Lorenzo
Lombardi
ab,
Alessandro
Cerveri
a,
Leonardo
Ceccon
a,
Riccardo
Pedrazzani
ab,
Magda
Monari
ab,
Giulio
Bertuzzi
*ab and
Marco
Bandini
*ab
aDipartimento di Chimica “Giacomo Ciamician”, Alma Mater Studiorum, Università di Bologna, via Selmi 2, Bologna 40126, Italy. E-mail: giulio.bertuzzi2@unibo.it; marco.bandini@unibo.it
bCenter for Chemical Catalysis – C3, Alma Mater Studiorum – Università di Bologna, via Selmi 2, Bologna, 40126, Italy
First published on 25th February 2022
A carboxylative Ni-catalyzed tandem C–C σ-bond activation of cyclobutanones followed by CO2-electrophilic trapping is documented as a direct route to synthetically valuable 3-indanone-1-acetic acids. The protocol shows an adequate functional group tolerance and useful chemical outcomes (yield up to 76%) when AlCl3 is adopted as an additive. Manipulations of the targeted cyclic scaffolds and a mechanistic proposal based on experimental evidence complete the investigation.
In this context, transition-metal catalyzed σ-bond activation of cyclobutanones represents an important landmark in the field, resulting in a direct synthetic route towards densely functionalized scaffolds.2 In this segment, following the pioneering reports by Dong,3 Cramer4 and Murakami,5 several Pd-catalyzed sequential ring-opening/nucleophilic cross-couplings have been documented (Scheme 1a).6 On the contrary, the employment of more convenient, largely available and bench-stable electrophilic trapping agents is still basically unexplored in the field. In fact, to the best of our knowledge, the recent Ni-catalyzed cyclobutanone C–C activation, studied by Wang, represents the only ring-opening/cross electrophile coupling (i.e. alkyl bromides and iodo-arenes as starting materials) reported so far.7
With the aim to address this important lack in the literature, we directed our attention to carbon dioxide as an emerging electrophilic C1-synthon in organic chemistry. Large abundance, non-toxicity and low cost justify the exponential efforts towards the realization of direct catalytic tools for CO2 fixation into organic scaffolds.8 In particular, the valorization of carbon dioxide via metal-, metal-free, photo- and electrocatalyzed cascade carboxylative processes has rapidly emerged as a valuable route towards molecular complexity.9–11
In this context, and in conjunction with our recent research interests towards the catalytic conversion of CO2 into added value carbonylic as well as carboxylic compounds,12 we envisioned the unprecedented employment of carbon dioxide as a late-stage electrophilic quencher of the incipient organometallic intermediate I, that might be directly accessible via metal-assisted C–C σ-bond activation of cyclobutanones (Scheme 1b). Remarkably, this process would result in a new reductive cross-electrophile coupling to rapidly access synthetically flexible 3-indanone-1-acetic acid scaffolds 213 by avoiding the use of hazardous carbon monoxide or its surrogates.14
In this report we disclose our initial findings in the field by electing 3-(2-haloaryl)cyclobutanones 1 as model substrates and nickel as a first-row transition-metal catalyst.
Aiming at optimizing the reaction conditions, we initially reacted the model substrate 1a with [Ni(dme)Cl2] (10 mol%) and 2,2′-bipyridine (20 mol%) as the ligand, in DMF under a CO2 atmosphere at room temperature. Under these conditions, no product was formed and a small amount of dehalogenated starting material (7a, vide infra) was observed, along with substantial recovery of untouched 1a (entry 1, Table 1). We reasoned that the addition of a Lewis/Brønsted acid could favor the overall process via activation of the carbonyl unit (entries 2–5). Interestingly, although no conversion was recorded with mono-valent lithium chloride (entry 2, complete recovery of 1a), when magnesium chloride was employed (1.5 equiv.) the desired product 2a was observed, albeit in low yield (15%, entry 3). A significant improvement in the isolated yield of 2a (30%) was observed by adopting a stronger Lewis acid, namely AlCl3 (entry 4), which proved to be the best additive (see SI for further screening). We then excluded that any adventitious traces of HCl deriving from AlCl3 could trigger a Brønsted-acid catalysis (entry 5).
