A Pd(0)-Catalyzed Diamination of Terminal Olefins at Allylic and Homoallylic Carbons via Formal C-H Activation under Solvent-Free Conditions

Link: JACS ASAP

Haifeng Du, Weicheng Yuan, Baoguo Zhao, and Yian Shi*

Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523

This is a new method di-amidation of terminal alkenes at the allylic and homoallylic positions using di-tert-butyldiaziridinone (2). A similar method was reported before with conjugated diene 1. In this method, terminal alkene 4 was used to give similar product.

The reaction is applicable to a variety of alkenes, affording products with trans-stereochemistry in modest to excellent yields.

The products of the current reaction is useful in further transforming to give 1,2-diamines such as 6.

In addition to mono alkenes, the reaction was also applied to bis-terminal alkenes. In case of 7, the products were formed as a mixture of 8a and 8b in a 1:1 ratio. In case of 9, while 11 was formed, both 10a and 10b were isolated and are believed to be intermediates in the reaction. Both 10a and 10b when subjected to Pd(PPh3)4 transformed give 11.

The mechanism of the reaction was proposed to be as followed:

Essentially, the reaction probably goes through intermediate diene 15 formed in situ. A more detailed mechanistic study is needed.

Rhodium-Catalyzed Aryl Transfer from Trisubstituted Aryl Methanols to alpha,beta-Unsaturated Carbonyl Compounds

Link: ACIEE EarlyView

Takahiro Nishimura,*, Taisuke Katoh, Tamio Hayashi*

Department of Chemistry, Graduate School of Science, Sakyo, Kyoto 606-8502, Japan

The method shown in the paper demonstrated the use of Rh to transfer aryl group from tertiray substituted methanol to alpha,beta-ketones and ester.

The Rh-Aryl bond is formed via beta-elimination of the tertiary alcohol. This transformation also paralleled to methods known previously using other metals.

In effecting this transformation, alcohol 1 was used as the source of aryl group. Other aryl sources were also studied (4m-8m for Ph, Scheme 3) but 1 was found to give the best result, yielding the desired 1,4-adduct 9 and ketone 2 as a byproduct.

The results using 1m-u are summarized in Table 1.

Additionally, the reaction could be conducted with stereoselectivity when (S,S)-Bn-bod* was used in place of cod on the Rh catalyst. This is demonstrated in the reaction between 3a and 1p in Scheme 4.

The mechanism was proposed as shown in Scheme 6.

Direct, Catalytic Hydroaminoalkylation of Unactivated Olefins with N-Alkyl Arylamines

Link: JACS ASAP

Seth B. Herzon and John F. Hartwig*

Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801

A new reaction which will probably become a name reaction: the Hartwig Hydroaminoalkylation.

This was based on the work done over two decades by Maspero and Nugent, according the scheme below.

The reaction essentially added aminoalkyl group across the double bond of an olefin. The aminoalkyl group is part of the N-methylaniline and. The catalyst was screened as presented in Table 1 and Ta[N(CH3)2]5 was found to be most optimal.

The reaction was found to work well with a variety of terminal olefins, which in most cases, providing methyl-branched products in good yields (except entry 2 below where a mixture of products was obtained).

A variety of arylamine partners could also be utilized as shown in Table 3.

The mechanism of the reaction is largely under investigation. Nonetheless, this is a neat reaction.

Cinchona Alkaloid-Catalyzed Enantioselective Monofluoromethylation Reaction Based on Fluorobis(phenylsulfonyl)methane Chemistry Combined with a Mannic

Cinchona Alkaloid-Catalyzed Enantioselective Monofluoromethylation Reaction Based on Fluorobis(phenylsulfonyl)methane Chemistry Combined with a Mannich-type Reaction

Link: JACS ASAP

Satoshi Mizuta, Norio Shibata,* Yosuke Goto, Tatsuya Furukawa, Shuichi Nakamura, and Takeshi Toru*

Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan

A new method for the overall alpha-monofluoromethylation of alpha-amino sulfone. After desulfonation, enantio-enriched compound of type 4 was obtained.

First, the catalysts were screened as shown in Table 1. The most optimal conditions were found to be in runs 10 and 11.

After the optimal conditions were identified, the reaction was screened with different substrates and results are summarized in Table 2 with yields of compounds of type 3.

The compounds of type 3 could be desulfonated under a variety of conditions. All of these conditions are summarized in Table 3, giving the final monofluoromethyl compounds of type 4 in excellent yields.

This is a quite nice two-step protocol to install monofluoromethyl group to alpha-amino sulfone in a quite good to excellent enantioselective manner using 1 effectively as a monofluoromethyl transferring reagent.

Pt(II)-Catalyzed Synthesis of 1,2-Dihydropyridines from Aziridinyl Propargylic Esters

Link: Org Lett ASAP

Massoud Motamed, Eric M. Bunnelle, Surendra W. Singaram, and Richmond Sarpong*

Department of Chemistry, University of California, Berkeley, California 94720

A neat reaction of aziridine, tethered to propargylic acetate, with PtCl2 catalyst as a way to access 1,2-dihydropyridines.

