Sames and coworkers have reported a Lewis-acid catalyzed [1,5] H-shift followed by C-C bond formation via reactive alkenyl oxocarbenium intermediates. Sames and coworkers have previously reported that expensive transition metal Lewis acids promoted cylizations of alpha,beta-unsaturated aldehydes and ketones, but were hampered with low yields and slow reaction times. The preparation of the corresponding acetals and ketals led to an improvement in the yield, reactivity and diastereoselectivity.  Thus, using the standard conditions of BF₃·Et₂O in CH₂Cl₂ at room temperature, a variety of tetrahydropyrans can be prepared, including those from more hindered and complex precursors. Finally, it was demonstrated that the acetals and ketals could be formed catalytically in situ when OHCH₂CH₂OH is added to the reaction mixture and that this method effects an increase in the rate (and in some cases, an increase in yield and diastereoselectivity) of the reaction, while also obviating the need for preparation of these precursors, and resulting in a binary catalytic system composed of BF₃·Et₂O as the catalyst and OHCH₂CH₂OH as the organocatalyst.

McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. ASAP.

Written by: Dr. Sharbil J. Firsan

A mild, regioselective protocol for the C–H functionalization of heteroarenes has been reported by Lu and Falck.  This method, which is a marked improvement over existing ones for the direct silylation of heteroarenes, employs [{Ir(OMe)(cod)}₂] as catalyst, Et₃SiH as the inexpensive silylating reagent, and 4,4-di-tert-butyl-2,2-bipyridine as ligand.  Some of the attractive features of this process are:

• Moderate-to-high yields and high regioselectivities are observed.
• Only a small excess (3 equiv) of the silylating reagent is needed.
• Protection of the NH group in indoles is not required.
• Electron-donating and electron-withdrawing substituents in the heteroarene are tolerated.
• 2-Norbornene is used as a promoter and is believed to function as a hydrogen sink for the hydrogen produced in the reaction.

(1) Lu, B.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 7508.

Lectka and coworkers have recently disclosed a catalytic, asymmetric alpha-fluorination of acid chlorides using NFSi (N-Fluorobenzenesulfonimide) as the source of electrophilic fluorine upon formation of the ketene enolate in the presence of benzoylquinidine (BQd-10 mol %), Hunig?s base, and (1,3-dppp)NiCl₂ or trans-(PPh₃)₂PdCl₂ (3 mol %). Upon quenching (a variety of nucleophiles can be employed, such as water, alcohols, amines, and thiols), the product is released in excellent yield and enantiopurity. Initial attempted development of the reaction was impeded by low yields; the addition of a metal co-catalyst resulted in higher yields. The mechanism proposed is based on previous work by Lectka and coworkers and relies on the formation of a key metal-bound zwitterionic ketene enolate species, which is followed by reaction with NFSi, and transacylation to form the observed products.

Paull, D.H.; Scerba, M.T.; Alden-Danforth, E.; Widger, L. R. Lectka, T. J. Am. Chem. Soc. ASAP.

Aldrich, a division of Sigma-Aldrich (Nasdaq: SIAL), has released its new "materials by application" Materials Science catalog. The catalog features more than 4,000 products for research in Alternative Energy, Organic Electronics, Metal & Ceramic Science, Nanomaterials, Micro/NanoElectronics and Polymer Science. Each chapter contains technical information and highlights from some of the latest advances in these fields.

"This catalog serves as a materials supply source as well as a tool to assist materials researchers working in the leading areas of modern materials research such as sustainable energy, bio- and soft-materials and electronics and photonics," said Dr. Shashi Jasty, initiative lead for Materials Science at Sigma-Aldrich.

"The structuring of the Aldrich Materials Science catalog is geared toward science and solutions to problems not just traditional materials," said Professor Joachim O. Radler with the Center of NanoScience and Department of Physics at Ludwig-Maximilians University, Munich, Germany. "That's what makes this catalog so valuable."

The printed catalog is a complement to Aldrich's online product catalog, which provides quick access to an easy-to-browse compilation of advanced materials.To request a complimentary copy of the Aldrich Materials Science catalog, please visit http://www.sigma-aldrich.com/mscat or send an email to matsci@sial.com.

Written By: Mark Redlich, Ph.D.

The first total synthesis of the fungal metabolite (+)-wasabidienone B₁ was achieved in 10 steps and 5% overall yield from 1,2,3-trimethoxybenzene.  The key step was an ortho-selective hydroxylative phenol dearomatization (HPD) mediated by stabilized IBX (SIBX), which proceeded cleanly to provide 1:1 diastereomeric mixtures of the target compound and the unnatural (–)-6-epi-wasabidienone B₁.  The target product could be further converted to its congener (–)-wasabidienone B₀ via a thermally induced ring-contracting isomerization in 52% yield.

Pouységu, L. et al. Org. Lett. 2008, 10, 5211.

Written by: Dr. Sharbil J. Firsan

The first catalytic, highly enantioselective synthesis of chiral N-benzoyl hemiaminals has recently been reported by Antilla and co-workers.  Their approach utilizes the direct addition of alcohols to imines derived from aromatic aldehydes, which is facilitated by a BINOL-derived, chiral phosphoric acid organocatalyst.  Some of the attractive features of this method include:

• Good-to-high yields and enantioselectivities
• Mild reaction conditions
• Wide alcohol scope: primary, secondary, tertiary, and cyclic secondary
• A range of substituents in the aryl portion of the imine are tolerated
• Double and triple bonds in the alcohol substrate are compatible with the reaction conditions

(1) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216.  (2) For a very recent review on the use of chiral phosphoric acid organocatalysts in asymmetric synthesis, see Adair, G.; Mukherjee, S.; List, B. Aldrichimica Acta 2008, 41, 31

We would like to invite our readers to become guest bloggers on Chemblogs.

Since Chemblogs inception two years ago, we have watched our community grow and would like to offer you the opportunity to share with us what you find noteworthy in chemistry. 

If you would like to write a blog about your current research or another topic in chemistry that interests you, please feel free to email your blog post to chemblogs@sial.com or Dawn.Redington@sial.com

 Written  by William Sommer, Ph D.

 The Grignard reaction has been around for almost one hundred years and proved to be a powerful tool for the addition of alkyl groups to another molecule. Studte et al, found a clever way to use Grignard reagents for sp³-sp³ coupling. Starting with various á-hydroxy ester triflates, the authors demonstrated enantiocontrol of the Grignard reagent addition using ZnCl₂ as catalyst. The versatility of the method was demonstrated with the reaction of various á-hydroxy ester triflates with various Grignard reagents including secondary acyclic, secondary cyclic, and functionalized reagents. This reaction showed great tolerance in the variation of either reactants with good yields and selectivities. This new reaction offers an alternative to enolate alkylation.

Studte, C.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 5451.

For those who missed the opportunity in October, due to strong interest the Sigma Aldrich Chemical Synthesis "Did You Know Challenge" will continue through the end of the year with one winner a week being select.  Enter for the chance to win a $250 Aldrich Voucher towards the purchase of Aldrich chemicals, books or labware or a $250 Apple Gift Card. For the people who have already registered your name will continue to be included in the contest.

