DOI: 10.1002/chem.201302453
BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald– Hartwig Amination of (Hetero)aryl Chlorides Sarah M. Crawford, Christopher B. Lavery, and Mark Stradiotto*[a] Abstract: Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e., Buchwald–Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst
system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ ligand catalyst system. We also established BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 as exhibiting the broadest demonstrated substrate scope for metal-catalyzed Keywords: amination · catalysis · chemoselectivity · cross-coupling · palladium
Introduction The palladium-catalyzed amination of aryl and heteroaryl halides and pseudohalides with NH-containing substrates (i.e., Buchwald–Hartwig amination, BHA) is an indispensACHTUNGREable component of the synthetic chemists toolkit and has been widely employed in the synthesis of pharmaceuticals, natural products and materials.[1] Given the ubiquitous nature of arylamines and arylazoles in compounds of synthetic interest, and the lack of alternative methodologies for their synthesis that are both mild and generally applicable, BHA remains a commonly employed methodology both academically and industrially.[2] The course of BHA reactions is largely ligand controlled; as such, ligand design has played a crucial role in the expansion of the field.[3] In most reaction settings, ligands must be designed to: promote the formation a monoligated Pd0 com-
[a] Dr. S. M. Crawford, C. B. Lavery, Prof. Dr. M. Stradiotto Department of Chemistry, Dalhousie University 6274 Coburg Rd., P. O. Box 15000 Halifax, NS, B3H 4R2 (Canada) E-mail:
[email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302453.
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cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new onepot, two-step synthesis of N-aryl heterocycles from ammonia, orthoalkynylhaloACHTUNGRE(hetero)arenes and (hetero) aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/ [PdACHTUNGRE(cinnamyl)Cl]2 also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties.
plex; activate the palladium center towards (hetero)aryl (pseudo)halide oxidative addition; provide steric protection to the palladium coordination sphere as a means of promoting selectivity; and encourage C N bond reductive elimination en route to arylamine products. These requirements typically necessitate that the ligand be both electron-rich and sterically demanding.[3] Adhering to these basic design principles, many classes of ligands have been developed in efforts to enable cross-coupling reactions of challenging NH-containing compounds (Figure 1). Representative examples from some of the major ligand classes include bulky, electron-rich trialkylphosphines (PACHTUNGRE(tBu)3[4] and cataCXium A[5]), bisphosphines with large bite angles (XantPhos[6] and JosiPhos[7]), sterically demanding carbenes (IPr[8]) and mixed P,N donor ligands (MorDalPhos[9] and MeDalPhos[10]), as well as (hetero)biaryl monophosphine ligands featuring large dialkylphosphino groups (RuPhos and BrettPhos,[1d, 11] BippyPhos,[12] Ad-BippyPhos[13]). Although many highly active catalyst systems for BHA have been reported beyond the representative ligands shown in Figure 1, from a practical perspective only those ligands (ligand precursors, or their respective palladium precatalysts) that offer robust tolerance of air and moisture, easily implemented catalytic protocols, wide substrate scope and commercial availability
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FULL PAPER offers such a diverse reactivity profile. We disclose the application of this catalyst system toward the arylation of ammonia, hydrazine, primary and secondary amines, diamines, amides, and indoles with a variety of functionalized aryl and heteroaryl halides at moderate to low catalyst loadings. The unprecedented scope of this catalyst system toward NH-containing substrates also facilitated the development of a new one-pot, two-step tandem synthesis of N-aryl heterocycles from ammonia, ortho-alkynylhaloarenes and (hetero)aryl halides. Moreover, the marked NH-substrate selectivity preference of the catalyst system was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct and potentially reactive NH-containing moieties.
Results and Discussion
Figure 1. A representative selection of commercially available ligands for use in Buchwald–Hartwig amination.
