University of Groningen
Carbon-carbon bond formations using organolithium reagents
Heijnen, Dorus
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Chapter 5 : Synthesis of chiral catalysts for palladium
catalyzed organolithium cross coupling reactions.
Attempts towards enantioselective synthesis using NHC-Pd complexes and organolithium reagents are described in this chapter. The synthesis of chiral Pd-PEPPSI derivatives that fit the requirements for organolithium cross coupling reactions has proven challenging. Stereogenic centres were installed at the diamine backbone as well as at the flanking alkyl fragments but the complete synthesis of the Pd-complex was unsuccessful. The use of chiral catalysts for enantioselective synthesis of a biaryl moiety using organolithium reagents remains a potentially promising method due to the low reaction temperatures, generally high yields (in the achiral cross-coupling) and ease of the preparation of starting materials.
5..1 Introduction
The chiral biaryl motif consists of two arenes, that are hindered in their rotation around the bond that connects them, due to 2 or more ortho-substituents (shown in figure 5.1).1a The construction of these compounds is relatively straightforward, and the products find use in a wide variety of applications, such as ligands, pharmaceuticals and chiral recognition or asymmetric transformation. It is therefore that the enantioselective synthesis of these atropoisomeric molecules has received a vast amount of attention in the past decades.1b-h It is the size and number of the substituents that determine the barrier and speed of rotation, which is by itself temperature dependent. Though structures such as the one shown in figure 5.1 are always chiral, they are only called atropoisomers if their half-life for rotary isomerization is above 1000 seconds at a given temperature.1i Strategies that generate atropoisomers include the asymmetric reduction of a lactone, followed by ring opening, yielding the corresponding chiral phenol, as well as methods that construct the second half of the biaryl by means of an annulation.1 The formation of the biaryl by the generation of the chiral axis can be performed by means of a chiral auxiliary attached to one of the coupling partners, generating a stoichiometric amount of waste, but can preferably also be achieved by means of chiral catalysts.2
Figure 5.1 Different approaches to atroposelective biaryl formation.
The bulky but achiral Pd-PEPPSI complex (scheme 5.1) has shown to be particularly active in the cross-coupling of hindered aryl halides and organolithium reagents.3 The large but flexible alkyl groups are hypothesised to facilitate a faster reductive elimination,4a and even larger substituents at the aryl ring have shown to improve similar cross-coupling reactions.4b With the commercially available Pd-PEPPSI-Ipent, conversion with alkyllithium reagents was observed at temperatures as low as -60 °C, unlike other ligands (such as phosphines and other NHC ligands) that were only active at or close to room temperature.5 This activity at low temperatures greatly enhances the possibility to design a catalytic system that is able to yield an enantio-(atropo-)selective reaction. The PEPPSI core (scheme 5.1) allows for functionalization in either the backbone (blue) or the flanking alkyl groups (red). The transformation shown below the PEPPSI structures, are organolithium based cross coupling reactions that have previously yielded the corresponding (racemic) products in high yields when these achiral catalyst were employed.
Scheme 5.1 Pd-PEPPSI catalyst complexes and examples of potential enantio(-atropo)-selective coupling.
5.2 Initial testing
Based on several preliminary experiments, the application of the above mentioned N-heterocyclic carbene complexes (scheme 5.1) appears crucial for catalytic turnover in the cross coupling with organolithium reagents. Some of the key features that make the complex suitable for this transformations are:
1) A direct nitrogen-aryl coupled motif on the imidazolium/imidazolinium ring (figure 5.2)
2) Bulky alkyl groups on the flanking aryl substituents
for hindered substrates and conversion at low temperature 3) Ex situ generation of the metal-carbene complexes.
Attempts to deviate from any of the structural features of this ligand led to inactive systems, or very low turnover numbers in our model reactions with 1-bromonaphthalene and phenyllithium (Scheme 5.2 top). The in situ formation of NHC-metal complexes by means of deprotonation of the corresponding imidazolium salts with organolithium reagents has shown feasible in allylic substitution reactions,6 but screening with commercial PEPPSI-SIpr (Scheme 5.1) and its imidazolinium salt precursor only showed catalytic turnover for the preformed complex. Attempts with saturated imidazolinium based complexes 4-6 showed modest to good (50-80%, Scheme 2) conversion for unhindered substrates (3a, 3b), but were unable to yield more hindered cross-coupled products such as 3c and 3d. Pd-PEPPSI complex 7 derived from an IPr-BOX ligand was synthesized,7 but it showed a reactivity similar to that of the complexes 4-6.
