Synthesis and characterization in solution and in the solid State of the palladium aryl bromide complexes [Pd(Ar)Br{(S)-BINAP}]: formation of cyclopalladated complexes and direct observation of a C-N reductive elimination to form heterocycles

Abstracts

The complexes resulting from the 1:4 mixture of [Pd2(dba)3] and P(o-tolyl)3 in benzene react with ortho substituted-arylbromides to generate in situ the corresponding bromide dimer [Pd(Ar)(m-Br){P(o-tolyl)3)}] 2. Addition of 2 equiv. of (S)-BINAP gave the corresponding [PdBr(o-RC6H4){(S)-BINAP}] in good yields (57-89%). The crystal structure of [PdBr(o-C6H4CH2 CON(H)Bn){(S)-BINAP}] (1) shows a square planar arrangement around palladium with the aryl ring positioned nearly perpendicular to the square-planar coordination plane. Since these complexes exhibit restricted rotation about the palladium-aryl bond and contain a chiral ligand, they exist as two distinct diastereoisomers discernable by 31P{¹H} NMR. The dynamic behavior of the complexes 1, 13CO-1, and 15N-1 in CDCl3 was studied by 31P{¹H} NMR spectroscopy. 13CO-labeled 1 was also studied by 13C{¹H} NMR. At temperatures below 0 ºC three species were detected on the 31P{¹H} and 13C{¹H} NMR time scale. They were assigned as the two diastereoisomers and the cationic complex [Pd(o-C6H4CH2 CON(H)Bn) {(S)-BINAP}]+Br. Above 40ºC only the two diastereoisomers were detectable. At higher temperatures rotation increased and at 80 ºC a coalescence of the signals was observed by 13C{¹H} NMR. However, no interconversion was observed for 1 in tol-d8 in the -35-120 ºC range on the NMR time scale. In addition, the existence of the interconversion between the two isomers was directly demonstrated by an inversion transfer 31P NMR experiment. The cyclopalladated complexes [Pd(o-C6H4CH2 CONBn)L2] [11 L2= DPPF, 68% yield; 12 L2 = (S)-BINAP, 88 yield] were obtained by treatment of the aryl bromide complexes with NaO-t-Pn. 31P{¹H} NMR spectra of the 15N labeled complexes 11 and 12 clearly showed a Pd-N bond. Decomposition of the palladacycle 12 afforded the heterocycle and the amide reduced product.

palladium; palladacycles; amidation; heterocycles; restricted rotation

As reações de uma mistura [Pd2(dba)3]/P(o-tolyl) 3 (1/4) com brometos de arila orto substituídos conduziram aos dímeros [Pd(Ar)(m-Br){P(o-tolyl)3)}] 2 que, após adição de 2 equiv. de (S)-BINAP formaram os complexos [PdBr(o-RC6H4){(S)-BINAP}] em bons rendimentos (57-89%). A estrutura molecular do complexo [PdBr(o-C6H4CH2 CON(H)Bn){(S)-BINAP}] (1) mostra o anel aromático aproximadamente perpendicular ao plano de coordenação com geometria quadrática plana ao redor do átomo de paládio. Como estes complexos apresentam rotação restrita da ligação paládio-aril e um ligante quiral, dois diastereoisômeros foram observados por 31P{¹H} NMR. O comportamento dinâmico do complexo 1 em solução de CDCl3 foi estudado por RMN de 31P{¹H} (1, 13CO-1 e 15N-1) a varias temperaturas. O complexo enriquecido com 13CO foi estudado também por RMN de 13C{¹H}. Três espécies foram detectadas por RMN de 31P{¹H} e 13C{¹H} a baixas temperaturas (< 0 ºC) e foram atribuídas como sendo os dois diastereoisomeros de 1 e o complexo catiônico [Pd(o-C6H4CH2 CON(H)Bn) {(S)-BINAP}]+Br-. Acima de 40 ºC observou-se somente os dois diastereoisômeros e a coalescência dos sinais pode ser observada por RMN de 13C{¹H} a 80 ºC. Não foi observada, na escala de tempo de RMN, nenhuma interconversão do complexo 1 em tol-d8 entre -35 at 120 ºC. Entretanto, a interconversão entre os dois diastereoisômeros foi evidenciada por experimento de transferência de inversão no RMN de 31P{¹H}. Os ciclopaladatos [Pd(o-C6H4CH2 CONBn)L2] [11 L2= DPPF, 68%; 12 L2 = (S)-BINAP, 88 %] foram obtidos a partir das reações entre os complexos com NaO-t-Pn. A análise de RMN de 31P{¹H} dos complexos 11 e 12 marcados com 15N mostrou a presença da ligação Pd-N. A decomposição térmica do paladaciclo 12 conduziu ao heterociclo esperado e a uma amida como produto de redução.

ARTICLE

Synthesis and characterization in solution and in the solid State of the palladium aryl bromide complexes [Pd(Ar)Br{(S)-BINAP}]. Formation of cyclopalladated complexes and direct observation of a C-N reductive elimination to form heterocycles

Adriano L. Monteiro¹,^* ; William M. Davis

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

ABSTRACT

The complexes resulting from the 1:4 mixture of [Pd₂(dba)₃] and P(o-tolyl)₃ in benzene react with ortho substituted-arylbromides to generate in situ the corresponding bromide dimer [Pd(Ar)(m-Br){P(o-tolyl)₃)}] ₂. Addition of 2 equiv. of (S)-BINAP gave the corresponding [PdBr(o-RC₆H₄){(S)-BINAP}] in good yields (57-89%). The crystal structure of [PdBr(o-C₆H₄CH₂ CON(H)Bn){(S)-BINAP}] (1) shows a square planar arrangement around palladium with the aryl ring positioned nearly perpendicular to the square-planar coordination plane. Since these complexes exhibit restricted rotation about the palladium-aryl bond and contain a chiral ligand, they exist as two distinct diastereoisomers discernable by ³¹P{¹H} NMR. The dynamic behavior of the complexes 1, ¹³CO-1, and ¹⁵N-1 in CDCl₃ was studied by ³¹P{¹H} NMR spectroscopy. ¹³CO-labeled 1 was also studied by ¹³C{¹H} NMR. At temperatures below 0 ^oC three species were detected on the ³¹P{¹H} and ¹³C{¹H} NMR time scale. They were assigned as the two diastereoisomers and the cationic complex [Pd(o-C₆H₄CH₂ CON(H)Bn) {(S)-BINAP}]⁺Br. Above 40 ^oC only the two diastereoisomers were detectable. At higher temperatures rotation increased and at 80 ^oC a coalescence of the signals was observed by ¹³C{¹H} NMR. However, no interconversion was observed for 1 in tol-d₈ in the –35-120 ^oC range on the NMR time scale. In addition, the existence of the interconversion between the two isomers was directly demonstrated by an inversion transfer ³¹P NMR experiment. The cyclopalladated complexes [Pd(o-C₆H₄CH₂ CONBn)L₂] [11 L₂= DPPF, 68% yield; 12 L₂ = (S)-BINAP, 88 yield] were obtained by treatment of the aryl bromide complexes with NaO-t-Pn. ³¹P{¹H} NMR spectra of the ¹⁵N labeled complexes 11 and 12 clearly showed a Pd-N bond. Decomposition of the palladacycle 12 afforded the heterocycle and the amide reduced product.

