University of Groningen
Carbon-carbon bond formations using organolithium reagents Heijnen, Dorus
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Chapter 9 : The Cross- Coupling of
Organo-lithium Reagents at Cryogenic
Temperatures
ABSTRACT: The coupling of organolithium reagents at cryogenic temperatures (as low as -78 C) has been achieved with a highly reactive Pd-NHC catalyst and is described in this chapter. A temperature dependent chemoselectivity has been developed for the selective coupling of bromides in the presence of chlorides. Building on this, a one-pot, sequential cross-coupling strategy has been developed for the rapid construction of advanced building blocks for synthesis (e.g., medicinal chemistry) and process-scale applications.
9.1 Introduction
Recent advancements in the cross-coupling of hard organometallic nucleophiles have been accelerated by the development of reactive catalysts with very high turnover frequencies. Published work on the coupling of Grignard and organolithium reagents offers new insights in the active palladium catalyst.1-6 High-reactivity catalysts allow for an increase in functional group tolerance by, for example, outcompeting 1,2-additions, ring-opening reactions or the deprotonation of acidic moieties. The use of hard (Li, Mg) organometallic reagents offer advantages in their ready commercial availability and ease of synthesis, but also in the reduction of (stoichiometric) waste generated when compared to organoboranes, for example, which often are derived from the corresponding Grignard or organolithium reagents.7-12 The methodology was steadily expanded to provide suitable reaction conditions for the synthesis of alkyl, heteroaryl, sterically demanding and radiolabelled products2, 6-11 (see also previous chapters).
The cross-coupling of Grignard or organolithium reagents proceeds in seconds to minutes at room temperature with a variety of (alkyl)phosphine-palladium catalysts, but only a few are competent at or below 0 C.2-4 Aryl-phosphine-palladium complexes have been shown to couple Knochel-type aryl Grignard reagents at temperatures below 0°C (Scheme 9.1a), but require several hours to reach complete conversion.13a Additionally, the reactions were allowed to warm to rt before the quenching agent was added.
Scheme 11 Previous examples of cross coupling at low temperatures.
For electrophiles with a strong electron-withdrawing group, iron catalyzed reactions with Grignard reagents have also been reported (Scheme 9.1b), but the scope was limited to just two examples.13b We have recently studied and subsequently optimized similar palladium-phosphine catalytic systems for the coupling of organolithium reagents and found that despite high turnover frequencies, coupling below -10 C was not feasible.2
The Pd-NHC (N-Heterocyclic-Carbene) catalyst family has also shown great stability and reactivity in the cross coupling of aryl- and alkyllithium nucleophiles (Scheme 9.2i) and has simultaneously proven to be a particularly active catalyst system for the cross-coupling of a variety of functionalized and challenging nucleophiles (R-ZnBr, R-B(OR)2, R-SnR3) in batch or flow (Scheme 9.2ii).14-21 Compared to simple NHC complexes, the design of the Pd-PEPPSI catalyst with increased bulk on the flanking aryl groups facilitates faster reductive elimination and has higher turnover numbers,20 while suppressing competing side reactions in the coupling of secondary alkyl substrates (branched vs linear ratio).16
Scheme 9.2 Overview of cross coupling reactions using Pd-PEPPSI catalysts
These same catalysts also facilitate the coupling of profoundly hindered starting materials to make structurally complex products (e.g., tetra ortho-substituted biaryls).22 The fact that these challenging coupling procedures can be conducted routinely at room temperature16,18,21,22 paves the way for applications in the synthesis of natural products, biologically active compounds and complex ligands for metal catalysis.
9.2 Catalyst design and SAR
The findings described in this chapter (Scheme 9.2iii, Table 9.1) that naphthalene electrophiles could be coupled to alkyl lithium reagents at temperatures far below conventional cross-coupling temperatures (i.e., < -20C) offers unique opportunities for organic synthesis. To explore the potential of this observation, we embarked on a structure-activity relationship (SAR) study on the NHC ligand to determine its impact on reactivity at low temperatures. The flexible aliphatic groups on the N-aryl substituent were systematically varied, while at the same time assessing the electronic and steric effect of substituents on the NHC backbone (see Table 1). Using sec-BuLi and 1-Br-naphthalene as a model reaction, we evaluated Pd-PEPPSI complexes at -62 C and -78 C temperatures at which a general successful cross-coupling method has yet to be reported.
Table 9.1. Structure-activity relationship (SAR) assessment of Pd-PEPPSI complexes with sec-BuLi.
Entry X Catalyst T (ºC)a Conversionb (%)b 1 Br C1 -78 0 2 Br C2 -78 0 3 Br C4 -78 10 4 Br C3 -78 22 5 Br C5 -78 37 6 Br C1 -62 0 7 Br C2 -62 88 8 Br C4 -62 80 9 Br C3 -62 91 10 Br C5 -62 99 11 I C5 -78 75c 12 Br C3 -62 98d 13 Br None -62 0 a
Reaction temperature was never allowed to rise and transformations were quenched at this temperature. bPercent conversion of 1-bromonaphthalene to 1-sec-butylnaphthalene as determined by 1H NMR of the crude
reaction mixture. cn-BuLi was used. d0.1 mol % catalyst was used.
Changing the size of the N-aryl, alkyl substituents (entries 1-3) had a noticeable impact on the coupling at -78 C, with a similar trend observed at -62 C (entry 6 - 8). Placing chlorides on the NHC core similarly improved reactivity at -78 C (entry 2 vs 4). Changing the substituents on the NHC core from chlorides to a fused acenaphtaquinone system yielded an active catalyst, both at -78 C (entry 5) and -62 C (entry 10). Changing the oxidative addition partner to the corresponding iodide (entry 11) saw conversion at -78 C jump to 75%, which is the first palladium catalyzed cross-coupling to proceed with high conversion below -65 C. As lower temperatures suppress catalyst deactivation, we were able to perform this reaction at a low catalyst loading (0.1 mol %, entry 12). The optimized conditions from entry 10 were used for further reactions.
9.3 Scope
The substrate scope was evaluated and substituted naphthalenes proved to be excellent substrates, as were (hetero)aromatic bromides (Scheme 9.3). When the nucleophile was changed from n/sec-butyllithium to other organolithium reagents, we observed a trend between the strength of the base
X Sec-BuLi (1.5 equiv.) (Addition over 1h) PEPPSI-Cat (0.05 equiv.) Temp, Toluene Pd Cl Cl N Cl N N R R R R R = iPr, Z = H; C1 (Pd-PEPPSI-IPr) R = 3-pentyl, Z = H; C2 (Pd-PEPPSI-IPent) R = 3-pentyl, Z = Cl; C3 (Pd-PEPPSI-IPentCl) R = 4-heptyl, Z = H; C4 (Pd-PEPPSI-IHept) Z Z R = 3-pentyl; C5 (Pd-PEPPSI-IPent-Acenapht) Pd Cl Cl N Cl N N R R R R
and the temperature cut-off (BuLi > TMS-CH2Li > PhLi).26 The strongest nucleophile provided cross coupled product at the lowest temperature, suggesting a possible role for the nucleophile in the ratedetermining step. In an important observation, near perfect bromide/chloride chemoselectivity at -22 °C (17 to 21) was obtained with dihalogenated (Br and Cl) oxidative addition partners. Even when the bromide was sterically hindered (18, 20) it was coupled preferentially over the chloride. Of special note, products arising from benzyne formation were not observed with ortho-chloro substrates (21).
