Some Items of Interest to Process R&D Chemists and Engineers

Highlights from the Literature pubs.acs.org/OPRD

Some Items of Interest to Process R&D Chemists and Engineers

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A PRACTICAL 11B NMR METHOD FOR BH3 TITER IN COMMERCIAL SOLUTIONS Degennaro and co-workers report a straightforward method for the determination of BH3 titer in commercial solutions of BH3·THF and BH3·SMe2 using 11B NMR (Synthesis 2017, 10.1055/s-0036-1588710). Borane (BH3) is a common reducing agent for a multitude of functional groups, as well as being employed for the hydroboration/oxidation of alkenes. Knowledge of the titer of commercial grade solutions of BH3 can greatly improve the reproducibility and safety of running such reactions by preventing significant over- or undercharges of solutions of unknown molarity. The method employs BF3·OEt2 as an internal standard and is accurate to the nearest 0.1 M using the pulse sequence disclosed. The authors assess the stability of commercially available solutions of BH3·THF in THF, BH3·SMe2 in THF, and BH3·SMe2 in 2-MeTHF, finding that BH3·THF is significantly less stable than the SMe2 complexes, having decomposed fully within 10 days of opening the bottle. The method should be applicable to the multiple commercial borane−amine complexes, although this is not disclosed.

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enantiopure product could be generated in 35% overall yield in a single flask without the need to switch solvents. Excess furan was removed under vacuum after Step 1, and the product was purified by chromatography, but the report outlines an alternative and potentially scalable route to this key fragment.

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IRIDIUM-CATALYZED REDUCTIVE STRECKER REACTION

ASYMMETRIC SYNTHESIS OF (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-OL Dixon and co-workers report the reductive cyanation of amides using Vaska’s complex and tetramethyldisilyloxane (TMDS) (Angew. Chem., Int. Ed. 2017, 10.1002/anie.201612367). Nitriles are valuable functional groups both for modulating biological activity as well as being synthetic handles for further modification. α-Amino nitriles, products of the Strecker reaction, are one of the simplest ways to synthesize α-amino acids. The reported reaction allows for the direct conversion of stable amides into α-amino nitriles using trimethylsilyl cyanide (TMSCN) as the nitrile source in toluene at room temperature. A wide substrate scope is explored including: electron-rich and -poor benzamides; primary, secondary, and tertiary alkyl amides; cyclic amides; and formamides. Notably, primary and secondary amides did not react, a fact the authors attribute to the lower Lewis basicity of such species. The authors applied their methodology to the formal synthesis of clopidogrel (via B) and to the late-stage functionalization of a number of natural products and commercial drugs, including zolpidem.

Optaz and co-workers report the three-step synthesis of the title compound from furan and Cbz-protected aldehyde A (J. Org. Chem. 2017, 82, 1218). The chiral furofuranol unit is a motif present in a number of HIV protease inhibitors including darunavir, which is on the WHO’s list of essential medicines. The three-step route disclosed in this paper simplifies a previous synthesis and renders the sequence amenable to be carried out in a single flask. The first step involves a photochemical [2 + 2]cycloaddition between furan and A; the authors finding that, although the reaction can be run in furan as solvent, employing MTBE as a cosolvent enabled full conversion with 5 equiv of furan. The removal of the protecting group and reduction of the alkene proceeded under typical hydrogenation conditions in MTBE with concomitant rearrangement to the racemic furofuranol. Finally, enzymatic resolution with porcine pancreatic lipase (PPL) and propionic anhydride in MTBE generated enantiopure furofuranol. Starting from 1.94 g of A, 0.455 g of © XXXX American Chemical Society

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RAPID KETONE AND ALDEHYDE HYDROBORATION

Marks and colleagues reported a La-catalyzed hydroboration of aldehydes and ketones under mild conditions (ACS Catalysis

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DOI: 10.1021/acs.oprd.7b00118 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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2017, 7, 1244). The method involved the use of 1.2 equiv of pinacolborane and tris[N,N-bis(trimethylsilyl)amide] lanthanum at low loadings. The reported conditions were used to accomplish selective hydroboration in the presence of alkene, alkyne, nitrile, nitro, and N,N-dimethyl aniline functionalities. Kinetic studies revealed that the reaction was first-order with respect to reagents and catalyst for ketone hydroboration. On the contrary, the reaction was found to be zero-order with respect to reagents and first-order in catalysts for aldehyde hydroboration. The paper quotes most yields as NMR solution yields, which are generally >99%.