Sawamura and coworkers have recently disclosed a synthesis of allenylboronates from propargylic carbonates catalyzed by Cu(I). In the presence of Cu(O-t-Bu), Xantphos, and two equivalents of bis(pinacolato)diboron, a variety of substitution patterns and functionalities are tolerated in the transformation, which is believed to proceed through an S_N2´ mechanism. In addition, in the presence of a Lewis acid, the allenylboronates generated are reacted with aldehydes to form homopropargylic alcohols, with reasonable syn selectivity, when relevant.

Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. ASAP.

Ellman and coworkers have reported a Rh(I)-catalyzed arylation reaction of pyridines and quinolines. While the analogous alkylation they developed requires use of an electron-rich Rh-catalyst, the authors found it was necessary to switch to a catalyst system composed of an electron-deficient metal center           ([RhCl(CO)₂]₂) for optimal yields. The substrate scope was examined with respect to branching of the pyridine derivatives and aryl bromide coupling partners were examined in the quinoline couplings (including electron-rich and electron-poor aryl halides).  This C-H arylation method does not necessitate any prefunctionalization and provides the desired functionalized heterocycle in good yield.

Berman A. M.; Lewis, J. C.; Bergman, R. G. Ellman, J. A. J. Am. Chem. Soc. ASAP.

Rovis and coworkers have recently communicated a Ni-catalyzed reductive carboxylation of styrene derivatives. The use of CO₂ is appealing because it is cheap, renewable, and widely available. However, its use in metal-catalyzed reactions has not been exhausted and often involves molecules with extensive pi-systems. The Ni-catalyzed hydrocarboxylation has reasonable substrate scope and is effective with electron-deficient and neutral ortho, meta, and para-substituted styrene derivatives. Additionally, only 1 atm of CO₂ is necessary in the presence of Ni(acac)₂, Cs₂CO₃, and the reductant Et₂Zn. The authors favor a distinct mechanism (from related stoichiometric work) revolving around a nickel-hydride species, which is believed to be the active catalyst. Insertion of styrene, followed by transmetalation from Ni to Zn, allows for net hydrozincation and regenerates the precatalyst Et-NiLn. After beta-hydride elimination, the active catalyst is generated (H-NiLn). Transmetalation back to Ni, insertion of CO₂, and a final transmetalation with Et₂Zn generates the precursor to the product (before the quench) and regenerates the precatalyst.

Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc. ASAP.

Written by: Dr. Sharbil J. Firsan

Professor Yamamoto and co-workers at the University of Chicago have recently reported a novel and highly enantioselective method of desymmetrizing meso secondary allylic and homoallylic alcohols to the corresponding optically active monoepoxides.  The method, which relies on the use of low loadings of a vanadium–bishydroxamic acid catalyst system, has the following beneficial features:

•  High stereoselectivities (dr = 87:13 to 99:1 and ee = 92–97%) and moderate-to-good yields (51–73%)
• More efficient than kinetic resolution, since the theoretical yield of the optically pure epoxy alcohol product could be as high as 100%
• Mild reaction conditions and easy workup procedure
• Tolerance of aqueous peroxide oxidizing agents

The method has been applied to the highly stereoselective synthesis of (2R,4R)-4-hydroxy-6-hepten-1,2-oxide, a highly valuable synthetic intermediate.

(1) Li, Z.; Zhang, W.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 7520.  (2) For a review on Trost’s DYKAT method, see Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.

Written by: Dr. Sharbil J. Firsan

While highly reactive and environmentally friendly, the organozinc reagents generally employed in the Negishi cross-coupling suffer from being air- and moisture-sensitive.  Knochel and co-workers have recently reported a practical, one-pot reaction sequence in which the Negishi cross-coupling is carried out with in situ generated organozincs.  In the cross-coupling step, PEPPSI™-IPr worked best as the precatalyst (e.g., shorter reaction times and higher yields than those obtained with Pd(PPh₃)₄).  This process:

• Avoids the need to manipulate the air- and water-sensitive organozincs.
• Is generally applicable to functionalized aryl-, heteroaryl-, alkyl-, and benzylzinc reagents.
• Works well for a wide range of electrophiles: functionalized aryl, heteroaryl, and vinyl halides and triflates undergo the cross-coupling smoothly to give moderate-to-high yields of the cross-coupled products.

(1) Sase, S.; Jaric, M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org. Chem. 2008, 73, 7380.  (2) For a recent review of Pd–NHC Catalysts, including the various PEPPSI™ catalysts, see Kantchev, E. S. B.; O’Brien, C. J.; Organ, M. G. Aldrichimica Acta 2006, 39(4), 97.  PEPPSI is a trademark of Total Synthesis Ltd.

Burke and coworkers have recently disclosed the extensive versatility of the MIDA boronate technology by demonstrating the stability of the MIDAs in the presence of an array of common synthetic reagents. For example, MIDA boronates were stable towards various oxidizing conditions such as Swern reaction conditions (COCl₂, DMSO), PDC, TPAP/NMO, and Dess-Martin periodinane. The MIDA boronates were also compatible under Jones conditions (H₂SO₄/CrO₃). Common synthetic transformations in the presence of the MIDA boronates such as the Evans aldol, Horner-Wadsworth-Emmons olefination, reduction with NaBH₄, debenzylation with DDQ all provided the desired product with the MIDA intact. Various functional group transformations are shown in the scheme below. Additionally, an efficient synthesis of (+)-crocacin C utilizing an acrolein substituted MIDA boronate as the precursor provided the natural product in nine steps (longest linear sequence).

Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. ASAP.

Sigma-Aldrich has announced an exclusive licensing agreement with the University of Illinois at Urbana-Champaign offering research-scale quantities of MIDA boronate esters, which are trivalent protecting groups for boronic acids, a technology recently developed by Dr. Martin Burke and coworkers. The MIDA boronates behave as boronic acid surrogates and allow for historically more difficult couplings. For example, though the preparation of polyene natural products using the Suzuki reaction is complicated by the instability of polyenylboronic acids, iterative Suzuki cross-coupling for the preparation of polyenes is now feasible using the MIDA boronates. The corresponding polyenyl MIDA boronates are more stable then the corresponding polyenylboronic acids and attenuate transmetallation due to their sp³ hydbridization. These assets coupled with the mild and readily deprotectable nature of the MIDA boronates allows for their use in a variety of more challenging Suzuki reactions. This chemistry was demonstrated earlier this year in the synthesis of the left half of amphotericin B using trans-2-bromovinylboronic acid MIDA ester in the first step of the iterative cross-coupling sequence.

Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466-468.

Heck carbonylation is a commonly employed method for the preparation of carboxylic acid derivatives. Giri and Yu have recently described a C-H activation/C-O insertion sequence, which allows for he preparation of dicarboxylic acids. Substituted benzene carboxylic acid derivatives are treated in the presence of CO with Pd(OAc)₂, Ag₂CO₃, and NaOAc in dioxane to provide the 1,2-dicarboxylic acids. Electron-rich arenes are the preferred substrates, which is suggestive of an electrophilic palladation pathway. Additionally, the scope of the C-H activation/C-O insertion was expanded to phenylacetic acid derivatives as well as one example of a carboxylation of a beta-vinyl C-H bond in an alpha,beta-unsaturated carboxylic acid derivative. Finally, the mechanism of this intriguing reaction was probed, which led to the observation of a cyclopalladated intermediate, and ultimately upon treatment with PPh₃ allowed for characterization of the first C-H insertion intermediate obtained from carboxylic acids.

Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. ASAP.

Did you know that Aldrich Chemistry has launched a NEW Chemical Synthesis Website loaded with new content.

Rychnovsky and coworkers have described a Re(VII)-catalyzed Prins cyclization using commercially available O₃ReOSiPh₃. Usually strong Bronsted or Lewis acids effectively promote Prins cyclizations and therefore the use of a Re(VII) catalyst in a Prins cyclization is novel and noteworthy. Additionally, the chemistry is effective with both electron-rich and electron-poor aldehydes and provides access to the alcohol in the 4-position resulting from equatorial positioning of the substituent. The mechanism is currently under investigation, but a the proposed rationale involves formation of the hemiacetal upon reaction with the aldehyde electrophile followed by formation of the Re-ester intermediate, solvolysis, and cyclization to the THP as shown below.

Tadpetch, K.; Rychnovsky, S. D. Org. Lett. ASAP.

Shen and Hartwig have recently described an efficient catalyst system comprised of PdCl₂ and (R)-1-[(S_P)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine for the amination of heteroaryl and aryl halides. Since the complex itself is air- and moisture-stable, it does not need to be prepared in situ, which consequently results in lower catalyst loadings (0.001-0.05 mol %). The amination was observed to be fastest with aryl bromides, followed by aryl chlorides, while aryl iodides required higher catalyst loadings (5-10 times higher). The amination reactions using [(CyPF-tBu)PdCl₂] are very generally and exhibit excellent functional group compatibility (cyano, ketone free carboxylates, amido, carboalkoxy, aromatic, and aliphatic hydroxyl and amino functional groups are all tolerated). Reactions containing any protic functional groups are conducted in the presence of 2 equiv of LiHMDS in place of NaOtBu.

Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109.

If you didn’t catch the September 15th Issue of Chemical & Engineering News yet, grab a copy and check out the article “Elements Achieve Internet Stardom”. C&EN reports that chemistry Professor Martyn Poliakoff (University of Nottingham, UK) has made the Period Table of Elements a YouTube star in its own right.

The documentary-styled videos debuted July 17th and have generated quite a buzz among Nobel Laureates, chemistry professors, students and their parents. With the appearance of a stereotypical mad scientist, this non-scientist found the videos entertaining and educational, and Professor Poliakoff simply oozing with British charm and humor. No more mysterious wall charts for me. No searching Wiki’s endlessly learning the elements. Just straight up information and fascinating demonstrations (some dangerous for even trained chemists – do not attempt these at home warnings included).

The videos can be found at www.youtube.com/periodicvideos and for those of you at schools or institutions who are blocked from YouTube visit http://www.periodicvideos.com/. ENJOY! I know I did.

The 3rd Negishi-Brown Lectures - CAOSS Short Course will take place October 13th & 14, 2008 at Purdue University in West Lafayette, Indiana USA. Come learn about the latest advances in asymmetric synthesis from such reknowned educators as:

M. P. Doyle (U. of Maryland)
S. Hanessian (U. of Montreal)
D. R. Williams (Indiana U.)
E. Negishi (Purdue U.)
P. Kündig (U. of Geneva)
M. Krische (U. of Texas, Austin)
T. V. RajanBabu (Ohio St. U.)
P. Walsh (U. of Pennsylvania)

Registration Fees

FREE Student or Postdoctoral Associate (inclds 2 lunches, refreshments & mixer on 10/13)
Outside Academician (beyond Post. Doc.) $50 (inclds 2 lunches, refreshments, & mixer on 10/13)
Industrial Chemist $I50 (inclds 2 lunches, refreshments &mixer on 10/13)

 Visit sigma-aldrich.com  for more information and registration form. Deadline for registration is September 26, 2008.

Basle and Li have described a regioselective sp³ C-H bond arylation of tetrahydroisoquinolines using an inexpensive copper catalyst (CuBr), and T-HYDRO^® (or O₂) in dimethoxyethane in the absence of a directing group. Tetrahydroisoquinolines are important moieties, which display pharmacological and physiological effects. The authors also began a preliminary investigation towards the development of an enantioselective version, and found the use of (R,R)-2,6-Bis(4,5-dihydro-4-phenyl-2-oxazolyl)pyridine (PhPyBox) ligand provided the product in combination with CuOTf as the copper source in 44% ee. Two possible mechanisms for the Cu-catalyzed C-H arylation were proposed, both of which proceed via a common iminium ion-Cu alkoxide intermediate (regioselectively likely a result of stabilized benzylic position). The more likely possibility involves Cu-catalyzed C-C bond formation between the iminium ion-Cu-alkoxide species and the aryl boronic acid.

 Basle, O.; Li, C-J. Org. Lett. 2008, 10, 3661.

Biaryls are present in a plethora of natural products, pharmaceuticals, polymers, sensors and ligands and their synthesis often involves a cross coupling reaction, such as a Stille, Suzuki, Negishi, or Hiyama coupling. Akai and coworkers have recently disclosed a three-component approach, involving a Diels-Alder reaction followed by a Hiyama coupling utilizing a silylated benzyne, a furan derivative, and an aryl iodide. The optimal silylated benzyne derivative contains a TBDMS group, which provided good regioselectivity in the Diels-Alder reaction. After regioselective cleavage (pTsOH·H₂O or [Cp*RuCl(cod)] ) of the epoxy ring to afford the alcohol, a Hiyama coupling (Ar-I, [(allyl)PdCl]₂, AsPh₃, Cs₂CO₃, DME, 60 °C) provides (after silyl group activation and migration to the neighboring alcohol) the cross-coupled biaryl. 

Akai, S.; Ikawa, T.; Takayanagi, S-i.; Morikawa, Y.; Mohri, S.; Tsubakiyama, M.; Egi, M.; Wada, Y.; Kita, Y. Angew. Chem. Int. Ed. 2008, 47, ASAP.

Belot and coworkers have recently demonstrated an enantioselective 1,4-addition of aldehydes to nitrodienes using a diphenylprolinol silyl ether organocatalyst. The reaction is feasible with a variety of substituted aldehydes and nitrodienes providing the 1,4-adduct with good levels of diastereo- and enantiocontrol using low loadings of  (S)-(?)-alpha,alpha-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether. The synthetic utility of the reaction was also demonstrated via treatment of the 1,4 adduct with NaBH₄ in MeOH to afford the alcohol, followed by treatment with PhSeCl to provide the tetrahydropyran. Additionally, hexen-5-al was converted to a cyclohexene derivative after the conjugate addition and treatment with the Grubbs II catalyst.

Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett. ASAP.

Lu and Falck have recently reported an iridium-catalyzed C-H functionalization/silylation of N-, S-, and O- heteroarenes, which allows access to silyl-substituted arenes that are prevalent and useful to both synthetic and materials scientists. Using [{Ir(OMe)(cod)}₂] as the catalyst, in the presence of Et₃SiH, 4,4-di-tert-butyl-2,2-bipyridine, and norbornene, the silylation of the heteroarene occurs readily at 80 °C, placing the silyl group in the 2-position (except in one case). The use of C-H bond functionalization for the preparation of aryl silanes is complementary and in some ways superior to other know methods for their preparation. While other C-H bond functionalization methods are often limited with respect to regioselectivity, harsh reaction conditions, substrate structural requirements, and unfeasible ratios of reagents relative to each other, Lu and Falck?s method is regioselective, mild, and tolerates a broad range of functionality. The mechanism has not yet been investigated, but the authors propose coordination of the catalyst to the N, O, or S, followed by insertion into the adjacent C-H bond.

