Desymmetrization of Cyclopentenediones via Organocatalytic Cross-Dehydrogenative Coupling

Article abstract of DOI:10.1002/adsc.201700917

An enantioselective synthesis of cyclopentenediones bearing a pyrazole unit has been achieved through an organocatalytic Michael addition/oxidation process. This desymmetrization reaction led to the desired pyrazole-cyclopentenediones with high yield and

Full text of DOI:10.1002/adsc.201700917

Title: Desymmetrization of Cyclopentenediones via Organocatalytic
Cross-Dehydrogenative Coupling
Authors: Fabrizio Vetica, Stephen Bailey, Pankaj Chauhan, Mathias
Turberg, Adjmal Ghaur, Gerhard Raabe, and Dieter Enders
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Desymmetrization of Cyclopentenediones via Organocatalytic
Cross-Dehydrogenative Coupling
Fabrizio Vetica, Stephen Bailey, Pankaj Chauhan, Mathias Turberg, Adjmal Ghaur,
Gerhard Raabe, and Dieter Enders *
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
E-mail: enders@rwth-aachen.de
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract:
cyclopentenediones bearing a pyrazole unit has been
achieved through an organocatalytic Michael
addition/oxidation process. This desymmetrization reaction
led to the desired pyrazole-cyclopentenediones with high
yield and good enantioselectivities. The postulated cross-
An
enantioselective
synthesis
of
a) Zimmermann reaction (1965)
O
NO2
Me
Me
O
Me
base
Me
+
NO2
Me
Me
O2N
excess
O2N
dehydrogenative
coupling-mechanism
has
been
investigated via preliminary control experiments.
Ar
O
H
N
O
Keywords: desymmetrization; organocatalysis; pyrazoles;
cross-dehydrogenative coupling; quaternary stereocenter
O
Me
Me
NO2
Me
O
N
O
The formation of a C-C bond through C-H
activation represents one of the most important and
b) Mukherjee (2015)
[1]
challenging transformations in organic synthesis.
O
O
O
Indeed, a plethora of outstanding methodologies have
been disclosed over the years to achieve such aim,
often involving mainly transition metal-catalysis.
Nevertheless, these procedures sometimes require
harsh reaction conditions and show incompatibility
with the presence of particular functional groups.
Over the last two decades, organocatalysis has
paved the way to the development of an exceptional
number of new methodologies to achieve complex
molecular architectures employing mild reaction
chiral urea (10 mol%)
R1
R2
R1
R2
+
R NO2
3
Na2CO3 (1.5 equiv.)
PhCF3, -10°C
R3
O
10 equiv.
c) This work
O
O
bifunctional
O
organocatalyst
R3
R3
HO
R1
R2
Me
N
Me
R1
N
N
O
O
N
R2
1 equiv.
1 equiv.
[2]
conditions via many activation modes. However,
the application of organocatalysis in direct or formal
C-H activations remains less explored. Only a few
examples of -functionalization of carbonyl
compounds, [1,5]-hydride transfer/ring closures, as
well as cross-dehydrogenative couplings (CDC) have
been recently explored.[
-
cross-dehydrogenative coupling
-atom economical
-
-
-
mild conditions
remote stereocontrol
quaternary stereocenter
Scheme 1. General outline of the strategy reported herein
and previous related work.
3]
An interesting example of metal-free formal CDC
is the Zimmermann reaction between enolates and
4]
1
,3-dinitrobenzene (Scheme 1, a).[ The initial base-
and achieving the formal coupling product.
catalysed Michael-type addition on the less hindered
position of the aromatic ring leads to the illustrated
transition state. Subsequently, 1,3-dinitrobenzene in
excess acts as an oxidant to drive the hydride
elimination, recovering the aromaticity
Within this context, the high abundance of five-
membered carbocyclic frameworks in bioactive
molecules stimulated the development of innovative
processes for their asymmetric synthesis. The
desymmetrization of pro-chiral cyclopentenediones
has proved to be an efficient method to accomplish
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
this aim, relying usually on a Michael addition by
reaction with several nucleophiles.[
Table 2. Optimization of the reaction conditions.[a]
5]
In 2015 Mukherjee et al. reported the
organocatalytic
desymmetrization
of
cyclopentenediones involving nitroalkanes as
[6]
alkylating agents. Despite the use of a strong excess
of nitroalkanes, they developed an efficient formal C-
H activation of cyclopentenediones relying on the
Entry Solvent
B[b] Additive Y[c] er[d]
elimination of HNO as leaving group (Scheme 1, b).