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PALLADIUM-CATALYZED ALKOXYCARBONYLATION OF UNACTIVATED SECONDARY ALKYL BROMIDES UNDER LOW PRESSURE The catalytic carbonylation of organohalides is a fundamental transformation of organometallic catalysis, most notably demonstrated by the Monsanto−Cativa acetic acid synthesis. However, there are few reported efficient catalytic carbonylations of unactivated alkyl halides. Alexanian and his co-worker at the University of North Carolina at Chapel Hill described a palladium-catalyzed transformation of an unactivated alkyl bromide into a diverse range of esters under a low pressure of carbon monoxide (J. Am. Chem. Soc. 2016, 138, 7520). The highest yields were obtained with 5 mol % Pd(PPh3)2Cl2 and 10 mol % of the N-heterocyclic carbene (NHC) ligand N,N′-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene (IMes) as the source of palladium and ligand, respectively. No reaction was observed in the absence of either the palladium catalyst or the strongly electron-donating NHC ligand. The utilization of the low pressure of CO (2 atm) was more effective than 1 atm (balloon). A range of secondary alkyl bromides, which included aromatic and heterocyclic substrates, were carbonylated in good yields. The reaction was tolerant of a variety of functional groups, including halide, ether, silyl ether, ester, and amide. Two equivalents of an alcohol were sufficient to generate a series of esters. This transformation is the first example of a catalytic carbonylation of an unactivated alkyl bromide with low pressure CO.

DEEP EUTECTIC SOLVENT SYSTEMS FOR THE SYNTHESIS OF POLY(3-ALKYLTHIOPHENE)

Lee and colleagues achieved the synthesis of poly(3-alkylthiophene) using deep eutectic solvents (DES) and ferric chloride catalyst (Green Chemistry 2017, 19, 910). DESs were obtained by heating an ammonium salt and a suitable hydrogen bond donor up to 100 °C followed by cooling. The polymerization rates in choline chloride−urea and choline chloride−thiourea−urea DESs were compared to those in chloroform and ionic liquids, and higher yields were obtained with the DES systems. Linear solvation energy relationships were explored in an attempt to identify approaches for improving solvent performance.

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Highlights from the Literature

VISIBLE-LIGHT MEDIATED ANTI-MARKOVNIKOV HYDRATION OF OLEFINS

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PALLADIUM-CATALYZED NEGISHI CROSS-COUPLING REACTION OF ARYL HALIDES WITH (DIFLUOROMETHYL)ZINC REAGENT Recently, interest in aromatic compounds bearing a difluoromethyl (−CF2H) group, which can be regarded as a bioisostere of alcohols and thiols, has grown in the pharmaceutical and agrochemical industries. The catalytic difluoromethylation of aryl halides with difluoromethyl reagents is conspicuously limited. Mikami and co-workers at the Tokyo Institute of Technology reported the palladium-catalyzed Negishi cross-coupling reaction of aryl halides with a (difluoromethyl)zinc reagent (Org. Lett. 2016, 18, 3690). The (difluoromethyl)zinc reagent was prepared by a reaction of commercially available diethyl zinc with difluoroiodomethane, followed by addition of an amine ligand. Diamine ligands, such as TMEDA, were found to thermally stabilize these zinc reagents. The Negishi cross-coupling was performed with Pd(dba)2 and DPPF as the catalyst and ligand, respectively. The cross-coupling was performed successfully with a range of aryl iodides and bromides. Good-to-excellent yields were obtained with both electron-withdrawing and electrondonating substituents on the aryl substrate. This practical and efficient methodology should find wide applicability for the introduction of this important functional group.

Lei and colleagues reported a catalytic method to achieve olefin hydration with anti-Markovnikov selectivity (ACS Catalysis 2017, 7, 1432). The method featured 9-mesityl-10-methylacridinium perchlorate as the photocatalyst and 1,2-diphenyldisulfide as a hydrogen transfer catalyst. A combination of kinetic studies using in situ FTIR spectroscopy and isotope labeling studies were utilized to propose a mechanism that involves single electron transfer from the olefin substrate to the excited triplet state of the photocatalyst followed by trapping of the radical cation intermediate by water. B




suggested that the reaction proceeded through an in situ generated phosphinimine. This synthetic transformation was extended to the production of polysubstituted isoquinolines by utilizing the corresponding alkynyl-substituted benzylazides as the starting materials.

