chemfiles volume 11 number 1 - sigma-aldrich

Aldrich

VOLUME 11 NUMBER 1 2011

Asymmetricc S Synynththhesesesiisisis

Catalysis

ChChememiciccicicalalalalal BB BBiioioiiololologygg

Organonomemetatatalllllliciciccssss

BuB ilding Bloockckss

SySyntnnthehetititicc c ReReReagagagenentsts

Sttabablele I Isosotopes

StStockroom m ReReagagagenenentststs

LaLaLabwb are NoNotetess

VOLUME 11 NUMBER 1 20201111

Cyclopropylboronic acid MIDA ester: a useful building block for use in

Suzuki-Miyaura reactions.

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Introduction 3

Haydn Boehm, Ph. D.Global Marketing Manager: Chemical Synthesis

[email protected]

Dear Chemists,

Welcome to the fi rst edition of the Aldrich ChemFiles for 2011.

Aldrich ChemFiles is our FREE quarterly newsletter written by

our experts in Product Management and R&D. Our aim is to

keep you keep informed of new Aldrich Chemistry products that facilitate the latest

research methodologies and trends, and allow you to access key starting materials and

reagents more effi ciently.

As well as introducing all the latest innovations across all our product lines, each

2011 edition of Aldrich ChemFiles will be themed to a product line. Aldrich ChemFiles

11.1 focuses on Organometallic Reagents, which is very timely as it aff ords me the

opportunity to welcome Dr. Aaron Thornton as our new Organometallic Reagents

Product Manager. Our cover molecule is cyclopropylboronic acid MIDA ester, which

is a new addition to our ever-growing MIDA boronate portfolio. Aaron also highlights

our latest trifl uoroborates, a complementary strategy to MIDA boronates for selective

Suzuki-Miyaura coupling reactions. This “Organometallics issue” also features our

latest organotin reagents for Stille couplings, as well as TurboGrignards for selective

metallations.

Aldrich ChemFiles 11.1 also introduces our new iridium catalysts (Catalysis),

indoles and thiazoles (Building Blocks), reagents for organometallic chemistry in water

(Synthetic Reagents) and ChemMatrix Resin for solid phase peptide synthesis (Chemical

Biology).

We hope that Aldrich ChemFiles enables you to expand your research toolbox and

advance your chemistry more eff ectively by implementing the latest innovative

synthetic strategies.

Kind Regards,

Haydn Boehm, Ph. D.

Global Marketing Manager: Chemical Synthesis

Table of Contents

Asymmetric Synthesis ...............................................................................................................................4

Catalysis ................................................................................................................................................................8

Chemical Biology ....................................................................................................................................... 10

Organometallic Reagents .................................................................................................................... 14

Building Blocks ............................................................................................................................................ 22

Synthetic Reagents ................................................................................................................................... 24

Stable Isotopes ............................................................................................................................................ 26

Stockroom Reagents ............................................................................................................................... 28

Labware Notes .............................................................................................................................................. 30

Volume 11, Number 1

Sigma-Aldrich Corporation

6000 N. Teutonia Ave.Milwaukee, WI 53209, USA

Editorial Team

Haydn Boehm, Ph.D.Wesley SmithDean LlanasSharbil J. Firsan, Ph.D.Weimin Qian, Ph.D.

Production Team

Cynthia SkaggsCarrie SpearChris LeinTom BeckermannChristian HagmannDenise de Voogd

Chemistry Team

Aaron Thornton, Ph.D.Daniel Weibel, Ph.D.Josephine Nakhla, Ph.D.Matthias Junkers, Ph.D.Mark Redlich, Ph.D.Troy Ryba, Ph.D.Todd Halkoski Paula FreemantleMike Willis

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

4

BASF’s ChiPros®: Optically Active Intermediates

on an Industrial Scale

In recent years, single-enantiomer drugs and drug candidates have

become more and more important in the pharmaceutical and agro-

chemical industry. Therefore, effi cient methods for the synthesis of small,

homochiral intermediates, which are frequently used as building blocks

for many pharmaceuticals and crop protection agents like herbicides,

fungicides and insecticides, but also resolving agents and chiral auxilia-

ries, are of central interest.

