Open Access Article
This Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence

Merging C–C σ-bond activation of cyclobutanones with CO2 fixation via Ni-catalysis

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

Received 10th January 2022 , Accepted 25th February 2022

First published on 25th February 2022


Abstract

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.


Nowadays, the employment of strained rings in site selective C–C σ-bond activation procedures is receiving growing credit for generating chemical diversity, via catalytic tandem functionalization processes.1

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


image file: d2cc00149g-s1.tif
Scheme 1 (a) C–C bond activation-cross coupling of 3-(2-aryl)cyclobutanones: nucleophilic and electrophilic approaches. (b) The present working plan. (c) An example of a bioactive 3-indanone-1-acetic acid derivative.

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).

Table 1 Optimization of the reaction conditions

image file: d2cc00149g-u1.tif

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[thin space (1/6-em)]:[thin space (1/6-em)]1 Ni[thin space (1/6-em)]:[thin space (1/6-em)]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).


image file: d2cc00149g-s2.tif
Scheme 2 Generality of the Ni-catalyzed tandem C–C bond activation-CO2 fixation process.

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).


image file: d2cc00149g-s3.tif
Scheme 3 Transformations of compound 2b. Conditions: (a) H2SO4 (1 drop), MeOH, reflux, 18 h. (b) NaBH4 (3 equiv.), MeOH, r.t., 1 h. (c) p-TSA (1 equiv.), PhMe, reflux, 18 h. (d) H-Ile-OMe (1 equiv.), EDC·HCl (1 equiv.), TEA (3 equiv.), HOBt (1.2 equiv.), DCM/DMF 3[thin space (1/6-em)]:[thin space (1/6-em)]1, 25 °C, 18 h. (e) Ph3PCH3I (2 equiv.), KOtBu (2.5 equiv.), THF, 0 °C to reflux, 18 h. p-TSA = p-toluene sulfonic acid; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; TEA = triethylamine; HOBt = hydroxybenzotriazole.

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[thin space (1/6-em)]:[thin space (1/6-em)]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 C[double bond, length as m-dash]O 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


image file: d2cc00149g-s4.tif
Scheme 4 Mechanistic proposal.

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 C[double bond, length as m-dash]O 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.

Conflicts of interest

There are no conflicts to declare.

