Switchable selectivity in Pd-catalyzed [3 + 2] annulations of γ-oxy-2-cycloalkenones with 3-oxoglutarates: C-C/C-C vs C-C/O-C bond formation

Article abstract of DOI:10.3762/bjoc.15.107

Two complementary [3 + 2] annulation protocols between 3-oxoglutarates and cyclic γ-oxy-2-cycloalkenones, simply differing on the reaction temperature, are disclosed. These domino transformations allow C-C/O-C or C-C/C-C [3 + 2] annulations at will, via an intermolecular Pd-catalyzed C-allylation/intramolecular O- or C-1,4-addition sequence, respectively. In particular, exploiting the reversibility of the O-1,4-addition step, in combination with the irreversible C-1,4-addition/decarboxylation path, the intramolecular conjugate addition step could be diverted from the kinetic (O-alkylation) to the thermodynamic path (C-alkylation) thanks to a simple temperature increase. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined step chronology in combination with the total chemoselectivity of the former step. This [3 + 2] C-C/O-C bond forming annulation protocol could be also extended to 1,3,5-triketones as well as 1,3-bis-sulfonylpropan-2-one bis-nucleophiles.

Full text of DOI:10.3762/bjoc.15.107

Switchable selectivity in Pd-catalyzed [3 + 2] annulations of
γ-oxy-2-cycloalkenones with 3-oxoglutarates: C–C/C–C vs
C–C/O–C bond formation
Yang Liu, Julie Oble* and Giovanni Poli*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1107–1115.
Sorbonne Université, Faculté des Sciences et Ingénierie, CNRS,
Institut Parisien de Chimie Moléculaire, IPCM, 4 place Jussieu, 75005
Paris, France
doi:10.3762/bjoc.15.107
Received: 31 March 2019
Accepted: 06 May 2019
Published: 16 May 2019
Email:
Julie Oble* - julie.oble@sorbonne-universite.fr; Giovanni Poli* -
giovanni.poli@sorbonne-universite.fr
Associate Editor: L. Ackermann
*
Corresponding author
© 2019 Liu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
,4-addition; annulation; decarboxylation; palladium; Pd-catalyzed
1
allylation reaction
Abstract
Two complementary [3 + 2] annulation protocols between 3-oxoglutarates and cyclic γ-oxy-2-cycloalkenones, simply differing on
the reaction temperature, are disclosed. These domino transformations allow C–C/O–C or C–C/C–C [3 + 2] annulations at will, via
an intermolecular Pd-catalyzed C-allylation/intramolecular O- or C-1,4-addition sequence, respectively. In particular, exploiting the
reversibility of the O-1,4-addition step, in combination with the irreversible C-1,4-addition/decarboxylation path, the intramolecu-
lar conjugate addition step could be diverted from the kinetic (O-alkylation) to the thermodynamic path (C-alkylation) thanks to a
simple temperature increase. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined
step chronology in combination with the total chemoselectivity of the former step. This [3 + 2] C–C/O–C bond forming annulation
protocol could be also extended to 1,3,5-triketones as well as 1,3-bis-sulfonylpropan-2-one bis-nucleophiles.
Introduction
The development of new strategies for the synthesis of com- they facilitate the synthesis of a variety of complex cycles in a
plex carbocyclic and heterocyclic structures remains a general single synthetic operation, through sequential and mechanisti-
topic for the synthetic chemists [1]. In the past decades, palla- cally independent bond-forming steps.
dium chemistry has gained an important place in the toolbox of
chemists, and its use became a privileged strategy for the selec- In the frame of our long-term project dedicated to domino se-
tive formation of carbon–carbon and carbon–heteroatom bonds quences [16-22] and Pd-catalyzed transformations [23-30], we
[
2-5]. Among the different types of palladium-catalyzed trans- recently reported a Pd(0)-catalyzed synthesis of bi- and tricyclic
formations, domino – alias cascade – transformations [6-11] as structures incorporating pyrrolidone rings (Scheme 1) [31]. In
well as annulation reactions [12-15] occupy a special place as this transformation, resonance-stabilized acetamides and cyclic
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Scheme 1: Previously developed bis-nucleophile/bis-electrophile [3 + 2] annulations.