With its ChiPros portfolio1, BASF off ers a broad and growing range of

chiral amines, alcohols, epoxides and carboxylic acids. The ChiPros tool-

box holds the best-in-class technologies of enzyme-based biocatalysis

including lipases, dehydrogenases, nitrilases, esterases, oxygenases, etc.

In addition, chemical methods such as catalytic asymmetric hydrogena-

tions and CBS reductions are utilized to further strengthen the technol-

ogy portfolio.2

ChiPros Chiral Amines

Chiral amines play an important role in stereoselective organic synthesis.

They are used directly as resolving agents, building blocks or chiral

auxiliaries. While classically available through racemic resolution with

optically active acids, biotechnological approaches also open a way to

chiral amines.3 BASF’s optimized lipase-catalyzed route to optically active

amines (Scheme 1) can be run at a scale of several thousand tons. Due

to the wide range of substrates tolerated by the enzymes, a large variety

of diff erent chiral amines and chiral aminoalcohols are commercially

available.

CH3

NH2

CH3

NH2

CH3

HN CH3

O

Lipase+

Scheme 1: Lipase-catalyzed resolution of racemic amines.

CH3

NH2

H3CO

H3CO

CH3

NH2

H3CO

H3CO

H3CCH3

NH2

CH3H3C

NH2

CH3Cl

NH2

CH3

NH2

OCH3

H3C CH3

NH2

CH3

NH2

F

CH3Br

NH2

H3C CH3

NH2

CH3

HN

CH3H3C

NH2

CH3

H3CCH3

CH3

NH2

CH3H3C

H3C CH3

NH2

CH3

NH2

CH3

CH3

NH2

CH3

NH2

H2N CH3

H3C

CH3

NH2

CH3

NH2

Cl

CH3

NH2

Cl

CH3

NH2

CH3H3C

H3C CH3

NH2

CH3

NH2

NH2

O

NH2

NH2NH2

O

NH2

O

NH2

O

H2N CH3

NH2

727288

727229

727172

727164 727156

727148

727105

727024

726974

726931

726915

726907

726850

726559

726583

726591

726621

726648726664

726680

726702

726710

726729

726737726796

726826

726540

726532 726524

726516

726494

726486

Asymmetric SynthesisDaniel Weibel, Ph.D. European Market Segment Manager, Chemical [email protected]

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

Asymmetric Synthesis 5

ChiPros Chiral Acids

Enantiopure α- and ß-hydroxy acids and esters are versatile building

blocks for the preparation of a wide range of active pharmaceutical

ingredients by incorporating them as esters, amides or ethers, or after

further derivatization, as diols, amino alcohols, thioethers.

Hydroxy acids are accessible via a range of biotransformations, among

them are the stereoselective hydrolysis of the racemic ester precursor or

reduction of the corresponding keto esters. Hydroxynitrile lyase (HNL)

processes catalyze the stereoselective addition of HCN to aldehydes and

ketones yielding single-enantiomeric nitriles.3 Application of nitrilases or

a combination of nitrile-hydratase plus amidase allows the transforma-

tion of the starting material into the desired enantiomer of the corre-

sponding acid in a dynamic kinetic resolution fi nally yielding mandelic

acid derivatives.

BASF developed proprietary processes based on dehydrogenases to off er

access to a wide range of α- and ß-hydroxy esters, starting from readily

available keto esters. Due to the large range of enzymes available, both

enantiomers can normally be made. Another established technology is

enzymatic resolution using lipases which only acylate one enantiomer.

OH

O

OH

H3C

726990

SO3

CH3

OH

O

H3C

NH3

727350

Cl OH

O

OH

727067

ChiPros Chiral Alcohols

Chiral alcohols form a versatile class of chiral synthons, since they can

be incorporated into the API structures directly as esters or ethers. They

can be starting materials for the formation of amines, amides, thiols,

thioethers. In addition, after transforming the hydroxyl function into a

leaving group by way of mesylation, tosylation or trifl ation, they can be

used to form new C–C bonds.