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COPPER-MEDIATED C−N COUPLING OF ARYLSILANES WITH NITROGEN NUCLEOPHILES Pharmaceuticals, agrochemicals, and natural products often contain arylamine units or derivatives of arylamines. Organosilanes are attractive alternatives to arylboronates as coupling partners. The catalytic silylation of aryl C−H bonds forms arylsilanes with regioselectivities that are higher than, and in some cases distinct from those of C−H borylation. Hartwig and co-workers at the University of California, Berkeley reported the amination of heptamethyltrisilyloxyarenes (HMTS-arenes) facilitated by copper(II) acetate (Org. Lett. 2016, 18, 5244). Arylsilanes are inexpensive, nontoxic, and more stable than their arylboronate analogues. The highest yield of the amination reaction occurred with three equivalents of copper(II) acetate, a 2-fold excess of the amine and sodium carbonate as the base. A variety of primary and secondary amines were coupled in good yield. Both electron-rich and electron-poor HTMS-arenes participated in the amination reaction; electron-rich substrates required the addition of a fluoride source to generate the product in acceptable yields. This methodology afforded direct access to many compounds that cannot be accessed via alternative C−H functionalization methods, including direct C−H amination or the combination of C−H borylation and amination.

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DIVERSE ortho-C(sp2)−H FUNCTIONALIZATION OF BENZALDEHYDES USING TRANSIENT DIRECTING GROUPS

Benzaldehydes are highly desirable substrates for directed C(sp2)−H functionalization due to their abundance and synthetic versatility. The development of such methodology is hampered by the aldehyde’s weak coordinating ability and susceptibility toward oxidation. Zhang and co-workers from Wuhan University of Technology, The Scripps Research Institute, and Bristol-Myers Squibb detailed a diverse set of ortho-C(sp2)−H functionalizations of benzaldehyde substrates utilizing a transient directing group (TDG) strategy (J. Am. Chem. Soc. 2017, 139, 888). The key to this technology was the in situ formation of a substituted imine that could direct the palladium catalyzed coupling to the adjacent position on the benzaldehyde ring. Substoichiometric quantities of the quaternary amino acid, 2-aminoisobutyric acid, afforded the highest yields in palladium catalyzed Suzuki−Miyaura ortho-arylations. Anthranilic acid was the preferred TDG for the ortho-halogenation with N-chlorosuccinimide. Optimized reaction conditions and TDGs were also developed for bromination with N-bromosuccinimide and amidation with tosyl azide. The reaction conditions tolerated a range of functional groups on the benzaldehyde substrate, including: ester, halo, and nitro. The transient directing group overrode the directing effects of a range of functional groups present in the aldehyde substrates. The utility of this methodology was further demonstrated by the late-stage functionalization of a drug analogue.

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PALLADIUM-CATALYZED SYNTHESIS OF INDOLES AND ISOQUINOLINES WITH IN SITU GENERATED PHOSPHINIMINE The indole ring system represents a key heterocyclic motif that occurs ubiquitously in biologically active natural products, as well as numerous therapeutic agents and in material science applications. Transition-metal-catalyzed carbene transfer reactions constitute one of the major domains of modern synthetic organic chemistry. Wang and co-workers at Peking University and the Chinese Academy of Sciences extended their work on carbene-based coupling reactions to the palladium-catalyzed, carbene-based coupling reaction to generate polysubstituted indoles in good yields (J. Org. Chem. 2017, 82, 48). The starting materials, alkynyl-substituted arylazides, are readily available. Extensive experimentation identified optimized reaction conditions for the cyclization/coupling. The preferred source of palladium was Pd2(dba)3, and the preferred ligand was 1,5bis(diphenylphosphino)pentane (dppe). Various functional groups, including acetal, ester, ether, halide, and nitrile were compatible with the reaction conditions. Control experiments C



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COPPER-MEDIATED DOMINO CYCLIZATION/TRIFLUOROMETHYLATION/ DEPROTECTION WITH TMSCF3: SYNTHESIS OF 4-(TRIFLUOROMETHYL)PYRAZOLES Trifluoromethylated heterocycles are a class of fluorinated molecules with substantial applications in pharmaceuticals and agrochemicals. In particular, trifluoromethylated pyrazoles are important structural motifs in biologically active compounds. Despite their importance, synthetic methodology for the production of 4-(trifluoromethyl)pyrazoles is severely limited. Tsui and co-workers from The Chinese University of Hong Kong described the one step synthesis of 4-(trifluoromethyl)pyrazoles from α,β-alkynic hydrazones (Org. Lett. 2017, 19, 658). The reaction is projected to proceed via an initial 5-endo-dig cyclization facilitated by copper, followed by trifluoromethylation and finally deprotection of the N-tosyl group. An inert atmosphere is not required for the reaction. The nucleophilic Ruppert−Prakash reagent, TMSCF3, was utilized as the source of the trifluoromethyl substituent. Extensive experimentation revealed that copper(II) triflate was the preferred source of copper for this reaction. DMF was the preferred reaction solvent; no reaction was observed in less polar solvents such as THF, CH2Cl2, and toluene. An N-tosyl group afforded the cleanest reaction profile, although other electron-withdrawing groups were also successful. A wide range of novel 4-(trifluoromethyl)pyrazoles were synthesized; uniformly high yields were obtained with electronwithdrawing or electron-donating groups on the aromatic substituents. Lower yields were obtained with alkyl substituted α,β-alkynic hydrazones. The mild reaction conditions and readily available raw materials translate into a very practical synthetic procedure to produce this important class of heterocycles.