α,β-unsaturated-γ-oxicarbonyl derivatives are used as bis-
nucleophile and bis-electrophile partners, respectively.
This process involves an intermolecular Pd(0)-catalyzed C-ally-
lation (Tsuji–Trost reaction)/intramolecular nitrogen 1,4-addi-
tion sequence (Scheme 1, top reaction). The success of this bis-
nucleophile/bis-electrophile [3 + 2] C–C/N–C bond-forming
annulation is due to the well-defined chronology of the steps
and the total chemoselectivity of the initial step (C-allylation).
Another non-trivial feature of this process is that the possible
undesired stoichiometric intermolecular 1,4-addition step (i.e.,
the potential initial addition of the nucleophile to the C-β of the
bis-electrophile) has to be slower than the intermolecular addi-
tion of the nucleophile to the catalytically generated η3-allylpal-
ladium complex, or it has to be at least a reversible process [32].
Furthermore, when the newly formed annulation product
contains an ortho-haloaryl moiety at the nitrogen substituent, an
additional intramolecular keto α-arylation step can be involved
in the cascade, thereby forming two new cycles and three new
Scheme 2: Concept: [3 + 2] C–C/C–C vs C–C/O–C bond-forming
annulations.
bonds in the same synthetic operation (Scheme 1, bottom reac-
tion).
We next decided to extend the scope of this strategy to dialkyl- II as the bis-electrophiles (Scheme 2). Interestingly, this new
-oxoglutarates I as the bis-nucleophile partners [33] in the bis-nucleophile/bis-electrophile combination may allow direct
reaction with cyclic α,β-unsaturated-γ-oxycarbonyl derivatives access to either fused bicyclic cyclopentanic (pentalene-,
3
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indene-, or azulene-type) structures via a γ-C-allylation/β-C-1,4 lytic systems: [Pd(η3-C3H5)Cl]2 (5 mol %), dppf (15 mol %)],
addition process, or annulated furan-based motifs through a and [Pd(OAc)2 (10 mol %), dppb (15 mol %)] in THF at room
γ-C-allylation/β-O-1,4 addition process, both motifs being in- temperature (Table 1, entries 1 and 2). These conditions
corporated into biologically relevant pharmaceuticals and/or promptly (ca. 1 hour) generated annulated product 4a arising
natural products (Figure 1) [34-38]. Indeed, we anticipated that from C-allylation (C–C bond forming)/intramolecular
the latter step might occur through either C-addition or O-addi- O-Michael addition (O–C bond forming) sequence. The purifi-
tion (Scheme 2, products III (or V) vs IV) [32,39-42]. There- cation of the crude reaction was easier using the Pd(OAc)2 and
fore, an inherent challenge associated to this ambident nucleo- dppb system (Table 1, entry 2), which was thus chosen to
phile is chemoselectivity control.
continue the optimization. The effect of the solvent was then
assessed. While no reaction took place in CH3CN (Table 1,
Herein we disclose two chemodivergent [3 + 2] annulation reac- entry 3), DMF (Table 1, entry 4) and DMSO (Table 1, entry 5)
tions taking place between dialkyl-3-oxoglutarates I and α,β- allowed the formation of 4a in 66% and 75% yield, respective-
unsaturated-γ-oxycarbonyl derivatives II that differ simply by ly. The use of another bidentate phosphine such as dppe gave no
the reaction temperature adopted. These methods allow the ex- improvement (Table 1, entry 6), showing only traces of 4a. The
clusive [3 + 2] C–C/C–C or C–C/O–C annulation at will, thus influence of the temperature in DMSO was examined next. The
providing an easy access to annulated cyclopentanic structures reaction performed at 75 °C gave a similar yield for compound
III or annulated furan-based motifs IV, respectively. Addition- 4a (compare entries 5 and 7 in Table 1), whereas the reaction
ally, in the case of C–C/C–C bond forming annulations, the carried out at 100 °C and 130 °C during 6 hours generated
products III can undergo two decarboxylation steps leading to solely bicyclo[4.3.0]nonane-3,8-dione (5a) with 50% and 69%
bis-cycloalkanone derivatives V.
