Synthesis of Amidines by Palladium-Mediated CO2 Extrusion

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

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Synthesis of Amidines by Palladium-Mediated CO2 Extrusion Followed by Insertion of Carbodiimides: Translating Mechanistic Studies to Develop a One-Pot Method Yang Yang,† Asif Noor,† Allan J. Canty,‡ Alireza Ariafard,‡ Paul S. Donnelly,*,† and Richard A. J. O’Hair*,†

Organometallics Downloaded from pubs.acs.org by UNIV OF RHODE ISLAND on 12/18/18. For personal use only.

†

School of Chemistry, Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Melbourne, Victoria 3010, Australia ‡ School of Physical Sciences, University of Tasmania, Private Bag 75, Hobart, Tasmania 7001, Australia S Supporting Information *

ABSTRACT: A palladium-mediated one-pot synthesis of amidines from aromatic carboxylic acids and carbodiimides (RNCNR) is reported as an isoelectronic adaption of CO2ExIn (ExIn = Extrusion−Insertion) reactions developed for the synthesis of thioamides from carboxylic acids and isothiocyanates (RNCS). Multistage mass spectrometry (MSn) experiments for model systems established “proof of concept”, demonstrating decarboxylation of [(L)Pd(O2CAr)]+ (L = 1,10-phenanthroline or py), to give [(L)PdAr]+, followed by reaction with a carbodiimide, RNCNR, to yield [(L)Pd(NRC(NR)Ar)]+ (R = isopropyl). DFT calculations predicted these reactions as highly exothermic and occurring via carbodiimide insertion into the Pd−Ph bond. 2,6-Dimethoxy and 2,4,6-trimethoxy substitution for the Pd−Ar moiety results in slower reactions with minor changes in mechanism. The individual reaction steps associated with the conversion of 2,6-dimethoxybenzoic acid and 2,4,6trimethoxybenzoic acid into amidines in solution was probed by 1H NMR spectroscopy as was the use of stoichiometric amounts of PdX2 salts (X = O2CCH3 and O2CCF3) and three different carbodiimides, RNCNR (R = iPr, cHex, and Ph). Use of palladium trifluoroacetate gives less of the undesired protodecarboxylation product formed by protonation of the Pd−Ar bond to release ArH. DFT studies for solution phase one-pot reactions provide support for the mechanism and explain competitive factors contributing to the desired insertion step or the alternative protonation step to release ArH. An understanding of mechanism obtained from the model studies encouraged development of a solution-phase one-pot synthesis of N,N′diisopropyl-2,6-dimethoxybenzamidine using stoichiometric amounts of palladium carboxylates. Reaction conditions, product isolation and characterization, yields, and the scope of the one-pot synthesis of N,N′-R2-2,6-dimethoxybenzamidine were established, in which borohydride is added in workup as a hydrogen source. Attempts to make the chemistry catalytic in palladium are described.

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INTRODUCTION Amidines continue to attract attention for a range of applications including organocatalysis,1,2 kinetic resolution of racemates,3 and ionic liquids,4 as well as stimulus-responsive materials in areas such as reversible binding of carbon dioxide and self-assembly of polymeric nanoparticles.5 Amidines are also of continued interest as ligands for metal-containing catalysts and coordination complexes.6−11 Amidines are found in natural products12 and have been used as selective nitric oxide synthases inhibitors,13 as regulators of arginine metabolism,14 as inhibitors of beta-secretase 1 an important therapeutic target for Alzheimer’s disease,15 and as agents against intracellular parasites.16 Amidines are strong bases and protonation gives rise to amidinium ions.17,18 Amidines can be prepared by several routes. For example, amide derivatives can undergo CX (Scheme 1A) or C−X bond activation (Scheme 1B).19 Alternatively, organometallic reagents can react with carbodiimides to form amidines.20,21 © XXXX American Chemical Society

More recently, various palladium-based methods have been developed including two-component reactions, in which a C− X bond is activated to form an organopalladium intermediate that then undergoes a reaction with a cyanamide (Scheme 1C),22,23 and three-component reactions.24−26 We recently reported a new class of “ExIn” (Extrusion− Insertion) reactions for thioamide synthesis (eq 1, Y = S): ArCO2 H + RNCY → ArC(Y)NHR + CO2

(1)

in which palladium is used to decarboxylate aromatic carboxylic acids to form an organopalladium intermediate which then undergoes insertion to form a thioamide (Scheme 1D, Y = S).27 The decarboxylation and insertion steps are directly related as CO2 and RNCS are isoelectronic. Received: October 25, 2018

A

DOI: 10.1021/acs.organomet.8b00776 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 1. Methods for Amidine Synthesisa

with eq 1 suggests that this reaction should be exothermic by around 30 kcal mol−1 for the systems shown in Scheme 2.31 The key steps are likely to involve the following: binding of the carboxylate to the metal center (eq 2, Scheme 2); decarboxylation (eq 3, Scheme 2);32,33 insertion of the carbodiimide, RNCNR, into the Pd−C bond (eq 4, Scheme 2);34,35 and reaction of the coordinated amidine (for reviews on the coordination chemistry of amidines, see refs 6−11) with a “hydrogen source” (acid or reducing agent such as NaBH4) to release the free amidine (eq 5, Scheme 2). While many of these individual steps have precedents (Scheme 1C,D), they have not been used together to achieve a one-pot synthesis of amidines directly from carboxylic acids (eq 1, Y = NR).

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RESULTS AND DISCUSSION Examining the Key Steps of Decarboxylation and Insertion in the Gas Phase. Multistage mass spectrometry (MSn) experiments and DFT calculations were used to examine two key steps associated with transformation of coordinated benzoates to coordinated amidines (eqs 3 and 4, Scheme 2). Electrospray ionization (ESI) of solutions containing 1,10-phenanthroline, palladium acetate, and the appropriate aromatic carboxylic acid, ArCO2H (where Ar = Ph, and 1A and 1B) generated abundant palladium complexes [(phen)Pd(O2CAr)]+, which all decarboxylated upon collision-induced dissociation (CID) to yield the desired organometallic cation [(phen)Pd(Ar)]+ (eq 3; for Ar = Ph, see ref 33, Ar = A and B see Figure S2,).36−39 Previous DFT calculations reveal that decarboxylation of the parent benzoate requires two transition states,27 which is also true for the dimethoxy- and trimethoxy-benzoates (Figure 1): TS6−7 involves transforming the chelating benzoate, 6, to the reactive conformation, 7, which then undergoes decarboxylation via TS7−8 to yield the four-coordinate complex, [(phen)Pd(Ar)(OCO)]+, 8. Complex 8 releases CO2 via TS8−9′ to give [(phen)Pd(Ar)]+, 9′. Various scans for loss of CO2 from 8 always led to TS8−9′, and thus to 9′. We explored a potential role for threecoordinate 9,40,41 but in the absence of detection of a transition state for formation of 9, we estimate a barrier of 18.2 kcal/mol (based on ΔH) using the protocol developed by Hartwig and Hall.42,43 Unlike the parent complex, [(phen)Pd(Ph)]+, the threecoordinate ortho-methoxy substituted arylpalladium complexes [(phen)Pd(Ar)]+, 9a and 9b, are less stable than isomers 9a′ and 9b′ in which one methoxy group is coordinated to the palladium center to form a four-coordinate complex. Thus, two processes for CO2 loss from 8 to generate 9′ were explored by DFT calculations (Figure 1, bottom). The isomerization process was found to have a smaller energy barrier to form 9a′ and 9b′ via a three-coordinated intermediate 9a and 9b. The coordinatively unsaturated organometallic ion, [(phen)Pd(C6H5)]+ (9c), readily undergoes an ion−molecule reaction (IMR) with diisopropyl carbodiimide (DIC) (Figure 2a; Scheme 2, ) to form [(phen)Pd((NiPr)C(NiPr)C6H5)]+ at the collision rate. In contrast, the reactions of diisopropyl carbodiimide (Figure 2b,c) with [(phen)Pd(C 6H3(2,6OMe)2)]+ (reaction efficiency at 1%) and [(phen)Pd(C6H2(2,4,6-OMe)3)]+ (rate is too slow to measure) are much slower, consistent with the four coordinate structures of 9a′ and 9b′ not having a vacant coordination site to allow coordination and subsequent insertion of the carbodiimide. To investigate “ligand-free” solution phase studies, the phenanthroline ligand was replaced by a pyridine ligand, which should

a

(A) C−X bond activation followed by C−N bond formation; (B) CX bond activation followed by CN bond formation; (C) palladium mediated C−X bond activation to form an organopalladium intermediate that then undergoes insertion; (D) ExIn approach used in this work: decarboxylation followed by insertion.

