Synthesis of Pd^II Complexes Bearing an Enantiomerically-Resolved Seven-Membered N-Heterocyclic Carbene Ligands and Initial Studies of their Use in Asymmetric Wacker-Type Oxidative Cyclization Reactions

Abstract

The development of enantiomerically-resolved, axially-chiral seven-membered N-heterocyclic carbene (⁷NHC) ligands for palladium is described. These ⁷NHC ligands are derived from enatiomerically pure 2,2′-diamino-6,6′-dimethylbiphenyl, which is transformed via a synthetic sequence consisting of ortho-arylation, N-alkylation, and cyclization to afford seven-membered-ring amidinium salts. Synthesis of the 7-membered amidinium salts benefits from microwave irradiation, and in-situ metalation of the amidinium salts yields ⁷NHC-Pd^II complexes. The chiral ⁷NHC-Pd complexes were examined as chiral catalysts under aerobic conditions in two intramolecular oxidative amination reactions of alkenes. In one case, enantioselectivities up to 63% e.e. were obtained, while the other substrate underwent cyclization to afford essentially racemic products. The catalytic data compare favorably to results obtained with a Pd^II catalyst bearing a chiral five-membered-ring NHC ligand and, thereby, highlight the potential significance of this new class of chiral NHC ligands.

1. Introduction

Chiral monodentate N-heterocyclic carbenes (NHCs) have broad potential utility in asymmetric catalysis, but successful applications of such ligands remain somewhat limited.^1,2 To our knowledge, only six transformations have been reported in which chiral monodentate NHC ligands have been employed to afford enantioselectivities above 90% e.e. (for representative examples, see Figure 1). The transformations include olefin metathesis, ³ 1,4-addition of arylboronic acids to enones, ⁴ hydrosilylation of ketones, ⁵ intramolecular alpha-arylation of amides,^6,7 copper-catalyzed conjugate addition to cycloheptenone with diethylzinc,⁸ and Ni-catalyzed reductive coupling of 1,2-dienes and aldehydes with triethylsilane⁹. All of these transformations utilize 5-membered-ring NHC ligands. Two strategies have been employed in the design of chiral monodentate 5-membered NHCs: “chiral relay” and the use of chiral nitrogen substituents. In the first strategy, developed by Grubbs and coworkers,³ chirality in the N-heterocycle induces an asymmetric conformation of the nonsymmetrical (but achiral) nitrogen substituents (Figure 1, ligand L¹). In the second strategy, the ligand chirality arises from the incorporation of chiral nitrogen substituents into the ligand, for example, by Buchwald-Hartwig amination of chiral cyclophanes (Figure 1, ligand L²)^5,4 or by reductive amination of 1,2-diones with chiral amines (Figure 1, ligands L³–L⁵).^6,7,8 Although attempts have been made to develop ligands that feature both chiral relay and chiral nitrogen substituents, only modest success has been achieved thus far.^8,10

Figure 1.

Asymmetric catalysis with chiral monodentate NHCs giving >90% e.e.

NHCs are excellent ligands for metal-catalyzed aerobic oxidation reactions because metal-NHC complexes are oxidatively stable.¹¹ NHC-Pd complexes have been employed as catalysts for aerobic oxidation of alcohols, ¹² Wacker-type cyclization of ortho-allyl phenols, ¹³ and intramolecular oxidative amination of olefins (Figure 2a, b, and c, respectively).¹⁴ We have been interested in the development of enantioselective aerobic oxidative amination reactions of alkenes, and the use of chiral NHC ligands was a logical starting point. In connection with these efforts, we have been exploring the development and application of a new class of NHCs based upon a seven-membered heterocyclic framework (Figure 3b).^15,16 These 7-membered NHCs (⁷NHCs) are attractive because they feature an axially-chiral heterocyclic framework that provides an out-of-plane projection of the nitrogen substituents (Figure 3b). This non-planarity contrasts the in-plane orientation of the nitrogen substituents in 5-membered NHCs (Figure 3a), and we reasoned that increased enantioselectivity might be achieved in asymmetric catalysis with ⁷NHCs. We have reported that a racemic ⁷NHC-Pd complex is an active catalyst for the intramolecular aerobic oxidative amination of o-crotyl tosylanilide (Figure 2c),¹⁴ but, at the time of this work, we had not yet succeeded in preparing enantiomerically resolved ⁷NHC-Pd complexes. Our initial synthesis of ⁷NHC-Pd complexes¹⁵ is not amenable to the synthesis of resolved analogs. Here, we describe the synthesis of enantiomerically resolved seven-membered-ring amidinium salts, metalation of the amidinium salts by Pd^II and the investigation of ⁷NHC– Pd^II complexes in intramolecular aerobic oxidative heterocyclization reactions. The enantioselectivity data from the catalytic reactions is modest (≤ 63% e.e.). Nevertheless, the ⁷NHC ligand proves to be substantially better than one of the most successful known ⁵NHC ligands.