Lu, B.; Falck, J. R. Angew. Chem. Int. Ed. ASAP.

Written by William Sommer, PhD

The development of gold catalysis has been an endeavor for the past 10 years.¹ One of the leaders in this field, professor Toste and coworkers, developed a new way to synthesize azepines via a gold catalyzed intermolecular [4+3]-annulation.² In this study, the authors demonstrated the efficiency of the transformation, catalyzed by PicAuCl₂, with a variety of substrates. It was noted that the substrates containing electron-rich N-aryl groups gave the highest yields. In a typical procedure, 2 to 10 mol% of the gold catalyst is needed in methylene chloride at room temperature. Good to excellent yields are obtained with good diastereomic ratios.

Zhou and Hartwig have described the first intermolecular catalytic asymmetric hydroamination reaction which proceeds in both high yield and enantioselectivity. Various aryl amines were used in combination with bicyclic alkenes in the presence of [Ir(coe)₂Cl]₂, either a Segphos (such as (R)-DTBM-Segphos below) or BIPHEP ligand, and catalytic KHMDS. The hydroamination products were further manipulated via Boc protection (BOC₂O) of the PMP-protected amine product and cleavage of the PMP group with CAN, ozonolysis followed by reaction with NaBH₄ to afford a diol substituted cyclopentane, and ring openng cross metathesis to afford the olefin-substituted aminocyclopentane derivative. Mechanistic studies implicate an arylamide ligand in each step of a parthway involving migratory insertion (into Ir-NHAr bond), and reductive elimination.

Zhou, J.; Hartwig, J. f. J. Am. Chem. Soc. ASAP.

Antilla and coworkers have described the first catalytic method for the enantioselective preparation of N,O-aminals. These moieties are widely prevalent in natural products and pharmaceuticals yet their preparation through asymmetric catalysis was unprecedented. The method relies on the reaction of a variety of electronically diverse imines with a wide range of alcohols (primary, secondary, and tertiary, hindered and unhindered) in order to prepare the N,O-aminals in the presence of a chiral anthryl-substituted phosphoric acid ((R)-3,3′-Bis(9-anthracenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate).

Li, G; Fronczek, F. R.; Antilla, J.C. J. Am. Chem. Soc. 2008, ASAP.

Smith and coworkers have demonstrated a straight-forward approach to the preparation of functionalized arenes utilizing ortho-TMS Benzaldehyde as a linchpin in a three-component coupling. Reaction of ortho-TMS Benzaldehyde with n-BuLi, MeLi, allyl lithium, vinyl lithium, as well as the anion formed from 2-methyl-1,3-dithiane provides the intermediate alcohol. In the presence of CuI and HMPA, a Brook Rearrangement ensues and reaction with a variety of electrophiles, including allyl bromide, propargyl bromide, Bu₃SnCl, and diphenyl disulfide (among others) occurs followed by deprotection of the protected alcohol that results to provide the funtionalized arene. This method was also applied to the synthesis of two "natural product-like" products.

Smith, A. B.; Kim, W.-S.; Wuest, W. M. Angew. Chem. Int. Ed. ASAP.

Iron catalysts are attractive from an environmental and economic perspective and therefore their use in C-C bond forming reactions is gaining widespread popularity. Li and coworkers have reported the C-H bond functionalization of compounds containing C-H bonds adjacent to heteroatoms. The C-H bond functionalization combines a plethora of substrates containing adjacent heteroatoms, including O, S, and N with a variety of dicarbonyls (including beta-keto esters, 1,3-diketones, and beta-keto amides). The method relies on the use of Fe₂(CO)₉ as the iron catalyst in combination with tBuOOtBu as the stoichiometric oxidant as illustrated in the example below. The mechanism of the reaction is currently being investigated but preliminary studies involving a competition experiment and deuterium labelling revealed a large kinetic isotope effect indicating the C-H bond cleavage step is rate-limiting as well as a lack of scrambling which ruled out the formation of an iron-carbene species, respectively.

Li, Z.; Yu, R.; Li, H. Angew. Chem. Int. Ed. ASAP.

The new ChemFiles 8.4 compiles all of our phosphine ligands in one convenient location. This new ChemFiles includes Phosphorus precursors, phosphine ligands, phosphine oxides, phosphonites/phosphinites/phosphites, polydentate phosphine ligands, Buchwald ligands, and cataCXium.

 

Written by: Dr. Sharbil Firsan

The Petasis reaction is an attractive way to prepare amino acids, since it takes place under mild conditions, utilizes readily available reagents, and engages three reactants in a single process.  Lou and Schaus have recently reported a catalytic, enantioselective variant of this reaction that involves the condensation of alkenylboronate esters with amines and aldehydes to form alpha-amino esters.   High enantiomeric ratios of the chiral alpha-amino ester products were made possible by the use of chiral biphenols, of which (S)-VAPOL was found to lead to the best yields and optical purities for a variety of alkenylboronate esters, secondary amines, and ethyl glyoxalate.  The reaction schematic shown here showcases the optimized reaction conditions that were developed.

Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

Written by: Dr. Sharbil Firsan

Fu, Snapper, and Hoveyda have recently reported a protocol for the enantioselective alkylation of alpha-ketonimines with Me₂Zn and Et₂Zn, catalyzed by Zr(Oi-Pr)₄•HOi-Pr and a chiral ligand derived from valine and phenylalanine.  Some of the advantages of this protocol include (i) the ease and efficiency with which the chiral ligand and the ketonimine substrate can be synthesized on a gram scale; (ii) its equal applicability to alkyl- as well as aryl-substituted alpha-ketonimines; (iii) the oxidative removal of the N-activating group not being adversely affected by the presence of a neighboring quaternary carbon; and (iv) the chiral amine products can be readily elaborated further.  Representative examples are shown below.

Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 5530.

Stoltz and coworkers have reported an elegant method for the preparation of synthetically challenging alpha-hydroxyesters and acids. The method involves alkylation of dioxanones, which are relatively difficult substrates to alkylate using classical methods because of competing ketone reduction, self-condensation, and decomposition. Conversely using the method developed by Stoltz, enol silanes were transformed to alpha-hydroxy ketones under asymmetric Pd-catalyzed allylation conditions employing Pd(dmdba)₂, TBAT, and (S)-tBuPHOX in the presence of various diallyl carbonates in toluene at room temperature. Conditions for the cleavage of the acetonide and further simple functionalization to the alpha-hydroxy methyl ester as well as the synthesis of a key advanced alpha-hydroxy acid intermediate en route to (-)-dramacidin F were also demonstrated.

Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem. Int. Ed. ASAP.

Movassaghi and Hill have recently reported a highly versatile modified Bischler-Napieralski reaction for the formation of isoquinolines and beta-carbolines, which constitute important moieties in a variety of natural products, pharmaceuticals, and fine chemicals. The simple reaction procedure involves treatment of the amide precursor with 2-chloropyridine (2-ClPyr), followed by addition of Tf₂O. The reaction mechanism likely involves activation of the amide precursor, intramolecular cyclization, and deprotonation to generate the azaheterocycle. The method allows for the facile preparation of a variety of these important derivatives, many of which cannot be accessed as efficiently using classical conditions, which often lead to oxidation, decomposition, and in cases employing optically active substrates, a greater degree of racemization.