Keywords: palladium, palladacycles, amidation, heterocycles, restricted rotation

RESUMO

As reações de uma mistura [Pd₂(dba)₃]/P(o-tolyl) ₃ (1/4) com brometos de arila orto substituídos conduziram aos dímeros [Pd(Ar)(m-Br){P(o-tolyl)₃)}] ₂ que, após adição de 2 equiv. de (S)-BINAP formaram os complexos [PdBr(o-RC₆H₄){(S)-BINAP}] em bons rendimentos (57-89%). A estrutura molecular do complexo [PdBr(o-C₆H₄CH₂ CON(H)Bn){(S)-BINAP}] (1) mostra o anel aromático aproximadamente perpendicular ao plano de coordenação com geometria quadrática plana ao redor do átomo de paládio. Como estes complexos apresentam rotação restrita da ligação paládio-aril e um ligante quiral, dois diastereoisômeros foram observados por ³¹P{¹H} NMR. O comportamento dinâmico do complexo 1 em solução de CDCl₃ foi estudado por RMN de ³¹P{¹H} (1, ¹³CO-1 e ¹⁵N-1) a varias temperaturas. O complexo enriquecido com ¹³CO foi estudado também por RMN de ¹³C{¹H}. Três espécies foram detectadas por RMN de ³¹P{¹H} e ¹³C{¹H} a baixas temperaturas (< 0 ^oC) e foram atribuídas como sendo os dois diastereoisomeros de 1 e o complexo catiônico [Pd(o-C₆H₄CH₂ CON(H)Bn) {(S)-BINAP}]⁺Br^-. Acima de 40 ^oC observou-se somente os dois diastereoisômeros e a coalescência dos sinais pode ser observada por RMN de ¹³C{¹H} a 80 ^oC. Não foi observada, na escala de tempo de RMN, nenhuma interconversão do complexo 1 em tol-d₈ entre –35 at 120 ^oC. Entretanto, a interconversão entre os dois diastereoisômeros foi evidenciada por experimento de transferência de inversão no RMN de ³¹P{¹H}. Os ciclopaladatos [Pd(o-C₆H₄CH₂ CONBn)L₂] [11 L₂= DPPF, 68%; 12 L₂ = (S)-BINAP, 88 %] foram obtidos a partir das reações entre os complexos com NaO-t-Pn. A análise de RMN de ³¹P{¹H} dos complexos 11 e 12 marcados com ¹⁵N mostrou a presença da ligação Pd-N. A decomposição térmica do paladaciclo 12 conduziu ao heterociclo esperado e a uma amida como produto de redução.

Introduction

The palladium-catalyzed amination developed by Buchwald and Hartwig is a powerful tool for producing nitrogen heterocycles, which are one of the most important classes of pharmacologically active compounds.^1,2 In particular, Buchwald reported that aryl bromides with pendant secondary amide groups could be cyclized to form tertiary amides.³ P(o-tolyl)₃ or P(2-furyl)₃ were the ligands used in conjunction with [Pd₂(dba)₃]. This methodology allows for easy access to a wide variety of nitrogen heterocycles. However, these cyclization protocols typically employed high catalyst loadings and often long reaction times were necessary. Furthermore, while this methodology did allow for the formation of five- and six-membered rings, the preparation of seven-membered rings proceeded in low overall yield. However, with the proper choice of palladium catalyst, ligand and base, five-, six-, and seven-membered rings are formed efficiently from secondary amide or secondary carbamates precursors (Scheme 1).⁴ While BINAP [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] and DPEphos [bis(2-diphenylphosphinophenyl)ether] are often suitable for the formation of five- and six-membered ring products MOP [2-(diphenylphosphino)-2'-methoxy-1-1'-binaphthyl] and Xantphos [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] are the ligands of choice for the formation of seven-membered rings. On the other hand, Xantphos is also effective for the intermolecular C-N bond-forming reactions between aryl halides and amides.⁵

In analogy with palladium-catalyzed aminations of aryl halides reactions, an oversimplified catalytic cycle is shown in Scheme 2.¹ Oxidative addition of the aryl bromide to L_nPd(0) complex gives the intermediate Pd(II) complex.⁶ Deprotonation gives the palladacycle that can reductively eliminate to produce the desired heterocycle and regenerate the Pd(0) catalyst.⁷ In the intramolecular process, the coordination of the amide prior to the deprotonation of the Pd(II) intermediate is facilitated by the linkage of the amine moiety to the aryl group. The difference of activity observed in the formation of the five-, six-, seven- and eight-member rings could be related to the stability of the palladacycle intermediate. Due to the central role of the palladium complex formed from the oxidative addition of aryl bromide to the Pd(0) as well the palladacycle complex in the overall catalytic cycle,⁸ we have been interested in the factors which influence both the formation and reactivity of these complexes. On the other hand, BINAP is an important ligand for the amination of aryl bromides.⁹ In this paper are report the synthesis and characterization of a series of [PdBr(o-substitutedAr){(S)-BINAP}] complexes , the reaction of these complexes with base giving the palladacycle complexes,and their reactivity.

Results and Discussion

Synthesis of the oxidative addition complexes [PdBr(o-substituted-Ar){(S)-BINAP}]

The complexes [Pd(Ar)Br{(S)-BINAP}] could not be obtained directly from the oxidative addition of aryl bromide to a mixture of [Pd₂(dba)₃] and (S)-BINAP. In fact, stirring a purple solution of [Pd₂(dba)₃], (S)-BINAP and aryl bromide at room temperature for 24 h gave an orange solution from which [Pd(BINAP)(dba)] was the only product detected by ³¹P NMR spectroscopy.¹⁰ The oxidative addition complex could be detected by ³¹P NMR spectroscopy when the reaction was carried out at 80 ^oC, but the selectivity was low for synthetic purposes. Buchwald has demonstrated that the palladium complexes [Pd(Ar)Br{(S)-BINAP}] can been obtained in two steps from [Pd₂(dba)₃].¹¹ First the palladium tri-o-tolyphosphine dimer [Pd(m-Br)(p-C₆H₄CN}{P( o-tolyl)₃}]₂ was isolated in good yield (75%) from the reaction of [Pd₂(dba)₃] with p-CNC₆H₄Br and P(o-tolyl)₃ in benzene.¹² Second, reaction of the complex [Pd(m-Br)(p-C₆H₄CN){P( o-tolyl)₃}]₂ with (S)-BINAP in dichloromethane gave the complex [PdBr(p-C₆H₄CN){(S)-BINAP}] in 80% yield. In order to obtain the BINAP-Pd complex in one step, we have carried out some modifications to the protocol. The complexes resulting from a 1:4 mixture of [Pd₂(dba) ₃] and P(o-tolyl)₃ in benzene react with arylbromide to generate in situ the corresponding bromide dimer [Pd(Ar)(m-Br){P(o-tolyl)₃}]₂ . Addition of 2 equivalents of (S)-BINAP gives the corresponding [Pd(Ar)(Br){(S)-BINAP}]. Using this procedure the complex [PdBr(p-C₆H₄CN){(S)-BINAP}] was isolated in 80% yield in one step. The ³¹P NMR {¹H} spectrum displayed two doublets at d 12.9 and 27.9 (³J_P-P 38 Hz), which characterized bidentate coordination of the phosphine ligand to the palladium center having two nonequivalent phosphorus containing groups.¹¹

The one-pot procedure was applied for the preparation of oxidative addition complexes containing o-substituted primary amide moieties on the aryl group, in good yields (equation 1 and Table 1). The complexes were characterized by standard spectroscopic techniques and elemental analysis and the structure of the complex 1 in the solid state was determined by an X-ray diffraction study . ³¹P{¹H} NMR analysis of [PdBr(o-C₆H₄CH₂ CON(H)Bn){(S)-BINAP}] (1) in C₆D₆ showed two distinct species, each having two doublets (d 10.2 and 26.3; d 11.6 and 24.8 respectively) with ³J_P-P 37 Hz. The ¹³C{¹H} NMR spectrum for ¹³C labeled 1a in C₆D₆ displayed two signals for ¹³C=O (d 171.4 and 171.5) and the ratio of these resonances was the same as observed in ³¹P NMR. ¹⁵N labeled 1b did not display any additional coupling in the ³¹P{¹H} NMR spectrum confirming that none of the species has nitrogen coordinated to the palladium atom.

The presence of two species in solution is not restricted to the complexes having an amido moiety in the ortho position (1-3). In fact, two species were also detected in ³¹P{¹H} NMR spectra for the complexes with a carbonyl (4), hydroxyl (5) or even alkyl moiety (6-8), and the ratio depends on the R group. These results can be explained by the restricted rotation about the palladium-aryl bond (Scheme 3).¹³ X-ray structural analysis of complex 1 showed that the aryl group is close to orthogonality to the coordination plane (see X-ray structure discussion). In the case of o-substituted aryl complexes, if the rotation is restricted and the chelating ligand is a C₂ symmetrical chiral ligand such as (S)-BINAP two diastereoisomer or rotamers are possible. However, if the chelating phosphine is symmetrical and achiral only one complex is expected. For comparison, a complex of the achiral ligand DPPF [1,1'-bis(diphenylphosphino)ferrocene] was prepared using the same procedure affording 79% of [PdBr(o-C₆H₄CH₂ CONHBn)(DPPF)] (9).¹⁴ This complex was fully characterized by standard spectroscopic techniques and elemental analysis and, as expected, only one species was observed by ³¹P{¹H} NMR (d 7.7 and 28.4; J 32 Hz).

