agreement with previous
observations.[3a,c]
O
O
O
XH (1 equiv)
CD3NO2
O
N
+
H2O
+
O
N
N
EtO
N
H
X
Ph
EtO
13
3h
Ph
Figure 2. 3D representations of 10aMe (left) and 1f•CF3SO3H (right) obtained by
monocrystal X-ray diffraction analyses. Ellipsoids are draw at the 50%
probability level and H atoms are draw as fixed-size spheres of 0.15 Å radius.[7]
An alternative synthetic approach was devised for the
spirobicyclic pyrazolidinone 3b not available by the above
sequence (Scheme 3). Cyclopentane 11, readily prepared by
double C-alkylation of the corresponding b-ketoester with 1,4-
dibromobutane,[8] was reacted with methyl hydrazine to give
Figure 3. Formation of the iminium ion derived from pyrazolidinone 3h and
cinnamaldehyde (13) at 25 ºC in d3-nitromethane. Conversions were
determined by 1H NMR.
3
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
The enantiomers of pyrazolidinones 3h, 3j and 3b were resolved
by semi-preparative HPLC on chiral stationary phases (see the
Supporting Information) and their catalytic properties evaluated,
together with those of racemic 1f, in the model enantioselective
(not for 1f) Diels–Alder cycloaddition between cinnamaldehyde
(13) and cyclopentadiene (14). Our best, but rather modest,
results are summarized in Scheme 4. Pyrazolidinone (+)-3h
promoted the reaction at an acceptable rate but with virtually no
stereoselectivity, while pyrazolidinone (+)-3j was found to induce
some enantioselectivity, 71% ee at best for the exo minor
diastereomer, but at a slower rate. Pyrazolidinone (+)-3b afforded
preferentially the exo diastereomer in 54% ee, while rac-1f
predominantly led to the endo diastereomer. The better rate
observed with (+)-3h was attributed to the presence of the
electron-withdrawing substituent at position 5.[9]
derivatives obtained in just a few steps from simple chemicals.
Notably, palladium-catalyzed cyclizations allowed the efficient
construction of tetracyclic backbones through aromatic C–H bond
activation. The catalytic properties of some selected
pyrazolidinones were evaluated for the enantioselective iminium
activation of cinnamaldehyde (13) in a model archetypal Diels–
Alder cycloaddition without significant improvement when
compared to known systems.
Experimental Section
General procedure for pyrazolidinones 2 and acylhydrazones 6: a solution
of hydrazine and aldehyde in anhydrous toluene (ca. 0.4 M) under an
argon atmosphere in a sealed tube containing a Teflon coated magnetic
stirring bar was irradiated at 140 °C for 5 minutes, cooled down to 55 °C
by airflow and concentrated in vacuo. To the resulting material placed
under argon atmosphere was added 2-diazo-cyclohexan-1,3-dione and
anhydrous toluene (ca. 0.4 M), and the reaction mixture was irradiated with
microwaves under the conditions mentioned in Table 1. The resulting
mixture was cooled down to 55 °C by airflow, concentrated in vacuo and
directly purified by flash chromatography. PE refers to petrol ether (bp 40–
60 °C) and melting points are reported for amorphous material unless
specified otherwise.
O
cat (20 mol%)
CF3SO3H (20 mol%)
O
(S)
+
+
Ph
Ph
(S)
MeOH, 25 ºC
Ph
O
exo
endo
13
14
O
N
O
O
O
NH
N
N
N
NH
(R)
NH
NH
Pyrazolidinone 2a: following the general procedure with benzaldehyde
(366 µL, 3.62 mmol), phenylhydrazine (359 µL, 3.62 mmol) and 2-diazo-
1,3-cyclohexanedione (500 mg, 3.62 mmol) in 9 mL of anhydrous toluene
at 140 °C for 10 min, and using EtOAc/PE 1:9 as eluent for the flash
chromatography, 2a was obtained as a white solid (953 mg, 86%). The 1H
NMR analysis of the crude material showed that no more than 3% of
acylhydrazone 6a (not isolated) was formed. Rf (EtOAc/PE 1:9) = 0.36. 1H
NMR (300 MHz, d ppm/CDCl3): 7.92 (dd, J = 1.2, 8.8 Hz, 2H), 7.44 – 7.31
(m, 7H), 7.15 (pseudo t, J = 7.4 Hz, 1H), 5.60 (d, J = 12.8 Hz, 1H), 4.66 (d,
J = 12.9 Hz, 1H), 2.73 (ddd, J = 13.5, 8.2, 8.2 Hz, 1H), 2.27 – 2.09 (m, 2H),
2.07 – 1.95 (m, 1H), 1.89 – 1.75 (m, 1H), 1.64 – 1.47 (m, 1H). These data
are in agreement with previously reported data for this compound.[5]
O
OEt
(+)-3b: 68% after 30 h
exo:endo = 1.3:1
exo = 54% ee
(+)-3h: 98% after 23 h
exo:endo = 1:1
exo = 11% ee
MeO
(+)-3j: 78% after 40 h
exo:endo = 1:1.4
exo = -71% ee
rac-1f: 42%
after 120 h
exo:endo = 1:2.4
endo = 24% ee
endo = 5% ee
endo = -21% ee
Scheme 4. Evaluation of the organocatalytic properties of 3h, 3j, 3b and 1f for
the enantioselective (not for 1f) iminium activation of cinnamaldehyde (13) in its
Diels–Alder cycloaddition with cyclopentadiene (14). The absolute
configurations of (+)-3h was confirmed as (R) by VCD techniques, the depicted
absolute configurations for (+)-3j and (+)-3b are arbitrary and unverified.
Pyrazolidinone 2b and acylhydrazone 6b: following the general procedure
with benzaldehyde (92 µL, 0.90 mmol), methylhydrazine (54 µL, 1.03
mmol) and 2-diazo-1,3-cyclohexanedione (125 mg, 0.90 mmol) in 3 mL of
anhydrous toluene at 140 °C for 10 min, and using AcOEt/PE 4:6 as eluent
for the flash chromatography, 6b and 2b were obtained, in that order, as a
white solids (6b : 100 mg, 45%; 2b :127 mg, 49%). For 6b: Rf (AcOEt/PE
The absolute configuration of (+)-3h was unambiguously
assigned as (R) by vibrational circular dichroism spectroscopy
(see the Supporting Information). The absolute configurations of
the major enantiomers of the cycloadducts obtained with (+)-3h
and (+)-3b were determined as (S) at the carbon atom bearing the
aldehyde by comparison with the cycloadducts obtained with the
MacMillan’s catalysts of known enantio-induction,[2a] and
pyrazolidinone (+)-3j induced opposite enantioselectivity. Overall,
these stereochemical considerations are fully consistent with an
approach of the cyclopentadiene (14) from the a face of the (E)-
configured iminium ions derived from (+)-3h, in full agreement
with earlier studies.
4:6) = 0.60. Mp 109.4 – 111.4 °C. HRMS (ESI+): [M+H]+ calcd for
+
C14H17N2O2 245.1285, found 245.1287. 1H NMR (300 MHz,
d
ppm/CDCl3): 7.74 (s, 1H), 7.65 – 7.61 (m, 2H), 7.44 – 7.35 (m, 2H), 4.44
(dd, J = 9.7, 9.7 Hz, 1H), 3.42 (s, 3H), 2.45 – 2.33 (m, 4H), 2.28 – 2.13 (m,
1H), 2.04 – 1.84 (m, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 214.0 (C),
171.6 (C), 140.0 (CH), 134.7 (C), 129.9 (CH), 128.9 (2CH), 127.3 (2CH),
53.1 (CH), 38.6 (CH2), 28.4 (CH3), 28.1 (CH2), 21.4 (CH2). For 2b: Rf
(AcOEt/PE 4:6) = 0.12. Mp 101.6 – 103.6 °C. HRMS (ESI+): [M+H]+ calcd
+
for C14H17N2O2 245.1285, found 245.1287. 1H NMR (300 MHz,
d
ppm/CDCl3): 7.39 – 7.33 (m, 3H), 7.30 – 7.26 (m, 2H), 5.22 (d, J = 12.0
Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 3.21 (s, 3H), 2.63 (ddd, J = 13.8, 8.2,
8.2 Hz, 1H), 2.21 – 1.88 (m, 4H), 1.73 (ddd, J = 13.7, 8.7, 5.3 Hz, 1H), 1.49
(m, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 216.2 (C), 171.1 (C), 133.4 (C),
129.3 (C), 129.1 (2CH), 127.5 (2CH), 70.7 (CH), 63.7 (C), 39.2 (CH2), 32.0
(CH3), 30.2 (CH2), 19.8 (CH2).
Conclusions
In summary, the (3+2) annulation reaction between a-oxoketenes
and hydrazones was confirmed as a powerful synthetic approach
to diverse, structurally complex, conformationally constraint and
Pyrazolidinone 2c: following the general procedure with p-nitro-
benzaldehyde (138 mg, 0.90 mmol), phenylhydrazine (91 µL, 0.90 mmol)
yet
stereodefined
polycyclic
pyrazolidinones
including
spirobicyclic, bis-spirotricyclic (previous work[5]) and tetracyclic
4
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
+
and 2-diazo-1,3-cyclohexanedione (125 mg, 0.90 mmol) in 3 mL of
anhydrous toluene at 140 °C for 10 min, and using EtOAc/PE 3:7 as eluent
for the flash chromatography, 2c was obtained as a red solid (286 mg,
90%). The 1H NMR analysis of the crude material showed that no more
than 3% of acylhydrazone 6c (not isolated) was formed. Rf (AcOEt/PE 3:7)
calcd for C15H19N2O3 275.1390, found 275.1389. 1H NMR (300 MHz, d
ppm/CDCl3): 7.68 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H),
4.39 (dd, J = 9.6. 9.6 Hz, 1H), 3.81 (s, 3H), 3.36 (s, 3H), 2.42 – 2.30 (m,
4H), 2.25 – 2.10 (m, 1H), 2.03 – 1.80 (m, 1H). 13C NMR (75 MHz, d
ppm/CDCl3): 214.1 (C), 171.4 (C), 161.1 (C), 139.8 (CH), 128.7 (2CH),
127.4 (C), 114.3 (2CH), 55.4 (CH3), 53.1 (CH), 38.5 (CH2), 28.2 (CH3),
28.1 (CH2), 21.3 (CH2). For 2f: Rf (AcOEt/PE 4:6) = 0.10. HRMS (ESI+):
+
= 0.28. Mp : 157.4 – 159.4 °C. HRMS (ESI+): [M+H]+ calcd for C19H18N3O4
352.1292, found 352.1291. 1H NMR: (300 MHz, d ppm/CDCl3): 8.26 (d, J
= 8.7 Hz, 2H), 7.89 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.39 (dd,
J = 7.9, 7.9 Hz, 2H), 7.17 (dd, J = 7.4. 7.4 Hz, 1H), 5.68 (d, J = 12.7 Hz,
1H), 4.80 (d, J = 12.7 Hz, 1H), 2.86 – 2.71 (m, 1H), 2.30 (ddd, J = 13.1,
7.7, 7.6 Hz, 1H), 2.22 – 2.08 (m, 2H), 1.95 – 1.80 (m, 1H), 1.71 – 1.56 (m,
1H). 13C NMR (300 MHz, d ppm/CDCl3): 215.3 (C), 169.2 (C), 148.4 (C),
140.6 (C), 138.5 (C), 129.0 (2CH), 128.6 (2CH), 125.2 (CH), 124.2 (2CH),
118.8 (2CH), 68.4 (CH), 65.2 (C), 39.5 (CH2), 30.3 (CH2), 19.9 (CH2).