are most likely to experience significant uptake by endusers. Despite significant advances in BHA catalysis, a number of challenges persist, including that of catalyst generality. Although palladium catalysts featuring the ligands in Figure 1 have each proven useful for multiple NH substrate classes, absent from the literature are reports of a single Pd/ ligand catalyst system with the demonstrated ability to promote the cross-coupling of aryl halides with structurally diverse NH-containing substrates ranging from relatively acidic azoles and amides, to amines, to more nucleophilic NH-containing substrates including hydrazine and ammonia. Although limited progress towards addressing deficiencies in the scope of the NH-containing coupling partner has been achieved through the use of multiple ligand catalytic systems,[11a] in general the practicing synthetic chemist is typically required to assemble and/or screen an inventory of ligACHTUNGREands for which only task-specific synthetic utility has been established; this is especially true when faced with a particular BHA application for which optimal conditions are not clearly specified in the literature.[3a, 11b] While the acquisition and use of a toolkit of commercially available ligands can accomplish some synthetic objectives, selecting a ligand and optimizing conditions for each NH-containing substrate is both cost and time ineffective, especially for the nonspecialist. In this regard, the identification of a single Pd/ligand catalyst system, derived from commercially available air-stable components, which could serve as a reliable “first-choice” for use in a diversity of BHA applications, would represent an important achievement in the quest to expand the scope, utility and usage of BHA chemistry in both academic and industrial settings. Herein we report on the development and application of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system, which
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Ligand selection: In our search to find a practical catalyst system with improved generality in the BHA of aryl chlorides with a wide range of NH-containing substrates, we started by screening representative commercially available ligands (Figure 1) in judiciously selected BHA reactions using adapted literature protocols.[9b–d, 10, 14] In this context, we investigated the N-arylation of primary amines, secondary amines, indole, and ammonia with chlorobenzene using 1 mol % [PdACHTUNGRE(cinnamyl)Cl]2 and 4 mol % ligand. [PdACHTUNGRE(cinnamyl)Cl]2 was selected as a palladium source as it is commercially available, easily prepared and handled on the benchtop,[15] has proven useful in combination with most of the ligands featured in Figure 1,[9b, c, 10, 16] and readily forms the desired ligated palladium(0) catalyst initiated by nucleophilic attack on the h3-bound cinnamyl group of the generated precatalyst complex.[3a, 17] We chose to focus primarily on rather challenging aryl chloride substrates because they are typically less expensive and more readily available from commercial sources in comparison to aryl bromides and iodides. It should be noted that there is literature precedent for the use of several of the commercial ligands featured in our preliminary BHA screen in some of the BHA transformations explored. However, direct reactivity comparisons between ligand classes based on literature data are difficult to make because additives, bases, solvents, palladium sources and concentration are not consistent. Full details of the screening reaction conditions and graphical representation of the results can be found in the Supporting Information. The ligand classes behaved as expected in the cross-coupling reactions screened, on the basis of literature reports of their N-arylation abilities,[1d, 4–6, 7c–e, 8a, c, 9b, d, 10–12, 18] thereby confirming that the results disclosed herein can serve as a valid platform for comparison between ligand classes. The majority of the catalyst systems were effective in the arylation of primary and secondary amines, with some exceptions: both cataCXium A and XantPhos gave low yields of N-phenyloctylamine whereas JosiPhos and BrettPhos gave low yields of N-phenylmorpholine. JosiPhos, BrettPhos, RuPhos, BippyPhos and Ad-BippyPhos were effective in the N-arylation of
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indole affording high yields of N-phenylindole, but only JosiPhos, MorDalPhos and BippyPhos were effective in the selective monoarylation of ammonia to generate aniline. Notably, of all the ligands screened, only BippyPhos gave appreciable yields of each desired C N cross-coupling product. Repeating the reaction screen with BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 at 0.5 mol % [PdACHTUNGRE(cinnamyl)Cl]2 loading resulted in a decrease in GC yield for the products of the N-arylation reactions of morpholine and indole of greater than 10 %, but no decrease in GC yield for the products generated with the other NH-containing cross-coupling partners. These encouraging results led us to focus on the further application of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system in the cross-coupling of functionalized (hetero)aryl halides with a wide range of NH-containing substrates, in an effort to establish a broadly useful catalyst system for BHA. The nonproprietary, air-stable ligand BippyPhos was first disclosed in 2006 by Singer and co-workers,[12a] along with a demonstration of its utility in the BHA of primary and secondary alkyl and aryl amines. An additional report in 2008 outlined a kilogram-scale synthesis of BippyPhos along with its further application in a limited selection of palladium-catalyzed C N, C O and C C cross-coupling reactions with aryl and heteroaryl chlorides.[12b] Following these initial reports, BippyPhos has been applied in a small number of other palladium-catalyzed C N and C O cross-coupling reactions, and is now commercially available from multiple sources (Figure 2).
Figure 2. Previous applications of Pd/BippyPhos catalyst systems in C N cross-coupling reactions.