2
1
2
3
4
5
CH
CHCl
PhCF
DCE
2
Cl
3
2
5
5
5
5
5
-
-
-
-
-
-
60
20
55
28
39
83:17
83.5:16.5
83:17
82:18
72:28
Inspired by this, we envisioned the possibility to
employ pyrazolone derivatives as nucleophiles to
perform a desymmetrization-CDC on prochiral
cyclopentenediones. The pyrazolones and pyrazoles
are very important scaffolds, finding applications in
pharmaceutical and agrochemical chemistry, as well
3
toluene
,4-
dioxane
Et
1
6
5
22
69:31
[7]
as dyes and chelating agents.
Moreover, the
7
8
9
1
1
1
1
1
1
1
1
2
O
5
5
5
5
2.5
5
10
5
5
5
-
-
-
-
-
-
-
-
62
76
65
85
43
65
99
51
95
87
70
96
88:12
84:16
90:10
90:10
87:13
90:10
88:12
88:12
91.5:8.5
89:11
93:7
reactivity of pyrazolones has been intensively
explored in recent times due to the high
THF
[
e]
[8]
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
nucleophilicity of the C-4 position.
desymmetrization could lead to a new library of
densely functionalised pyrazole-derived
This
[
[
[
[
f]
f]
f]
f]
0
1
2
3
4
5
6
7
cyclopentenediones bearing an all carbon quaternary
stereocenter and promising applications in
pharmaceutical chemistry.
Initially we choose the pyrazolone 1a and the
cyclopentenedione 2a as model substrates in
[
g]
[f]
f]
[
4 Å MS
4 Å MS
4 Å MS
3 Å MS
[
[
h]
i]
[f]
[f]
5
5
[
f]
Table 1. Catalyst screening.[a]
18
90.5:9.5
4
+
Å MS
1
9[j]
MTBE[f]
5
77
90.5:9.5
PhCO
2
H
[
a]
Unless otherwise stated the reaction conditions were: 1a
0.2 mmol), 2a (0.2 mmol), solvent (1.0 mL) at rt.
Yield of 3a after column chromatography
%]. Determined by SFC on a chiral stationary phase.
[
b]
(
[
[
[
c]
mol%].
[
d]
[e]
[
f]
Technical grade MTBE was used.
Anhydrous MTBE
(
Sigma-Aldrich, 99.8 % purity, <0.003 % water) was used.
[g]
[h]
2
.0 mL of solvent were used. The reaction was carried
[
i]
[j]
out at 4°C. The reaction was carried out at –20°C.
mol% of PhCO H was used.
5
2
equimolar amounts to perform a test reaction
catalyzed by the commercially available bifunctional
thiourea A (Table 1). To our delight, the coupling
product 3a was obtained as single product in 50%
yield and a 20:80 er, even in the absence of an
oxidant additive. Encouraged by this initial result, we
proceeded with the catalysts screening employing
different thioureas B and E, squaramides C, D and
thiocarbamate F. The thiourea B was identified as the
best catalyst, as it provided the desired product 3a in
6
0% yield and 83:17 er. The two dimeric Cinchona
alkaloids G and H gave lower yields and
enantioselectivities compared to catalyst B.
Once we had identified the best catalyst, we
focused on the further optimization of the reaction
conditions by testing the effects of different solvents
(
Table 2, entries 1-10). The screening revealed that
the reaction in absolute MTBE provides the best er of
0:10 and best yield of 85% (Table 2, entry 10). After
9
[
a]
Unless otherwise stated the reaction conditions were: 1a
0.2 mmol), 2a (0.2 mmol), solvent (1.0 mL) at rt.
the optimization of the catalyst loading, temperature,
presence of additives, as well as concentration, the
(
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
best results were achieved by employing thiourea
catalyst B in 5 mol%, absolute MTBE as solvent, and
adding 4Å MS to the reaction mixture to provide the
corresponding products (3f,g, and m) with good
ervalues, despite a lower reactivity when the
substituent is in the ortho-position (3g). It was also
1
corresponding
desymmetrized
pyrazole-
possible to introduce a methyl group as R substituent
cyclopentenedione 3a with excellent yield of 95%
and good enantioselection (91.5:8.5 er, Table 2, entry
achieving similar results (3h). Various alkyl
2
substituents (R ) at the C3 position of the pyrazolone
1
5).