Here we examine related ExIn reactions for the preparation of amidines using carbodiimides (Scheme 1D, Y = NR), with the aim of developing a one-pot method for the synthesis of the amidines (Scheme 2). We restrict the scope of our study to Scheme 2. One-Pot Method for the Synthesis of Amidinesa

a

L: phenanthroline and pyridine in gas phase or DMSO in solution phase; X = “+” in gas phase or O2CCH3 or O2CCF3 in solution phase. A total of six amidines were prepared and they are designated according to descriptors of the Ar group (shown in the left box as A or B) and the R group (shown in the right box as I, II, or III).

three carbodiimides, including diisopropyl carbodiimide which has a suitable boiling point to allow vaporization for the gasphase studies. We restricted our study to 2,6-dimethoxy- and 2,4,6-trimethoxy-benzoic acids as monosubstituted benzoic acids can undergo competing Pd-mediated C−H bond activation reactions at the positions ortho to the carboxylate group.28−30 A consideration of the thermochemistry associated B


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Organometallics

Figure 1. Key species associated with the decarboxylation of the palladium complexes palladium complexes [(phen)Pd(O2CAr)]+: (a) Ar = 2,6(OMe)2C6H3; (b) Ar = 2,4,6-(OMe)3C6H2. The relative Gibbs and enthalpy energies (in parentheses) are given in kcal/mol and were calculated at B3LYP-D3BJ/BS2//M06/LANL2DZ6-31G(d) level.

Figure 2. LTQ MS3 spectra of ion−molecule reactions in the gas-phase between diisopropyl carbodiimide and: (a) [(phen)Pd(C6H5)]+ (9c, reaction time: 200 ms); (b) [(phen)Pd(C6H3(2,6-OMe)2)]+ (9a, reaction time: 5000 ms); (c) [(phen)Pd(C6H2(2,4,6-OMe)3)]+ (9b, reaction time: 5000 ms). (d) [(py)Pd(C6H3(2,6-OMe)2)]+ (9d, reaction time: 300 ms). The inserts show the peak shape of the ion−molecule reaction products. The concentration of DIC in all four IMRs is 6.4 × 109 molecules cm−3. The mass-selected organometallic ions are denoted by *.

Unfortunately, unlike in our previous study,27 we have not be able to prepare suitable “authentic structures” of [(phen)Pd((NR)C(NR)Ar)]+ in order to compare their CID spectra to those of the products of the ion−molecule reactions shown in Figure 2. Nonetheless, the CID spectra of m/z 489 is consistent with the coordinated amidine [(phen)Pd((NiPr)C(NiPr)C6H5)]+ (it fragments via loss of NiPr, as in Figure S4a, while those of m/z 549 and 579 in Figure 2b,c are consistent with complexes with weakly bound carbodiimide (Figure S4b,c).44 Finally, the product of [(py)Pd(C6H3(2,6-OMe)2)]+

free up a vacant coordination site and thus switch on the insertion reaction. The organometallic ion [(py)Pd(C6H3(OMe)2)]+, readily formed from CID of [(py)2Pd(O2CC6H3(OMe)2)]+ via the combined losses of CO2 and a pyridine ligand (eq 6, Figure S3), undergoes a reaction with diisopropyl carbodiimide at the collision rate. [(py)2 Pd(O2 CC6H3(OMe)2 )]+ → [(py)Pd(C6H3(OMe)2 )]+ + CO2 + py

(6) C


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Organometallics

Figure 3. Key species associated with the insertion reactions of the palladium complexes [(phen)Pd(Ar)]+ with diisopropyl carbodiimide: (a) Ar = C6H3(2,6-OMe)2; (b) Ar = C6H2(2,4,6-OMe)3; (c) Ar = Ph. The relative Gibbs and enthalpy energies (in parentheses) are given in kcal/mol and were calculated at the B3LYP-D3BJ/BS2//M06/LANL2DZ6-31G(d) level of theory.

Figure 4. Key species associated with the insertion reactions of the palladium complex [(py)Pd(C6H3(OMe)2)]+ (py trans to OMe) with diisopropyl carbodiimide. The relative Gibbs and enthalpy energies (in parentheses) are given in kcal/mol and were calculated at the B3LYPD3BJ/BS2//M06/LANL2DZ6-31G(d) level of theory.

and diisopropyl carbodiimide at m/z 448 loses either diisopropyl carbodiimide or one pyridine (Figure S4d). The latter is also consistent with the formation of an amidine. The formation of coordinated amidines versus weakly bound complexes is consistent not only with the observed rates of reactivity and their CID reactions but also with the peak shapes of the product complexes (insets of Figure 2). Thus, the [(phen)Pd(O2CAr)]+ complexes where Ar = 2,6-(OMe)2C6H3

(Figure 2b) and Ar = 2,4,6-(OMe)3C6H2 (Figure 2c) exhibit the phenomenon of “peak fronting” which occurs for weakly bound complexes as they are ejected from the ion trap during the detection event.45,46 DFT calculations predict that the reaction between [(phen)Pd(C6H5)]+ (9c), and diisopropyl carbodiimide (Scheme 2, eq 4) to form [(phen)Pd((NR)C(NR)C6H5)]+ is highly exothermic and occurs via insertion into the Pd−C D


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olefination of arene carboxylates where a palladium salt screening was carried out,28 stoichiometric amounts of either Pd(O2CCH3)2 or Pd(O2CCF3)2 as the source of Pd2+ in DMSO-d6 were in investigated in order to monitor the transformation of 2,6-dimethoxybenzoic acid to N,N′-diisopropyl-2,6-dimethoxybenzamidine. Addition of Pd2+ to an aromatic carboxylic acid resulted in formation of [(DMSO)nPd(X)(O2CAr)] (X = O2CCH3, Figure S6b; X = O2CCF3, Figure 5a; eq 2, Scheme 2). Decarboxylation at 70 °C over 6 h resulted in the formation of the organometallic complex [(DMSO)nPd(O2CCF3)(Ar)], where the resonances attributed to Hpara shifted upfield from δ 7.28 to 7.06 ppm with

bond to give coordinated amidinate 12c (Figure 3a). The initially formed complex [(phen)Pd(C6H3(2,6-OMe)2)(RNCNR)]+ (10a) undergoes the insertion reaction via TS10a-11a to give coordinated amidine 11a, which can isomerize via TS11a-12a to give 12a where the amidine acts as a bidentate ligand to give a 4-membered chelate ring. In contrast, four-coordinate complexes 9a′ and 9b′ lack a vacant coordination site, so they will not react the same way as 10a and [(phen)Pd(C6H5)]+ (9c). We have not been able to locate “SN2-like” or associative (A) pathways for the reaction of 9a′ and 9b′ with diisopropyl carbodiimide to give 10a and 10b.47 An “SN1-like” or dissociative (D) or interchange dissociative (Id) pathway, in which 9a′ and 9b′ overcome isomerization barriers to form reactive three-coordinated complexes 9a and 9b, allows insertion to proceed (Figure 3).40,41 The energy for these barriers is above the energy of the separated reactant, explaining why insertion is not experimentally observed under the near thermal conditions of the ion trap.48 Replacing the bidentate phen ligand with a single monodentate pyridine ligand to form [(py)Pd(C6H3(2,6OMe)2)]+ (9d), allows the carbodiimide to coordinate to give 10d and thus switches on the insertion reaction (Figure 4). There are two isomeric three-coordinate complexes: 9d has the pyridine ligand trans to the methoxy and is more stable than 9e where the pyridine ligand is cis (Figure S5). The carbodiimide coordinates to a vacant coordination site to generate four-coordinate complexes 10d and 10e. In order for insertion to proceed, 10d isomerizes to give the threecoordinate complex 10d′, which can then proceed via TS10d′-11d to give coordinated amidine, 11d, which in turn undergoes a series of changes in coordination mode to ultimately give 12d. The DFT calculations are entirely consistent with the experimental results: Three-coordinate [(phen)Pd(C6H5)]+ 9c reacts rapidly with diisopropyl carbodiimide to form [(phen)Pd((NR)C(NR)C6H5)]+ 10c, while four-coordinate complexes [(phen)Pd(Ar)]+ 9a and 9b react very slowly with diisopropyl carbodiimide to only form more weakly bound complexes. The three-coordinate [(py)Pd(C6H3(OMe)2)]+ 9d reacts rapidly with diisopropyl carbodiimide to form a product that can either undergo pyridine or diisopropyl carbodiimide loss (Figure S4d). Solution Phase Experiments: Using 1H NMR Spectroscopy to Monitor the Transformation of 2,6Dimethoxybenzoic Acid to N,N′-Diisopropyl-2,6-dimethoxy-benzamidine Using Stoichiometric Pd(O2CCF3)2. That decarboxylation (eq 3, Scheme 2) readily occurs in the gas-phase and that insertion occurs for species with a vacant coordination site (eq 4, Scheme 2) encouraged the investigation of the conversion of aromatic carboxylic acids into amidines using stoichiometric quantities of palladium salts. The individual reaction steps (eqs 2−5, Scheme 2) were examined by 1H NMR spectroscopy. The conversion of aromatic carboxylic acids into amidines requires the insertion reaction (eq 3, Scheme 2) to be favored over protonation of the organometallic complex (eq 7), a reaction that leads to protodecarboxylation (eq 8).29,30 [(L)n Pd(X)(Ar)] + HX → [(L)n Pd(X)2 ] + ArH