Notes and references

  1. (a) M. Suginome, T. Matsuda and Y. Ito, J. Am. Chem. Soc., 2000, 122, 11015–11016 CrossRef CAS; (b) T. Matsuda and H. Kirikae, Organometallics, 2011, 30, 3923–3925 CrossRef CAS; (c) T. Xu, A. Dermenci and G. Dong, Top. Curr. Chem., 2014, 346, 233–257 CrossRef CAS PubMed; (d) L. Souillart and N. Cramer, Chem. Rev., 2015, 115, 9410 CrossRef CAS PubMed; (e) N. Murakami and N. Ishida, J. Am. Chem. Soc., 2016,(138), 13759–13769 CrossRef PubMed; (f) M. H. Shaw and J. F. Bower, Chem. Commun., 2016, 52, 10817–10829 RSC; (g) G. Fumagalli, S. Stanton and J. F. Bower, Chem. Rev., 2017, 117, 9404–9432 CrossRef CAS PubMed.
  2. (a) U.-H. Dolling, P. Davis and E. J. J. Grabowski, J. Am. Chem. Soc., 1984, 106, 446–447 CrossRef CAS; (b) T. Ito, T. Tanaka, M. Iinuma, K. Nakaya, Y. Takahashi, R. Sawa, J. Murata and D. Darnaedi, J. Nat. Prod., 2004, 67, 932–937 CrossRef CAS PubMed; (c) R. E. McDevitt, M. S. Malamas, E. S. Manas, R. J. Unwalla, Z. Xu, C. P. Miller and H. A. Harris, Bioorg. Med. Chem. Lett., 2005, 15, 3137–3142 CrossRef CAS PubMed; (d) A. Morrell, M. Placzek, S. Parmley, B. Grella, S. Antony, Y. Pommier and M. Cushman, J. Med. Chem., 2007, 50, 4388–4404 CrossRef CAS PubMed; (e) B. Alcaide, P. Almendros and C. Lázaro-Milla, Chem. – Eur. J., 2019, 25, 7547–7552 CrossRef CAS PubMed; (f) Y. Chen, Z. Ding, Y. Wang, W. Liu and W. Kong, Angew. Chem., Int. Ed., 2021, 60, 5273–5278 CrossRef CAS PubMed; (g) F.-S. He, P. Bao, F. Yu, L.-H. Zeng, W.-P. Deng and J. Wu, Org. Lett., 2021, 23, 7472–7476 CrossRef CAS PubMed.
  3. (a) M. K. Ko and G. Dong, Nat. Chem., 2014, 6, 739–744 CrossRef PubMed; (b) X. Zhou and G. Dong, J. Am. Chem. Soc., 2015, 137, 13715–13721 CrossRef CAS PubMed; (c) X. Zhou and G. Dong, Angew. Chem., Int. Ed., 2016, 55, 15091–15095 CrossRef CAS PubMed.
  4. (a) L. Souillart, E. Parker and N. Cramer, Angew. Chem., Int. Ed., 2014, 53, 3001–3005 CrossRef CAS PubMed; (b) L. Souillart and N. Cramer, Angew. Chem., Int. Ed., 2014, 53, 9640–9644 CrossRef CAS PubMed; (c) E. Parker and N. Cramer, Organometallics, 2014, 33, 780–787 CrossRef CAS.
  5. (a) M. Murakami, H. Amii and Y. Ito, Nature, 1994, 370, 540–541 CrossRef CAS; (b) T. Matsuda, M. Shigeno, M. Makino and M. Murakami, Org. Lett., 2006, 8, 3379–3381 CrossRef CAS PubMed; (c) T. Matsuda, M. Shigeno and M. Murakami, J. Am. Chem. Soc., 2007, 129, 12086–12087 CrossRef CAS PubMed; (d) L. Liu, N. Ishida and M. Murakami, Angew. Chem., Int. Ed., 2012, 51, 2485–2488 CrossRef CAS PubMed.
  6. For a representative collection of examples see: (a) Y.-L. Sun, X.-B. Wang, F.-N. Sun, Q.-Q. Chen, J. Kao, Z. Xu and L.-W. Xu, Angew. Chem., Int. Ed., 2019, 58, 6747–6751 CrossRef CAS PubMed; (b) J. Kao, L. Chen, F.-N. Sun, Y.-L. Sun, K.-Z. Jiang, K.-F. Yang, Z. Xu and L.-W. Xu, Angew. Chem., Int. Ed., 2019, 58, 897–901 CrossRef PubMed; (c) F.-N. Sun, W.-C. Yang, X.-B. Chen, Y.-L. Sun, J. Kao, Z. Xu and L.-W. Xu, Chem. Sci., 2019, 10, 7579–7583 RSC; (d) W.-C. Yang, X.-B. Chen, K.-L. Song, B. Wu, W.-E. Gan, Z.-J. Zheng, J. Kao and L.-W. Xu, Org. Lett., 2021, 23, 1309–1314 CrossRef CAS PubMed.
  7. D. Ding, H. Dong and C. Wang, iScience, 2020, 23, 101017 CrossRef CAS PubMed.
  8. (a) M. Aresta, Carbon Dioxide as Chemical Feedstock, Wiley VCH, Weinheim, 2010 CrossRef; (b) T. Sakakura, J.-C. Choi and Y. Yasuda, Chem. Rev., 2007, 107, 2365–2387 CrossRef CAS PubMed; (c) J. R. Cabrero-Antonino, R. Adam and M. Beller, Angew. Chem., Int. Ed., 2019, 58, 12820–12838 CrossRef CAS PubMed; (d) S. Dabral and T. Schaub, Adv. Synth. Catal., 2019, 361, 223–246 CrossRef CAS.
  9. (a) Q. Liu, L. Wu, R. Jackstell and M. Beller, Nat. Commun., 2015, 6, 5933 CrossRef PubMed; (b) M. Aresta, A. Dibenedetto and A. Angelini, Chem. Rev., 2014, 114, 1709–1742 CrossRef CAS PubMed.
