Synthesis of Six-Membered N-Heterocyclic Carbene Precursors Based on Camphor

The endo- and exo-N-heterocyclic carbene precursors based on camphor were prepared diastereoselectively in five synthetic steps starting from (1S)-(+)-ketopinic acid. The obtained N-heterocyclic carbene precursors were investigated in an asymmetric benzoin reaction. All new compounds were fully characterized, and the absolute configurations were determined via X-ray diffraction and NOESY measurements.


Introduction
Within the chiral pool of building blocks, camphor is a privileged scaffold available in both enantiomeric forms.Camphor undergoes a wide range of different chemical transformations.These include rearrangements, such as the Wagner-Meerwein rearrangement and fragmentation reactions.In addition, these reactions enable the functionalization of apparently inactivated (remote) positions (Figure 1).Accordingly, they enable the synthesis of structurally and functionally very different products [1,2].

Synthesis
The starting point for the synthesis was commercially available (1S)-(+)-ketopinic acid (1) (Scheme 1), which can alternatively be prepared from the much cheaper (1S)-(+)-10-camphorsulfonic acid according to procedures described in the literature [25][26][27].First, (1S)-(+)-ketopinic acid (1) was treated with thionyl chloride.After the removal of volatiles, crude acid chloride 2 was reacted with aniline in the presence of excess triethylamine in anhydrous toluene to give amide 3 [28] in 94% yield.The treatment of ketone 3 with excess aniline in the presence of catalytic amounts of para-toluenesulfonic acid with azeotropic removal of water using 4 Å molecular sieves gave imine 4 in 49% yield.Attempts to reduce both amide and imine functionality in one step to obtain diamines 6a/6b with excess LiAlH4 or BH3•THF resulted in complex product mixtures.Therefore, sequential reduction was performed.A diastereoselective reduction in imine 4 with NaCNBH3 [29] in methanol in the presence of acetic acid afforded exo-aminoamide 5a a 91% yield with high diastereoselectivity (dr 93:7).A reduction in imine 4 with sodium [21,22] in n-propanol at 95 °C gave a mixture of products containing endo-epimer 5b in an estimated 94% combined yield.The diastereoselectivity of this reduction could not be determined.A reduction in imine 4 with Zn in the presence of KOH and catalytic hydrogenation with Pd-C in methanol failed.A reduction in epimeric amides 5a and 5b with excess LiAlH4 gave diamines 6a and 6b in 64% and 61% yields, respectively.Diamines 6a and 6b were isolated with a diastereoselectivity of 99:1 and 90:10, respectively.Finally, cyclic amidinium salts 7a-c were isolated in 65-72% yield by treating diamines 6a and 6b in triethyl orthoformate in the presence of ammonium tetrafluoroborate or ammonium chloride at an elevated temperature [30,31].The exo-amidinium salts 7a and 7b were isolated in 99:1 dr, while the endo-salt 7c was isolated in 91:9 dr (Scheme 1).The recrystallization of 7c from i-PrOH did not improve the diastereomeric ratio.

Synthesis
The starting point for the synthesis was commercially available (1S)-(+)-ketopinic acid (1) (Scheme 1), which can alternatively be prepared from the much cheaper (1S)-(+)-10camphorsulfonic acid according to procedures described in the literature [25][26][27].First, (1S)-(+)-ketopinic acid (1) was treated with thionyl chloride.After the removal of volatiles, crude acid chloride 2 was reacted with aniline in the presence of excess triethylamine in anhydrous toluene to give amide 3 [28] in 94% yield.The treatment of ketone 3 with excess aniline in the presence of catalytic amounts of para-toluenesulfonic acid with azeotropic removal of water using 4 Å molecular sieves gave imine 4 in 49% yield.Attempts to reduce both amide and imine functionality in one step to obtain diamines 6a/6b with excess LiAlH 4 or BH 3 •THF resulted in complex product mixtures.Therefore, sequential reduction was performed.A diastereoselective reduction in imine 4 with NaCNBH 3 [29] in methanol in the presence of acetic acid afforded exo-aminoamide 5a a 91% yield with high diastereoselectivity (dr 93:7).A reduction in imine 4 with sodium [21,22] in n-propanol at 95 • C gave a mixture of products containing endo-epimer 5b in an estimated 94% combined yield.The diastereoselectivity of this reduction could not be determined.A reduction in imine 4 with Zn in the presence of KOH and catalytic hydrogenation with Pd-C in methanol failed.A reduction in epimeric amides 5a and 5b with excess LiAlH 4 gave diamines 6a and 6b in 64% and 61% yields, respectively.Diamines 6a and 6b were isolated with a diastereoselectivity of 99:1 and 90:10, respectively.Finally, cyclic amidinium salts 7a-c were isolated in 65-72% yield by treating diamines 6a and 6b in triethyl orthoformate in the presence of ammonium tetrafluoroborate or ammonium chloride at an elevated temperature [30,31].The exo-amidinium salts 7a and 7b were isolated in 99:1 dr, while the endo-salt 7c was isolated in 91:9 dr (Scheme 1).The recrystallization of 7c from i-PrOH did not improve the diastereomeric ratio.

