Thursday, May 24, 2007

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


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.

Substituted Diarylmethylamines by Stereospecific Intramolecular Electrophilic Arylation of Lithiated Ureas


Jonathan Clayden,* Jérémy Dufour, Damian M. Grainger, and Madeleine Helliwell

School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom

This is a neat and remarkable methodology for the synthesis of diarylmethylamines. The reaction starts with N-aryl-N'-methylaryl-urea. Upon treatment with sec-BuLi, the bezylic position is deprotonated. This benzylic lithium then adds across the urea carbonyl to the ipso-position of the other aryl group on the other nitrogen. The complex formed then rearranges to give the aryl-migrated product, ie 3. This product can serve as a precursor to diarylmethylamine 4 upon reduction or hydrolysis.
The reaction was found to be stereosepcific, that is the configuration of the benzylic position in the SM is retained in the product. The reaction was found to be widely applicable regardless of electronic character of the aryl ring being transferred.

And as mentioned above, the reaction is stereospecific. In case of chiral SM, the configuration of the stereogenic center is retained. This is summarized in the table below.

The stereospecificity of the reaction was further demonstrated in the synthesis of chiral 7.
The reaction was found to be intramolecular as proven by the absence of cross-over products in a cross-over experiment. The intermediate of the reaction was found to be 9 as proven by the isolations of 10o and 10p upon exposure of the intermediates to dry air, thus fully proving the mechanism of the reaction. In this reaction, DMPU was added to help promote the dearomatization reaction for the formation of intermediate 9 (both DMPU and HMPA are known to promote such reaction).

This is a neat reaction which can provide a ready access to racemic or enantio-enriched diarylmethylamines.

Sunday, May 20, 2007

The First Sequential Reaction Promoted by Manganese: Complete Stereoselective Synthesis of (E)-alpha,beta-Unsaturated Esters from 2,2-Dichloroesters


José M. Concellón,* Humberto Rodríguez-Solla, Pamela Díaz, and Ricardo Llavona

Departamento de Química Orgnica e Inorgnica, Facultad de Química, Universidad de Oviedo, Julin Clavería 8, 33071 Oviedo, Spain

Mn has increasingly received much interest as a reagent/catalyst in organic transformation with its reactivity profile similar to SmI2 and CrCl2 but much less toxic and less expensive. In this current paper, activated Mn (Mn*) was used in refluxing THF to effect the following transformation with high stereoselectivity giving products in high yields.
Importantly, the Mn* system was able to transform inexpensive dichloroacetate ester derivatives in the presence of aldehydes to give both di- and trisubstituted alpha,beta-unsaturated esters in refluxing THF. The system also worked with dibromoacetate ester derivatives at rt. However, the dibromoacetate ester derivatives are generally more expensive than the dicholo-counterparts. Enolizable aldehydes could be used to effectively form the desired ester product without problem. However, when ketone was used in place of aldehyde, mixture of unidentifiable products was formed.

For the transformation below, activated Mn* was prepared by treatment of mixture of MnCl2 (13 mmol) and LiCl (26 mmol) with a slurry of lithium powder (26 mmol) at rt.

In comparative studies, some of these transformations to disubstituted products were compared with results using SmI2 and CrCl2 and Mn* was found to be superior in most cases as shown in Table 1.

To show versatility of this reaction, trisubstituted products could also be made. And these results are summarized in Table 2.
All products, both di- and trisubstituted enoates, were formed stereoselectively to yield only E-enoates. All of these transformations were believed to be a sequential processes starting from aldol reaction, followed by beta-elimination, all in one step. Selectivity of the reaction was believed to stem from TS-I where bulky R1 was placed in the pseudo-equatorial position. This is also illustrated in Fisher projection of TS-II. Scheme 2 demonstrates the proposed mechanism and transition states.

Saturday, May 19, 2007

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.

Synthesis of the Tricyclic Core of Colchicine via a Dienyne Tandem Ring-Closing Metathesis Reaction

Link: Org Lett ASAP

François-Didier Boyer and Issam Hanna*

Unité de Chimie Biologique, AgroParisTech, INRA, F-78026 Versailles, and Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France

This paper presented a very neat use of RCM and quite clever strategy to construct the 7,7-fused core of colchicine. For the first time, the 7,7-fused bicyclic system could be accessed very quickly in a single step. This main strategy is summarized in the retrosynthetic analysis below.

Therefore, substrate 4 was needed for the RCM step and it was constructed according to the following scheme.

The key reactions were formylation of 6 mediated by SnCl4 to give 7 and the synthesis of propargylic alcohol 14 which was achieved in three steps from 5, using the Ohira-Bestman reagent in the last step.

Next, sequential RCM reactions were performed on 14 using Grubbs' second generation catalyst (15) after the protection of the OH group with TMS. The reaction proved to be very efficient, providing the desired 16 in 74% yield from 14.

This intermediate 16 was further elaborated as shown in Scheme 4 via oxidative rearrangement. Compound 18 could be obtained in high yield. However, going along a more well-known route of previous total syntheses of colchicine, intermediate 19 could be obtained in modest yield, along with 20, from 17. This latter route effectively constituted a formal synthesis of colchicine. The final completion of this molecule by a novel sequence is currently under investigation.

Overall, the double RCM (enyne RCM and RCM) in constructing the 7,7-core of colchicine presented in this paper is quite ingenius.

Ring-Closing Reaction of Allenic/Propargylic Anions Generated by Base Treatment of Sulfonylallenes

Link: Org Lett ASAP

Shinji Kitagaki, Satoshi Teramoto, and Chisato Mukai*

Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan

This is a report of a very neat and novel ring closing reaction. The reaction involves the allenic moiety substituted with an EWG and a strategically placed electrophile tethered to the allene.