X-ray structure of [PdBr(o-C₆H₄CH₂CON(H)Bn){(S) -BINAP}] (1)

The crystal structure of complex 1 was examined by X-ray diffraction. Selected bond lengths and angles are listed in Table 2. The structure obtained is shown in Figure 1 and reveals a distorted-square planar arrangement about the palladium atom. The C31-Pd-P1 angle is 173.3(2) and the P2-Pd-Br angle is 170.4(7) rather than the ideal 180^o. The sum of the four angles at Pd involving P1, P2, C31, and Br is 360.7^o. The bite angle of the BINAP ligand (92.57(8)^o) is in the range observed for BINAP-Pd complexes (90.7-95.8^o).¹⁵ As observed by others [PdArXL₂] (L₂ = bidentate ligand, X= halogen) complexes and expected by the trans influence, the Pd-P bond length trans to the aryl is longer than Pd-P bond length trans to the halogen, 2.396(2) and 2.269(2) Å, respectively.^16-18 The aryl group is not perfectly orthogonal with the coordination plane [torsion angles (C32(ortho)-C31(ipso))- (Pd-P2) = 103.9^o, (C36(ortho)-C31(ipso))- (Pd-P2) = 81.4^o, (C36(ortho)-C31(ipso))- (Pd-Br) = 89.1^o, (C32(ortho)-C31(ipso))- (Pd-Br) = 85.6^o). Another similarity with other [PdArXL₂] (L₂ = bidentate ligand, X= Cl¹⁸, Br¹⁷, I¹⁶) complexes, is that the X-Pd-aryl angle is shorter than X-Pd-P [Br-Pd-C31 = 85.7(2)^o and Br-Pd-P1 = 89.45(6)]. Since the distance N---Br is 3,573 Å (Br----H-N = 169^o), no interaction or a very weak intramolecular hydrogen bond is involved.

NMR observations on [PdBr(o-C₆H₄CH₂CON(H)Bn){(S) -BINAP}] (1)

The NMR spectra of 1 are very dependent on the solvent used. As already mentioned, ³¹P{¹H} NMR analysis of 1 shows two distinct species, each one having two doublets with ³J_P-P 37 Hz C₆D₆ (d 10.2 and 26.3; d 11.6 and 24.8). However, ³¹P{¹H} NMR spectrum of 1 in DMF-d₇ displayed two very broad signals centered at d 10.0 and 28.0. A more complicated pattern was observed in CDCl₃. Figure 2 shows the ³¹P{¹H} NMR spectra for the ¹³C labeled 1a in the –35-80 ^oC range. It is important to note that variable temperature ³¹P{¹H} NMR analysis of 1, and ¹³C labeled 1a in CDCl₃ give rise to identical spectra.

The ³¹P{¹H} NMR spectrum at room temperature displayed one pair of doublets (d 10.8 and 28.5, J 37.0 Hz) instead of the two observed in C₆D₆ or tol-d₈. Besides this pair of doublets, three broad signals centered at d 12.1, 25.4 and 38.7 were also observed (Figure 2). When the temperature was lowered to 0 ^oC the broad signals centered at d 25.4 and 38.7 became partially resolved into doublets, while the broad signal at d 13 was split into two partially resolved doublets. Three sharp pairs of doublets were observed at –25 ^oC evidencing the existence of three species containing the bidentate BINAP ligand coordinated to the palladium [A: d 10.8 and 28.5 (J 37.0 Hz); B: d 12.2 and 28.5 (J 38.0 Hz); C: d 13.9 and 38.9 (J 43.0 Hz)]; there is no change in the shape and position of the pair of doublets observed at room temperature (species A). However, the relative ratio of the three species changes with temperature and the species C characterized by the doublets at d 13.8 and 38.8 is favored at low temperatures. The fluxional behavior of 1a in CDCl₃ was also investigated by ¹³C{¹H} NMR analysis of the ¹³C- labeled carbonyl group (Figure 3). One relative sharp signal at d 172.8 and one broad signal at d 173.5 were observed at room temperature. At 0 ^oC the broad signal decreased in intensity and a third broad signal appeared at d 174.6. By lowering the temperature these signals became sharp and, in agreement with ³¹P NMR, the presence of three species was also evidenced. When the temperature was lowered to –35 ^oC the relative intensity of the signal at d 174.6 increased showing that this carbonyl resonance was related to species C with ³¹P{¹H} NMR resonances at d 13.8 and 38.8. ³¹P{¹H} and ¹³C{¹H} NMR spectra above room temperature indicated two species between 40 and 80 ^oC, with a coalescence temperature at 80 ^oC in ¹³C{¹ H} NMR. From this coalescence temperature, an approximate rate of 10² s^-1 and a free energy of activation (D G^¹) of 17 Kcal/mol were calculated. These results are similar to those obtained for other arylpalladium complexes with restricted rotation, but the coalescence temperature is higher (80^o versus room temperature).¹⁹

By comparison with the chemical shift of complexes 2 to 8 and also with 1 in C₆D₆, the species A and B, characterized by the pair of doublets at d 10.8/28.5 and 12.2/25.9 in CDCl₃, can be assigned as two diasteroisomers that can interconvert by rotation around the Pd-C_ipso bond. In the case of the complex [PdBr{o-C₆H₄(CH₂ CH₂OH)}(tmeda)], van Koten proposed that the rapid rotation of the aryl group around the Pd-C_ipso bond was induced by an intramolecular substitution of the bromide ligand by hydroxyl group leading to a cationic intermediate.¹⁹ In order to verify this possibility, complex 1 was partially dissolved in acetone-d₆ and reacted with excess of AgOTf. ³¹P{¹H} NMR before reaction displayed two pairs of relatively broad doublets but the chemical shifts (d 11.1/28.6 and 11.9/27) are similar to those obtained in CDCl₃. After stirring the mixture and filtration, the yellow solution displayed only one sharp pair of doublets at d 14.7 and 39.0 (J 44 Hz), very close to the chemical shift for the third species observed at low temperatures. The reaction was also carried out with the ¹³C-labeled complex 1a giving a chemical shift of 175.8 for the carbonyl group of the cationic complex (compared with d 174.6 for species C in CDCl₃). It is interesting to note that a very small coupling (2 Hz) was observed for this resonance. ³¹P{¹H} NMR analysis of the ¹⁵N-labeled complex 1b showed a doublet of doublets only for the resonance at d 39.0 (J_P-P 44 Hz and J_P-N 2 Hz). The chemical shift observed and the presence of very small couplings for the complexes 1a and 1b are in agreement with a cationic complex with the amido group coordinated to palladium by the oxygen atom. Scheme 4 summarizes the fluxional behavior of the complex 1 in CDCl₃. At low temperatures (below 0 ^oC) the two diastereoisomers and the cationic complex are detectable on the NMR time scale. Above 40 ^oC only the two diastereoisomers are detectable. When the temperature is raised the rotation became faster and at 80 ^oC a coalescence of the signals was observed. The interconversion of the diastereoisomers can occur via the cationic complex and/or by simple rotation by 180^o of the aryl ring around the Pd-C_ipso bond.

