Volume 10, Number 1 • 2010

Aldrich

Asymmetric Synthesis

Catalysis

Chemical Biology

Organometallic Reagents

Building Blocks

Synthetic Reagents

Stockroom Reagents

Labware Notes

Chemistry Services

COMU - Safer and More Efficient Peptide Coupling Reagent

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Prof. Karl A. Scheidt (Northwestern U.) Discovering New Reactions with N-Heterocyclic Carbene Catalysis

Prof. André B. Charette (U. of Montreal) Synthesis and Applications of Diorganozinc Reagents: Beyond Diethylzinc

Prof. Carolyn R. Bertozzi (UC, Berkeley) Copper-Free Click Chemistry

Prof. James L. Leighton (Columbia U.) Strained Chiral Silacycles: A Powerful and Versatile Family of Reagents for Asymmetric Synthesis

Prof. Bruce H. Lipshutz (UC, Santa Barbara) New PTS-Enabled Transformations in Water at Room Temperature

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3

Introduction

Volume 10, Number 1

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Aldrich

Dr. Haydn BoehmGlobal Marketing Manager: Chemical Synthesis

haydn.boehm@sial.com

Dear Chemists,

It seems incredible to think that ten years have elapsed since I read the first edition of ChemFiles back in 2000, while completing my PhD. I remember the mission of ChemFiles was to provide a forum to highlight

the latest products and services from Aldrich Chemistry to advance chemists' research. Over the years ChemFiles has varied from product guides to product directories and supplement issues in order to best support the requirements of its readers.

In 2009, I took over the role of editor of ChemFiles and as we approached our 10th anniversary edition I wanted to take the opportunity to speak with several chemists, both readers and non-readers, in order to learn how we could improve the format to further support their research. A key learning from the discussions with non-readers was that many of them had not made the connection that ChemFiles was in fact an Aldrich publication. The Aldrich name has become synonymous with excellent quality research chemicals, fast delivery, as well as superior customer and technical service. Therefore it would seem logical to rename the publication "Aldrich ChemFiles" in order to build upon this solid brand association. The name also dovetails with our other print publications, the Aldrich Chemistry Handbook and the Aldrichimica Acta, both publications are industry standards in their own right, with the Aldrichimica Acta having recently been ranked the #1 journal by Impact Factor* among 55 organic chemistry journals for the seventh time in the last eight years. The Aldrichimica Acta, like Aldrich ChemFiles is FREE to all chemists by simply subscribing at aldrich.com/acta.

Globally, our customers tell us to "Continue making innovative, quality research chemicals" and "Make them easy to find". In order to address these comments we launched Chem Product Central in 2006. Chem Product Central is our on-line product directory, which qualifies our research chemicals according to their application area and compound class (aldrich.com/chemcentral). The new format of the Aldrich ChemFiles will mimic the Chem Product Central focus areas, and within each issue our readers can learn about our latest innovative products and services for: Asymmetric Synthesis, Catalysis and Inorganic Reagents, Chemical Biology, Organometallic Reagents, Specialty Synthesis, Building Blocks, Synthetic Reagents, Stockroom Reagents, Labware and Chemistry Services. Hopefully whatever your chemistry focus area, within each issue of Aldrich ChemFiles there will be articles that will interest you and help you advance your research.

Reader feedback on our email and web newsletters has empowered us to consolidate both ChemNews and ChemBlogs into a single monthly e-newsletter, the Aldrich-e ChemFiles. The e-Aldrich ChemFiles will have an analogous format to the print publication, but will be a monthly update of our latest innovation-enabling products. The printed Aldrich ChemFiles will be a quarterly publication, which will feature more expansive articles relating to the origins, literature precedent, and applications of the products featured in the monthly e-version.

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Introduction

Dr. Haydn BoehmGlobal Marketing Manager: Chemical Synthesis

4 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Asym

met

ric S

ynth

esis

OHOH

OHOH

OHHN

Boc

OHHN

Boc

OHHN

Boc

OHHN

Boc

OHHN

Boc

OHHN

Boc

OHOH

OHOH

713945 725757

713880 713899 713953 713961

713988 713996

713902 713937

Asymmetric SynthesisDr. Daniel WeibelProduct Manager

daniel.weibel@sial.com

Lautens Chiral Building BlocksProfessor Mark Lautens and his group at the University of Toronto have developed a powerful catalytic asymmetric ring

opening reaction enabling the production of highly functionalized hydronaphthalene scaffolds in enantioenriched form. This method is providing access to a myriad of highly functionalized scaffolds from achiral, readily available low-cost starting materials.1 Josiphos type ligands2 complexed to Rh promote the ring opening of meso oxabicyclic and azabicyclic alkenes with heteroatom nucleophiles such as alcohols, phenols, aliphatic amines, carboxylates, malonates and sulfides with very high enantioselectivities (Scheme 1).

O

OHNu

[Rh(COD)Cl]2 (227951 or 683132)/Josiphos (88719)(0.25-1.0 mol % cat.)

nucleophile (4-5 eq.), THF, 80 °C

Nu = ROH, RNH2, RSH80-99%; 90-99%, ee

Scheme 1

The hydronaphthalene skeleton is found in a wide range of compounds possessing diverse biological activities, thus these chiral building blocks have proven to be extremely useful in the synthesis of biologically active molecules of pharmaceutical interest.3 A number of drug candidates in various clinical phases, as well as natural and launched products, is shown in Figure 1.

HCl·HNCH3

ClCl

H NH3C

OCl

ClN N

OOHH3C

N

O

O

OCH3

OCH3H3C

H

H2N

OH

HNH

H

OH

OH

sertraline analgesic dopamine agonist

homochelidonine dihydrexidine

H

H

Figure 1

In a very recent study the Lautens and Tomaszewski groups have synthesized a small library of amides and amines of 1-aminotetralin scaffolds via this methodology.4 Screening of these libraries against human opioid receptors led to the identification of a high-affinity selective m ligand (IC50 m = 5 nM, k= 707 nM, d= 3,795 nM) displaying agonist/antagonist properties due to its partial agonism (EC50 = 2.6 mM Emax = 18%). Drugs with a similar profile have proved beneficial in the treatment of pain as well as for the treatment of drug addiction particularly due to their low dependence-inducing potential (buprenorphine, a partial m agonist is used in both analgesia and the treatment of heroin addiction).

X

(X = O, NR) XHNu

HNS OCH3

NN

PhN O

SH3CO Cl

Rh-cat. ring opening

m = 5.2 nM m = 58 nM

Scheme 2

Sigma-Aldrich is pleased to offer our first selection of highly useful chiral building blocks, and we intend to continually expand our chiral building blocks product portfolio.

References: (1) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48. (2) For a list of available chiral ligands from Solvias, see: sigma-aldrich.com/solvias (3) (a) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967. (b) Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465. (c) Fan, E.; Shi, W.; Lowary, T. J. Org. Chem. 2007, 72, 2917. (d) Madan, S.; Cheng, C. J. Org. Chem. 2006, 71, 8312. (4) Dockendorff, C.; Jin, S.; Olsen, M.; Lautens, M.; Coupal, M.; Hodzic, L.; Spear, N.; Payza, K.; Walpole, C.; Tomaszewski, M. J. Bioorg. Med. Chem. Lett. 2009, 19 1228.

Lautens Building Blocks

For more information, visit aldrich.com/lautens

5Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

Asymm

etric Synthesis

N

N

OH

O

OH

O

PhPh

Ph

PhPh

Ph N

N

OH

O

OH

O

PhPh

Ph

PhPh

PhN

N

OH

O

OH

OPh

Ph

Ph

Ph

N

N

OH

O

OH

OPh

Ph

Ph

Ph

700533 700541 700576 700592

N

N

OH

O

OH

O

CH3

CH3

H3C

CH3H3C

CH3

CH3

CH3

N

N

OH

O

OH

O

CH3

CH3

H3C

CH3H3C

CH3

CH3

CH3

700568 700584

CBHA LigandsYamamoto and his group developed a new type of ligands based on the C2-symmetric chiral bishydroxamic acid (CBHA). These bidentate ligands have pendant "arms" that can be substituted with a variety of substituents allowing for a fine-tuning of the ligand potency. A variety of these ligands have been synthesized and the reactivity was probed in a variety of asymmetric oxidation reactions.

Asymmetric Epoxidation of Allylic AlcoholsChiral epoxides have become a common building block used in the synthesis of natural products and biologically active substances. These enantiomerically enriched compounds can be obtained through different protocols such as the Sharpless asymmetric epoxidation using a titanium-tartrate complex or the Jacobsen epoxidation catalyst using a salen-manganese complex. One of the drawbacks of these reactions is the use of high catalyst loading and long reaction time. Moreover, the scope of these catalysts is somewhat limited.