yield, respectively (Table 1, entries 8 and 9). This product plau-
sibly arises from a C-allylation step followed by an intramolec-
ular C-conjugate addition/decarboxylation sequence, although
throughout this study the putative intermediate 3a proved
Results and Discussion
Optimization
We started our investigation using dimethyl 3-oxoglutarate (1a) always elusive. Using DMF and DMA as solvents at 130 °C
and 2-cyclohexenone 4-benzoate (2a) [43,44] as bis-nucleo- (Table 1, entries 10 and 11), and [Pd(η3-C3H5)Cl]2, dppf] as the
phile and bis-electrophile model substrates, respectively catalytic system in DMSO (Table 1, entry 12) did not allow
(
Table 1). In line with our previously developed standard reac- further improvements for the formation of compound 5a.
tion conditions for [3 + 2] C–C/N–C bond-forming annulation Furthermore, after 1 h at 130 °C under microwave irradiation,
[
31], the first tests were performed with the following two cata- the desired compound 5a was isolated in 69% yield (Table 1,
Figure 1: Examples of annulated cylopentanic (top) and furan-based (bottom) substructures in natural products.
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Table 1: Optimization of the reaction conditions.
Entry
[Pd]
Liganda
Solvent
Temp (°C), time (h)
Product, yield %b
1
2
3
4
5
6
7
8
9
[Pd(η3-C3H5)Cl]2c
Pd(OAc)2
dppf
THF
rt, ≈1
4a:5a = 1:0, 59
4a:5a = 1:0, 35
nrd
dppb
dppb
dppb
dppb
dppe
dppb
dppb
dppb
dppb
dppb
dppf
THF
rt, ≈1
Pd(OAc)2
CH3CN
DMF
rt, ≈1
Pd(OAc)2
rt, ≈1
4a:5a = 1:0, 66
4a:5a = 1:0, 75
4a, traces
Pd(OAc)2
Pd(OAc)2
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
rt, ≈1
rt, ≈1
Pd(OAc)2
75, ≈1
4a:5a = 1:0, 73
4a:5a = 0:1, 50
4a:5a = 0:1, 69
5a, trace
Pd(OAc)2
100, 6
Pd(OAc)2
Pd(OAc)2
130, 6
10
11
12
13
14
15
16
130, 6
Pd(OAc)2
DMA
130, 6
4a:5a = 0:1, 62
4a:5a = 0:1, 33
4a:5a = 0:1, 69
nrd
[Pd(η3-C3H5)Cl]2c
Pd(OAc)2
DMSO
DMSO
DMSO
DMSO
DMSO
130, 6
dppb
dppb
130 (MW, 1)
rt → 100, 6
rt → 100, 6
rt → 100, 6
Pd(OAc)2
nrd
nrd
adppf: bis(diphenylphosphino)ferrocene, dppb: 1,4-bis(diphenylphosphino)butane, ddpe: 1,4-bis(diphenylphosphino)ethane; bisolated yields after
completion of 1a monitored by TLC; c5 mol %; dno reaction.
entry 13). Finally, separated control experiments carried out by cloalkanones 4a and 4c in good yields (Scheme 3). Further-
omitting the Pd source or the ligand resulted in the exclusive more, the protocol could be scaled up to 1 mmol without signif-
recovery of the starting materials, which confirmed the need of icant yield erosion. Treatment of cyclopentenone 4-benzoate
the catalytic system for the catalytic process (Table 1, entries (2b) under conditions A did not allow the formation of the cor-
1
4–16).
responding C–C/O–C annulated product. Instead, elimination of
the benzoate anion, very likely from the transiently formed
The above work allowed obtaining the optimal reaction condi- η3-allylpalladium complex, gave cyclopentadienone, which
tions for the generation of the furocycloalkanone 4a [Pd(OAc)2 underwent the known self-Diels–Alder cycloaddition to form
(
10 mol %), dppb (15 mol %) in DMSO, 1 h at rt (conditions dimer 6 [45].