(7)

ArCO2 H → ArH + CO2

(8)

Figure 5. Pd(O2CCF3)2 induced transformation of 2,6-dimethoxybenzoic acid to N,N′-diisopropyl-2,6-dimethoxyl-benzamidine monitored using 1H NMR spectroscopy (600 Hz) in DMSO-d6 (only the resonances due to the aromatic protons are shown): (a) 2,6dimethoxybenzoic acid binding to the Pd2+ (eq 2, Scheme 2); (b) decarboxylation for 6 h (eq 3, Scheme 2); (c) showing decarboxylation under longer reaction times to yield little protodecarboxylation product (eq 8); (d) insertion of iPrNC NiPr into the Pd−C bond (eq 4, Scheme 2) and (e) reaction of the palladium amidinate with NaBH4 to release the free amidine (eq 5, Scheme 2). (f) ESI/HRMS spectrum of the NMR sample showing formation of the protonated amidine. *: peaks due to the product of protodecarboxylation, 1,3-dimethoxybenzene. Ligand L is DMSO or trifluoroacetate or both. iPr = isopropyl.

Guided by Kozlowski’s mechanistic study on protodecarboxylation29,30 and Myer’s work on decarboxylative Heck-type E


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Organometallics

Figure 6. DFT calculation of insertion and protodecarboxylation in solution phase using palladium salts, PdX2: (a) X = O2CCH3, (b) X = O2CCF3. The relative Gibbs and enthalpy energies (in parentheses) are given in kcal/mol and were calculated at the B3LYP-D3BJ/BS3//M06/BS1 level of theory in DMSO using the CPCM approach. (a) X = O2CCH3; (b) X = O2CCF3.

by ESI-HRMS analysis of the NMR sample (Figures 5f and S12). Given that the use of Pd(O2CCH3)2 resulted in higher yields of the unwanted protodecarboxylation product, 1,3-dimethoxybenzene (Figure S6), when compared to Pd(O2CCF3)2 (Figure 5), Pd(O2CCF3)2 was used for 1H NMR monitoring experiments for all other combinations shown in Scheme 2. The results of these experiments are given in Figures S7−S11. For all these other systems, similar changes to the chemical shifts of the aromatic proton were observed, and ESI/HRMS analysis of the NaBH4 treated NMR samples confirmed the formation of the [M + H]+ of free amidines (Figures S12− S17). Computational Studies on Solution-Phase Decarboxylation and the Competition between Insertion and Protonation. Although the DFT calculations suggested that gas-phase amidine formation was viable and suggested plausible mechanistic features for the decarboxylation and insertion (Figure 1 and 3), some aspects of the solution-phase chemistry are different so additional DFT calculations were

peak broadening (Figure 5b; eq 3, Scheme 2). Continued heating at 70 °C for 14 h led to the minor protonation byproduct 1,3-dimethoxybenzene (Figure 5c, eq 7). The formation of 1,3-dimethoxybenzene was more prominent when Pd(O2CCH3)2 was used (Figure S6c) compared to the Pd(O2CCF3)2. Indeed, complete protodecarboxylation can be observed after 24 h (Figure S6d). When diisopropyl carbodiimide was added to the solution of the organometallic complex [(DMSO)nPd(X)(Ar)] at room temperature, the coordinated amidinate was formed by insertion (Figure 5d; eq 4, Scheme 2) with a clearly observed chemical shift of the resonance attributed to the Hpara proton, for example, 7.06− 7.51 ppm, Δδ = 0.46 ppm for Pd(O2CCF3)2 salt. In contrast, when Pd(O2CCH3)2 was used, significant competition with the protodecarboxylation reaction leads to a more complicated spectrum (Figure S6d). Addition of NaBH4 to the Pd(O2CCF3)2 system allows detection of the free amidine (Figure 5e; eq 5, Scheme 2), leading to a downfield shift of the resonance attributed to the Hpara proton (7.51−7.21 ppm, Δδ = 0.30 ppm). The formation of the amidine was confirmed F


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Organometallics pursued. The use of phenanthroline or pyridine auxiliary ligand is important to allow the formation well-defined cationic species required for MS manipulation and detection. Auxiliary ligands are not required for the solution phase reactions and DMSO coordinates in their place. The presence of a reservoir of acid (CH3CO2H or CF3CO2H) in solution, which is absent in the gas-phase, leads to the formation of substituted benzene byproducts, so the competition between insertion and protonation of the organopalladium requires further investigation. The role of the different anions, CH3CO2− and CF3CO2−, on protonation and insertion reaction was also explored. To consider the solvation effect of DMSO on the optimized structures, a continuum medium was employed using the conductor polarizable continuum model (CPCM). One DMSO ligand is coordinated to the Pd center, and another DMSO ligand is involved in the equilibria between 13a1 and 13a2 as well as 13b1 and 13b2. Thus, appropriate entropic corrections were applied (see the section “DFT Calculation”).49 Mechanistic aspects of the decarboxylation and protodecarboxylation of benzoates coordinated to a Pd(II) center has been already been investigated with DFT calculations,27,50,51 so we focused solely on the competition between protonation and insertion of diisopropyl carbodiimide with organopalladium compounds 13 in both systems, Pd(O2CCH3)2 (Figure 6a) and Pd(O2CCF3)2 (Figure 6b). Insertion starts with a simple associative substitution reaction in which one of the coordinating O atoms of the bidentate acetate ligand is replaced by the nitrogen atom of the carbodiimide via transition structure TS13−14 to give complex 14. This is followed by the insertion of carbodiimide into the Pd−Ar bond to afford 15. In comparison, in the other pathway, 13 is substituted by an acetic acid to form intermediate 16. The resultant intermediate is then involved in a proton transfer reaction leading to formation of 17. When comparing Pd(O2CCH3)2, a, and Pd(O2CCF3)2, b, the transition state TS16−17 in the protonation step has a higher energy barrier with CF3CO2− ligands (12.4 kcal/mol) than that with CH3CO2− ligands (10.1 kcal/mol). This is consistent with the experimental result that during the decarboxylation less protonation product is formed in the Pd(O2CCF3)2 system. Although the energy barrier for protonation in the Pd(O2CCF3)2 system is higher, the energy barrier for the insertion pathway is also increased which can also explain the longer time for insertion reactions in the Pd(O2CCF3)2 system. Solution Phase Experiments: Development of a OnePot Method for the Synthesis of Substituted Amidines. Having used 1H NMR spectroscopy to establish the solution transformation of 2,6-dimethoxybenzoic acid to N,N-diisopropyl-2,6-dimethoxybenzamidine, we next scaled up the procedure. The scope of the reaction was investigated with different RNCNR substrates (Table 1). Following addition of NaBH4, products could be isolated in modest yields ranging from 18−70% (Table 1). The yields are influenced by both the nature of the substituted benzoic acid (yields are higher for the dimethoxybenzoate; entries 1−6 versus 6−8) and the carbodiimide (yields are lowest when R = iPr; entries 2 and 6). When changing from Pd(O2CCH3)2 to Pd(O2CCF3)2, the isolated yields increased for both 5AI (39 → 45%, entry 1 versus 2) and 5AI (44 → 70%, entry 1 versus 2). Gratifyingly, this is consistent with both the 1H NMR experiments (Figures 5 and S6) and the DFT calculated