[M+H]+ calcd for C15H19N2O3 275.1390, found 275.1390. Mp 131.4 –
+
133.4 °C. 1H NMR (300 MHz, d ppm/CDCl3): 7.20 (d, J = 8.7 Hz, 2H), 6.87
(d, J = 8.7 Hz, 2H), 5.14 (s, 1H), 4.45 (s, 1H), 3.80 (s, 3H), 3.20 (s, 3H),
2.61 (d, J = 3.1 Hz, 1H), 2.13 (d, J = 1.5 Hz, 1H), 1.97 (s, 2H), 1.79 (s, 1H),
1.50 (s, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 216.4 (C), 171.0 (C), 160.2
(C), 128.7 (2CH), 125.3 (C), 114.4 (2CH), 70.3 (CH), 63.7 (C), 55.4 (CH3),
39.2 (CH2), 31.9 (CH3), 30.2 (CH2), 19.8 (CH2).
Pyrazolidinone 2d and acylhydrazone 6d: following the general procedure
with p-nitro-benzaldehyde (138 mg, 0.90 mmol), methylhydrazine (54 µL,
1.03 mmol) and 2-diazo-1,3-cyclohexanedione (125 mg, 0.90 mmol) in 3
mL of anhydrous toluene at 140 °C for 10 min, and using AcOEt/PE 3:7
then 4:6 as eluent for the flash chromatography, 6d and 2d were obtained,
in that order, as orange and yellow solids, respectively, (6d : 222 mg, 89%;
2d :12 mg, 5%). A similar reaction performed at 200 ºC for 30 min afforded
the same products 6d and 2d in 19% and 56% yield, respectively. For 6d:
Pyrazolidinone 2g: following the general procedure with 2-methyl-
benzaldehyde (420 µL, 3.62 mmol), methylhydrazine (213 µL, 4.07 mmol)
and 2-diazo-1,3-cyclohexanedione (500 mg, 3.62 mmol) in 12 mL of
anhydrous toluene at 170 °C for 45 min, and using EtOAc/PE 4:6 as eluent
for the flash chromatography, 2g was obtained as a yellow solid (643 mg,
43%). The 1H NMR analysis of the crude material evidenced the formation
of ca. 39% of acylhydrazone 6g (not isolated). Rf (AcOEt/PE 4:6) = 0.12.
+
Mp 164.6 – 166.6 °C. HRMS (ESI+): [M+H]+ calcd for C15H19N2O2
Rf (AcOEt/PE 3:7) = 0.47. HRMS (ESI+): [M+H]+ calcd for C14H16N3O4
259.1441, found 259.1440. 1H RMN (300 MHz, d ppm/CDCl3): 7.29 – 7.18
(m, 4H), 5.22 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 3.18 (s, 3 H),
2.70 – 2.56 (m, 1H), 2.51 (s, 3H) 2.26 – 1.93 (m, 3H), 1.86 (dddd, J = 18.7,
8.8, 4.4, 1.6 Hz, 1H), 1.51 – 1.39 (m, 1H). 13C RMN (75 MHz, d
ppm/CDCl3): 216.2 (C), 171.0 (C), 133.5 (C), 129.3 (CH), 129.1 (2CH),
127.5 (2CH), 70.7 (CH), 63.8 (C), 39.2 (CH2), 32.0 (CH3), 30.2 (CH2), 19.8
(CH2).
+
290.1135, found 290.1135. Mp 166.4 – 168.4 °C. 1H NMR (300 MHz, d
ppm/C6D6): 7.85 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H),
4.31 (dd, J = 10.4, 8.8 Hz, 1H), 2.77 (s, 3H), 2.37 (dddd, J = 12.7, 10.4,
10.4, 6.9 Hz, 1H), 1.99 – 1.83 (m, 3H), 1.74 – 1.59 (m, 1H), 1.42 – 1.25 (m,
1H). 13C NMR (75 MHz, d ppm/CDCl3): 213.5 (C), 171.5 (C), 140.7 (C),
136.9 (CH), 127.7 (2CH), 124.2, (2CH), 110.1 (C), 52.8 (CH), 38.6 (CH2),
28.7 (CH3), 27.8 (CH2), 21.2 (CH2). For 2d: Rf (AcOEt/CH2Cl2 4:6) = 0.25.
+
Mp 156.0 – 157.0 °C. HRMS (ESI+): [M+H]+ calcd for C14H16N3O4
Pyrazolidinone 2h and acylhydrazone 6h: following the general procedure
with ethyl glyoxalate (50% in toluene, 716 µL, 3.62 mmol),
methylhydrazine (213 µL, 4.07 mmol) and 2-diazo-1,3-cyclohexanedione
(500 mg, 3.62 mmol) in 9 mL of anhydrous toluene at 180 °C for 25 min,
and using AcOEt/PE 4:6 as eluent for the flash chromatography, 6h and
2h were obtained, in that order, as white solids (6h : 490 mg, 56%; 2h :87
mg, 10%). For 6h : Rf (EtOAc/PE 4:6) = 0.54. Mp 68.3 – 70.3 °C. HRMS
(ESI+): [M+H]+ calcd for C11H17N2O4+ 241.1183, found 241.1182. 1H NMR
(400 MHz, d ppm/CDCl3): 7.00 (s, 1H) 4.30 (q, J = 7.1 Hz, 2H), 3.97 (dd, J
= 9.8, 9.8 Hz, 1H), 3.29 (s, 3H), 2.70 (ddd, J = 19.4, 9.8, 9.8 Hz, 1H), 2.35
(m, 3H), 2.21 (s, 1H) 1.99 – 1.80 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, d ppm/CDCl3): 213.3 (C), 172.3 (C), 162.7 (C), 129.2(CH), 61.4
(CH2), 54.5 (CH), 37.7 (CH2), 28.6 (CH3), 27.9 (CH2), 21.4 (CH2), 14.2
(CH3). For 2h : Rf (AcOEt/PE 4:6) = 0.27. Mp 98.4 – 100.4 °C. HRMS
(ESI+): [M+H]+ calcd for C11H17N2O4+ 241.1183, found 241.1183. 1H NMR
(300 MHz, d ppm/CDCl3): 5.13 (d, J = 11.3 Hz, 1H), 4.24 – 4.10 (m, 3H),
3.04 (s, 3H), 2.62 – 2.48 (m, 1H), 2.42 – 2.10 (m, 4H), 2.15 – 1.98 (m, 1H).
13C NMR (75 MHz, d ppm/CDCl3): 215.5 (C), 168.8 (C), 168.0 (C), 65.1
(CH), 62.1 (CH2), 60.1 (C), 38.6 (CH2), 31.8 (CH2), 31.7 (CH3), 19.9 (CH2),
14.1 (CH3).
290.1135, found 290.1137. 1H NMR (300 MHz, d ppm/CDCl3): 8.23 (d, J =
8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 5.28 (d, J = 12.3 Hz, 1H), 4.66 (d, J
= 12.3 Hz, 1H), 3.21 (s, 3H), 2.77 – 2.60 (m, 1H), 2.31 – 2.15 (m, 1H), 2.18
– 1.99 (m, 2H), 1.88 – 1.71 (m, 1H), 1.68 – 1.47 (m, 1H). 13C NMR (75
MHz, d ppm/CDCl3): 215.6 (C), 170.2 (C), 148.3 (C), 140.9 (C), 128.5
(2CH), 124.1 (2CH), 69.2 (CH), 63.5 (C), 39.4 (CH2), 32.1 (CH2), 30.3
(CH3), 19.9 (CH2).
Pyrazolidinone 2e: following the general procedure with p-methoxy-
benzaldehyde (440 µL, 3.62 mmol), phenylhydrazine (359 µL, 3.62 mmol)
and 2-diazo-1,3-cyclohexanedione (500 mg, 3.62 mmol) in 9 mL of
anhydrous toluene at 180 °C for 20 min, and using EtOAc/PE 2:8 as eluent
for the flash chromatography, 2e was obtained as an orange solid (1095
mg, 90%). The 1H NMR analysis of the crude material showed that no more
than 3% of acylhydrazone 6e (not isolated) was formed. Rf (EtOAc/PE 2:8)
+
= 0.19. Mp 160.9 – 162.9 °C. HRMS (ESI+): [M+H]+ calcd for C20H21N2O3
337.1547, found 337.1544. 1H NMR (300 MHz, d ppm/CDCl3): 7.95 – 7.87
(m, 2H), 7.37 (dd, J = 8.7, 7.3 Hz, 2H), 7.28 – 7.24 (m, 2H), 7.19 – 7.10
(m, 1H), 6.91 (d, J = 8.7 Hz, 2H), 5.50 (d, J = 12.8 Hz, 1H), 4.60 (d, J =
12.7 Hz, 1H), 3.82 (s, 3H), 2.71 (ddd, J = 13.8, 8.1, 8.1 Hz, 1H), 2.29 –
1.94 (m, 3H), 1.90 – 1.77 (m, 1H), 1.64 – 1.49 (m, 1H). 13C NMR (75 MHz,
d ppm/CDCl3): 216.0 (C), 170.1 (C), 160.3 (C), 138.9 (C), 128.9 (2CH),
128.8 (2CH), 125.1 (C), 124.8 (CH), 118.8 (2CH), 114.6 (2CH), 69.4 (CH),
65.5 (C), 55.4 (CH3), 39.4 (CH2), 30.3 (CH2), 19.8 (CH2).