Pd/BippyPhos catalyst systems have been used to facilitate the C N cross-coupling of primary and secondary amines,[12] substituted hydroxylamines,[19] ureas[20] and, in two examples, imidazoles[21] (Figure 2). In addition to C N bond formation, there are several examples in which a Pd/ BippyPhos catalyst system is used to facilitate C O bond formation, with primary alcohols[12b, 13b] and hydroxide,[22] and C C bond formation.[12b, 23] The first crystal structure of a BippyPhos palladium(II) complex was reported by our group recently,[22] which revealed the ability of BippyPhos to bind in a k2-P,C-bidentate fashion through phosphorus and the ipso carbon of the lower pyrazole ring, in a manner very similar to the binding mode observed in palladium(II) complexes of the ubiquitous biarylphosphine ligand family developed by Buchwald.[1d]
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Having established for the first time the unusual ability of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 mixtures to catalyze the monoarylation of the rather divergent coupling partners, such as ammonia and indole, we set about investigating BHA reactions involving challenging NH-containing cross-coupling partners, for which the utility of Pd/BippyPhos catalysts had yet to be demonstrated prior to our report herein. Cross-coupling of ammonia and hydrazine: The selective monoarylation of ammonia with aryl chlorides by use of BHA protocols has proven to be a considerable challenge. Difficulties in achieving appropriate levels of catalytic activity and selectivity in such transformations can be attributed in part to preferential uptake of the product aniline leading to di- and triarylation, and the decreased propensity of requisite [LPd(Ar)NH2] intermediates to undergo reductive elimination.[24] These challenges were largely overcome through the development of the JosiPhos/[Pd(PACHTUNGRE(o-tol)3)2] catalyst system, which proved capable of selectively monoarylating ammonia with aryl halides and sulfonates,[7e] as well as the MorDalPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system, which is able to selectively monoarylate ammonia with a variety of functionalized (hetero)aryl halides under mild conditions with low catalyst loadings.[9b] The recent development of the BHA of ammonia with aryl halides has been reviewed in detail.[25] Although the reaction now has precedent, there are still relatively few reported catalyst systems capable of achieving this selective transformation. In addition to sharing the aforementioned challenges associated with employing ammonia as a reaction partner in BHA, hydrazine presents additional difficulties owing to its strong reducing abilities and the potential for side reactions involving N N bond cleavage. In 2010, we disclosed the first examples of the selective monoarylation of hydrazine, by use of the MorDalPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system at loadings of 5-10 mol % Pd.[9c] Following our study, only one other report of palladium-catalyzed hydrazine cross-coupling has appeared, which employed as catalysts palladacycles derived from Buchwalds biaryl monophosphine ligACHTUNGREands.[26] Encouraged by the observation in our screening exercise that BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 mixtures catalyze the selective monoarylation of ammonia using chlorobenzene, we turned our attention to exploring further this chemistry. As a starting point, we employed published conditions developed for the BHA of ammonia[9b] and hydrazine[9c] in combination with selected representative (hetero)ACHTUNGREaryl chlorides (Figure 3). We were pleased to find that BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 afforded the desired monoarylated aniline products (Figure 3 a) in high isolated yields (62–83 %, 1-1–13). Representative electron-rich (1-1), electron poor (1-2), and heterocyclic (1-3) aryl chlorides were each successfully cross-coupled with ammonia; a more detailed examination of ammonia monoarylation in the context of indole synthesis employing BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 is provided later. Extension of the catalyst system to the challenging monoACHTUNGREarylation of hydrazine required a secondary derivatization
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Buchwald–Hartwig Amination of (Hetero)aryl Chlorides
FULL PAPER give 1-4 in 62 % yield. Although the catalyst loadings used herein are higher than those reported recently by Buchwald in a continuous flow system,[26] they are within the same range used for the MorDalPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system.[9c] The BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system also has an advantage over MorDalPhos/[PdACHTUNGRE(cinnamyl)Cl]2 in that it can accommodate electron-rich aryl chloride substrates (1-8, 1-9, 1-10) in synthetically useful isolated yields (69–74 %).
Figure 3. The BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyzed cross-coupling of ammonia or hydrazine with (hetero)aryl chlorides (mol % [PdACHTUNGRE(cinnamyl)Cl]2 (x) given in parentheses; isolated yields).