In opposition, no fluxional behavior was observed in tol-d₈, and complex 1 was characterized by two sharp pairs of doublets in the –35-120 ^oC range. Thus, no interconversion between the two diastereoisomeric forms was observed on the NMR time scale. However, the existence of the interconversion between the two isomers was directly demonstrated by an inversion transfer ³¹P NMR experiment. Selective inversion of the doublet at d 11.4 results, after an appropriate evolution time, in a significant change in the intensity of the doublet at d 12.9 (see electronic supplementary information). A maximum decrease in relative intensity for the doublet at d 12.9 was observed using a evolution time of 0.5 seconds, while the doublets at d 26.0 and 27.4 remained unchanged for all the evolution time evaluated. In the same way, selective inversion of the doublet at d 27.4 results in a significant change only for the doublet at d 26.0, and a maximum decrease in intensity was also observed for a evolution time of 0.5 seconds. These results show the existence of an exchange process between the phosphorus atoms characterized by the resonances at d 11.4 and 12.9, and between the phosphorus atoms characterized by the resonances at d 26.0 and 27.4. The doublets at d 11.4 and 12.9 were assigned to the phosphorus cis to the bromine for each isomer, and the doublets at d 26.0 and 27.4 as the phosphorus cis to the aryl moiety for each isomer (vide infra). The exchanges observed by the inversion transfer experiment can be explained by an interconversion between the two isomers caused by simple 180^o rotation of the aryl ring around the Pd-C_ipso bond or via a cationic complex as observed in CDCl₃. However, the interconversion in tol-d₈ is slower and can only be observed using a inversion transfer experiment.

Synthesis and characterization of the cyclopalladated complexes [Pd(o-C₆H₄CH₂CONBn)L ₂]

In order to obtain the palladacycle, the aryl bromide complexes were reacted with a base in benzene. Effective bases for palladium-catalyzed cyclization of secondary amides and carbamates, such as Cs₂CO₃ and K₂CO₃, were completely inactive at room temperature, and the starting complex 1 was recovered unchanged at the end of the reaction. Only decomposition to metallic palladium was observed by increasing the temperature (up to 100 ^oC). However, the palladacycle [Pd(o-C₆H₄CH₂ CONBn)(DPPF)] (10) was isolated free from NaBr and excess alkoxide in 68% yield by treatment of the aryl bromide complex [PdBr(o-C₆H₄CH₂ CONHBn)(DPPF)] (9) with NaO-t-Pn in benzene at room temperature (equation 2).

Palladacycle 10 was characterized by spectroscopy and elemental analysis. A comparison with selected data from the starting complex is shown in Table 5. For example, its IR spectrum shows the disappearance of the n_N-H absorption and a carbonyl absorption at 1594 cm^-1 (compared with 1679 cm^-1 for the starting complex) characteristic of a M-NCOR complex.²⁰³¹P{¹H} NMR spectrum displayed two doublets at d 10.0 and 25.4 (²J_P-P 35 Hz) for the palladacycle and two doublets at d 7.7 and 28.4 (²J_P-P 32 Hz) for the starting aryl bromide palladium complex 9. ³¹P{¹H} NMR analysis of the reaction of the ¹⁵N-labeled complex 10 with NaO-t-Pn established nitrogen coordination to palladium. In fact, the resulting complex displayed a doublet of doublets for signals at d 10.0 and 25.4 with a ²J_P-N of 3.7 and 47.6 Hz, respectively. Trans-²J_P-N values are higher than those for cis couplings.^21,22 For instance, it has been reported that cis ²J_P-N couplings for Pd(II), Pt(II) and Au(III) complexes are very small compared with trans couplings (<2 Hz and ~50 Hz, respectively).²¹ In complex 10, the low frequency resonance (d 10.0) must therefore be assigned to the phosphorus cis to the nitrogen, and the high frequency resonance (d 25.4) corresponds to the phosphorus trans to nitrogen. By analogy, the resonances at d 7.7 and 28.4 in complex 9 can be assigned to the phosphorus cis and trans to the bromine, respectively.

In the same way, the palladacycle [Pd(o-C₆H₄CH₂ CONBn){(S)-BINAP}] (11) was isolated in 88% yield by treatment of the aryl bromide complex [PdBr(o-C₆H₄CH₂ CONHBn){(S)-BINAP}] (1) with NaO-t-Pn in benzene at room temperature (Scheme 5). Palladacycle 11 was characterized by spectroscopy and elemental analysis, and a comparison with selected data from the starting complex is shown in Table 5. Similar results with those observed for the DPPF-cyclopalladated complex 10 were obtained for the (S)-BINAP-cyclopalladated complex 11. IR analysis showed carbonyl absorption at 1558 cm^-1 (compare with 1669 cm^-1 for the starting complex) and the disappearance of the n_N-H absorption. For the starting complex 1, two isomers were observed by ³¹P{¹H} NMR analysis for the deprotonated complex 11 (Scheme 5). For each isomer the phosphorus at low field is characterized as a doublet of doublets (³J_P-N 46 Hz and ³J_P-P 36 Hz) evidencing the presence of a palladium-nitrogen bond and that these resonances at low field must be assigned to a phosphorus trans to the nitrogen and cis to the aryl moiety. In the palladacycle 11, pyramidal inversion of the nitrogen atom must be very slow or has ceased completely and the conjunction of a chiral nitrogen and a chiral BINAP ligand generates two diastereoisomers [Pd{(S)-o-C₆H₄CH₂ CONBn}{(S)-BINAP}] and [Pd{(R)-o-C₆H₄CH₂ CONBn}{(S)-BINAP}]. When complex 11 is heated at 100 ^oC in toluene decomposition to metallic palladium with formation of the heterocycle 12 and the amide 13 was observed. It is interesting to note that in catalytic conditions the amide 13 is observed as by-product but in very low proportions (<2%) under optimized conditions.

Conclusions

In conclusion, o-substituted aryl palladium complexes are obtained in one step in good yields (57-89%). Since these complexes exhibit restricted rotation about the palladium-aryl bond and contain a chiral ligand, they exist as two distinct diastereoisomers discernable at rt by ³¹P{¹H} NMR. Only the complex [PdBr{o-C₆H₄CH₂ CONHBn){(S)-BINAP}] 1 in CDCl₃ is dynamic on the NMR time scale at room temperature. At low temperatures (below O^oC) three species were detectable on the ³¹P and ¹³C NMR time scale. They are assigned as the two diastereoisomers and the cationic complex [Pd(o-C₆H₄CH₂ CON(H)Bn){(S)-BINAP}]⁺Br^-. Above 40 ^oC only the two diastereoisomers are detectable. When the temperature is raised the rotation became faster and at 80 ^oC a coalescence of the signals was observed in ¹³C{¹H} NMR. The interconversion of the diastereoisomers can occur via the cationic complex and/or by simple rotation by 180^o of the aryl ring around the Pd-C_ipso bond. In opposition, no interconversion was observed for 1 in tol-d₈ in the –35 to 120 ^oC temperature range on the NMR timescale. However, the existence of the interconversion between the two isomers was directly demonstrated by an inversion transfer ³¹P NMR experiment. Such observations of large rotational barriers about the palladium-aryl bond in o-substituted aryl palladium complexes, associated with the dependence on the group R and the diastereoselectivities observed in BINAP complexes, could be useful for understanding the asymmetric cross-coupling reaction using ortho-substituted aryl halides.

The palladacycle complexes were obtained in good yields by treatment of the aryl bromide complexes with NaO-t-Pn in benzene at room temperature. The heterocycle formed from the reductive elimination of complex [Pd(o-C₆H₄CH₂ CONBn){(S)-BINAP}] was obtained with metallic palladium when the complex was heated at 100 ^oC in toluene. The species described in this work corresponds to the postulated intermediate for the palladium-catalyzed intramolecular amidation reaction and a correlation with a mechanistic study under catalytic conditions should follow.

Experimental

General methods

[Pd₂(dba)₃], arylbromides, and phosphines were manipulated in air. All other manipulations were performed under an atmosphere of nitrogen or argon in a glovebox or by standard Schlenk techniques. NMR spectra were recorded on a Varian Unity-300, Varian Mercury-300 or Varian 500 at 23 ^oC unless otherwise noted. ¹H and ¹³C (75.6 MHz) spectra were referenced relative to the residual solvent peak. ³¹P NMR (121.5 MHz) spectra were referenced relative to external 85% H₃PO₄. IR spectra were recorded on a ASI ReactIR 1000 spectrometer. Elemental analyses were performed by E&R Microanalytical Laboratories (Parsippany, NJ).