Pyrazolidinone 2i and acylhydrazone 6i: following the general procedure
with benzyl glyoxalate (188 mg, 1.14 mmol), methylhydrazine (66 µL, 1.26
mmol) and 2-diazo-1,3-cyclohexanedione (220 mg, 1.14 mmol) in 3 mL of
anhydrous toluene at 180 °C for 35 min, and using AcOEt/PE 4:6 as eluent
for the flash chromatography, 6i and 2i were obtained, in that order, as
white solids (6i : 226 mg, 65%; 2i :79 mg, 23%). For 6i : Rf (EtOAc/PE 4:6)
Pyrazolidinone 2f and acylhydrazone 6f: following the general procedure
with p-methoxy-benzaldehyde (112 µL, 0.90 mmol), methylhydrazine (54
µL, 1.03 mmol) and 2-diazo-1,3-cyclohexanedione (125 mg, 0.90 mmol) in
3 mL of anhydrous toluene at 170 °C for 30 min, and using AcOEt/PE 4:6
as eluent for the flash chromatography, 6f and 2f were obtained, in that
order, as a colorless oil and a white solid, respectively, (6f : 97 mg, 39%;
2f :104 mg, 42%). For 6f: Rf (AcOEt/PE 4:6) = 0.30. HRMS (ESI+): [M+H]+
+
= 0.65. Mp 107.5 – 108.5 °C. HRMS (ESI+): [M+H]+ calcd for C16H19N2O4
303.1339, found 303.1339. 1H NMR (300 MHz, d ppm/CDCl3): 7.41 – 7.35
(m, 5H), 7.03 (s, 1H), 5.33 – 5.22 (m, 2H), 3.95 (dd, J = 10.0, 10.0 Hz, 2H),
3.28 (s, 3H), 2.63 – 2.49 (m, 1H), 2.36 – 2.26 (m, 2H), 2.26 – 2.17 (m, 1H),
2.16 – 2.04 (m, 1H), 1.91 – 1.73 (m, 1H). 13C NMR (75 MHz, d ppm/CDCl3):
213.1 (C), 172.3 (C), 162.4 (C), 135.2 (C), 128.7 (CH), 128.6 (2CH), 128.5
5
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
(CH), 128.4 (2CH), 67.1 (CH2), 54.5 (CH), 37.6 (CH2), 28.6 (CH3), 27.9
(CH2), 21.3 (CH2). The structure of 6i was further ascertained by COSY
and HSQC 2D NMR experiments. For 2i : Rf (AcOEt/PE 4:6) = 0.25. Mp
147.0 – 149.0 °C. HRMS (ESI+): [M+H]+ calcd for C16H19N2O4+ 303.1339,
found 303.1339. 1H NMR (300 MHz, d ppm/CDCl3): 7.31 – 7.37, (m, 5H),
5.25, (d, J = 11.6 Hz, 1H), 5.18, (d, J = 11.0 Hz, 1H), 5.09 (d, J = 11.6 Hz,
1H), 4.19 (d, J = 11.0 Hz, 1H), 3.06 (s, 3H), 2.58 – 2.49 (m, 1H), 2.32 –
2.06 (m, 3H), 1.99 – 1.81 (m, 2H). 13C NMR (75 MHz, d ppm/CDCl3): 215.3
(C), 168.8 (C), 167.9 (C), 134.5 (C), 129.0 (CH), 129.0 (2CH), 128.8 (2CH),
67.8 (CH2), 65.1 (CH) 60.6 (C), 38.4 (CH2), 31.7 (CH3), 31.7 (CH2), 19.8
(CH2). The structure of 2i was further ascertained by COSY, HSQC and
HMBC 2D NMR experiments.
EtOAc/PE 2:8 as eluent for the flash chromatography, 7aMe was obtained
as a yellow solid (499 mg, 88%). Rf (AcOEt/PE 2:8) = 0.21. Mp 140.9 –
+
141.5 °C. HRMS (ESI+): [M+H]+ calcd for C16H19N2O4 303.1339, found
303.1341. 1H RMN (300 MHz, d ppm /CDCl3): 7.40 – 7.25 (m, 3 H), 7.12 –
7.02 (m, 2H), 5.33 (s, 1H), 3.83 (s, 3H), 3.46 (s, 3H), 2.52 – 2.39 (m, 1H),
2.34 – 2.00 (m, 5H). 13C RMN (75 MHz, d ppm/CDCl3): 210.6 (C), 170.1
(C), 158.2 (C), 136.0 (C), 128.9 (2CH), 128.6 (CH), 126.2 (2CH), 71.0 (CH),
63.2 (C), 54.1 (CH3), 38.5 (CH2), 35.2 (CH2), 34.3 (CH3), 20.0 (CH2).
Carbamate 7aBn: following the general procedure with 2b (1405 mg, 5.75
mmol), benzylchloroformate (1.60 mL, 11.5 mmol) and a 2 M solution of
Na2CO3 (8.6 mL, 17.2 mmol) in 60 mL of THF for 4 h, and using EtOAc/PE
2:8 as eluent for the flash chromatography, 7aBn was obtained as a white
solid (1695 mg, 78%). Rf (AcOEt/PE 2:8) = 0.15. Mp 101.1 – 102.1 °C.
Pyrazolidinone
2j:
following
the
general
procedure
with
+
phenylacetaldehyde (423 µL, 3.80 mmol), methylhydrazine (213 µL, 4.07
mmol) and 2-diazo-1,3-cyclohexanedione (500 mg, 3.62 mmol) in 9 mL of
anhydrous toluene at 180 °C for 35 min, and using EtOAc/PE 3:7 as eluent
for the flash chromatography, 2j was obtained as a colorless oil (700 mg,
75%). The 1H NMR analysis of the crude material showed that no more
than 3% of acylhydrazone 6j (not isolated) was formed. Rf (AcOEt/PE 3:7)
HRMS (ESI+): [M+H]+ calcd for C22H23N2O4 379.1652, found 379.1654.
1H NMR (300 MHz, d ppm/CDCl3): 7.41 – 7.28 (m, 8H), 7.07 (dd, J = 7.6,
2.0 Hz, 2H), 5.32 (s, 1H), 5.28 (d, J = 12.2 Hz, 1H), 5.17 (d, J = 12.2 Hz,
1H), 3.45 (s, 3H), 2.53 – 2.29 (m, 1H), 2.27 – 1.93 (m, 5H). 13C NMR (75
MHz, d ppm/CDCl3): 210.8 (C), 170.1 (C), 157.7 (C), 136.0 (C), 135.2 (C),
128.9 (2CH), 128.8 (2CH), 128.8 (CH), 128.7 (CH), 128.3 (2CH), 126.4
(2CH), 71.0 (CH), 68.9 (CH2), 63.2 (C), 38.5 (CH2), 34.9 (CH2), 34.5 (CH3),
19.9 (CH2).
+
= 0.14. HRMS (ESI+): [M+H]+ calcd for C15H19N2O2 259.1441, found
259.1440. 1H RMN (300 MHz, d ppm/CDCl3): 7.35 – 7.25 (m, 3H), 7.21 –
7.16 (m, 2H), 4.60 (d, J = 12.1 Hz, 1H), 3.79 (ddd, J = 12.1, 8.1, 6.8 Hz,
1H), 3.00 – 2.83 (m, 2H), 2.51 – 2.29 (m, 2H), 2.28 – 2.05 (m, 2H), 1.65 –
1.51 (m, 2H). 13C RMN (75 MHz, d ppm/CDCl3): 216.7 (C), 171.4 (C), 136.7
(C), 129.0 (2CH), 128.9 (2CH), 127.3 (CH), 66.7 (CH), 61.3 (C), 40.0 (CH2),
34.2 (CH2), 31.8 (CH3), 30.9 (CH2), 20.0 (CH2).
Carbamate 7dMe: following the general procedure with 2d (527 mg, 1.82
mmol), methylchloroformate (170 µL, 2.19 mmol) and a 2 M solution of
Na2CO3 (1.8 mL, 3.6 mmol) in 19 mL of THF for 4 h, and using
EtOAc/CH2Cl2 4:6 as eluent for the flash chromatography, 7dMe was
obtained as a yellow solid (632 mg, 99%). Rf (AcOEt/DCM 4:6) = 0.63. Mp
186.8 – 188.8 °C. HRMS (ESI+): [M+H]+ calcd for C16H18N3O6+ 348.1190,
found 348.1190. 1H NMR (300 MHz, d ppm /CDCl3): 8.20 (d, J = 9.0 Hz, 2
H), 7.25 (d, J = 9.0 Hz, 2 H), 5.39 (s, 1 H), 3.85 (s, 3 H), 3.47 (s, 3 H), 2.59
– 2.47 (m, 1H), 2.39 – 2.20 (m, 3H), 2.18 – 2.01 (m, 2H). 13C NMR (75
MHz, d ppm/CDCl3): 211.0 (C), 169.4 (C), 158.0 (C), 147.8 (C), 143.2 (C),
127.4 (2CH), 124.0 (2CH), 70.0 (CH), 62.9 (C), 54.4 (CH3), 38.9 (CH2),
35.4 (CH2), 34.3 (CH3), 20.1 (CH2).
Pyrazolidinone 2k: a solution of tert-butylhydrazine hydrochloride (541 mg,
4.34 mmol), potassium bicarbonate (750 mg, 5.43 mmol) and
benzaldehyde (366 µL, 3.62 mmol) in 9 mL anhydrous dichloromethane
under an argon atmosphere in a sealed tube containing a Teflon coated
magnetic stirring bar was irradiated at 140 °C for 10 minutes, cooled down
to 55 °C by airflow and concentrated in vacuo. The resulting material was
dissolved/suspended in 9 mL toluene and filtered. The liquid phase was
placed under argon atmosphere in a sealed tube containing a Teflon
coated magnetic stirring bar, 2-diazo-cyclohexan-1,3-dione (500 mg, 3.62
mmol) was added and this mixture was irradiated at 160 °C for 15 min. The
resulting reaction mixture was cooled down to 55 °C by airflow,
concentrated and purify by flash chromatography using EtOAc/PE 1:9 as
eluent to afford 2k as a white solid (500 mg, 48%). The 1H NMR analysis
of the crude material showed that no more than 3% of acylhydrazone 6k
(not isolated) was formed. Rf (AcOEt/PE 1:9) = 0.30. Mp 110.3 – 112.3 °C.
Carbamate 7fBn: following the general procedure with 2f (550 mg, 2.00
mmol), benzylchloroformate (440 µL, 3.10 mmol) and a 2 M solution of
Na2CO3 (2.5 mL, 5.0 mmol) in 20 mL of THF for 4 h, and using EtOAc/PE
2:8 as eluent for the flash chromatography, 7fBn was obtained as a
colorless oil (674 mg, 82%). Rf (AcOEt/PE 2:8) = 0.23. HRMS (ESI+):
+
[M+H]+ calcd for C23H25N2O5 409.1758, found 409.1764. 1H NMR (300
MHz, d ppm/CDCl3): 7.38 – 7.33 (m, 3H), 7.31 – 7.25 (m, 2H), 7.01 (d, J =
8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.27 (d, J = 11.6 Hz, 1H), 5.25 (s,
1H), 5.16 (d, J = 11.6 Hz, 1H), 3.78 (s, 3H), 3.43 (s, 3H), 2.38 (m, 1H), 2.12
(m, 4H), 1.97 (m, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 210.8 (C), 170.3
(C), 159.8 (C), 157.7 (C), 135.3 (C), 128.8 (2CH), 128.8 (CH), 128.2 (2CH),
128.2 (C), 127.8 (2CH), 114.3 (2CH), 70.7 (CH), 68.9 (CH2), 63.1 (C), 55.4
(CH3), 38.4 (CH2), 34.9 (CH2), 34.6 (CH3), 19.9 (CH2).