Figure 2.

Palladium-catalyzed aerobic oxidation reactions that have employed NHC ligands.

Figure 3.

(a) Planarity of 5-membered NHCs (⁵NHCs). (b) Non-planarity of 7-membered NHCs (⁷NHCs).

2. Results and Discussion

2.1 Strategy

At the time this work began, there were only two reported examples of chiral monodentate ⁵NHCs employed in reactions that achieved e.e.'s above 90%.^3c,4 The chiral ⁵NHCs developed by Grubbs et al. (L¹, Figure 1)³ were not useful for our goal of accessing NHC-Pd(O₂CR)₂ catalysts for asymmetric aerobic Wacker-type oxidation reactions because such catalysts were not synthetically accessible.¹⁷ The chiral ⁵NHCs developed by Andrus et al. (L², Figure 1)⁴ proved to be prohibitively difficult to synthesize. Within this context, we turned our attention to the development of new chiral NHC ligands, and our efforts led to the ⁷NHC derivatives. After achieving preliminary success in the preparation of racemic ⁷NHC-Pd complexes,¹⁵ we envisioned two potential strategies to access resolved derivatives of ⁷NHC ligands: (1) incorporation of substituents ortho to the nitrogens (the 3 and 3′ positions of the biphenyl moiety), and (2) use of resolved biphenyl diamines (i.e. biphenyl diamines with substituents in the 6 and 6′ positions). In the first strategy, we reasoned (and obtained preliminary support from computational modeling) that steric interactions between the ortho groups and the nitrogen substituents should prevent racemization of the ⁷NHC. This strategy proved unattractive, however, because it would require independent resolution of each new amidinium salt (the ⁷NHC precursor).¹⁸ We therefore focused our efforts on executing the second strategy, which would allow many resolved ⁷NHC complexes to be synthesized from a single stock of resolved diamine.

As we have reported previously,^15a the use of 2,2′-diamino-1,1′-binaphthyl (DABN) for the synthesis of resolved DABN-derived seven-membered-ring amidinium salts was successful only with neopentyl groups as nitrogen substituents (e.g. Figure 4a); the corresponding amidinium salt bearing N-(2-adamantyl) or N-aryl groups were not accessible (e.g. Figure 4b).^{15, 19} These observations were problematic because palladium complexes bearing ⁷NHCs with primary nitrogen substituents proved to be unstable. The instability of ⁷NHC-Pd complexes bearing primary alkyl nitrogen substituents appears to arise from decreased steric protection of the carbene carbon relative to those with secondary nitrogen substituents. Based on this hypothesis, we reasoned that substituents in the ortho positions (i.e., the 3 and 3′ positions of the biphenyl moiety) could provide additional steric protection of the carbene carbon and, thereby, permit primary alkyl nitrogen substituents to be employed (Figure 4c). Based on this proposal, we explored methods to access ortho substituted biaryl diamines.

Figure 4.

(a) Stable ⁷NHC-[M] complexes are not stable with primary alkyl nitrogen substituents. (b) Resolved ⁷NHC-HBF₄ salts are not accessible with secondary alkyl nitrogen substituents. (c) Proposed access to stable resolved ⁷NHC-[M] complexes.

2.2 Development of the Daugulis-Zaitsev ortho-arylation for the synthesis of m-quaterphenyl-2′,2″-diamines, and access to resolved ⁷NHC-Pd complexes

Installation of steric bulk ortho to the nitrogen substituents of biaryl diamines required an ortho functionalization strategy. We recently reported that application of an ortho C–H arylation reaction developed by Daugulis and Zaitsev²⁰ provides ready access to ortho diarylated biaryl diamines (Scheme 1).²¹ An important result from this study is that the ortho-arylation reaction is more effective for 2,2′-diamino-6,6′-dimethylbiphenyl (4) than for DABN, and we therefore turned our attention completely to the resolved diamine 4.²² We next examined the synthesis of [⁷NHC-H]⁺ salts derived from these new resolved quaterphenyl diamines.

Scheme 1.

Synthesis of resolved quaterphenyl diamines.

This synthetic access to ortho-functionalized biaryldiamines enabled us to test the hypothesis that primary nitrogen substituents could be used in the preparation of stable NHC-Pd complexes. Our initial studies were carried out on the inexpensive and readily available diamine 6, which was synthesized by acetylation, Dagulis-Zaitsev arylation, and deacetylation of 2,2′-diaminobiphenyl.²¹ Sequential addition of 1-naphthaldehyde and lithium aluminum hydride to the quaterphenyl diamine 6²¹ furnished the di-N-alkylated quaterphenyl diamine 7 in high yield. Cyclization of this diamine afforded the desired amidinium tetrafluoroborate salt 8. Addition of [Pd(allyl)Cl]₂ and KOtBu to 8 furnished the stable NHC-Pd(allyl)Cl complex 9, albeit in low yield (Scheme 2). The structure of 9 was verified by X-ray crystallographic analysis (Figure 5).²³ Synthesis of the stable NHC-Pd complex 9 bearing primary nitrogen substituents supported our hypothesis that incorporation of steric bulk in the ortho-positions of the biphenyl diamine could provide steric protection of the NHC and permit the synthesis of stable NHC-metal complexes bearing primary nitrogen substituents.