step, as the arylhydrazine products resulting from the initial cross-coupling reaction were found to be of varying stability. Reaction in neat acetylacetone (110 8C) of the arylhydrazine intermediates generated following the successful C N crosscoupling of hydrazine and the aryl chloride afforded the corresponding N-arylpyrazole derivatives, which in turn were isolated and characterized. Application of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 to hydrazine monoarylation (Figure 3 b) afforded the corresponding N-arylpyrazoles in good isolated yields (46–93 %, 1-4–1-12). A variety of electron-neutral (1-4, 1-5), electron-rich (1-8, 1-9) and ortho-substituted (1-6, 1-7, 1-9, 1-12) aryl chlorides were accommodated at a 5–10 mol % Pd loading. A heteroaryl chloride was accommodated (1-11), albeit in lower isolated yield. The reaction also displays functional group tolerance and chemoselectivity with a silyl-protected alcohol (17) and a secondary amine (1-12) each being accommodated under the reaction conditions. Attempts to employ 1-chloro4-fluorobenzene in the reaction resulted in defluorination to
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Complementary routes for accessing substituted indoles: The indole core structure is arguably one of the most studied organic frameworks in synthetic medicinal chemistry, and is featured in a diverse array of pharmaceutical compounds.[27] Limitations associated with more traditional preparative routes to indoles have inspired the development of efficient, selective and modular metal-catalyzed protocols that in turn have transformed modern indole synthesis.[28] One conceptually attractive route to substituted indoles involves the metal-catalyzed N-arylation of NH-indoles with aryl halides; however, such reactions have proven challenging owing to the relatively poor nucleophilicity and high NH acidity of NH-indoles, as well as the potential for competing N- and C-arylation.[3a] In 2000 and 2002, Buchwald and coworkers disclosed breakthrough catalyst systems based on Pd2dba3/biarylphosphine[14b] or CuI/diamine[29] mixtures, respectively, which are capable of promoting such transformations. However, practical drawbacks still exist with these and other reported catalysts systems, including in the case of copper systems the need for high metal/ligand loadings as well as the poor reactivity observed with (hetero)aryl chloride reagents. Furthermore, no single Pd/ligand catalyst system that exhibits broad reactivity scope in the N-arylation of NH-indoles with aryl halides has been reported to date, and among those reports that have appeared in the literature, successful transformations involving the use of (hetero)aryl chlorides are very few. Inspired by the success of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system for the N-arylation of indole as observed in our preliminary ligand screening, we identified conditions that address some of the important shortcomings associated with the cross-coupling of NH indoles with (hetero)aryl (pseudo)halides. Under the conditions outlined in Figure 4, a selection of (hetero)aryl chlorides and bromides featuring electron-donating and withdrawing substituents were found to be well-accommodated, forming the corresponding N-arylated indoles in synthetically useful isolated yields (71–93 %, 2-1–2-14). Specifically, when employing the parent indole as the coupling partner, both chlorobenzene and phenyl tosylate (as proof-of-principle), were shown to be well-tolerated with no appreciable difference in reactivity observed (2-1). Aryl chlorides featuring 4-methoxy or 4-trifluoromethyl groups proved to be successful coupling partners (2-2, 2-3), as did 2-chloropyridine (2-4). Although ortho-substitution on the aryl halide was in general not well tolerated (2-chlorotoluene and 2,6-dimethylchlorobenzene were not effective
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Figure 4. The BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyzed N-arylation of indoles and related heterocycles (isolated yields); [a] 4 mol % Pd, 8 mol % ligand; [b] K3PO4 used as the base.
coupling partners), bromonapthalene was shown to be an effective coupling partner, leading to 2-5. Substrates featuring synthetically relevant keto, phenol and benzyl ether moieties were each well-accommodated (2-6–2-8). Carbazole and pyrrole were also shown to be effective coupling partners with chlorobenzene (2-9, 2-10). Finally, the more sterically demanding 2-phenylindole was selectively cross-coupled with a representative collection of (hetero)aryl chlorides (2-11–214), thereby demonstrating that C2-substituted indoles can be accommodated. Although more varied substitution has previously been demonstrated in this transformation by employing (hetero)aryl iodides and bromides, to the best of our knowledge the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system featured herein exhibits the broadest known substrate scope for the metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. A number of complementary palladium-catalyzed synthetic strategies exist for accessing functionalized N-aryl indoles beyond the aforementioned arylation of preformed NH indoles.[28] One attractive route involves the cross-coupling of