+
HRMS (ESI+): [M+H]+ calcd for C17H23N2O2 calcd 287.1754, found:
287.1754. 1H NMR (400 MHz, d ppm/CDCl3): 7.38 – 7.33 (m, 3H), 7.29 –
7.27 (m, 2H), 5.12 (d, J =11.0 Hz , 1H), 4.37 (d, J = 11.0 Hz, 1H), 2.66 –
2.53 (m, 1H), 2.18 – 2.06 (m, 1H), 2.04 – 1.87, (m, 2H), 1.80 – 1.70, (m,
1H), 1,51, (s, 9H), 1.50 – 1.42 (m, 1H). 13C NMR (101 MHz, d ppm/CDCl3):
216.5 (C), 171.0 (C), 133.9 (C), 123.1 (CH), 129.03 (2CH), 127.5 (2CH),
70.5 (CH), 65.4 (C), 58.0 (C), 39.5 (CH2), 30.0 (CH2), 28.0 (3CH3), 19.8
(CH2).
Carbamate 7gMe: following the general procedure with 2g (502 mg, 1.94
mmol), methylchloroformate (180 µL, 2.32 mmol) and a 2 M solution of
Na2CO3 (1.9 mL, 3.8 mmol) in 19 mL of THF for 2 h, and using EtOAc/PE
4:6 as eluent for the flash chromatography, 7gMe was obtained as a white
solid (607 mg, 99%). Rf (AcOEt/PE 4:6) = 0.25. Mp 157.3 – 159.0 °C.
General procedure for carbamates 7: to a solution of pyrazolidinone 2 (1
equiv) in THF (ca. 0.1 M) was added slowly the appropriate chloroformate
(1.2 – 2 equiv) follow by a 2 M solution of sodium carbonate in water (2 –
3 equiv). The resulting solution was stirred at room temperature until full
conversion (monitored by TLC). The solution was diluted with brine and
+
HRMS (ESI+): [M+H]+ calcd for C17H21N2O4 317.1496, found 317.1496.
1H NMR (300 MHz, d ppm /CDCl3): 7.25 – 7.17 (m, 2H), 7.10 (ddd, J = 6.5,
6.5, 4.0 Hz, 2H), 5.58 (s, 1H), 3.84 (s, 3H), 3.44 (s, 3H), 2.57 – 2.44 (m,
1H), 2.39 – 2.16 (m, 4H), 2.14 – 2.01 (m, 1H). 13C NMR (75 MHz, d
ppm/CDCl3): 209.9 (C), 170.3 (C), 158.1 (C), 134.1 (C), 133.9 (C), 130.5
(CH), 128.4 (CH), 126.5 (CH), 126.1 (CH), 68.1 (CH), 61.8 (C), 54.1 (CH3),
38.9 (CH2), 35.8 (CH2), 33.8 (CH3), 20.1 (CH2), 19.5 (CH3).
extracted
3 times with dichloromethane. The organic layers were
combined, dried over anhydrous sodium sulfate, concentrated in vacuo
and purified by flash chromatography.
Carbamate 7aMe: following the general procedure with 2b (457 mg, 1.87
mmol), methylchloroformate (290 µL, 3.74 mmol) and a 2 M solution of
Na2CO3 (3.6 mL, 7.2 mmol) in 19 mL of THF for 1 h 45, and using
6
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
Carbamate 7hBn: following the general procedure with 2h (690 mg, 2.87
mmol), benzylchloroformate (490 µL, 3.45 mmol) and a 2 M solution of
Na2CO3 (2.9 mL, 5.8 mmol) in 28 mL of THF for 4 h, and using EtOAc/PE
4:6 as eluent for the flash chromatography, 7hBn was obtained as a
colorless oil (858 mg, 80%). Rf (AcOEt/PE 4:6) = 0.64. HRMS (ESI+):
(2CH), 120.0 (CH), 118.1 (q, J = 323 Hz, CF3), 70.0 (CH), 61.8 (C), 54.2
(CH3), 35.0 (CH2), 33.9 (CH3), 26.4 (CH2). 19F NMR (282 MHz,
d
ppm/CDCl3): -74.1 (s, 3F).
Triflyl enol ether 8aBn: following the general procedure with 7aBn (800 mg,
2.11 mmol), Tf2NPh (863 mg, 2.42 mmol) and KHMDS 0.5 M in toluene
(6.2 mL, 3.1 mmol) in 21 mL of anhydrous THF, and using EtOAc/PE 2:8
as eluent for the flash chromatography, 8aMe was obtained as a white solid
(908 mg, 84%). Rf (AcOEt/PE 2:8) = 0.52. Mp 134.5 – 136.5 °C. HRMS
(ESI+): [M+H]+ calcd for C23H22F3N2O6S+ 511.1145, found 511.1146. 1H
NMR (400 MHz, d ppm/CDCl3): 7.46 – 7.30 (m, 8H), 7.12 – 7.06 (m, 2H),
5.85 (dd, J = 2.6, 2.6 Hz, 1H), 5.37 (s, 1H), 5.32 (d, J = 12.1 Hz, 1H), 5.19
(d, J = 12.2 Hz, 1H), 3.46 (s, 3H), 2.64 – 2.32 (m, 3H), 2.10 – 1.96 (m, 1H).
13C NMR (101 MHz, d ppm/CDCl3): 169.8 (C), 157.7 (C), 144.8 (C), 135.6
(C), 135.2 (C), 128.9 (2CH), 128.9 (CH), 128.8 (2CH), 128.7 (CH), 128.3
(2CH), 126.0 (2CH), 119.9 (CH), 118.1 (q, J = 321 Hz, CF3), 70.13 (CH),
69.0 (CH2), 61.8 (C), 34.7 (CH2), 34.0 (CH3), 26.2 (CH2). 19F NMR (282
MHz, d ppm/CDCl3): -74.08 (s, 3F).
+
[M+H]+ calcd for C19H23N2O6 375.1551, found 375.1549. 1H NMR (300
MHz, d ppm/CDCl3): 7.45 – 7.32 (m, 5H), 5.30 (d, J = 12.1 Hz, 1H), 5.20
(d, J = 12.1 Hz, 1H), 4.81 (s, 1H), 4.18 (dq, J = 11.8, 7.1 Hz, 2H), 3.30 (s,
3H), 2.51 – 2.27 (m, 3H), 2.23 – 2.13 (m, 1H), 2.10 – 1.93 (m, 2H), 1.26 (t,
J = 7.1 Hz, 3H). 13C NMR (101 MHz, d ppm/CDCl3): 211.1 (C), 170.5 (C),
167.1 (C), 156.7 (C), 135.0 (C), 128.9 (CH), 128.9 (2CH), 128.4 (2CH),
69.2 (CH2), 67.9 (CH), 62.2 (CH2), 60.9 (C), 38.7 (CH2), 34.7(CH3), 34.7
(CH2), 20.0 (CH2), 14.0 (CH3). The structure of 7hBn was further
ascertained by an HSQC 2D NMR experiment.
Carbamate 7iBn: following the general procedure with 2i (1580 mg, 5.23
mmol), benzylchloroformate (890 µL, 6.27 mmol) and a 2 M solution of
Na2CO3 (6.5 mL, 13.0 mmol) in 130 mL of THF for 4 h, and using EtOAc/PE
2:8 as eluent for the flash chromatography, 7iBn was obtained as a
colorless oil (1180 mg, 52%). Rf (AcOEt/PE 2:8) = 0.30. HRMS (ESI+):
Triflyl enol ether 8dMe: following the general procedure with 7dMe (541 mg,
1.56 mmol), Tf2NPh (568 mg, 1.59 mmol) and KHMDS 0.5 M in toluene
(4.4 mL, 2.2 mmol) in 16 mL of anhydrous THF, and using EtOAc/CH2Cl2
1:9 as eluent for the flash chromatography, 8dMe was obtained as a white
solid (528 mg, 71%). Rf (EtOAc/CH2Cl2 3:7) = 0.83. Mp 152.0 – 154.0 °C.
HRMS (ESI+): [M+H]+ calcd for C17H17F3N3O8S+ 480.0683, found
480.0682. 1H NMR (400 MHz, d ppm /CDCl3): 8.24 (d, J = 8.7 Hz, 2H),
7.29 (d, J = 8.6 Hz, 3H), 5.93 (s, 1H), 5.48 (s, 1H), 3.88 (s, 3H), 3.50 (s,
3H), 2.74 – 2.47 (m, 3H), 2.27 – 2.20 (m, 1H). 13C NMR (101 MHz, d
ppm/CDCl3): 169.0 (C), 158.1 (C), 148.2 (C), 144.2 (C), 142.8 (C), 127.2
(2CH), 124.4 (2CH), 120.8 (CH), 117.9 (q, J = 322 Hz, CF3), 69.3 (CH),
61.8 (C), 54.6 (CH3), 34.9 (CH2), 34.1 (CH3), 26.5 (CH2). 19F NMR (282
MHz, d ppm /CDCl3): -74.2 (s, 3F).
[M+H]+ calcd for C24H25N2O6+ 437.1707, found 437.1709; [M+NH4]+ calcd
+
for C24H28N3O6 454.1973, found 454.1978. 1H NMR (300 MHz,
d
ppm/CDCl3): 7.43 – 7.31 (m, 10H), 5.29 (d, J = 11.9 Hz, 1H), 5.18 (d, J =
12.3 Hz, 2H), 5.06 (d, J = 11.9 Hz, 1H), 4.85 (s, 1H), 3.24 (s, 3H), 2.50 –
2.24 (m, 3H), 2.23 – 1.88 (m, 3H). 13C NMR (75 MHz, d ppm/CDCl3): 211.2
(C), 170.4 (C), 167.0 (C), 156.9 (C), 135.0 (C), 134.8 (C), 129.0 (CH),
129.0 (2CH), 128.9 (2CH), 128.8 (CH), 128.8 (2CH), 128.5 (2CH), 69.3
(CH2), 68.2 (CH2), 68.0 (CH), 61.0 (C), 38.7 (CH2), 34.8 (CH2), 34.7 (CH3),
20.0 (CH2).
