Indium-Mediated Stereoselective Allylation - Accounts of Chemical

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Indium-Mediated Stereoselective Allylation Dinesh Kumar, Sandeep R. Vemula, Narayanaganesh Balasubramanian, and Gregory R. Cook* Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108-6050, United States

CONSPECTUS: Stereoselective indium-mediated organic reactions have enjoyed tremendous growth in the last 25 years. This is in part due to the insensitivity of allylindium to moisture, affording facile and practical reaction conditions coupled with outstanding functional group tolerance and minimal side reactions. Despite the plethora of articles about allylindium, there is much yet to be discovered and exploited for efficient and sustainable synthesis. In this Account, we describe indium-mediated synthetic methods for the preparation of chiral amines with the aim to present a balance of practical method development, novel asymmetric chemistry, and mechanistic understanding that impact multiple chemical and materials science disciplines. In 2005, we demonstrated the indium-mediated allylation of chiral hydrazones with complete diastereoselectivity (>99:1) and quantitative yields. Further, we revealed the first example of enantioselective indiummediated allylation of hydrazones using catalytic (R)-3,3′-bis(trifluoromethyl)-BINOL ligands to afford homoallylic amines with high enantioselectivity. The use of enantiopure perfluoroalkylsulfonate BINOLs greatly improved the indium-mediated allylation of N-acylhydrazones with exquisite enantiocontrol (99% yield, 99% ee). This laboratory has also investigated indium-mediated asymmetric intramolecular cyclization in the presence of amino acid additives to deliver biologically relevant chromanes with excellent diastereoselectivity (dr >99:1). The effect of amino acid additives (N-Boc-glycine) was further investigated during the indium-mediated allylation of isatins with allyl bromide to yield homoallylic alcohols in excellent yields in a short time with a wide range of functional group tolerance. Critical mechanistic insight was gained, and evidence suggests that the additive plays two roles: (1) to increase the rate of formation of allylindium from allyl bromide and In(0) and (2) to increase the nucleophilicity of the allylindium reagent, probably through disruption of aggregates and coordination to the metal. We recently reported the palladium-catalyzed umpolung allylation of hydrazones with allyl acetates in the presence of indium(I) iodide (InI) with excellent diastereoselectivity (up to 99:1). The conversion was found to be inversely proportional to the phosphine concentration, providing insight into the mechanism of the critical redox transmetalation process that has implications for other Pd-catalyzed umpolung-type allylation processes. A detailed overview of the work in our lab is presented with the intention of stimulating further research interest in organoindium chemistry and its application in organic synthesis.

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INTRODUCTION

has been made, control of the chemo-, regio-, and stereoselectivity has been challenging. In this context, the use of chiral auxiliaries to effect diastereoselective addition has met with some success. The effect of Lewis acids on the asymmetric induction in indium-mediated allylation has had limited success, probably because of Lewis acid interference with the wellknown Zimmerman−Traxler transition state.4 An emerging strategy in asymmetric transformations is the use of chiral ligands to bind both the substrate and allylindium, accelerating

Since the first report of indium-mediated carbon−carbon bond formation by Chao and Rieke in 1975,1 examples of indiumpromoted reactions have proliferated.2 Furthermore, organoindium reagents display low basicity and selective nucleophilicity, thereby offering outstanding functional group tolerance, chemoselective transformations, minimal side reactions, and low toxicity.3 Over the last 25 years, allylindium has emerged as a mild and effective reagent for the allylation of carbonyl compounds and imines to generate homoallylic alcohols and amines, respectively.2 Although remarkable growth in these reactions © 2016 American Chemical Society

Received: July 13, 2016 Published: October 4, 2016 2169

DOI: 10.1021/acs.accounts.6b00362 Acc. Chem. Res. 2016, 49, 2169−2178

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Accounts of Chemical Research the chiral pathway relative to the background reaction. However, the use of chiral ligands to facilitate enantioselectivity in indium allylations has been difficult because of the low heterophilicity of allylindium. In our decade-long effort to explore the synthetic utility of organoindium reagents and improve their efficiency and applicability, we have developed several new avenues in indium-mediated synthetic methodology5 for the construction of chiral alcohols and amines. We have utilized both chiral and achiral N-acylhydrazones as versatile imino acceptors, which upon N−N bond cleavage after the allylation produce chirally pure primary amines. Apart from stoichiometric indium reactions, we have also investigated catalytic In(III) Lewis acid-catalyzed reactions; however, these are not discussed here.6 Thus, the present Account aims to address our findings and unexpected discoveries that provide insight on fundamental mechanistic questions whose answers have the potential to transform the field of organoindium research.