Scheme 2.

Primary N-substituents with ortho-aryl groups afford a stable NHC-Pd complex.

Figure 5.

Solid-state molecular structure of 9. Hydrogen atoms are omitted for clarity. Only the preferred orientation of the disordered atom C2 is shown, which is disordered over two positions in an 85:15 ratio. Thermal ellipsoids are shown at 30% probability.

The next important challenge was to demonstrate that this synthetic approach could be used with resolved biphenyl diamines. Toward this end, (S)-5 was alkylated via sequential reductive amination with cyclohexane carboxyladehyde and LiAlH₄ to afford (S)-10 in 94% yield (Scheme 3). Initial attempts to cyclize (S)-10 using published conditions^15,24 with HC(OEt)₃ and NH₄BF₄ to form amidinium salt (S)-11 were largely unsuccessful, providing a thick dark reaction mixture after prolonged reaction times, from which only a small amount of nearly pure amidinium salt could be extracted; shorter reaction times provided very low yields as well. We ultimately found the cyclization reaction could be achieved by employing microwave irradiation.²⁵ The amidinium salt (S)-11 was obtained in 38% yield, and workup of the crude mixture was not as challenging. Metalation of amidinium salt (S)-11 with KOtBu and [Pd(allyl)Cl]₂ afforded the ⁷NHC-Pd(allyl)Cl complex (S)-12 in 29% yield (Scheme 3). As NHC-Pd(carboxylate)₂ complexes are of catalytic relevance,^11,12 we sought to make such a complex from (S)-12. Addition of ethereal HCl to (S)-12 to afford the [NHC-PdCl₂]₂ complex (S,S)-13 followed by addition of AgO₂CCF₃ (AgTFA) afforded the NHC-Pd(TFA)₂(OH₂) complex (S)-14 (Scheme 4). The molecular structure of (S)-14 was confirmed in the solid state by X-ray diffraction analysis (Figure 6).²³ Unfortunately, the yields of amidinium salt and NHC-Pd(allyl)Cl are quite low, despite extensive attempts to improve them. ²⁶ Nonetheless, these results represented the first successful preparation of resolved ⁷NHC complexes of this type.

Scheme 3.

Synthesis of the first resolved metal complexes bearing a chiral ⁷NHC.

Scheme 4.

Synthesis of the catalytically relevant resolved ⁷NHC-Pd complex (S)-14.

Figure 6.

Solid-state molecular structure of (S)-14. Only one symmetry-independent molecule is shown. All hydrogen atoms except those on the aqua ligand are omitted for clarity. Thermal ellipsoids are shown at 30% probability.

2.3 Initial effort to apply resolved ⁷NHC-Pd complexes to asymmetric intramolecular aerobic oxidative amination of alkenes

The [NHC-PdCl₂]₂ complex (S,S)-13 was first examined as a catalyst for the asymmetric aerobic oxidative cyclization of substrate 15 (Table 1).²⁷ This substrate was examined because it is the only substrate reported to undergo palladium-catalyzed asymmetric aerobic oxidative amination.²⁸ Yang and coworkers achieved up to 86% e.e. in the oxidative cyclization of this substrate with a (–)-sparteine-Pd catalyst. NHC ligands have not been tested previously in this oxidative cyclization reaction. Representative screening data in Table 1 reveal only modest success with the use of the ⁷NHC-Pd complex (S,S)-13 as the catalyst. In the best case, the product 16 was obtained in 63% e.e., albeit in rather low yield (Table 1 entry 3). Other conditions examined resulted in significantly lower e.e. or no formation of 16. For example, base was shown to facilitate substrate oxidation by Pd^II, but iPr₂NEt was the only base among those tested (including Na₂CO₃, NaOAc, NaO₂CPh, MgO, Ca(OH)₂, NEt₃) that led to even modest levels of catalytic turnover. The origin of these observations is not currently known.

Table 1.

Aerobic oxidative cyclization of substrate 15 catalyzed by (S,S)-13.

entry	AgX	additive(s)	% yielda	% e.e.b
1	AgTFA	iPr2NEt	24%	27%
2c	AgTFA	iPr2NEt	25%	20%
3	AgTFA	iPr2NEt, 3Å MS	35%	63%
4	AgOAc	iPr2NEt	∼0%	--
5	AgOBz	iPr2NEt	∼0%	--
6	AgOTs	iPr2NEt	∼0%	--
7	Ag2CO3	iPr2NEt	∼0%	--

^aYield determined by GC relative to internal standard.