Scheme 9.3 Substrate scope for organolithium cross-coupling using a Pd-PEPPSI complex.a a
Reaction conditions: (hetero)aryl bromide, toluene, 5 mol% catalyst, organolithium reagent (1.5 equiv), 1 h addition of organolithium reagent. The temperature of the reaction was never allowed to rise and the transformation was quenched at this temperature. Yields of isolated products after column chromatography.
bIn addition : 89% isolated yield at -42 C in just 10 min/reaction. cSee supporting information for details. d 4-Iodoanisole was used.
TMS TMS O O TMS S S Br R-Li, C5, R Toluene, Temp, 1h TMS Cl Cl Cl TMS Cl Cl TMS Chemoselective 1 (-62°C, 90%)b 4 (-62°C, 89%) 7 (-42°C, 93%) 10 (-22°C, 77%) 11 (-42°C, 90%) 8 (-62°C, 94%) 5 (-62°C, 87%) 3 (-42°C, 81%) 6 (-22°C, 79%) 9 (-42°C, 91%) 12 (-22°C, 61%) 16 (-42°C, 73%)d 13 (-62°C, 87%) 2 (-62°C, 92%) 17 (-22°C, 75%) 18 (-22°C, 80%) 19 (-22°C, 67%) 20 (-34°C, 78%) 21 (-22°C, 70%) O 14 (-22°C, 63%) O 15 (-22°C, 63%) >95% selectivityc
9.3.1 Sequential coupling
While chemoselectivity (i.e., I>Br~OTf>Cl) in cross-coupling reactions is known,1,4,23 it has been achieved primarily with catalysts that are simply unreactive with the less active electrophiles. In order to take advantage of this ‘selectivity’, a different reaction setup with new solvents/reagents/catalysts is necessary to achieve subsequent coupling with a second nucleophile. The catalytic turnover from C3 at a temperature of -62 C shows that it is one of the most reactive catalysts yet reported for this transformation. With this in mind we envisioned a one-pot methodology where a single catalyst would be capable of sequentially coupling multiple nucleophiles in a chemoselective fashion where a jump in temperature is used as the selectivity trigger. This methodology would allow divergent synthesis to be achieved in an efficient manner, providing a powerful tool for quick SAR studies. Methodology for the sequential coupling of two sp2 hybridized organometallic reagents with a dihalide electrophile is known, but a general cross-coupling procedure in which one of the coupling partners is a sp3 hybridized nucleophile is less prevalent.23 Small alkyl fragments, and in particular secondary (branched) alkyl moieties, are crucial for the development of potent bio-medically active compounds that bind with high selectivity to their protein targets.24 The importance of such motifs in the structure of electronic materials is also well demonstrated.25 Therefore, the development of an operationally simple, one-pot procedure to readily install such alkyl substituents on (hetero)aromatic core structures is highly desirable.
Organolithium reagents coupled smoothly at -22 °C with bromo-chloro aromatics to provide intermediates that were subsequently submitted to Suzuki-Miyaura (22), Negishi (23, 25), or Murahashi (24, 26, 27) cross-coupling procedures (Scheme 9.4).27 Not limited to carbon nucleophiles, amine arylation (28 - 35) and sulfination (36 - 38)28 reactions also proceeded well to give highly functionalized, advanced building blocks. The additional functionalization steps make catalyst C3 preferred over catalyst C5, as the C3 IPent-Cl PEPPSI complex has previously shown to be the catalyst of choice for aminations and sulfinations. Functional groups that were tolerated in the second cross coupling step include esters, amines, ethers, nitriles, protected alcohols, and a heterocycle. For all the reactions, additional catalyst or indermediate purification was unnecessary, and products were obtained in a one-pot procedure by simply adding the required reagents for the second coupling and warming as required.
Scheme 9.4 One-pot sequential approach to divergent synthesis of functionalized molecules.
Overall yield of isolated products following two-step process after column chromatography are reported in brackets. Conditions for second coupling: aArB(OH)2, (1.5 equiv.), NaOMe (3 equiv.), THF (3 mL), 75 C 18h.;
bArZnBr (1.5 equiv.), 23 C, 18 h; cArLi, dropwise addition, 1h. 40 C, dAr-NH
2 or Ar-NHMe (1.2 equiv), KOtBu (1.5 equiv), 23 C, 18 h; eAr-NH2 (1.2 equiv), Cs2CO3 (3 equiv), 80 C, 18 h;
f
Ar-SH (1.2 equiv), KOtBu (2 equiv), 80 C, 18 h; gAr-SH (1.2 equiv), KOtBu (2 equiv), 23 C, 18 h.
The new method for the chemoselective coupling with chloro-arylbromides distinguishes itself from other procedures, where sequential coupling is often achieved by means of two aryl (sp2) coupling partners. The quick, cheap and selective installation of alkyl fragments provides potential application in pharmaceuticals bearing these moieties such as displayed in figure 9.1.
Figure 9.1 Pharmaceuticals bearing small alkyl fragments
The direct alkyl coupling on to heterocycles remains a major challenge in sequential cross coupling procedures. Though palladium catalysed organolithium cross coupling in the presence of indoles, pyrroles (chapter 7), and even pyridines (chapter 3) has previously been shown, functionalization with small alkyl fragments has not yet been achieved at low temperatures with the above mentioned catalytic setup. For widespread application in the synthesis of pharmaceutical compounds, the lowering of the catalyst loading, and the incorporation of these heterocycles in the scope have yet to be achieved.
9.3.2 Attempts at improving the scope
Having a procedure that couples several alkyllithium reagents at temperatures below -60C, we were intrigued to see if we would be able to expand the existing scope of our organometallic coupling partner to include unstable alkyllithium reagents. Figure 9.2 shows a selection of alkyl and aryllithium reagents that are known to be stable at cryogenic temperatures, but degrade at or near room temperature. TMS-substituted alkyllithium 39 could successfully be synthesized via carbolithiation of the vinylsilane (as confirmed by MeI quench), but due to the necessity of THF as the solvent (see chapter 1) for its preparation, only yielded dehalogenation upon attempted cross coupling with 1-bromonaphthalene 44.29a Direct lithiation of Boc-protected piperidines (40) or pyrolidines at -65 C yields the alpha-lithio nitrogen compound, and has previously been transmetallated to provide stable cross coupling partners.26 The presence of THF or activating agents such as TMEDA or sparteine, however, are required and the formed organolithium reagent therefore behaves much like compound 39, giving dehalogenated product exclusively. Phthalide 4129b and benzamide 4226 were also prepared according to literature procedures, but following the trend shown above (a more stable organolithium reagent requires higher reaction temperatures) did not afford any product at -60 C, and degraded upon attempted coupling at higher temperatures (-25 C).
Figure 9.2 Attempted unstable organolithium reagents and electrophiles.
Finally, substituted epoxide 43 could have provided a valuable coupling partner if successfully converted to the desired product, but only starting material could be observed after the reaction. The degradation products arising from this organolithium reagent were too volatile to detect/isolate.29c In an attempt to avoid lithium halogen exchange, aryl triflate 45 was used to substitute 44, but it was inactive at low temperatures (also with n-butyllithium in a control experiment)
Having attempted cross-coupling conditions with several unstable organolithium reagents, we changed our focus to the scope of the electrophile, employing several functional groups that are susceptible to organolithium addition. In a competition experiment, we decided to add a stoichiometric amount of a single additional electrophile that has not been successfully cross coupled with organolithium reagents to date (Scheme 9.5).