Scheme 1. In(0)-Mediated Diastereoselective Allylation of Hydrazone 1a

templates (3a−d) indicated complete diastereoselectivity except for 3a, with excellent yields in each case. With valinol-based substrate 3c, the scope of indiummediated allylation was examined (Scheme 2). Reaction with

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INDIUM-MEDIATED DIASTEREOSELECTIVE ALLYLATION OF CHIRAL HYDRAZONES Chiral amines are important building blocks for the synthesis of biologically active compounds and natural products, and they also find utility as ligands for asymmetric catalysis.7 One of the most direct methods for their preparation is the addition of carbon nucleophiles to CN bonds.8 However, relative to carbonyls, imine derivatives are generally less reactive, usually demanding the use of strong organometallic reagents, thereby making enolization and functional group intolerance common impediments. The use of chiral auxiliaries to affect an indiummediated diastereoselective allylation of imines such as chiral sulfinimine,9 valine-derived imines, 10 and α-keto chiral sultams11 has been made with some success prior to this work. These methods generally suffer from modest yields, poor diastereoselectivity, relatively long reaction times, and the use of auxiliaries that are difficult to cleave. Hydrazones are relatively stable imine equivalents. However, their poor reactivity demands a stronger organometallic addition compared with imines, limiting their utility as precursors for chiral amine compounds. Therefore, the addition of carbon fragments to CNX bonds (where X = stabilizing group) and related compounds is increasingly being used for the synthesis of chiral amines. The use of a stabilizing group allows a chiral auxiliary to be incorporated and cleaved without affecting the efficiency of the process. Friestad reported the allylation of chiral hydrazones utilizing fluoride-induced allylation with allylsilane in the presence of a Lewis acid with high selectivity.12 The hydrazine products were readily cleaved with SmI2 to afford homoallylic amines. Although the chemistry is quite elegant and works well in most cases, the selectivity with aliphatic aldehyde-derived substrates is lower. In addition, the reaction times are quite long, as the reaction requires 2 days to reach completion. We envisioned that allylindium reagents would offer improvements in rate, selectivity, and overall ease of the process compared with allylsilanes. Systematic examination of the reaction conditions for the allylation of chiral hydrazone 1a to form 2a (Scheme 1) led to the identification of optimal conditions as 2 equiv of In(0) and 3 equiv of allyl iodide in THF at room temperature. The stoichiometric requirements suggested that an allylindium sesquihalide species was necessary for the reaction.13 Screening of different oxazolidinone

Scheme 2. In(0)-Mediated Diastereoselective Allylation of Chiral Hydrazonesa

a

Yields and selectivities in parentheses were obtained with added In(OTf)3 Lewis acid.

aromatic-aldehyde-derived substrates gave overall excellent yields and diastereoselectivities with the exception of p-nitro derivative 2g (50%, >99:1) and p-methoxy substrate 2h (96%, >86:14). Allylation of the cinnamaldehyde-derived hydrazone proceeded with essentially no selectivity (2i). Aliphatic substrates also reacted with poor selectivity (2j−l). The chiral auxiliary was readily cleaved as reported by Friestad.12 Interestingly, we observed that the selectivity changed depending on the scale of the reaction. With excess allylindium reagent under more dilute conditions, the reaction favored better selectivity. The dependence of the diastereoselectivity on the concentration suggested that excess In(III) in solution 2170


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Accounts of Chemical Research could be coordinating the substrate as a Lewis acid. The addition of In(OTf)3 to the chiral hydrazone increased both the selectivity and the rate of the reaction (Scheme 2), and in fact, the sluggish aliphatic substrates also gave excellent diastereoselectivity with added In(OTf)3 (2i−l). Presumably, In(OTf)3 coordinated the hydrazone in a chelating fashion both to activate the substrate and to restrict the conformational mobility, allowing greater reactivity and selectivity (Figure 1).