Yamamoto and co-workers used the CBHA ligands that were developed for the epoxidation of a variety of allylic alcohols. Using 2 mol % of the BHA ligand with 1 mol % of VO(O-iPr)3 (404926) with tert-butyl hydroperoxide (TBHP, 458139) under air at 0 °C to –20 °C afforded the desired epoxy alcohol with both high enantioselectivities and good yields. The procedure proved to be effective for both small and complex epoxy alcohols (Scheme 3).1

N

N

OH

OPh

Ph

OH

OPh

Ph

R3

R2

R1

OHR3

R2

R1

OHO

O

(2 mol %)VO(O-i-Pr)3 (1 mol %)

TBHP (70% aq.), DCM

84%; 97%, ee 53%; 97%, ee 84%; 97%, ee

H

PhH3C

HO

OPh

HO

O

HO

Ph

Scheme 3

Asymmetric Epoxidation of OlefinsThe asymmetric epoxidation of olefins has become an important reaction to obtain essential chiral building blocks. One of the most practical methods reported for this reaction is the manganese-salen catalyst that Jacobsen and co-workers reported in 1990. However, the low reaction temperature required for the reaction and the lack of selectivity for Z olefins made this method limited. Yamamoto and co-workers expanded the use of their CBHA ligands with the asymmetric epoxidation of olefins using a molybdenum complex. This new method proved to be efficient for the asymmetric oxidation of mono-, di- and trisubstituted olefins. The reaction is performed under mild conditions and under air giving good yields and excellent selectivity.

N

N

OH

O

OH

O

R4

R3

R2

R1R4

R3

R2

R1

(2 mol %)MoO2(acac)2 (2 mol %)

TBHP, DCM, rt.

27%; 96%, ee 87%; 91%, ee 7%; 70%, ee

O

OO

O

Ph

Ph

PhPh

PhPh

Scheme 4

Asymmetric Oxidation of SulfidesThe preparation of enantiopure sulfoxides has become of utmost importance as building blocks for the synthesis of drugs and natural products. Several methods exist to synthesize these chiral sulfoxides, but they usually require several steps, stringent conditions and in most cases, result in low enantioselectivity. Yamamoto and co-workers used their newly developed CBHA ligands with a molybdenum complex for the asymmetric oxidation of sulfides to generate chiral sulfoxides. The reaction is carried out under air with only 2 mol % of catalyst required for good yield.

N

N

OH

O

OH

O

(2 mol %)MoO2(acac)2 (2 mol %, 227749)

THP, DCM, 0°C

83%; 68%, ee

Ph

Ph

PhPh

PhPh

SH3C S

H3C

O

Scheme 5

References: (1) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem. Int. Ed. 2005, 44, 4389. (2) Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2006, 45, 5849. (3) Basak, A.; Barlan, A. U.; Yamamoto, H. Tetrahedron: Asymmetry 2006, 17, 508.

CHBA Ligands

For more information, visit aldrich.com/cbha

6 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Asym

met

ric S

ynth

esis

Entry

Substrate

Product

Yield (%)

er ((+)-sparteine

surrogate)

er ((–)-

sparteine)1

NBoc

NBoc

SiMe3

84 95:5 5:95

2 Ph O N(i-Pr2)

O

Ph O N(i-Pr2)

OBu3Sn

84 96:4 1:99

3

H3CP CH3

BH3

t-BuH3C

PBH3

t-Bu

OH

PhPh

78 96:4 12:88

4 O OHH

H

70 81:19 17:83

5

O

O

O

CO2H

COPh

78 89:11 9:91

6

OHOH

OHOH

86 99:1 4:96

Table 1

H3CN

N

H HN

N

O

690279 712264

(+)-Sparteine SurrogateUntil recently, sparteine, a widely used ligand in asymmetric synthesis1 was only commercially available in one enantiomeric form. O'Brien and his coworkers have designed several (+)-sparteine surrogates, which possess most of the three-dimensional architecture of (+)-sparteine. However the N-methyl derivative 690279 shown in Figure 2 turned out to be the most versatile and widely applicable one.2

N

NH

H

N

NH

H

(−)-sparteine (+)-sparteine

H3CN

N

H

(+)-sparteine surrogate

Figure 2

A simple, three-step synthesis starting from Laburnum anagyroides cytisus seeds, subsequent N-protection, diastereoselective pyridone hydrogenation, and lithium aluminum hydride reduction synthesized (Scheme 6).3

H3CN

N

HN

N

H3CO

O

O

HN

N

O

CH3CO2Cl, Et3N

DCM, 0°C to rt., 4h

1. H2, PtO2MeOH, rt., 5h

2. LiAlH4THF, reflux, 16h

(+)-sparteine surrogate(−)-cytisine (712264)

Scheme 6

In a diverse range of examples collected in Table 1, it was shown that all of the products show opposite enantioselectivity and a relatively equal high degree of enantioselection when using the (+)-sparteine surrogate 690279 to those when using (-)-sparteine.2,3

Lithiations and subsequent rearrangement or electrophilic trapping are particularly successful (Entries 1–4). The use of (+)-sparteine surrogate 690279 is not limited to organolithium-mediated processed reactions, magnesium, copper, and palladium are also successful. Exceptional examples include sparteine-mediated Grignard reactions in the desymmetrization of meso-anhydrides (Entry 5), and the copper(II)-mediated dynamic thermodynamic resolution of racemic BINOL (Entry 6).

Sigma-Aldrich is pleased to now offer (+)-sparteine surrogate 690279 thus allowing access to a range of products of opposite absolute configuration to those obtained by using (-)-sparteine.References: (1) (a) Hoppe, D.; Hense, T . Angew. Chem., Int. Ed. Engl., 1997, 36, 2282 (b) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S. ;Thayumanavan, S. Acc. Chem. Res., 1996, 29, 552 (c) Clayden, J. Organolithiums: Selectivity for Synthesis, Pergamon, New York, 2002 (d) Gawley, R. E.; Coldham, I. The Chemistry of Organolithium Com-pounds, in The Chemistry of Functional Groups, ed. Z. Rappoport and I. Marek, Wiley, Chichester, 2004, p. 997 (e) Hoppe D.; Christoph, G. ibid., p. 1077. (2) (a) O'Brien, P. Chem. Commun. 2008, 655 (b) Dearden, M. J.; McGrath, M. J.; O'Brien, P. J. Org. Chem. 2004, 69, 5789. (3) Dixon, A. J.; McGrath, M. J.; O'Brien, P. Org. Synth. 2006, 83, 141.

(+)-Sparteine Surrogate & (-)-Cytisine

For more information, visit aldrich.com/sparteine

Sample Preparation and Purification Solutions

Supelco offers a wide range of products for sample preparation and purification including:

• Solid phase extraction cartridges for sample cleanup

• Flash cartridges for Isco, Biotage and Analogix flash systems

• Glass flash chromatography columns

• TLC plates, hardware and reagents

• Polymeric resins for low-pressure liquid chromatography

For more information, please visit sigma-aldrich.com/spe

8 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Cata

lysis

CatalysisDr. Josephine NakhlaProduct Manager

josephine.nakhla@sial.com

Air-Stable Precatalysts for Amination

C–N bond forming cross-couplings typically require a palladium (Pd) source along with the associated ligands. Most Pd(0) sources are not air-stable, while the commonly employed air-stable Pd(0) source, Pd2(dba)3, contains associated ligands which could impede the reaction. Stable Pd(II) precursors require reduction under the reaction conditions. In either case, a ligand must be added to the reaction in order to lead to the active Pd-species. Buchwald and coworkers recently reported the use of highly-active air- and moisture-stable precatalysts, which, under the standard reaction conditions, form the active monoligated Pd-species directly. These precatalysts are exceptionally efficient even under challenging conditions, such as coupling electron-poor anilines with deactivated aryl chlorides (Scheme 1). These catalyst precursors also offer other advantages including low catalyst loadings and short reaction times.1

NH2

+

ClR

K2CO3, t-BuOH, 1h, 110 °C

HN

EtO2COCH3

86%

HN

NC

OCH3

OCH3

HN

O2N n-Bu

PdNH2Cl

i-Pr

i-Pr

i-Pr

PCy2

1 mol %

99% 97%

704954EWG

HN

EWG R

HN

i-Pr

i-Pr CHO90%

(with 707589)

Scheme 1: The use of 704954 in N-arylations of electron-poor amines with electron-rich aryl chlorides.

Reference: (1) Biscoe, M. R. et al. J. Am. Chem. Soc. 2008, 130, 6686.

