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

As reações de uma mistura [Pd 2 (dba) 3 ]/P(o-tolyl) 3 (1/4) com brometos de arila orto substituídos conduziram aos dímeros [Pd(Ar)(μ-Br){P(o-tolyl) 3 )}] 2 que, após adição de 2 equiv. de (S)-BINAP formaram os complexos [PdBr(o-RC 6 H 4 ){(S)-BINAP}] em bons rendimentos (57-89%). A estrutura molecular do complexo [PdBr(o-C 6 H 4 CH 2 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 P{H} NMR. O comportamento dinâmico do complexo 1 em solução de CDCl 3 foi estudado por RMN de P{H} (1, CO-1 e N1) a varias temperaturas. O complexo enriquecido com CO foi estudado também por RMN de C{H}. Três espécies foram detectadas por RMN de P{H} e C{H} a baixas temperaturas (< 0 C) e foram atribuídas como sendo os dois diastereoisomeros de 1 e o complexo catiônico [Pd(o-C 6 H 4 CH 2 CON(H)Bn) {(S)-BINAP}]Br. Acima de 40 C observou-se somente os dois diastereoisômeros e a coalescência dos sinais pode ser observada por RMN de C{H} a 80 C. Não foi observada, na escala de tempo de RMN, nenhuma interconversão do complexo 1 em tol-d 8 entre –35 at 120 C. Entretanto, a interconversão entre os dois diastereoisômeros foi evidenciada por experimento de transferência de inversão no RMN de P{H}. Os ciclopaladatos [Pd(oC 6 H 4 CH 2 CONBn)L 2 ] [11 L 2 = DPPF, 68%; 12 L 2 = (S)-BINAP, 88 %] foram obtidos a partir das reações entre os complexos com NaO-t-Pn. A análise de RMN de P{H} dos complexos 11 e 12 marcados com N 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. 1,2In particular, Buchwald reported that aryl bromides with pendant secondary amide groups could be cyclized to form tertiary amides. 3P(o-tolyl) 3 or P(2-furyl) 3 were the ligands used in conjunction with [Pd 2 (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 sixmembered 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 fiveand 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 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 n Pd(0) complex gives the intermediate Pd(II) complex. 6protonation gives the palladacycle that can reductively eliminate to produce the desired heterocycle and regenerate the Pd(0) catalyst. 7In 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. 9n 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.

Synthesis of the oxidative addition complexes [PdBr(osubstituted-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 [Pd 2 (dba) 3 ] and (S)-BINAP.In fact, stirring a purple solution of [Pd 2 (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 31 P NMR spectroscopy. 10The oxidative addition complex could be detected by 31 P NMR spectroscopy when the reaction was carried out at 80 o C, 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 [Pd 2 (dba) 3 ]. 11First the palladium tri-o-tolyphosphine dimer [Pd(µ-Br)(p-C 6 H 4 CN}{P(o-tolyl) 3 }] 2 was isolated in good yield (75%) from the reaction of [Pd 2 (dba) 3 ] with p-CNC 6 H 4 Br and P(o-tolyl) 3 in benzene. 12Second, reaction of the complex [Pd(µ-Br)(p-C 6 H 4 CN){P(o-tolyl) 3 }] 2 with (S)-BINAP in dichloromethane gave the complex [PdBr(p-C 6 H 4 CN){(S)-BINAP}] in 80% yield.In order to obtain the BINAP-Pd complex in one step, we have carried out some 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{ 1 H} NMR analysis of [PdBr(o-C 6 H 4 CH 2 CON(H)Bn){(S)-BINAP}] (1) in C 6 D 6 showed two distinct species, each having two doublets (δ 10.2 and 26.3; δ 11.6 and 24.8 respectively) with 3 J P-P 37 Hz.The 13 C{ 1 H} NMR spectrum for 13 C labeled 1a in C 6 D 6 displayed two signals for 13 C=O (δ 171.4 and 171.5) and the ratio of these resonances was the same as observed in 31 P NMR. 15 N labeled 1b did not display any additional coupling in the 31 P{ 1 H} 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 31 P{ 1 H} 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). 13X-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 C 2 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-C 6 H 4 CH 2 CONHBn)(DPPF)] (9). 14This complex was fully characterized by standard spectroscopic techniques and elemental analysis and, as expected, only one species was observed by 31 P{ 1 H} NMR (δ 7.7 and 28.4; J 32 Hz).