Many manufacturing routes make use of asymmetric hydrogenation

methods.4 The two most important biocatalytical processes for the forma-

tion of chiral alcohols apply lipases and dehydrogenases, respectively.3

The latter off ers the advantage that only the requested enantiomer is

obtained. Enzyme-catalyzed acylations using lipases, however, achieve

the resolution of racemic mixtures of alcohols but with an inherent 50

percent maximum yield of the total amount of starting material. One

enantiomer of the racemic mixture remains unchanged while the antipo-

dal enantiomer is esterifi ed (Scheme 2).

H3COO

O

CH3CH3

OH

R

CH3

OH

R

CH3

O

R

OOCH3

Lipase+ +

Scheme 2: Lipase-catalyzed resolution of aryl-substituted alcohols.

Thanks to a variety of commercial and proprietary enzymes at its disposal,

BASF off ers a wide range of aliphatic and cycloaliphatic and aryl-substituted

single-enantiomer alcohols under the ChiPros brand.

726753 726672

726567

727059

CH3

OH

CH3H3C

OH

CH3H3C

OH

CH3H3C

OH

O

O

CH3

OH

727210

H3C CH3

NH2

H3C CH3

NH2

NH2

CH3

CH3Br

NH2

CH3

NH2

CH3H3C

NH2

CH3H3C

NH2

Br

CH3

NH2

H3CO

CH3

NH2

CH3

NH2

CH3

NH2

H3CO

CH3

NH2

CH3

HN

NH2

CH3

NCO

727342

727180

727083

727032

726958

726923

726893

726885

726869

726842

726605

726613

726656

726818

726761


6

ChiPros Chiral Epoxides

Oxiranes are very valuable building blocks which allow

derivatization:

by forming C-X bonds (through reactions with alcohols, • ammonia, amines, phenolates etc.)

or by forming new C–C bonds (through reactions with cyanide, • malonates, allyl silyl reagents, metal-organic reagents, e.g. Mg, Zn,

Li organyls)

There are several alternative routes towards chiral aryl-substituted epox-

ides, among them Jacobsen’s asymmetric epoxidation5 or his hydrolytic

kinetic resolution6 method, Sharpless’s asymmetric epoxidation7 using

catalytic titan(IV)- isopropylate/diethyl tartrate complexes and tert-butyl-

hydroperoxide, complemented by Shi’s reaction8 using peroxomonosul-

fate with a chiral ketone as catalyst, or among the enzymatic methods,

application of epoxide hydrolases, lipases or monooxygenases. The ste-

reoselective reduction of α-chlorinated acetophenones using dehydro-

genases, however, aff ords a very versatile and more cost-effi cient access

to a wide range of oxiranes, including both enantiomers of styrene oxide

as well as very diff erently substituted phenyl oxiranes (Scheme 3).

CH3

O OX

O

RR

OHX

R R

Base

Scheme 3: Stereoselective synthesis of oxiranes.

O

726508

OCl

726699

O

726834

OF

727253

Aldrich Chemistry is proud to off er ChiPros in small quantities (up to

kilograms). A total of 79 products from the ChiPros portfolio are available

from Aldrich Chemistry, including chiral amines, alcohols, epoxides and

carboxylic acids.

References:

(1) http://www.chipros.com (2) Karl, U.; Simon, A. Chimica Oggi/Chemistry Today 2009,

27, 5. (3) Breuer, M.; Ditrich, K. et al. Angew. Chem. Int. Ed. 2004, 43, 788-824. (4) Blaser, H.

U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale, Wiley-VCH. 2004 (5) Zhang, W.;

Loebach, J. L. et al. J. Am. Chem. Soc. 1990, 112, 2801-2803. (6) White, D. E.; Jacobsen, E. N.

Tetrahedron: Asymmetry 2003, 14, 3633-3638. (7) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem.

Soc. 1980, 102, 5974-5976. (b) Review: Hüft, E. Top. Curr. Chem. 1993, 164, 63-77.

(8) (a) Wang, Z.-X.; Tu, Y. et al. J. Am. Chem. Soc. 1997, 119, 11224-11235; (b) Ager, D.;

Anderson, K. et al., Org. Proc. Res. Dev. 2007, 11, 44-51; (c) Aldrich Chemfi les 2010, 3, 4-5.