Scheme 9.5 competition studies with electrophiles
Since arylbromide 44 gave perfect conversion at -68 C with n-butyllithium, we envisioned that at this low temperature, we would have the best chance of outcompeting unwanted side reactions. We ran a series of experiments in which one of the electrophiles (46-49) was added in a equimolar amount with respect to the arylbromide (scheme 8.4), and evaluated the product distribution between the desired cross coupling, and nucleophilic attact on the additional electrophile. Benzonitrile (46) yielded the ketone exclusively (after acidic aqueous workup), whereas
acetophenone 47 yielded both the corresponding tertiary alcohol, and unreacted starting material, due to competition between 1,2-addition and the deprotonation of alpha-protons. Benzophenone 48 also proved to outcompete the palladium catalyst in the consumption of organolithium reagent, and yielded the n-butyl-diphenyl tertiary alcohol exclusively. Finally, N,N dimethylbenzamide 49 gave a mixture of starting materials, ketone and tertiary alcohol, originating from a second alkyllithium addition after collapse of the tetrahedral intermediate (see also chapter 4). With these results, the expansion of the functional group tolerance seemed challenging and was not further investigated.
9.4 Conclusion
In conclusion, the unprecedented coupling of organolithium reagents at cryogenic temperatures has been attained using highly reactive Pd-NHC catalysts. A ‘thermal trigger’ was used for the two-step, one-pot sequential coupling of alkyl and more functionalized nucleophiles. This methodology allows for rapid, sequential, and divergent preparation of highly functionalized molecules and building blocks with potential applications in the medicinal chemistry/drug discovery and materials science, as well as offering opportunities for telescoped synthesis in process chemistry and fine-chemical manufacturing. Further optimization of the process could lead to the lowering of the catalyst loading, and the addition of heterocycles to the reaction scope, thereby greatly improving its applicability in the large scale synthesis of pharmaceutical compounds.
9.5 References
(1) Kalvet, I.; Sperger, T.; Scattolin, T.; Magnin, G.; Schoenebeck, F. Angew. Chem. Int. Ed. 2017, 56, 7078-7082.
(2) Heijnen, D.; Tosi, F.; Vila, C.; Stuart, M. C. A.; Elsinga, P. H.; Szy- manski, W.; Feringa, B. L. Angew.
Chem. Int. Ed. 2017, 56, 3354-3359.
(3) Aufiero, M.; Scattolin, T.; Proutière, F.; Schoenebeck, F. Organometallics 2015, 34, 5191–5195. (4) Kalvet, I.; Magnin, G.; Schoenebeck, F. Angew. Chem. Int. Ed. 2017, 56,1581-1585.
(5) Snelders, D. J. M.; Kreiter, R.; Firet, J. J.; Van Koten. G.; Klein Gebbink, R. J. M. Adv. Synth. Catal. 2008, 350, 262 – 266.
(6) Hornillos, V.; Pinxterhuis, E. B.; Giannerini, M.; Feringa B.L. Nat. Commun. 2016, DOI: 10.1038/ncomms11698.
(7) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 5, 667–672.
(8) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett. 2015, 17, 2262– 2265.
(9) Buter, J.; Heijnen, D.; Vila, C; Hornillos, V.; Otten, E.; Giannerini, M.; Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int. Ed. 2016, 55, 3620 –3624.
(10) Heijnen, D.; Gualtierotti, J.; Hornillos, V.; Feringa, B. L. Chem. Eur. J. 2016, 22, 3991–3995. (11) Hornillos, V.; Giannerini, M.; Vila, C.; Fañanás-Mastral, M.; Feringa, B. L. Org. Lett. 2013, 15, 5114-5117.
(12) Çalimsiz, S.; Sayah, M.; Mallik, D.; Organ, M. G. Angew. Chem. Int. Ed. 2010, 49, 2014–2017. (13) a) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844-3845; b) Kleimark, J.; Larsson, P. F.; Emamy, P.; Hedström, A.; Norrby, P. O. Adv. Synth. Catal. 2012, 354, 448 – 456.
(14) Dowlut, M.; Mallik, D.; Organ M. G. Chem. Eur. J. 2010, 16, 4279 – 4283.
(15) Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org. Chem. 2010, 4343–4354. (16) a) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Chem. Eur. J. 2016, 22, 14531-14534; b) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2015, 54, 9502 –9506; c) Pompeo, M.; Froese, R. D. J.; Hadei, N. Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 11354 –11357; d) McCann, L. A.; Organ, M. G. Angew. Chem. Int. Ed. 2014, 53, 4386-4389; e) Farmer, J.; Hunter, H. N.; Organ, M. G. J. Am.
Chem. Soc. 2012, 134, 17470−17473; f) McCann, L. C,; Hunter, H. N.; Clyburne, J. A. C.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 7024-7027.
(17) a) Khadra, A.; Mayer, S.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Organometallics 2017, 36, 3573−3577; b) Khadra, A.; Mayer, S.; Organ, M. G. Chem. Eur. J. 2017, 23, 3206-3212.
(18) a) Sharif, S.; Day, J.; Hunter, H. N.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. J. Am. Chem. Soc. 2017,139, 18436–18439; b) Lombardi, C.; Day, J.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Farmer, J. L.; Organ, M. G. Organometallics 2017, 36, 251-254; c) Lombardi, C.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G. Eur. J. Org. Chem 2017, 2017,1510-1513; d) Sharif, S.; Mitchell, D.; Rodriguez, M. J.; Farmer, J. L.; Organ, M. G. Chem. - Eur. J. 2016, 22, 14860−14863; e) Sharif, S.; Rucker; R. P.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2015, 54, 9507-9511; f) Farmer, J. L.; Pompeo, M.; Lough, A. J.; Organ, M. G.
Chem. Eur. J. 2014, 20, 15790-15798; g) Pompeo, M.; Farmer, J. L.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2014, 53, 3223-3226; h) Hoi, K. H.; Coggan, J. A.; Organ, M. G. Chem. Eur. J.
2013, 19, 843–845; i) Hoi, K. H.; Organ, M. G. Chem. Eur. J. 2012, 18, 804-807; j) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2012, 18, 145-151; k) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086-3090.
(19) a) Price, G. A.; Hassan, A.; Chandrasoma, N.; Bogdan, A. R.; Djuric, S. W.; Organ, M. G. Angew.
Chem. Int. Ed. 2017, 56. 13347-13350; b) Price, G. A.; Bogdan, A. R.; Aquirre, A. L.; Iway, T.; Djuric, S.
W.; Organ, M. G. Catal. Sci. Technol., 2016, 6, 4733-4742.
(20) a) Valente, C.; Calimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 3314 – 3332; b) Froese, R. D. J.; Lombardi, C.; Pompeo, M.; Rucker, R. P.; Organ, M. G. Acc.
Chem. Res. 2017, 50, 2244−2253; c) Valente, C.; Pompeo, M.; Sayah, M.; Organ, M. G. Org. Proc. Dev. Res. 2014, 18, 180-190; d) Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org. Chem.
2010, 23, 4343-4354.