Diethyl ether was distilled from solutions of sodium/benzophenone under argon. CDCl₃, C₆D₆, and PhMe-d₈ (Cambridge Isotopes) were dried over 4A^o molecular sieves and degassed by three freeze/thaw cycles before use. [Pd₂(dba)₃], P(o-tolyl)₃, DPPF (Strem), (S)-BINAP (Pfizer), anhydrous benzene, anhydrous hexane, anhydrous pentane, anhydrous dichloromethane, o-bromobenzylbromide, thionyl chloride, benzylamine, sodium t-butoxide, o-bromophenethyl alcohol, 2-bromotoluene, 2-bromo-m-xylene (Aldrich), 2-bromobiphenyl, 2-bromoisopropylbenzene (Lancaster), K¹³CN (Cambridge Isotopes), benzylamine-¹⁵N were used as received. N-Benzyl-2-o-bromophenylethylamide, ³N-benzyl-3-(o-bromophenyl)propionylamide, ³ N-acetylyl-2-o-bromophenylethylamine, ³ and 4-(2-Bromophenyl)-2-butanone²³ were synthesized as described in the literature.

Synthesis of ¹³C- and ¹⁵N- labeled N-Benzyl-2-o-bromophenylethylamide

¹³CN-o-bromophenylacetonitrile. The procedure described for o-bromophenylacetonitrile was adapted using ¹³KCN.²⁴

o-Bromophenylacetonitrile.o-Bromobenzyl bromide (3.76 g, 15.1 mmol) was added to a solution of K¹³CN (1 g, 15.1 mmol) in 15 mL of ethanol and 10 mL of water. The mixture was refluxed for 1 h, and 100 mL of ice water were added. The mixture was extracted with ether (2 x 100 mL). The organic extracts were combined, washed with aqueous saturated NaHCO₃ (3 x 100 mL), water (3 x 100 mL), brine (2 x 50 mL), dried over anhydrous MgSO₄, filtered and concentrated giving a colorless oil (2.64 g, 90%). ¹H NMR (CDCl₃, 300 MHz) d 3.85 (d, 2H, J 10.4 Hz), 7.23 (t, 1H, J 7.6 Hz), 7.37 (t, 1H, J 7.5 Hz), 7.53 (d, 1H, J 7.7 Hz), 7.61 (d, 1H, J 8.0). ¹³C{¹H} NMR (CDCl₃, 75.4 MHz) d 25.0 (d, J 58.9 Hz), 117.1, 123.8 (d, J 4.5 Hz), 128.3, 129.9 (d, J 2.6 Hz) 130.1, 133.3. IR (neat) n_max/cm^-1: 3065, 2934, 2196 (n¹³_CºN), 1594, 1571, 1471, 1440, 1413, 1027, 749, 660. GC/MS (m/z) 117, 196, 198, 89, 116, 63, 115, 50.

¹³CO-o-Bromophenylacetic acid. The procedure described for o-bromophenylacetonitrile was employed using ¹³CN-o-bromophenylacetonitrile. A mixture of ¹³CN -o-bromophenylacetonitrile (2.44 g, 12.4 mmol), sulfuric acid (26 mL )and water (35 mL) was refluxed for 4 h. The reaction mixture was poured over ice and, after cooling to room temperature, extracted with ether (3 x 70 mL). The organic extracts were combined and evaporated giving a yellow solid. The crude product was dissolved with aqueous 15% KOH (100 mL), and extracted with ether (2 x 100 mL). The aqueous layer was acidified with aqueous 10% hydrochloric acid giving a white precipitate. After addition of ether (100 mL) the layers were separated and the aqueous layer was washed with ether (100 mL). The organic layers were combined, washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give a white solid (1.69 g, 63%). mp 107-109 ^oC. ¹H NMR (CDCl₃, 300 MHz) d 3.84 (d, 2H, J 8.0 Hz), 7.13-7.19 (m, 1H), 7.25-7.30 (m, 2H), 7.57 (d, 1H, J 8.0 Hz). ¹³C{¹H} NMR (CDCl₃, 75.4 MHz) d 41.6, 125.3, 127.8, 129.3, 131.7, 133.1, 133.7, 177.1. IR (neat solid) n_max/cm^-1: 2926, 1668 (n¹³_C=O), 1444, 1401, 1343, 1289, 1231, 1197, 1027, 934, 760, 726, 675. Anal Calcd for C₇¹³CH₇O₂ Br: C, 44.94; H, 3.27%. Found: C, 44.76; H, 3.25%.

General procedure for preparation of N-benzylamides. To solid carboxylic acid (4-10 mmol) in a round bottom flask was added thionyl chloride (8 mL). The solution was stirred at room temperature for 4 h. Excess thionyl chloride was removed in vacuo and dichloromethane (5 mL) was added. This solution was slowly added to a solution of benzylamine (2.5 eq.) in dichloromethane (5 mL) at 0 ^oC; and a white solid precipitated. The reaction mixture was stirred at 0 ^oC for 30 min, then warned at room temperature and stirred for 1h. The reaction mixture was then diluted with dichloromethane (150 mL), washed with saturated aqueous sodium bicarbonate (50 mL), and washed with brine (2 x 50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was then purified further by flash chromatography on silica gel.

¹³CO-N-Benzyl-2-o-bromophenylethylamide.¹³CO-o-Bromophenylacetic acid was used, and the general procedure gave 1.96 g (87%) of a white solid; mp 133-135 ^oC. ¹H NMR (CDCl₃, 500 MHz) d 3.79 (d, 2H, J 7.3 Hz), 4.45 (dd, 2H, J 5.5 and 3.0 Hz), 5.73 (br, 1H), 7.16-7.39 (m, 8H), 7.60 (d, 1H, J 7.9 Hz). ¹³C{¹H} NMR (CDCl₃, 75.4 MHz) d 43.8, 44.5, 125.1, 127.6, 127.7, 128.3, 128.8, 129.4, 132.0, 133.3, 134.9, 138.2, 169.6.. IR (neat solid) n_max/cm^-1: 3273 (n_N-H), 3053, 3030, 2922, 2872, 1606 (n¹³_C=O), 1536, 1413, 1235, 1027, 733, 691. Anal Calcd for C¹³C₁₄H₁₄NOBr: C, 59.36; H, 4.62%. Found: C, 59.31; H, 4.53%.

¹⁵N-Benzyl-2-o-bromophenylethylamide.¹⁵N-benzyl amine was used, and the general procedure gave 0.860 g (84%) of a white solid. mp 131-132 ^oC. ¹H NMR (CDCl₃, 500 MHz) d 3.79 (s, 2H), 4.45 (d, 2H, J 5.5 Hz), 5.72 (dt, 1H, J 90.6 and 5.8 Hz), 7.15-7.39 (m, 8H), 7.60 (d, 1H, J 7.9 Hz). ¹³C{¹H} NMR (CDCl₃, 75.4 MHz) d 43.8 (d, J 10.5 Hz), 44.2 (d, J 8.4 Hz), 125.1, 127.6, 127.7, 128.2, 128.7, 129.3, 131.9, 133.3, 134.9, 138.2, 169.6 (d, J 15 Hz). IR (neat solid) n_max/cm^-1: 3266 (n¹⁵_N-H), 3030, 2961, 2922, 1644 (n_C=O), 1529, 1455, 1413, 1366, 1339, 1239, 1027, 733, 695. Anal Calcd for C₁₅H₁₄¹⁵NOBr: C, 59.04; H, 4.62%. Found: C, 59.10; H, 4.69%.

General procedure for preparation of [Pd(Ar)(Br){(S)-BINAP}]. A purple solution of [Pd₂(dba)₃] (382 mg, 0.418 mmol), P(o-tolyl)₃ (510 mg, 1.68 mmol) and aryl bromide (1.02 mmol) in benzene (30 mL) was stirred at room temperature for 16 h. (S)-BINAP (520 mg, 0.835 mmol) and benzene (5 mL) were added and the solution was stirred at room temperature for 6 h. The solution was filtered through Celite, and benzene was evaporated under vacuum. The oily residue was dissolved in ether (25 mL) and stirred at room temperature for 16 h. The resulting precipitate was filtered, washed with ether and dried under vacuum.