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The application of visible-light photoredox catalysis (VLPC) to the direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron-deficient aryl and heteroaryl cyanides was reported recently (Vega, J. A., et al. Org. Lett. 2017, 19, 938). As shown in the graphic, structurally complex α,α′-diaryl-N,Ncycloalkylhydrazones could be obtained in moderate yields by sequential VLPC treatment (5 examples) in a flow manner. The paper has 22 examples of single VLPC products.

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VISIBLE-LIGHT DRIVEN PHOTOCASCADE CATALYSIS IN FLOW TOWARD THE UNION OF N,N-DIMETHYLANILINES AND α-AZIDOCHALCONES

The continuous flow coupling of N,N-dimethylanilines and α-azidochalcones under the visible-light photocascade catalysis driven by Ru(bpy)3(PF6)2 catalyst was successfully developed (Gokulnath, S., et al. J. Org. Chem. 2017, 82, 2249). As shown in the graphic, dual photocatalysis by white LED resulted in two sp3 C−H bond functionalizations of N,N-dimethylanilines leading to the creation of one C−C and two C−N new bonds. In addition, the versatility of this methodology was demonstrated by the synthesis of 20 different 1,3-diazabicyclo[3.1.0]hexanes in good yields (55−71%).

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FLOW SYNTHESIS OF CYCLIC α-DIAZO-β-KETO SULFOXIDES Stable isolable α-diazo-β-keto sulfoxides were first synthesized from diazo transfer to β-keto sulfoxides (Maguire, A. R., et al. J. Org. Chem. 2017, 10.1021/acs.joc.7b00172), such as monocyclic and benzofused ketone derived β-keto sulfoxides. Compared with to standard batch conditions, enhanced yields of the desired compounds with short reaction times, an increased safety profile, and the potential to scale up could be realized by

CONTINUOUS FLOW α-ARYLATION OF N,N-DIALKYLHYDRAZONES UNDER VISIBLE-LIGHT PHOTOREDOX CATALYSIS

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using a continuous flow process. The paper concludes with 5 examples comparing flow and batch yields.

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groups instead of the phenyl groups at the 4- and 5-positions of the ligand’s imidazole fragment, furnished the product in significantly higher enantioselectivity. Under an optimized protocol, substituted phenylacetylenes add in high enantioselectivity to benzylidene Meldrum’s acid itself under these conditions; ee’s are typically ≥90%. Remarkably, several alkyl-substituted terminal alkynes may be used with similar selectivities. In addition, other aryl-substituted methylidene Meldrum’s acids may be used and still lead to highly enantioselective reactions, although isolated yields suffer somewhat. The authors note that, for substrates with negligible water solubility, toluene may be used as a cosolvent, giving rise to a “homogenous” biphasic liquid−liquid mixture.

CONTINUOUS ASYMMETRIC ROBINSON ANNULATIONS WITH A POLYMER-SUPPORTED CATALYST

It is known that the Robinson annulation of enantiopure building blocks (such as the Wieland−Miescher (W−M) and Hajos− Parrish (H−P) ketones) was challenging because of the need for high catalyst loading or extremely long reaction times. A fast and broad-scope enantioselective Robinson annulation reaction was reported by using a heterogenized organocatalyst based on Luo’s diamine (Pericàs, M. A., et al. ACS Catal. 2017, 7, 1383), giving a wide range of chiral bicyclic enones under mild conditions within 60 min (batch process). As shown in the graphic, the polystyrenesupported diamine catalyst in a fixed-bed reactor also afforded an up to 24 h continuous flow experiment with a residence times of 10 min, giving desired products in high-yield (up to 90%) and high enantioselectivity (up to 93% ee). The paper reports 14 examples. There are several advantages for this type of supported catalyst system: (1) a notable increase in catalytic activity compared with its homogeneous counterpart; (2) unprecedented examples where some previously reported cases gave poor or no enantioselectivity; (3) the heterogenized catalyst was demonstrated to be reusable (10 cycles) in batch and thus applicable to the flow process. The potential of the flow process was then illustrated by the large-scale preparation of the Wieland− Miescher ketone (65 mmol in 24 h of operation, TON of 117) and by a sequential flow experiment leading to a library of eight enantioenriched diketone compounds. Moreover, a straightforward formal synthesis of the antibiotic and antifeedant sesquiterpene (−)-isovelleral was also developed by using one enantiopure product as the starting material.