Scheme 3. Chiral Additives for In(0)-Mediated Enantioselective Allylation of Hydrazone 4a

Figure 1. Hydrazone rotamers.

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INDIUM-MEDIATED ENANTIOSELECTIVE ALLYLATION OF HYDRAZONES Enantioselective allylation of imines has received much attention recently.14 The silicon-mediated allylation of Nacylhydrazones has been especially successful in this regard.15 Leighton’s modified allylsilanes16 and Kobayashi’s sulfoxide/ allyltrichlorosilane combination17 provide good selectivity (up to 93% ee). Kobayashi further demonstrated that chiral BINAP oxides used in substoichiometric amounts can promote this reaction.18 Chiral bis(allylpalladium) catalysts have also been employed in enantioselective allylation of imines with allylsilanes and allylstannanes (up to 94% ee).19 Using allylindium, Loh was the first to report enantioselective reactions using stoichiometric addition of cinchona alkaloids and PYBOX ligands,20 and Singaram employed stoichiometric chiral amino alcohols for asymmetric induction.21 On the basis of our work on allylation of chiral hydrazones,5a we sought to develop an enantioselective variation utilizing an achiral oxazolidinone template (Scheme 3). After a survey of different chiral additives (6a−j) for the allylation of 4a, (R)BINOL (6h) emerged as a promising early lead, affording a modest yield (45%) and selectivity (40% ee). This encouraged us to investigate other BINOL derivatives to optimize the selectivity. 3,3′-Diiodo-BINOL (6i) demonstrated improved selectivity, and 3,3′-bis(trifluoromethyl)-BINOL (6j) performed the best, affording a 78% yield of 5a with 70% ee. Gratifyingly, with a catalytic amount of chiral BINOL 6j (10 mol %), the selectivity for the allylation of 4a was retained (70% ee, 77% yield) (Scheme 4). However, stoichiometric addition of 6j under these conditions improved the selectivity slightly (84% ee). Ortho-substituted imines offered the highest enantioselectivity, with the o-bromobenzaldehyde-derived hydrazone affording the best overall yields and selectivity in both catalytic (5g, 85% ee) and stoichiometric (5g, 97% ee) reactions. The use of 100 mol % ligand yielded chiral homoallylic amines of aliphatic and cinnamyl derivatives (5j− l) with ≥90% ee, which was very rewarding in view of the fact that these substrates suffer significantly from competing achiral background reactions, as evidenced by the lower selectivity obtained with catalytic ligand. To the best of our knowledge, this was the first successful example of the use of catalytic amounts of chiral additive in indium-mediated allylations. Following this, Jacobsen reported a selective urea-based catalyst that induces 76−95% ee in an analogous process.22 In order to gain insight into the role of the BINOL ligand, we examined several analogues, and the results are presented in