^b% e.e. determined by GC or HPLC.

^cReaction run at 80° C.

We next turned our attention to the aerobic oxidative amination of substrate 2, which has been shown by us to be an effective substrate for aerobic oxidative amination catalyzed by NHC-Pd complexes, including one of our racemic ⁷NHC ligands (Figure 2).¹⁴ The conditions employed in entries 1-6 of Table 2 resemble the best conditions for the reported racemic cyclization of 2,¹⁴ whereas the conditions employed in entry 7 mirrored the best conditions for the cyclization of 15. Although modest yields of product 3 were obtained, the cyclization product was nearly racemic in every case (Table 2).

Table 2.

Attempts at asymmetric aerobic oxidative cyclization of substrate 2 by (S,S)-13.

entry	AgX	additive(s)	% yielda	% e.e.b
1	AgOAc	--	31%	9%
2	AgOAc	BzOHc	27%	-3%
3	AgOAc	Na2CO3d	63%	2%
4	AgTFA	--	22%	1%
5	AgTFA	BzOHc	20%	1%
6	AgTFA	Na2CO3d	26%	-7%
7	AgTFA	iPr2NEt,d 3Å MS	12%	0%

^aYield determined by GC relative to internal standard.

^b% e.e. determined by HPLC.

^c20 mol %.

^d2 equivalents.

2.4 Use of a resolved ⁵NHC-Pd complex in asymmetric aerobic oxidative Wacker-type cyclization reactions

When the oxidative cyclization studies described above were nearly complete, Kündig and coworkers reported the use of chiral ⁵NHC ligands in Pd-catalyzed intramolecular α-arylation reactions (Figure 1d).^6,7 The latter work, which provided the first highly-enantioselective reaction (>90% e.e.) employing a chiral NHC-Pd catalyst, prompted us to examine the most successful ⁵NHC ligand from this work in Wacker-type oxidative cyclization reactions.

Synthesis of palladium complexes derived from the amidinium iodide salt 1 (Figure 1d) were carried out by combining 1 with [Pd(allyl)Cl]₂ and KOtBu to afford the NHC-Pd(allyl)Cl complex 17, followed by protonolysis of the allyl ligand with ethereal HCl to afford the [NHC-PdCl₂]₂ complex 18.²⁹ Anion metathesis with silver(I)-carboxylate salts did not furnish the desired NHC-Pd(carboxylate)₂ complexes, but instead led to formation of the cyclometalated complexes 19 and 20 (Scheme 5). The solid-state molecular structure of 19 was unambiguously determined by X-ray diffraction analysis (Figure 7).²³ Although complexes 19 and 20 were not the targeted NHC-Pd(carboxylate)₂ catalysts, we nonetheless tested these complexes as catalysts for the oxidative cyclization reactions of substrates 2 and 15.

Scheme 5.

Synthesis of catalytically relevant palladium complexes bearing Kündig's chiral NHC.

Figure 7.

Solid-state molecular structure of 19. Hydrogen atoms are omitted for clarity. Thermal ellipsoids are shown at 50% probability.

In the aerobic oxidative cyclization of substrate 15 with catalysts 19 and 20, improved yields could be obtained relative to those with catalyst (S,S)-13; however, the product 16 was racemic in every case (Table 3). The aerobic oxidative cyclization of 2 with catalysts 19 and 20 proceeded in excellent yield (Table 4), but, once again, the product was always racemic. The improved yields with the ⁵NHC-Pd catalysts may reflect the smaller size of the ⁵NHC ligand compared to the ⁷NHC ligand.

Table 3.

Aerobic oxidative cyclization of substrate 15 catalyzed by 19 and 29.

entry	catalyst	additive(s)	% yielda	% e.e.b
1	19	--	57%	2%
2c	19	20% BzOH	15%	5%
3	19	2 equiv Na2CO3	66%	7%
4	19	2 equiv iPr2NEt, 3Å MS	34%	0%
5	20	--	5%	0%
6	20	20% BzOH	7%	0%
7	20	2 equiv Na2CO3	13%	4%
8	20	2 equiv iPr2NEt, 3Å MS	2%	0%

^aYield determined by GC relative to internal standard.

^b% e.e. determined by HPLC.

^cReaction run at 80° C.

Table 4.

Aerobic oxidative cyclization of substrate 2 catalyzed by 19 and 20.

entry	catalyst	additive(s)	% yielda	% e.e.b
1	19	--	90%	5%
2	19	BzOHc	91%	4%
3	19	Na2CO3d	90%	6%
4	20	--	82%	5%
5	20	BzOHc	85%	4%
6	20	Na2CO3d	83%	0%

^aYield determined by GC relative to internal standard.