1 also worked well in terms of er and yield,
regardless of the increased steric hindrance (3j-l).
With the optimized conditions in hand, different
substrates were probed to demonstrate the general
Instead, the introduction of a CF group in the same
3
applicability of the cross-dehydrogenative coupling
position showed poor reactivity (14% yield).
Differently substituted cyclopentenediones 2 bearing
electron-withdrawing and electron-donating were
also probed and reacted well providing good yields
and enantioselectivities (3b-e).
1
(
Table 3). The variation on the N substituent (R )
with aryl groups bearing electron-withdrawing and
donating groups led to the formation of the
Table 3. Substrate scope of the cross-dehydrogenative
coupling.
The absolute configuration was determined to be R
by comparison of the electronic circular dichroism
(
ECD) spectrum measured of product 3a and its
calculated counterpart (Figure 1).
Figure 1. Determination of the absolute configuration of
3
a by comparison of its experimental electronic circular
dichroism (ECD) spectrum at room temperature in
[
9]
acetonitrile (top) with its calculated counterpart (bottom).
Interestingly, in none of the implemented cases the
products derived from a Michael addition of the
pyrazolones on the cyclopentenediones were
detectable. In 2015, the group of Wang reported a
similar reactivity for the reaction between 4-
substituted-pyrazolones and p-quinones, but the
[10]
authors did not investigate the reaction mechanism.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
With the aim of better understanding the features of
this kind of transformation we carried out a series of
preliminary control experiments.
we stirred compound 1a, catalyst B, and TEMPO in
MTBE and DCM, respectively. The solution in
Initially, we focused on the role played by the
enolization of the carbonyl group of the pyrazole
moiety and the resulting aromaticity. Indeed, after the
supposed initial Michael addition, the carbonyl group
of the pyrazolone tautomerizes to achieve the
aromatic system. Thus, we performed a test reaction
using 4-methyl-pyrazolone 1’ and the model
cyclopentenedione 2a as substrates, to block the
eventual aromatization. Interestingly, only the
product of the Michael addition 4 was isolated with
O
O
Bn
Me
+
N
Me
N
Ph
O
O
O
B
H
Bn
O
H
Me
Ph
N
N
Me
N
MeO
H
CF3
B
S
N
H
N
N
CF3
H
H
Ph
O
O
N
N
O
Cat.*
H
N
Me
O
Bn
O
H
Me
Me
Ph
N
O
N
Me
-H2
O
O
Bn
Bn
O
HO
N
Me
Me
Ph
N
O
Ph
O
keto-enol
tautomerization
Scheme 2. Reaction with a 4-substituted pyrazolone 1’ and
isolation of the Michael product 4.
N
N
Me
Me
Scheme 3. Postulated reaction mechanism.
good dr (4:1), good yield (80%), and moderate er
(
74:26 er) (Scheme 2). The oxidation process was not
MTBE showed the complete quenching of
observed, proving that the enolation of the carbonyl
on the pyrazolone and the consequent aromaticity are
essential for the oxidation reaction. Furthermore, this
confirms that the cross-dehydrogenative coupling
proceeds via conjugate addition.
[11]
pyrazolone 1a after 12 hours.
From these two experiments it is possible to
assume that the mechanism of the oxidation is neither
radical nor oxygen mediated. Since a heterolytic bond
cleavage has therefore to take place, a plausible
pathway could involve hydride elimination in a
similar fashion than other accepted mechanisms like
Further evidence of the crucial role of the extended
conjugation in the oxidized product is the lack of
reactivity of the product 3a under reduction
conditions. In fact, we investigated the reduction of
the desymmetrized product 3a in the presence of
Pd/C (5 mol%) and H
used by the group of Mukherjee in 2015 to reduce the
analogous products. The product 3a did not react in
contrast to the products synthesised by Mukherjee et
al., evidencing the high stability due to the
conjugation.