(21) a) Sayah, M.; Organ, M. G. Chem. Eur. J. 2013, 19, 16196-16199; b) Sayah, M.; Lough, A.; Organ, M. G. Chem. Eur. J. 2013, 19, 2749-2756; c) Sayah, M.; Organ, M. G. Chem. Eur. J. 2011, 17, 11719-11722.
(22) a) Çalimsiz, S.; Sayah, M.; Mallik, D.; Organ, M. G. Angew. Chem. Int. Ed. 2010, 49, 2014–2017; b) Organ, M. G.; Çalimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem. Int. Ed. 2009, 48, 2383– 2387.
(23) a) Dobrounig, P.; Trobel, M.; Breinbauer, R. Monatsh Chem, 2017, 148:3–35; b) Hadei, N.; Achonduh, G. T.; Valente, C.; O’Brien, C. J.; Organ, M. G. Angew. Chem. Int. Ed. 2011, 50, 3896 –3899. (24) a) Lovering, F. Med. Chem. Commun. 2013, 4, 515−519; b) Damdapani, S.; Marcaurelle, L. A.
Curr. Opin. Chem. Biol. 2010, 14, 362−370; c) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009,
52, 6752−6756.
(25) See the following review and references cited therein: Xu, S.; Kim, E. H.; Wei, A.; Negishi, E.-i.
Sci. Technol. Adv. Mater. 2014,15, 044201.
(26) Lithium Compounds in Organic Synthesis, Renzo Luisi, Vito Capriati, 2014 Wiley VCH Verlag
GmbH & Co. KGaA ISBN : 9783527333431 b) The Chemistry of Organolithium Compounds,Z. Rappoport, I. Marek, 2004, John Wiley & Sons (Verlag), ISBN: 978-0-470-02110-1
(27) New Trends in Cross-Coupling: Theory and Applications, Thomas Colacot, 2014 RSC Publishing ISBN : 978-1-84973-896-5
(28) P. Ruiz-Castillo and Buchwald S. L. Chem. Rev., 2016, 11(19), 12564-12649.
(29) a) D. Hodgson, B. Stefane, T. Miles, J. Witherington, J. Org.Chem. 2006 vol. 71, 8510 – 8515. b) R. Marsden, D.B. MacLean, Tetrahedron Letters, 1983 vol. 24, 2063 - 2066c) Berger,
Markus; Rehwinkel, Hartmut; Zollner, Thomas; May, Ekkehard; Hassfeld, Jorna; Schacke, Heike US2009/137564, 2009, A1
Acknowledgements
This work described in this chapter was performed in collaboration with York university in Toronto. Catalyst design and synthesis, initial chemoselectivity tests and part of the scope were performed by Narayan Sinha.
9.6 Experimental section
All experiments were carried out under an argon atmosphere in oven-dried or flame-dried glassware using standard Schlenk techniques unless noted otherwise. Glovebox manipulations were performed in an MBraun Unilab glove-box under an argon atmosphere. All reagents were purchased from Sigma-Aldrich or Alfa Aesar and were used without further purification unless noted otherwise. Except Pd-PEPPSI-IPent-Acenapht, all other Pd-PEPPSI precatalysts and 2,6-di(pentan-3-yl)aniline were provided by Total Synthesis Ltd (Toronto, Ontario, Canada). THF was distilled under argon over sodium/benzophenone prior to use. Toluene was distilled under argon over calcium hydride prior to use. Analytical thin layer chromatography (TLC) was performed on EMD 60 F254 pre-coated glass plates and spots were visualized with UV light (254 nm) or a staining solution (KMnO4 or CAM). Column chromatography purifications were carried out using either the flash technique on EMD silica gel 60 (230 – 400 mesh) or the Biotage Isolera Four with 10 g SNAP cartridges. NMR spectra were recorded on Bruker 400 AVANCE or Bruker 300 AVANCE spectrometer. The chemical shifts for 1H NMR spectra are given in parts per million (ppm) referenced to the residual proton signal of the deuterated solvent ( = 7.28 ppm for CDCl3); coupling constants are expressed in Hertz (Hz). 13C{1H} NMR spectra were referenced to the carbon signals of the deuterated solvent ( = 76.9 ppm for CDCl3). The following abbreviations are used to describe peak multiplicities: s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, and m = multiplet. High Resolution Mass Spectrometry (HRMS) analysis was performed by the Mass Spectrometry and Proteomics Unit at Queen’s University in Kingston, Ontario.
Synthesis of Pd-PEPPSI-IPent-Acenapht1
Synthesis of compound S2
To a 100 mL round bottom flask containing a stir bar was added acenaphthenequinone (1.0 g, 5.489 mmol) and 40 mL acetonitrile. The resulting suspension was heated to reflux for 1 h, 10 mL glacial acetic acid was added, and the reaction mixture was heated to reflux until acenaphthenequinone dissolved completely. To this hot mixture was then added 2,6-di(pentan-3-yl)aniline, S1 (3.2 g, 13.723 mmol) dropwise, and then the resultant solution heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature and the resulting orange-yellow solid was filtered, and the filtrate was kept in a -4 C freezer for several hours to induce further crystallization. Then the combined orange-yellow solid was washed with 5 mL of cold ethanol, and dried in vacuo to give 2.18 g of S2 (65% yield). 1H NMR (400 MHz, CDCl3) 7.87 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.25-7.18 (m, 6H), 6.71 (d, J = 7.2 Hz, 2H), 2.68-2.61 (m, 4H), 1.72-1.66 (m, 4H), 1.63-1.57 (m, 4H), 1.54-1.48 (m, 4H), 1.46-1.37 (m, 4H), 0.85 (t, J = 7.2 Hz, 12H), 0.54 (t, J = 7.4 Hz, 12H); 13C{1H} (100 MHz, CDCl3) 160.3, 149.6, 140.4, 132.6, 130.8, 129.6, 128.5, 127.3, 124.5, 123.7, 123.1, 42.4, 27.5, 26.0, 11.73, 11.68; HRMS (EI, positive ions): m/z = 612.4449 (calculated for [S2]+ = 612.4443).
Synthesis of Compound S3
To a screw-cap Schlenk flask containing a stir bar was added S2 (1.0 g, 1.631 mmol) and the flask was evacuated and back filled with argon (3 times). Then methoxymethylether (2.63 g, 32.620 mmol) was added. The resulting reaction mixture was heated to 100 C for 18 h. After cooling the reaction mixture at ambient temperature, 100 mL diethyl ether was added, resulting in the formation of a yellow precipitate. The precipitate was filtered and washed
with diethyl ether (3 10 mL) and dried in vacuo to obtain 0.99 g of S3 (92% yield) as a yellow powder. 1H NMR (400 MHz, CDCl3) 10.06 (br, s, 1H), 8.08 (d, J = 8 Hz, 2H), 7.77 (t, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 2H), 7.45 (d, J = 8 Hz, 4H), 7.24 (d, J = 6.8 Hz, 2H), 2.30-2.24 (m, 4H), 1.84-1.76 (m, 8H), 1.64-1.56 (m, 8H), 0.90 (t, J = 6.4 Hz, 12H), 0.59 (t, J = 7.2 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) 142.5, 139.5, 138.1, 132.2, 131.3, 131.2, 130.5, 129.9, 128.0, 126.0, 124.2, 122.2, 43.3, 28.5, 27.8, 12.2, 11.9; HRMS (ESI, positive ions): m/z = 625.4537 (calculated for [S3-Cl]+ = 625.4522).