Buchwald Precatalysts

For more information on these and related ligands and catalysts, visit aldrich.com/buchwald

Ultra-Fast Initiating Ruthenium Catalysts for Low-Temperature MetathesisTraditional Grubbs catalyst systems are five-coordinate ruthenium complexes containing two neutral ligands, one of which is typically a phosphine, or in the case of the Hoveyda-Grubbs catalysts, a styrenyl ether. Ligand dissociation is required to provide the active catalyst, but is slow at low temperatures and, therefore, traditional Grubbs catalysts suffer from decreased reactivity at low temperatures. The Piers group developed preformed 4-coordinate cationic complexes that do not require ligand dissociation prior to reaction, allowing for efficient metathesis at lower temperatures. The reaction progress was examined for the cyclization of diethyldiallylmalonate to provide the corresponding cyclopentene derivative using both the Piers catalyst and the Grubbs catalyst at 0 °C (Scheme 2). At this temperature, the Grubbs catalyst (2nd Generation) was found to be a weak initiator and, after 4 hours, the reaction had progressed only to 25% completion, while the cationic complex had progressed to >90% completion after 2 hours. The initiation rate of the cationic catalyst at 0 °C was found to be comparable to the initiation rate of the Grubbs catalyst (2nd Generation) at 35 °C. In a subsequent study, Piers and coworkers examined the intermediates in an olefin metathesis reaction by NMR at –50 °C. This was the first direct observation of a ruthenacyclobutane intermediate and provided evidence for a symmetrical intermediate. It also illustrated the stabilizing effect of the N-heterocyclic carbene ligand on the Ru(IV) species.1

EtO

O

OEt

O

EtO

O

OEt

O(1 mol %)

CD2Cl2, 0 °C, 2h

RuPCy3

Cl

Cl

NN

BF4

>90% conversion

25% completion with Grubbs Catalyst (2nd Generation)

Scheme 2: Fast initiating ruthenium catalysts for low-temperature metathesis.

The Piers-Grubbs Catalysts

US Patent No. 7,365,140 (and associated foreign equivalents) owned by UTI Limited Partnership and licensed to Materia, Inc. apply. Sale of this product conveys to the buyer a limited-use research license. For full details of this license please see sigma-aldrich.com/materialicense. For questions please contact us at aldrich@sial.com or Materia at info@materia-inc.com.

For more information on our olefin metathesis portfolio, visit aldrich.com/metathesiscatalysts

PdNH2Cl

i-Pr

i-Pr

i-Pr

PCy2

PdNH2Cl

PCy2OCH3

OCH3

PdNH2Cl

PCy2Oi-Pr

Oi-Pr

PdNH2Cl

i-Pr

i-Pr

i-Pr

P t-Bu2

704954(from XPhos)

704946(from SPhos)

707589(from RuPhos)

708739(from t-BuXphos)

Ru

PCy3

PCy3

Cl

Cl

BF4

RuPCy3

Cl

Cl

NN

BF4

707961Piers-Grubbs

1st Generation Catalyst

707988Piers-Grubbs

2nd Generation Catalyst

9Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

Catalysis

Ring-Closing Alkyne Metathesis (RCAM)Alkyne metathesis has been a useful tool for C–C bond formation since the discovery of structurally well-defined metal alkylidynes by Schrock and coworkers.2 These complexes have found use in the synthesis of complex natural products and in material science.3 The limitations of these catalysts include air- and moisture-sensitivity as well as incompatibilities with substrates that contain donor sites. Fürstner and co-workers have recently developed an air-stable molybdenum catalyst for alkyne metathesis, which proved versatile and compatible with substrates containing donor sites.4 The authors also examined the use of this catalyst in the ring-closing cross metathesis (RCAM) of a variety of alkynes in generating various macrocycles in good yields (Scheme 3).

Mo

N

Ph3SiO OSiPh3

Ph3SiO N

(20 mol %)

O

OO

O

87%

NO

54%

Scheme 3: Air-Stable molybdenum catalyst for alkyne metathesis

Mo

N

Ph3SiO OSiPh3

Ph3SiO N

Mo

CH3

NO

O

t-BuH3C

H3CH3C

H3C t-Bui-Pr

i-PrCH3

719684 73022

The Grubbs Catalysts

For more information on our olefin metathesis portfolio, visit aldrich.com/metathesiscatalysts

Except for 577944 one or more of the following US Patent No.: 6,111,121; 7,329,758; 5,969,170: 6,759,537; 6,921,735; 7,365,140 (and associated foreign equivalents of the foregoing) apply. US Patent Application No. 11/094,102 (and associated foreign equivalents of the foregoing) apply for 682381. Sale of these products conveys to the buyer a limited-use research license. For full details of this license please see sigma-aldrich.com/materialicense. For questions, please contact us at aldrich@sial.com or Materia at info@materia-inc.com.

References: (1) (a) Romero, P. E. et al. Angew. Chem. Int. Ed. 2004, 43, 6161. (b) Romero, P. E.; Piers, W. E. J. Am. Chem. Soc. 2005, 127, 5032. (2) Schrock, R. R. Chem. Rev. 2002, 102, 145. (3) (a) Fürstner, A. et al. Chem. Commun. 2005, 2307. (b) Schrock, R. R. et al. Adv. Synth. Catal. 2007, 349, 55. (4) Bindl, M. et al. J. Am. Chem. Soc. 2009, 131, 9468.

Molybdenum Metathesis Catalysts

RuPh

PCy3

Cl

Cl

NN

Ru

PCy3

PhPCy3

Cl

ClRu

PhN

Cl

Cl

NN

N

Br

Br

Ru

PCy3

O

Cl

Cl

Ru

O

Cl

Cl

NN

RuPCy3

Cl

Cl

NN

BF4

Ru

PCy3

PCy3

Cl

Cl

BF4

Ru

PCy3

PCy3

Cl

Cl

Ru

PCy3

Cl

Cl

NN

Ru

N

Cl

Cl

NN

Ru

O

Cl

Cl

NN

RuPh

PCy3

Cl

Cl

NN

579726Grubbs 1st

Generation Catalyst

569747Grubbs 2nd

Generation Catalyst

682330Grubbs 3rd

Generation Catalyst

577944Hoveyda-Grubbs

1st Generation Catalyst

569755Hoveyda-Grubbs

2nd Generation Catalyst

707961Piers-Grubbs

1st Generation Catalyst

707988Piers-Grubbs

2nd Generation Catalyst

578681

682365 682381 682284 682373

For more information on our olefin metathesis portfolio, visit aldrich.com/metathesiscatalysts

10

Chem

ical

Bio

logy

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Chemical BiologyDr. Matthias JunkersProduct Manager

matthias.junkers@sial.com

COMU—Safer and More Efficient Peptide Coupling Reagent Proteins and peptides are ubiquitous in

all living systems. The chemical synthesis of peptidic structures for scientific research or drug discovery relies heavily on efficient coupling reagents. This is especially true for solid phase peptide synthesis—only reagents that yield quantitative results with short reaction times allow the economical synthesis of large peptides. Furthermore, a low tendency for racemization is a key requirement.

A plethora of methods for the formation of the amide bond have been reported. The most successful approaches known today involve active ester formation with uronium/guanidinium salts. The most popular members of this family are peptide synthesis reagents based on a zobenzotriazole and benzotriazole derivatives, such as HOBt or HOAt, both of which are also commonly used as additives in carbodiimide-mediated peptide coupling (Scheme 1).

NN

N

OHN N

NN

OH

HOBt HOAt

N NN

N

O-

HBTU (TBTU) HATU

NN+

NN

N

O-

NN+

PF6-

CH3

H3C

CH3

CH3CH3

H3C

CH3

CH3

+ +PF6- (BF4

-)

Scheme 1: A zobenzotriazole and benzotriazole based coupling reagents

and additives.

HBTU, TBTU, and HATU are the most common peptide coupling reagents based on HOBt and HOAt. How can these successful reagents be improved further? Recent findings in the groups of Fernando Albericio in Spain and Ayman El-Faham in Egypt, showed that the incorporation of a hydrogen bond acceptor in the iminium part of the coupling reagent resulted in a significant performance improvement. Replacing one dimethylamino moiety with a more polar morpholino group proved to enhance stability, solubility, and reactivity of the reagent.1

Some safety concerns also lead to a strong demand for improvements. HOBt derivatives have generally been regarded as potential explosives. Recent transportation reclassifications have made economical shipping and storage increasingly difficult. Currently, HOBt can only be offered commercially in the form of a hydrate. In search for efficacious replacements for benzotriazoles, the Albericio and El-Faham groups demonstrated that ethyl (hydroxyimino)cyanoacetate (Oxyma) is a potent alternative to HOBt or HOAt (Scheme 2).2

OHN

CNO

OH3C

Oxyma COMU

N+ N

O

O

H3C

CH3

N

CNO

OH3CPF6

-

Scheme 2

In direct comparison to HOBt and HOAt, ethyl (hydroxyimino)cyanoacetate (Oxyma) showed a remarkable capacity to inhibit racemization as an additive in carbodiimide-mediated amide bond formation. Impressively, its coupling efficiency in solid and liquid phase peptide coupling is superior to HOBt, and at least comparable to HOAt.2 DSC and ARC studies of Oxyma show only low thermal risks.