Table 1. Scope of Palladium Mediated Decarboxylative Synthesis of Amidines in Terms of the Carbodiimide Substrates and Additives Used

entry 1 2 3 4 5 6 7 8 9b 10c

Ar = A A A A A B B B A A

2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3 2,4,6-(MeO)3C6H2 2,4,6-(MeO)3C6H2 2,4,6-(MeO)3C6H2 2,6-(MeO)2C6H3 2,6-(MeO)2C6H3

R=

X=

product

yield (%)a

I iPr I iPr IIHexc IIcHex III Ph I iPr IIHexc III Ph IIHexc IIHexc

O2CCH3 O2CCF3 O2CCH3 O2CCF3 O2CCF3 O2CCF3 O2CCF3 O2CCF3 O2CCF3 O2CCF3

5AI 5AI 5AII 5AII 5AIII 5BI 5BII 5BIII 5AII 5AII

39 45 44 70 68 18 20 50 49 22

a Yield calculated based on the isolated free amidine. bMicrowave variant that utilizes 10 eq. of HCOOH instead of NaBH4. cMicrowave variant that is catalytic in palladium (Scheme 3).

energies for the barriers associated with insertion versus protonation (Figure 6). In order to develop a catalytic variant, we explored the use of a microwave reactor to synthesize amidine 5AII. Unlike the one-pot method where the decarboxylation and insertion steps can be carried out a different temperatures, under microwave conditions both of these steps occur at elevated temperatures. The use of a stoichiometric amount of palladium salt in DMSO in the microwave gave the amidine with a 49% yield (entry 9); although this was lower than that achieved with the one-pot method (70%, entry 9), we were sufficiently encouraged to adapt conditions suggested by Rydfjord et al.23 Using a catalyst loading of 5%, 6-methyl-2,2′-bipyridine as a ligand (7.5%) and NMP as the solvent, a modest yield of 22% of 5AII was achieved (entry 10 and Scheme 3). The 1H NMR spectra of amidines 5AI, 5AII, 5BI, and 5BII with isopropyl or cyclohexyl group show two sharp N−H peaks as doublets integrating to a 1:1 ratio, while for 5AIII and 5BIII, the 1H NMR spectra show two N−H peaks as broad singlets integrating to a 1:1 ratio. This is consistent with conformations of the amidinium cation ArC(NHR)NHR+ where, in the NMR time scale, the two N−H bonds are in nonequivalent environments.52,53 Single crystals of the hydrochloride salts of 5AII and 5AIII suitable for characterization by X-ray crystallography were obtained by slow evaporation of compounds dissolved in a mixture of pentane and dichloromethane (1:1). The amidinium cations undergo hydrogen bonding with either chloride or water (Figure 7a,b). In both cases, the E,E configuration of the amidinium group is observed, which corresponds to protonation of E,anti neutral amidine isomer (see isomer 5−2 in Figure S1).54 On the basis of two different N−H protons being observed in the 1H NMR experiments, it is likely that the hydrogen bonding environment in the crystal enforces a different configuration of the amidinium group to that in solution. In hydrochloride salt 5AII, two different C−N bond lengths of 1.3176(12) and 1.3208(12) Å are observed and arise from the different orientations of the cyclohexyl groups. In contrast, for hydrochloride salt 5AIII, the bond distances of two C−N G


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Organometallics Scheme 3. Catalytic Variant for the Synthesis of Amidine 5AII Using Microwave Irradiation

Figure 7. ORTEP representation of the X-ray structures of (a) 5AII·HCl·H2O; (b) hydrochloride salt of 5AIII·HCl·H2O. The thermal ellipsoids are shown at the 50% probability level. for the reactivity studies of [(phen)M(CH3)]+.58−60 Briefly, 10 μL of a methanolic solutions of palladium trifluoroacetate (5 mM), aromatic carboxylic acid (10 mM), and phenanthroline (10 mM) or pyridine (20 mM) were mixed and then diluted to a final concentration of 0.05 mM in Pd. The solution was transferred via syringe pump operating at 5 μL min−1 to the electrospray source of a LTQ Linear Ion Trap (LIT) Mass Spectrometer (Thermo, Bremen, Germany) previously modified to allow the introduction of neutral reagents into the ion trap.61,62 Typical electrospray source conditions were as follows: CID: sheath gas = 10 arbitrary units, auxilliary gas = 5 arbitrary units, sweep gas = 0 arbitrary units, spray voltage = 4 kV, capillary temp. = 250 °C, capillary voltage = 2 V, tube lens voltage = 75 V. The precursor ion was mass selected with a window of 1 m/z and collision induced dissociation was carried out using the helium bath gas by activating the ion with an activation time of 30 ms. A normalized collision energy (NCE) was chosen to deplete the precursor ion to 10%. IMR: sheath gas = 10 arbitrary units, auxiliary gas = 5 arbitrary units, sweep gas = 0 arbitrary units, spray voltage = 4 kV, capillary temp. = 250 °C, capillary voltage = 2 V, tube lens voltage = 75 V. DFT Calculation. Gaussian 0963 was used to fully optimize all structures at the M06 level of density functional theory (DFT).64 For the DMSO system (in solution), the effective-core potential of Hay and Wadt with a double-ξ valence basis set (LANL2DZ) was chosen to describe Pd.65 The 6-31G(d) basis set was used for other atoms.66 A polarization function of ξf = 1.472 was also added for Pd.67,68 This basis set combination will be referred to as BS1. Solvation effects of DMSO on the optimized structures were accounted for using the CPCM model.69 For the phenanthroline and pyridine system in the gas phase, we employed the same basis set. Frequency calculations were carried out at the same level of theory as those for the structural optimization. Transition structures were located using the Berny algorithm. Intrinsic reaction coordinate (IRC) calculations and potential energy surface scans were used to confirm the connectivity between transition structures and minima. To further refine the energies obtained from the M06/BS1 calculations, we carried out single-point energy calculations for all of the structures with a larger basis set (BS2) at the B3LYP-D3BJ level of theory.70−73 BS2 utilizes def2-TZVP11 for all atoms along with the effective core potential

bonds are 1.3213(13) Å, where similar orientations of the phenyl groups occur. These C−N bonds lengths exhibit partial double bond character and fall in the range of other aryl amidine salts, which vary from 1.293 to 1.34.55−57 Finally, the waters of crystallization in these salts result in the formation intermolecular H bonding networks. Due to hydrogen bonding between the Cl and the O−H of two water molecules and the N−H groups of 5AII·H+, 5AII·HCl·H2O forms a dimer (Figure S24). In contrast, the hydrogen bonded arrangement in 5AIII·HCl·H2O is different. Here two water molecules are bridged between a Cl anion and the 5AIII·H+ cation forming a hydrogen-bonded zigzag chain in an extended array (Figure S25).

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CONCLUSIONS Here we have used a mechanism based approach that blends fundamental gas-phase ion chemistry, 1H NMR experiments to monitor the formation of key intermediates and DFT calculation to develop a new transformation of aromatic carboxylic acids to substituted amidines. These studies directed the development of a one-pot synthetic method, which involves heating a DMSO solution containing a mixture of 2,6-dimethoxybenzoic acid or 2,4,6-trimethoxybenzoic acid and palladium(II) trifluoroacetate at 70 °C for 6 h under a N2 atmosphere and then cooling to room temperature. Addition of a carbodimide followed by borohydride allows the isolation of the corresponding amidine. The ExIn chemistry developed takes advantage of the fact that amidines are isoelectronic with CO2. We are examining the scope of a range of neglected ExIn transformations that use other heterocumulenes for the installation of other functional groups.