Scheme 5.2 attempted Pd-PEPPSI-complexes
5.3 Design of potential chiral ligands for atroposelective coupling.
5.3.1 Chiral backbone
With the initial testing of the Pd-NHC structures performed, a strategy for the synthesis of a suitable chiral Pd-NHC complex could be made. Since the ortho-substituted phenyl rings appear to be crucial for (chiral) product formation, a combination of bulky isopentyl (or isoheptyl) groups, and a chiral imidazolinium ring could provide a suitable structural motif. The coupling of these chiral diamine complexes with phenyl, mono substituted or mesityl halides is well described,8 but at the time of this research, no method for the Buchwald-Hartwig coupling of very hindered (di-ortho-isopropyl or larger) substrates had been reported. Our attempts at the formation of this crucial C-N bond are presented in Table 5.1. The commonly used combination of Pd2dba3 and racemic BINAP did not yield any of the desired product, with either the sterically hindered aryl bromide or iodide (entry 1, 3, 5). Only under more forcing conditions, a small amount of the desired product could be observed (entry 6). Alternatively, Pd-PEPPSI-IpentCl was also employed in the attempted coupling of aryl iodides and bromides (entry 2 and 4) without any success. In order to test the quality of the reagents and reaction setup, mesitylbromide was coupled in presence of Pd2dba3 and racemic BINAP, which gave 81% isolated yield of the desired compound.
Table 5.1 Buchwald Hartwig coupling with chiral diamines
Entry Catalyst Arylhalide Result
1 Pd2dba3/BINAP R1=R2= Ipr X =Br s.m.
2 Pd-PEPPSI-IPentCl R1=R2= Ipr X =Br s.m.2
3 Pd2dba3/BINAP R1=R2= IPent X =I s.m.
4 Pd-PEPPSI-IPentCl R1=R2= IPent X =I s.m.
5 Pd2dba3/BINAP R1=R2= IPent X =Br s.m.
6 Pd2dba3/BINAP R1=R3=Me, R2=IPent X = I s.m.2 7 Pd2dba3/BINAP R1=R2=R3=Me X=Br 81% isolated yield 1
Reaction conditions : Diamine (1 eq.), aryl bromide (2,5 eq.), catalyst (5%) and base (KOtBu) (3 eq.) suspended in toluene in a closed vial at 110°C. 2 Under more forcing conditions (140°C, 72 h) ~10% of product isolated.
The viability of the desired coupling of the above mentioned chiral diamine with sterically hindered aryl halides was proven by the group of Montgomery in 2017,9 using a tailor made imidazolium salt, harsh reaction conditions and prolonged reaction times. The reproduced synthesis of the imidazolinium salt, and consecutive Pd-complexation to afford Pd-PEPPSI-IPr* is shown in Scheme 5.3. The key Buchwald-Hartwig coupling was performed in trifluorotoluene, with Pd2dba3 and imidazolium salt IPrMe-Cl, yielding the corresponding dicoupled amine 9 in 52% isolated yield. Ring closure was achieved by means of triethylorthoformate in the presence of NH4BF4 and catalytic amount of formic acid, to yield the tetrafluoborate imidazolinium salt 10. Complexation with palladiumchloride could be performed from the BF4 salt, as well from the corresponding chloride, which was obtained after ion exchange.
Scheme 5.3 Synthesis of Pd-PEPPSI-IPr*9
With the successful synthesis of chiral imidazolium salts 10 and 10b, and the corresponding Pd complex Pd-PEPPSI-IPr*, the catalyst was applied in the coupling of the standard coupling partners, to yield the trisubstituted biaryl 3c in 47%10 (scheme 5.4). The coupling of phenyllithium was used to compare the activity of the catalyst in the coupling of unhindered substrates 3a, which gave a satisfactory 98% yield.10
Based on the sharp decline in yield when switching between constructing a mono (3a) or a trisubstituted (3c) biaryl, it was much to our surprise that the homocoupling of naphthalene 1c gave the binol derivative 3e in high yields. Chiral HPLC analysis, however, showed the product to be racemic. Since no chiral induction was observed, further investigations into the catalysts were not conducted.