X-ray structure of [PdBr(o-C 6 H 4 CH 2 CON(H)Bn){(S)-BINAP}] (1)
The crystal structure of complex 1 was examined by Xray 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

NMR observations on [PdBr(o-C 6 H 4 CH 2 CON(H)Bn){(S)-BINAP}] (1)
The NMR spectra of 1 are very dependent on the solvent used.As already mentioned, 31 P{ 1 H} NMR analysis of 1 shows two distinct species, each one having two doublets with 3 J P-P 37 Hz C 6 D 6 (δ 10.2 and 26.3; δ 11.6 and 24.8).However, 31 P{ 1 H} NMR spectrum of 1 in DMF-d 7 displayed two very broad signals centered at δ 10.0 and 28.0.A more complicated pattern was observed in CDCl 3 .Figure 2 shows the 31 P{ 1 H} NMR spectra for the 13 C labeled 1a in the -35-80 o C range.It is important to note that variable temperature 31 P{ 1 H} NMR analysis of 1, and 13 C labeled 1a in CDCl 3 give rise to identical spectra.
The 31 P{ 1 H} NMR spectrum at room temperature displayed one pair of doublets (δ 10.8 and 28.5, J 37.0 Hz) instead of the two observed in C 6 D 6 or tol-d 8 .Besides this pair of doublets, three broad signals centered at δ 12.1, 25.4 and 38.7 were also observed (Figure 2).When the temperature was lowered to 0 o C the broad signals centered at δ 25.4 and 38.7 became partially resolved into doublets, while the broad signal at δ 13 was split into two partially resolved doublets.Three sharp pairs of doublets were observed at -25 o C evidencing the existence of three species containing the bidentate BINAP ligand coordinated to the palladium [A: δ 10.8 and 28.5 (J 37.0 Hz); B: δ 12.2 and 28.5 (J 38.0 Hz); C: δ 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 δ 13.8 and 38.8 is favored at low temperatures.The fluxional behavior of 1a in CDCl 3 was also investigated by 13 C{ 1 H} NMR analysis of the 13 Clabeled carbonyl group (Figure 3).One relative sharp signal at δ 172.8 and one broad signal at δ 173.5 were observed at room temperature.At 0 o C the broad signal decreased in intensity and a third broad signal appeared at δ 174.6.By lowering the temperature these signals became sharp and, in agreement with 31 P NMR, the presence of three species was also evidenced.When the temperature was lowered to -35 o C the relative intensity of the signal at δ 174.6   increased showing that this carbonyl resonance was related to species C with 31 P{ 1 H} NMR resonances at δ 13.8 and 38.8. 31 P{ 1 H} and 13 C{ 1 H} NMR spectra above room temperature indicated two species between 40 and 80 o C, with a coalescence temperature at 80 o C in 13 C{ 1 H} NMR.From this coalescence temperature, an approximate rate of 10 2 s -1 and a free energy of activation (∆ G ≠ ) 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 comparison with the chemical shift of complexes 2 to 8 and also with 1 in C 6 D 6 , the species A and B, characterized by the pair of doublets at δ 10.8/28.5 and 12.2/25.9 in CDCl 3 , 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-C 6 H 4 (CH 2 CH 2 OH)}(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. 19In order to verify this possibility, complex 1 was partially dissolved in acetone-d 6 and reacted with excess of AgOTf. 31P{ 1 H} NMR before reaction displayed two pairs of relatively broad doublets but the chemical shifts (δ 11.1/28.6 and 11.9/27) are similar to those obtained in CDCl 3 .After stirring the mixture and filtration, the yellow solution displayed only one sharp pair of  doublets at δ 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 13 C-labeled complex 1a giving a chemical shift of 175.8 for the carbonyl group of the cationic complex (compared with δ 174.6 for species C in CDCl 3 ).It is interesting to note that a very small coupling (2 Hz) was observed for this resonance. 31P{ 1 H} NMR analysis of the 15 N-labeled complex 1b showed a doublet of doublets only for the resonance at δ 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 CDCl 3 .At low temperatures (below 0 o C) the two diastereoisomers and the cationic complex are detectable on the NMR time scale.Above 40 o C only the two diastereoisomers are detectable.When the temperature is raised the rotation became faster and at 80 o C 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-d 8 , and complex 1 was characterized by two sharp pairs of doublets in the -35-120 o C 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 31 P NMR experiment.Selective inversion of the doublet at δ 11.4 results, after an appropriate evolution time, in a significant change in the intensity of the doublet at δ 12.9 (see electronic supplementary information).A maximum decrease in relative intensity for the doublet at δ 12.9 was observed using a evolution time of 0.5 seconds, while the doublets at δ 26.0 and 27.4 remained unchanged for all the evolution time evaluated.In the same way, selective inversion of the doublet at δ 27.4 results in a significant change only for the doublet at δ 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 δ 11.4 and 12.9, and between the phosphorus atoms characterized by the resonances at δ 26.0 and 27.4.The doublets at δ 11.4 and 12.9 were assigned to the phosphorus cis to the bromine for each isomer, and the doublets at δ 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 CDCl 3 .However, the interconversion in tol-d 8 is slower and can only be observed using a inversion transfer experiment.