Structure Determination
The structures of novel camphor derivatives 4-8 were determined using spectroscopic methods ( 1 H and 13 C NMR, 2D NMR, HRMS, and IR).The endo-amine 5b could not be isolated in pure form.It was used directly in further transformation.
The configurations at the newly formed stereogenic centers (C-2) in endo-diamine 6b and endo-amidine 7c were determined using NOESY spectroscopy.The cross-peak between the exo-H(2) and the Me-C(8) group was consistent with the (2S)-configuration (Figure 2).Similarly, the (2R)-configuration at C-2 in exo-camphoramine 5a was in line with the NOE between the Me-C(8) and the exo-NH group (see Supplementary Materials).The endo-stereochemistry of diamine 6b and cyclic amidine 7c was additionally confirmed on the basis of a chemical shift and multiplicity of the endo-H-C(3), which appear as a doublet of doublet at 0.93 ppm (6b) and 0.97 ppm (7c) (Figure 2) ( [21,23], see Supplementary Materials).

Structure Determination
The structures of novel camphor derivatives 4-8 were determined using spectroscopic methods ( 1 H and 13 C NMR, 2D NMR, HRMS, and IR).The endo-amine 5b could not be isolated in pure form.It was used directly in further transformation.
The configurations at the newly formed stereogenic centers (C-2) in endo-diamine 6b and endo-amidine 7c were determined using NOESY spectroscopy.The cross-peak between the exo-H( 2) and the Me-C(8) group was consistent with the (2S)-configuration (Figure 2).Similarly, the (2R)-configuration at C-2 in exo-camphoramine 5a was in line with the NOE between the Me-C(8) and the exo-NH group (see Supplementary Materials).The endo-stereochemistry of diamine 6b and cyclic amidine 7c was additionally confirmed on the basis of a chemical shift and multiplicity of the endo-H-C(3), which appear as a doublet of doublet at 0.93 ppm (6b) and 0.97 ppm (7c) (Figure 2) ( [21,23], see Supplementary Materials).
Finally, the structures of compounds 4 and 7a were unambiguously determined using X-ray diffraction (Figure 3) (see Supplementary Materials).

Performance of Camphor-Derived NHC Precursors in Benzoin Reaction
The model reaction for evaluating the efficiency of the procatalyst 7a-c was the benzoin reaction with benzaldehyde, in which 10 mol% of the procatalyst was used (Scheme 2).Various bases were used for the in situ formation of the nucleophilic carbene catalyst.With aqueous Na 2 CO 3 [32] as a base, no reaction took place, and the NHC precursors remained unchanged.Since the estimated pKa values of amidinium salts 7a-c were in the range of 24 to 26 [33][34][35], stronger bases were used to obtain the NHCs.Reactions in the presence of tBuONa, LiHDMS, and LDA in anhydrous THF or 1,4-dioxane [36] did not give the benzoin product, while the amidinium salts 7a-c decomposed, presumably due to the traces of water present in the reaction mixture or during workup.The attempts to confirm the formation of the carbene catalyst in situ (in the NMR tube) were also unsuccessful, and only the decomposition products were observed.To verify the hydrolysis of amidinium salt 7 under basic conditions and to identify the decomposition product, the amidinium salt ent-7c (dr = 82:18; prepared from (1R)-(−)-ketopinic acid) was hydrolyzed in a mixture of THF and water with two equivalents of NaOH.After 18 h, the amidinium starting salt ent-7c was quantitatively hydrolyzed to an aminoamide mixture 8/8 in the ratio 81:19.The crystallization of the crude product yielded single crystals of 8 (dr = 95:5) suitable for X-ray analysis, which confirmed the structure of hydrolyzed product 8 (Figure 4).The absolute configuration at position 2 was additionally confirmed using the NOESY measurement ( [21,23], see Supplementary Materials) Amidinium salts ent-7c are hydrolytically unstable even in the presence of traces of water and are, therefore, not suitable as precursors of NHCs under applied reaction conditions.cessful, and only the decomposition products were observed.To verify the hydrolysis of amidinium salt 7 under basic conditions and to identify the decomposition product, the amidinium salt ent-7c (dr = 82:18; prepared from (1R)-(-)-ketopinic acid) was hydrolyzed in a mixture of THF and water with two equivalents of NaOH.After 18 h, the amidinium starting salt ent-7c was quantitatively hydrolyzed to an aminoamide mixture 8/8′ in the ratio 81:19.The crystallization of the crude product yielded single crystals of 8 (dr = 95:5) suitable for X-ray analysis, which confirmed the structure of hydrolyzed product 8 (Figure 4).The absolute configuration at position 2 was additionally confirmed using the NOESY measurement ( [21,23], see Supplementary Materials) Amidinium salts ent-7c are hydrolytically unstable even in the presence of traces of water and are, therefore, not suitable as precursors of NHCs under applied reaction conditions.