Carbamate 7jBn: following the general procedure with 2j (600 mg, 2.32
mmol), benzylchloroformate (660 µL, 4.65 mmol) and a 2 M solution of
Na2CO3 (2.9 mL, 5.8 mmol) in 20 mL of THF for 4 h, and using EtOAc/PE
2:8 as eluent for the flash chromatography, 7jBn was obtained as a
yellowish solid (711 mg, 78%). Rf (AcOEt/PE 2:8) = 0.28. HRMS (ESI+):
Triflyl enol ether 8fBn: following the general procedure with 7fBn (600 mg,
1.47 mmol), Tf2NPh (672 mg, 1.88 mmol) and KHMDS 0.5 M in toluene
(4.4 mL, 2.2 mmol) in 15 mL of anhydrous THF, and using EtOAc/PE 2:8
as eluent for the flash chromatography, 8fBn was obtained as a white solid
(580 mg, 73%). Rf (AcOEt/PE 2:8) = 0.18. Mp 103.9 – 105.9 °C. HRMS
(ESI+): [M+H]+ calcd for C24H24F3N2O7S+ 541.1251, found 541.1251. 1H
NMR (300 MHz, d ppm/CDCl3) : 7.40 – 7.30 (m, 5H), 7.01 (d, J = 8.6 Hz,
2H), 6.87 (d, J = 8.7 Hz, 2H), 5.84 (dd, J = 2.8, 2.6 Hz, 1H), 5.32 (d, J =
12.2 Hz, 1H), 5.32 (s, 1H), 5.18 (d, J = 12.2 Hz, 1H), 3.79 (s, 3H), 3.44 (s,
3H), 2.64 – 2.30 (m, 3H), 2.05 – 1.95 (m, 1H). 13C NMR (75 MHz, d
ppm/CDCl3): 170.0 (C), 160.2 (C), 157.7 (C), 145.0 (C), 135.3 (C), 128.9
(2CH), 128.9 (CH), 128.4 (2CH), 127.8 (C), 127.3 (2CH), 119.9 (CH),
114.5 (2CH), 69.9 (CH), 69.0 (CH2), 61.8 (C), 55.6 (CH3), 34.7 (CH2), 34.1
(CH3), 26.3 (CH2). Resonance for CF3 not detected due to a low S/N ratio.
19F NMR (282 MHz, d ppm/CDCl3): -74.15 (s, 3F).
+
[M+H]+ calcd for C23H25N2O4 393.1809, found 393.1809. 1H NMR (300
MHz, d ppm/CDCl3): 7.43 – 7.09 (m, 10H), 5.17 – 5.08 (m, 2H), 4.60 (dd,
J = 7.0, 7.0 Hz, 1H), 3.27 (s, 3H), 3.07 – 2.87 (m, 2H), 2.42 – 1.88 (m, 5H),
1.83 – 1.68 (m, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 212.7 (C), 170.9
(C), 157.95 (C), 136.79 (C), 135.26 (C), 129.8 (2CH), 128.8 (2CH),
128.7(CH), 128.5 (2CH), 128.2 (2CH), 126.9 (CH), 69.0 (CH), 68.7 (CH2),
61.3 (C), 39.3 (CH2), 36.7 (CH2), 34.5 (CH2), 34.1 (CH3), 20.0 (CH2).
General procedure for triflyl enol ethers 8: to a solution of ketone 7 (1
equiv) and Tf2NPh (1.2 equiv) in anhydrous THF (ca. 0.1 M) at -80 °C was
added a 0.5 M solution of KHMDS in toluene (1.5 equiv). The solution was
stirred at this temperature during 1 h then allowed to warm to room
temperature and stirred for an additional 2 h at this temperature. The
resulting mixture was poured into a saturated solution of ammonium
chloride and extracted with three times with dichloromethane. The organic
layers were combined, dried with anhydrous sodium sulfate and
concentrated in vacuo to give the crude product, which was purified by
flash chromatography.
Triflyl enol ether 8gMe: following the general procedure with 7gMe (498 mg,
1.57 mmol), Tf2NPh (675 mg, 1.89 mmol) and KHMDS 0.5 M in toluene
(4.8 mL, 2.4 mmol) in 18 mL of anhydrous THF, and using EtOAc/PE 4:6
as eluent for the flash chromatography, 8gMe was obtained as a white solid
(469 mg, 67%). Rf (EtOAc/PE 4:6) = 0.83. Mp 134.0 – 135.1 °C. HRMS
+
Triflyl enol ether 8aMe: following the general procedure with 7aMe (456 mg,
1.51 mmol), Tf2NPh (653 mg, 1.83 mmol) and KHMDS 0.5 M in toluene
(4.8 mL, 2.4 mmol) in 17 mL of anhydrous THF, and using EtOAc/PE 4:6
as eluent for the flash chromatography, 8aMe was obtained as a white solid
(583 mg, 89%). Rf (EtOAc/PE 4:6) = 0.50. Mp 181.2 – 181.7 °C. HRMS
(ESI+): [M+H]+ calcd for C17H18F3N2O6S+ 435.0832, found 435.0832. 1H
NMR (300 MHz, d ppm/CDCl3): 7.40 – 7.31 (m, 3H), 7.09 (dd, J = 7.2, 2.5
Hz, 2H), 5.88 (s, 1H), 5.38 (s, 1H), 3.85 (s, 3H), 3.48 (s, 3H), 2.74 – 2.39
(m, 3H), 2.19 (dd, J = 11.8, 7.1 Hz, 1H). 13C NMR (75 MHz, d ppm/CDCl3):
169.8 (C), 158.2 (C), 144.9 (C), 135.6 (C), 129.0 (2CH), 128.8 (CH), 126.0
(ESI+): [M+H]+ calcd for C18H20N2O6SF3 449.0989, found 449.0990. 1H
NMR (400 MHz, d ppm/CDCl3): 7.24 – 7.14 (m, 3H), 7.03 – 6.99 (m, 1H),
5.83 (dd, J = 2.6, 2.6 Hz, 1H), 5.72 (s, 1H), 3.85 (s, 3H), 3.49 (s, 3H), 2.70
– 2.56 (m, 2H), 2.55 – 2.44 (m, 1H), 2.31 (s, 3H), 2.25 (ddd, J = 13.0, 7.4,
1.9 Hz, 1H). 13C NMR (101 MHz, d ppm/CDCl3): 169.9 (C), 158.1 (C), 145.2
(C), 134.6 (C), 134.2 (C), 131.0 (CH) 128.7 (CH), 126.8 (CH), 125.4 (CH),
120.2, (CH), 118.1 (q, J = 322 Hz, CF3), 67.3 (CH), 61.4 (C), 54.2 (CH3),
35.2 (CH2), 33.9 (CH3), 26.7 (CH2), 19.5 (CH3). 19F NMR (282 MHz, d
ppm/CDCl3): -74.0 (s, 3F).
7
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
Triflyl enol ether 8hBn: following the general procedure with 7hBn (820 mg,
2.19 mmol), Tf2NPh (861 mg, 2.40 mmol) and KHMDS 0.5 M in toluene
(6.6 mL, 3.3 mmol) in 22 mL of anhydrous THF, and using EtOAc/PE 2:8
as eluent for the flash chromatography, 8hBn was obtained as a white solid
(515 mg, 46%). Rf (AcOEt/PE 2:8) = 0.35. Mp 122.4 – 122.9 °C. HRMS
(ESI+): [M+H]+ calcd for C20H22F3N2O8S+ 507.1043, found 507.1042. 1H
NMR (300 MHz, d ppm/CDCl3): 7.45 – 7.32 (m, 5H), 6.02 (dd, J = 2.6, 2.6
Hz, 1H), 5.32 (d, J = 12.0 Hz, 1H), 5.19 (d, J = 12.0 Hz, 1H), 4.90 (s, 1H),
4.30 – 4.09 (m, 2H), 3.30 (s, 3H), 2.62 – 2.44 (m, 2H), 2.29 (ddd, J = 13.1,
8.2, 7.0 Hz, 1H), 1.94 (ddd, J = 13.2, 7.1, 3.2 Hz, 1H), 1.28 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, d ppm/CDCl3): 170.4 (C), 167.1 (C), 156.8 (C),
143.4 (C), 135.0 (C), 129.0 (CH), 128.9 (2CH), 128.6 (2CH), 121.3 (CH),
69.3 (CH2), 67.5 (CH), 62.6 (CH2), 59.8 (C), 34.7 (CH3), 33.5 (CH2), 26.3
(CH2), 13.9 (CH3). Resonance for CF3 not detected due to a low S/N ratio.
19F NMR (282 MHz, d ppm/CDCl3): -73.51 (s, 3F).
359.1604. 1H NMR (300 MHz, d ppm/CDCl3): 7.47 – 7.30 (m, 5H), 6.19 –
6.13 (m, 1H), 5.34–5.28 (m, 1H), 5.30 (d, J = 12.1 Hz, 1H), 5.20 (d, J =
12.1 Hz, 1H), 4.76 (s, 1H), 4.25 – 4.13 (m, 2H), 3.28 (s, 3H), 2.52 – 2.42
(m, 2H), 2.20 – 2.06 (m, 1H), 1.95 – 1.84 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, d ppm/CDCl3): 175.1 (C), 168.1 (C), 156.9 (C), 139.2
(CH), 135.3 (C), 128.8 (2CH), 128.8 (CH), 128.3 (2CH), 126.5 (CH), 69.2
(CH), 68.9 (CH2), 61.7 (CH2), 60.9 (C), 34.8 (CH3), 34.8 (CH2), 31.8 (CH2),
14.2 (CH3).
Olefin 9iBn : following the general procedure with 8iBn (584 mg, 1.03 mmol),
Pd(OAc)2 (46 mg, 0.20 mmol), PPh3 (162 mg, 0.62 mmol), formic acid (77
µL, 2.04 mmol) and nBu3N (734 µL, 3.09 mmol) in anhydrous DMF (10
mL), and using EtOAc/PE 2:8 as eluent for the flash chromatography, 9iBn
was obtained as a yellowish oil (332 mg, 77%). Rf (AcOEt/PE 3:7) = 0.64.
+
HRMS (ESI+): [M+H]+ calcd for C24H25N2O5 421.1758, found 421.1758.