Table 1. A key observation was that the electronic demands, but not the steric demands, of the BINOL were crucial for both the reactivity and selectivity. Changing the 3,3′ substituents from CF3 to Me to TMS (Table 1, entries 3−5) resulted in a marked decrease in the enantioselectivity, while bromine at the 6 and 6′ positions led to higher selectivity (Table 1, entry 6). Larger substituents with electron-withdrawing groups at the 3 and 3′ positions also did not improve the selectivity (Table 1, entries 7 and 8). Thus, in general electron-deficient BINOL derivatives performed better than electron-rich ones, suggesting that the acidity of the BINOL was important. An NMR study suggested that 6j did not interact directly with the hydrazone but did react with the in situ-generated allylindium23, as evidenced by an upfield shift of the aromatic 1H signals. This was consistent with an increase in electron density arising from BINOL deprotonation by the relatively nonbasic allylindium reagent. Thus, an in situ chiral Lewis acid catalyst appeared to be operational. As the allylation reaction 4a → (±)-5a proceeded readily in the absence of BINOL, high catalyst activity was a prerequisite for higher enantioselectivity. On this basis, we sought more Brønsted acidic BINOLs, leading to increased Lewis acidity of the indium BINOLate catalyst. Sulfones in general and perfluoroalkylsulfones in particular are significantly more electron-withdrawing substituents than CF3. Thus, enantiomerically pure 3,3′-bis(triflone)-, 3,3′bis(nonaflone), and 3,3′-bis(heptadecaflone)-BINOL systems (6p−r, respectively) were prepared in two steps from 3,3′-Y2BINOLs (Y = H, Br) via double thia-Fries rearrangement in collaboration with Prof. Lloyd-Jones (Scheme 5).24 Excess Grignard reagent (RHMgBr) readily displaced CF3 from 6p without the requirement for phenolic protection, yielding alkylsulfones 6s and 6t.25 An analogous procedure employing 1 equiv of LDA afforded monosulfones 6u and 6v. The newly synthesized BINOLs 6p−v were examined at 10 mol % catalyst 2171


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Accounts of Chemical Research Scheme 4. In(0)-Mediated Enantioselective Allylation of Achiral Hydrazones

Table 1. Investigation of BINOL Derivatives for the Enantioselective Allylation of 4aa

a

Reactions were carried out using 2 equiv of chiral additive, 2 equiv of In(0), and 3 equiv of allyl iodide. bIsolated yields. cDetermined using chiral HPLC.

loading in the allylation reaction, and the results are shown in Table 2. A stark contrast emerged between 6j (Table 2, entries 1 and 2) and the new SO2RF ligands 6p−r and 6u (Table 2, entries 3−9). The presence of two SO2RF substituents was found to be crucial. The SO2RH catalysts 6s and 6t afforded markedly lower selectivity, particularly for 4k (Table 2, entries 7 and 8), and the unsymmetric catalyst 6u gave only 9−11% ee (Table 2, entry 9). The remarkable efficacy of bis(SO2RF)BINOL 6p was also manifested in a more extensive study. The greater activity of catalyst 6p was sufficient to facilitate a switch to an allyl bromide-derived indium reagent, affording even higher selectivity (compare entries 3 and 4 in Table 2). Hydrazones possessing an ortho substituent gave particularly excellent results (94−99% ee, 5e−g and 5m; Scheme 6), facilitating lower catalyst loadings. An aliphatic substrate also gave significantly improved enantioselectivity (5j, 74% ee) compared with the first-generation ligand 6j (34% ee). This was

Scheme 5. Synthesis of New Perfluoroalkylsulfone BINOL Ligands

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first examined the cyclization of 7a to form 8a in the presence of In(0), but no reaction occurred (Table 3, entry 1). Addition

Table 2. BINOL Derivatives for Enantioselective Allylation of 4a and 4ka 4a (R = Ph)

4k (R = styryl)

entry

BINOL

yield (%)b

ee (%)c

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9

6j 6j (200 mol %) 6p 6pd 6qd 6r 6s 6t 6u

77 78 95 82 68 72 49 98 59

70 70 88 90 89 88 49 68 11

79 − 85 87 − − 71 87 70

34 − 90 97 − − 44 10 09

Table 3. Effect of Additives on the Cyclization of 7aa

a

Reactions were carried out using 10 mol % chiral additive, 2 equiv of In(0), and 3 equiv of allyl iodide. bIsolated yields. cDetermined using chiral HPLC. dUsing allyl bromide.

the highest ee ever reported for a catalytic asymmetric allylation of an aliphatic imine derivative. Thus, a very efficient enantioselective allylation of hydrazones was developed using tunable 3,3′-bis(perfluoroalkylsulfone)-BINOLs.