A)] as well as for the formation of the bicyclo[4.3.0]nonane-
,8-dione (5a) [Pd(OAc)2 (10 mol %), dppb (15 mol %) in We next turned our attention to the [3 + 2] C–C/C–C annula-
DMSO at 130 °C, 6 h (conditions B), or 1 h under microwave tion by using the conditions B and C in DMSO at 130 °C
3
irradiation (conditions C)].
(Scheme 4). The 2-cyclohexenone 4-benzoate (2a) afforded the
expected bicyclo[4.3.0]nonane-3,8-dione (5a) in 69% yield
(64% from 1.0 mmol of 1a) under either thermal conditions or
Scope
The scope of the C–C/O–C [3 + 2] annulation between dimethyl microwave irradiation. Surprisingly, application of these proto-
-oxoglutarate (1a) and six- (2a), five- (2b) and seven-mem- cols to the seven-membered bis-electrophile 2c led to the corre-
3
bered (2c) cyclic α,β-unsaturated-γ-oxycarbonyls was next sponding bicyclo[5.3.0]decane-3,9-dione (5c) with a low yield
studied (Scheme 3). Under the optimized conditions A, at room of 24% under thermal conditions B, while microwave irradia-
temperature in DMSO, the six- (2a) as well as the seven-mem- tion was ineffective. Moderate yields of bicyclo[3.3.0]octane-
bered (2c) bis-electrophiles reacted smoothly giving the furocy- 3,7-dione (5b) [46] were obtained from five-membered bis-
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Scheme 3: C–C/O–C bond forming annulations with dimethyl 3-oxoglutarate (1a).
Scheme 4: C–C/C–C bond-forming annulations with dimethyl 3-oxoglutarate (1a).
electrophile 2b under both conditions. This result suggests that The reaction between the 1,3-activated 1,3-propanones bis-
the undesired Pd-catalyzed elimination from a γ-acyloxycy- nucleophiles other than 1a was then considered in the reaction
clopentenone (to give cyclopentadienone which in turn with 2-cyclohexenone 4-benzoate (2a, Scheme 5). Thus, under
promptly dimerizes; see above), can be, at least in part, allevi- conditions A, diacetylacetone 1b afforded the expected product
ated by performing the reaction at high temperature.
in 43% yield as a 1:9 keto/enol (7:7’) mixture. Passing from
DMSO to THF (conditions A’) led to a slight increase of the
However, in the specific case of this latter [bis-nucleophile/bis- yield (53%) and eased the work-up. Similarly, under conditions
electrophile] couple, the desired bicyclo[3.3.0]octane-3,7-dione A', moderate to good yields of the annulated products were also
structure can be better obtained under basic conditions (and in obtained with dibenzoylacetone 1c (products 8:8’) and 1,3-bis-
the absence of Pd catalysis), as reported by Winterfeldt and (benzenesulfonyl)propan-2-one (1d, product 9), respectively.
Osterthun in the seventies [47].
On the other hand, despite several trials using various condi-
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Scheme 5: C–C/C–O bond-forming annulations with various bis-nucleophiles.
tions (temperature, time, and solvent) attempted conversion of microwave irradiation), this decarboxylative rearrangement
the two triketones 1b,c or the ketodisulfone 1d into the corre- appears to require a rather high activation barrier. This activa-
sponding 1,3-disubstitued bis-cycloalkanones 3 met always tion barrier might be even greater in the case of the triketones
with failure.
1b,c and 1,3-bis(benzenesulfonyl)propan-2-one (1d), which
would explain the impossibility to access the corresponding 1,3-
disubstitued bis-cycloalkanone derivatives.