[
12]
[13]
the Cannizzaro
and Chichibabin
reactions as
well as the Zimmermann reaction.
Taking into account what has indicated from the
control experiments, inspired by the mechanism of
the Zimmermann reaction (Scheme 1, a), and on the
basis of the observed absolute configuration of the
products we propose a possible reaction pathway for
the disclosed transformation (Scheme 3).
2
(1 atm) in MeOH, conditions
[6]
Initially, the bifunctional catalyst B could
coordinate to enhance the electrophilicity of the
carbonyl group of the cyclopentenedione 2a with the
hydrogen bonding thiourea function. Simultaneously,
the quinuclidine moiety could deprotonate the
pyrazolone 1a increasing the nucleophilicity and
driving the first Michael addition selectively on the
Re-face of the –position of the cyclopentenedione.
Subsequently the Michael adduct can be further
deprotonated by the catalyst after re-aromatization of
the pyrazole system. This could lead to a hydride
elimination driven from the generation of an extended
conjugated system, after tautomerization to the
aromatic enol form of 3a.
Furthermore, we conducted two other experiments
aiming to explain the oxidation process. The model
substrates 1a and 2a were employed for the reaction
under the best conditions and: a) in the presence of a
radical scavenger (TEMPO, 1 equiv.); b) in the
absence of O
2
(argon atmosphere and degassed
solvent). In both cases the reaction proceeded
efficiently, yielding the product 3a with no losses of
yield (respectively 60% and 92% yield). The reaction
with TEMPO had to be carried out in DCM instead of
MTBE since the reduction potential of the pyrazolone
in MTBE resulted to be too low, leading to the
quenching of the pyrazolone and TEMPO via a SET
mechanism (the yield of the reaction in DCM without
TEMPO is 60% as well, Table 2, entry 1). This
reactivity was proven by two test reactions in which
In order to prove the practical and preparative
application of the methodology we carried out a
scale-up synthesis of product 3c using the optimized
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
conditions (Scheme 4). The desired product was
obtained in 85% yield with unchanged er value (93:7).
V. Varun, J. Dhineshkumar, K. R. Bettadapur, Y.
Siddaraju, K. Alagiri, K. R. Prabhu, Tetrahedron Lett.
2
017, 58, 803.
[
2] For selected reviews on organocatalysis see: a) D.
Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. Int.
Ed. 2007, 46, 1570; b) D. W. C. MacMillan, Nature
2
008, 455, 304; c) A. Dondoni, A. Massi, Angew.
Chem. Int. Ed. 2008, 47, 4638; d) S. Bertelsen, K. A.
Jørgensen, Chem. Soc. Rev. 2009, 38, 2178; e) Ł.
Albrecht, H. Jiang, K. A. Jørgensen, Angew. Chem. Int.
Ed. 2011, 50, 8492; f) C. M. R. Volla, L. Atodiresei, M.
Rueping, Chem. Rev. 2014, 114, 2390; g) F. Vetica, R.
M. de Figueiredo, M. Orsini, D. Tofani, T. Gasperi,
Synthesis 2015, 47, 2139; h) F. Vetica, P. Chauhan, S.
Dochain, D. Enders, Chem. Soc. Rev. 2017, 1661.
3] Y.-L. Zhao, Y. Wang, Y.-C. Luo, X.-Z. Fu, P.-F. Xu,
Tetrahedron Lett. 2015, 56, 3703.
Scheme 4. Scale-up synthesis of product 3c.
[
[
In summary, we have developed an efficient
methodology to achieve densely functionalised
pyrazoles bearing a quaternary stereocenter. The
desired potentially bioactive compounds 3 were
obtained with high yield and good enantioselectivities
4] a) T. Nambara, M. Kato, Chem. Pharm. Bull. 1965, 13,
1
435; b) M. Kato, M. Ohnishi, T. Nambara, Chem.
Pharm. Bull. 1968, 16, 2398.