Synthesis of Compound C5
To a Schlenk flask was added S3 (0.40 g, 0.605 mml), PdCl2 (0.11 g, 0.611 mmol), Cs2CO3 (0.99 g, 3.025 mmol), and a stir bar. The flask was then evacuated and backfilled with argon (3 times), and 4 mL of 3-chloropyridine was added. Then the resulting mixture was heated to 80 C for 36 h. After cooling the reaction mixture to ambient temperature dichloromethane was added and the resulting mixture/suspension filtered through a pad of silica and celite, and washed with dichloromethane until the filtrate became colorless. The filtrate was evaporated in vacuo and the excess 3-chloropyridine was distilled off. The residue thus obtained was dissolved in dichloromethane and filtered through a pad of silica and Celite, and washed with dichloromethane until the filtrate became colorless. The filtrate was then evaporated to dryness and then triturated with pentane. The residue was dried in vacuo to obtain 0.49 g of C5 (88% yield) as a bright yellow solid. 1H NMR (400 MHz, CDCl3) 8.68 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 8 Hz, 2H), 7.59 (t, J = 8 Hz, 3H), 7.39 (d, J = 8 Hz, 4 H), 7.32 (t, J = 7.6 Hz, 2H), 7.11 (dd, J = 8, 5.6 Hz, 1H), 6.70 (d, J = 7.2 Hz, 2H), 3.30-3.24 (m, 4H), 2.05-1.83 (m, 8H), 1.43-1.36 (m, 4H), 1.28-1.19 (m, 4H), 1.12 (t, J = 7.2 Hz, 12H), 0.52 (t, J = 7.6 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) 157.9, 150.6, 149.5, 144.5, 140.6, 137.3, 135.4, 131.9, 129.4, 129.0, 128.8, 127.9, 126.9, 126.7, 126.5, 124.3, 121.7, 40.7, 26.4, 26.2, 12.4, 9.7; HRMS (ESI, positive ions): m/z = 914.2996 (calculated for [C5+H]+ = 914.2966).
General procedure for cross-coupling
General procedure A: The low temperature cross-coupling of aryl bromides and organolithium reagents
A dry Schlenk flask, equipped with a stir bar was charged (Pd-PEPPSI-IPent-Acenapht (13.7 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to the indicated temperature (-22 C to -78 C). The corresponding alkyl- or aryllithium reagent (1.5 equiv) was diluted with toluene to reach 1 mL, and was added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, the reaction mixture was quenched with methanol (1 mL) at the indicated temperature (-22 C to -78 C). The mixture was warmed to room temperature, Celite was added and all liquids evaporated under reduced pressuer. Dichloromethane (5 mL
2) was added and filtered through a small pad of Celite and the filtrate was evaporated and the residue was purified by column chromatography.
General procedure B: The low temperature chemo-selective cross-coupling of aryl bromides over chlorides and organolithium reagents
A dry Schlenk flask, equipped with a stir bar was charged Pd-PEPPSI-IPent-Acenapht (13.7 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to the indicated temperature (-22 C to -34 C). The corresponding alkyl- or aryllithium reagent(1.2-1.5 equiv) was diluted with toluene to reach 1 mL, and was added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, the reaction mixture was quenched with methanol (1 mL) at the indicated temperature (-22 C to -34 C). Then the flask was warmed to room temperature, Celite was added and all volatiles/liquids evaporated. Dichloromethane (5 mL 2) was added and filtered through a small pad of Celite and the filtrate was evaporated and the residue was purified by column chromatography.
General procedure C: Sequential cross-coupling of aryl halides, organolithium reagents, and organometallic reagents (ArB(OH)2 or ArZnX or ArLi)
In a dry Schlenk flask, Pd-PEPPSI-IPentCl (5 mol%, 0.025 mmol, 21 mg) and the aryl bromide (0.5 mmol) were dissolved in 4 mL of dry toluene at room temperature, and the mixture was subsequently cooled down to -20 °C by means of a cooling bath. The corresponding commercial alkyllithium reagent (1.05 equiv) was diluted with toluene to reach 1.0 mL; this solution was added over 1 h by the use of a syringe pump. After the addition was completed, the second organometallic reagent (1.5 equiv) was added, and the mixture was heated to the indicated temperature for the appropriate time. After the reaction was completed, it was quenched with 1.0 mL of methanol, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was directly purified by column chromatography.
General procedure D: Sequential cross-coupling of aryl halides, organolithium reagents, and anilines
A dry Schlenk flask, equipped with a stir bar was charged with Pd-PEPPSI-IPentCl (12.9 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to -22 C. The corresponding alkyl lithium reagent (1.2 equiv) was diluted with toluene to reach 1 mL, and added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, aniline (1.2 equiv), and base (KOtBu (1.5 equiv) or Cs2CO3 (3 equiv.)) was added to the reaction mixture under Argon at the indicated temperature. The resulting mixture was warmed up to ambient temperature and stirred for 16 h or heated to 80 C for 16 h. Subsequently, dichloromethane (10 mL) was
added and the mixture filtered through a pad of Celite followed by washing with dichloromethane. The filtrate was evaporated and the residue was purified by column chromatography.
General procedure E: Sequential cross-coupling of aryl halides, organolithium reagents, and thiophenols
A dry schlenk flask, equipped with a stir bar was charged with Pd-PEPPSI-IPentCl (12.9 mg, 0.015 mmol, 5 mol%), and, if solid, the aryl halide (0.3 mmol, 1 equiv), after which it was evacuated and backfilled with Argon (3 times). If liquid, the aryl halide was added via microliter syringe after evacuation/backfilling process. Toluene (2 mL) was added and the resulting mixture was cooled to -22 C. The corresponding alkyllithium reagent (1.2 equiv) diluted with toluene to reach 1 mL, and this was added to the cold reaction mixture over 1 h by using a syringe pump. After the addition was complete, KOtBu (2.0 equiv) and thiophenol (1.2 equiv) were added to the reaction mixture under Argon at the indicated temperature. The resulting mixture was warmed up to ambient temperature and stirred for 16 h or heated to 80 C for 16 h. After that aqueous NaOH (2 mL, 1M) was added and the resulting sollution extracted with dichloromethane (3 5 mL). The combined organic extracts were washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated in vacuo. The residue thus obtained was purified by column chromatography.
Table S1. Chemoselective cross-coupling of aryl bromide over chloride with organolithium reagents (selectivity study):
Figure S1. 1H NMR spectrum (400 MHz, CDCl3) obtained from reaction mixture (Entry 1, Table S1). monocoupled product dicoupled product dicoupled product monocoupled product dichloromethane toluene
Figure S2. 1H NMR spectrum (400 MHz, CDCl3) obtained from reaction mixture (Entry 2, Table S1).
Figure S3. 1H NMR spectrum (400 MHz, CDCl3) obtained from reaction mixture (Entry 3, Table S1).