^b% e.e. determined by HPLC.

^c20 mol %.

^d2 equivalents.

3. Conclusions

In this study, we have achieved preparation of the first enantiomerically resolved ⁷NHC-Pd complexes and investigated their reactivity in aerobic oxidative cyclization reactions of alkenes. The ⁷NHC-precursor amidinium salt is accessible through a sequence involving a Pd-catalyzed ortho-arylation of the biaryl ring, incorporation of nitrogen substituents via reductive amination, and cyclization using HC(OEt)₃ and NH₄BF₄ under microwave irradiation. The ortho-arylation reaction is critical to access stable ⁷NHC-Pd complexes. These ligands were employed with mixed success in Pd-catalyzed aerobic oxidative cyclization reactions. In one case, up to 63% e.e. was achieved in a Pd-catalyzed intramolecular oxidative amination reaction. Although this level of enantioselectivity is relatively modest, the result is significantly better than that obtained with Pd-catalysts bearing chiral five-membered NHC ligands (≤7% e.e.). These observations highlight the prospects for the use of chiral seven-membered NHCs of the type described here in asymmetric catalysis.

4. Experimental

4.1 General considerations

Reactions which were performed under nitrogen were run in column-dried solvents,³⁰ whereas reactions performed in a glove box were run in ketyl-dried solvents. ¹H and ¹³C NMR spectra were recorded on 300 or 500 MHz spectrometers. ¹H chemical shifts (δ) are reported in ppm relative to SiMe₄ (0.0 ppm) while ¹³C chemical shifts are reported in ppm relative to deuterated solvent (77.23 ppm for CDCl₃ or 128.06 for benzene-d₆).

4.2 General screening conditions for oxidative Wacker-type cyclization reactions

Screening was conducted in disposable Borosilicate Heavy Wall 13 × 100 mm Culture Tubes (Fisherbrand). Catalyst and solid additives were weighed into reaction tubes, which were then loaded onto a custom 48-well parallel reactor mounted on a Large Capacity Mixer (Glas-Col). The headspace was purged under a positive flow of dioxygen with mild vortexing for fifteen minutes. A stock solution of the substrate in toluene (0.1M) was added to the reaction tubes, which were then vortexed for 18 h under 1 atm dioxygen at 80 °C, after which time the reactions were filtered over celite and the solvent was removed from each tube under reduced pressure prior to analysis by ¹H NMR spectroscopy, gas chromatography, and/or HPLC.

4.3 Synthesis and characterization data

N,N′-bis(1-naphthylmethyl)-2′,2″-diamino-m,m-quaterphenyl (7)

470 mg diamine 6 was combined with 778 μL 1-naphthaldehyde and a few crystals of p-TsOH in ∼250 mL toluene. A Dean-Stark apparatus was attached, and the reaction was heated to reflux for 48 h. Solvent was then removed in vacuo and the residue was taken up in 25 mL dry THF. 339 mg LiAlH₄ (6.4 equiv) was added slowly and the solution was heated to 50 °C for two hours. After cooling to room temperature, the reaction was carefully quenched by sequential addition of 0.3 mL H₂O, 0.6 mL 10% NaOH_(aq), then 0.9 mL H₂O. The solid that formed was removed by filtration, and the filtrate was concentrated in vacuo. Product was purified by column chromatography (SiO₂ packed with 5% NEt₃ in toluene, then flushed with toluene before loading crude) using a gradient eluent (pure toluene to 1:1 toluene-EtOAc) to afford 605 mg 7 as a light yellow oil (70% yield). HRMS: m/z (ESI) calculated [MH]⁺ = 617.2956, measured 617.2963 (Δ = 1.1 ppm). ¹H NMR (300 MHz, CDCl3) 3.99 (s, 4H) 6.90 (d, J = 6.0 Hz, 2H), 7.01 (t, 7.5 Hz, 2H), 7.14 - 7.36 (m, 22H), 7.60 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H). ¹³C NMR (75MHz, CDCl₃) 50.6, 121.8, 123.6, 125.4, 125.6, 126.3, 127.2, 127.9, δ128.5, 128.5, 129.4, 130.9, 131.1, 132.5, 133.8, 134.2, 135.6, 140.9, 145.0.