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EXPERIMENTAL SECTION

Gas-Phase Experiments. The gas-phase CID of [(phen)Pd(O2CAr)]+ to form [(phen)Pd(Ar)]+ for subsequent ion−molecule reaction studies were conducted in a similar manner to those reported H


Article

Organometallics including scalar relativistic effects for Pd.74 The solvent effect using the CPCM approach was considered for the DMSO system in the single point calculations. The B3LYP-D3BJ calculations were used to overcome the deficiency of the M06 level in incorporating long-range correlation for dispersion forces. To estimate the corresponding enthalpy, ΔH, and Gibbs energies, ΔG, the corrections were calculated at the M06/BS1 levels and finally added to the corresponding single-point energies. Entropy calculations for the DMSO system were adjusted by the method proposed by Okuno.75 An additional correction was made to account for the fact that DMSO participates in the equilibrium between 13a and 13b. Thus, when calculating the energy profiles for Figure 6 the concentration of DMSO was set using the method of Keith and Carter (we utilized eq 6 of their paper).76 We have used the corrected enthalpy and Gibbs free energies obtained from the B3LYP-D3BJ/BS2//M06/BS1 calculations throughout unless otherwise stated. Solution-Phase Experiments. General Experimental Details and Materials. Unless otherwise stated, all reagents were purchased from commercial sources and used without further purification. Flash column chromatography was carried out using silica gel (40−63 μm) as the stationary phase. 1H and 13C NMR spectra were recorded either on a 600 MHz Varian/Agilent 600-MR or 400 MHz AR spectrometer at 298 K. Chemical shifts are reported in parts per million (ppm) and referenced to residual solvent peak. Coupling constants (J) are reported in Hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: m = multiplet, quint. = quintet, q = quartet, t = triplet, d = doublet, s = singlet, br = broad. Electrospray ionization high-resolution mass spectra (ESI-HRMS) were collected on a Thermo OrbiTrap Fusion Lumos mass spectrometer. 1 H NMR Monitoring Experiments. A round-bottomed flask was charged with 2,6-dimethoxybenzoic acid or 2,4,6-trimethoxybenzoic acid (0.2 mmol), and palladium(II) trifluoroacetate or palladium(II) acetate (0.22 mmol) and purged with N2. DMSO-d6 (2 mL) was added under N2, and the mixture was stirred for 5 min at room temperature. For all sequential NMR experiments used to monitor reaction outcomes, 50 μL aliquots of the reaction mixture were withdrawn from the sample tube and transferred to an NMR tube, diluted via the addition of 600 μL DMSO-d6, and then a 1H NMR spectrum was recorded. The mixture was then warmed to 70 °C for 6 h for trifluoroacetate and 65 °C for 4 h for acetate. 1H NMR spectra were recorded for every hour, and the formation of arylpalladium species were confirmed by the upfield shifts and peak broadening of the aromatic protons Hpara and Hmeta (Figures 5 and S5−S10). The mixture was cooled to room temperature. RNCNR (2 equiv) was added, and then a 1H NMR spectrum was recorded every hour until the organometallic intermediate was consumed. NaBH4 (5 equiv) was then added to the NMR sample, and the mixture was stirred for another 1 h at room temperature. A final 1H NMR spectrum was recorded. The recorded stacked spectra are shown in Figures 5 and S6−S10. HRMS analyses were conducted on the final NMR sample by diluting in methanol. General Procedure for One-Pot Synthesis of Amidines. To a solution of 2,6-dimethoxybenzoic acid or 2,4,6-trimethoxybenzoic acid (eq 1) in dry DMSO (10 mL) was added the palladium(II) salt (1.1 equiv). The mixture was heated to 70 °C for 6 h for trifluoroacetate and 65 °C for 4 h for acetate under N2, then cooled to room temperature. RNCNR was added, and the mixture was then stirred for 3 h at room temperature. NaBH4 (5 equiv) was added and the reaction mixture was further stirred for an additional 1 h at room temperature. Methanol (5 mL) was added to the mixture followed by water (100 mL), and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with water (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol/DCM = 1:50) to give amidines 5AI−5AIII and 5BI-5BIII. N,N′-Diisopropyl-2,6-dimethoxy-benzamidine, 5AI. The general procedure above was followed by using these reagents: 2,6dimethoxybenzoic acid (91 mg, 0.5 mmol), palladium(II) trifluor-

oacetate (165 mg, 0.55 mmol), or palladium(II) acetate (123 mg, 0.55 mmol), N,N′-diisopropyl-carbodiimide (126 mg, 1.0 mmol), and NaBH4 (92 mg, 2.5 mmol). Column chromatography (silica gel, methanol/DCM = 1:20), light yellow liquid (59 mg, 45% and 51 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 8.5 Hz, 1H), 9.04 (d, J = 9.3 Hz, 1H), 7.53 (t, J = 8.5 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 4.24−3.99 (m, 1H), 3.81 (s, 6H), 3.25−3.06 (m, 1H), 1.18 (d, J = 6.3 Hz, 6H), 1.10 (d, J = 6.5 Hz, 6H). 13C NMR (400 MHz, DMSO-d6) δ 157.40, 156.74, 133.88, 107.06, 105.01, 56.80, 48.95, 44.60, 22.63, 21.45. HRMS (m/z): [M + H]+ calcd for C15H26N2O2, 265.19105. Found, 265.19107. N,N′-Dicyclohexyl-2,6-dimethoxy-benzamidine, 5AII. The general procedure above was followed by using these reagents: 2,6dimethoxybenzoic acid (91 mg, 0.5 mmol), palladium(II) trifluoroacetate (165 mg, 0.55 mmol) or palladium(II) acetate (123 mg, 0.55 mmol), N,N′-dicyclohexyl-carbodiimide (206 mg, 1.0 mmol), and NaBH4 (92 mg, 2.5 mmol). Column chromatography (silica gel, methanol/DCM = 1:50), light yellow solid (120 mg, 70% for Pd(O2CCF3)2 and 75 mg, 44% for Pd(O2CCH3)2). 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 8.9 Hz, 1H), 7.53 (t, J = 8.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 3.80 (s, 6H), 3.79− 3.73 (m, 1H), 2.85−2.73 (m, 1H), 2.05−1.53 (m, 10H), 1.54−0.84 (m, 10H). 13C NMR (400 MHz, DMSO-d6) δ 157.44, 156.78, 133.92, 107.12, 105.05, 56.80, 56.07, 51.15, 32.70, 31.23, 25.18, 25.07, 24.96, 24.51. HRMS (m/z): [M + H]+ calcd for C21H34N2O2, 345.25365. Found, 345.25365. N,N′-Diphenyl-2,6-dimethoxy-benzamidine, 5AIII. The general procedure above was followed by using these reagents: 2,6dimethoxybenzoic acid (91 mg, 0.5 mmol), palladium(II) trifluoroacetate (165 mg, 0.55 mmol), N,N′-diphenyl-carbodiimide (194 mg, 1.0 mmol), and NaBH4 (92 mg, 2.5 mmol). Column chromatography (silica gel, methanol/DCM = 1:50), light brown solid (113 mg, 68%). 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.62 (s, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.48−7.39 (m, 1H), 7.22 (t, 2H), 7.15 (t, J = 8.4 Hz, 1H), 6.97 (t, 2H), 6.90 (t, J = 7.4 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 6.58 (d, J = 7.5 Hz, 2H), 6.51 (d, J = 8.4 Hz, 2H), 3.66 (s, 6H). 13C NMR (400 MHz, DMSO-d6) δ 130.81, 129.22, 128.66, 128.04, 121.57, 121.17, 119.13, 118.60, 104.22, 56.02. HRMS (m/z): [M + H]+ calcd for C21H22N2O2, 333.15975. Found, 333.15993. N,N′-Diisopropyl-2,4,6-trimethoxy-benzamidine, 5BI. The general procedure above was followed by using these reagents: 2,4,6trimethoxybenzoic acid (106 mg, 0.5 mmol), palladium(II) trifluoroacetate (165 mg, 0.55 mmol), N,N′-diisopropyl-carbodiimide (126 mg, 1.0 mmol), and NaBH4 (92 mg, 2.5 mmol). Column chromatography (silica gel, methanol/DCM = 1:20), white solid (26.5 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 8.0 Hz, 1H), 6.38 (s, 2H),4.10−3.97 (m, 1H), 3.83 (s, 3H), 3.79 (s, 6H), 3.28−3.18 (m, 1H), 1.16 (d, J = 6.3 Hz, 6H), 1.10 (d, J = 6.5 Hz, 6H). 13C NMR (400 MHz, DMSO-d6) δ 164.22, 158.44, 156.85, 99.78, 91.67, 56.76, 56.25, 48.81, 44.52, 22.65, 21.46. HRMS (m/z): [M + H]+ calcd for C16H28N2O3, 295.20162. Found, 295.20174. N,N′-Dicyclohexyl-2,4,6-trimethoxy-benzamidine, 5BII. The general procedure above was followed by using these reagents: 2,4,6trimethoxybenzoic acid (106 mg, 0.5 mmol), palladium(II) trifluoroacetate (165 mg, 0.55 mmol), N,N′-dicyclohexyl-carbodiimide (206 mg, 1.0 mmol), and NaBH4 (92 mg, 2.5 mmol). Column chromatography (silica gel, methanol/DCM = 1:20), light brown solid (37.4 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 8.2 Hz, 1H), 8.81 (d, J = 8.8 Hz, 1H), 6.38 (s, 2H), 3.84 (s, 3H), 3.78 (s, 6H), 3.76−3.69 (m, 1H), 2.86−2.78 (m, 1H), 1.99−1.36 (m, 10H), 1.35−0.88 (m, 10H). 13C NMR (400 MHz, DMSO-d6) δ 158.51, 91.70, 56.77, 56.23, 55.92, 51.09, 47.94, 33.79, 32.73, 31.24, 25.77, 25.19, 25.08, 24.91, 24.51. HRMS (m/z): [M + H]+ calcd for C22H36N2O3, 375.26422. Found, 375.26442. N,N′-Diphenyl-2,4,6-trimethoxy-benzamidine, 5BIII. The general procedure above was followed by using these reagents: 2,4,6trimethoxybenzoic acid (106 mg, 0.5 mmol), palladium(II) trifluoroacetate (165 mg, 0.55 mmol), N,N′-diphenyl-carbodiimide (194 mg, 1.0 mmol), and NaBH4 (92 mg, 2.5 mmol). Column I