Combining the above findings—the advantageous influence of a morpholino group in the peptide coupling reagent, and the potency of ethyl (hydroxyimino)cyanoacetate (Oxyma) to substitute the benzotriazole moiety as a leaving group—the groups of Albericio and El-Faham dveloped COMU (712191) as a safer and more efficient coupling reagent.3 Is this rising star able to beat its predecessors?

HBTU, HATU, and similar peptide coupling reagents based on benzotriazoles predominantly exist in the less reactive guanidinium or N-form, which is less reactive than the uronium or O-form.4 (Scheme 3)

N N+N

N

O-

NN+

PF6-

N NN

N

O

PF6-

N

N+

CH3

H3C

CH3

CH3

H3CCH3

CH3

CH3

Scheme 3: Guanidinium and uronium form of HATU (also called N- and

O-form)

Notably, COMU solely exists as the more reactive uronium structure. Comparative studies proved that COMU exhibits a similar capacity as peptide coupling reagent as the current gold standard, HATU.3 As an outstanding example, the highly demanding synthesis of the Aib-analog of the Leu-enkephalin pentapeptide H-Tyr-Aib-Aib-Phe-Leu-NH2 impressively underlines the superior qualities of COMU. Using COMU, allows the desired product to get synthesized with quantitative yields. Only traces of deletion sequences are found while other coupling reagents including HBTU and HATU, give considerably poorer results. (Table 1)

Reagent Pentapeptide yield Des-Aib deletion sequenceHBTU 47.0% 53.0%

HATU 83.0% 17.0%HOTU 99.0% 1.0%COMU 99.7% 0.26%

Table 1: Coupling efficiency of different coupling reagents

233412 712191

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Chemical Biology

In a recent investigation Albericio and El-Faham could also show that COMU is fully compatible with microwave-assisted peptide synthesis. Using the same model synthesis of the Aib-analog of the Leu-enkephalin pentapeptide as above COMU clearly outperformed other coupling reagents like HATU or HBTU in direct comparison.5

COMU features optimal properties as a peptide coupling reagent. In addition to its high and fast coupling efficiency, it shows very low or non-existent tendencies for racemization. Epimerization during fragment coupling appears to be lessened with COMU than with HOBt or HATU. COMU is very soluble with remarkable stability in most commonly employed peptide coupling solvents, such as DMF or NMP, which makes it ideally suited for solid phase peptide synthesis. It is equally attractive for solution phase synthesis since by-products formed by COMU are water-soluble and can be separated by simple extraction. A color change during the reaction allows visual or colorimetric reaction monitoring (Figure 1). DSC and ARC data indicate a substantial reduction in the likelihood of a thermal event with COMU.

Figure 1: Coupling reaction 2 minutes after the addition of COMU with TMP as base (left) and after 1 h with the reaction completed (right).

COMU can be used with nearly identical protocols that apply for common coupling reagents such as HBTU, TBTU, PyBOP, or HATU. Dedicated procedures for the utilization of COMU in solution and solid phase peptide synthesis have been published.6 In circumstances where racemization is a major concern, COMU allows modifications of typical protocols: COMU's morpholino group acts as an internal base during the coupling reaction. Consequently, the addition of external base may be reduced from two to one equivalent. Additionally, the commonly applied DIEA (diisopropylethylamine) can be replaced by the less basic TMP (2,2,6,6-tetramethylpiperidine).

Advantages of COMUEqual or even superior performance to HATU•Non-explosive (does not contain benzotriazole moiety)• Equally suitable for both solution and solid phase •peptide synthesis

Suitable for microwave-assisted solid phase peptide synthesis•Utmost retention of configuration–low to non-existent •racemization observed

High solubility and stability in all typical solvents•Visual or colorimetric reaction monitoring possible•Easy removal of water-soluble by-products•

References: (1) El-Faham, A.; Albericio, F. J. Org. Chem. 2008, 73, 2731. (2) Oxyma: An Efficient Additive for Peptide Synthesis to Replace the Benzotriazole-Based HOBt and HOAt with a Lower Risk of Explosion; Subirós-Funosas, R.; Prohens, R.; Barbas, R. El-Faham, A. Albericio, F. Chem. Eur. J. 2009, 15, 9394. (3) COMU: A Safer and More Effective Replacement for Benzotriazole-Based Uronium Coupling Reagents; El-Faham, A. Subirós-Funosas, R. Prohens, R. Albericio, F. Chem. Eur. J. 2009, 15, 9404. (4) Carpino, L.A. et al. Angew. Chem., Int. Ed. 2002, 41, 441. (5) Microwave irradiation and COMU: a potent combination for solid-phase peptide synthesis; Subiros-Funosas, R.; Acosta, G.; El-Faham, A.; Albericio, F. Tet. Lett. 2009, 50, 6200. (6) El-Faham, A.; Albericio, F. J. Pept. Sci. 2010, 16, 6.

Peptide Coupling

712191 233412 445460 12804

N+N

O

O

CH3

CH3

N

NC

O

O CH3

PF6-

CN

NO

OHO CH3N N

NN

O

NCH3

CH3

NCH3

CH3

PF6N

N

NO

N CH3

N CH3

H3C

CH3

PF6

12806 02576 711489 41996

NO

NN

N+

N

CH3

CH3

CH3H3C

BF4– N+

NO

CN

NO

OCH3H3C

CH3

CH3

CH3

PF6–

NN

N

OH

• xH2O N NN

N

OH

115754

NH

H3CH3C

CH3

CH3

For more informaton please visit aldrich.com/comu

12 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Org

anom

etal

lic R

eage

nts

Organometallic ReagentsDr. Josephine NakhlaProduct Manager

josephine.nakhla@sial.com

MIDA Boronates for Suzuki–Miyaura Cross-CouplingsBurke and coworkers recently prepared retinal using newly-developed

methodology, which employs boronic acid surrogates, termed MIDA boronates (retinal synthesis employed key MIDA building block BB1—Scheme 1) in Suzuki-Miyaura cross coupling reactions. The caged boronic acid derivatives are suitable for various historically challenging couplings as well as iterative Suzuki couplings for the preparation of other complex molecules. The many advantages to the MIDA boronate platform include the air and moisture stability, stability under anhydrous cross-coupling conditions, compatibility in the presence of common and harsh reagents, solubility in various organic solvents, silica gel compatibility, and the ability to undergo slow release cross-coupling.

CH3

CH3H3C CH3

B(OH)2

BO

N

OOBr

BB1

BO

N

OO

CH3

CH3

H3C CH3

Pd(OAc)2, SPhos, K3PO4

23 °C, 78%toluene

1. aq. NaOH, THF, 23 °C

2.

23 °C, 66%

CH3

CH3

H3C CH3CH3 H

OBr

CH3

O

H

Pd(OAc)2, SPhos, K3PO4, THF

703478

H3C

H3C

O

O

all-trans-retinal

Scheme 1: Iterative Suzuki cross-coupling reaction in the synthesis of all-trans-retinal

Discover MIDA Boronates

Reference: (1) Lee, S. J. et al. J. Am. Chem. Soc. 2008, 130, 466.

For more information on MIDA boronates and a complete product listing visit aldrich.com/mida.