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HYDROGEN-BORROWING CATALYSIS WITH SECONDARY ALCOHOLS: A NEW ROUTE FOR THE GENERATION OF β-BRANCHED CARBONYL COMPOUNDS Donohoe and co-workers have used a borrowing hydrogen approach (sometimes referred to as hydrogen autotransfer or dehydrogenative coupling) to couple substituted acetophenones with secondary aliphatic alcohols, whereas most prior reports only deal with primary alcohols (J. Am. Chem. Soc. 2017, 139, 2577). By using a pentamethylphenyl ketone as the nucleophile, the authors suppress reduction of this carbonyl group, a potentially deleterious competing reaction, and thus avoid oligomerization of this cosubstrate. As an added benefit of using this class of aryl ketone, carboxylic acid bromides may be obtained upon

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ENANTIOSELECTIVE ALKYNE CONJUGATE ADDITION ENABLED BY READILY TUNED ATROPISOMERIC P,N-LIGANDS Mishra et al. have reported a new, enantioselective β-alkynylation reaction of benzylidene-substituted Meldrum’s acid derivatives (J. Am. Chem. Soc. 2017, 139, 3352). The reaction is catalyzed by Cu(I), and the optimal ligand identified proved to be a new derivative of the research group’s recently introduced StackPhos biaryl ligand architecture. Although StackPhos itself performed admirably in the alkynylation of (4-methoxybenzylidene) Meldrum’s acid (phenylacetylene as the nucleophile), ultimately they found that Me-StackPhos, with two methyl E




anti-Markovnikov hydroamination of variously substituted alkenes (Science 2017, 355, 727). The chemistry addresses the longstanding problem of alkene hydroamination, a process which is virtually thermoneutral at best and is often accomplished by indirect means or the use of amine surrogates. The new reaction’s design entails the use of an Ir-based photocatalyst that would undergo photoexcitation, leading to single-electron oxidation of an amine substrate. The aminium radical cation so produced undergoes anti-Markovnikov addition to an alkene cosubstrate, generating a C−N bond, a protonated trialkyl ammonium ion, and a carbon-centered radical. This reactive new intermediate then abstracts hydrogen from a thiol additive, and the resulting thiyl radical undergoes single-electron reduction by the reduced form of the Ir photocalalyst. Finally, the thiolate generated quenches the ammonium cation, leading to product formation and regeneration of the thiol cocatalyst. In practice, the chemistry works well: a number of cyclic and some acyclic secondary amines proved to be competent substrates for the reaction, and an even broader range of alkenesincluding monosubstituted, 1,1- and 1,2-disubstitued, trisubstituted, tetrasubstitued, silyl enol ethers, and enamidescould be aminated. Finally, the authors also demonstrated the utility of this chemistry for intramolecular cyclizations and discuss some mechanistic details.

treatment of the reaction products with Br2 via a retro-Friedel− Crafts reaction, permitting excellent substrate diversification through amide or ester formation. The catalyst of choice is [Cp*IrCl2]2, while sodium or potassium tert-butoxide are optimal bases. Acyclic and cyclic secondary alcohols are viable cosubstrates, and even a few intramolecular dehydrogenative couplings are presented.

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ASYMMETRIC Cu-CATALYZED INTERMOLECULAR TRIFLUOROMETHYLARYLATION OF STYRENES: ENANTIOSELECTIVE ARYLATION OF BENZYLIC RADICALS Liu and his associates have reported an enantioselective alkene difunctionalization reaction that relies on scalemic Cu(II) bis(oxazoline) complexes for both homolytic fragmentation of a Togni reagent (the source of trifluoromethyl radical in this reaction design) as well as control of asymmetry in the trapping of a benzylic radical (J. Am. Chem. Soc. 2017, 139, 2904 ). The use of substituted styrenes as substrates directs the regiochemical

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CATALYTIC INTERMOLECULAR HYDROAMINATIONS OF UNACTIVATED OLEFINS WITH SECONDARY ALKYL AMINES Chemists from Princeton University and Bristol-Myers Squibb led by Knowles have published a photocatalytic method for

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With this change, as well as the use of a 1:1 THF:DMSO solvent system, the authors were able to extend their enantioselective three-component coupling reaction to (hetero)aryl halide electrophiles and commercially available vinyl Grignard reagents. The substrate scope is broad, and the functional group compatibility is impressive and is based on the fast and irreversible ate formation.

addition of trifluoromethyl radical to the unsubstituted terminus of the alkene and radical generation at the benzylic position. The donor aryl group derives from an aryl boronic cosubstrate, usually used in excess, and is installed by reductive elimination from a transient Cu(III) species, itself derived from enantioselective radical−Cu(II) recombination. The studies encompass simple substituted styrenes, higher polycyclic homologues, and some heterocyclic substrates (e.g., substituted quinolines). In addition, the use of numerous boronic acids was demonstrated. The functional group compatibility is good, with the following groups were tolerated: halides, ethers, esters, nitriles, nitro, acetal, and others.