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a primary amine with an ortho-alkynylhaloarene, proceeded by a base-promoted[30] intramolecular cyclohydroamination of the intermediate 2-aminophenylacetylene, as developed by Ackermann and co-workers.[31] The modular nature of this transformation provides an appealing avenue to functionalized indoles, as structural variation can easily be incorporated into the alkynyl group by use of Sonogashira techniques and various substitution at nitrogen can be integrated through the selection of the amine coupling partner.[28a] A number of catalysts have been identified that are capable of promoting such cross-couplings,[28a] collectively enabling the incorporation of NH-containing substrates ranging from very small nucleophilic amines, such as ammonia[7a] and methylamine,[32] to more sterically demanding alkyl-[31b] and (hetero)aryl amines.[32] Nonetheless, there are some important limitations in this chemistry. For example, in the only report of such transformations involving ammonia,[7a] which makes use of JosiPhos/[PdACHTUNGRE(cinnamyl)Cl]2, scope in the ortho-alkynylhaloACHTUNGRE(hetero)arene reagent was limited to bromide variants; furthermore, heteroaryl halides as well as ortho-alkynylbromoarenes featuring sp3-substituents at the alkyne terminus proved incompatible with this JosiPhosbased catalyst system. In the quest to overcome these notable limitations, and in an effort to harness the unusual capabilities of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system in the monoarylation of both ammonia and NH indoles (vide supra), we sought to develop unprecedented one-pot, two-step syntheses of functionalized N-arylated indoles directly from ammonia in which three distinct C N bonds are formed in a highly selective manner. We envisioned two possible routes for accessing N-arylated indoles from ammonia in this manner: 1) monoarylation of ammonia with an ortho-alkynylhaloarene in the presence of excess base to form an NH indole that can then be cross-coupled with an aryl halide to form the corresponding N-arylated indole (method A, Figure 5); or 2) monoarylation of ammonia with an aryl halide to form an aniline that can then be cross-coupled with an ortho-alkynylhaloarene in the presence of excess base to form the corresponding substituted N-arylated indole (method B, Figure 5). BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 mixtures proved capable of catalyzing the formation of substituted N-arylated indoles through each of these reaction pathways, providing access to a variety of functionalized indoles and related heterocyclic derivatives in synthetically useful isolated yields (54–85 % total over both steps, 2-11–2-14 and 3-1–3-12). Under the conditions outlined in Figure 5, 2-phenylindole 2-11 could be readily accessed via method A or B by employing either 1-bromo- or 1-chloro-2-(phenylethynyl)benzene and chlorobenzene in the appropriate steps. The successful combination of ammonia with an ortho-alkynylchloroarene in step 1 of method A represents an important practical advancement in this transformation, in that previously only ortho-alkynylbromoarenes could be employed (vide supra).[7a] In exploring this chemistry further, N-aryl indoles featuring methoxy, trifluoromethyl, 2-pyridyl, and naphthyl N-aryl
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FULL PAPER
Figure 5. Scope of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyzed synthesis of substituted indoles from ammonia by way of a one-pot, two-step procedure (isolated yields). Method A conditions: step 1: ArX (1 equiv), ammonia (3 equiv), if X = Br, BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (4 mol %/1 mol %), if X = Cl, BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (8 mol %/2 mol %), KOtBu (3 equiv), 1,4-dioxane, 110 8C, 8 h; step 2: ArX (1 equiv), BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (4 mol %/ 1 mol %), NaOtBu (1.4 equiv), toluene, 110 8C, 12 h. Method B conditions: ArX (1 equiv), ammonia (3 equiv), BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (4 mol %/ 1 mol %), NaOtBu (1.4 equiv), 1,4-dioxane, 110 8C, 3–6 h; step 2: Ar-X (1 equiv), BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (4 mol %/1 mol %), KOtBu (1.4 equiv), toluene, 110 8C, 8 h. [a] Method A, step 2, BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (8 mol %/2 mol %). [b] Reaction conducted under air.
groups were also efficiently prepared via method A employing 1-chloro-2-(phenylethynyl)benzene in step 1 along with the appropriate (hetero)aryl chlorides in step 2 (2-12–2-14 and 3-1). Notably, indoles 2-12–2-14 could also be straightforwardly prepared via method B by use of appropriate (hetero)aryl chloride reagents. In exploring the scope of method B further, 2,6-chloro-meta-xylene was employed successfully, affording the corresponding doubly ortho-substituted N-aryl indole (3-2) in 82 % isolated yield. When repeating the synthesis of 3-2 by employing method B under air, no significant difference in reactivity was observed (78 %
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isolated yield). We next turned our attention to investigating substitution on the ortho-alkynylhaloarene, using chlorobenzene as the standard reaction partner in step 2 of method A and 2,6-chloro-meta-xylene in step 1 of method B. We were pleased to observe that both methylated and fluorinated derivatives of 1-bromo-2-(phenylethynyl)benzene were well tolerated in methods A and B, affording the corresponding indoles (3-3–3-6) in high isolated yield (79–85 %). The use of ortho-alkynylhaloarenes featuring heteroaromatic substitution at the alkynyl terminus as well as within the alkynylarene backbone was also successful. Specifically, a thio-
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phen-3-yl moiety on the alkynyl terminus was well-tolerated in both methods A and B, yielding the corresponding N-substituted indoles featuring a thiophen-3-yl fragment in the C2 position (3-7, 3-8). It is worthy of mention that the use of 3-chloro-2-(phenylethynyl)pyridine in method A to form the corresponding 4-azaindole (3-9, 88 %) represents the first successful reaction of an ortho-alkynylhaloheteroarene with ammonia in such palladium-catalyzed indole syntheses. Similarly, 3-bromo-2-(phenylethynyl)thiophene could easily be accommodated in method B to form the respective thienopyrrole (3-10, 83 %). Finally, ortho-alkynylhaloarenes featuring alkyl substitution at the alkynyl terminus, in the form of a tert-butyl group in method A and an n-propyl group in method B, were successfully converted to the corresponding N-aryl indoles featuring alkyl substitution in the C2 position (3-11, 3-12). The success of 1-bromo-2-(3,3-dimethylbut-1yn-1-yl)benzene in method A leading to 3-11 represents the first example of an ortho-alkynylhaloarene featuring alkyl substitution at the alkynyl terminus to be successfully crosscoupled with ammonia, thereby further demonstrating the robust scope and utility of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system. Cross-coupling of amides and sulfonamides: Amides are challenging substrates for intermolecular C N cross-coupling reactions due to their low nucleophilicity and ability to bind in a bidentate fashion to a metal center once deprotonated, providing an additional barrier to the reductive elimination of N-arylamide products.