The reaction mechanism was proposed to be as shown below.

The authors explored this chemistry in continuation from their earlier work of a similar reaction with the epoxide derivative as shown.

The reactions were found to proceed well. Scope of the reaction was studied and illustrated in the table below.

Cases where the Ts group aziridine nitrogen was substituted with acyl group were also studied. In these cases although desired pyridine products were formed in good yields, byproducts of type 18 (as shown) were also formed.

This byproduct was formed by participation of acyl C=O group as proposed in the mechanism below.

As shown in Scheme 4, the dihydropyridine 5b could be used as a precursor to pyridine 20 demonstrating the utility of the products.The reaction was also shown to be stereospecific, that is the stereochemistry in the starting material was effectively transferred to the product as shown in the scheme where stereochemistry of carbon bearing the phenyl group in 1a was retained in product 5a.

A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Me

A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Mediated Intramolecular Cyclopropanation of (R)-1,2-Epoxyhex-5-ene

Link: Org Proc & Dev ASAP

Anthony D. Alorati, Matthew M. Bio, Karel M. J. Brands, Ed Cleator,* Antony J. Davies, Robert D. Wilson, and Chris S. Wise

Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, EN11 9BU, UK

The method is pretty unique in obtaining fused 3,5-bicyclic system as shown in 1.

This was achieved by treatment of epoxide 2 with LiTMP. The hindered base would deprotonate the alpha-carbon of epoxide trans- to the beta-alkyl side chain. Then stereospecific cyclization of the carbenoid species would follow to give bicyclic alcohol 4. The reaction could be conducted with catalytic amount of TMP (with slight excess of n-BuLi). The rate of n-BuLi addition (not too fast) was crucial in a successful catalytic reaction.

Compound 4 was found to be acid-sensitive. Compound 4 can be utilized in further transformations. TEMPO/NaOCl treatment of 4 successfully led to 1 in greater than 99.5% ee. This reaction sequence was demonstrated to be amenable to preparing 1 on a 7.5 kg scale. pH of the oxidation step had to be carefully controlled. If the pH was too low (5-8), oxidation was incomplete. If pH was too high (>11), dibrominated compound 12 was formed as a sginificant byproduct.

A Vaulted Biaryl Phosphoric Acid-Catalyzed Reduction of alpha-Imino Esters: The Highly Enantioselective Preparation of alpha-Amino Esters

Link: JACS ASAP

Guilong Li, Yuxue Liang, and Jon C. Antilla*

Department of Chemistry, University of South Florida, 4202 East Fowler Avenue CHE205A, Tampa, Florida 33620

This is a new organocatalytic method for enantioselective reduction of acyclic alpha-imino esters to form the corresponding alpha-amino esters (and subsequently alpha-amino acids). The method employed sterically hindrance chiral biaryl phosphoric acid as a ligand and Hantzsche ester as hydrogen source in a transfer hydrogenation process. Several biaryl phosphoric acids were initally considered.

In the initial studies, imino esters 2a-c were screened in the reaction using using phosphoric acid (PA) 1e to investigate the effect of solvents and it was found that non-polar, non-coordinating solvents such as benzene and toluene gave the best results, especially with imino ester 2a-b while ester 2c did not work too well presumably due to its steric hindrance.

Next, all PAs in Figure 1 were screened using 2a as a test substrate and PA 1e was found to be the most optimal acid for the reaction.

Generality of the reaction was established in the following table, where several alpha-imino esters were subjected to the optimal reaction conditions. In all cases, the reactions proceeded in excellent yields to give products in excellent ees.

In general, the imino esters were pre-formed before subjecting to the reactions. When the imino esters were formed in situ before the reductions, yields were lower (10-20%). However, in the cases of the alkyl-substituted imino esters (Table 3, entries 9-11), yields were found to be good to excellent, indicating that this reduction could be performed with an alpha-imino ester generated in situ in one pot.

Chiral Calcium Complexes as Brnsted Base Catalysts for Asymmetric Addition of -Amino Acid Derivatives to ,-Unsaturated Carbonyl Compounds

Link: JACS ASAP

Susumu Saito, Tetsu Tsubogo, and Sh Kobayashi*

Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO, Japan Science Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

This paper presented a novel metal catalyst system in conducting a 1,4-addition of glycine derivative to alpha,beta-unsaturated carboxylic acid derivative to give glutamic acid derivative as a product. The novel catalyst being used in the reaction was Ca2+ salt in conjunction with chiral ligand.

Initially, reaction was screened to find the most optimal conditions. This included the screening of metal salts and ligands and the results are summarized as followed.

In the end, ligand 4 was found to be the most optimal ligand along with Ca(Oi-Pr)2 salt. Upon identifying the best conditions, the scope of the reaction was investigated. The reactions with various substrates were mostly found to proceed in great yields and stereoselectivity as seen in Table 2.