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PHOTOREDOX DUAL CATALYSIS FOR DIRECT C(sp3)−H CROSS-COUPLING WITH ARYL HALIDES

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PALLADIUM-CATALYZED CONJUNCTIVE CROSS-COUPLING BETWEEN GRIGNARD-DERIVED BORON “ATE” COMPLEXES AND C(sp2) HALIDES OR TRIFLATES: NaOTf AS A GRIGNARD ACTIVATOR AND HALIDE SCAVENGER The Morken group has published a full account (J. Am. Chem. Soc. 2017, 139, 3153) of their previously disclosed methodology (Science 2016, 351, 70) on the three-component coupling of organometallic nucleophiles, alkyl or aryl boronates, and C(sp2)electrophiles under Pd(0) catalysis. Although the prior report laid out the conceptual groundwork for this methodology as well as a preliminary substrate scope, opportunities remained to expand the breadth of the organometallic coupling partner and aryl electrophiles. The authors began their new investigations by studying the role of halide ions independent of the coupling reaction and focused first on the role of “ate” formation using vinylmagnesium bromide as an archetypal organometallic nucleophile. Using 11B NMR spectroscopy, they determined that ate complex formation was largely incomplete in the presence of halide ions. However, the outright failure of the three-component cross-coupling reaction despite the presence of even 20 mol % of ate complex implicated additional deleterious effects of halides on the reaction. Additional control studies centering on reaction poisoning by exogenous or endogenous halide supported this hypothesis: while ee’s remained high, the yields observed were diminished drastically by halides. To overcome this issue, the group identified NaOTf and KOTf as excellent halide scavengers applicable to both the ate formation and the cross coupling overall (the solubility of lithium halide salts preclude the use of LiOTf).

The application of free radical reactions in organic synthesis is one of the areas that are under-explored because of high reactivity and often uncontrollable nature of the radical species. Recently, reactions involving radicals such as nickel-catalyzed alkyl crosscoupling have attracted much attention from the chemistry community. Doyle and her co-worker of Princeton University reported a C(sp3)−H cross-coupling reaction under nickel and photoredox catalysis conditions (J. Am. Chem. Soc. 2016, 138, 12719). A reaction of aryl chlorides with ethers in the presence of photocatalyst (Ir(dFCF3ppy)2(dtbbpy)PF6) and cross-coupling catalyst (Ni(cod)2) with irradiation of blue LED at room temperature produced the corresponding arylated ethers. A chlorine radical, formed from irradiation of LnNiIII(Ar)Cl (generated from LnNiII(Ar)Cl via a SET process with *IrIII, abstracts an α-C(sp3)−H of the ether. The resulting carboncentered radical reacts with LnNiII(Ar) to form LnNiIII(Ar) (alkyl) complex whose reductive elimination provides the products in good yields (the paper has over 15 examples).

In the same issue, a report (J. Am. Chem. Soc. 2016, 138, 12715) by Molander and co-workers of University of Pennsylvania described a similar C(sp3)−H arylation reaction system. Instead of aryl chlorides, the Molander group utilized aryl bromides as the bromine radical source. The researchers hypothesized that the reaction proceeds via intermediates G




[LnNiII(Ar)Br]* (formed from energy transfer process between LnNiII(Ar)Br and [IrIII]*) and LnNiIII(Ar)alkyl, and the reductive elimination of the latter affords the C(sp3)-H cross-coupling products.

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epimerization of the trans-product to the more stable cis-product via enolization. The paper has over 25 examples.

ALKYLATION OF ARYL HALIDES WITH 4-ALKYL-1,4-DIHYDROPYRIDINES These radical cyclization cascades were extended to other radicals, generated under photoredox catalysis conditions.

■ The nickel-catalyzed cross-coupling reaction under mild photoredox catalysis conditions has attracted great attention. Recently, Nishibayashi and co-workers of the University of Tokyo, Japan disclosed a nicked- and photoredox-catalyzed cross-coupling reaction of aryl halides with 4-alkyl-1,4-dihydropyridines (Angew. Chem., Int. Ed. 2016, 55, 14106). Oxidation of 4-alkyl-1,4-dihydropyridines under photoredox catalysis conditions generates alkyl radicals via C−C bond cleavage of the resulting cation radicals. The addition of the alkyl radicals to a nickel(0) complex gives the corresponding nickel(I)−alkyl complex (A). The subsequent oxidative addition of the nickel(I)−alkyl complex to aryl halides would afford the key intermediate Ni(III) complex (B). Studies show that the reaction tolerates a broad range of functional groups in the aryl iodides including methoxy, chlorine, amino, hydroxy, and so forth. Compared with aryl iodides, reactions of less reactive aryl chlorides gave lower product yields.