Following general procedure A (at -62 C), 50 mg of 1 (90% yield) was isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 8.12 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.58-7.50 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 3.13 (t, J = 7.6 Hz, 2H), 1.83-1.76 (m, 2H), 1.56-1.46 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 138.9, 133.8, 131.8, 128.6, 126.3, 125.8, 125.5, 125.4, 125.3, 123.8, 32.9, 32.7, 22.8, 13.9. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -62 C, 0.5 mmol scale reaction), 77 mg of 2 (92% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.61 (m, 2H), 7.46 (dd, J = 8.2, 7.1 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 2.56-2.29 (m, 1H), 1.21-1.09 (m, 2H), 0.92-0.81 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 139.3, 133.67, 133.65, 128.6, 126.7, 125.8, 125.7, 125.6, 124.6, 123.9, 13.4, 6.6. The spectral data are consistent with those reported in the literature.3
Following general procedure A (at -42 C), 46 mg of 3 (81% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.91 (d, J = 8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.12 (s, 1H), 2.90 (t, J = 7.2 Hz, 2H), 1.83-1.76 (m, 2H), 1.55-1.46 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 140.4, 139.1, 137.1, 123.9, 123.6, 122.8, 121.7, 120.7, 31.2, 28.2, 22.6, 13.9. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -62 C), 49 mg of 4 (89% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1
H NMR (400 MHz, CDCl3) 8.20 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 7.77 (d, J = 8Hz, 1H), 7.59-7.50 (m, 3H), 7.45 (d, J = 7.2 Hz, 1H), 3.64-3.55 (m, 1H), 1.98-1.88 (m, 1H), 1.84-1.74 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 143.6, 133.8, 131.7, 128.8, 126.1, 125.5, 125.4, 125.1, 123.2, 122.4, 35.2, 30.5, 21.1, 12.2. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -62 C), 48 mg of 5 (87% yield) were isolated after flash chromatography (n-Pentane). 1H NMR (400 MHz, CDCl3) 7.86 (t, J = 7.2 Hz, 3H), 7.67 (s, 1H), 7.53-7.46 (m,
2H), 7.43-741 (d, J = 8.4 Hz, 1H), 2.88-2.79 (m, 1H), 1.80-1.72 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 145.0, 133.6, 132.1, 127.7, 127.5, 127.4, 125.8, 125.7, 125.1, 124.9, 41.7, 30.9, 21.8, 12.2. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -22 C), 38 mg of 6 (79% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.64 (d, J = 7.6 Hz, 2H), 7.51-7.39 (m, 5 H), 7.37-7.32 (m, 1H); 13C NMR (100 MHz, CDCl3) 142.3, 135.8, 128.7, 127.0, 126.4, 126.3, 126.1, 120.2. The spectral data are consistent with those reported in the literature.4
Following general procedure A (at -42 C), 60 mg of 7 (93% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1
H NMR (400 MHz, CDCl3) 8.02-7.99 (m, 1H), 7.89-7.87 (m, 1H), 7.67 (d, J = 8 Hz, 1H), 7.54-7.48 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 2.6 (s, 2H), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) 137.2, 133.9, 131.6, 128.5, 125.4, 125.3, 125.2, 124.9, 124.7, 124.6, 23.4, -1.26. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -62 C), 52 mg of 8 (94% yield) were isolated after flash chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.87-7.82 (m, 3H), 7.67 (s, 1H), 7.53-7.45 (m, 2H), 7.40 (dd, J = 1,6, 8.4 Hz, 1H), 2.84 (t, J = 8 Hz, 2H), 1.80-1.72 (m, 2H), 1.51-1.42 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 140.3, 133.6, 131.9, 127.6, 127.5, 127.4, 127.3, 126.2, 125.7, 124.9, 35.7, 33.5, 22.3, 13.9. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -42 C), 64 mg of 9 (91% yield, branch product / linear product = 48:1) were isolated after flash chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 8.83-8.80 (m, 1H), 8.76-8.71 (m, 1H), 8.27-8.24 (m, 1H), 7.94-7.90 (m, 1H), 7.71-7.68 (m, 3H), 7.66-7.63 (m, 2H), 3.63-3.54 (m, 1H), 2.08-1.97 (m, 1H), 1.87-1.77 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 141.6, 131.9, 131.2, 130.7, 129.3, 128.2, 126.4, 126.3, 125.84, 125.79, 123.8, 123.2, 122.9, 122.3, 35.3, 30.1, 20.8, 12.2. The spectral data are consistent with those reported in the literature.5
Following general procedure A (at -22 C), 46 mg of 10 (77% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 8.00-7.97 (m, 2H), 7.94 (d, J = 8 Hz, 1H), 7.62-7.55 (m, 6H), 7.49-7.28 (m, 3H); 13C NMR (100 MHz, CDCl3) 140.7, 140.2, 133.7, 131.6, 130.0, 128.2 (2C), 127.6, 127.2, 126.9, 125.9 (2C), 125.7, 125.3. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -42 C), 58 mg of 11 (90% yield) were isolated after flash chromatography (n-Pentane) as a colorless solid. 1H NMR (400 MHz, CDCl3) 7.84 (d, J = 8 Hz, 1H), 7.78 (t, J = 8 Hz, 2H), 7.47 (br m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 2.3 (s, 2H), 0.09 (s, 9H); 13C NMR (100 MHz, CDCl3) 138.2, 133.8, 130.9, 127.8, 127.5, 127.4, 126.9, 125.7, 125.1, 124.2, 27.3, -1.9. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -22 C), 36 mg of 12 (61% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.16 (t, J = 7.6 Hz, 1H), 6.67-6.62 (m, 2H), 6.58 (s, 1H), 3.81 (s, 3H), 2.09 (s, 2H), 0.03 (s, 9H); 13C NMR (100 MHz, CDCl3) 159.4, 142.1, 128.9, 120.6, 113.7, 109.0, 54.9, 27.1, -1.9. The spectral data are consistent with those reported in the literature.6
Following general procedure A (at -62 C, 0.5 mmol scale reaction), 74 mg of 13 (87% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 8.17 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 – 7.39 (m, 4H), 3.79 (hept, J = 6.8 Hz, 1H), 1.44 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 147.3, 136.6, 134.0, 131.6, 128.9, 128.32, 128.31, 127.9, 125.9, 124.4, 31.2, 26.2. The spectral data are consistent with those reported in the literature.7
Following general procedure A (at -42 C, from 4-iodoanisole), 36 mg of 15 (73% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.13 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H), 2.58 (t, J = 7.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.42-1.33 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 157.5, 134.9, 129.1, 113.5, 55.1, 34.6, 33.8, 22.2, 13.9. The spectral data are consistent with those reported in the literature.2
Following general procedure A (at -22 C), 31 mg of 16 (63% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.23 (d, J = 8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76-6.74 (m, 2H), 3.83 (s, 3H), 2.64-2.55 (m, 1H), 1.65-1.58 (m, 2H), 1.25 (d, J = 7.2 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 159.4, 149.4, 129.0, 119.4, 112.9, 110.6, 54.9, 41.6, 30.9, 21.7, 12.1. The spectral data are consistent with those reported in the literature.8
Following general procedure A (at -22 C), 31 mg of 17 (63% yield) were isolated after flash column chromatography (n-Pentane/ether: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.22 (m, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76-6.74 (m, 2H), 3.83 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 1.67-1.61 (m, 2H), 1.43-1.32 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 159.5, 144.5, 129.0, 120.8, 114.0, 110.7, 55.0, 35.6, 33.4, 22.3, 13.8. The spectral data are consistent with those reported in the literature.9
Following general procedure A (at 23 C, 2.5 equiv. TMSCH2Li was used), 56 mg of S5 (75% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 6.88 (s, 4H), 2.04 (s, 4H), 0.01 ppm (s, 18H); 13C NMR (100 MHz, CDCl3) 135.4, 127.7, 26.1, -2.00. The spectral data are consistent with those reported in the literature.10
Following general procedure B (at -22 C), 46 mg of 18 (75% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.20 (d, J = 8 Hz, 2H), 6.94 (d, J = 8 Hz, 2H), 2.07 (s, 2H), 0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) 138.9, 129.4, 129.1, 128.1, 26.4, -2.1. The spectral data are consistent with those reported in the literature.11
Following general procedure B (at -22 C), 51 mg of 19 (80%) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1
H NMR (400 MHz, CDCl3) 7.12 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 2.22 (s, 3H), 2.08 (s, 2H), 0.03 (9H); 13C NMR (100
MHz, CDCl3) 137.4, 136.2, 129.7, 129.6, 129.1, 125.5, 23.1, 20.1, -1.6; HRMS (EI, positive ions): m/z = 212.0779 (calculated for [19]+ = 212.0788).