1H NMR (300 MHz, d ppm/CDCl3): 7.42 – 7.26 (m, 10H), 6.09 (ddd, J = 5.8,
2.4, 2.4 Hz, 1H), 5.30 (d, J = 12.0 Hz, 1H), 5.23 – 5.09 (m, 4H), 4.82 (s,
1H), 3.23 (s, 3H), 2.45 (dddd, J = 7.1, 4.6, 2.4, 2.4 Hz, 2H), 2.12 (ddd, J =
13.1, 8.6, 7.1 Hz, 1H), 1.89 (ddd, J = 13.2, 6.7, 4.6 Hz, 1H). 13C NMR (75
MHz, d ppm/CDCl3): 174.9 (C), 168.0 (C), 156.8 (C), 139.3 (CH), 135.3 (C),
134.8 (C), 128.9 (2CH), 128.8 (2CH), 128.8 (CH), 128.7 (2CH), 128.7 (CH),
128.4 (2CH), 126.5 (CH), 69.1 (CH), 69.0 (CH2), 67.5 (CH2), 61.0 (C), 34.8
(CH2), 34.8 (CH3), 31.8 (CH2).
Triflyl enol ether 8iBn: following the general procedure with 7iBn (1100 mg,
2.52 mmol), Tf2NPh (1152 mg, 3.22 mmol) and KHMDS 0.5 M in toluene
(7.6 mL, 3.8 mmol) in 25 mL of anhydrous THF, and using EtOAc/PE 2:8
as eluent for the flash chromatography, 8iBn was obtained as a white solid
(584 mg, 41%). Rf (AcOEt/PE 2:8) = 0.40. HRMS (ESI+): [M+H]+ calcd for
C25H24F3N2O8S+ 569.1200, found 569.1200. 1H NMR (300 MHz,
d
ppm/CDCl3): 7.42 – 7.28 (m, 10H), 6.04 (dd, J = 2.7, 2.7 Hz, 1H), 5.30 (d,
J = 12.0 Hz, 1H), 5.21 (d, J = 8.8 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 5.09 (d,
J = 12.0 Hz, 1H), 4.97 (s, 1H), 3.20 (s, 3H), 2.55 – 2.44 (m, 2H), 2.24 –
2.36 (m, 1H), 1.95 (ddd, J = 13.4, 6.9, 3.7 Hz, 1H). 13C NMR (75 MHz, d
ppm/CDCl3): 170.3 (C), 166.9 (C), 156.7 (C), 143.4 (C), 135.0 (C), 134.5
(C), 129.0 (CH), 128.9 (2CH), 128.8 (2CH), 128.7 (2CH), 128.5 (2CH),
127.0 (CH), 121.2 (CH), 118.5 (q, J = 322 Hz, CF3), 69.2 (CH2), 68.4 (CH2),
67.5 (CH), 59.9 (C), 34.6 (CH3), 33.4 (CH2), 26.3 (CH2). 19F NMR (282
MHz, d ppm/CDCl3): -73.33.
Olefin 9jBn : following the general procedure with 8jBn (597 mg, 1.14 mmol),
Pd(OAc)2 (51 mg, 0.23 mmol), PPh3 (179 mg, 0.68 mmol), formic acid (81
µL, 2.15 mmol) and nBu3N (860 µL, 3.62 mmol) in anhydrous DMF (23
mL), and using EtOAc/PE 2:8 as eluent for the flash chromatography, 9jBn
was obtained as a yellowish oil (380 mg, 89%). Rf (AcOEt/PE 2:8) = 0.26.
+
HRMS (ESI+): [M+H]+ calcd for C23H25N2O3 377.1860, found 377.1860.
1H NMR (300 MHz, d ppm/CDCl3): 7.38 – 7.30 (m, 3H), 7.30 – 7.23 (m,
3H), 7.21 – 7.14 (m, 2H), 7.14 – 7.07 (m, 2H), 6.23 – 6.15 (m, 1H), 5.68 –
5.61 (m, 1H), 5.06 (dd, J = 14.5, 12.7, 3H), 4.46 (dd, J = 11.4, 3.4 Hz, 1H),
3.27 (s, 3H), 2.84 (dd, J = 14.0, 3.5 Hz, 1H), 2.59 (dd, J = 13.8, 11.8 Hz,
1H), 2.51 – 2.40 (m, 2H), 2.16 – 2.01 (m, 1H), 1.94 – 1.81 (m, 1H). 13C
NMR (75 MHz, d ppm/CDCl3) : 175.5 (C), 158.0 (C), 138.5 (CH), 137.5 (C),
135.5 (C), 129.4 (2CH), 128.6 (2CH), 128.4 (2CH), 128.4 (CH), 127.9
(2CH), 127.1 (CH), 126.7 (CH), 70.6, (CH), 68.2 (CH2), 62.0 (C), 36.8
(CH2), 34.3 (CH2), 33.9 (CH3), 31.7 (CH2).
Triflyl enol ether 8jBn: following the general procedure with 7jBn (709 mg,
1.81 mmol), Tf2NPh (826 mg, 2.31 mmol) and KHMDS 0.5 M in toluene
(5.4 mL, 2.7 mmol) in 25 mL of anhydrous THF, and using EtOAc/PE 2:8
as eluent for the flash chromatography, 8jBn was obtained as a white solid
(800 mg, 84%). Rf (EtOAc/PE 2:8) = 0.49. HRMS (ESI+): [M+H]+ calcd for
C24H24F3N2O6S+ 525.1302, found 525.1302. Mp 103.3 – 103.7 °C. 1H NMR
(300 MHz, d ppm/CDCl3): 7.35 – 7.24 (m, 6H), 7.20 – 7.15 (m, 2H), 7.08 –
7.03 (m, 2H) 6.02 (dd, J = 2.5, 2.5 Hz, 1H), 5.06 – 4.98 (m, 2H), 4.58 (dd,
J = 11.7, 3.8 Hz, 1H), 3.30 (s, 3H), 2.91 – 2.68 (m, 2H), 2.49 – 2.41 (m,
2H), 2.30 – 2.17 (m, 1H), 1.86 (ddd, J = 13.1, 6.4, 3.1 Hz, 1H). 13C NMR
(75 MHz, d ppm/CDCl3): 170.6 (C), 157.7 (C), 145.0 (C), 136.8 (C), 135.1
(C), 129.4 (2CH), 128.7 (2CH), 128.6 (CH), 128.5 (2CH), 128.0 (2CH),
126.9 (CH), 121.3 (CH), 118.5 (q, J = 320 Hz, CF3), 69.3 (CH), 68.6 (CH2),
60.0 (C), 36.6 (CH2), 34.1 (CH3), 33.3 (CH2), 26.2 (CH2). 19F NMR (282
MHz, d ppm/CDCl3): -73.7 (s, 3F).
General procedure for tetracyclic compounds 10: to a solution of 8 in
anhydrous DMF (ca 0.1 M) under an argon atmosphere was added
palladium diacetate (20 – 50 mol%), triphenylphosphine (60 – 100 mol%)
and tributylamine (3 equiv). The resulting mixture was heated at 80 °C and
stirred at this temperature for 1–23 h. After cooling to room temperature,
the mixture was diluted with ethyl acetate, washed twice 1 M HCl and twice
with brine. The organic layer was dried over anhydrous sodium sulfate,
filtrated and concentrated in vacuo to afford the crude product, which was
purified by flash chromatography.
General procedure for olefins 9: to a solution of 8 in anhydrous DMF (ca
0.1 M) under an argon atmosphere was added palladium diacetate (20 –
50 mol%), triphenylphosphine (60 – 100 mol%), formic acid (2 equiv) and
tributylamine (3 equiv). The resulting mixture was heated at 80 °C and
stirred at this temperature for 4 h. After cooling to room temperature, the
mixture was diluted with ethyl acetate, washed twice 1 M HCl and twice
with brine. The organic layer was dried over anhydrous sodium sulfate,
filtrated and concentrated in vacuo to afford the crude product, which was
purified by flash chromatography.
Tetracyclic compound 10aMe: following the general procedure with 8aMe
(494 mg, 1.14 mmol), Pd(OAc)2 (128 mg, 0.57 mmol), PPh3 (298 mg, 1.14
mmol) and nBu3N (810 µL, 3.41 mmol) in anhydrous DMF (11 mL) for 1.5
h, and using EtOAc/PE 4:6 as eluent for the flash chromatography, 10aMe
was obtained as a yellow solid (321 mg, 99%). Rf (EtOAc/PE 4:6) = 0.53.
+
Mp 152.0 – 154.0 °C. HRMS (ESI+): [M+H]+ calcd for C16H17N2O3
285.1234, found 285.1235. 1H NMR (300 MHz, d ppm/CDCl3): 7.50 – 7.41
(m, 2H), 7.38 – 7.26 (m, 2H), 6.14 (dd, J = 3.4, 2.0 Hz, 1H), 5.43 (s, 1H),
3.92 (s, 3H), 3.35 – 3.21 (m, 1H), 3.10 (s, 3H), 2.73 (ddd, J = 12.4, 8.7, 3.5
Hz, 1H), 2.37 (dd, J = 12.4, 6.5 Hz, 1H), 2.12 – 2.02 (m, 1H). 13C NMR (75
MHz, d ppm/CDCl3): = 173.8 (C), 158.4 (C), 147.0 (C), 146.1 (C), 135.5
(C), 129.6 (CH), 128.9 (CH), 126.0 (CH), 123.2 (CH), 122.4 (CH), 68.3
(CH), 66.9 (C), 54.0 (CH3), 37.6 (CH2), 34.3 (CH3), 33.2 (CH2).
Olefin 9hBn : following the general procedure with 8hBn (400 mg, 0.79
mmol), Pd(OAc)2 (89 mg, 0.40 mmol), PPh3 (207 mg, 0.79 mmol), formic
acid (60 µL, 1.59 mmol) and nBu3N (565 µL, 2.38 mmol) in anhydrous DMF
(16 mL), and using EtOAc/PE 2:8 as eluent for the flash chromatography,
9hBn was obtained as a colorless oil (161 mg, 57%). Rf (EtOAc/PE 2:8) =
+
0.27. HRMS (ESI+): [M+H]+ calcd for C19H23N2O5 359.1601, found
8
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
Tetracyclic compound 10dMe: following the general procedure with 8dMe
(425 mg, 0.89 mmol), Pd(OAc)2 (100 mg, 0.45 mmol), PPh3 (233 mg, 0.89
mmol) and nBu3N (630 µL, 2.65 mmol) in anhydrous DMF (9 mL) for 4 h,
and using EtOAc/PE 5:5 as eluent for the flash chromatography, 10aMe
was obtained as a yellow solid (288 mg, 98%). Rf (EtOAc/PE 5:5) = 0.46.
with EtOAc/PE 2:8 afforded 12 (320 mg, 99%) as a white solid. Rf
(AcOEt/PE 2:8) = 0.50. Mp 89.8 – 91.2 °C. HRMS (ESI+): [M+H]+ calcd
forC14H17N2O+ 229.1335, found 229.1337. 1H NMR (300 MHz,
d
ppm/CDCl3): 7.77 – 7.71 (m, 2H), 7.43 – 7.38 (m, 3H), 3.32 (s, 3H), 2.21 –
1.90 (m, 8H). 13C NMR (75 MHz, d ppm/CDCl3): 180.8 (C), 161.3 (C), 130.7
(C), 129.9 (CH), 128.9 (2CH), 126.3 (2CH), 56.9 (C), 36.0 (2CH2), 31.5
(CH3), 27.5 (2CH2).