For a complete list of Chiral Building Blocks available from

Aldrich Chemistry, visit Aldrich.com/chiralbb

Q-Tubes are affordable alternatives to a microwave synthesizer

and feature a safe pressure-release system (patent pending) that

prevents accidental explosions due to overpressurization. Starter

kits contain all items needed for immediate use.

New Q-Tube™ Pressure Reactors

Q-Tube Benefi ts:

Better yield•

Cleaner product•

Reduced reaction time•

Higher reproducibility•

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Aff ordability•

Maintenance-free•

Q-Tube Starter Kits:

Kits contain all items needed for immediate use.

View accessory product listings and technical information

about Q-Tubes on our website at

sigma-aldrich.com/qtube

Q-Tube Size Cat. No.

12 mL Z567671

35 mL Z567736

Q-Block™ Heating BlocksThese anodized-aluminum heating blocks are designed for

use with 12-mL and 35-mL Q-Tubes. The maximum working

temperature is 204 °C. Blocks have a safety locking plate, safety

shield, thermally stable silicone tubing, and an internal cooling

channel for fast cooling (nitrogen, compressed air, or vacuum).

There is also a thermocouple well for accurate temperature

measurement.

Q-Tube Size Cat. No.

12 mL Z567914

35 mL Z567922


8

Ir(I)-Catalyzed C–H

Borylation

Arylboronic acids and esters are invaluable tools for the chemical com-

munity. These powerful reagents are used for a variety of transformations,

most notably the Suzuki-Miyaura cross-coupling reaction. This reaction

is used to selectively construct C–C bonds through the combination of

an organo-boron nucleophile with a suitable aryl, alkenyl, or alkyl halide

or trifl ate. While the Suzuki-Miyaura reaction has become commonplace

within the synthetic community, one limitation of this method is the

limited ability to access the requisite organo-boron species.

Historically, methods for the synthesis for aryl C–B bonds have relied

upon the use of harshly basic reaction conditions or substrates contain-

ing prefunctionalized carbon centers. These shortcomings require that

additional steps must be taken to either protect sensitive functionality

or install the necessary functional handle prior to C–B bond formation

(Scheme 1).

RX

X = Cl, Br, I

R'MXR

MX B(OR'')3R

B(OR'')2

RDG

R'LiR

DG B(OR'')3R

DG

H

RX

X = Br, I, OTf

Pd(0), BaseR

B(OR'')2

HB(OR'')2

(OR'')2B B(OR'')2

or

Li B(OR'')2

• Harshly basic reaction conditions• Multiple steps and manipulations• Requires prefunctionalized starting materials

Scheme 1: Classical methods for C–B bond formation.

The direct formation of aryl C–B bonds from aryl C–H bonds thus repre-

sents a powerful strategy for streamlining the synthesis of these useful

reagents (Scheme 2).1

RH

RB(OR'')2

HB(OR'')2

(OR'')2B B(OR'')2

or

[M]

• No harsh reagents or reaction conditions

• Atom economical• No need for prefunctionalization

Scheme 2: Metal-catalyzed direct C–H borylation.

CatalysisJosephine Nakhla, Ph.D.Market Segment ManagerOrganometallics and [email protected]

Building upon their previous work within the area,2 Professor John F.

Hartwig has disclosed a method for the direct conversion of aryl C–H

bonds to aryl C–B bonds through the use of an Ir(I) catalyst and B2pin2

(Table 1).3 This powerful system displays excellent regioselectivity that

can be easily predicted by sterics and leads to the rapid synthesis of

highly useful arylboronic esters.

arene product

RH

RBpin1/2[IrCl(COD)]2/bpy

B2pin2, 80 oC, 16 h.

Bpin95 %

Bpin

83 %

Bpin

86 %

Bpin

83 %

Bpin58 %

Bpin

86 %

Bpin

72 %

Bpin

73 %

CH3

H3C

CH3

H3C

H3COOCH3 OCH3

H3CO

ClCl Cl

Cl

CH3

H3C

CH3

H3C

CH3

H3CO

Br

H3CO

H3C

CH3

H3C

CH3

CH3

H3CO

H3CO

Br

arene productyield yield

H

H

H

H H

H

H

H

Table 1: Ir(I)-Catalyzed aryl C–H borylation.