Next, the reaction was screened with crotyl carboxylic acid derivatives. It was surprisingly found that instead of the 1,4-addition addition product, pyrrolidine derivative 7 was obtained in a formal [3+2] cycloaddition reaction. Several substrates were then explored and the results are summarized below. In most cases, the reactions proceeded in excellent yields and diastereo- and enantioselectivities.

The catalytic cycle was proposed to be as followed.

In a regular 1,4-addition, intermediate 10 was protonated to give product 6. But when the amide derivative was used as the Michael acceptor, the intermediate 10 became more reactive and intramolecular cyclization occurred to give pyrrolidine 7. However, from both Tables 1 and 2, this distinction was not very clear as the only difference in conditions between the two reactions seemed to be the reaction time. Therefore (in my opinion), it is more likely that the reaction intramolecularly cyclized faster (in 3 h). But when the reaction was allowed to react longer (12 h), retrocyclization occurred and the initial pyrrolidine derivative product (formal [3+2]) was transformed to the glutamic derivative product (1,4-addition).

Ligand 4 was suspected to be an anionic ligand as when structurally-related ligand 8 (which was expected to form a neutral complex) was used instead of 4 in a reaction between methyl acrylate and 1a, the reaction proceeded in only 31% and provided the product in racemic form.

An Alkoxide-Directed Intermolecular [2+2+1] Annulation

An Alkoxide-Directed Intermolecular [2+2+1] Annulation: A Three-Component Coupling Reaction for the Synthesis of Tetrasubstituted alpha,beta-Unsaturated gamma-Lactams

Link: ACIEE EarlyView

Martin McLaughlin, Masayuki Takahashi, Glenn C. Micalizio*

Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520-8107, USA

This is a method to make 1,5-unsaturated amino alcohol and alpha,beta-unsaturated gamma-lactams employing [2+2+1] annulation catalyzed by titanium complex. The type of coupling is presented in the general scheme below.

The coupling relied on the ability of the homopropagylic hydroxyl group of alkyne to coordinate to titanium and direct the addition of the alkyne to the imine partner. This methodology was found to work well as illustrated with the alkyne substrates in Table 1.

It should be noted in entry 4 that the coupling of internal alkyne substituted with TMS group occurred at the alpha carbon. This was in contrast to a typical coupling of TMS-substituted alkynes where the TMS group directed the reaction to occur at the beta carbon. This effect was only possible because of the directing effect of the hydroxyl group on the titanium center which overrode the effect of the TMS group.

In a Pauson-Khand type coupling in the presence of CO2, alpha,beta-unsaturated gamma lactams could be synthesized as illustrated between various alkyne and imine substrates in Table 2.

It should be noted in entry 5 that when ortho-substituted aromatic group of imine 21 was used, the reaction occurred diastereoselectively to give a 4:1 atropisomeric mixture.

When the imine coupling partner carried a stereogenic center, the reaction was also found to occur stereoselectively both in the syntheses of 1,5-amino alcohols and gamma-lactam (Scheme 2). As for the synthesis of the amino alcohols 28 and 29, the diastereoselectivity seemed to depend on the size of the R group on the alkyne coupling partners.

A Practical Buchwald-Hartwig Amination of 2-Bromopyridines with Volatile Amines

Link: JOC ASAP

Jie Jack Li,* Zhi Wang, and Lorna H. Mitchell

Department of Chemistry, Michigan Laboratories, Pfizer Global Research & Development, Ann Arbor, Michigan 48105

This is a quick-read paper on a method to improve Buchwald-Hartwig amination using volatile amines as coupling partners.

The authors stated that in order to conduct an amination reaction of 2-bromopyridine using volatile amine such as methylamine (bp, -6.2 C), the process would have to utilize methyl benzylamine for amination and debenzylation of the coupling product (Scheme 1), which sometimes destroys that integrity of the molecule.

Another available method is to use methylamine-HCl salt as a precursor to the amine, as illustrated in Scheme 2. However, the process employs large excess of NaOt-Bu and cannot be applied to free amines.

The answer to these problems was to conduct the reaction in a sealed tube. Thus substrate, such as 1 was added with excess of volatile amine via condensation at -78 C, followed by addition of NaOt-Bu, Pd-catalyst and phosphine bidentate ligand in toluene. The tube was sealed and heated at 80 C overnight to give the desired product in 77% yield.

The volatilities of amines at 80 C in term of vapor pressure are as followed: methylamine, 20 atm; dimethylamine, 10 atm; ethylamine, 7.5 atm; and 3.5 atm for propylamine and cyclopropylamine.

The results of cross-couplings for other substrates are summarized in Table 1. In general, secondary amines gave better results than primary amines, presumably because the tertiary amines products were less readily to undergo further side-reactions, such as further cross-coulping, or N-oxidation with light.

And as seen in entry 10, 2-chloropyridine derivative did not work as well as the bromo counterpart in previous entries. The authors also noted that the current method did not yield any product with 2-chloropyridine and 2-bromopyridine.