Materials and General Methods
The solvents for the extractions and chromatography were of technical quality and distilled prior to use.The extracts were dried over technical-grade anhydrous Na2SO4.Melting points were determined on a Kofler micro hot stage and using the SRS OptiMelt MPA100-Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA).IR spectra were recorded using a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA).Mass spectra were recorded using an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA).NMR spectra were recorded with a Bruker UltraShield 500 plus (Bruker, Billerica, MA, United States) at 500 MHz for the 1 H nucleus and 126 MHz for the 13 C nucleus using CDCl3 with TMS as the internal standard solvent.Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035-0.070mm (Sigma-Aldrich, St. Louis, MO, USA)).All commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO,

Materials and General Methods
The solvents for the extractions and chromatography were of technical quality and distilled prior to use.The extracts were dried over technical-grade anhydrous Na 2 SO 4 .Melting points were determined on a Kofler micro hot stage and using the SRS OptiMelt MPA100-Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA).IR spectra were recorded using a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA).Mass spectra were recorded using an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA).NMR spectra were recorded with a Bruker UltraShield 500 plus (Bruker, Billerica, MA, United States) at 500 MHz for the 1 H nucleus and 126 MHz for the 13 C nucleus using CDCl 3 with TMS as the internal standard solvent.Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035-0.070mm (Sigma-Aldrich, St. Louis, MO, USA)).All commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA).