This method provides a simple and direct route to arylboronic esters that

fully avoids the use of harshly basic reaction conditions and does not

require multiple reaction steps and manipulations. Importantly, this reac-

tion employs catalysts and reagents that are all readily accessible, and

now available from Aldrich.

Reference: (1) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka Jr., R. E.; Smith III, M. R.

Science, 2002, 295, 305 (2) (a) Chen, H.; Hartwig, J. F. Angew. Chem. Int. Ed. Engl. 1999, 38,

3391. (b) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.

(3) Hartwig, J. F. et al. J. Am. Chem. Soc. 2002, 124, 390. (4) Hartwig, J. F.

et al. Chem. Rev. 2010, 110, 890.


9Catalysis

Iridium(I) Catalysts, Bipyridine Ligands, and Borylation Reagents from Aldrich:

For a complete list of C–H borylation reagents available from Aldrich

Chemistry, please visit Aldrich.com/borylation

Carboranes as Superweak Anions

The chemistry of weakly coordinating anions, or superweak anions,

continues to be actively investigated within many laboratories for a

variety of purposes. These useful molecules often allow for the isolation

of extremely reactive salts of cations, making them applicable to the ever

growing list of chemical tasks that require highly reactive cations. These

uses include the catalytic polymerization of olefi ns, the catalytic formation

of C–C bonds, the manufacture of high-current-density lithium batteries,

and the activation of C–H bonds. Discover how carboranes from Aldrich

can advance your research.

Carboranes from Aldrich:

BB

B

B

B

B

BB

B

B

B

B

F

F

F

F

F

FF

F

FF

F F

Cs

CsBB

B

B

B

B

BB

B

B

B

B

F

F

F

F

F

FF

F

FF

F F

K

K

723509 720887

N N

t-Bu t-Bu

515477

N N

H3C CH3

569593

N N

513040

H3C CH3

N N

H3CO OCH3

536040

N N

36759 473294

655856

473286

188913

518808

B BO

OO

O

H3CH3C

H3CH3C

CH3

CH3

CH3

CH3

BO

OCH3

CH3

CH3

CH3

H

B BO

OO

O

BO

OH

OB

OB

O

O CH3

CH3

H3C

H3C

683094

685062

377155

685011

Ir(I) Catalysts Bipyridine Ligands Borylation Reagents

IrIrCl

Cl

Ir

IrOCH3

OCH3

Ir

[Ir(COE)2Cl]2

Frustrated Lewis Pairs as Hydrogenation

Catalysts

The hydrogenation of organic substrates with molecular hydrogen (H2)

has been used for purposes ranging from the large-scale upgrading of

crude-oil, to the synthesis of fi ne chemicals used in food, agriculture, and

the pharmaceutical industry. While the majority of methods rely on the

use of costly precious metal catalysts, recent work from the lab of Profes-

sor Douglas W. Stephan has illustrated the use of frustrated Lewis pairs

for the same purpose.1,2 These powerful non-metallic catalysts contain

both Lewis acidic (borane) and Lewis basic (phosphine) moieties that

cannot be quenched internally due to steric constraints. Because of this

unquenched reactivity, these organic catalysts are used to activate a vari-

ety of small molecules, including the heterolytic cleavage of H2, leading to

a powerful catalyst system for the hydrogenation of imines and aziridines

(Scheme 3).

Scheme 3: Frustrated Lewis pairs for the hydrogenation of imines

and aziridines.

Reference: (1) Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W. Science 2006, 314,

1124. (2) (a) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007,

46, 8050. (b) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007,

46, 9136.