[33] In 2000, Yin and Buchwald reported the use of the XantPhos/PdACHTUNGRE(OAc)2 system, which was capable of promoting the intermolecular crosscoupling of aryl halides, including activated aryl chlorides with primary amides and sulfonamides at catalyst loadings between 1–4 mol % Pd.[34] Subsequent use of a biaryl monophosphine/PdACHTUNGRE(OAc)2 catalyst system allowed for the crosscoupling of a broader scope of aryl chlorides and aryl mesylates at 1 mol % Pd,[35] and moving to JackiePhos/[PdACHTUNGRE(allyl)Cl]2 allowed for the cross-coupling of aryl chlorides with acyclic secondary amides and carbamates.[36] Notwithstanding these selected advances, reports of the palladiumcatalyzed amidation of aryl chlorides remain limited. In an initial publication, Singer and co-workers reported on the poor catalytic performance of BippyPhos/PdACHTUNGRE(OAc)2 mixtures for the cross-coupling of aryl chlorides and amides.[12b] Subsequently, BippyPhos/Pd2ACHTUNGRE(dba)3 has been reported to couple aryl bromides and chlorides to a variety of aryl, benzyl and aliphatic ureas,[20a] and BippyPhos/[PdACHTUNGRE(allyl)Cl]2 has been employed successfully in the coupling of an aryl bromide with methanesulfonamide, although this catalyst system was not applied to a broader aryl chloride or amide substrate scope.[37] Despite these few recent reports, a BippyPhos/Pd catalyst system for cross-coupling aryl halides and amides with broad scope has not been reported to date. Our initial efforts in amide cross-coupling focused on the identification of suitable conditions for the cross-coupling of chlorobenzene and acetamide with the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system. Preliminary investigations in-
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dicated that 1,4-dioxane and tert-butanol were the optimal solvents and both potassium carbonate and potassium phosphate were effective bases for this transformation. The standard optimized conditions involved heating the amide or sulfonamide (1.0 equiv) with the aryl chloride (1.0 equiv), potassium carbonate (2 equiv), BippyPhos (2–5 mol %) and [PdACHTUNGRE(cinnamyl)Cl]2 (0.5–1.25 mol %) at 90 8C for 18 h in 1,4-dioxane. Using these standard conditions, functionalized (hetero)aryl chlorides were successfully cross-coupled with a variety of amides and sulfonamides in synthetically useful yields (44–99 %, 4-1–4-23; Figure 6). Chlorobenzene was successfully cross-coupled under the standard conditions with amides (4-1, 4-9, 4-15) and sulfonamides (4-18, 4-19). Substi-
Figure 6. Scope for the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyzed cross-coupling of amides and sulfonamides with (hetero)aryl chlorides (mol % [PdACHTUNGRE(cinnamyl)Cl]2 (x) given in parentheses; isolated yields). [a] K3PO4 used as base; [b] tBuOH used as solvent.
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tution in the ortho-position was also tolerated and 2-chlorotoluene was successfully cross-coupled with amides (4-4, 414, 4-17). Electron-poor 4-chlorobenzotrifluoride was also cross-coupled with amides (4-3, 4-11, 4-16), sulfonamides (4-21, 4-22) and formamide (4-23). Electron-rich 4-chloroanisole proved to be a more challenging coupling partner. Under the standard cross-coupling conditions at a catalyst loading of 2.5 mol % Pd, 4-2 was only isolated in 59 % and 4-10 in 54 %. However, changing the base to K3PO4 and the solvent to tert-butanol allowed 4-chloroanisole to be accommodated in the reaction at a 2.5 mol % Pd loading to give 4-2 in a 92 % yield and 4-10 in a 99 % yield. 2-Chloropyridine and 3-chloropyridine were each successfully coupled with representative amides (4-7, 4-8, 4-12, 4-13) when using BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 in tert-butanol solvent. 2Chloropyridine could also be coupled with p-tolylbenzenesulfonamide (4-20), albeit in a low yield. The functional group tolerance of the catalyst system was further demonstrated by the successful cross-coupling of two other heterocyclic aryl chlorides (4-5, 4-6) with acetamide. Under the standard conditions, N-butylacetamide, an acyclic secondary amide, could not be cross-coupled with chlorobenzene. Attempts were made to optimize the base, solvent and reaction temperature; nonetheless, the product could not be isolated in a synthetically useful yield. Despite this particular scope limitation, we have established herein that the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system can accommodate a broad scope of functionalized (hetero)aryl chlorides in combination with primary amides or sulfonamides as cross-coupling partners. Cross-coupling of amines: Although the BippyPhos/PdACHTUNGRE(OAc)2 catalyst system has proven capable of cross-coupling both primary and secondary amines with aryl halides at 0.5– 1.0 mol % Pd,[12] we were interested in investigating the application of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 to a few select examples of challenging secondary amine substrates. Using this catalyst system, dihexylamine (5-1) and heptaethyleneimine (5-2) each were successfully arylated in synthetically useful yields using 2 mol % Pd (Figure 7). In our hands, these substrates proved difficult to arylate when using XantPhos, MeDalPhos or IPr under analogous conditions. To our knowledge, there are very few reports of cross-coupling of these particular secondary amines with aryl chlorides.[38]
Figure 7. Selected application of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system for the cross-coupling of challenging secondary amines with chlorobenzene (isolated yields).