New Reagents for Selective Metalation, Deprotonation, and 1,2-Additions Selective Metalations using i-PrMgCl•LiCl and s-BuMgCl•LiCl While halogen-metal exchange reactions are among the most common methods for preparing organometallic reagents, Li-halogen exchange reactions typically require low temperatures and offer limited compatibility with other functionalities. On the other hand, Mg-halogen exchange requires higher temperatures and the reagents are sometimes prone to elimination of HX (generating an olefin) because of their lower reactivity. Knochel and coworkers found the use of salt additives increased both the rate and the efficiency of the Mg-halogen exchange reaction. The most effective reagents were generated with R-MgCl (R = i-Pr, s-Bu) and 1.0 equiv of LiCl (termed TurboGrignards). The increased reactivity may be due to the breakup of polymeric aggregates known to exist in typical Grignard reagents as well as an increase in reactivity due to a negative charge on magnesium in i-PrMgCl2-Li+. TurboGrignards allow the conversion of a variety of functionalized and highly sensitive substrates (including those containing functionalities such as CO2R, CN, OMe, and halogens)to their corresponding functionalized organometallic reagents, including both aryl- and heteroarylmagnesium derivatives. While rate enhancements are observed with the TurboGrignards, this increased reactivity does not have a negative impact on the overall scope of the reaction, permitting transformations to occur in the presence of a broad range of functional groups (Table 1).1

Br

FG

MgCl LiCl

FG

•

(TurboGrignard)

FG = CO2R', CN, OCH3, halogen

i-PrMgCl LiCl•

THF, -15 °C to 25 °CE

E

FG

656984

or heteroaryl halide

MgCl LiCl•

i-PrO O OO

Ph 80a

N

MgCl LiCl•Br

MgCl LiClN

S

•

N

AllylBr

N

S

OH

ElectrophileReagentEntry

2

3

Product IsolatedYield

93b

87

Allyl bromide

PhCHO

PhCHO

1

aThe halogen-metal exchange was conducted in THF/DMPU.bGrignard was transmetalated with CuCN 2LiCl before addition of E.•

Ph

Table 1: Aryl/Heteroaryl Grignards prepared using i-PrMgCl•LiClandreaction with electrophiles

697311 698709 700231 708828

BO

N

OOO

H3C

H2CB

O

N

OOO

H3C

B

O

N

O

OO

HC

H3C

B

O

N

O

OO

H3C

S

707252 704415 700908 699179

BO

N

OOO

H3C

CH2

H3C B

O

N

O

OO

H3C

H2C BO

N

OOO

NCl

H3C

BO

N

OOO

N

H3C

13Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

Organom

etallic Reagents

In summary, the advantages of the TurboGrignards include:

Increased functional group compatibility•Mild reaction conditions•Convenient range of temperatures•Side reactions inhibited•Preparation of functionalized heteroaryl organometallics•Large-scale production is feasible •

Reference: (2) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333. (b) Knochel, P EP 1582 524 A1.

Turbo Grignards

For more information on these new reagents, visit aldrich.com/metalations

Selective Deprotonations using Knochel-Hauser-BaseDeprotonation and functionalization of aromatics is a key synthetic transformation. However, common strong organic bases such as alkyllithiums or lithium amides cause competing addition reactions (Chichibabin reactions). Additionally, many amides must be generated in situ due to their low stability in solution. Finally, the low temperatures required when using these bases makes their use somewhat inconvenient. Knochel and coworkers have reported the use of 2,2,6,6-Tetramethylpiperidinylmagnesium chloridelithiumchloride(TMPMgCl•LiCl)(Knochel-Hauser-Base)for regioselective deprotonation of arenes and heteroarenes. After further elaboration via addition of an electrophile, regioselective access to functionalized arenes and heteroarenes in excellent yields is achieved.3TMPMgCl•LiCloffersabroadenedreactionscopeandtolerates a variety of functional groups, while preventing undesired side reactions (Table 2). The authors believe that oligomeric aggregatesarebrokenupinthepresenceofTMPMgCl•LiCl.

NH3CH3C CH3

CH3

MgCl• LiCl

703540DG

H

FG

DG

FG(Knochel-Hauser-Base)

MgCl LiCl•

FG = CO2R, CN, CORDG = directing group, e.g. OBoc, CO2R, etc.

or heteroarene

E

DG

FG

E

TMPMgCl LiCl•

TMPMgCl LiCl =•

ElectrophileGrignard ReagentaEntry

1

2

3

4

5

Product IsolatedYield

90

94

aLiCl and TMPH are complexed to the Grignard reagent.bDeprotonation reaction conditions

N MgCl

Br Br

O

S

N

S

S

N

MgCl

MgCl

MgCl

MgCl

DMF

PhCHO

DMF

DMF

I2

N CHO

Br Br85

OCHO

SCHO

N

S

Ph

OH

S

NI 98

81

T [°C], t [h]b

-25, 0.5

25, 24

25, 24

0, 0.1

0, 0.1

Table 2: HeteroarylGrignardspreparedusingTMPMgCl•LiClandreactionwith electrophiles

In summary, the advantages of the Knochel-Hauser-Base includes the following:

High functional group tolerance•High kinetic activity due to LiCl•Regioselective metalation of arenes/heteroarenes•No Chichibabin reactions•Increased basicity•Solubility in THF•

Reference: (3) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958. (b) P. Knochel, EP 04008081.4

Knochel-Hauser-Base

For more information on these new reagents, visit aldrich.com/metalations

656984 703486

CH3

H3C MgCl LiCl•

MgCl LiCl•

703540

NH3CH3C CH3

CH3

MgCl• LiCl

14 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Org

anom

etal

lic R

eage

nts

Selective 1,2-Additions with LaCl3•2LiClLanthanide salts have been shown to prevent competing reduction and enolization side reactions in the nucleophilic addition to ketones. However, both the solubility as well as the nature of the drying method of lanthanide complexes have historically limited the scope of their use. The addition of LiCl has resulted in enhanced reactivity of several organometallic reagents; thus, Knochel and coworkers prepared LaCl3•2LiClandfounditto be soluble in THF. In the presence of the oxophilic LaCl3•2LiCl,even sterically hindered and or enolizable ketones and Michael acceptors as well as unactivated imines can undergo 1,2-additions cleanly to provide the desired product resulting in a much improved reaction scope (Table 3).4

i-PrMgCl

KetoneGrignardReagentEntry

1

2

3

Productwith

LaCl3 2LiClc

92

92

81

•

N

MgCl LiCl•

Br

OPh Ph EtO2C

Bn

OHBn

PhO Ph

OH

N

Br

no additivesa

3-5

with CeCl3b

72

39 11

35 __

•

Yield (%)

aIsolated yield of product based on reaction between ketone and Grignard reagentbIsolated yield of product in the presence of 1.5 eq CeCl3 (Dimitrov Method)cIsolated yield of product in the presence of 1.0 eq LaCl3 • 2LiCl

OOH

i-Pr

MgCl LiCl

EtO2C

R1MgCl +R3

OR2

R3

OMgClR2

0 °C, 10 min-6h

703559LaCl3 2LiCl•

R1

Table 3: LaCl3•2LiClmediatedadditiontoketones

Subsequent to the initial studies with the lanthanide salt-LiCl complexes, Knochel and coworkers reported that sub-stoichiometric quantities of the lanthanide salt were sufficient to promote the desired 1,2-addition, as demonstrated in the addition of i-PrMgCl•2LiCltounactivatediminederivatives(Scheme 2). This protocol was amenable to use of alkyl, aryl, and heteroaryl Grignard reagents.5

OMe

N

Ph

•+

LaCl3 LiCl•

(10 mol %)

THF, rt, 12h

OMe

HN

Ph i-Pr

84%i-PrMgCl LiCl

Scheme 2: 1,2-Addition of organomagnesium reagents in the presence of catalytic LaCl3•2LiCl

In summary, the advantages of LaCl3•2LiClincludethefollowing:

Low water content•No pretreatment necessary•Ease of handling•Results in homogenous reactions•Convenient reaction conditions•

Reference: (4) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 497. (5) Metzger, A.; Gavryushin, A.; Knochel, P. Syn Lett 2009, 1433.

Lanthanum(III) chloride bis(lithium chloride) complex solution

For more information on these new reagents, visit aldrich.com/metalations

Sold in collaboration with

703559LaCl3 2LiCl•

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Build

ing

Bloc

ks

Building BlocksDr. Mark RedlichProduct Manager

mark.redlich@sial.com

Unprotected Amino AldehydesProfessor Andrei Yudin and his students have recently described the preparation

of bench-stable, unprotected a-amino aldehydes.1 These kinetically amphoteric molecules exist as dimers (eq 1), and due to the strain of the aziridine ring, resist inter- and intramolecular iminium ion formation. Furthermore, the two functionalities remain orthogonal to each other throughout their transformations, allowing for the reaction of the aldehyde without the requirement of an additional protecting group.

H

ON

R

ON

R N

OH

R

H H

(eq 1)

Whereas the reductive amination of protected amino aldehydes has significant limitations due to epimerization or overalkylation, these Yudin amino aldehyde dimers do not suffer from either limitation, due to a negligible concentration of free aldehyde during the reaction. This allows the researcher facile access to a method for the creation of complex polycyclic skeletons2 or peptidomimetic conjugates3 with a high degree of stereocontrol. Nucleophilic additions,4 Wittig and related olefination reactions, can be carried out with high selectivities and yields.

More recently, the Yudin group has reported the use of the amino aldehydes as electrophiles in a domino aza-Michael/aldol reaction, which generated aminohydroxy a, b-unsaturated aldehydes in high yields (Scheme 1).5 The products from this transformation are not accessible through the more common Baylis–Hillman reaction due to the substitution pattern on the olefin.