Synthesis and characterization of the cyclopalladated complexes [Pd(o-C 6 H 4 CH 2 CONBn)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 Cs 2 CO 3 and K 2 CO 3 , 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 o C).However, the palladacycle [Pd(o-C 6 H 4 CH 2 CONBn)(DPPF)] (10) was isolated free from NaBr and excess alkoxide in 68% yield by treatment of the aryl bromide complex [PdBr(o-C 6 H 4 CH 2 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 ν 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. 20 31P{ 1 H} NMR spectrum displayed two doublets at δ 10.0 and 25.4 ( 2 J P-P 35 Hz) for the palladacycle and two doublets at δ 7.7 and 28.4 ( 2 J P-P 32 Hz) for the starting aryl bromide palladium complex 9. 31 P{ 1 H} NMR analysis of the reaction of the 15 N-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 δ 10.0 and 25.4 with a 2 J P-N of 3.7 and 47.6 Hz, respectively.Trans-2 J P-N values are  higher than those for cis couplings. 21,22For instance, it has been reported that cis 2 J 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). 21In complex 10, the low frequency resonance (δ 10.0) must therefore be assigned to the phosphorus cis to the nitrogen, and the high frequency resonance (δ 25.4) corresponds to the phosphorus trans to nitrogen.By analogy, the resonances at δ 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-C 6 H 4 CH 2 CONBn){(S)-BINAP}] (11) was isolated in 88% yield by treatment of the aryl bromide complex [PdBr(o-C 6 H 4 CH 2 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 ν N-H absorption.For the starting complex 1, two isomers were observed by 31 P{ 1 H} NMR analysis for the deprotonated complex 11 (Scheme 5).For each isomer the phosphorus at low field is characterized as a doublet of doublets ( 3 J P-N 46 Hz and 3 J 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-C 6 H 4 CH 2 CONBn}{(S)-BINAP}] and [Pd{(R)-o-C 6 H 4 CH 2 CONBn}{(S)-BINAP}].When complex 11 is heated at 100 o C 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 31 P{ 1  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 crosscoupling 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-C 6 H 4 CH 2 CONBn){(S)-BINAP}] was obtained with metallic palladium when the complex was heated at 100 o C 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 [Pd 2 (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 o C unless otherwise noted. 1 H and 13 C (75.6 MHz) spectra were referenced relative to the residual solvent peak. 31P NMR (121.5 MHz) spectra were referenced relative to external 85% H 3 PO 4 .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.CDCl 3 , C 6 D 6 , and PhMe-d 8 (Cambridge Isotopes) were dried over 4A o molecular sieves and degassed by three freeze/thaw cycles before use.

General procedure for preparation of [Pd(Ar)(Br){(S)-BINAP}].
A purple solution of [Pd 2 (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.