[PdBr[o-C₆H₄CH₂ CON(H)Bn]{(S)-BINAP}] (1). The general procedure gave 662 mg (76%) of a pale yellow solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (C₆D₆, 300 MHz) (major + minor isomers) d 3.89 (d, J 13.9 Hz), 4.20-4.65 (m), 4.93 (d, J 13.9 Hz), 5,15 (d, J 14.1 Hz), 6.14-8.21 (m). ³¹P{¹H} NMR (C6D6, 121.5 MHz) major isomer (54%): d 10.2 (d, J 37.2 Hz), 26.3 (d, J 37.8 Hz); minor isomer (46%): d 11.6 (d, J 38.4 Hz), 24.8 (d, J 37.2 Hz). IR (neat solid) n_max/cm^-1: 3301 (n_N-H), 3051, 1669 (n_C=O), 1534, 1497, 1480, 1437, 1308, 1148, 1094, 1021, 872, 816, 739, 691. Anal Calcd for C₅₉H₄₆NOBrPdP₂: C, 68.58; H, 4.49%. Found: C, 68.36; H, 4.18%.

[PdBr(o-C₆H₄CH₂ ¹³CON(H)Bn){(S)-BINAP}] (1a). The general procedure gave 682 mg (79%) of a pale yellow solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (C₆D₆, 300 MHz) (major + minor isomers) d 3.89 (dd, J 13.5 and 8.3 Hz), 4.19-4.63 (m), 4.93 (dd, J 13.5 and 6.4 Hz), 5,15 (dd, J 14.2 and 6.4 Hz), 6.13-8.21 (m). ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) major isomer (54%): d 10.2 (d, J 37.2 Hz), 26.3 (d, J 37.8 Hz); minor isomer (46%): d 11.6 (d, J 38.5 Hz), 24.8 (d, J 38.4 Hz). IR (neat solid) n_max/cm^-1: 3305 (n_N-H), 3053, 1630 (n¹³_C=O), 1571, 1526, 1480, 1437, 1308, 1254, 1148, 1094, 1025, 872, 816, 739, 691. Anal Calcd for C₅₈¹³CH₄₆NOBrPdP ₂: C, 68.76; H, 4.49%. Found: C, 68.64; H, 4.18%.

[PdBr(o-C₆H₄CH₂ CO¹⁵N(H)Bn){(S)-BINAP}] (1b). The general procedure gave 666 mg (77%) of a pale yellow solid that contained traces of ether (< 5%) and P(o-tolyl)₃ (<1%) by ¹H and ³¹ P NMR analysis. ¹H NMR (C₆D₆, 300 MHz) (major + minor isomers) d 3.89 (d, J 12.8 Hz), 4.25-4.66 (m), 4.93 (d, J 13.6 Hz), 5,15 (d, J 14.2 Hz), 6.20-8.21 (m). ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) major isomer (54%): d 10.2 (d, J 37.2 Hz), 26.3 (d, J 37.8 Hz); minor isomer (46%): d 11.6 (d, J 38.5 Hz), 24.8 (d, J 38.5 Hz). IR (neat solid) n_max/cm^-1: 3290 (n¹⁵_N-H), 3053, 1669 (n_C=O), 1571, 1555, 1520, 1497, 1480, 1437, 1308, 1272, 1258, 1144, 1094, 1023, 872, 816, 741, 693. Anal Calcd for C₅₉H₄₆¹⁵NOBrPdP ₂: C, 68.66; H, 4.49%. Found: C, 68.79; H, 4.18%.

[PdBr(o-C₆H₄CH₂ CH₂CON(H)Bn){(S)-BINAP}] (2). The general procedure gave 645 mg (74%) of a pale yellow solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (CDCl₃, 300 MHz) major + minor isomers: d 2.77-2.93 (m), 3.23-3.38 (m), 3.64-3.70 (m), 4.15-4.38 (m), 6.47 (d, J 8.5 Hz), 6.55-8.13 (m). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) major isomer (62%): d 9.9 (d, J 37.8 Hz), 26.9 (d, J 38.4 Hz); minor isomer (38%): d 11.9 (d, J 39.1 Hz), 25.2 (d, J 39.1 Hz). IR (neat solid) n_max/cm^-1: 3452 (n_N-H), 3053, 1681 (n_C=O), 1573, 1555, 1505, 1436, 1191, 1092, 1025, 870, 818, 745, 697. Anal Calcd for C₆₀H₄₈NOBrPdP₂: C, 68.75; H, 4.45%. Found: C, 68.81; H, 4.62%.

[PdBr(o-C₆H₄CH₂ CH₂N(H)COCH₃){(S)-BINAP}] (3). The general procedure gave 563 mg (69%) of a pale yellow solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (CDCl₃, 300 MHz) major + minor isomers: d 1.67 (s, CH₃, minor isomer), 1.82 (s, CH₃, major isomer), 2.60-2.64 (m), 3.17-4.20 (m), 6.51 (d, J 8.2 Hz), 6.58-8.01 (m). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) major isomer (75%): d 10.5 (d, J 38 Hz), 27.4 (d, J 38 Hz); minor isomer (25%): d 12.5 (d, J 39 Hz), 26.1 (d, J 39 Hz). IR (neat solid) n_max/cm^-1: 3336 (n_N-H), 3054, 2885, 1663 (n_C=O), 1536, 1436, 1094, 874, 818, 739, 691. Anal Calcd for C₅₄H₄₄NOBrPdP₂: C, 66.78; H, 4.52%. Found: C, 65.91; H, 4.58%.

[PdBr(o-C₆H₄CH₂ CH₂COCH₃){(S)-BINAP}] (4). Using a scale of 0.207 mmol in [Pd₂(dba)₃], the general procedure gave 243 mg (61%) of a pale yellow solid that contained traces of ether by ¹H NMR analysis (<5%). ¹H NMR (CDCl₃, 300 MHz) major + minor isomers: d 2.20 (s, CH₃, minor isomer), 2.27 (s, CH₃, major isomer), 2.56-2.88 (m), 3.23 (td, J 12.5 and 5.0 Hz), 3.45-3.63 (m), 3.85 (td, J 12.7 and 3.7 Hz), 6.51 (d, J 8.7 Hz), 6.52-8.24 (m). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) major isomer (59%): d 9.7 (d, J 37.8 Hz), 27.0 (d, J 37.8 Hz); minor isomer (41%): d 12.0 (d, J 39.7 Hz), 25.5 (d, J 39.1 Hz). IR (neat solid) n_max/cm^-1: 3049, 1710 (n_C=O), 1573, 1556, 1502, 1478, 1436, 1309, 1158, 1092, 815, 745, 695. . Anal Calcd for C₅₉H₄₃OBrPdP₂: C, 67.83; H, 4.53%. Found: C, 67.93; H, 4.44%.

[PdBr(o-C₆H₄CH₂ CH₂OH){(S)-BINAP}] (5). Using a scale of 0.207 mmol in [Pd₂(dba)₃], the general procedure gave 302 mg (79%) of a pale brown solid that contained traces of ether by ¹H NMR analysis (<5%). ¹H NMR (CDCl₃, 300 MHz) major + minor isomers: d 2.17 (t, J 5.4 Hz), 2.35 (t, J 5.7 Hz), 2.90-3.00 (m), 3.23-3.30 (m), 3.51-3.70 (m), 4.00-4.30 (m), 6.48-8.15 (m). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) major isomer (55%): d 10.2 (d, J 38.4 Hz), 22.7 (d, J 38.4 Hz); minor isomer (45%): d 11.8 (d, J 39.1 Hz), 24.8 (d, J 39.1 Hz). IR (neat solid) n_max/cm^-1: 3436 (n_O-H), 3049, 1499, 1480, 1457, 1436, 1304, 1092, 1028, 820, 741, 670. Anal Calcd for C₅₂H₄₁OBrPdP₂: C, 67.24; H, 4.45%. Found: C, 67.17; H, 4.41%.