R1NH

O

H+

20 mol % benzoic acid20 mol % pyrrolidine

MeCN, rt

O

H

R2

O

H

R2

R1NH

OH

80 - 90%dr >20:1

Scheme 1

Additionally, the Yudin amino aldehydes are also easily olefinated through a Wittig protocol in good to excellent yield (Scheme 2). These vinylaziridines can then be employed in the construction of azepines or heterobicycles though a ring-opening or a cascade ring-opening/ring-contraction route, respectively (Scheme 3).6

R1NH

O

HR1

NH Ph3P

R3

CO2Et

TFE, rtR3

OEt

O

63 - 98%

R3 PPh3R2

R2 Br

t-BuOK, THF, 3 hR3

R1NH

65 - 88%

R2

Scheme 2

PhNH

CO2MeMeO2C

MeO2C CO2Me

toluene, rt, 3h

DMSO, rt, 3h

N

MeO2CCO2Me

Ph

R1NH

R2

NR1

R2

CO2MeCO2Me

H

Scheme 3

Unprotected Amino Aldehydes

To browse these and other aziridines from Sigma-Aldrich, visit aldrich.com/aziridines

Halogenated PyridinesPyridines continue to be extremely popular building blocks for synthetic chemists across a number of disciplines. The pyridine moiety is found in a wide range of synthetic targets with applications in catalysis, drug design, molecular recognition, and natural product synthesis. Halogenated pyridines in particular are attractive building blocks for various cross-coupling methodologies. Sigma-Aldrich is pleased to offer these useful halogenated pyridines for your research.

For more Halogenated Pyridines, visit aldrich.com/hal-pyr

695521 695556 707686 695513

O

HNH

S

O

HNH

O

HNH

O

HNH

TBDMSO

714593 707341 704474 692816

N F

H2N

N NH2

F

N NH2

I

N OCH3

I

716030 707333 711365 710830

N Cl

I

N Cl

O H

N Cl

Cl

H

O

N Cl

Cl

OH

O

709646 706299 707376 714623N Cl

O H

Cl N Cl

O OH

Cl

N F

CF3

OH

O

N NH2

Cl NH2

715727 714674

N Br

H3C Br

N

Br BrBr

17Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

Building Blocks

New Amines

701343 715662 700940 711357

H3CNH

NH2

O

H3CNH

OH NH

N

H2N

O

NH2

706582 688819

684090 683078

N

NH2

Boc

OH

NH2

• HCl

N NH2

NH2

O NH2

CH3

CH3

CH3

H3C

H3CH3C

713732

718335

S

NCN

H2N

N NH2

New Aldehydes and Acetals

708356NH2

OH

Br

710849

714577

N

NH2

O OH

N

OH

NH2

710814 709727 703281 709344Br

H

OHO

H

O

Si(CH3)3 ON

Cl

H3C

O

H

SH

O

SH3C

710229 710156 710113 710202

OCH3

OCH3CH3

OCH3

OCH3

CH3

OCH3

OCH3H3CO

OCH3

OCH3OCH3

References: (1) Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2006, 128, 14772. (2) Yudin, A. K.; Hili, R. Chem.—Eur. J. 2007, 13, 6538. (3) Li, X.; Yudin, A. K. J. Am. Chem. Soc. 2007, 129, 14152. (4) Hili, R.; Yudin, A. K. Angew. Chem. Int. Ed. 2008, 47, 4188. (5)Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2009, 131, 16404. (6) Baktharaman, S. et al. Org. Lett. 2010,12, 240.

For a comprehensive list of Building Blocks, visit Chem Product Central at aldrich.com/chemprod

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Synt

hetic

Rea

gent

s

Synthetic ReagentsDr. Mark RedlichProduct Manager

mark.redlich@sial.com

PTS: Powerful Amphiphile for Organic Reactions in WaterPolyoxyethanyl a-tocopheryl sebacate,

PTS, is a nonionic amphiphile recently introduced by Professor Bruce Lipshutz of UC-Santa Barbara that is proving to be a versatile "solubilizer" for organic molecules in water.1 Lipophilic substrates and catalysts can efficiently enter the 25-nm micelles formed by PTS in water leading to important cross-coupling reactions such as metathesis,2 Suzuki–Miyaura,3 Heck,4 and Sonogashira reactions5 at room temperature. Importantly, there is no need for a co-solvent to enhance water solubility of lipophilic substrates in these reactions. One simply places the requisite amount of PTS (15 wt % in water) into a test tube with a stir bar and adds the organic substrate(s) and catalyst. Reactions are generally complete within 3–24 hours and can be accelerated if needed upon mild heating to 40–50 °C. Work-up is also very simple, involving either extraction of the reaction mixture with EtOAc-hexane or deposition onto a bed of silica gel and elution with EtOAc.

In the past couple of years, Lipshutz and co-workers have been rapidly expanding the range of successful applications of micellar catalysis using PTS in water. Palladium-catalyzed allylic aminations of allylic alcohols proceed smoothly in water giving good to excellent yields with good selectivity. The allylic amination was applied to a one-pot synthesis of the antifungal agent naftifine at room temperature, which previously was accessible only through multi-step or high temperature processes (Scheme 1).6

+

cat. Pd(0), biphep

K2CO3 (3 equiv)

2% PTS/H2O, rt

HCO2Me (4 equiv)OH

PhNH

CH3 NCH3

Ph

naftifine, 83%

Scheme 1

Functionalized allylic ethers were also found to be reliable substrates for Suzuki–Miyaura coupling using PTS in water at ambient temperatures (Scheme 2).3c Catalyst loadings could be reduced as low as 0.5 mol % in some cases when the reaction is gently heated to 40 °C.

+2 mol % PdCl2(DPEphos)

Et3N, 2% PTS/H2O, rtPh OPh Ar B(OH)2 Ph Ar

70 - 99%

Scheme 2

An alternative to Negishi-type coupling was also reported by Lipshutz wherein palladium-catalyzed, zinc-mediated C–C bond forming occurs without requiring a preformed organometallic coupling partner (i.e., RZnI). Primary alkyl iodides react readily with aryl bromides in the presence of fresh zinc powder, a palladium catalyst and TMEDA in 2 wt % PTS in water to generate the adduct in good to very good yields (Scheme 3).7

+

(2 mol %)

2% PTS/H2O, rt

65 - 96%

R X

X = I, Br

Br

R'

Pd P(t-Bu)2(t-Bu)2PCl

(CH3)2N N(CH3)2

Cl

R

R'Zn, diamine

Scheme 3

The micellar catalysis methodology has recently been extended to the synthesis of allylic silanes from allylic ethers and readily available disilanes.8 The couplings are very efficient, and occur with well-controlled selectivity. The mildness of the reaction conditions in PTS-H2O media allowed for a one-pot chemoselective amination/silylation sequence to provide a dibenzylated methallylsilane in good yield, without the need for any organic solvent (Scheme 4).

2% PTS/H2O, rt

OAc OPhBn2NH, K2CO3

cat. [allylPdCl]2Xantphos

Bn2N OPh

Et3N, 2% PTS/H2O, rt

cat. PdCl2(DPEphos)[SiMe2Ph]2

Bn2N SiMe2Ph

70%

Scheme 4

Polyoxyethanyl-a-tocopheryl sebacate (PTS), 15 wt.% in water

O

O

OO

O H4

O

n

n = ca. 13

698717

19Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.

Synthetic Reagents

Raines Phosphine for Conversion of Azides to Diazo Compounds Due to difficulties with their preparation, especially when sensitive functional groups are present, diazo compounds are often overlooked in synthesis despite their synthetic versatility. Raines and Myers have developed a mild method to convert an azido group in the presence of delicate functional groups using a phosphine reagent, resulting in a diazo compound (Scheme 5).9 Formally, this reaction is a reductive fragmentation of the azide, like the venerable Staudinger reaction and is highly selective in most chemical environments.

ON

OO

OP

R1 R2

N3

R1 R2

N2

1.05 eq

715069

1) THF/H2O (20:3), 3-12 h

2) Sat. aq. NaHCO3, 15 min - 12 h

49 - 97%

Scheme 5

N-Succinimidyl 3-(diphenylphosphino)propionate, 95%

ON

OO

OP

715069

Ethyl 5-[(4-methylphenyl)sulfonyl]- 3-oxopentanoate: A Bench-Stable Precursor for Nazarov's ReagentNazarov's reagent is a commonly used annulating agent, but its synthesis is often fraught with poor yields or difficulties isolating the material. De Risi and coworkers recently reported the synthesis and application of ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate, which is a bench-stable powder that can be stored at room temperature without any special precautions, and demasked under various conditions to form ethyl 3-oxopent-4-enoate (Nazarov's reagent) in situ to generate annulated products (Scheme 6).10

OEtS

O OO

OH3C

718327

O

O

KF, MeOH, rt, 24 h

H3CO

CO2EtO

50%Scheme 6

Ethyl 5-[(4-methylphenyl)sulfonyl]-3-oxopentanoate, 95%

OEtS

O OO

OH3C

718327

Potassium 2-isocyanoacetate: Quenching Reagent for MetathesisDiver and co-workers recently described an efficient metathesis clean-up procedure using potassium 2-isocyanoacetate,11 which addresses the challenges associated with removal of the ruthenium at the end of a metathesis reaction. Upon quenching with the polar isocyanide, a benzylidene insertion of the mesityl group occurs, thus destroying the catalyst and imparting increased polarity for easy removal (Scheme 7). Potassium 2-isocyanoacetate was successfully used to quench a range of metathesis reactions and the authors demonstrated it can be employed with various highly utilized Grubbs' complexes.