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FULL PAPER Beyond applying the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system to BHA reactions involving the particularly challenging NH-containing substrates discussed thus far (vide supra), we were also interested in investigating its efficiency in cross-coupling 4-chloroanisole (a representative electronically deactivated aryl chloride) with a series of more commonly employed and synthetically relevant primary and secondary amines over the course of 24 h (unoptimized) at 110 8C (Figure 8).
Figure 8. BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyzed cross-coupling of primary and secondary amines with 4-chloroanisole at low catalyst loadings. Conversions were determined on the basis of GC analysis of reaction mixtures. A GC calibration curve was generated with 4-chloroanisole using the internal standard calibration method with dodecane as an internal standard. Product identity was determined on the basis of retention time comparison with authentic product samples.
We were pleased to observe quantitative conversion of 4-chloroanisole to form the target cross-coupling product (6) with a range of primary and secondary alkyl- and arylamines employing catalyst loadings as low as 0.05–0.3 mol % Pd (Pd/BippyPhos, 1:2). At the outset, the lowest catalyst loadings at which full conversion of 4-chloroanisole could be achieved were determined for the sterically differing primary alkylamines methylamine (0.1 mol % Pd), n-octylACHTUNGREamine (0.05 mol % Pd) and 1-adamantylamine (0.3 mol % Pd). Although aniline (0.3 mol % Pd) was also easily accommodated at such low catalyst loadings, the more hindered 2,6-dimethylaniline proved somewhat more challenging under similar conditions, requiring a slightly higher catalyst loading (0.5 mol % Pd) to achieve full conversion. Finally, we confirmed that these protocols could be extended to the hydrazine derivative, 4-methylpiperazin-1-amine (0.3 mol % Pd), and the secondary alkylamine, morpholine (0.3 mol % Pd) as coupling partners. Collectively, these results further
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exemplify the broadly useful nature of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system in BHA chemistry involving commonly encountered primary and secondary amine reaction partners, and bring to light the preference of this catalyst system for smaller, more nucleophilic primary amines over both primary arylamines and secondary alkylamines. To further demonstrate the substrate preferences of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system, a set of amine arylation competition experiments were carried out using chlorobenzene. Indeed, under the conditions outlined in Figure 9, the catalyst system preferentially and selectively cross-coupled the primary amines 4-methylpiperazin-1-
cation of highly effective catalysts for BHA that are capable of chemoselectively arylating diamine substrates featuring two different and potentially competitive NH moieties remains a persistent challenge and has recently begun to attract attention in the chemical literature.[7b, 9d, 40] Given the distinct preference exhibited by BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 in our low catalyst loading (Figure 8) and amine competition experiments (Figure 9) for relatively small, nucleophilic primary amines, we envisioned that this catalyst system should be capable of chemoselectively arylating appropriate diamine substrates. We were delighted to observe that BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 mixtures could indeed be applied successfully in such chemoselective transformations, affording a number of structurally varied monoarylated diamine products in high isolated yields (73–93 %, 8-1–8-10) as the only observed products under the conditions employed (Figure 10). In keeping with our observed trends (vide supra), the selective monoarylation of the primary alkylamine moiety in N1-phenylethane-1,2-diamine was achieved with a range of hindered or unhindered (hetero)aryl chlorides featuring electron-donating or withdrawing groups (8-1–8-5).
Figure 9. Application of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 in amine competition experiments. Conversions were determined on the basis of GC analysis of reaction mixtures. A GC calibration curve was generated with chlorobenzene using the internal standard calibration method with dodecane as an internal standard. Product identity was determined on the basis of retention time comparison with authentic product samples.
amine or n-octylamine over morpholine to produce a single product, despite the fact that morpholine had proven to be a competent substrate in this chemistry (Figure 8). Interestingly, when employing n-octylamine and indole as the competing NH-containing substrates, no conversion of chlorobenzene was observed. Evidently indole acts as a catalyst inhibitor at the low loadings employed, effectively shutting down the otherwise feasible n-octylamine arylation reaction. This latter phenomenon is consistent with our observation that higher loadings of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (4 mol %/1 mol %) are needed in order to promote the efficient cross-coupling of chlorobenzene and indole (2-1, Figure 5). Chemoselective arylation of diamines: The many difficulties associated with chemoselective palladium-catalyzed transformations have been described.[39] Among these, the identifi-
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Figure 10. Scope of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyzed chemoselective monoarylation of diamine substrates (isolated yields). [a] Experiment was conducted under air. [b] BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 (10 mol %, 2.5 mol %) [c] K2CO3 (1.5 equiv), 1,4-dioxane, 90 8C.