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entry

additive (equiv)

time (h)

yield (%)b

drc

1 2 3 4 5 6 7 8 9 10

none InBr3 (1.3) aq. HCl (6) H3PO4 (6) CH3SO3H (6) TFA (6) Boc-L-Pro-OH (1.5) Boc-L-Phe-OH (1.5) Boc-Gly-OH (1.5) Boc-Gly-OH (2)

10 48 10 10 10 10 12 12 12 12

0 99:1 >99:1 >99:1 >99:1 >99:1

a

Reactions were carried out on a 0.58 mmol scale. bIsolated yields. Diastereomeric ratios were determined by 1H NMR analysis of the major isomer 8a shown vs the three other possible isomers.

c

INDIUM-MEDIATED DIASTEREOSELECTIVE INTRAMOLECULAR ALLYLATION OF CHIRAL HYDRAZONES The increased demand for enantiopure medicinal compounds26 encourages the development of synthetic methods for biologically active heterocycles. To complement the success of intermolecular diastereoselective allylation,5a we sought to develop an intramolecular version for the synthesis of biologically relevant chromanes.27 We anticipated that an allylic bromide-tethered hydrazone would offer the framework for the core chromane structure. We

of an In(III) Lewis acid was explored, but the results were discouraging, as only a trace of 8a was obtained (Table 3, entry 2). The use of non-carboxylic acids also proved ineffective (Table 3, entries 3−5). However, with trifluoroacetic acid, the reaction ensued with good efficiency to produce 8a as a single isomer (Table 3, entry 6). The marked effect of the carboxylic acid on the cyclization of 7a led us to investigate other carboxylic acid additives. As shown in Table 3, the addition of N-Boc-protected amino acids demonstrated a similar improve-

Scheme 6. In(0)-Mediated Enantioselective Allylation of Hydrazones Using 6p

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The synthetic usefulness of the stereoselective intramolecular annulation was demonstrated by the preparation of 9b, a key intermediate for the synthesis of chromane antibiotic 10 (Scheme 8).29 Reductive cleavage of the hydrazine was

ment in reactivity and selectivity. The optimal reaction was obtained with 2 equiv each of Boc-Gly-OH and In(0), affording 8a in 72% isolated yield (Table 3, entry 10). Under the optimal conditions, a variety of chiral hydrazones were effectively converted into the analogous cyclized products in good to excellent yields with complete stereocontrol to give the syn products (Scheme 7). Substrates bearing an electron-

Scheme 8. Synthetic Route to 9b, a Key Intermediate of a Chromane Antibiotic

Scheme 7. Asymmetric Synthesis of Aminochromanes via Intramolecular In(0)-Mediated Allylation

accomplished by acylation with trifluoroacetic anhydride followed by treatment with SmI2 to give 9a. Ozonolysis followed by hydrolysis of the trifluoracetate afforded amino alcohol 9b. It should be pointed out that 9a possesses latent functionality in the olefin that could be utilized for further manipulation to generate a library of compounds with potential biological applications. In order to gain insight into the effect of amino acid additives in the indium-mediated intramolecular allylation,5d we explored the utility of N-Boc-glycine (Boc-Gly-OH) in the allylation of isatins.30 To our delight, treatment of isatin 11 with allyl bromide in the presence of In(0) and 2 equiv of Boc-Gly-OH in MeOH at room temperature resulted in the formation of 12 (98%) in only 10 min (Scheme 9). In stark contrast, the reaction in the absence of Boc-Gly-OH produced 12 in only 70% yield even after 24 h.

donating group para to the allyl ether moiety and meta to the hydrazone resulted in the highest yield (91%, 8d). On the other hand, placing an electron-donating group meta to the allyl ether moiety and para to the hydrazone resulted in a lower yield (68%, 8e). This was the first reported asymmetric indiummediated intramolecular cyclization. The role of the carboxylic acid in promoting the reaction and guiding the stereochemical outcome is unclear but may involve templating and activating the transition state. Group 13 allyl metal halides are well-recognized to form bridged dimers28 that would likely be unable to cyclize in an intramolecular allylation. The carboxylic acid may aid in breaking up aggregated organometallic intermediates. As shown in Figure 2, a chair transition state encompassing the allylic indium and imine moieties would offer the cis-aminochromane product. The acid may help in activating the reaction through hydrogen bonding to the oxazolidinone carbonyl while concurrently increasing the nucleophilicity of the allylindium by donation from the acid carbonyl to the indium metal.