Movassaghi, M.; Hill, M. D. Org. Lett. ASAP.

Gaspar and Carreira have recently addressed a well-known limitation in the literature for the catalytic hydrochlorination of unactivated olefins using a cobalt-derived catalyst. Most hydrochlorinations are inherently limited since common methods are restricted to strained olefins or alkenes providing stabilized intermediates or require the use of HCl, which is not conducive in the synthesis of molecules containing acid-sensitive functionalities. The reaction developed by Gaspar and Carreira proceeds with complete regioselectivity providing the Markovnikov product under two similar sets of reaction conditions?using cobalt Catalyst 1, PhSiH₃, EtOH, and TsCl as the chloride source or using Co(BF₄)₂·6H₂O (6-12 mol %), Ligand 1 (SALDIPAC), t-BuOOH (30 mol%), PhSiH₃, TsCl, and EtOH. The authors propose a radical pathway to explain the formation of the hydrochlorination products, which presumably is initiated by formation of a cobalt-hydride complex (from the Co-catalyst and PhSiH₃). Hydrocobaltation followed by capturing by TsCl, either via an alkyl radical or via direct reaction with the organocobalt species provides a general means for the regioselective formation of organochlorides, including monosubstituted olefins.

 Gaspar, B. and Carreria, E. M. Angew. Chem. Int. Ed. 2008, 47, ASAP.

Written by: Dr. Sharbil J. Firsan

1-Ethynylcyclohexanol acts as an effective acetylene substitute in the efficient synthesis of monarylated (85–99% isolated yields) and diarylated acetylenes (24–95% isolated yields) by the Sonogashira coupling.  In that regard, it is comparable to 2-methyl-3-butyn-2-ol and trimethylsilylacetylene in some cases, but it surpasses them in several others.  Its main advantages are:

•  The unsymmetrical diarylacetylenes can be synthesized in a one-pot sequence of two Sonogashira couplings without isolating the intermediate monoarylated acetylenes, which can be only moderately stable.
• Following the second Sonogashira coupling reaction, the chemically inert cyclohexanone is released as a byproduct.
• It is commercially available and moderately priced.

Csékei, M.; Novák, Z.; Kotschy, A. Tetrahedron 2008, 64, 975.

Written By: Dr. Sharbil J. Firsan 

Dirhodium(II) tetracarboxylates, in particular Rh₂(esp)₂, effectively catalyze a novel reaction cascade leading to sterically congested, fused 5,7 and 6,7 bicyclic ring systems.  This metallonitrene–alkyne metathesis sequence leads to the formation of new C–N, C–O, and C–C bonds intramolecularly from simple starting materials.  This reaction series tolerates alkyl and aryl substituents at either end of the alkyne, and allyl and benzyl groups are cleanly transferred.  Since the initially formed imine products are sensitive to hydrolysis on purification, they are more conveniently isolated as the corresponding amines after in situ reduction with sodium borohydride.

Thornton, A. R.; Blakey, S. B. J. Am. Chem. Soc. 2008, 130, 5020.

Indoles and their derivatives constitute an important class of compounds due to their frequent occurrence in natural products, bioactive compounds and pharmaceuticals, and organic materials. Various Pd-catalyzed methods have been developed for substituting on the indole ring including the N1, C2, C3 positions; however, methods for further C-3 functionalization on already substituted and hindered 2,3-disubstituted indoles to generate indolenines with concomitant formation of a quaternary center has been a known challenge. Rawal and coworkers have developed a nice method for allylation of sterically congested 2,3-disubstituted indoles. Substitution occurs selectively in the 3-position using allyl ester electrophiles and an optimal catalyst system consisting of a combination of Pd₂(dba)₃ and P(2-fur)₃ as the ligand. Allyl indolenines were prepared in good to excellent yields (63-99% isolated yields). Substituted olefins also proved successful in providing more complex indolenines. Finally, the method was investigated in an increasingly complex setting utilizing several indole-containing natural products. The method is remarkably robust and allows for the facile preparation of novel allylated derivatives of (+/-)-geissoschiol (single diastereomer), yohimbine (single diastereomer), and reserpine (1:1 dr).
 
 

Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381.

Written by: Dr. Sharbil Firsan

Zhou and co-workers have reported a practical, efficient, and highly enantioselective hydrogenation of cyclic sulfimidates to the corresponding sulfamidates.  These sulfamidates are versatile precursors of chiral amines, which are ubiquitous in natural products and are highly useful building blocks, ligands, and auxiliaries.  Under the optimized reaction conditions [Pd(CF₃CO₂)₂, (S,S)-f-binaphane, TFE, rt, 12h] yields of 92–99% and enantiomeric excesses of 90–99% have been observed.  To demonstrate the utility of this approach, two optically active sulfamidates obtained by this method were readily converted into the corresponding amino alcohol and aminomethylphenol without any loss of optical purity.

Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G. Org. Lett. 2008, 10, 2071.

The preparation of enantiopure alpha-amino acids and related moieties represents an important undertaking to chemists due to their significance in various applications across the fields of both chemistry and biology. The preparation of enantiopure beta,gamma-alkenyl alpha-amino esters has been dependent on the use of chiral auxiliaries.  You and coworkers have accomplished the asymmetric synthesis of beta,gamma-alkenyl alpha-amino esters using a chiral phosphoric acid catalyzed transfer hydrogenation of the precursor beta,gamma-alkynyl alpha-imino esters. The method relies on the reaction of beta,gamma-alkynyl alpha-imino esters with the hydrogen donor Hantzsch ester in the presence of the bulky anthryl-substituted phosphoric-acid based organocatalyst to provide only the trans-substituted alkenyl alpha-amino ester products in good to moderate yields and excellent levels of enantioselectivities. Several parameters were investigated including the optimization of the solvent (toluene provided the highest level of enantioselectivity), ester substitution (bulkier esters provided the best chemical yield), and electronics of the alkyne (27-64%, 83-96% ee). The mechanism of the reaction was also considered with respect to the order of events and it was concluded that the carbon-carbon triple bond was reduced prior to the reduction of the imine.

Kang, Q.; Zhao, Z.-A.; You, S.-L. Org. Lett. 2008, 10; 2031.

Written by: Dr. Sharbil J. Firsan 

The first examples of the successful Pd(II)-catalyzed cross-coupling of sp³ C–H bonds beta to a carbonyl group with alkyl- and arylboronic acids has recently been disclosed by Yu and co-workers of The Scripps Research Institute.  This reaction protocol provides the cross-coupling products in moderate-to-good yields, and is noteworthy for:

• Using air, not Ag₂O or Ag₂CO₃, as a stoichiometric oxidant in the newly developed C–H activation/C–C coupling steps.
• The suppression of the homocoupling and beta-hydride elimination side reactions by:
  • derivatizing the carboxylic acid substrates as the corresponding and stronger-binding O-methyl hydroxamic acids, and
  • utilizing 2,2,5,5-tetramethyltetrahydrofuran in the dual role of solvent and sterically bulky ligand.
•  Employing as catalyst Pd(OAc)₂, a widely available and relatively inexpensive reagent.
• The O-methyl hydroxamic acid functional group can be readily converted into other highly synthetically useful functional groups such as acids, esters, and amides.

Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190

Written By: Dr. Sharbil J. Firsan

Coates and co-workers have recently reported the use of [Ph₃SiCo(CO)₄] as a precatalyst in the high-yield, stereoselective conversion of 4- or 5-substituted oxazolines into the corresponding 4- or 5-substituted 2-aryl-oxazin-6-ones.  Some of the attractive features of this method are:

• The oxazoline starting materials are readily available in racemic or optically pure form, either commercially or by synthesis from the corresponding alpha-amino acids.
• The oxazinone products are easily hydrolyzed to the corresponding beta-amino acids.
• Retention of configuration is observed for the 4-substituted substrates, while inversion of configuration is observed for the 5- substituted ones.
• Overall, the method serves as convenient and general way of readily converting alpha-amino acids into their one-carbon homologues.

Byrne, C. M.; Church, T. L.; Kramer, J. W.; Coates, G. W. Angew. Chem., Int. Ed. 2008, 47, 3979.  For a review of enantioselective syntheses of beta-amino acids, see Juaristi, E.; Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3.

Written by: Dr. Sharbil J. Firsan

A new catalyst system and protocol have been developed for the mild, high-yield hydration of organic nitriles—a transformation that is of great importance in organic synthesis.  The new method generates the active catalyst in situ from the commercially available [{Rh(OMe)(cod)}₂] and tricyclohexylphosphine (PCy₃).  The product amides are obtained in generally excellent yields, with little or no acid or ester byproducts observed.  The mild and pH-neutral reaction conditions are compatible with various functional groups, including formyl and olefinic ones, and tolerate a wide range of nitrile starting materials.  In one case, an optically active nitrile was converted into the corresponding optically active amide with retention of configuration.

Goto, A.; Endo, K.; Saito, S. Angew. Chem., Int. Ed. 2008, 47, 3607.

Written by: Dr. Sharbil J. Firsan

A new twist on the Hiyama cross-coupling reaction has recently been reported by Alacid and Najera.  It features a ligandless, Pd-catalyzed cross-coupling that is carried out with aqueous sodium hydroxide as promoter and tetra-n-butylammonium bromide (TBAB) as additive at 120 ^oC under conventional or microwave heating.  Good yields, stereoselectivities, low catalyst loadings, and ease of recovery of the Pd catalyst are characteristics of this reaction protocol.

Alacid, E.; Najera, C. J. Org. Chem. 2008, 73, 2315.  See also Denmark, S. E.; Ober, M. H. Aldrichimica Acta 2003, 36, 75.

Written by: Dr. Sharbil J. Firsan

Dennis Hall and co-workers have recently disclosed the remarkable ability of ortho-bromo- and ortho-iodophenylboronic acids, [2-BrC₆H₄B(OH)₂] and [2-IC₆H₄B(OH)₂], to catalyze the direct amidation of free carboxylic acids with amines and the Diels–Alder reaction of free alpha,beta-unsaturated carboxylic acids with simple dienes.  The noteworthy features of this discovery are:

• 2-BrC₆H₄B(OH)₂ and 2-IC₆H₄B(OH)₂ are better catalysts for the direct amidation than the hitherto most efficient catalyst for the reaction, namely 3,4,5 F₃C₆H₂B(OH)₂.
• Both reactions take place at room temperature in an atom-economical, byproduct-free fashion.
• Both are operationally simple affording the pure products after a simple filtration and acid–base extractions (no chromatographic separations required).
• The boronic acid catalyst is recovered from the basic aqueous phase in high yield.
• The direct amidation reaction is broad in scope, and the Diels–Alder reaction remarkably selective.
• The two reactions can be combined in an efficient, one-pot, two-step cascade sequence that is promoted by a single catalyst.

Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876.  For selected recent reviews on organocatalysis, see: (a) Longbottom, D. A.; Franckevicius, V.; Kumarn, S.; Oelke, A. J.; Wascholowski, V.; Ley, S. V. Aldrichimica Acta 2008, 41, 3.  (b) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79.

Written by: Dr. Sharbil J. Firsan

Bolshan and Batey recently reported the copper-catalyzed, stereoselective cross-coupling of amides with potassium alkenyltrifluoroborates, leading to high yields of the corresponding enamides, which are valuable synthetic intermediates and important structural features in many natural products.  Under optimized conditions, this reaction offers the following advantages over other enamide syntheses:

• Potassium alkenyltrifluoroborates are air- and moisture-stable, and are readily available.
• The process is catalytic in copper and does not require a base or a heterocyclic ligand.
• It takes place under mild temperatures.
• Is general in scope and gives rise to high yields and stereoselectivities
  
  

  

Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109.

Written by: Dr. Sharbil J. Firsan

A highly enantioselective and organocatalytic Michael addition of a-substituted aldehydes to nitroethylene has been reported by Gellman and co-workers.^1,2  The metal-free catalyst system consists of (S)-diphenylprolinol silyl ether as the catalyst (2 mol %) and 3-nitrobenzoic acid as the co-catalyst (20 mol %).  When followed by NaBH₄ reduction of the aldehyde group of the addition product, the method leads to beta-substituted delta-nitrobutanols in excellent yields and enantioselectivities.  In turn, these butanols can be readily converted into the corresponding N-protected gamma²-amino acids—important building blocks for gamma-peptides and heterogeneous-backbone foldamers—by a short and operationally simple sequence of hydroxyl group oxidation, nitro group reduction, and amino group protection.

(1) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, ASAP.  (2) For a recent review on organocatalytic conjugate additions utilizing pyrrolidinyltetrazoles as organocatalysts, see Longbottom, D. A.; Franckevicius, V.; Kumarn, S.; Oelke, A. J.; Wascholowski, V.; Ley, S. V. Aldrichimica Acta 2008, 41, 3.

Written by: Dr. Sharbil J. Firsan

An efficient and straightforward method for the direct amination of aryl halides has been developed by a team of researchers at Takasago International Corp.  The method relies on the use of Mo-Phos, di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, as a new, hybrid phosphine ligand for the palladium catalyst.  Primary and secondary amines and carbazole have successfully undergone the reaction to give rise to the corresponding di- or triarylamines in high yields.

Suzuki, K.; Hori, Y.; Kobayashi, T. Adv. Synth. Catal. 2008, 350, 652.
 

Written by: Sandy Adam

On Monday, April 7th, Sigma-Aldrich will be participating in an event hosted by the American Chemical Society at the Spring Meeting in New Orleans. The event is in essence a virtual trade show that will follow the Sci-Mix Interdivisional Poster Session that is running from 8 to 10 PM CST, at the Morial Convention Center in Hall A.  Immediately following the "real world" Sci-Mix, virtual SciMix will open on ACS Island in Second Life®. Read more about it on Helium: Life on ACS Island or visit ACS Island (if you do not have Second Life® installed you will be prompted to create an account at no charge).