[PdBr(o-C₆H₄CH₃ ){(S)-BINAP}] (6). Using a scale of 0.207 mmol in [Pd₂(dba)₃], the general procedure gave 333 mg (89%) of a pale yellow solid that contained traces of ether (<5%) and P(o-tolyl)₃ (<1%) by ¹H and ³¹P NMR analysis. ¹H NMR (CDCl₃, 300 MHz) major (65%) + minor (35%) isomers: d 2.57 (CH₃, minor isomer), 2.86 (CH₃, major isomer), 6.43 (s, br), 6.58-8.08 (m). ³¹P NMR (CDCl₃, 121.5 MHz) major isomer (67%): d 9.7 (d, J 38.5 Hz), 27.4 (d, J 38.4 Hz); minor isomer (33%): d 10.9 (d, J 38.4 Hz), 24.5 (d, J 38.5 Hz). ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) major isomer (63%): d 10.0 (d, J 37.8 Hz), 26.5 (d, J 37.8 Hz); minor isomer (37%): d 10.7 (d, J 38.5 Hz), 23.5 (d, J 38.5 Hz). IR (neat solid) n_max/cm^-1: 3054, 1588, 1561, 1499, 1478, 1436, 1318, 1308, 1092, 1027, 870, 820, 735, 697. Anal Calcd for C₅₁H₃₉BrPdP₂: C, 68.05; H, 4.37%. Found: C, 68.27; H, 4.33%.

[PdBr(o-C₆H₄-iPr){(S)-BINAP}] (7). Using a scale of 0.207 mmol in [Pd₂(dba)₃], the general procedure gave 183 mg (59%) of a pale yellow solid that was recrystallised from dichloromethane-pentane giving pale yellow needles. ¹H NMR (CDCl₃, 300 MHz) major isomer (87%) d 0.75 (d, CH₃, J 6.9 Hz), 1.44 (d, CH₃, J 6.8 Hz), 3.75-3.85 (m, CH), 6.6-8.0 (m). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) major isomer (87%): d 12.0 (d, J 37.8 Hz), 26.6 (d, J 38.5 Hz); minor isomer (13%): d 12.0 (d, J 39.1 Hz), 25.0 (d, J 39.7 Hz). IR (neat solid) n_max/cm^-1: 3053, 2973, 2956, 2935, 2865, 1588, 1573, 1468, 1449, 1436, 1378, 1092, 1032, 1019, 822, 745, 727, 695. Anal Calcd for C₅₃H₄₃BrPdP₂: C, 68.58; H, 4.67%. Found: C, 67.16; H, 4.07%.

[PdBr(o-C₆H₄Ph){(S)-BINAP}] (8). Using a scale of 0.207 mmol in [Pd₂(dba)₃], the general procedure gave 233 mg (59%) of a pale pink solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (CDCl₃, 300 MHz) d 5.62 (dd, 1H, J 11.5 and 8.7 Hz), 5.78 (s, br, 1H), 6.06 (s, br, 1H), 6.45-7.55 (m, 34 H), 7.74 (s, br, 2H), 8.01 (td, 1H, J 6.7 and 2.9 Hz), 8.37 (s, br, 1H). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) major isomer (99%): d 14.0 (d, J 40.1 Hz), 26.3 (d, J 39.0 Hz); minor isomer (1%): d 11.4 (d, J 38.0 Hz), 25.8 (d, J 38.1 Hz). IR (neat solid) n_max/cm^-1: 3053, 1586, 1569, 1478, 1436, 1304, 1096, 1019, 816, 741, 695. Anal Calcd for C₅₆H₄₁BrPdP₂: C, 69.99; H, 4.30%. Found: C, 69.59; H, 3.85%.

[PdBr(o-C₆H₄CH₂ CONHBn)(DPPF)] (9). Using DPPF instead of (S)-BINAP, the general procedure gave 643 mg (79%) of a yellow solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (CDCl₃, 300 MHz) d 3.00 (d, 1H, J15.2 Hz), 3.53 (s, 1H), 3.63 (s, 1H), 4.01 (d, 1H, J 14.7 Hz), 4.14-4-45 (m, 6H), 4.65 (s, 1H), 5.01 (s, 1H), 6.51-7-49 (m, 23 H), 7.89-8.15 (m, 6H). ³¹P{¹H} NMR (CDCl₃, 121.5 MHz) d 8.7 (d, J 32.4 Hz), 29.8 (d, J 31.7 Hz). ³¹P NMR (C₆D₆, 121.5 MHz) d 7.7 (d, J 32.4 Hz), 28.4 (d, J 31.7 Hz). IR (neat solid) n_max/cm^-1: 3315 (n_N-H), 3085, 3056, 2973, 2898, 2858, 1679 (n_C=O), 1574, 1534, 1505, 1482, 1434, 1301, 1275, 1264, 1167, 1098, 1036, 1025, 756, 737, 695. Anal Calcd for C₄₉H₄₂NOBrFePdP₂: C, 60.99; H, 4.39%. Found: C, 61.10; H, 4.43%.

[PdBr(o-C₆H₄CH₂ ¹³CONHBn)(DPPF)] (9a). A solution of {[P(o-tolyl)₃]Pd[o-C₆ H₄CH₂¹³CON(H)Bn](Br)} ₂ (10 mg, 0.007 mmol) and ddpf (9 mg, 0.016 mmol) in C₆D₆ (2 mL) was stirred at room temperature overnight in a glovebox. The solution was analyzed without isolation by ³¹P and ¹³C NMR spectroscopy. ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) d 7.7 (d, J 32.3 Hz), 28.4 (d, J 31.7 Hz).¹³C{¹H} NMR (C₆D₆, 75.4 MHz) d¹³CO 174.4.

[Pd(o-C₆H₄CH₂ CO¹⁵NHBn)(DPPF)] (9b). A solution of {[P(o-tolyl)₃]Pd[o-C₆ H₄CH₂CO¹⁵N(H)Bn](Br)} ₂ (20 mg, 0.014 mmol) and ddpf (20 mg, 0.036 mmol) in C₆D₆ (2 mL) was stirred at room temperature overnight into a glovebox. The solution was analyzed without isolation by ³¹P NMR spectroscopy. ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) d 7.7 (d, J 31.7 Hz), 28.4 (d, J 31.7 Hz).

General procedure for the preparation of [Pd(Ar)Br{P(o-tolyl)₃}]₂. ²⁵ A purple solution of [Pd₂(dba)₃] (382 mg, 0.418 mmol), P(o-tolyl)₃ (510 mg, 1.68 mmol) and aryl bromide (1.02 mmol) in benzene (30 mL) was stirred at room temperature for 16 h. The solution was filtered through Celite, and the benzene was removed under vacuum. The oily residue was dissolved in ether (25 mL) and stirred at room temperature for 16 h. The resulting precipitate was filtered, washed with ether and dried under vacuum.

[PdBr(o-C₆H₄CH₂ CONHBn){P(o-tolyl)₃}]₂. The general procedure gave 510 mg (87%) of a yellow solid that contained traces of ether by ¹H NMR analysis (< 5%). ¹H NMR (CDCl₃, 300 MHz, 50 ^oC) d 1.47 (br ), 2.38 (br), 3.60 (br), 4.49 (br), 6.57-7-45 (m). %). ³¹P{¹H} NMR (CDCl₃, 300 MHz, 50^oC) d 31.3 (s br). IR (neat solid) n_max/cm^-1: 3242 (n_N-H), 3092, 3056, 1609 (n_C=O), 1449, 1283, 1202, 1164, 1028, 805, 753, 699. Anal Calcd for C₇₂H₇₀N₂O₂ Br₂Pd₂P₂: C, 60.48; H, 4.93%. Found: C, 60.61; H, 4.77%.

[PdBr(o-C₆H₄CH₂ ¹³CONHBn){P(o-tolyl)₃}]₂ . The general procedure gave 466 mg (78%) of a yellow solid that contained traces of ether by ¹H NMR analysis (<5%). ¹H NMR (CDCl₃, 300 MHz, 50 ^oC) d 1.49 (br), 3.52 (br), 4.39 (br), 6.23-7-66 (m). %). ³¹P{¹H} NMR (CDCl₃, 300 MHz, 50 ^oC) d 31.3 (s br). IR (neat solid) n_max/cm^-1: 3244 (n_N-H), 3064, 1569 (n_C=O), 1449, 1337, 1283, 1200, 1133, 1028, 805, 753, 742, 699. Anal Calcd for C₇₁¹³CH₇₀N₂ O₂Br₂Pd₂P₂ : C, 60.69; H, 4.94%. Found: C, 60.99; H, 4.94%.