Scheme 9. Effect of Boc-Gly-OH on the In(0)-Mediated Allylation of Isatin 11

The influence of Boc-Gly-OH on other main-group metals (Bi, Zn, Sn, and Mg) renowned for their ability to form nucleophilic allylmetal reagents was also examined. A parallel rate improvement for Bi, Zn, and Sn was seen. The degree of the effect of Boc-Gly-OH was greatest for indium and followed the trend In > Zn > Sn > Bi. No effect of Boc-Gly-OH was observed in the case of Mg, perhaps because of rapid protonation and destruction of the allylmagnesium bromide in methanol. We determined that Boc-Gly-OH facilitates the nucleophilic transfer of allyl moieties from the allylindium to the carbonyl, presumably by disrupting aggregates and/or activating the allylindium reagent, thus increasing the efficacy and yield, and as a result, the reaction requires only a stoichiometric amount of the allyl bromide. The nature of this interaction was not clear, and further exploration is being undertaken to evaluate the additive effect. In addition to modulating the reagent

Figure 2. Possible transition state for the carboxylic acid-promoted Inmediated allylation. 2174


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Figure 3. 1H NMR spectra showing the formation of allylindium species with or without Boc-Gly-OH: (A) In(0) + allyl bromide, 10 min; (B) In(0) + allyl bromide, 30 min; (C) In(0) + allyl bromide + Boc-Gly-OH, 5 min; (D) In(0) + allyl bromide + Boc-Gly-OH, 10 min.

reactivity, we speculated about whether the additive plays any role in the formation of the allylindium reagent itself. We followed the formation of allylindium by 1H NMR spectroscopy in the presence and absence of Boc-Gly-OH. When BocGly-OH was present, the allylindium species was quickly detected (by the appearance of allylic protons at 1.75 and 1.93 ppm)2f within 5 min (Figure 3C). In stark contrast, practically no allylindium was observed even after 10 min in the absence of the additive (Figure 3A), and only a trace was detected after 30 min (Figure 3B). This strongly suggested that Boc-Gly-OH facilitates the formation of the allylindium, which could increase the rate of indium-mediated allylation. Thus, we propose that the additive plays two roles in promoting this process.

Scheme 10. Optimized Conditions for Pd/In Allylation of Chiral Hydrazones

Scheme 11. Pd/In Allylation of Different Chiral Hydrazones

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INDIUM-MEDIATED PALLADIUM-CATALYZED ALLYLATION OF CHIRAL HYDRAZONES Generally, indium-mediated allylation employs an allylic halide as the allyl metal precursor. In 2000 a new reductive transmetalation protocol catalyzed by Pd(0) was reported by Araki for the preparation of allylindium reagents from allylic acetates and alcohols.31 This method was beneficial as it avoided the use of more sensitive allylic halides and widened the scope of nucleophiles that may be used. Conventionally, umpolung Pd-catalyzed allylation methods have been used with aldehyde electrophiles, and their application with imines is uncommon.32 To the best of our knowledge, stereoselective Pd-catalyzed indium-mediated allylation had not been investigated comprehensively for imine substrates before our work. We anticipated that the operational ease and simplicity of handling would be beneficial for the allylation of chiral hydrazones by using allylic acetates as precursors employing Pd catalysis rather than allylic halides. The treatment of hydrazone 13a with allyl acetate in the presence of InI and Pd(PPh3)4 resulted the formation of homoallylic hydrazine 14a with high diastereoselectivity at room temperature in methanol or a combination of THF and water (optimized conditions, Scheme 10). Different chiral hydrazones containing isopropyl-, benzyl-, and phenyl-substituted oxazolidinones were examined (Scheme 11). Not surprisingly, the isopropyl auxiliary performed extremely well and produced the homoallylic hydrazines 14b−I with complete control of the diastereoselectivity. The substrate having an ester functionality adjacent to the imine was the exception, producing 14f as an 80:20 mixture. The inferior selectivity could be due to the presence of an additional coordinating group for In(III) to bind and chelate the imine, permitting the oxazolidinone auxiliary freedom to rotate from an s-cis to an s-