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IRIDIUM-CATALYZED SYNTHESIS OF 3-AMINOPYRIDINES

Pyridine derivatives are useful organic intermediates that are ubiquitous in organic synthesis. Searching for efficient and sustainable synthetic methods to access such pyridine derivatives has been an appealing research area. Kempe and co-workers of University of Bayreuth, Germany developed an iridium-catalyzed synthesis of 3-aminopyridines (Angew. Chem., Int. Ed. 2017, 56, 371). The German scientists utilized a reaction of β-amino alcohols with γ-amino alcohols in the presence of iridium catalyst stabilized by pincer ligand to furnish 3-aminopyridine products in good yields. The β-amino alcohols could be prepared from 1,2-diols via an iridium-catalyzed borrowing hydrogen (BH) and hydrogen autotransfer (HA) processes. It should be, however, noted that the reaction was carried out at 130 °C and generated three molar equivalent hydrogen byproduct, which is a potential operational challenge when scaling up.

BASE-CATALYZED RADICAL CYCLIZATION CASCADES

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Recently, free radical reaction attracts increasing interest in the synthetic organic chemistry community, lending itself to applications toward the synthesis of complicated organic compounds. A base-catalyzed radical cascade reaction was disclosed by Liu et al. (Org. Lett. 2016, 18, 5284) for the access of fused ring systems. The treatment of a mixture of ketones with tethered alkynyl group and Togni’s reagent with catalytic amounts of organic base in acetonitrile at 80 °C afforded the desired tricyclic products in good yields and diastereoselectivity. The reaction was proposed to proceed through three key radical species: A, B, and C. The σ-type vinyl radical A, formed from the addition of trifluoromethyl radical to alkynyl group, undergoes 1,5-H atom migration to afford a relatively stable radical B. Subsequently, a radical 5-exo-trig cyclization of the radical B takes place to provide a radical C, which sets the stage for the final radical cyclization. The high diastereoselectivity (dr >20:1) is presumably due to the

BRøNSTED ACID-CATALYZED, ENANTIOSELECTIVE AZA-DIELS−ALDER REACTION FOR THE DIRECT SYNTHESIS OF CHIRAL PIPERIDONES Piperidones are versatile synthetic intermediates often used for the elaboration of chiral piperidines. Schneider and co-workers from Leipzig in Germany discovered that the aza-Diels−Alder reaction of imines was feasible providing that the dienolate is substituted with a β-alkyl group (Chem. Eur. J. 2017, 23, 513). Building on their previous work on the vinylogous Mukaiyama− Mannich reaction, the authors screened chiral BINOL-based 3,3′-substituted phosphoric acids to favor the cycloaddition process versus the production of the linear adduct. A ternary mixture of solvent in combination with chiral Brønsted acid catalyst (see scheme above) was found to promote the three-component reaction of (hetero)aromatic aldehydes, para-methoxyphenyl H



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IRIDIUM-CATALYZED RADICAL CONJUGATE ADDITION OF NITROGEN HETEROCYCLES

Approaches toward the selective alkylation of nitrogen heterocycles encompass a large number of metal-catalyzed processes such as the Minisci reaction and the cross-coupling of halogenated heteroarenes with alkyl metals or halides. Jui and co-workers from Atlanta have recently described a complementary photoredox-catalyzed methodology that allows the reductive Meerwein arylation of electron deficient alkenes (Chem. Sci. 2017, 10.1039/C7SC00243B). The heteroaromatic radical is regiospecifically generated by a photoinduced electron transfer using an iridium catalyst in conjunction with irradiation with a blue LED. The radical is allowed to react with Michael acceptor to afford the corresponding alkylated adduct after reduction with the Hantzsch ester. Worthy of note is the importance of the solvent composition on the outcome of the reaction. Indeed, upon increasing the amount of water as cosolvent, the solubility of the reducing agent decreases, favoring the reductive radical addition over direct dehalogenation. The scope of the reaction is large with bromo- and iodo-pyridines, pyrimidines, and pyrazines being competent radical precursors and a handful of common functional groups including free OH and NH moiety being well-tolerated.

aniline, and various dienolates leading to the chiral piperidones in moderate-to-high yields and good-to-perfect enantioselectivities. A few examples of the conversion of the products to 2,4,6- and 3,4,6-trisubstituted piperidines by subsequent fully diastereoselective transformations are also provided.