Entry | L | Conditionsa | Additive | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions A and B: 1a (0.1 mmol, 0.1 M), additive (0.15 mmol), Zn (0.3 mmol), CO2 (1 atm). b Isolated yield after flash chromatography. c 4 mol% of HCl was used (4 M in 1,4-dioxane). d LiCl = 0.45 mmol. e 40 °C. f 60 °C. NR = no reaction. | ||||
1 | L1 | A | None | NR |
2 | L1 | A | LiCl | NR |
3 | L1 | A | MgCl2 | 15 |
4 | L1 | A | AlCl3 | 30 |
5 | L1 | A | HClc | NR |
6 | L1 | A | Al(OTf)3 | NR |
7 | L1 | A | Al(OTf)3 + LiCld | NR |
8 | L2 | A | AlCl3 | 43 |
9 | L3 | B | AlCl3 | 59 |
10 | L4 | B | AlCl3 | Traces |
11 | L5 | B | AlCl3 | 12 |
12 | L6 | B | AlCl3 | 18 |
13 | L7 | B | AlCl3 | 64 |
14e | L7 | B | AlCl3 | 70 |
15f | L7 | B | AlCl3 | 45 |
It is worth noting that the presence of AlCl3 is mandatory for the desired process to proceed, as related Al(OTf)3 was found to be ineffective, even in the presence of an external chloride source (entries 6, 7, complete recovery of 1a). Then, we turned our attention to the role of the ligand L. Encumbered and electron-rich ligand L2 (entry 8) provided 2a in higher yield than L1 (43% yield). Prompted by these achievements, we focused our attention on C2-symmetric ligands L3-715 sharing similar tethering backbones (entries 9–13). Our investigation pointed to bipyridine (R,R)-L7 as the optimal one, delivering 2a in 64% yield (entry 13).16 This ligand displays a 6,6′-Me2 substitution pattern and a cyclic tethering 3,3′-ether backbone, readily accessible from (S,S)-2,5-hexanediol (see ESI† for details). Aiming at obtaining high reproducibility in the chemical outcomes we isolated the precatalyst [Ni(L7)Cl2] in 90% yield by reacting enantiopure (R,R)-L7 and Ni(dme)Cl2 in DMF. The resulting brown solid was fully characterized. Single-crystal X-ray diffraction showed a 1:
1 Ni
:
L7 ratio with the Ni atom displaying a distorted tetrahedral geometry being coordinated by two chloride ligands and two pyridinic nitrogen atoms with a (N–Ni–N) bite angle of 83.0(1)°. The dihedral angle between the two pyridine rings is significant (27.6(2)°) as a consequence of the formation of the ten-membered ring in L7. While ligand L3, formally deriving from (S,S)-2,4-pentanediol, performed similarly to L7 (59% yield, entry 9), (S,S)-2,3-butanediol-derived L4 failed to promote the desired reaction (entry 10), highlighting the importance of the size of the cyclic ether scaffold (Scheme 2).
Similarly, ligands L5, lacking methyl groups on the tethering moiety (entry 11) and L6, lacking 6,6′-methyl groups (entry 12) delivered the desired product in low yields.
Finally, a slight improvement in the catalytic performance was observed by running the reaction at 40 °C (70% yield, entry 14) while a higher temperature proved detrimental (45% yield at 60 °C, entry 15).
With the optimal reaction conditions in hand (Table 1, entry 14, conditions B), we assessed the generality of the process by subjecting a range of 3-(2-bromoaryl)cyclobutanones 1b–n to the carboxylative ring-opening process. Hydrocarbyl (1b–d) as well as electron-donating (1e–h) substituents could be effectively accommodated at positions 4-, 5- and 6- of the aromatic ring, providing the corresponding 3-indanone-1-acetic acids 2b–h up to high yields (43–76%).