+
Mp 189.0 – 191.0 °C. HRMS (ESI+): [M+H]+ calcd for C16H16N3O5
330.1084, found 330.1086. 1H NMR (300 MHz, d ppm/CDCl3): 8.25 (d, J =
2.0 Hz, 1H), 8.16 (dd, J = 8.4, 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.35
(dd, J = 3.4, 2.0 Hz, 2H), 5.50 (s, 1H), 3.94 (s, 3H), 3.40 – 3.26 (m, 1H),
3.11 (s, 3H), 2.80 (ddd, J = 14.9, 8.7, 3.6 Hz, 1H), 2.42 (dd, J = 12.5, 6.5
Hz, 1H), 2.18 – 2.08 (m, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 172.7 (C),
158.3 (C), 152.5 (C), 149.5 (C), 144.9 (C), 136.9 (C), 127.1 (CH), 126.9
(CH), 123.9 (CH), 117.5 (CH), 67.9 (CH), 67.3 (C), 54.3 (CH3), 37.8 (CH2),
34.3 (CH3), 33.4 (CH2).
Spirobicyclic pyrazolidinone 3b: to a solution of 12 (243 mg, 1.06 mmol) in
methanol (18 mL) was added 10% Pd/C (113 mg) and the solution was
placed under an atmosphere of hydrogen with vigorous stirring for three
days at room temperature. The resulting suspension was filtered over
celite, concentrated in vacuo and purified by flash chromatography eluted
with EtOAc/CH2Cl2 4:6 to afford pure 3b (143 mg, 59%) as a white solid.
Rf (AcOEt/CH2Cl2 4:6) = 0.24. HRMS (ESI+): [M+H]+ calcd for C14H19N2O+
231.1492, found 231.1491. 1H NMR (300 MHz, d ppm/CDCl3): 7.39 – 7.29
(m, 3H), 7.23 – 7.18 (m, 2H), 4.73 (broad s, 1H), 4.31 (s, 1H), 3.15 (s, 3H),
2.17 – 2.04 (m, 1H), 1.89 – 1.75 (m, 2H), 1.72 – 1.55 (m, 3H), 1.42 – 1.31
(m, 1H), 1.29 – 1.15 (m, 1H). 13C NMR (75 MHz, d ppm/CDCl3): 176.5 (C),
138.0 (C), 128.7 (2CH), 128.1 (CH), 127.1 (2CH), 69.1 (CH), 56.2 (C), 35.8
(CH2), 31.8 (CH3), 30.7 (CH2), 25.5 (CH2), 25.5 (CH2).
Tetracyclic compound 10fBn: following the general procedure with 8fBn
(550 mg, 1.02 mmol), Pd(OAc)2 (46 mg, 0.20 mmol), PPh3 (160 mg, 0.61
mmol) and nBu3N (727 µL, 3.06 mmol) in anhydrous DMF (20 mL) for 4 h,
and using EtOAc/PE 5:5 as eluent for the flash chromatography, 10fBn was
obtained as a white solid (388 mg, 98%). Rf (AcOEt/PE 2:8) = 0.14. Mp
122.3 – 124.3 °C. HRMS (ESI+): [M+H]+ calcd for C23H23N2O4+ 391.1652,
1
found 391.1654. H NMR (300 MHz, d ppm/CDCl3): 7.43 – 7.37 (m, 5H),
7.34 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.84 (dd, J = 8.4, 2.5 Hz,
1H), 6.11 (dd, J = 3.5, 2.0 Hz, 1H), 5.40 (s, 1H), 5.35 (d, J = 12.1 Hz, 1H),
5.29 (d, J = 12.1 Hz, 1H), 3.81 (s, 3H), 3.19 – 3.33 (m, 1H), 2.71 (ddd, J =
16.6, 8.1, 3.5 Hz, 1H), 2.32 (dd, J = 12.5, 6.6 Hz, 1H), 2.02 (ddd, J = 12.5,
9.4 Hz, 1H). 13C NMR (75 MHz, d ppm/CDCl3) : 173.9 (C), 161.1 (C), 157.7
(C), 147.0 (C), 138.1 (C), 136.8 (C), 135.6 (C), 128.9 (2CH), 128.7 (CH),
128.2 (2CH), 126.8 (CH), 123.1 (CH), 116.3 (CH), 106.3 (CH), 68.7 (CH2),
68.0 (CH), 67.5 (C), 55.7 (CH3), 37.5 (CH2), 34.4 (CH3), 33.0 (CH2).
Spirobicyclic pyrazolidinone 3h: to a solution of 9hBn (510 mg, 1.42 mmol)
in methanol (100 mL) was added 10% Pd/C (151 mg) and the solution was
placed under an atmosphere of hydrogen with vigorous stirring for five
days at room temperature. The resulting suspension was filtered over
celite, concentrated in vacuo and purified by flash chromatography eluted
with EtOAc/PE 6:4 to afford pure 3h (250 mg, 78%) as a colorless oil. Rf
(EtOAc/PE 4:6) = 0.20. HRMS (ESI+): [M+Na]+ calcd for C11H18N2O3Na+
249.1210, found 249.1212. 1H NMR (300 MHz, d ppm/CDCl3): 4.79 (d, J =
11.1 Hz, 1H), 4.25 (qd, J = 7.3, 1.7 Hz, 2H), 4.03 (d, J = 11.1 Hz, 1H), 3.05
(s, 3H), 2.28 – 2.15 (m, 1H), 1.89 – 1.64 (m, 6H), 1.53 – 1.42 (m, 1H), 1.31
(t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, d ppm/CDCl3): 175.6 (C), 169.9 (C),
67.2 (CH), 61.7 (CH2), 54.1 (C), 34.9 (CH2), 31.9 (CH2), 31.8 (CH3), 26.4
(CH2), 26.0 (CH2), 14.3 (CH3).
Tetracyclic compound 10gMe: following the general procedure with 8gMe
(400 mg, 0.89 mmol), Pd(OAc)2 (100 mg, 0.44 mmol), PPh3 (234 mg, 0.89
mmol) and nBu3N (640 µL, 2.69 mmol) in anhydrous DMF (9 mL) for 23 h,
and using EtOAc/PE 3:7 as eluent for the flash chromatography, 10gMe
was obtained as a yellow solid (246 mg, 93%). Rf (EtOAc/PE 3:7) = 0.44.
+
Mp 170.0 – 170.8 °C. HRMS (ESI+): [M+H]+ calcd for C17H19N2O3
Spirobicyclic pyrazolidinone 3j: to a solution of 9jBn (310 mg, 0.82 mmol)
in methanol (40 mL) was added 10% Pd/C (88 mg) and the solution was
placed under an atmosphere of hydrogen with vigorous stirring for three
days at room temperature. The resulting suspension was filtered over
celite, concentrated in vacuo and purified by flash chromatography eluted
with EtOAc/PE 6:4 to afford pure 3h (134 mg, 67%) as a colorless oil. Rf
(AcOEt/PE 4:6) = 0.10. HRMS (ESI+): [M+H]+ calcd for C15H21N2O+
245.1648 found 245.1647. 1H NMR (300 MHz, d ppm/CDCl3): 7.37 – 7.22
(m, 5H), 4.14 (broad s, 1H), 3.47 (dd, J = 9.7, 2.5 Hz, 1H), 3.03 (s, 3H),
2.87 (dd, J = 14.0, 2.5 Hz, 1H), 2.67 (dd, J = 14.0, 10.6 Hz, 1H), 2.14 –
2.01 (m, 1H), 1.98 – 1.49 (m, 7H). 13C NMR (75 MHz, d ppm/CDCl3): 177.6
(C), 138.5 (C), 129.1 (2CH), 128.6 (2CH), 126.7 (CH), 66.4 (CH), 54.8 (C),
35.1 (CH2), 34.6 (CH2), 31.8 (CH3), 29.4 (CH2), 26.2 (CH2), 25.6 (CH2).
299.1390, found 299.1390. 1H NMR (400 MHz, d ppm/CDCl3): 7.28 (d, J =
7.6 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.09
(dd, J = 3.3, 1.9 Hz, 1H), 5.54 (s, 1H), 3.92 (s, 3H), 3.25 (dddd, J = 16.5,
9.2, 6.6, 2.0 Hz, 1H), 3.10 (s, 3H), 2.71 (ddd, J = 16.5, 8.7, 3.5 Hz, 1H),
2.40 (s, 3H), 2.36 (dd, J = 12.2, 6.6 Hz, 1H), 2.10 – 2.01 (m, 1H). 13C NMR
(101 MHz, d ppm/CDCl3): 173.9 (C), 158.8 (C), 147.0 (C), 143.0 (C), 137.3
(C), 135.7 (C), 130.5 (CH), 129.7 (CH), 122.7 (CH), 119.9 (CH), 68.9 (CH),
66.6 (C), 54.0 (CH3), 37.5 (CH2), 34.2 (CH3), 32.9 (CH2), 18.2 (CH3).
Ketoester 11: to a solution of phenyl 3-oxobutanoate (2.50 g, 13 mmol) in
32 mL of anhydrous DMF was added K2CO3 (3.59 g, 26 mmol), 1,4-
dibromobutane (4.7 mL, 39 mmol) and nBu4NI (480 mg, 1.3 mmol), and
the resulting mixture was stirred at room temperature for 2 days. Brine (30
mL) and ethyl acetate (30 mL) were added and the organic layer separated.
The aqueous layer was extracted twice with EtOAc and the combined
organic layers were dried over anhydrous Na2SO4, concentrated in vacuo
and purified by flash chromatography eluted with EtOAc/PE 1:9 to afford
11 as a colorless oil (1.46 g, 46%). Rf (ACOEt/PE 1:9) = 0.40. 1H NMR
(300 MHz, d ppm/CDCl3): 7.85 (dd, J = 8.3, 1.4 Hz, 2H), 7.55 – 7.45 (m,
1H), 7.44 – 7.35 (m, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.49 – 2.21 (m, 4H),
1.86 – 1.60 (m, 4H), 0.96 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, d
ppm/CDCl3): 196.2 (C), 174.8 (C), 135.56 (C), 132.7 (CH), 128.9 (2CH),
128.5 (2CH), 63.8 (C), 61.37 (CH2), 35.2 (2CH2), 26.4 (2CH2), 13.8 (CH3).