5.3.2 Chiral flanking groups
Since the large alkyl fragments have such a major influence on the conversion of hindered coupling substrates, their effect on the reductive elimination and the enantiodetermining step could not be ruled out. The synthesis of chiral alkyl fragments was therefore pursued simultaneously with the chiral diamine strategy shown above. Initially, the coupling of alkene fragments to the 2,6- dibromoaniline seemed like a viable synthetic route towards to precursor 12 that (upon asymmetric reduction) would give chiral aniline 13 (Scheme 5.5). This route was substituted by the previously reported direct diastereoselective coupling of menthyl derivatives by means of a Negishi coupling due to expected difficulties in the enantioselective reduction of the alkene fragment (methyl vs ethyl differentiation).11 Unfortunately, the double coupling of the menthyl-zinc-bromide complex yielded a mixture of starting material, mono and di-coupled product 14 which were inseparable via chromatography or crystallization. The mono coupling with xylene derivative 15, however, gave the desired product 16 in 60% yield.11
Scheme 5.5 Synthesis of chiral aniline derivatives
Having the chiral aniline 16 in hand, our goal was to synthesize an unsymmetric imidazolium salt (Scheme 5.6) as well as a symmetric variant (Scheme 5.7). Using a literature procedure,12 ring formation with oxazolinone 17 was expected to yield acetate intermediate 18, which upon elimination by means of thionylchloride would generate the corresponding perchlorate imidazolium
salt 19. NMR analysis of the crude reaction mixture indeed showed the expected signal of the proton between the two nitrogen atoms around 10 ppm, as well as all the aliphatic and aromatic signals, but the product repeatedly degraded upon attempted purification using column chromatography.
Scheme 5.6 Attempted synthesis of mono-menthyl chiral imidazolium salts
Alternatively, the synthesis of a bis-menthyl imidazolium core was attempted by condensation of monomenthyl aniline 16 with glyoxal to yield bis-imine 20 which was subjected to ring closure using the reaction conditions shown in scheme 5.7. Though the triflate and chloride imidazolium salts 21 and 22 were detected in crude 1H-NMR analysis by means of their characteristic signals around 10 ppm, the products were found to be unstable during the purification step, much like perchlorate imidazolium salt 19.
5.4 Conclusions and outlook
The synthesis of chiral derivatives of the bulky Pd-PEPPSI-family that match with the requirements for organolithium cross couplings has proven very challenging. Related Pd-carbene catalysts that lacked crucial steric hindrance were successfully prepared, and gave significant turnover in the coupling of less challenging substrate, but lacked reactivity in the desired synthesis of tri and tetra-ortho substituted biaryl compounds. Despite several synthetic approaches, the envisioned catalyst containing both large flexible side groups as well as a chiral imidazolinium backbone was only obtained for the IPr variant by the use of a recently reported procedure.9 Initial testing of the catalyst showed similar activity to the other Pd-carbene catalysts that were capable of coupling unhindered substrates, but failed to sufficiently provide turnover for sterically demanding starting materials. Switching the coupling procedure to the in situ preparation of the aryllithium reagent, the product was obtained in good yield, but without e.e. It is therefore that the enantioselective coupling using organolithium reagents was not further pursued. Since the chiral backbone seems to have little effect on the enantiodetermining step, future attempts might focus on the initially abandoned synthesis of chiral alkyl fragments such as in compound 13 via asymmetric reduction, in which the synthesis of the complex could be more successful than the menthyl derived catalysts.
5.5 References
1) a) Introduction to Stereochemistry, K.Mislow, 1965, W. A. Benjamin, Inc, 193, Stereochemistry and Stereoselective Synthesis: An Introduction, M. Nógrádi, L. Poppe, J. Nagy, G. Hornyánszky, Z. Boro,