Amidinium salt 8

3.1 g diamine 7 was combined with 560 mg NH₄BF₄ in 150 mL HC(OEt)₃. The reaction was heated to 130 °C for 48 h. The reaction was then concentrated in vacuo to a thick oil and taken up in minimal methylene chloride. Excess hexanes were added to drive the product out of solution, and the suspension was cooled in a freezer overnight. Tan solid was collected by filtration and washed with pentane. The solid was then taken up in minimal refluxing ethanol and cooled in a freezer. The resultant powder was collected by filtration, washed with pentane, and dried under high vacuum to afford 1.7 g pure 8 as a tan solid (47% yield). HRMS: m/z (ESI) calculated [MH]⁺ = 627.2795, measured 627.2805 (Δ = 1.6 ppm). ¹H NMR (300 MHz, CDCl₃) 4.35 (d, J = 14.4 Hz, 2H), 4.82 (d, J = 14.4 Hz, 2H), 6.73 (br. s, 4H), 7.04 (ddd, J = 8.1, 6.9, 1.2 Hz, 2H), 7.10 - 7.15 (m, 4H), 7.21 (ddd, J = 8.4, 6.9,1.2 Hz, 2H), 7.28 - 7.31 (m, 4H), 7.36 - 7.54 (m, 10H), 7.61 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 8.4 Hz), 9.49 (s, 1H). ¹³C NMR (75MHz, CDCl₃) 57.1, 122.2, 125.9, 126.0, 126.7, 128.0, 128.9, 129.1, 129.3, 129.6, 130.1, 130.2, 132.2, 132.4, 133.8, 134.3, 136.9, 137.2, 142.1, 179.1.

NHC-Pd(allyl)Cl complex 9

756 mg 8 (1.06 mmol), KOtBu (132.2 mg, 1.1 equiv), and [Pd(allyl)Cl]₂ (230 mg, 0.60 equiv), were combined in 30 mL dry THF in a glove box. The reaction was stirred at room temperature for 20 h, after which it was removed from the glove box. The suspension was filtered over celite and the solvent removed in vacuo. 9 was purified by column chromatography (SiO₂) using a gradient eluent (40% Et₂O in hexanes to pure Et₂O) as a lightly yellow solid (100 mg, 12% yield). The product is a 1.5:1 mixture of allyl rotamers by ¹H NMR spectroscopy. HRMS: m/z (ESI) calculated [M(-Cl)]⁺ = 771.2169, measured 771.2178 (Δ = 1.2 ppm). ¹H NMR (300 MHz, CDCl3) (all peaks are quite broad. Identity is known from X-ray crystal structure, but NMR spectra are difficult to interpret) 1.64 (m, 1.5H), 2.25 (m, 1H), 2.38 (m, 1H), 2.84 (m, 1.5H), 3.31 (m, 2.5H), 4.29 (m, 1.5H), 4.72 (m, 1H), 5.00 (m, 1.5H), 5.24 (m, 1H), 6.94 - 7.64 (m, 45H). ¹³C NMR (75MHz, CDCl₃) 58.2 (br. peak), 115.7, 116.4, 125.0, 125.7, 127.7, 127.9, 128.4, 129.1, 132.0, 133.4, 136.2, 140.1, 144.9 (br. peak).

(S)-N,N′-bis(cyclohexylmethyl)-2′,2″-diamino-4′,4″-dimethyl-m,m-quaterphenyl ((S)-10)

2.0 g diamine (S)-5 was combined with 1.7 mL cyclohexane carboxaldehyde (2.5 equiv) and a few crystals of p-TsOH in 120 mL toluene in a Dean-Stark apparatus. The reaction was heated to reflux for 60 h, cooled to room temperature, and solvent was removed in vacuo. The resultant residue was taken up in 50 mL dry THF and 650 mg LiAlH₄ was carefully added portionwise. The reaction was stirred at 50 °C for 2 h, cooled to room temperature, and carefully quenched by sequential addition of 1 mL H₂O, 2 mL 10% NaOH_(aq), and 3 mL H₂O. The solid which had crashed out was removed by filtration, and solvent was removed from the filtrate in vacuo to afford (S)-10 in 95% yield. HRMS: m/z (ESI) calculated [MH]⁺ = 557.3891, measured 557.3883 (Δ = 1 ppm). ¹H NMR (300 MHz, CDCl3) 0.41 (br. q, J = 12.3 Hz, 4H), 0.90 - 1.09 (m, 8H), 1.20 - 1.28 (m, 4H), 1.48 - 1.55 (m, 4H), 2.02 (s, 6H), δ2.27 (m, 4H), 3.27 (br. s, 2H), 6.87 (dd, J = 7.8, 0.8 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 7.27 - 7.30 (m, 2H), 7.35 - 7.40 (m, 4H), 7.49 - 7.52 (m, 4H). ¹³C NMR (75MHz, CDCl₃) 20.5, 26.1, 26.7, 30.9, 31.0, 38.8, 54.5, 121.9, 126.5, 127.6, 128.4, 129.1, 131.3, 137.1, 142.4, 145.8.