Article

Organometallics Accession Codes

chromatography (silica gel, methanol/DCM = 1:20), light brown solid (94 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 7.79 (br, 2H), 7.23 (br, 2H),7.04 (br, 3H), 6.79 (br,1H), 6.62 (br, 2H), 6.09 (s,2H), 3.70 (s, 3H), 3.65 (s, 6H). 13C NMR (600 MHz, DMSO-d6) δ 159.23, 159.02, 158.80, 158.57, 153.12, 130.69, 128.97, 128.39, 127.84, 125.09, 124.47, 91.47, 91.41, 56.79, 56.19. HRMS (m/z): [M + H]+ calcd for C22H24N2O3, 363.17032. Found, 363.17055. Stoichiometric Microwave Synthesis of N,N′-Dicyclohexyl-2,6dimethoxy-benzamidine, 5AII. A 2 mL Pyrex glass vial was charged with ArCOOH (0.1 mmol), Pd(O2CF3)2 (0.1 mmol), dicyclohexylcarbodiimide (0.2 mmol), and N-methyl-pyrrolidine (1 mL). The vial was capped in air and exposed to microwave heating for 60 min at 130 °C, with subsequent addition of formic acid (1 mmol) and stirring for 30 min at room temperature. Column chromatography (silica gel, methanol/DCM = 1:50), light yellow solid (16.9 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 8.9 Hz, 1H), 7.53 (t, J = 8.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 3.80 (s, 6H), 3.79−3.73 (m, 1H), 2.85−2.73 (m, 1H), 2.05−1.53 (m, 10H), 1.54− 0.84 (m, 10H). HRMS (m/z): [M + H]+ calcd for C21H34N2O2, 345.25365. Found, 345.25307. Catalytic Microwave Synthesis of N,N′-Dicyclohexyl-2,6-dimethoxy-benzamidine, 5AII. A 2 mL Pyrex glass vial was charged with ArCOOH (0.1 mmol), Pd(O2CF3)2 (0.005 mmol), dicyclohexylcarbodiimide (0.2 mmol), 6-methyl-2,2’bipyridine (0.0075 mmol), and N-methyl-pyrrolidine (1 mL). The vial was capped in air and exposed to microwave heating for 60 min at 130 °C. Column chromatography (silica gel, methanol/DCM = 1:50), light yellow solid (7.6 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 8.9 Hz, 1H), 7.53 (t, J = 8.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 3.80 (s, 6H), 3.79−3.73 (m, 1H), 2.85−2.73 (m, 1H), 2.05−1.53 (m, 10H), 1.54−0.84 (m, 10H). HRMS (m/z): [M + H]+ calcd for C21H34N2O2, 345.25365. Found, 345.25359. X-ray Crystallography. The molecular structures of synthesized benzamidines 5AII and 5AIII as their hydrochloride salts were confirmed by X-ray crystallography. For both compounds, single crystals suitable for X-ray diffraction were obtained by slow evaporation of compounds dissolved in a mixture of pentane and dichloromethane (1:1). X-ray data for amidines were collected at 130 K on an Agilent Technologies Dual source Supernova system using Mo and Cu Kα radiation, and data were treated using CrysAlisPro software.77 The structures were solved using SHELXT running within the WinGX package program.78 Further details are given in the Supporting Information. The crystallographic data (excluding structure factors) for the HCl salts of 5AII and 5AIII have been deposited with the Cambridge Crystallographic Data Centre as CCDC 1836504 and 1836505 (X-ray), respectively.

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CCDC 1836504−1836505 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *Phone: +613 8344-2452. Fax: +613 9347-5180. E-mail: [email protected]. ORCID

Allan J. Canty: 0000-0003-4091-6040 Alireza Ariafard: 0000-0003-2383-6380 Paul S. Donnelly: 0000-0001-5373-0080 Richard A. J. O’Hair: 0000-0002-8044-0502 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.J.C., P.S.D., and R.A.J.O. thank the ARC for funding (DP180101187), and the National Computing Infrastructure. We thank the Bio21 Mass Spectrometry and Proteomics Facility for access to the Thermo OrbiTrap Fusion Lumos mass spectrometer.

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REFERENCES

(1) Nagasawa, K.; Sohtome, Y. Chiral guanidine and amidine organocatalysts. Sci. Synth., Asymmetric Organocatal. 2012, 2, 1−40. (2) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Amidines, isothioureas, and guanidines as nucleophilic catalysts. Chem. Soc. Rev. 2012, 41, 2109−2121. (3) Li, X.; Jiang, H.; Uffman, E. W.; Guo, L.; Zhang, Y.; Yang, X.; Birman, V. B. Kinetic Resolution of Secondary Alcohols Using Amidine-Based Catalysts. J. Org. Chem. 2012, 77, 1722−1737. (4) Nowicki, J.; Muszynski, M.; Mikkola, J.-P. Ionic liquids derived from organosuperbases: en route to superionic liquids. RSC Adv. 2016, 6, 9194−9208. (5) Quek, J. Y.; Davis, T. P.; Lowe, A. B. Amidine functionality as a stimulus-responsive building block. Chem. Soc. Rev. 2013, 42, 7326− 7334. (6) Edelmann, F. T. Recent Progress in the Chemistry of Metal Amidinates and Guanidinates: Syntheses, Catalysis and Materials. Adv. Organomet. Chem. 2013, 61, 55−374. (7) Edelmann, F. T. Lanthanide amidinates and guanidinates in catalysis and materials science: a continuing success story. Chem. Soc. Rev. 2012, 41, 7657−7672. (8) Collins, S. Polymerization catalysis with transition metal amidinate and related complexes. Coord. Chem. Rev. 2011, 255, 118−138. (9) Edelmann, F. T. Advances in the coordination chemistry of amidinate and guanidinate ligands. Adv. Organomet. Chem. 2008, 57, 183−352. (10) Coles, M. P. Application of neutral amidines and guanidines in coordination chemistry. Dalton Trans. 2006, 985−1001. (11) Barker, J.; Kilner, M. The coordination chemistry of the amidine ligand. Coord. Chem. Rev. 1994, 133, 219−300. (12) Kumamoto, T. Amidines and guanidines in natural products and medicines. In Superbases for Organic Synthesis; Wiley. 2009; pp 295−313. (13) Re, N.; Fantacuzzi, M.; Maccallini, C.; Paciotti, R.; Amoroso, R. Recent Developments of Amidine-like Compounds as Selective NOS Inhibitors. Curr. Enzyme Inhib. 2016, 12, 30−39.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00776. Tables of DFT calculated thermochemistry for transformation of aromatic carboxylic acids into amidines; mass spectra showing decarboxylation and fragmentation reactions of adducts of organopalladium cations and carbodiimide; table of gas-phase kinetic data for ion− molecule reactions; 1H NMR spectra monitoring ExIn reactions in solution; 1H NMR and HRMS spectra of all isolated amidines; discussion of crystallographic studies; figures of intermolecular hydrogen bonding from crystallographic studies; tables for crystal data and structure refinement; 3D structures and energies for all DFT calculated species (PDF) Cartesian coordinates (XYZ) J