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BORINIC ACID CATALYZED REDUCTION OF TERTIARY AMIDES WITH HYDROSILANES

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COPPER-CATALYZED ENANTIOSELECTIVE ALKYLATION OF ENOLIZABLE KETIMINES WITH ORGANOMAGNESIUM REAGENTS

During the past decade, the organo-catalytic reduction of amides has witnessed significant progresses with boron derivatives being prominent but requiring forcing conditions. Blanchet and co-workers from Caen in France have recently described the borinic acid catalyzed reduction of tertiary amides with hydrosilanes (Chem. Eur. J. 2017, 23, 2005). The reaction takes place under quite mild conditions (20−45 °C) neat or in toluene with phenylsilane as a reductant. While the structure of the borinic acid (see scheme above) has a profound impact on the outcome of the reaction, nonanhydrous conditions are tolerated providing the reaction is performed under an inert atmosphere. The chemoselectivity under the optimized conditions is impressive with nitro, alkenes, and alkynes (even conjugated with the amide to be reduced) being well-tolerated. From a mechanistic point of view, the authors to propose a slightly different pathway than the one currently accepted for the related BARf mediated silane reduction in which an amine borane complex is involved. I




Asymmetric addition to imines provides a direct access to valuable enantiomerically enriched α-chiral amines. While a number of methods have been disclosed for the addition to aldimines, the low reactivity of the azomethine carbon of ketimines have thus far prevented the development of efficient protocol for ketone derived imines. Harutyunyan and co-workers from Groningen in The Netherlands have reported the copper-catalyzed enantioselective addition of Grignard reagents on enolizable N-sulfonyl ketimines (Angew. Chem., Int. Ed. 2017, 56, 3041). Keys to the success of the reaction are the nature and steric bulk of the sulfonyl group of the ketimine. Use of the bulky tert-butylsulfonyl group in combination with a Josiphos derived ligand for copper (see structure above) in a mixture of methyl-tert-butyl ether and diethyl ether affords the addition product in uniformly high yields and enantioselectivities. The scope of the reaction is limited to non α-branched imines with a π-system, but electrophilic functional groups such as esters or nitriles are tolerated.

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James A. Schwindeman Rohner Inc., 4066 Belle Meade Circle, Belmont, North Carolina 28012, United States

David S. B. Daniels Chemical Research & Development, Pfizer, Sandwich, Kent CT13 9ND, U.K.

Carlos Guerrero Chemical and Synthetic Development, Bristol Myers Squibb, New Brunswick, New Jersey 08903, United States

Robert Kargbo Department of Process Chemistry, AMRI, 26 Corporate Circle, Albany, New York 12212, United States

Arjun Raghuraman Polyurethane Process R&D, The Dow Chemical Co., Freeport, Texas 77541, United States

John Knight*

TRIFLUOROMETHYL-RADICAL-INDUCED THREE-COMPONENT COUPLING OF BORONIC ESTERS WITH FURANS

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JKonsult Ltd., Meadow View, Cross Keys, Hereford, HR1 3NT, U.K.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

AUTHOR STATUS E-mail: [email protected]; [email protected]; sg@ novalix-pharma.com; [email protected]; david.daniels@pfizer.com; [email protected]; robert. [email protected]; [email protected].

Pursuing its work on transition metal-free cross-coupling reaction of boronic esters, Aggarwal’s group from Bristol has recently described the three-component coupling of furans with boronic esters induced by trifluoromethyl radicals (Angew. Chem., Int. Ed. 2017, 56, 1810). The key finding was that Umemoto’s reagent was capable of triggering the 1,2-metalate rearrangement of the boronate complex formed by lithio furan addition on a boronic ester when the reaction was performed in an acetonitrile/ methanol mixture. A screening of reagents allowed the authors to identify a combination of iodine and potassium carbonate to eliminate the boronic ester and generate the furan product. Under the developed conditions, a number of 2-trifluoromethylfurans can be synthesized in moderate-to-good yields. Worthy of note are that the reaction is highly diastereo- and enantioselective and is not limited to furan, with both thiophene and N-Boc pyrroles being tolerated as nucleophilic partners. Electron paramagnetic resonance was used to shed light on the mechanism and demonstrated the involvement of trifluoromethyl radicals.

Wenyi Zhao Jacobus Pharmaceutical Co. Inc., Princeton, New Jersey 08540, United States

Dongbo Zhao ChulanST Wuhan Co. Limited, 3-4-5 Wanghiadun, Xudong Avenue, Wuchang District Wuhan 430063, Hubei Province, P. R. China

Sylvain Guizzetti NovAlix, Building A: Chemistry, Bioparc, Bld Sébastien Brant BP 30170, 430063 Illkirch Cedex, France J


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