Written by: Dr. Sharbil J. Firsan

A practical, functional-group-tolerant method for the direct arylation of a range of pharmaceutically relevant heterocycles has been reported by Ellman, Bergman, and co-workers.  The method relies on the use of rhodium as the transition-metal catalyst in combination with (Z)-1-tert-butyl-2,3,6,7-tetrahydro-1H-phosphepine (Ellman’s Ligand) as a bidentate ligand.  A variety of azoles, including unprotected N–H azoles, and functionalized aryl bromides have been successfully used as coupling partners.  Many of these partners are not normally compatible with other direct arylation methods that utilize Pd(0) or Cu(I) catalysts.  The present method offers the following advantages:

• It can be conducted in THF, rather than in high-boiling solvents, which greatly simplifies the isolation of products.
• When the HBF₄ salt of Ellmans’ Ligand is used, the starting reaction mixture can be set up outside a glovebox and without using highly purified reagents.
• When the reaction is conducted in a microwave reactor, excellent yields of the coupling products are obtained in 2 hours or less.

Lewis, J. C.; Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493.

Written by: Dr. Sharbil J. Firsan

Alkane- and alkenesulfonyl chlorides are reported to undergo smooth desulfinylative C–C cross-coupling reaction with Grignard reagents in the presence of a catalytic amount of environmentally friendly Fe(acac)₃.  Under optimized conditions, these relatively inexpensive reagents react to produce moderate-to-good yields of the cross-coupling products, without the need to use any additional ligand with the iron catalyst.

Rao Volla, C. M.; Vogel, P. Angew. Chem., Int. Ed. 2008, 47, 1305.

Written by: William Sommer, PhD. 

The Sigma-Aldrich toolbar and deskbar are now available to be downloaded on our website. Save time when looking for chemicals by entering the CAS, name, product number, MDL number or MSDS in the toolbar. You will be directed to the page results with the availability of the products. Go to the following to download the toolbar or the deskbar.

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Sigma-Aldrich also offers a plethora of tools to accelerate your research. On the main page of our website, scroll down and click on "Web Toolbox" to get access to them.

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Written by: Dr. Sharbil J. Firsan

An operationally simple, efficient, and diastereoselective synthesis of alpha-aryl glycines from Weinreb amides has been reported by Somfai and co-workers.  The Weinreb amide starting materials were readily prepared from the corresponding N-methyl-O-alkylhydroxylamine hydrochlorides.  The reaction produces good-to-high yields of the corresponding alpha-arylated amides, and tolerates electron-donating and electron-withdrawing substituents in the aryl group.  The alpha-arylamide products can then be readily converted into the corresponding alpha-aryl amino acids by established methods.  A high diastereomeric ratio of the alpha-arylamide products was also observed in the case of the asymmetric variant of the reaction shown below.

Hirner, S.; Panknin, O.; Edefuhr, M.; Somfai, P. Angew. Chem., Int. Ed. 2008, 47, 1907.

Written By: Matthias Junkers, Ph.D

“Staudinger Ligation: A Gift to Chemical Biology” was the title of an excellent review article published in 2004.¹
One of the outstanding applications of the Staudinger ligation depends on a class of phosphine reagents introduced simultaneously by the groups of Bertozzi and Raines in 2000. The “traceless” variant of the Staudinger ligation developed by these groups allows the formation of a native peptide bond between a thioester and an azide.^2,3
Among the suitable reagents the Raines ligation reagent diphenylphosphinemethanethiol exhibits the best reactivity profile and has already found widespread application. Two exceptional examples may highlight the potential of diphenylphosphinemethanethiol: Maarseveen and co-workers used it for intramolecular ring-closures forming medium-sized lactams.⁴ Wong and co-workers synthesized a large series of glycopeptides.⁵

Sigma-Aldrich is excited to offer acteylthiomethyl-diphenylphosphine borane complex 670359 as a convenient source for the Raines ligation reagent (Sold under license for research and development purposes only. U.S. patent 6,974,884 and related patents apply.). Obtain the active reagent easily from this shelf-stable precursor by treatment with DABCO^® at 40°C followed by basic ester cleavage.

References:
(1) “Staudinger Ligation: A Gift to Chemical Biology” Angew. Chem. Int. Ed. 2004, 43, 3106.
(2) “A ‘Traceless’ Staudinger Ligation for the Chemoselective Synthesis of Amide Bonds” Saxon, E.; Armstrong, J.I.; Bertozzi, C.R. Org. Lett. 2000, 2, 2141.
(3) “Staudinger Ligation: A Peptide from a Thioester and Azide” Nilsson, B.L.; Kiessling, L.L.; Raines, R.T. Org. Lett. 2000, 2, 1939.
(4)  “Intramolecular Staudinger Ligation: A Powerful Ring-Closure Method To Form Medium-Sized Lactams” David, O.; Meester, W.J.N.; Bieräugel, H.; Schoemaker, H.E.; Hiemstra, H.; van Maarseveen, J.H. Angew. Chem. Int. Ed. 2003, 42, 4373.
(5) “Convergent Glycopeptide Synthesis by Traceless Staudinger Ligation and Enzymatic Coupling” Liu, L.; Hong, Y.-Y., Wong, C.-H. ChemBioChem 2006, 7, 429.

Written by: Dr. Sharbil J. Firsan

Stawinski and co-workers report that iodine exerts an accelerating effect on the silylation of alcohols in the presence of N-methylimidazole.¹  This silylation is 5–30 times faster than the one that takes place under the standard Corey–Venkateswarlu silylation conditions.²  Under Stawinski’s optimized reaction conditions (see Scheme), the silylation reaction times are reduced from several hours to as little as 5 minutes at room temperature.  As expected, the reactivity of alcohols under this protocol follows the order primary > secondary > tertiary.  The reaction takes place in a variety of organic solvents and is compatible with double and triple bonds as well as common functional groups.  Other noteworthy findings relating to this new method are:

• The nature of the solvent does not noticeably affect the silylation rate.
• Iodine alone does not accelerate the silylation; it requires the presence of a heteroaromatic base such as pyridine or N-methylimidazole.
• On the other hand, strong bases such as Et₃N or (i-Pr)₂NEt are incompatible with the reaction conditions.
• The silylation can be carried out with a number of silylating reagents, such as (t-Bu)Me₂SiCl (TBDMSCl), (t-Bu)Ph₂SiCl (TBDPSCl), or (i-Pr)₃SiCl (TIPSCl).
• The reaction is straightforward to carry out and work up, and leads to high yields of the silyl ethers.

(1) Bartoszewicz, A.; Kalek, M.; Nilsson, J.; Hiresova, R.; Stawinski, J. Synlett 2008, 1, 37.  (2) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.

Written by: Dr. Sharbil J. Firsan

A dinuclear zinc–bis-ProPhenol complex is reported to efficiently catalyze the asymmetric Friedel–Crafts alkylation of unprotected pyrroles with nitroalkenes.  The resulting products are 2-alkyl-substituted and 2,5-dialkyl-substituted pyrroles containing a chiral center at C-1 of the alkyl substituent.  The significance of this transformation lies in the fact that pyrroles are relatively unstable in the acidic environments of the classical Friedel–Crafts reaction and that unprotected pyrroles can be used directly in the reaction.  The current alkylation is carried out at room temperature in THF and gives rise to moderate-to-high yields and enantioselectivities.

Trost, B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438.

Written by: Dr. Sharbil J. Firsan

The title compound is conveniently prepared in high yield from 1-methylimidazole and dimethyl carbonate.¹  This colorless, crystalline solid serves as a starting material for the facile, room-temperature, one-pot synthesis of the interesting and potentially useful imidazolium-2-phosphane ionic liquids.²

(1) Holbrey, J. D.; Reichert, W. M.; Tkatchenko, I.; Bouajila, E.; Walter, O.; Tommasi, I.; Rogers, R. D. Chem. Commun. 2003, 28.  (2) Azouri, M.; Andrieu, J.; Picquet, M.; Richard, P.; Hanquet, B.; Tkatchenko, I. Eur. J. Inorg. Chem. 2007, 4877.