Amidinium salt (S)-11

Diamine (S)-10, NH₄BF₄ (1.3 equiv), and 100 mL HC(OEt)₃ were combined and subjected to microwave irradiation (equilibration time to 100 °C = 10 minutes, 2 h at 100 °C, max power = 250 watts). Concentration on a rotary evaporator, dissolving in minimal hot toluene, and crashing out with hexanes afforded some powder and a sticky orange semi-solid. The powder was filtered away, and the semi-solid was again taken up in hot toluene and crashed out with hexanes. This procedure was repeated as necessary until no more powder formed. Dissolved filtered powder in dichloromethane and filtered to remove excess NH₄BF₄. Removed solvent from filtrate to afford a sticky solid, which was re-dissolved in minimal dichloromethane and added dropwise to a 250 mL graduated cylinder filled with hexanes (powder forms immediately on addition of each drop). After complete addition, let suspension sit for 30 minutes then decanted the hexanes. Dissolved solid in dichloromethane and transferred to a flask. Solvent was removed in vacuo to afford 38% yield (1.35 g) of (S)-11 as a tan powder. HRMS: m/z (ESI) calculated [MH]⁺ = 567.3734, measured 567.3736 (Δ = 0.4 ppm). ¹H NMR (300 MHz, CDCl3) 0.39 (qd, J = 11.7 Hz, 2H), 0.52 - 0.71 (m, 4H), 0.81 - 0.97 (m, 4H), 1.10 - 1.35 (m, 6H), 1.39 -1.43 (m, 6H), 2.29 (s, 6H), 2.93 (dd, J = 13.8, 5.1 Hz, 2H), 3.37 (14.0, 6.1 Hz, 2H), 7.27 - 7.35 (m, 6H), 742 - 7.49 (m, 4H), 7.55 - 7.61 (m, 4H), 9.05 (s, 1H). ¹³C NMR (75MHz, CDCl₃) 19.6, 25.6, 25.7, 25.8, 29.7, 30.0, 40.1, 61.4, 127.7, 128.9, 130.1, 131.0, 132.6, 132.8, 134.4, 137.6, 138.3, 145.4, 175.8.

NHC-Pd(allyl)Cl complex (S)-12

This complex was synthesized analogously to compound 9. Product was purified by column chromatography (SiO₂) using 1:1 Et₂O-hexanes as the eluent. Product was isolated in 29 % yield (195 mg) as a lightly yellow solid. Peaks in NMR spectra are challenging to assign, and this structure is assigned from previous precedent, ¹H NMR spectroscopy (d.r. ∼ 2.2 : 1), and from reactivity ((S)-14 is derived quantitatively from this species, which has been fully characterized using ESI-MS, ¹H and ¹³C NMR spectroscopy, and single-crystal X-ray diffraction analysis). ¹H NMR (300 MHz, CDCl3) 0.47 - 1.40 (m, 31.9H), 2.15 - 2.53 (m, 10.15H), 2.53 - 3.05 (m, 4.8H), 3.34 - 3.65 (m, 4.25 H), 4.33 (m, 2H), 5.23 (m, 0.45H), 5.39 (m, 1H), 7.09 - 7.37 (m, 20.3H).

[NHC-PdCl₂]₂ complex (S,S)-13

195 mg (S)-12 (0.26 mmol) was dissolved in 50 mL Et₂O, and 3.25 mL 2.0 M ethereal HCl (25 equiv) was added via syringe. This mixture was stirred at room temperature for 6 h, over which time the solution turned bright yellow. Removed solvent in vacuo and dried under high vacuum to afford 195 mg of a bright yellow compound which reacts as the drawn compound when combined with AgO₂CCF₃ (below). ¹H NMR spectroscopy revealed two large broad peaks, in the alkyl and aryl regions, but no distinct peaks were observed. Peaks in NMR spectra are challenging to assign, and this structure is assigned from previous precedent,¹⁵ and from reactivity ((S)-14 is derived quantitatively from this species, which has been fully characterized using ESI-MS, ¹H and ¹³C NMR spectroscopy, and single-crystal X-ray diffraction analysis).

NHC-Pd(O₂CCF₃)₂(OH₂) complex (S)-14

83 mg (S,S)-13 (0.056 mmol) was combined with 54.2 mg (4.4 equiv) AgO₂CCF₃ in dichloromethane. This reaction mixture was stirred at room temperature for 1.5 h, during which time a white solid was observed to have formed. Filtration over celite and removal of solvent under vacuum afforded (S)-14 as a tan-yellow solid in quantitative yield. The identity of this species was confirmed by X-ray crystallographic analysis (Figure 11). ESI-MS: m/z (major peak containing Pd) 707.7 ([NHC-Pd(OH₂)(OH)]⁺). ¹H NMR (300 MHz, CDCl3) 0.39 - 0.51 (m, 4H), 0.83 - 1.44 (m, 18H), 2.19 (s, 6H), 3.23 (dd, J = 13.5, 5.1 Hz, 2H), 4.32 (dd, J =13.2, 8.1 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H), 7.31 (d, J= 7.5 Hz, 2H), 7.46 - 7.52 (m, 10H). ¹³C NMR (75MHz, CDCl₃) 19.6, 25.5, 25.9, 26.1, 29.8, 30.8, 38.4, 60.3, 128.5, 128.6, 129.4, 129.7, 132.0, 133.3, 134.3, 137.6, 139.4, 145.1, 201.8. [α]_D²⁵ +3.6 (c 5.5, CH₂Cl₂).