trans conformation. The benzyl-derived auxiliary offered slightly lower diastereoselectivity (14j−l) compared with the isopropyl auxiliary. On the other hand, the phenyl auxiliary gave the lowest diastereoselectivity (14m). This is possibly due to the planar nature of the phenyl ring, which can rotate perpendicular to the plane of the imine, thus providing inefficient shielding of the imine face. 2175


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Accounts of Chemical Research In the context of substrate scope, we should especially mention the excellent selectivity of the Pd/In protocol in the allylation of aliphatic hydrazones compared with In(0)mediated allylation, while noting that it complements the In(0)/In(OTf)3 protocol. While outstanding selectivity was accomplished, we frequently observed variability in starting material consumption. In some cases the Pd-catalyst would precipitate out of solution, killing the reaction. While umpolung-type reactions using palladium catalysis are welldocumented,33 the mechanism of the key redox step for the transfer of the allyl ligand from the Pd(II) intermediate to the reducing metal is not much understood (Scheme 12).

Scheme 13. Mechanistic Hypothesis for the Role of Phosphine in the Inhibition of Allylation

Scheme 12. Pd-Catalyzed Allylmetal Formation

results in a lower concentration of B, inhibiting the formation of C and ultimately the reaction progress. This allows degradation pathways resulting in Pd black to compete with successful transmetalation. Although no reports of Pd(II)− In(I) complexes are available, examples of Pd(0)−In(I) coordination complexes have been reported, demonstrating that In(I) can form coordinative bonds to Pd.35 A Pd(II)−In(I) complex would be prone to undergo redox rapidly to form Pd(0) and In(III). Confirmation of the inhibition of the reaction with increased phosphine concentration hinted that an intermediate involving a Pd−In bond is vital for the formation of nucleophilic allylindium species.

As the initial formation of a Pd(II)−allyl complex via oxidative addition of Pd(0) to allyl acetate is very well established,34 we hypothesized that the difficulties faced in the reactions were likely associated with incompetent reductive transmetalation. To investigate the consequence of the ligand in the reaction, the role of the phosphine concentration in the conversion of 13d to 14d was investigated. A Pd(0) catalyst without phosphine ligands, Pd2dba3, was used, and the amount of Ph3P ligand was methodically changed (Table 4). With 5 Table 4. Effect of the Phosphine Concentration on Pd/InMediated Allylation

entry

X (mol %)

Y (mol %)

P/Pd ratio

isolated yield (%)

1 2 3 4 5 6

5 5 5 5 5 5

0 2.5 5 10 20 30

0 0.25 0.5 1.0 2.0 3.0

0 78 75 65 54 37

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CONCLUSIONS AND OUTLOOK The demand for new synthetic methods for the synthesis of chiral amines continues. In this Account, we have discussed the development of diastereoselective and enantioselective indiummediated allylation of both aromatic and aliphatic aldehydederived hydrazones to generate chiral amines. In this context, the discovery of catalytic bis(SO2RF)-BINOL ligands to facilitate enantioselective indium-mediated imine allylation (>99% ee) is particularly appealing as it offers significant opportunities for exploiting fluorous phase technologies for ligand recovery. Further, the BINOL catalyst system can be easily recovered (by silica gel chromatography) and recycled without loss of activity or selectivity. The asymmetric indiummediated intramolecular cyclization of hydrazones to construct aminochromane ring systems opens a new opportunity for further manipulation via the latent olefin functionality to generate a diverse library of compounds with potential biological applications. Insight gained from the studies of additive affects continues to illuminate ways to improve the efficiency and efficacy of In-mediated allylation. We have uncovered mechanistic insight into the Pd/In umpolung allylation reactions suggesting the involvement of an intermediate Pd(II)−In(I) complex that has an impact on other related reductive transmetalation processes. Better understanding of the mechanism of redox transmetalation will allow greater control of reactions and has implications beyond the indium-mediated allylation. While allylindium has been utilized time and time again for the last 25 years, there is much to be learned about the mechanism that will propel its practical and efficient use. Toward this end, we are exploring new allylation methods that utilize only a catalytic amount of the metal in sustainable and environmentally benign ways.