  10. (a) M. Börjesson, T. Moragas, D. Gallego and R. Martin, ACS Catal., 2016, 6, 6739–6749 CrossRef PubMed; (b) J. Luo and I. Larrosa, ChemSusChem, 2017, 10, 3317–3332 CrossRef CAS PubMed; (c) M. Gaydou, T. Moragas, F. Julià-Hernàndez and R. Martin, J. Am. Chem. Soc., 2017, 139, 12161–12164 CrossRef CAS PubMed; (d) Y.-G. Chen, X.-T. Xu, K. Zhang, Y.-Q. Li, L.-P. Zhang, P. Fang and T. S. Mei, Synthesis, 2018, 35–48 Search PubMed; (e) Z. Zhang, J.-H. Ye, T. Ju, L.-L. Liao, H. Huang, Y.-Y. Gui, W.-J. Zhou and D.-G. Yu, ACS Catal., 2020, 10, 10871–10885 CrossRef CAS; (f) X. Gou, Y. Wang, J. Chen, G. Li and J.-B. Xia, Chin. J. Org. Chem., 2020, 40, 2208–2220 CrossRef; (g) J.-H. Ye, T. Ju, H. Huang, L.-L. Liao and D.-G. Yu, Acc. Chem. Res., 2021, 54, 2518–2531 CrossRef CAS PubMed; (h) Y. Yi, W. Hang and C. Xi, Chin. J. Org. Chem., 2021, 41, 80–93 CrossRef.
  11. For our recent review see: G. Bertuzzi, A. Cerveri, L. Lombardi and M. Bandini, Chin. J. Chem., 2021, 39, 3116–3126 CrossRef CAS.
  12. (a) A. Cerveri, S. Pace, M. Monari, M. Lombardo and M. Bandini, Chem. – Eur. J., 2019, 25, 15272–15276 CrossRef CAS PubMed; (b) A. Cerveri, R. Giovanelli, D. Sella, R. Pedrazzani, M. Monari, O. N. Faza, C. S. Lòpez and M. Bandini, Chem. – Eur. J., 2021, 27, 7657–7662 CrossRef CAS PubMed.
  13. P. Jimonet, Y. Ribeill, G. A. Bohme, A. Boireau, M. Chevé, D. Damour, A. Doble, A. Genevois-Borella, F. Herman, A. Imperato, S. Le Guern, F. Manfré, J. Prat, J. C. R. Randle, J.-M. Stutzmann and S. Mignani, J. Med. Chem., 2000, 43, 2371–2381 CrossRef CAS PubMed.
  14. During the preparation of the manuscript, similar bicyclic scaffolds were obtained under Pd-catalyzed manipulation of iodo-arenes in the presence of CO and CO surrogates: (a) C. Chen, H. Zhao, Y. Pu, L. Tang, J. Wang and Y. Shang, Chem. Commun., 2021, 57, 12944–12947 RSC; (b) K.-L. Song, B. Wu, W.-E. Gan, W.-C. Yang, X.-B. Chen, J. Kao and L.-W. Xu, Org. Chem. Front., 2021, 8, 3398–3403 RSC.
  15. X. Gao, B. Wu, W.-X. Huang, M.-W. Chen and Y.-G. Zhou, Angew. Chem., Int. Ed., 2015, 54, 11956–11960 CrossRef CAS PubMed.
  16. The enantiomeric excess of 2a prepared in the presence of enantiopure ligands L3, L4, L6 and L7 was in all cases lower than 20% (18% ee with ligand L7). Rac-2,5-hexanediol is commercialized only as a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture with the meso-isomer. Preparation of the corresponding 2,2′-bipyridine ligand led to an inseparable mixture of rac-L7 and meso-L7, that proved ineffective in the present transformation. Therefore, enantiopure (R,R)-L7 was selected as the optimal ligand.
  17. At present, a catalytic process involving a Ni(I) species undergoing oxidative addition with 1a cannot be ruled out.
  18. K. J. Garcia, M. M. Gilbert and D. J. Weix, J. Am. Chem. Soc., 2019, 141, 1823–1827 CrossRef CAS PubMed and references therein. The possible involvement of the in situ generated Zn(II) salts in co-activating the cyclobutanone ring towards Ni–Ar condensation cannot be ruled out at present.
  19. At present, a conclusive rationale for the specific role of AlCl3 in promoting the carboxylation reaction is not available. Among many possible roles, both facilitation of the final de-nickelation steps from the carboxylate intermediate and the possible electrophilic co-activation of CO2 cannot be excluded: (a) M. Gu and Z. Cheng, Ind. Eng. Chem. Res., 2014, 53, 9992–9998 CrossRef CAS; (b) M. Gu and Z. Cheng, J. Mater. Sci. Eng., 2015, 3, 103–108 CAS.
  20. For an example of different impacts of Cl and OTf in carboxylation reactions see: D. J. Charboneau, G. W. Brudvig, N. Hazari, H. M. C. Lant and A. K. Saydjari, ACS Catal., 2019, 9, 3228–3241 CrossRef CAS PubMed.
  21. (a) F. S. Menges, S. M. Craig, N. Tötsch, A. Blumfield, S. Ghosh, H.-J. Krüger and M. A. Johnson, Angew. Chem., Int. Ed., 2016, 55, 1282–1285 CrossRef CAS PubMed; (b) T. Fujihara, K. Nogi, T. Xu, J. Terao and Y. Tsuji, J. Am. Chem. Soc., 2012, 134, 9106–9109 CrossRef CAS PubMed.
  22. R. J. Somerville, C. Odena, M. F. Obst, N. Hazari, K. H. Hopmann and R. Martin, J. Am. Chem. Soc., 2020, 142, 10936–10941 CrossRef CAS PubMed.

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
Click here to see how this site uses Cookies. View our privacy policy here.