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For proof-of-principle, the synthesis of 8-2 was reexamined under air, and separately using phenyl tosylate as an aryl pseudohalide coupling partner; in both cases only modest decreases in yield were observed. The ability of BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 to arylate n-octylamine is inhibited in the presence of indole (or accompanying substrate impurities) at the 1 mol % Pd loading level (Figure 9). However, at higher catalyst loadings (5 mol % Pd, 10 mol % BippyPhos) the presence of an indole moiety within a diamine is accommodated, as evidenced by the selective monoarylation of the primary amine fragment in tryptamine (8-6). The preferential arylation of the primary alkylamine moiety could also be achieved in diamine substrates featuring competing primary arylamine (8-7) and secondary cyclic dialkylamine (8-9) fragments. Despite the preferential arylation of primary alkylamines over arylamines that was established for this catalyst system (Figure 8), primary arylamine fragments were selectively monoarylated in diamine substrates featuring contending sulfonamide (8-8) and secondary arylamine (8-10) functionalities. In the case of 8-8, further support for the spectroscopic identification of the product was obtained by use of single-crystal X-ray diffraction techniques (see the Supporting Information).
Conclusion In summary, the results presented herein establish the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system as accommodating the largest scope of NH-containing substrates in Buchwald– Hartwig amination (BHA) reported to date for a single Pd/ ligand catalyst system. Utilizing BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 in the cross-coupling of functionalized (hetero)aryl halides, we have expanded significantly the previously known reactivity profile for BippyPhos/Pd catalysts[12, 13b, 19–22] to now include the sterically/electronically varied and challenging NH-containing substrates ammonia, hydrazine, indole, amides, and sulfonamides (Figure 11). During the course of this research, we have established that the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system exhibits the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles reported thus far in the literature. Furthermore, we were able to exploit the broadly useful nature of BippyPhos/ [PdACHTUNGRE(cinnamyl)Cl]2 in the development of a new and versatile one-pot, two-step synthesis of N-aryl indoles and related heterocyclic derivatives involving three sequential and selective C N bond-forming steps starting from ammonia. Through a series of low catalyst loading and amine competition experiments, a clear catalyst preference for smaller, more nucleophilic primary amine coupling partners was delineated and subsequently exploited in the chemoselective monoarylation of a range of substrates featuring two distinct and potentially competitive NH moieties. Although not exhaustively explored, proof-of-principle experiments confirmed the ability of the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system to operate under air.
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FULL PAPER
Figure 11. Broad scope of N-arylated products accessible employing BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2.
While not a “universal” catalyst for BHA, the unprecedented breadth and depth of scope established herein for the BippyPhos/[PdACHTUNGRE(cinnamyl)Cl]2 catalyst system, in terms of the NH-containing coupling partner, offers an important practical advance to the many users of this ubiquitous C N bond-forming reaction. In particular, by establishing a single and reliable “first-choice” for use in addressing the diversity of challenging BHA applications that are faced by synthetic chemists, we hope to increase the accessibility and utility of the methodology for nonspecialists in both academia and industry.
Acknowledgements We are grateful to NSERC of Canada and Dalhousie University for their support of this work. Digital Specialty Chemicals is thanked for a gift of BippyPhos and Dr. Scott Laneman (DSC) is thanked for helpful discussions. Dr. Michael Lumsden (NMR-3, Dalhousie) is thanked for technical assistance in the acquisition of NMR spectroscopy data and Mr. Xiao Feng (Maritime Mass Spectrometry Laboratories, Dalhousie) is thanked for technical assistance in the acquisition of mass spectrometric data. Dr. Robert MacDonald (X-Ray Crystallography Laboratory, Alberta) is thanked for the acquisition of X-ray data and Dr. Craig Wheaton (Dalhousie) is thanked for structural solution and refinement of compound 8-8.
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FULL PAPER Buchwald, Org. Lett. 2008, 10, 3505 – 3508; f) B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 2008, 130, 13552 – 13554; g) J. L. Henderson, S. L. Buchwald, Org. Lett. 2010, 12, 4442 – 4445; h) X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 6653 – 6655; i) L. Jean, J. Rouden, J. Maddaluno, M.-C. Lasne, J. Org. Chem. 2004, 69, 8893 – 8902; j) F. Perez, A. Minatti, Org. Lett. 2011, 13, 1984 – 1987. Received: June 26, 2013 Published online: November 4, 2013
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