[
5] For selected reviews on desymmetrization reactions
and examples on desymmetrising synthesis of
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J. Am. Chem. Soc. 2007, 129, 10346; b) K. Aikawa, T.
Okamoto, K. Mikami, J. Am. Chem. Soc. 2012, 134,
(
up to 95% yield, up to 91.5:8.5 er). Moreover, a
series of preliminary control experiments have been
accomplished with the aim to clarify the reaction
mechanism. This facile desymmetrizing cross-
dehydrogenative coupling relies on an initial Michael
addition followed by a combination of aromaticity
and extensive conjugation driving to an oxidant- and
metal-free hydride elimination. This interesting new
reactivity could pave the way to new organocatalytic
CDC-based reactions and methodologies.
1
5
2
0329; c) M. S. Manna, S. Mukherjee, Chem. Sci. 2014,
, 1627; d) T. Das, P. Saha, V. K. Singh, Org. Lett.
015, 17, 5088; e) A. Borissov, T. Q. Davies, S. R.
Ellis, T. A. Fleming, M. S. W. Richardson, D. J. Dixon,
Chem. Soc. Rev. 2016; f) X. P. Zeng, Z. Y. Cao, Y. H.
Wang, F. Zhou, J. Zhou, Chem. Rev. 2016, 116, 7330;
g) Y. Zhi, K. Zhao, A. Wang, U. Englert, G. Raabe, D.
Enders, Adv. Synth. Catal. 2017, 359, 1867.
Experimental Section
[
[
6] M. S. Manna, S. Mukherjee, J. Am. Chem. Soc. 2015,
1
37, 130.
To a solution of cyclopentenedione 2 (0.2 mmol, 1 equiv.)
and catalyst A (0.01 mmol, 0.05 equiv.) in MTBE (1 mL,
7] For selected examples on bioactive pyrazoles and
pyrazolones see: a) M. P. Clark, S. K. Laughlin, M. J.
Laufersweiler, R. G. Bookland, T. A. Brugel, A.
Golebiowski, M. P. Sabat, J. A. Townes, J. C. VanRens,
J. F. Djung, M. G. Natchus, B. De, L. C. Hsieh, S. C.
Xu, R. L. Walter, M. J. Mekel, S. A. Heitmeyer, K. K.
Brown, K. Juergens, Y. O. Taiwo, M. J. Janusz, J. Med.
Chem. 2004, 47, 2724; b) V. Hadi, Y.-H. Koh, T. W.
Sanchez, D. Barrios, N. Neamati, K. W. Jung, Bioorg.
Med. Chem. Lett. 2010, 20, 6854; c) S. R. Mandha, S.
Siliveri, M. Alla, V. R. Bommena, M. R. Bommineni, S.
Balasubramanian, Bioorg. Med. Chem. Lett. 2012, 22,
0
.2 M) were added 4Å MS (50 mg) and the pyrazolone 1
(
0.2 mmol, 1 equiv.). The mixture was stirred at room
temperature until complete conversion of the substrates
were achieved by TLC monitoring. The product 3 was
isolated after flash chromatography on silica gel
(
pentane/EtOAc).
Acknowledgements
We thank the BASF SE for the donation of chemicals and
Cornelia Vermeeren for SFC measurements.
5
272; d) V. Kumar, K. Kaur, G. K. Gupta, A. K.
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5
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
L. Hodgson, M. Namazian, S. E. Bottle, M. L. Coote, J.
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6
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Advanced Synthesis & Catalysis
10.1002/adsc.201700917
COMMUNICATION
organocatalyzed cross-
dehydrogenative coupling
O
O
O
O
Desymmetrization of Cyclopentenediones via
Organocatalytic Cross-Dehydrogenative Coupling
O
B (5 mol%)
R3
R3
HO
R1
R2
Me
N
Me
R1
N
MTBE, rt
N
4Å MS, 2.5 d
N
R2
Adv. Synth. Catal. Year, Volume, Page – Page
1
4 examples
N
MeO
up to 95% yield
up to 93.5:6.5 er
H
Fabrizio Vetica, Stephen Bailey, Pankaj Chauhan,
Mathias Turberg, Adjmal Ghaur, Gerhard Raabe,
and Dieter Enders *
NH
NH
S
N
CF3
B
F3C
7
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