2016, Wiley VCH, ISBN: 978-3-527-33901-3. b) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner, M. Breuning; Angew. Chem. Int. Ed. 2005, 44, 5384. c) K. Kamikawa, M. Uemura, Synlett 2000, 938. d) O. Baudoin; Eur. J. Org. Chem. 2005, 4223-4229. e) G. Bringmann, T. Gulder, T.A.M. Gulder; Asymmetric Synthesis 2007, 246. f) A. H. Cherney, N. T. Kadunce, and S. E. Reisman. Chem. Rev., 2015, 115 (17), pp 9587–9652. g) C. Zhao, D. Guo, K.Munkerup, K. Huang, F. Li & J. Wang. Nature Communications, 2018, 9, 611 doi:10.1038/s41467-018-02952-3. h) G. Bringmann, D. Menche, J. Kraus, J.Mühlbacher, K. Peters, E.Peters, R.Brun, M. Bezabih, B. M. Abegaz. J. Org. Chem., 2002, 67 (16), pp 5595–5610. i) Ōki, Michinori, Recent Advances in Atropisomerism, in Topics in Stereochemistry, Vol. 14 Hoboken, NJ:John Wiley & Sons, 2007, DOI: 10.1002/9780470147238.ch1 2) a) J. Malineni, R. L. Jezorek, N. Zhang, V. Percec, Synthesis, 2016, 48, 2795-2807.b) S. K. Gurung, S. Thapa, A. Kafle, D. A. Dickie, R. Giri, Org. Lett., 2014, 16, 1264-1267. c) T. Hatakeyama, M. Nakamura, J. Am. Chem. Soc., 2007, 129, 9844-9845
3) V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral, B. L. Feringa, Org. Lett., 2013, 15, 5114-5117. This thesis
4) a) M. G. Organ, s. Calimsiz, M.Sayah, K. Hou Hoi, A. J. Lough, Angew. Chem. Int. Ed. 2009, 48, 2383 –2387 b) B. Atwater, N. Chandrasoma, D. Mitchell, M.J. Rodriguez, M. G. Organ Chem. Eur. J. 2016, 22, 4531, 4534 and references therein
5) Unpublished results
6) S. Guduguntla, V. Hornillos,R. Tessier, M. Fananas-Mastral, and B. L. Feringa. Org. Lett. 2016, 18, 252−255
7) D.l Janssen-Muller, C. Schlepphorst, F.Glorius. Chem. Soc. Rev., 2017, 46, 4845—4854, b) F. Glorius, G. Altenhoff, R. Goddarda C. Lehmanna Chem. Commun., 2002,0, 2704-2705
8) For example : Charles, M. D., Schultz, P. & Buchwald, S. L. Org. Lett. 7, 2005, 3965–3968. 9) H.Wang, G. Lu, G. J. Sormunen, H. A. Malik, P. Liu, J.Montgomery. J. Am. Chem. Soc, 139, 2017 10) As determined by GCMS analysis
11) Zhai, Feng; Jordan, Richard F. - Organometallics, 2017, vol. 36, # 15, p. 2784 - 2799
12) G. A. Price, A. Hassan, N. Chandrasoma, A. R. Bogdan, S. W. Djuric, M. G. Organ, Angew. Chem. Int. Ed. 2017, 56, 13347 –13350
5.6 Experimental section
All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. THF and toluene were dried and distilled over sodium. Chromatography: Grace Reveleris X2 flash chromatography system used with Grace® Flash Cartridges, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and phosphomolybdic Acid (PMA) or potassium permanganate staining. Progress and conversion were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: 7.26 for 1H, 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration.
Pd-PEPPSi-IPr* was synthesised using the corresponding imidazolinium salt (made via a literature procedure)9 by mixing with Cs2CO3 (5.0 eq.) and PdCl2 (1.1 eq.) in 3-Cl-pyridine overnight. All liquids were removed under reduced pressure, the product crashed out by the addition of pentane, and isolated by filtration as a yellow solid. (74%) 1H NMR (400 MHz, Chloroform-d) δ 8.72 (d, J = 2.3 Hz, 1H), 8.63 (dd, J = 5.6, 1.4 Hz, 1H), 7.54 (ddd, J = 8.2, 2.4, 1.3 Hz, 1H), 7.27 (d, J = 1.5 Hz, 11H), 7.10 – 7.07 (m, 1H), 7.05 (d, J = 2.2 Hz, 2H), 6.89 (d, J = 2.2 Hz, 2H), 3.62 (dhept, J = 19.8, 6.6 Hz, 4H), 2.85 (p, J = 6.9 Hz, 2H), 1.63 (dd, J = 10.8, 6.4 Hz, 12H), 1.49 (d, J = 6.7 Hz, 6H), 1.22 (dd, J = 6.9, 1.1 Hz, 13H), 0.37 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 153.01, 151.90, 151.29, 150.73, 148.69, 140.65, 139.96, 134.73, 134.63, 131.57, 131.42, 130.95, 127.07, 125.59, 125.29, 77.59, 36.37, 32.21, 31.13, 30.85, 29.10, 28.11, 27.15, 26.51, 26.40.
Pd-PEPPSI-IBox 7. was synthesised using the corresponding imidazolinium salt (170 mg, 1 eq) (made via a literature procedure)7b by mixing with Cs2CO3 (5.0 eq.) and PdCl2 (1.1 eq.) in 3-Cl-pyridine overnight (4 ml). All liquids were removed under reduced pressure, the product crashed out by the addition of pentane, and isolated by filtration as a yellow solid. (65 mg, 17%) 1H NMR (400 MHz, Chloroform-d) δ 8.98 (d, J = 2.4 Hz, 1H), 8.89 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.36 – 7.27 (m, 1H), 4.94 – 4.82 (m, 4H), 4.72 (dd, J = 8.1, 3.5 Hz, 2H), 3.25 (pd, J = 7.2, 3.9 Hz, 2H), 1.12 (dd, J = 10.3, 6.9 Hz, 12H). 13C NMR (101 MHz, Chloroform-d) δ 150.34, 149.30, 143.99, 138.01, 127.08, 124.82, 109.99, 61.79, 31.20, 18.63, 15.71.