Following general procedure B (at -22 C), 34 mg of 20 (67% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.63-1.56 (m, 2H), 1.41-1.32 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 141.2, 131.1, 129.6, 128.2, 34.9, 33.4, 22.1, 13.8. The spectral data are consistent with those reported in the literature.12
Following general procedure B (at -34 C), 43 mg of 21 (78% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1
H NMR (400 MHz, CDCl3) 7.15 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 2.58 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.62-1.52 (m, 2H), 1.46-1.37 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 139.4, 137.6, 130.9, 129.9, 129.7, 125.7, 32.3, 32.2, 22.5, 19.1, 13.9; HRMS (EI, positive ions): m/z = 182.0869 (calculated for [21]+ = 182.0862).
Following general procedure B (at -22 C), 42 mg of 22 (70% yield) were isolated after flash column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.33-7.28 (m, 1H), 7.17-7.12 (m, 1H), 7.09-7.02 (m, 2H), 2.31 (s, 2H), 0.07 (s, 9H); 13C NMR (100 MHz, CDCl3) 138.7, 132.5, 129.7, 129.3, 126.3, 125.2, 24.2, -1.6. The spectral data are consistent with those reported in the literature.11
Following general procedure C, 85 mg of 23 (55% yield, two step) were isolated after flash column chromatography (n-Pentane/Dichloromethane = 96:4) as a colorless oil. The corresponding boronic acid (1.5 equiv) and sodium methoxide (3 equiv) were added as solids. Degassed THF (3 ml) was subsequently added, and the reaction carried out at 75 C overnight. 1
H NMR (400 MHz, CDCl3) 8.11 (d, J = 8.0 Hz, 2H), 7.70-7.60 (m, 2H), 7.36-7.28 (m, 3H), 7.04 (dt, J = 6.9, 1.7 Hz, 1H), 3.94 (s, 3H), 2.17 (s, 2H), 0.04 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 167.1, 146.1, 141.3, 139.9, 130.1, 128.8, 127.9, 127.1(2C), 126.9, 123.1, 52.1, 27.3, -1.8; HRMS (ESI, positive ions): m/z = 299.1461 (calculated for [23+H]+ = 299.1467).
Following general procedure C (second step at room temperature, stirring for 18 h), 92 mg of 24 (75% yield, two step) were isolated after flash column chromatography (n-Pentane/Ethyl acetate = 99:1) as a colorless oil. The corresponding organozinc reagent was synthesized via literature procedure.13 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 3.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 161.5, 160.4, 147.6, 146.4, 132.2, 131.4, 131.2, 126.9, 124.9, 122.4, 109.3, 63.5, 31.5, 18.3, 17.1; HRMS (ESI, positive ions): m/z = 245.1172 (calculated for [24+H]+ = 245.1178).
Following general procedure C, with addition of the second organolithium reagent (4-lithio anisole) over 1 h at 40 °C, compound 25 was obtained in 43% yield (two step). The 4-lithio anisole was prepared via a literature procedure.12 Due to difficulties in separating the title compound from 4-methoxy-biphenyl, the yield was determined via NMR with internal standard (tetrachloroethane), and an aliquot was purified via Preperative HPLC (n-Pentane). 1
H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.6 Hz, 2H), 7.40 (s, 1H), 7.38-7.31 (m, 2H), 7.18 (d, J = 6.9 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 2.96 (hept, J = 6.9 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); GC-MS: 226/211/179/105.
Following general procedure C (second step at room temperature, stirring for 18 h), 106 mg of 26 (82% yield, two step) were isolated after flash column chromatography (n-Pentane/Ethyl acetate = 99:1) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.60 (dd, J = 7.8, 1.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 3.4 Hz, 1H), 7.21 (s, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.96 (hept, J = 6.9 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.29 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 161.6, 160.5, 152.2, 146.4, 132.2, 131.5, 129.7, 125.6, 125.1, 122.5, 109.3, 63.5, 36.8, 26.6, 17.1; HRMS (ESI, positive ions): m/z = 259.1330 (calculated for [26+H]+ = 259.1334).
Following general procedure C, with addition of the second organolithium reagent (2-(methoxymethoxy)phenyl)lithium) over 1 h at 40 °C, 61 mg of 27 (48% yield, two step) were isolated after column chromatography (n-Pentane/Ethyl acetate = 97:3) as a colorless oil.
Cyclopropyllithium,7 and 2-(methoxymethoxy)phenyllithium12 were prepared via literature procedure. 1H NMR (400 MHz, CDCl3) δ 7.36-7.27 (m, 4H), 7.21 (dd, J = 8.2, 1.2 Hz, 2H), 7.15-6.98 (m, 2H), 5.12 (s, 2H), 3.41 (s, 3H), 1.95 (tt, J = 8.4, 5.1 Hz, 1H), 1.05-0.90 (m, 2H), 0.80-0.67 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 154.3, 143.7, 138.7, 132.2, 131.1, 128.7, 127.9, 126.9, 126.8, 124.5, 122.4, 115.8, 95.2, 56.2, 15.6, 9.4; GC-MS: 254/221/207/181.
Following general procedure C, with addition of the second organolithium reagent (4-lithio anisole) over 1 h at 40 °C, 78 mg of 28 (58% yield, two step) were isolated after column chromatography (n-Pentane) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 9.3 Hz, 2H), 7.26 (d, J = 5.5 Hz, 2H), 7.19 (s, 1H), 7.03-6.91 (m, 3H), 3.86 (s, 3H), 2.15 (s, 2H), 0.03 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 159.1, 141.0, 140.8, 134.3, 128.6, 128.3, 126.6, 126.6, 122.6, 114.3, 55.5, 27.3, -1.7; GC-MS: 270/255/73.
Following general procedure D (-22
C, 23 C), 60 mg of 29 (78% yield, two step) were
isolated after flash column chromatography
(hexane/ethylacetate: 05%) as a 1 H NMR (400 MHz, CDCl3) 7.20-colorless oil. 7.12 (m, 3H), 6.07 (d, J = 8Hz, 2H), 6.64 (d, J = 7.6 Hz, 2H), 6.49-6.47 (m, 1H), 5.66 (s, 1H), 3.81 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.45-1.36 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) 160.6, 145.3, 140.1, 136.2, 129.9, 129.1, 119.1, 109.4, 105.4, 102.4, 55.1, 34.9, 33.7, 22.3, 13.9; HRMS (EI, positive ions): m/z = 255.1629 (calculated for [29]+ = 255.1623).