Ru

Cl

Cl

PhPCy3

NNNN

Ru C NCN CH2CO2KKO2CCH2

PCy3

NCO2K

C

705438

MeOH, rt, 30 minPh

metathesis-inactivepolar & easy to remove

metathesis-active

Cl

Cl

Scheme 7

Potassium 2-isocyanoacetate

NCOK

O

705438

References: (1) Sold under license from Zymes, LLC. (2) a) Lipshutz, B. H. et al. Org. Lett. 2008, 10, 1325. b) Lipshutz, B. H. et al. Adv. Synth. Catal. 2008, 350, 953. (3) a)Lipshutz, B. H. et al. Org. Lett. 2008, 10, 1333. b) Lipshutz, B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329. c) Nishikata, T.; Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 12103. (4) a)Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329. b) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta, 41, 59. (5) Lipshutz, B. H. et al. Org. Lett. 2008, 10, 3793. (6) Lipshutz, B. H.; Nishikata, T. Org. Lett. 2009, 11, 2377. (7) Krasovskiy, A. et al. J. Am. Chem. Soc. 2009, 131, 15592. (8) Moser, R. et al. Org. Lett. 2009, 11, ASAP. (9) Myers, E. L Raines, R. T. Angew. Chem. Int., Ed. 2009, 48, 2359. (10) Benetti, S. et al. Synlett 2008, 2609. (11) Galan, B. R. et al. Org. Lett. 2007, 9, 1203.

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m R

eage

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Stockroom ReagentsTodd HalkoskiMarket Segment Manager Solvents

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Sigma-Aldrich® is a leading global supplier and manufacturer of high quality, stockroom and

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Aldrich NM

R Solvents

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Aldrich NMR SolventsChallenge Us... and see why our Quality is Unsurpassed!

High quality NMR solvents are essential for satisfying the most rigorous demands of NMR-based research and analyses. At Aldrich, we are passionate about providing this high level of quality to our customers and work continuously to meet these requirements. We offer the widest range of NMR solvents with the highest isotopic enrichment available along with excellent chemical purity. We consistently review and improve our methods for solvent purification and for the reduction of water content in our already high quality NMR solvents. All of our NMR solvents undergo thorough quality control testing during the manufacturing and packaging processes to verify that the product quality is preserved.

Aldrich also offers unparalleled convenience and service. Our award-winning website allows for quick product searching, easy ordering, and a wealth of valuable tools and information to aid your research efforts. We also offer on-site stocking programs for NMR solvents so they are available to you for immediate use. If you have technical questions, you can feel comfortable knowing our knowledgeable and well-trained technical service specialists can answer your toughest questions.

New! NMR Solvents Brochure

Extensive product lists•Specialty solvents•NMR reference data•Additional products for NMR•

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For a complete listing of all NMR-related products and information, visit aldrich.com/nmr

Most deuterated NMR solvents readily absorb moisture. To minimize the chance of water contamination, use carefully dried NMR tubes and handle NMR solvents in a dry atmosphere.

How to Obtain a Nearly Moisture-free Surface1. Dry glassware at ~150 °C for 24 hours and cool under an inert

atmosphere.

2. Rinse the NMR tube with the deuterated solvent prior to preparing the sample. This allows for a complete exchange of protons from any residual moisture on the glass surface.

3. For less demanding applications, a nitrogen blanket over the sample preparation setup may be adequate.

How to Avoid Sources of Impurities and Chemical Residues1. Use clean, dry glassware and PTFE accessories.

2. Use a vortex mixer instead of shaking the tube contents. The latter action can introduce contaminants from the NMR tube cap.

3. Residual chemical vapor from equipment can be a source of impurities; residual acetone in pipette bulbs is a common example.

How to Remove Solvent Residue1. Protonated solvent residue can be removed by co-evaporation.

2. Use a small quantity of the desired deuterated solvent, a brief high vacuum drying (5–10 min), and then prepare the NMR sample.

3. Solvents such as chloroform-d, benzene-d6, and toluene-d8, also remove residual water azeotropically.

How to Avoid TMS Evaporation1. Extended storage of TMS-containing solvents can lead to some loss of

TMS. Storing these solvents in Sure/Seal™ bottles virtually eliminates such a loss.*

2. Purchase TMS-containing solvents in single-use ampules.* To dispense the product from Sure/Seal™ bottle or septum vials, use standard syringe needle techniques. For details and recommended procedures, please refer to Aldrich Technical Bulletin AL-134 or visit our Web site at aldrich.com.

Use and Handling of NMR Solvents

22

Aldr

ich

NM

R So

lven

ts

TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.sigma-aldrich.com

Cat. No.

Solution

Application

Tube size (O.D. x Length)

611778 1% Chloroform in acetone-d6 (99.9 atom % D) 1H line shape 3 mm × 8 in.487163 1% Chloroform in acetone-d6 (99.9 atom % D) 1H line shape 5 mm × 8 in.487759 5% Chloroform in acetone-d6 (99.9 atom % D) 1H line shape 5 mm × 8 in.551341 5% Ethylbenzene, 2% TMS in chloroform-d (99.8 atom % D) 1H sensitivity 5 mm × 8 in.487112 0.1% Ethylbenzene, 0.01% TMS in chloroform-d (99.8 atom % D) 1H sensitivity 3 mm × 8 in.487104 0.1% Ethylbenzene, 0.01% TMS in chloroform-d (99.8 atom % D) 1H sensitivity 5 mm × 8 in.612065 0.1% Ethylbenzene, 0.01% TMS in chloroform-d (99.8 atom % D) 1H sensitivity 10 mm × 8 in.487147 1% 1,2-Dichlorobenzene in acetone-d6 (99.9 atom % D) 1H resolution 5 mm × 8 in.551333 12% TMS in chloroform-d (99.8 atom % D) 1H reference 5 mm × 8 in.487139 0.1 mg/mL Gadolinium(III) chloride, 0.1% DSS, 1.0% water in deuterium oxide (99.9 atom % D) Auto test 5 mm × 8 in.612073 40% 1,4-Dioxane, 5 mg/mL chromium(III) acetylacetonate in benzene-d6 (99.6 atom % D) 13C PW90, sensitivity 3 mm × 8 in.611905 40% 1,4-Dioxane, 5 mg/mL chromium(III) acetylacetonate in benzene-d6 (99.6 atom % D) 13C PW90, sensitivity 5 mm × 8 in.551368 40% 1,4-Dioxane in benzene-d6 (99.6 atom % D) 13C PW90, sensitivity 5 mm × 8 in.551384 90% Formamide in dimethyl sulfoxide-d6 (99.9 atom % D) 15N sensitivity 5 mm × 8 in.487155 1% Iodomethane-13C, 0.2% chromium(III) acetylacetonate, 1% trimethyl phosphite in chloro-

form-d (99.8 atom % D)Indirect detection test 3 mm × 8 in.

551406 0.05% a,a,a-Trifluorotoluene in benzene-d6 (99.6 atom % D) 19F sensitivity 5 mm × 8 in.611921 25% Hexamethyldisiloxane in benzene-d6 (99.6 atom % D) 29Si sensitivity 5 mm × 8 in.551392 0.0485M Triphenyl phosphate in chloroform-d (99.8 atom % D) 31P sensitivity 5 mm × 8 in.611735 0.0485M Triphenyl phosphate in chloroform-d (99.8 atom % D) 31P sensitivity 10 mm × 8 in.612162 85% Phosphoric acid in deuterium oxide (99.9 atom % D) 31P sensitivity 5 mm × 8 in. (Coaxial)

NMR Reference StandardsAldrich is a well-established supplier of solvents and reagents to the NMR community. We also offer high quality NMR reference standards to verify instrument performance. These standards allow the user to monitor key operational parameters such as PW90, sensitivity, resolution, and line shape. The Stable Isotope Group at Aldrich also provides NMR reference standards for Fluorine and Phosphorus sensitivity verification along with other applications.