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Organometallics (14) Maccallini, C.; Fantacuzzi, M.; Amoroso, R. Amidine-Based Bioactive Compounds for the Regulation of Arginine Metabolism. Mini-Rev. Med. Chem. 2013, 13, 1305−1310. (15) Stamford, A.; Strickland, C. Inhibitors of BACE for treating Alzheimer’s disease: a fragment-based drug discovery story. Curr. Opin. Chem. Biol. 2013, 17, 320−328. (16) Soeiro, M. N. C.; Werbovetz, K.; Boykin, D. W.; Wilson, W. D.; Wang, M. Z.; Hemphill, A. Novel amidines and analogues as promising agents against intracellular parasites: a systematic review. Parasitology 2013, 140, 929−951. (17) Raczynska, E. D.; Gal, J.-F.; Maria, P.-C. Enhanced Basicity of Push-Pull Nitrogen Bases in the Gas Phase. Chem. Rev. 2016, 116, 13454−13511. (18) Ishikawa, T.; Harwood, L. M. Organic superbases: the concept at a glance. Synlett 2013, 24, 2507−2509. (19) Tsutomu, I.; Takuya, K. Amidines in organic synthesis. Superbases for Organic Synthesis: Amidines in Organic Synthesis; Wiley, 2009; pp 49−91. (20) Pornet, J.; Miginiac, L. Behavior of phenylic, saturated, and allylic organometallics towards carbodiimides. Bull. Soc. Chim. Fr. 1974, 994−998. (21) Zhang, Z.; Huang, B.; Qiao, G.; Zhu, L.; Xiao, F.; Chen, F.; Fu, B.; Zhang, Z. Tandem Coupling of Azide with Isonitrile and Boronic Acid: FacileAccess to Functionalized Amidines. Angew. Chem., Int. Ed. 2017, 56, 4320−4323. (22) Saevmarker, J.; Rydfjord, J.; Gising, J.; Odell, L. R.; Larhed, M. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates. Org. Lett. 2012, 14, 2394−2397. (23) Rydfjord, J.; Svensson, F.; Trejos, A.; Sjoeberg, P. J. R.; Skoeld, C.; Saevmarker, J.; Odell, L. R.; Larhed, M. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation. Chem. - Eur. J. 2013, 19, 13803−13810. (24) Saluste, C. G.; Whitby, R. J.; Furber, M. A Palladium-Catalyzed Synthesis of Amidines from Aryl Halides. Angew. Chem., Int. Ed. 2000, 39, 4156−4158. (25) Zhu, F.; Li, Y.; Wang, Z.; Orru, R. V. A.; Maes, B. U. W.; Wu, X.-F. Palladium-Catalyzed Construction of Amidines from Arylboronic Acids under Oxidative Conditions. Chem. - Eur. J. 2016, 22, 7743−7746. (26) Dai, Q.; Jiang, Y.; Yu, J.-T.; Cheng, J. Palladium-catalyzed three-component reaction of N-tosyl hydrazones, isonitriles and amines leading to amidines. Chem. Commun. 2015, 51, 16645−16647. (27) Noor, A.; Li, J.; Khairallah, G. N.; Li, Z.; Ghari, H.; Canty, A. J.; Ariafard, A.; Donnelly, P. S.; O’Hair, R. A. J. A one-pot route to thioamides discovered by gas-phase studies: palladium-mediated CO2 extrusion followed by insertion of isothiocyanates. Chem. Commun. 2017, 53, 3854−3857. (28) Myers, A. G.; Tanaka, D.; Mannion, M. R. Development of a decarboxylative palladation reaction and its use in a Heck-type olefination of arene carboxylates. J. Am. Chem. Soc. 2002, 124, 11250−11251. (29) Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Development of a Catalytic Aromatic Decarboxylation Reaction. Org. Lett. 2007, 9, 2441−2444. (30) Dickstein, J. S.; Curto, J. M.; Gutierrez, O.; Mulrooney, C. A.; Kozlowski, M. C. Mild Aromatic Palladium-Catalyzed Protodecarboxylation: Kinetic Assessment of the Decarboxylative Palladation and the Protodepalladation Steps. J. Org. Chem. 2013, 78, 4744−4761. (31) Over 40 years ago Shaw noted that it was embarrassing for a thermochemist to report on the lack of experimental data for amidines: Shaw, R. In The Chemistry of Amidines and Imidates; Patai, S., Ed.; Wiley, 1975; Chapter 11. The situation has not improved! For the most recent review of the sparse data, see Pihlaja, K. In The Chemistry of Amidines and Imidates; Patai, S., Rappoport, Z., Ed.; Wiley, 1991; Vol. 2, Chapter 6. Thus, we have turned to DFT calculations to evaluate the enthalpy and Gibbs free energy (298 K, gas phase) change associated with eq 1 (Y = NR) for representative

carboxylates and carbodiimides. Full results are given in the Supporting Information. (32) Rodríguez, N.; Gooßen, L. J. Decarboxylative coupling reactions: a modern strategy for C−C-bond formation. Chem. Soc. Rev. 2011, 40, 5030−5048. (33) Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Carboxylic Acids as Substrates in Homogeneous Catalysis. Angew. Chem., Int. Ed. 2008, 47, 3100−3120. (34) Vicente, J.; Abad, J.-A.; López-Sáez, M.-J.; Jones, P. G.; Bautista, D. Reactivity of ortho-Substituted Aryl-Palladium Complexes towards Carbodiimides, Isothiocyanates, Nitriles, and Cyanamides. Chem. Eur. J. 2010, 16, 661−676. (35) Fernández-Rodríguez, M.-J.; Martínez-Viviente, E.; Vicente, J.; Jones, P. G. Reactivity towards nitriles, cyanamides, and carbodiimides of palladium complexes derived from benzyl alcohol. Synthesis of a mixed Pd2Ag complex. Dalton Trans. 2016, 45, 820−830. (36) O’Hair, R. A. J. The 3D Quadrupole Ion Trap Mass Spectrometer as a Complete Chemical Laboratory for Fundamental Gas Phase Studies of Metal Mediated Chemistry. Chem. Commun. 2006, 1469−1481. (37) O’Hair, R. A. J. Gas Phase Ligand Fragmentation to Unmask Reactive Metallic Species. In Reactive Intermediates. MS Investigations in Solution; Santos, L. S., Ed.; Wiley-VCH: Weinheim, 2010; Chapter 6, pp 199−227. (38) O’Hair, R. A. J.; Rijs, N. J. Gas Phase Studies of the Pesci Decarboxylation Reaction: Synthesis, Structure, and Unimolecular and Bimolecular Reactivity of Organometallic Ions. Acc. Chem. Res. 2015, 48, 329−340. (39) O’Hair, R. A. J. Gas-Phase Studies of Metal Catalyzed Decarboxylative Cross-Coupling Reactions of Esters. Pure Appl. Chem. 2015, 87, 391−404. (40) Three-coordinate complexes are now well-established for Pd(II): Stambuli, J. P.; Bü hl, M.; Hartwig, J. F. Synthesis, Characterization, and Reactivity of Monomeric, Arylpalladium Halide Complexes with a Hindered Phosphine as the Only Dative Ligand. J. Am. Chem. Soc. 2002, 124, 9346−9347. (41) For a review on the role of three-coordinate complexes of Pt(II) as reaction intermediates, see Ortuño, M. A.; Conejero, S.; Lledós, A. True and masked three-coordinate T-shaped platinum(II) intermediates. Beilstein J. Org. Chem. 2013, 9, 1352−1382. (42) Hartwig, J. F.; Cook, K. S.; Hapke, M.; Incarvito, C. D.; Fan, Y.; Webster, C. E.; Hall, M. B. Rhodium Boryl Complexes in the Catalytic, Terminal Functionalization of Alkanes. J. Am. Chem. Soc. 2005, 127, 2538−2552. (43) Wei, C. S.; Jiménez-Hoyos, C. A.; Videa, M. F.; Hartwig, J. F.; Hall, M. B. Origins of the Selectivity for Borylation of Primary over Secondary C−H Bonds Catalyzed by Cp*-Rhodium Complexes. J. Am. Chem. Soc. 2010, 132, 3078−3091. (44) The exact nature of these complexes is unknown. For rare examples of five coordinate monocationic Pd complexes established from X-ray crystallography, see (a) Garrone, R.; Romano, A. M.; Santi, R.; Millini, R. Synthesis, Structure, and Reactivity of the Novel Pentacoordinate Palladium Complex [Pd(Phen)2(CO2CH3)](PF6). Organometallics 1998, 17, 4519−4522. (b) Milani, B.; Corso, G.; Zangrando, E.; Randaccio, L.; Mestroni, G. Crystal Structure and Dynamic Behavior of a New Class of Monocationic Organometallic PdII Compounds with Two Molecules of Bidentate Ligands: [Pd(L− L)(N−N)(CH2NO2)][PF6] (L−L = N−N, dppp). Eur. J. Inorg. Chem. 1999, 1999, 2085−2093. (c) Milani, B.; Marson, A.; Zangrando, E.; Mestroni, G.; Ernsting, J. M.; Elsevier, C. J. New monocationic methylpalladium(II) compounds with several bidentate nitrogen-donor ligands: synthesis, characterisation and reactivity with CO. Inorg. Chim. Acta 2002, 327, 188−201. (45) Murphy, J. P.; Yost, R. A. Origin of mass shifts in the quadrupole ion trap: dissociation of fragile ions observed with a hybrid ion trap/mass filter instrument. Rapid Commun. Mass Spectrom. 2000, 14, 270−273. (46) McClellan, J. E.; Murphy, J. P.; Mulholland, J. J.; Yost, R. A. Effects of Fragile Ions on Mass Resolution and on Isolation for K