Written by: Dr. Sharbil J. Firsan

Tris(pentafluorophenyl)borane (B(C₆F₅)₃)—a thermally and air-stable, water-tolerant, and environmentally benign Lewis acid—catalyzes the efficient and chemoselective, room-temperature tritylation of primary alcohols to give the corresponding trityl ethers in excellent isolated yields.  Some of the more remarkable aspects of this highly practical transformation are:

• Primary alcohols can be selectively tritylated in the presence of secondary or phenolic hydroxyl groups.
• Oxygen-protecting groups such as THP, TBDMS, TBDPS, MOM, PMB, and Ts; and the acid-labile ones acetonide, ketal, and benzyl; are stable under the reaction conditions.
• Common functional groups, such as esters and carbamates, are also unaffected under the reaction conditions.
• Unlike some of the other traditional tritylating reagents, B(C₆F₅)₃ and Ph₃COH (TrOH) are commercially available.

Reddy, Ch. R.; Rajesh, G.; Balaji, S. V.; Chethan, N. Tetrahedron Lett. 2008, 49, 970.

Written by: Dr. Sharbil J. Firsan 

Ellman and co-workers have reported the first rhodium-catalyzed, enantioselective addition of arylboronic acids to N-Boc imines.  Cleavage of the initially formed addition product with a mild base under anhydrous conditions leads to the corresponding alpha-arylated N-Boc amines.  This highly practical synthetic method utilizes (R,R)-DeguPhos as the chiral ligand and offers the following advantages over related procedures:

• Boc is the most commonly used nitrogen-protecting group and is easily cleaved under acidic conditions, generating volatile byproducts that simplify the isolation and purification of the deprotected amines.
• While N-Boc imines are hydrolytically labile, they can be readily and conveniently generated in situ under the reaction conditions from their alpha-carbamoyl sulfone precursors, which are easily prepared and are stable, crystalline compounds.
• A large number of structurally diverse arylboronic acids are commercially available.
• The addition reaction is tolerant of substituents and functional groups both in the imine and in the arylboronic acid.
• Good yields and high enantioselectivities are observed for both electron-rich and electron-deficient imines.
  

Nakagawa, H.; Rech, J. C.; Sindelar, R. W.; Ellman, J. A. Org. Lett. 2007, 9, 5155.

Written by: Dr. Sharbil J. Firsan 

Excellent yields and high enantiomeric excesses are reported for the Cu(I)-catalyzed beta-boration of acyclic alpha,beta-unsaturated carbonyl compounds in the presence of the nonracemic, ferrocene-based, diphosphine ligands Josiphos and Mandyphos®.  The optimum conditions for the reaction of bis(pinacolato)diboron (B₂Pin₂) with beta-alkyl- or beta-aryl-substituted acyclic alpha,beta-unsaturated esters and nitriles consist of B₂Pin₂ (1.1 equiv), CuCl (2–3 mol %), NaOt-Bu (3 mol %), and chiral ligand (3–4 mol %) at room temperature in THF.   The nitriles were more reactive, and generally gave better enantioselectivities, than the esters; whereas the beta-substituent in the substrate and the alcohol moiety of the ester had little influence on the level of enantioselectivity. 

Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145.  For a related transformation, see Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856.
Mandyphos is a registered trademark of Umicore AG & Co. KG.

Written by: Daniel Weibel, Ph.D

TRISPHAT and BINPHAT are configurationally stable, enantiopure synthetic anions. The octahedral geometry of pentavalent hexacoordinated phosphorus allows the formation of chiral anions as lambda or delta-enantiomers by complexation of a central phosphorus atom with three dianionic bidentate ligands.

Both TRISPHAT and BINPHAT are effective diamagnetic NMR shift reagents. They form tightly associated diastereomeric ion pairs with chiral cations such as quaternary ammonium, phosphonium, thiiranium, [4]-helicenium cations and ruthenium or (eta⁶-arene)manganese complexes. They are as well capable of enantiodifferentiating neutral planar chiral (eta⁶-arene)chromium and -palladium complexes by charge-dipole interactions enabling their efficient resolution by NMR spectroscopy. The TRISPHAT anion seems to be more efficient with cationic metallo-organic and organometallic substrates whereas the BINPHAT anion often shows superior chiral shift properties when associated with organic cations.

Furthermore, due to its lipophilic nature the TRISPHAT anion confers to its salts an affinity for organic solvents. Thus, TRISPHAT is capable of resolving racemic cationic substrates such as above depicted [Ru(bipy)₃] cation by preferential extraction of one enantiomer from water into immiscible organic solvents. Selectivity ratios of 35:1 were obtained for the cationic enantiomers in the organic and aqueous layers. Similarly, the BINPHAT anion was used in selectively precipitating one diastereomeric salt of above shown helicenium cation.

TRISPHAT and BINPHAT Key Features
· Configurationally stable enantiopure anions
· Efficient NMR resolving agents for chiral cations
· Selective enantiospecific extractions and precitipations of racemic cations

(1) Lacour, J.; Frantz, R. Org. Biomol. Chem. 2005, 3, 15.

 Written by: Dr. Sharbil J. Firsan

 gamma-Substituted allyl beta-ketocarboxylates undergo a highly regio- and enantioselective decarboxylative allylic alkylation in the presence of [Ir(cod)Cl]₂ and a chiral phosporamidite ligand.  Under optimized conditions, the reaction takes place over 3–22 hours in refluxing dichloromethane in the presence of 2 equivalents of DBU to give moderate-to-high yields, high ratios of the branched-to-linear alkylated products, and high-to-excellent enantioselectivities of the branched product.  Electron-donating and electron-withdrawing substituents in the substrates are well tolerated.

He, H.; Zheng, X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007, 9, 4339.

Written By: Dr. Sharbil J. Firsan 

Professor Beller’s group has recently reported a general, inexpensive, and environmentally benign method for the conversion of alkyl, aryl, and heteroaryl aldehydes into their corresponding primary alcohols.  The highly chemoselective method relies on the use of a catalyst system made up of iron(II) acetate and tricyclohexylphosphine in the initial hydrosilylation of the aldehydes to give (polymeric) silyl ether intermediates.  Upon basic workup of the reaction mixture, these intermediates decompose to give the primary alcohols in good-to-high yields.  Poly(methylhydrosiloxane) (PMHS) is used as a stable, nontoxic, and easy-to-handle hydride source.

Shaikh, N. S.; Junge, K.; Beller, M. Org. Lett. 2007, 9, 5429

Written By: Dr. Sharbil J. Firsan 

The first example of a Cu(I)-catalyzed, highly enantioselective allylic substitution with a heteroatom nucleophile has recently been reported by Ito, Sawamura, and co-workers.  The reaction leads to alpha-chiral allylboronates, which are highly valuable reagents that are capable of a near-perfect chirality transfer in their additions to carbonyl compounds leading to chiral building blocks.  Of the various Cu(I)–phosphine catalyst combinations tested, the one consisting of Cu(I)–(R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)­quinoxaline gave the best yields and enantiomeric excesses.

Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856