The EWG could be sulfone, ketone and ester and electrophile could be halide, aldehyde and alpha,beta-unsat ester. The reaction conditions were quite mild and even TBAF could be used as a base, as well as a more potent base such as NaH. When EWG was sulfone, and the electrophile was either OTs group or I, the reactions proceeded to give the expected cyclic propargylic sulfone as shown in Table 1.

But when electrophile was an aldehyde, product of type 9 could be obtained in good yields, except in entry 14 of Table 2 where 10, instead of the expected 9, was also obtained in 26% presumably via addition of enolate of the aldehyde to the allene in the endo-mode.

In addition, when electrophile was alpha,beta-unsat ester and the base used was KOt-Bu, the expected product (12) was obtained in good yields.
Finally, when EWG was something else other than a sulfone, and the elctrophile was a terminal iodide, the reaction proceeded to give the ring-closing product of type 14 in modest to excellent yields (except 14c).

Asymmetric Amine-Intercepted Nazarov Cyclization


Francis Dhoro, Tor E. Kristensen, Vegar Stockmann, Glenn P. A. Yap, and Marcus A. Tius*

Department of Chemistry, 2545 The Mall, University of Hawaii, Honolulu, Hawaii 96822, and Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716

This is a work on amine-intercepted Nazarov cyclization. The reaction yielded alpha'-amino-, alpha, beta-unstaturated cyclobutenone. Initial result is as shown in Scheme 1.

In this paper, a camphor-derived derivative of 1 was used in the studies as shown in Scheme 2.

Subsequently, the following substrates were used in the study, all were made from addition of the organolithium to the corresponding morpholine amide.

The reaction conditions were very mild, essentially on exposure to activated silica gel, alumina, or florisil. For 12, reaction did not work well and mixture of unidentifiable products were obtained. Otherwise, the products obtained from other substrates are summarized in Table 1.

The structures of these products were assigned based on the x-ray crystal structure of the picrate salt of 20. Streochemistry observed was the result of conrotatory electrocyclic ring closure.

Additionally, the intermediate of type 8 as in Scheme 2 could be trapped intramolecularly by a tethered amino group as in 26 to give a unique compound 27 in good yield. Interestingly, due to the steric constraint, trapping of nitrogen occurred on the same face of the cyclopentenone (which is different from other intermolecular trapping cases, see Table 1).

The products from this reaction could be further utilized. The TIPS group and chiral auxiliary are easily cleaved from the products. Exposure of 23 to tetra-n-butylammonium fluoride in THF led to rapid cleavage of the TIPS group (28, 92% yield). Subsequent exposure of the product to chlorotrimethylsilane in methanol at 0 °C led to cleavage of the chiral auxiliary (29, 93% yield). (See the paper and the Supporting Information for details.)

Amine-Catalyzed Direct Aldol Addition


Morris Markert, Michael Mulzer, Bernd Schetter, and Rainer Mahrwald*

Institut für Chemie der Humboldt-Universität zu Berlin, Brook-Taylor Strasse 2, 12 489 Berlin, Germany

A new method emerged for tertiary amine-catalyzed cross aldol reaction between aldehydes and hydroxyl acetone. This method is different from previous method where tertiary amine was used in conjunction with LiClO4. The initial results are as seen in Scheme 1 of the reactions catalyzed by DBU.In the subsequent scheme, further utilities of the reaction is illustrated, using Hunig's base as catalyst. In some of these reactions, cyclic acetal was obtained along with the expected aldol adduct.As is readily seen, the reaction predominantly afforded syn-aldol product. The selectivity was probably stemed from the effect of hydrogen-bonding - a welcome complement to the previously known anti-selectivity.

The method is applicable to enolizable aldehyde. The reaction is also regioselective with regards to enolate counterpart, namely only alpha-carbon bearing OH group was observed to add to the aldehyde. In the scheme below, the method was used effectively in the synthesis of furanose 8 and sorbose 9.In addition to DBU and Hunig's base, alkaloid such as cinchonine was also found to be an effective catalyst as demonstrated in the example below.

Enantioselective Organocatalytic Singly Occupied Molecular Orbital Activation: The Enantioselective alpha-Enolation of Aldehydes


Hye-Young Jang, Jun-Bae Hong, and David W. C. MacMillan*

Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

In continuing their investigation in the newly discovered mode of organocatalysis - the singly occupied molecular orbital, or SOMO activation - MacMillan group presented a new reaction. In the original contribution, alpha-allylation of aldehyde using allylsilane was recently reported.

This time alpha-enolation of aldehyde and enolsilane using the same catalyst system was reported for the first time. The mode of activation is through a single-electron activation with CAN, as shown in the scheme below, to give the corresponding electron-deficient radical cation.

Based on a DFT calculation, the enolsilane or the "SOMOphile" would approach the "SOMO-catalyst" on the si-face to avoid the bulky t-Bu group of 1, establishing the enantioselectivity of the reaction.
Thus, using enolsilane 3 as a somophile, reactions with various aldehydes proceeded in good yields and ees as shown in Table 1.

In addition, several somophiles were used to react with octanal to give the expected products in good to excellent yields and excellent ees (Table 2).

In addition, the reaction was found to be very mild and chemoselective as illustrated in Eqs 5 and 6. In a normally difficult-to-control intramolecular radical cyclization of 4, when reaction was conducted in the presence of enolsilane, the corresponding alpha-enolation product was obtained selectively in excellent yield and ee.

SOMO-activation has become more important in the field of organocatalysis. One could expect to see much more of this in the near future.