Tetracyclic pyrazolidinone 10a: to a solution of 10aMe (162 mg, 0.57 mmol)
in anhydrous methanol (6 mL) was added LiOH (14 mg, 0.58 mmol) and
the resulting solution was stirred for five days at room temperature. Brine
(10 mL) was then added and the aqueous layer was extracted three times
with dichloromethane. The combined organic layers were dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to give the
crude product, which was purified by flash chromatography eluted with
EtOAc/CH2Cl2 4:6 to afford pure 10a (47 mg, 39%) as a yellow solid.
Recrystallization of this material from dichloromethane gave
monocrystalline prisms suitable for X-ray diffraction analysis.[7] Rf
(EtOAc/DCM 4:6) = 0.15. Mp 217.0 – 219.0 °C. HRMS (ESI+): [M+H]+
calcd for C14H15N2O+ 227.1179, found 227.1177; [M+Na]+ calcd for
Acylhydrazone 12: ketoester 11 (350 mg, 1.42 mmol) and methylhydrazine
(230 µL, 4.39 mmol) were allowed to react neat at room temperature for 3
days. Purification of the resulting material by flash chromatography eluted
C14H14N2ONa+ 249.0998, found 249.0996. 1H NMR (400 MHz,
d
ppm/CDCl3): 7.48 (dd, J = 6.6, 2.0 Hz, 1H), 7.43 (dd, J = 6.3, 2.5 Hz, 1H),
9
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
7.34 – 7.27 (m, 2H), 6.11 (dd, J = 3.5, 1.9 Hz, 1H), 4.96 (broad s, 1H), 4.52
(s, 1H), 3.39 – 3.26 (m, 1H), 2.94 (s, 3H), 2.73 (ddd, J = 16.5, 8.8, 3.5 Hz,
1H), 2.40 (dd, J = 12.2, 6.6 Hz, 2H), 2.05 (dd, J = 12.2, 9.3, 9.3 Hz, 1H).
13C NMR (75 MHz, d ppm/CDCl3): 173.7 (C), 148.3 (C), 148.2 (C), 135.7
(C), 129.1 (CH), 128.6 (CH), 126.1 (CH), 122.1 (CH), 122.0 (CH), 67.9 (C),
65.4 (CH), 37.5 (CH2), 33.1 (CH2), 31.9 (CH3).
Catalysts, and Additional Topics (Ed.: K. Maruoka), Thieme, Stuttgart,
2012; c) Comprehensive Enantioselective Organocatalysis, (Ed.: P. I.
Dalko), Wiley-VCH, Weinheim, 2013, Vol. 1–3.
[2]
[3]
[4]
Seminal work and catalysts in Figure 1a: a) K. A. Ahrendt, C. J. Borths,
D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243–4244; b) S. P.
Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,
125, 1192–1194; c) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2005, 44, 794–797; d) Y. Hayashi, H.
Gotoh, T. Hayashi, M. Shoji, Angew. Chem. Int. Ed. 2005, 44, 4212–4215.
Reviews: e) A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107,
5416–5470; f) M. Nielsen, D. Worgull, T. Zweifel, B. Gschwend, S.
Bertelsen, K. A. Jørgensen, Chem. Commun., 2011, 47, 632–649; g) B.
S. Donslund, T. K. Johansen, P. H. Poulsen, K. S. Halskov, K. A.
Jørgensen, Angew Chem. Int Ed. 2015, 54, 13860-13874; h) S. Meninno,
C. Volpe, A. Lattanzi, ChemCatChem, 2019, 11, DOI:
10.1002/cctc.201900569.
Tetracyclic pyrazolidinone 1f: to a solution of 10fBn (380 mg, 1.05 mmol)
in methanol (49 mL) was added 10% Pd/C (104 mg) and the solution was
placed under an atmosphere of hydrogen with vigorous stirring for four
days at room temperature. The resulting suspension was filtered over
celite, concentrated in vacuo and purified by flash chromatography eluted
with EtOAc/PE 6:4 to afford pure 1f (230 mg, 85%) as a colorless oil. Rf
+
(AcOEt/PE 4:6) = 0.15. HRMS (ESI+): [M+H]+ calcd for C15H19N2O2
259.1441, found 259.1442. It was not possible to obtain a well-resolved 1H
NMR spectrum at 294 K. It was thus decided to analyze the corresponding
trifluoromethanesulfonate salt 1f•TfOH, which was prepared from a
solution of 1f in dichloromethane and 1 equiv triflic acid followed by
evaporation of volatiles in vacuo. The amorphous solid obtained was
recrystallized from ethyl acetate to give monocrystalline prisms suitable for
X-ray diffraction analysis.[7] For the trifluoromethanesulfonate salt
1f•TfOH: Mp 238 – 239 °C. 1H NMR (300 MHz, d ppm/C6D6): 7.77 (d, J =
8.5 Hz, 1H), 6.78 (dd, J = 8.6, 2.4 Hz, 1H), 6.40 (broad s, 1H), 5.22 (s, 1H),
3.79 – 3.68 (m, 2H), 3.23 (s, 3H), 3.12 (s, 3H), 2.21 – 2.09 (m, 1H), 1.88 –
1.70 (m, 2H), 1.55 – 1.45 (m, 1H), 1.39 – 1.26 (m, 1H), 1.15 – 0.79 (m, 2H).
13C NMR (75 MHz, d ppm/CDCl3): 174.1 (C), 163.2 (C), 149.4 (C), 127.3
(CH), 125.6 (C), 115.5 (CH), 109.7 (CH), 71.3 (CH), 61.1 (C), 56.6 (CH),
55.7 (CH3), 36.2 (CH2), 34.3 (CH2), 31.4 (CH3), 26.8 (CH2). Resonance for
CF3 not detected due to a low S/N ratio.
a) M. Lemay, W. W. Ogilvie, Org. Lett. 2005, 7, 4141–4144; b) M. Lemay,
W. W. Ogilvie, J. Org. Chem. 2006, 71, 4663–4666; c) M. Lemay, L.
Aumand, W. W. Ogilvie, Adv. Synth. Catal. 2007, 349, 441–447; d) H.
He, B.-J. Pei, H.-H. Chou, T. Tian, W.-H. Chan, A. W. M. Lee, Org. Lett.
2008, 10, 2421–2424; e) Y. Langlois, A. Petit, P. Rémy, M.-C.
Scherrmann, C. Kouklovsky, Tetrahedron Lett. 2008, 49, 5576–5579; f)
E. Gould, T. Lebl, A. M. Z. Slawin, M. Reid, A. D. Smith, Tetrahedron
2010, 66, 8992–9008; g) F. Jakob, E. Herdtweck, T. Bach, Chem. Eur. J.
2010, 16, 7537–7546; h) I. Suzuki, M. Ando, R. Shimabara, A. Hirata, K.
Takeda, Org. Biomol. Chem. 2011, 9, 3033–3040; i) E. Gould, T. Lebl, A.
M. Z. Slawin, M. Reid, T. Davies, A. D. Smith, Org. Biomol. Chem.
2013,11, 7877–7892; j) N. O. Häggman, B. Zank, H. Jun, D. Kaldre, J. L.
Gleason, Eur. J. Org. Chem. 2018, 5412–5416.
Reviews: a) W. Kirmse, Eur. J. Org. Chem. 2002, 2193–2256; b) Y.
Coquerel, J. Rodriguez in Molecular Rearrangements in Organic
Synthesis (Ed.: C. Rojas), Wiley, Hoboken, 2015, pp. 59–84.
M. Presset, K. Mohanan, M. Hamann, Y. Coquerel, J. Rodriguez, Org.
Lett. 2011, 13, 4124–4127.
Acknowledgments
[5]
[6]
Financial support from the Agence Nationale de la Recherche
(ANR-13-JS07-0002-01), Aix Marseille Université, Centrale
Marseille, and the Centre National de la Recherche Scientifique
(CNRS) is gratefully acknowledged. We warmly thank Dr. Michel
Giorgi (Aix-Marseille Université) for the X-ray structural analyses,
Dr. Nicolas Vanthuyne (Aix-Marseille Université) and Ms. Marion
Jean (CNRS) for analytical and semi-preparative HPLC on
stationary phases, Dr. Jean-Valère Naubron (CNRS) for
vibrational circular dichroism spectroscopy, and Prof. Dr. Cyril
Bressy (Aix-Marseille Université) for advices with the synthesis of
3b.
For precedents, see: a) M. C. Willis, C. K. Claverie, M. F. Mahon, Chem.
Commun. 2002, 832–833; b) A. C. F. Cruz, N. D. Miller, M. C. Willis, Org.
Lett. 2007, 9, 4391–4393; c) M. R. Albicker, N. Cramer, Angew. Chem.
Int. Ed. 2009, 48, 9139–9142; d) D. T. Ngoc, M. Albicker, L. Schneider,
N. Cramer, Org. Biomol. Chem. 2010, 8, 1781–1784.
[7]
CCDC 1922280 for 1f•CF3SO3H and CCDC 1922281 for 10a contain the
supplementary crystallographic data for this paper. These data are
available free of charge from the Cambridge Crystallographic Data
Centre website.
[8]
[9]
S. Muthusamy, B. Gnanaprakasam, Tetrahedron Lett. 2005, 46, 635–
638.
J. B. Brazier, T. J. K. Gibbs, J. H. Rowley, L. Samulis, S. Chak Yau, A.
R. Kennedy, J. A. Platts, N. C. O. Tomkinson, Org. Biomol. Chem. 2015,
13, 133–141.
Keywords: Diastereoselectivity • C-H activation •
Organocatalysis • Spiro compounds • Synthetic methods
[1]
a) Science of Synthesis Asymmetric Organocatalysis 1; Lewis Base and
Acid Catalysts (Ed.: B. List), Thieme, Stuttgart, 2012; b) Science of
Synthesis Asymmetric Organocatalysis 2: Brønsted Base and Acid
10
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10.1002/ejoc.201900989
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
R1
R1
O
Synthetic methods
O
O
N
N
R1
R2
N2
H
O
O
NH
NH
R1
H
N
Fabien Perez, Thibault Leveille, Mathilde
Bertolotti, Jean Rodriguez* and Yoann
Coquerel*
O
O
N
+
+
or
or
or
NH
NH2
O
R2
R3
R3
H
R3
Page No. – Page No.
The stereoselective syntheses of spirobicyclic and tetracyclic pyrazolidinones are
reported based on a (3+2) annulation between in situ generated hydrazones and a-
oxoketenes. Notably, palladium-catalyzed cyclizations allowed the efficient
construction of tetracyclic backbones through aromatic C–H bond activation. Some
of these molecules were evaluated as organocatalysts for the iminium activation of
enals in a model Diels–Alder cycloaddition.
Spirobicyclic and tetracyclic
pyrazolidinones: syntheses and
properties
11
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