On the other hand, electron-withdrawing groups (i.e. F and CF3) on the 2-bromoaryl moiety of cyclobutanones 1i–k, led to a slight decrease in efficiency (25–45% yield), probably due to a reduced nucleophilicity of the corresponding Ar–Ni(II) intermediates (vide infra). Additionally, the possibility to decorate the quaternary stereogenic center at the C1-position (2) with different alkyl groups was also successfully demonstrated. In this regard, 3-indanone-1-acetic acids 2l and 2m, carrying a n-butyl and a phenethyl substituent respectively, were formed in high yield. On the contrary, thienyl-substituted substrate 1n was unproductive in the reactive sequence, probably due to a poisoning coordination operated by the sulfur-based heterocycle on the catalytically active metal species.
To prove the synthetic utility and chemical versatility of the newly synthesized 3-indanone-1-acetic acids 2, product 2b was subjected to a range of relevant transformations (Scheme 3). After esterification of the carboxylic moiety (a), reduction of the keto-group with NaBH4 afforded alcohol 3b in quantitative yield as an equimolar mixture of diastereoisomers (b).
A successive dehydration (p-TSA, c) was also documented, yielding the corresponding indene 4b in 65% yield. On the other hand, Wittig olefination rendered methylene–indanes 6b–6b′ carrying an exocyclic C–C double bond, chemoselectively. Importantly, as a proof-of-concept for bioconjugation of 2, we showed that the carboxylic acid moiety of 2b underwent peptide-bond formation with isoleucine methyl ester (H-Ile-OMe) to afford amide 5b in 52% yield and 1.5:
1 dr.
Mechanistically, the catalytic cycle depicted in Scheme 4 is proposed based on experimental evidence as well as previous reports on metal-catalyzed C–C bond activation-cross coupling reactions of cyclobutanones.6,7 An aryl–Ni(II) species A could be conveniently formed via initial oxidative insertion of a Ni(0)-complex on 1a.17 This organometallic intermediate can undergo CO nucleophilic addition on the LA-activated carbonyl unit to give the alkoxy-Ni intermediate B.18 Alternatively, Zn-mediated reduction towards A-Ni(I) can occur, with subsequent delivery of the adduct Cvia C–C(O) oxidative insertion. Given the fundamental role played by AlCl3 in the present reaction, and the absence of benzoic acid 8a, we could tentatively propose intermediate B as the more likely formed.19,20
Subsequently, β-carbon elimination, followed by Zn-mediated reduction, would result to the alkyl-Ni(I) species D. Trapping of CO221 and regeneration of the catalytically active Ni(0)-catalyst would close the reaction machinery. Importantly, while the formation of substantial amounts of dehalogenation by-product 7a were often observed in the crude reaction mixtures, conceivable by-products 9a/10a (often encountered in tandem carboxylation processes) were never formed in detectable amounts in the present methodology. This suggests that the CO insertion step might be kinetically demanding and the carboxylation of alkylnickel(I) intermediate D is faster than protodenickelation (9a) and dimerization processes (10a).22 This conclusion is also in line with the superior catalytic performance displayed by electron-rich bypyridines.
In conclusion, we have documented an unprecedented carboxylative nickel-catalyzed C–C σ-bond activation of cyclobutanones combined with final electrophilic trapping of CO2 at low pressure. The protocol enabled a range of synthetically useful functionalized 3-indanone-1-acetic acids to be prepared in moderate to high yield (up to 76%). Proof of the synthetic flexibility of the resulting indanones and mechanistic insights completed the present investigation. Studies towards the realization of an enantioselective variant of the present protocol are currently underway in our laboratories and will be presented in due course.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 2129543. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d2cc00149g |
This journal is © The Royal Society of Chemistry 2022 |