phenylnaphthalene 3a was synthesised using the general procedure described in chapter 2 : 1-Bromonaphthalene (0.3 mmol) and Pd-PEPPSI-IPr* complex (5 mol %) were dissolved in toluene (2 ml) in a dried Schlenk flask under inert atmosphere, and the mixture stirred for 5 min. Subsequently, a solution of Ph-Li in dibutylether (0.45 mmol, 1.5 eq.) diluted to 1 ml (to reach a final concentration of 0.45 M) with toluene was added over 1h by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining Ph-Li. A sample was taken, and analyzed by GC-MS, showing the desired product in 98% yield.
1-(2,6-dimethoxyphenyl)naphthalene 3c was synthesized using the general procedure described in chapter 2 : 1-Bromonaphthalene (0.3 mmol) and Pd-PEPPSI-IPr* complex (5 mol %) were dissolved in toluene (2 ml) in a dried Schlenk flask under inert atmosphere, and the mixture stirred for 5 min.
Subsequently, a solution of aryllithium (see chapter 6) in THF (0.45 mmol, 1.5 eq.) diluted to 1 ml (to reach a final concentration of 0.45 M) with toluene was added over 1h by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining aryl-Li. A sample was analyzed by GC-MS.
2,2'-dimethoxy-1,1'-binaphthalene 3e was synthesized using the general procedure described in chapter 3 : In a dry Schlenk flask, Pd-PEPPSI-iPr* (5 mol%) and 1-bromo-2-methoxynaphthalene (0.3 mmol) were dissolved in 2 mL of dry toluene and the solution was stirred at room temperature. tBuLi (0.7 eq., 0.21 mmol, 0.12 mL of 1.7 M commercial solution) was diluted with toluene to reach the concentration of 0.21 M; this solution was slowly added (flow rate=1 mL/h) by the use of a syringe pump. After complete addition, MeOH (1ml) was added to quench the remaining tBuLi. A sample was taken, and analyzed by GC-MS as wel as chiral HPLC (OJ-H, 95:5 heptane/isopropanol, 0.5 ml/min). No e.e. was observed.
Typical procedures for C-N coupling with sterically hindered arylbromides
A mixture of Pd2dba3 (5%) , Binap (10%) (or instead, Pd-PEPPSI-IPENT (5%)) and NaOtBu 3.4 eq. was prepared in a glovebox (argon). Toluene was added, and the reaction mixture was stirred for 30 min at rt. A solution of chiral diamine in toluene and arylhalide in toluene were added slowly, and the reaction stirred at 105°C for 18h. The reaction was checked for conversion by TLC and 1H NMR. Generally, only starting material was isolated (see table 5.1).
Preparation of menthyl-bisimine 20
Menthyl dimethyl aniline 16 (480 mg, 1.8 mmol, 2 eq. made according to literature procedure)1 was dissolved in EtOH (2ml) . Glyoxal (110 mg, 1.26 mmol, 1.4 eq.) and formic acid (4 drops) were added, and the reaction mixture was stirred overnight. Filtration and trituration with cold MeOH gave the crude product as a yellow solid (277 mg), which was used without further puricifation.
General methods for attempted syntheses of imidazolium salts.
Bisimine 20 was dissolved in THF at 70°C, the solution subsequently cooled down rt, and 1 eq. of ZnCl (1.1 eq) was added at rt. The reaction mixture was heated to 70°C for 5 min, and cooled down to rt, before adding paraformaldehyde (1.1 eq.). The mixture was reheated to 70°C, and cooled down to rt before adding a solution of HCL in dioxane (1,5 eq.). The mixture was then heated to 60°C for 18h. The expected signal at 10 ppm in the crude 1H-NMR suggested the formation of product, but the imidazolium salt degraded upon column chromatography.
Alternatively, Silver triflate (1.5 eq.) was weighed out in a microwave vial in a glovebox (Ar), capped and taken out. DCM was added to the capped vial, followed by the addition of a solution of bisimine 20 in DCM, and chloromethylpivalate (1.5 eq.). The reaction mixture was stirred overnight at 45 °C. Filtration and evaporation of the solvent gave the crude reaction mixture that showed the expected signal at 10 ppm in the crude 1H-NMR suggesting the formation of product. Similar to the imidazolium salt made via the procedure given above, the product degraded upon column chromatography with silica.
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