Mechanistic studies
Considering that the change of reaction outcome of the
dimethyl 3-oxoglutarate (1a) only depends on the variation of With these considerations in mind, a plausible mechanism for
temperature in DMSO, we surmised that in the above annula- this annulation is proposed for the reaction between dimethyl
tion the C–C/O–C adducts 4 are the kinetic products, while the 3-oxoglutarate (1a) and 2-cyclohexenone 4-benzoate (2a). The
C–C/C–C adducts 5 are the thermodynamic ones. Indeed, reaction starts with an oxidative addition of the bis-electrophile
heating compound 4a in DMSO at 130 °C gave compound 5a 2a onto the Pd(0) complex to generate η3-allyl complex B from
(
Scheme 6). This result strongly supports the hypothesis that 4a the transient η2-alkene complex A (steps a and b). Deproton-
is the kinetic C–C/O–C annulated product, which, upon heating, ation of the pro-nucleophile 1a by the counter-anion of the
rearranges to the thermodynamic C–C/C–C [3 + 2] annulated η3-allyl-Pd complex exchanges the benzoate for the enolate
compound before undergoing two decarboxylation to give 5a. anion (step c) [50], and following C–C bond formation from the
This type of thermal 1,3-oxygen-to-carbon rearrangement was resulting anion-scrambled complex C leads to the Pd(0) com-
already described by Trost in the early 80’s [48,49]. In view of plex D (step d). Pd(0) decoordination closes the catalytic cycle
the high temperature needed (130 °C for several hours or under delivering intermediate E(keto) (step e) (Scheme 7).
Scheme 6: Decarboxylative rearrangement of 4a into 5a.
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The following spontaneous intramolecular O-conjugate addi- final bicyclo[4.3.0]nonane-3,8-dione (5a, steps k, l, Scheme 8,
tion of one of the two possible enol tautomers of E(keto) affords bottom line).
the kinetic C–C/O–C adduct 4a through steps (f, g), or (h, i, j)
(
Scheme 8, top and middle lines) [51]. At room temperature and Conclusion
standard reaction times, the reaction stops at this level. Howev- In conclusion, we have successfully developed two totally
er, at 130 °C the reversibility of the sequence leading to 4a selective and chemodivergent methods for the palladium-cata-
becomes important and the system has enough energy to rapidly lyzed [3 + 2] annulation between dialkyl 3-oxoglutarates and
undergo the irreversible intramolecular C-conjugate addition of cyclic α,β-unsaturated-γ-oxycarbonyl derivatives differing
enol E(enol 2) followed by double decarboxylation to give the simply on the variation of the reaction temperature. These new
Scheme 7: Proposed mechanism for the Pd-catalyzed part of the [3 + 2] annulation reaction.
Scheme 8: Proposed mechanism for the temperature dependent cyclization part of the [3 + 2] annulation.
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domino transformations allow a switchable (C–C/O–C to C–C/ Acknowledgements
C–C) [3 + 2] annulation through an [intermolecular Pd-cata- The authors would like to acknowledge Horizon 2020 ERANet-
lyzed C-allylation/intramolecular (oxygen or carbon) 1,4-conju- LAC project CelluloseSynThech as well as CNRS, Sorbonne
gate addition] sequence. In particular, the conjugate addition Université and Labex Michem (Investissements d'Avenir
becomes reversible if the temperature is increased, allowing to program under reference ANR-11-IDEX-0004-02). Support
pass from the O-alkylation to C-alkylation product. Overall, the through CMST COST Action, CA15106 (CHAOS) is also
success of these [3 + 2] annulations is due to the total chemose- gratefully acknowledged. Y. L. thanks the China Scholarship
lectivity of the initial step (C-allylation) as well as to the well- Council for financial support.
defined chronology of the following steps. Further work is cur-
rently ongoing to develop enantioselective versions of these ORCID® iDs
new transformations.
Julie Oble - https://orcid.org/0000-0002-4002-255X
Giovanni Poli - https://orcid.org/0000-0002-7356-1568
Experimental
Conditions A – [3 + 2] C–C/O–C bond-forming annulations. References
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