Article

Organometallics Tandem Mass Spectrometry in the Quadrupole Ion Trap Mass Spectrometer. Anal. Chem. 2002, 74, 402−412. (47) There is a dearth of information on gas-phase ligand exchange reactions of 4 coordinate group 10 metal complexes proceeding via associative mechanisms. For a rare example involving Pt(II) complexes, see Wee, S.; O’Hair, R. A. J.; McFadyen, W. D. Gas Phase Ligand Loss and Ligand Substitution Reactions of Platinum(II) Complexes of Tridentate Nitrogen Donor Ligands. Rapid Commun. Mass Spectrom. 2004, 18, 1221−1226. (48) Donald, W. A.; Khairallah, G. N.; O’Hair, R. A. J. The Effective Temperature of Ions Stored in a Linear Quadrupole Ion Trap Mass Spectrometer. J. Am. Soc. Mass Spectrom. 2013, 24, 811−815. (49) Few studies have independently synthesized and structurally characterized aryl palladium (trifluoro)acetate complexes related to 13a and 13b. For an X-ray structure of an aryl palladium trifluoroacetate complex related to 13b2, see Tanaka, D.; Romeril, S. P.; Myers, A. G. On the Mechanism of the Palladium(II)-Catalyzed Decarboxylative Olefination of Arene Carboxylic Acids. Crystallographic Characterization of Non-Phosphine Palladium(II) Intermediates and Observation of Their Stepwise transformation in Heck-like Processes. J. Am. Chem. Soc. 2005, 127, 10323−10333. (50) Zhang, S.-L.; Fu, Y.; Shang, R.; Guo, Q.-X.; Liu, L. Theoretical Analysis of Factors Controlling Pd-Catalyzed Decarboxylative Coupling of Carboxylic Acids with Olefins. J. Am. Chem. Soc. 2010, 132, 638−646. (51) Xue, L.; Su, W.; Lin, Z. A DFT study on the Pd-mediated decarboxylation process of aryl carboxylic acids. Dalton Trans. 2010, 39, 9815−9822. (52) Hammond, G. S.; Neuman, R. C., Jr. Amidinium ions. I. Hindered internal rotation. J. Phys. Chem. 1963, 67, 1655−1659. (53) Wang, J.; He, Z.; Chen, X.; Song, W.; Lu, P.; Wang, Y. Efficient access to polysubstituted amidines, benzimidazoles and pyrimidines from amides. Tetrahedron 2010, 66, 1208−1214. (54) Boeré, R. T.; Klassen, V.; Wolmershäuser, G. Synthesis of some very bulky N,N′-disubstituted amidines and initial studies of their coordination chemistry. J. Chem. Soc., Dalton Trans. 1998, 4147− 4154. (55) Thailambal, V. G.; Pattabhi, V.; Guru Row, T. N. Structure of benzamidine hydrochloride monohydrate. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1986, 42, 587−589. (56) Peters, L.; Fröhlich, R.; Boyd, A. S. F.; Kraft, A. Noncovalent Interactions between Tetrazole and an N,N‘-Diethyl-Substituted Benzamidine. J. Org. Chem. 2001, 66, 3291−3298. (57) Irrera, S.; Portalone, G. 4-Methoxybenzamidinium acetate. Acta Crystallogr., Sect. E: Struct. Rep. Online 2012, 68, o3277. (58) Woolley, M. J.; Khairallah, G. N.; da Silva, G.; Donnelly, P. S.; Yates, B. F.; O’Hair, R. A. J. Role of the Metal, Ligand, and Alkyl/Aryl Group in the Hydrolysis Reactions of Group 10 Organometallic Cations, [(L)M(R)]+. Organometallics 2013, 32, 6931−6944. (59) Woolley, M. J.; Khairallah, G. N.; da Silva, G.; Donnelly, P. S.; O’Hair, R. A. J. Direct versus Water-Mediated Protodecarboxylation of Acetic Acid Catalyzed by Group 10 Carboxylates, [(phen)M(O2CCH3)]+. Organometallics 2014, 33, 5185−5197. (60) Woolley, M. J.; Ariafard, A.; Khairallah, G. N.; Kwan, K. H.-Y.; Donnelly, P. S.; White, J. M.; Canty, A. J.; Yates, B. F.; O’Hair, R. A. J. Decarboxylative-Coupling of Allyl Acetate Catalyzed by Group 10 Organometallics, [(phen)M(CH3)]+. J. Org. Chem. 2014, 79, 12056− 12069. (61) Donald, W. A.; McKenzie, C. J.; O’Hair, R. A. J. C−H Bond Activation of Methanol and Ethanol by a High-Spin FeIVO Biomimetic Complex. Angew. Chem., Int. Ed. 2011, 50, 8379−8383. (62) Lam, A. K. Y.; Li, C.; Khairallah, G. N.; Kirk, B. B.; Blanksby, S. J.; Trevitt, A. J.; Wille, U.; O’Hair, R. A. J.; da Silva, G. Gas-phase reactions of aryl radicals with 2-butyne: An experimental and theoretical investigation employing the N-methyl-pyridinium-4-yl radical cation. Phys. Chem. Chem. Phys. 2012, 14, 2417−2426. (63) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.

P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009. (64) Zhao, Y.; Truhlar, D. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215−241. (65) (a) Hay, P. J.; Wadt, W. R. Ab initio effective core potentials for molecular calculations. Potentials for the transition metal atoms Sc to Hg. J. Chem. Phys. 1985, 82, 270−283. (b) Wadt, W. R.; Hay, P. J. Ab initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi. J. Chem. Phys. 1985, 82, 284−298. (66) Hariharan, P. C.; Pople, J. A. The influence of polarization functions on molecular orbital hydrogenation energies. Theor. Chim. Acta. 1973, 28, 213−222. (67) Ehlers, A. W.; Böhme, M.; Dapprich, S.; Gobbi, A.; Höllwarth, A.; Jonas, V.; Köhler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. A set of f-polarization functions for pseudo-potential basis sets of the transition metals Sc-Cu, Y-Ag and La-Au. Chem. Phys. Lett. 1993, 208, 111−114. (68) Höllwarth, A.; Böhme, M.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.; Jonas, V.; Köhler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. A set of d-polarization functions for pseudo-potential basis sets of the main group elements Al-Bi and f-type polarization functions for Zn, Cd, Hg. Chem. Phys. Lett. 1993, 208, 237−240. (69) Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102, 1995−2001. (70) Becke, A. D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098−3100. (71) Lee, C.; Yang, W.; Parr, R. G. Development of the ColleSalvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (72) Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648−5652. (73) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623−11627. (74) Weigend, F.; Furche, F.; Ahlrichs, R. Gaussian basis sets of quadruple zeta valence quality for atoms H−Kr. J. Chem. Phys. 2003, 119, 12753−12754. (75) Okuno, Y. Theoretical Investigation of the Mechanism of the Baeyer-Villiger Reaction in Nonpolar Solvents. Chem. - Eur. J. 1997, 3, 212−218. (76) Keith, J. A.; Carter, E. A. Quantum Chemical Benchmarking, Validation, and Prediction of Acidity Constants for Substituted Pyridinium Ions and Pyridinyl Radicals. J. Chem. Theory Comput. 2012, 8, 3187−3206. (77) CrysAlis PRO Software; Agilent Technologies: Yarnton, Oxfordshire, England, 2012. (78) Farrugia, L. J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837−838.

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