We offer standards in various sizes from 1.7 mm to 10 mm O.D. and we welcome your custom requests.

Over the years, we have produced approximately 150 different types of NMR reference standards. Here are some of our more popular listings:

Our CommitmentWe realize that merely reacting to customers’ requests is not enough to maintain a leadership position in this industry. This is why we work proactively to anticipate future quality needs that are associated with the progression towards higher field NMRs.

Whether you need high quality NMR solvents, customized solvent mixtures, buffers, or NMR reference standards, we are here to assist you. Please contact your local Sigma-Aldrich representative or the Stable Isotope Technical Services Group for additional information.

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Labw

are

Not

es

Labware NotesPaula FreemantleProduct Manager

labware@sial.com

Pure Solv™ Micro Solvent Purification Systems Easy Access to Freshly Prepared Anhydrous Solvents

Many organic and organometallic reactions require solvents that are free of water and oxygen. Classically, the anhydrous solvents are prepared in the laboratory by refluxing the solvent in the presence of an active metal. This is an intrinsically hazardous operation.

The dangers of this method of solvent purification led Professor Robert Grubbs to investigate alternative methods. In collaboration with Dow, Grubbs published a method to remove water from organic solvents using activated alumina [Organometallics, 15 1558 (1996)].

This approach uses dry nitrogen or argon to push solvent at ambient temperature through a column containing the drying agent. Oxygen is removed by bubbling inert gas through the solvent reservoir prior to pushing it through the drying column.

Pure Solv Micro is a bench scale, self-contained system that permits the easy dispensing of small quantities of dry solvent at the turn of a valve. These systems are engineered for safety because they operate at very low pressure, require no electricity, and are bonded and grounded to remove hazards associated with electrostatic discharge.

How Pure Solv Micro Works1. Fill the stainless steel solvent storage reservoir with 4 L of

HPLC-grade raw solvent.

2. Degas the solvent by connecting the nitrogen line to the reservoir.

3. Pressurize the solvent reservoir to push solvent through the drying column.

4. Dry solvent is stored inside the drying column ready for immediate use.

5. Attach a collection flask to the dispensing joint.

6. Degas the collection flask using vacuum and inert gas cycling.

7. Turn the dispense valve to allow solvent to flow into the collection flask.

8. Refill the flask with inert gas.

9. Your collected solvent is now ready to use.

For additional information about Pure Solv Micro Solvent Purification Systems or to have a sales representative contact you please visit our website at aldrich.com/puresolv

7 Micron Filter

Solvent Dispense Line

Pressure Flex Quick DisconnectLine for Reservoir and Sparging

Quick DisconnectSolvent Flex Line

Solvent Reservoir

Solvent PurifyingColumn

Metering Valve

Swagelok® Value Controls:Dispense Vacuum Gas Purge

to Regulated Gas Supply

to Vacuum Source

Pressure Regulator w/Pressure Relief Valve

Pure Solv Diagram

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Labware N

otes

Wrap-It-TiesOne-piece nylon self-locking fasteners excellent for:

Securing rubber septa to glass joints•Attaching tubing to hose barbs• Closing plastic bags or •drum liners

Simply position the tie around the septum, tubing, or bag, and push the narrow end of the fastener through the locking mechanism until finger tight. Complete the operation by clinching the tie with an installing tool (shown in photo). Ties are easily removed with a side cutter or similar tool.

For more details visit aldrich.com/labwarenotes

Storage Vessels for Air-Sensitive ReagentsIf a reagent is to be used repeatedly for small scale reactions or if an unused portion is to be stored for an extended length of time, the material should be transferred from the Sure/Seal™ bottle to a suitable storage bottle or flask. Shown below are examples of storage vessels for air-sensitive reagents, left to right, Aldrich® Sure/Stor™ flask, storage bottles without joint, solvent storage flask, solvent storage/dispensing bottle.

For a complete listing of air-sensitive chemicals, solvents and Labware for handling them visit the Air-Sensitive Products Guide at aldrich.com/asguide

News and Innovation

Aldrich® solvent storage/dispensing flask, septum-inlet, with PTFE inlet valve

Designed for use with Pure Solv Micro systems with a 24/40 dispensing joint. PTFE inlet valve may be closed after filling to isolate dry solvent and to remove flask from Pure Solv system and take to different location for use. 100 mL capacity, 24/40 joint. Use septum Z565695 or Z565679.

Cat. No. Z568538

For more details visit aldrich.com/labwarenotes

KNF Laboport® PTFE vacuum pumpThis reliable Laboport pump is a chemically-resistant, double-head, dry-running vacuum pump that can be used in a wide range of laboratory applications. These pumps transfer and pump down without contamination. At the heart of this compact pump is a structured diaphragm which allows a smaller pump design while increasing the diaphragm service life.

Features

Pure transfer, evacuation and compression•Highly compatible with vapors and condensation• Chemically-resistant - suitable for aggressive or corrosive gases •and vapors

Maintenance-free•Environmentally friendly•Gastight-leakage rate 6 × 10• –3 mbar x l/s

For more details visit aldrich.com/labwarenotes

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vice

s

Chemistry ServicesMike WillisMarket Segment Manager, Chemistry Services

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The Chemistry Services group at Aldrich provides products and services to help you identify and procure the materials you need to accelerate early

stage discovery chemistry. Our businesses encompass several areas, including custom packaged reagents from DiscoveryCPR, our traditional Rare Chemical Library, procurement services, and Compound Management. It is with great pleasure that we introduce our newest addition to the lineup of Chemistry Services, ChemNavigator®. Now, by combining the capabilities of our custom packaging groups, inventory of rare and off-the-shelf chemistry, sourcing expertise, and a database of millions of compounds, Chemistry Services from Aldrich can help bridge your experiment from concept to completion, allowing you to use your internal resources more efficiently.

Our DiscoveryCPR service provides custom packaging of both Sigma-Aldrich catalog products as well as millions of other chemicals for compound library synthesis. Building blocks, catalysts, and other materials are available from stock and can be quoted within 48 hours, packaged and labeled to your stringent requirements.

The Aldrich Rare Chemical Library began in 1966 as an ancillary business to the traditional Aldrich Chemistry Handbook. Over 145,000 unique compounds are available from stock in standard packaging or can be custom packaged through our DiscoveryCPR service.

Our Chemical Sourcing service can help optimize the purchasing process, specifically for hard-to-find materials, by consolidating to a single vendor you know and trust, Sigma-Aldrich. Our procurement services help to find building blocks and compounds—simply choose what materials you require and we provide a quotation with lead-time and pricing in local currency.

Compound Management Services provides a centralized location and dedicated facilities and personnel to provide management and operation of your company's compound collections, including filling and worldwide distribution of your compounds on demand.

The addition of ChemNavigator to Aldrich's Chemistry Services group now allows researchers in medicinal, computational, and synthetic chemistry as well as chemical procurement professionals access to identify and procure the chemistry needed for drug discovery and related research.

The iResearch Library™ is the most comprehensive database of chemistry for early stage discovery efforts, tracking over 95 million chemical products represented by over 55 million unique chemical structures. These products range from drug-like compounds for testing in molecular screening to synthetic building blocks for use in chemical synthesis. You can rapidly explore a research hypothesis by purchasing existing chemical samples for testing rather than taking months to synthesize compounds in-house. Registration for access to the iResearch Library is simple and requires only a no-charge license agreement.

You can use this online access to search via substructure, keyword, or product name to find building blocks and compounds, create sets for your screening activities, and use our Chemistry Procurement Service to buy your selected compounds. In combination with our DiscoveryCPR offer, we can now supply configured material to meet all your requirements in ready-to-use formats. Lists of compounds can also be supplied to our DiscoveryCPR team to provide a simple quotation for one to thousands of compounds and building blocks from hundreds of suppliers in one easy process to simplify your buying experience.

Our ChemNavigator informatics software toolbox is also available by subscription for robust virtual screening, chemical data management, and compound library acquisition. These tools are designed to interact with the iResearch Library directly from within your research environment to complement the tools you currently utilize. Please contact us for additional information on our cheminformatics capabilities or a demo of our screening tools.

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Solar Energy•Hydrogen Economy•Batteries•Supercapacitors•Alternative Fuels•Relevant events and conferences are also highlighted.•

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Alternative EnergyPhotovoltaics, Ionic Liquids, and MOFs

Solar light is energy for everyone

Effi cient Dye-Sensitized Solar Cells for Direct Conversion of Sunlight to Electricity

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The Relentless Rise of Disruptive PhotovoltaicsIonic Liquids for Energy Storage Applications

Selected Applications of Metal-Organic Frameworks in Sustainable Energy Technologies

TM

Vol. 4, No. 4

MHC73074-504740

03-2010

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