Synthesis of (1R,4R,E)-7,7-Dimethyl-N-phenyl-2-(phenylimino)bicyclo[2.2.1]heptane-1-carboxamide (4)
To a solution of amide 3, (10 mmol, 2.573 g) in anhydrous toluene (40 mL) under argon were added aniline (50 mmol, 4.556 mL) and para-toluenesulfonic acid monohydrate (2 mmol, 380 mg).The flask was fitted with a Dean-Stark trap filled with activated 4 Å molecular sieves and a reflux condenser.The reaction mixture was refluxed for 20 h.In a cooled reaction mixture, EtOAc (30 mL) and H 2 O (30 mL) were added, and the phases were separated.The aqueous phase was extracted with EtOAc (2 × 20 mL).The combined organic phase was washed with brine (10 mL), dried under anhydrous Na 2 SO 4 , filtered, and the volatiles were evaporated in vacuo.The crude product was purified using CC (Silica gel 60, EtOAc/petroleum ether = 1:5).The fractions containing pure product 4 were combined, and the volatiles were evaporated in vacuo.Yield: 1.629 g (4.9 mmol, 49%) of orange solid; mp = 138-140  (12 mmol, 794 mg, ω = 0.95) was added to a solution of imine 4 (332 mg, 1 mmol) in anhydrous MeOH (15 mL) under argon.Then, a catalytic amount of anhydrous acetic acid (0.2 mL) was added, and the reaction mixture was stirred at room temperature for 5 h.The reaction was stopped by adding a saturated solution of NaHCO 3 (5 mL) and EtOAc (10 mL), and the phases were separated.The aqueous phase was extracted with EtOAc (10 mL), and the combined organic phase was washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , which was filtered, and the volatiles were evaporated in vacuo.Yield: 304 mg (0.91 mmol, 91%, dr 93:7) of a dirty white solid; mp = 174-175   Imine 4 (3 mmol, 997 mg) was dissolved in n-PrOH (100 mL), and the mixture was heated to 95 • C.Then, the first sodium piece was added to the reaction mixture, followed by another sodium piece after the first sodium piece had reacted, then the third, and so on.After 2 h at 95 • C, when the last sodium piece had reacted, H 2 O (100 mL) and Et 2 O (100 mL) were added to the cooled reaction mixture, and the phases were separated.The aqueous phase was extracted with Et 2 O (2 × 100 mL), and the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered, and the volatiles were evaporated in vacuo.The crude amine 5b was further reacted without additional purification.Yield: 943 mg (2.82 mmol, 94%) of grey oil.
To a solution of compound 5b (0.5 mmol, 201 mg) in anhydrous THF (2 mL) under argon at room temperature was added LiAlH 4 (2.4 M in THF, 1.0 mL) dropwise.After this addition, the reaction mixture was stirred for 20 h at 60 • C. The reaction was cooled (0 • C) and quenched by the careful addition of a mixture of H 2 O and THF in a 1:5 ratio.The reaction mixture was filtered, and the cake was washed with EtOAc (3 × 15 mL).The collected liquid was dried over anhydrous Na 2 SO 4 , filtered, and the volatiles were evaporated in vacuo.The crude product was purified using CC (Silica gel 60, EtOAc/petroleum ether = 1:10).The fractions containing pure product 6b were combined, and the volatiles were evaporated in vacuo.Yield: 98 mg (0.305 mmol, 61%, dr 90:10) of grey semisolid.

General Procedure for the Catalytic Asymmetric Benzoin Condensation Reaction with Benzaldehyde
To a solution/suspension of amidinium salt 7 (10 mol%) in anhydrous THF or 1,4dioxane (in the case of Na 2 CO 3 , water was used as solvent), benzaldehyde (0.75 mmol) and then a base (10 mol%; tBuONa, LiHDMS, and LDA (1 M in THF/hexanes)) were added.The resulting reaction mixture was stirred for 24 h at room temperature.The reaction mixture was concentrated under reduced pressure.Part of the residue was used for 1 H-NMR measurements, and the rest was subjected to column chromatography.

X-ray Crystallography
Single-crystal X-ray diffraction data were collected with an Agilent Technologies Su-perNova Dual diffractometer with an Atlas detector using monochromatic Cu-Kα radiation (λ = 1.54184Å) at 150 K. CrysAlis PRO was used to process the data [37].Olex2.1.2[38] was used to solve the structures using the direct methods implemented in SHELXS [39] or SHELXT [40] and refined using a full matrix least squares method based on F2 and SHELXT-2014/7 [41].All non-hydrogen atoms were refined anisotropically.The hydrogen atoms were placed at geometrically calculated positions and refined with a riding model.Mercury [42] and Platon [43] were used for the drawings and the analysis of bond lengths, bond angles, and intermolecular interactions.Structural and other crystallographic details for data collection and the refinement of compounds 4, 7a, and 8 were deposited with the Cambridge Crystallographic Data Centre under CCDC Deposition Numbers 2302865, 2302861, and 2307379, respectively.These data are available free of charge at https://www.ccdc.cam.ac.uk/structures/, accessed on 13 November 2023 (or

Molecules 2023 , 12 Figure 2 .
Figure 2. Determination of the absolute configuration at the C-2 based on the observed NOE correlation spectroscopy cross peaks (top) and chemical shift correlations in the series of C-2 endo-isomers (bottom).

Figure 2 .
Figure 2. Determination of the absolute configuration at the C-2 based on the observed NOE correlation spectroscopy cross peaks (top) and chemical shift correlations in the series of C-2 endoisomers (bottom).

Figure 2 .
Figure 2. Determination of the absolute configuration at the C-2 based on the observed NOE correlation spectroscopy cross peaks (top) and chemical shift correlations in the series of C-2 endo-isomers (bottom).

Figure 4 .
Figure 4.The molecular structure of compound 8. Thermal ellipsoids are shown at a 50% probability.

Figure 4 .
Figure 4.The molecular structure of compound 8. Thermal ellipsoids are shown at a 50% probability. .