[PdBr(o-C₆H₄CH₂ CO¹⁵NHBn) {P(o-tolyl)₃}]₂. The general procedure gave 305 mg (51%) of a yellow solid that contained traces of ether by ¹H NMR analysis (< 5%) %). ¹H NMR (CDCl₃, 300 MHz, 50 ^oC) d 1.47 (br), 3.48 (br), 4.49 (br), 6.57-7-45 (m). %). ³¹P{¹H} NMR (CDCl₃, 300 MHz, 50^oC) d 31.2 (s br).IR (neat solid) n_max/cm^-1: 3220 (n_N-H), 3058, 1603 (n_C=O), 1573, 1553, 1449, 1283, 1202, 1164, 1133, 1028, 805, 751, 741, 716, 700, 679. Anal Calcd for C₃₆H₃₅¹⁵NOBrPdP: C, 60.40; H, 4.93%. Found: C, 61.61; H, 4.63%.

Syntheses of cyclometallated [Pd(o-C₆H₄CH₂CONBn)L ₂]

[Pd(o-C₆H₄CH₂CONBn){(S)-BINAP}] (11). A mixture of [PdBr(o-C₆H₄CH₂ CONHBn){(S)-BINAP}] (246 mg, 0.238 mmol) and NaO-t-Bu (32 mg, 0.33 mmol) in benzene (20 mL) was stirred at room temperature for 16 h. The solution was filtered through Celite, and concentrated to approximately 3 mL. Addition of hexane (40 mL) gave a precipitate that was filtered, washed with pentane and dried under vacuum to give 200 mg (88%) of a yellow solid that contained traces of pentane by ¹H NMR analysis (<5%). ¹H NMR (C₆D₆, 300 MHz) major + minor isomers: d 3.00 (d, J 14.2 Hz), 4.01 (d, J 15.6 Hz), 4.20 (d, J 12.4 Hz), 5.24 (br), 6.18-8.16 (m). ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) major isomer (59%): d 13.3 (d, J 34.8 Hz), 28.9 (d, J 36.0 Hz); minor isomer (41%): d 12.3 (d, J 38.5 Hz), 30.3 (d, J 39.1 Hz). IR (neat solid) n_max/cm^-1: 3054, 2960, 1594 (n_C=O), 1580, 1501, 1478, 1437, 1376, 1308, 1098, 1027, 814, 739, 697. Anal Calcd for C₅₉H₄₅NOBrPdP₂: C, 74.43; H, 4.77%. Found: C, 74.64; H, 4.88%.

[Pd(o-C₆H₄CH₂ ¹³CONBn){(S)-BINAP}] (11a). NaOCPh₃ (8 mg, 0.028 mmol) was added to a solution of [(S)-BINAP]Pd[o-C₆H₄CH ₂¹³CON(H)Bn] (20 mg, 0.019 mmol) in C₆D₆ (2 mL) and the mixture was stirred at room temperature overnight in a glovebox. The solution was filtered through Celite and analyzed without isolation by ³¹P and ¹³C NMR spectroscopy. ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) ) major isomer (57%): d 13.3 (d, J 36.0 Hz), 28.8 (d, J 36.0 Hz); minor isomer (43%): d 12.4 (d, J 36.6 Hz), 30.3 (d, J 36.6 Hz).¹³C{¹H} NMR (C₆D₆, 75.4 MHz) d¹³CO 174.7 and 175.8.

[Pd(o-C₆H₄CH₂ CO¹⁵NBn){(S)-BINAP}] (11b). NaOCPh₃ (8 mg, 0.028 mmol) was added to a solution of [(S)-BINAP]Pd[o-C₆H₄CH ₂CO¹⁵N(H)Bn] (20 mg, 0.019 mmol) in C₆D₆ (2 mL) was stirred at room temperature overnight in a glovebox. The solution was filtered through Celite and analyzed without isolation by ³¹P spectroscopy. ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) major isomer (57%): d 13.3 (d, J 36.0 Hz), 28.8 (dd, J 46.0 and 36.0 Hz); minor isomer (43%): d 12.4 (d, J 38.5 Hz), 30.3 (dd, J 44.5 and 38.51 Hz).

[Pd(o-C₆H₄CH₂ CONBn)(DPPF)] (10). A mixture of PdBr(o-C₆H₄CH₂ CONHBn(DPPF) (200 mg, 0.207 mmol) and NaO-t-Bu (30 mg, 0.312 mmol) in benzene (20 mL) was stirred at room temperature for 16 h. The solution was filtered through Celite, and concentrated to approximately 3 mL. Addition of hexane (40 mL) gave a precipitate that was filtered, washed with hexane and dried under vacuum to give gave 125 mg (68%) of a yellow solid that contained traces of pentane by ¹H NMR analysis (<5%). ¹H NMR (C₆D₆, 300 MHz) d 2.99 (d, 1H, J 15.4 Hz), 3.61 (d, 2H, J 7.9 Hz), 3.68 (d, 2H, J 1.0 Hz), 3.85 (d, 1H, J 9.6 Hz), 4.02-4.08 (m, 3H), 5.04 (d, 1H, J 12.3 Hz), 5.52 (dd, 1H, J 15.4 and 9.6 Hz), 6.50 (m, 2H), 6.85 (m, 4H), 6.97-7.47 (m, 19 H), 7.64 (m, 2H), 8.02-8.08 (m, 2H). ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) d 10.0 (d, J 35.4 Hz), 25.4 (d, J 34.8 Hz). IR (neat solid) n_max/cm^-1: 3054, 2960, 1594 (n_C=O), 1580, 1501, 1478, 1437, 1376, 1308, 1098, 1027, 814, 739, 670. Anal Calcd for C₄₉H₄₁NOFePdP₂: C, 66.57; H, 4.67%. Found: C, 65.84; H, 4.58%.

[Pd(o-C₆H₄CH₂ ¹³CONBn)(DPPF)] (10a). NaOCPh₃ (11 mg, 0.028 mmol) was added to the solution of PdBr(o-C₆H₄CH₂ ¹³CONHBn)(DPPF) (obtained in situ from the reaction of PdBr(o-C₆H₄CH₂ ¹³CONHBn){P(o-tolyl)₃}] ₂ (10 mg, 0.007 mmol) and dppf (9 mg, 0.016 mmol) in C₆D₆ (2 mL)) and stirred at room temperature for 16 h in a glove box. The solution was filtered through Celite and analyzed without isolation by ³¹P and ¹³C spectroscopy. ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) d 10.1 (d, J 35.4 Hz), 25.4 (d, J 35.4 Hz). ¹³C{¹H} NMR (C₆D₆, 75.4 MHz) d¹³CO 174.4.

[Pd(o-C₆H₄CH₂ CO¹⁵NBn)(DPPF)] (11b). NaOCPh₃ (11 mg, 0.054 mmol) was added to the solution of PdBr(o-C₆H₄CH₂ CO¹⁵NHBn)(DPPF) (obtained in situ from the reaction of [PdBr(o-C₆H₄CH₂ CO¹⁵NHBn){P(o-tolyl)₃}] ₂ (20 mg, 0.014 mmol) and dppf (20 mg, 0.036 mmol) in C₆D₆ (2 mL) )and stirred at room temperature for 16 h in a glove box. The solution was filtered through Celite and analyzed without isolation by ³¹P and ¹³C spectroscopy. ³¹P{¹H} NMR (C₆D₆, 121.5 MHz) d 10.1 (dd, J 36.0 and 3.7 Hz), 25.4 (dd, J 47.6 and 35.4 Hz).

X-ray crystallography

Acknowledgment

A. L. Monteiro thanks Professor S. L. Buchwald for his stay in Buchwald's group, for helpful support and discussions, for financial support and also for permission to publish this work. A. L. Monteiro also thank Dr. John Spencer (UK) for proofreading the manuscript, and CNPq-Brazil for a postdoctoral fellowship.

Supplementary Information

Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Data Center as Supplementary Publication No. CCDC- 219507 . These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [e-mail]).

Electronic Supplementary Information

Inversion transfer experiments available as PDF file at http://jbcs.sbq.or.br

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Received: May 6, 2003

Published on the web: February 3, 2004

Publication Dates

• Publication in this collection
  25 May 2004
• Date of issue
  Feb 2004

History

• Accepted
  03 Feb 2004
• Received
  06 May 2003