NHC-Pd(allyl)Cl complex 17

In a glove box, amidinium salt 1 (285 mg, 0.552 mmol), [Pd(allyl)Cl]₂ (131 mg, 0.65 equiv), and KOtBu (80 mg, 1.3 equiv) were combined in 20 mL THF. The reaction stirred at room temperature in the dark for 12 h, after which time the reaction flask was removed from the glove box and exposed to ambient conditions. Solvent was removed on a rotary evaporator, and product was isolated by column chromatography (SiO₂) using 1 : 1 Et₂O-hexanes as the eluent to afford a light tan solid with a ¹H NMR spectrum which could be consistent with the drawn product, but was not conclusive. Carried material forward without full characterization. Identity is based on formation of 19 and 20.

[NHC-PdCl₂]₂ complex 18

To crude 17 was added 1 mL ethereal HCl (2.0 M, 3.6 equiv compared to amidinium salt 1). The reaction was stirred at room temperature for 2h. Solvent was removed on a rotary evaporator to afford 141 mg 18 as an orange-brown solid in 45% yield over two steps. Again, the ¹H NMR spectra was consistent with the drawn product, but inconclusive. Assignment is based on formation of 19 and 20. ¹H NMR (300 MHz, CDCl3) (all peaks are broad) 1.06 - 1.16 (m, 36H), 3.29 (s, 6H), 3.34 (s, 6H), 6.92 (s, 2H), 7.07 - 7.23 (m, 12H), 7.38 (s, 2H), 7.66 (s, 4H).

Pd-complex 19

81 mg 18 (0.072 mmol) was combined with 49 mg AgOAc (4.1 equiv) in dichloromethane. The reaction stirred at room temperature in the dark for two hours, after which time the reaction was filtered through celite to remove the AgCl. Solvent was removed in vacuo to afford 74 mg 6 (86% yield) as a brown solid. The structure of 19 was unambiguously assigned by X-ray diffraction analysis (Figure 4): X-ray-quality crystals were obtained from slow evaporation of a CDCl₃-solution of 6 in a round-bottom flask. An X-ray-quality crystal of 6 was re-dissolved in CDCl₃, and gave a ¹H NMR spectrum which was identical to the bulk material. HRMS: m/z (ESI) calculated [M-OAc]⁺ = 491.1836, measured 491.1830 (Δ = 1.0 ppm). ¹H NMR (300 MHz, CDCl3) 1.09 (s, 9H), 1.26 (s, 9H), 2.11 (br. s, 6H), 2.32 (s, 3H), 2.94 (s, 3H), 5.13 (s, 1H), 6.26 (s, 1H), 6.79 - 6.99 (m, 2H), 6.99 (d, J = 2.1 Hz, 1H), 7.10 - 7.16 (m, 4H), δ7.37 - 7.48 (m, 2H), 7.49 (dd, J = 5.4, 4.1 Hz, 1H). ¹³C NMR (75MHz, CDCl₃) 21.8, 22.1, 27.4, 29.3, 37.3, 37.7, 66.1, 71.8, 118.0, 123.0, 125.5, 126.1, 127.2, 127.8, 128.2, 131.4, 131.5, 134.0, 135.7, 136.4, 138.9, 139.2, 162.2, 174.2.

Pd-complex 20

Prepared from 18 analogously to the above synthesis of 19, using AgO₂CCF₃ in place of AgOAc. Product was obtained in ∼100% yield (67 mg) as a dark brown solid. HRMS: m/z (ESI) calculated [M]⁺ = 491.3426, measured 491.3437 (Δ = 2.2 ppm). ¹H NMR (300 MHz, CDCl3) (all peaks are rather broad) 1.03 - 1.29 (m, 36H), 2.33 (m, 6H), 2.51 (m, 6H), 5.84 - 5.92 (m, 4H), 7.03 - 7.91 (m, 16H), 8.89 (br. s, 2H). ¹³C NMR (75MHz, CDCl₃) 15.5, 21.4, 21.7, 27.1, 27.4, 27.6, 28.2, 38.3, 39.4, 66.1, 66.9, 72.4, 118.7, 123.1, 124.7, 125.0, 127.3, 128.4, 129.3, 129.6, 132.0, 133.2, 134.1, 137.0, 137.3, 146.7, 147.4.