Following general procedure D (-22 C, 80 C), 40 mg of 30 (47% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 010%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.92 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 7.11 (d, J = 8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.01 (s, 1H), 3.89 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.44-1.35 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) 166.9, 148.6, 138.14, 138.10, 131.4, 129.3, 121.1, 120.4, 113.9, 51.6, 34.9, 33.6, 22.2, 13.9; HRMS (EI, positive ions): m/z = 283.1566 (calculated for [30]+ = 283.1572).
Following general procedure D (-22 C, 80 C), 45 mg of 31 (60% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 010%) as a light yellow oil. 1H NMR (300 MHz, CDCl3) 7.30-7.26 (m, 2H), 7.24-7.22
(m, 2H), 7.17-7.08 (m, 2H), 7.06-7.03 (m, 2H), 5.57 (s, 1H), 2.59 (t, J = 7.5 Hz, 2H), 1.63-1.53 (m, 2H), 1.44-1.32 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) 146.2, 138.5, 136.4, 130.4, 130.0, 127.0, 124.8, 123.2, 122.6, 119.6, 119.2, 117.7, 113.0, 32.2, 31.1, 22.5, 13.9;
Following general procedure D (-22 C, 80 C), 36 mg of 32 (40% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 010%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 7.59-7-53 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.27-7.23 (m, 2H), 7.21-7.15 (m, 1H), 7.12-7.02 (m, 2H), 5.52 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.66-1.56 (m, 2H), 1.44-1.36 (m, 5H), 0.94 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) 166.7, 144.9, 139.9, 134.3, 131.6, 130.1, 129.2, 126.8, 123.2, 120.9 (2C), 120.4, 117.5, 60.9, 31.9, 31.1, 22.6, 14.3, 13.9;
Following general procedure D (-22 C, 23 C), 36 mg of 33 (50% yield, two step) were isolated after flash column chromatography (n-pentane) as a light yellow oil. 1H NMR (400 MHz, CDCl3) 7.33-7.26 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8 Hz, 2H), 6.92 (t, J = 7.2 Hz, 1H), 3.34 (s, 3H), 2.62 (m, 1H), 1.66-1.59 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 149.2, 146.6, 141.5, 129.1, 128.9, 127.7, 121.8, 120.3, 119.8, 118.5, 40.9, 40.2, 31.2, 21.7, 12.2; HRMS (EI, positive ions): m/z = 239.1679 (calculated for [33]+ = 239.1674).
Following general procedure D (-22 C, 23 C), 61 mg of 34 (80% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.29-7.27 (m, 1H), 7.18-7.13 (m, 4H), 6.94-6.85 (m, 3H), 6.15 (s, 1H), 3.94 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.48-1.39 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H); 13
C{1H} NMR (100 MHz, CDCl3) 147.8, 140.0, 136.0, 133.7, 129.0, 120.7, 119.3, 119.1, 113.7, 110.3, 55.5, 34.9, 33.7, 22.3, 13.9; HRMS (EI, positive ions): m/z = 255.1619 (calculated for [34]+ = 255.1623).
Following general procedure D (-22 C, 23 C), 64 mg of 35 (79% yield; two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) 7.08 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.78-6.76 (m, 2H), 5.41 (s, 1H), 3.84 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.29 (s, 3H), 1.61-1.54 (m, 2H),
1.47-1.41 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 154.7, 142.5, 136.8, 136.5, 132.7, 129.5, 121.2, 118.1, 114.5, 113.7, 55.5, 32.7, 32.2, 22.6, 19.4, 14.0;
Following general procedure D (-22 C, 23 C), 51 mg of 36 (56% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) 7.14 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.79 (br s, 2H), 5.4 (s, 1H), 3.90 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.29 (s, 3H), 1.59-1.53 (m, 2H), 1.46-1.39 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 149.7, 141.2, 137.6, 136.9, 133.8, 129.6, 122.9, 120.8, 119.2, 117.9, 114.8, 113.2, 56.6, 32.6, 32.2, 22.6, 19.4, 14.0;
Following general procedure E (-22 C, 80 C), 41 mg of 37 (53% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.30-7.27 (m, 4H), 7.14 (br d, J = 7.1 Hz, 4H), 2.62 (t, J = 7.4 Hz, 2H), 2.37 (s, 3H), 1.66-1.58 (m, 2H), 1.44-1.34 (m, 2H), 0.96 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 141.8, 136.9, 132.8, 132.2, 131.1, 130.7, 129.8, 129.2, 35.1, 33.4, 22.2, 21.0, 13.9. The spectral data are consistent with those reported in the literature.14
Following general procedure E (-22 C, 23 C), 52 mg of 38 (64% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.42 (d, J = 7.5 Hz, 2H), 7.18 (d, J = 7.3 Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 3.85 (s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 1.64-1.57 (m, 2H), 1.42-1.34 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 159.4, 141.0, 135.3, 134.4, 129.0 (2C), 125.3, 114.8, 55.3, 35.1, 33.5, 22.2, 13.9. The spectral data are consistent with those reported in the literature.15
Following general procedure E (-22 C, 80 C), 40 mg of 39 (52% yield, two step) were isolated after flash column chromatography (hexane/ethylacetate: 05%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 7.27-7.22 (m, 4H),
7.19-7.14 (m, 4H), 2.63 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.67-1.59 (m, 2H), 1.45-1.35 (m, 2H), 0.97 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 141.8, 138.7, 135.0, 131.7, 131.4, 130.8, 130.3, 129.3, 127.0, 126.5, 35.1, 33.4, 22.3, 20.4, 13.9;
References
(1) The synthesis of Pd-PEPPSI-IPent-Acenapht is slightly differing from the very recently published procedure; see Lu, D.-D.; He, X.-X.; Liu, F.-S. J. Org. Chem. 2017, 82, 1089810911.
(2) Heijnen, D.; Tosi, F.; Vila, C.; Stuart, M. C. A.; Elsinga, P. H.; Szymanski, W.; Feringa, B. L. Angew. Chem. Int. Ed. 2017, 56, 33543359.
(3) Molander, G. A.; Beaumard, F.; Niethamer, T. K. J. Org. Chem. 2011, 76, 81268130. (4) Ogawa, H.; Yang, J.-K.; Minami, H.; Kojima, K.; Saito, T.; Wang, C.; Uchiyama, M. ACS Catal. 2017, 7, 39883994.
(5) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389391.
(6) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett. 2015, 17, 22622265.
(7) Vila, C.; Giannerini, M.; Hornillos, V.; Fañanás-Mastral, M.; Feringa, B. L. Chem. Sci. 2014, 5, 13611367.
(8) Li, L.; Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, M. R. J. Am. Chem. Soc. 2014, 136, 1402714030.
(9) Jia, Z.; Liu, Q.; Peng, X.-S.; Wong, H. N. C. Nat. Commun. 2016, 7, 10614, doi: 10.1038/ncomms10614.
(10) Gómez, C.; Huerta, F. F.; Yus, M. Tetrahedron 1997, 53, 1389713904.
(11) Protti, S.; Ravelli, D.; Mannucci, B.; Albini, A.; Fagnoni, M. Angew. Chem. Int. Ed. 2012, 51, 85778580.
(12) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 5, 667–672. (13) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 60406044.
(14) Liu, X.; Cao, Q.; Xu, W.; Zeng, M.-T.; Dong, Z.-B. Eur. J. Org. Chem. 2017, 57955799.