mol % Pd catalyst and no additional phosphine, the reaction did not ensue (Table 4, entry 1). This was possibly due to the absence of formation of the initial Pd−allyl complex. Adding a small amount of phosphine (P/Pd ratio = 0.25) resulted in the formation of 14d in 78% yield (Table 4, entry 2). Increasing the P/Pd ratio incrementally from 0.5 to 3.0 had a deleterious effect on conversion, as reflected in the isolated yield (Table 4, entries 3−6). Unreacted starting material accounted for the remaining mass balance. To explain the inhibitory effect of the phosphine ligand, we postulated that a Pd(II)−In(I) coordinative bond is required for effective redox and allyl ligand transfer (Scheme 13). In order to formulate the bimetallic complex C, the πallylpalladium complex A must dissociate a ligand to open up a coordination site and form B. Only when the Pd complex is coordinatively unsaturated can InI bind. The phosphine concentration has a direct effect on the equilibrium of A and B. A higher concentration favors the saturated complex A and 2176


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AUTHOR INFORMATION

Corresponding Author

*Address: Department of Chemistry and Biochemistry, P.O. Box 6050, North Dakota State University, Fargo, North Dakota 58108-6050, USA. E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Dinesh Kumar received his B.Pharm. from Manipal University, India. Subsequently, he moved to the National Institute of Pharmaceutical Education and Research, Mohali (NIPER-M) and earned his M.S. (Pharm.) and a Ph.D. in medicinal chemistry under the guidance of Prof. Asit K. Chakraborti. Currently he is working as postdoctoral fellow with Prof. Gregory R. Cook at North Dakota State University (NDSU). His current research focuses on green chemistry including sustainable organoindium chemistry, catalysis including C−H functionalization, and medicinal chemistry. Sandeep R. Vemula was born in Telangana, India. He received his B.Sc. from Kakatiya Degree College, Osmania University, and his M.Sc. in chemistry from the National Institute of Technology, Warangal in 2011. After working at GVK Biosciences Pvt Ltd for a year and a half, he joined NDSU in 2013 for his graduate studies under the guidance of Prof. Gregory R. Cook. His current research interest includes the development of stereoselective indium-catalyzed allylation and palladium-catalyzed allylation reactions. Narayanaganesh Balasubramanian received his B.Sc. and M.Sc. in chemistry from St. Joseph’s College, Tamil Nadu, India. After the completion of his M.Sc., he worked in a pharmaceutical company for 3 years in the area of analytical research and development. He completed his Ph.D. at NDSU under the guidance of Prof. Gregory R. Cook. He is currently serving as research scientist and manager at The Center for Protease Research at NDSU. His current research focuses on biomolecular mass spectrometry, omics, and precision medicine. Gregory R. Cook received his undergraduate degree from Olivet College, Olivet, Michigan, and completed M.S. and Ph.D. work at Michigan State University. After spending two years as an NIH Postdoctoral Fellow in the laboratories of Prof. Barry M. Trost at Stanford University, he joined NDSU as an assistant professor in 1996 and became a full professor in 2008. Currently he is serving as chair of Department of Chemistry and Biochemistry. His research interests lie in the development of sustainable synthetic methodologies utilizing allyl organometallics for enantioselective allylation reactions and catalysis for the synthesis of bioactive molecules.

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ACKNOWLEDGMENTS G.R.C. acknowledges the contributions of all former group members for their keen insight and sincere hard work on the indium-mediated reactions. We also gratefully acknowledge the National Institutes of Health (NCRR-P20-RR15566) and the National Science Foundation (CHE-0316618, CHE-0616485, CHE-1012295) for their generous support of this research.

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REFERENCES

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