Frustrated Lewis Pairs from Aldrich:

For a complete list of Frustrated Lewis pairs available from Aldrich

Chemistry, please visit Aldrich.com/fl p

B

H

FF

F

FF F

F

PF

FF

F

FF

F

H+

t-Bu

t-Bu

BH

F

FF

FF

F FF

FF

F

FF

F

P

H3C CH3

CH3

CH3

H3C CH3

H+

703087 703095

N

PhH

t-Bu NH

PhH

t-Bu

H2

703087 5 mol %

10 mol %

5 atm H

25 atm HPh

N

Ph

PhNH

Ph

Ph703095

Ph

98 %

98 %


10

ChemMatrix® Resin – A major advance in solid

phase peptide synthesis

ChemMatrix® is a proprietary, 100% PEG (polyethylene glycol) based

resin from PCAS BioMatrix. It combines the strengths of two major

resin systems — the chemical stability of polystyrene resins and the

superior performance of PEG grafted resins making it the ultimate

choice for the solid supported synthesis of large or hydrophobic

peptides and even proteins.

In the past decades polystyrene resins have been the primary choice for

solid supported peptide synthesis due to their good results in the syn-

thesis of small peptides. Nevertheless, with the growing amino acid chain

during the synthesis, the tendency of the peptide to form secondary

structures increases. The hydrophobic environment of the polystyrene

resin amplifi es the aggregational behavior of the peptide making the

synthesis of large peptides extremely diffi cult or even impossible. Crude

products of large peptides synthesized on polystyrene resins exhibit a

mixture of deletion sequences and uncompleted fragments. PEG grafted

resins have helped to reach better crude peptide purities by making the

resin more polar and improving the swelling properties in both polar

and unpolar solvents. As a drawback such PEG grafted resins only allow

smaller loadings and are less chemically stable leading to potential leach-

ing during the cleavage step.

ChemMatrix resin was designed from scratch starting with a new type of

monomer building block. The fi nal polymer resin is built exclusively on

primary ether bonds and therefore exhibits high chemical stability, avoid-

ing leaching (Figure 1).1

Figure 1: The scaff old of Aminomethyl-ChemMatrix resin is built completely on

chemically stable polyether bonds (left). Microscopic image of ChemMatrix beads

(right).

H2N OO

O NH2

H2N OO

O NH2

H2N OO

O NH2

n

n

n

OO

On

Chemical BiologyMatthias Junkers, Ph.D.Product [email protected]

At the same time, the increased polarity of the resin allows the use of var-

ious polar solvents, including: water, THF, DMF, methanol and acetonitrile,

in which the resin displays excellent swelling properties (Figure 2). High

swelling properties should be considered during practical use as the wet

ChemMatrix resin will consume considerably more space in the reaction

vessel than conventional polystyrene resins. Typical loading ranges are

between 0.4 and 0.7 mmol/g which is a comparable binding capacity as

polystyrene resins.

Aceto

nitrile

DCMDMF

NMP

DMSO

Methanol

TFAWater

Polystyrene

Aminomethyl-ChemMatrix

Swel

ling

(mL/

g)

1816141210

86420

Figure 2: Swelling properties of ChemMatrix resin compared to

polystyrene resin.

Two recent independent publications give remarkable evidence for

the unmatched performance of ChemMatrix resin. For the synthesis of

HIV–1 protease, a large peptide of 99 amino acids, ChemMatrix resin

was compared directly to polystyrene.2 As the following chromatograms

clearly show, the desired peptide is the main component of the crude

product using ChemMatrix as the solid support (Figure 3). Polystyrene

resins only deliver crude mixtures preventing the direct, linear synthesis

of long peptides.


11Chemical Biology

1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00

7.02

5

Minutes

Minutes

1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00

Figure 3: HPLC chromatograms of HIV–1 protease (99 amino acids) after

78 amino acids. The synthesis on ChemMatrix resin yields the desired peptide

directly without further purifi cation (top) whereas polystyrene

resin only yields a very crude mixture (bottom).2

In a second amazing example, Bacsa et al. reported in 2010, the solid

supported, microwave assisted synthesis of the polypeptide Aβ(1–42).3

Aβ (1–42) plays a crucial role in the pathogenesis of Alzheimer’s disease

in that it forms β–sheet structures and amyloid fi brils which induce

neurotoxicity. Thus, it is a key material needed to further investigate the

molecular mechanisms of Alzheimer’s disease and potential drugs for its

treatment. Due to its aggregational behavior this peptide is highly diffi cult

to synthesize. ChemMatrix resin allows the direct, linear synthesis with a

standard Fmoc/t–Bu synthesis strategy applying DIC/HOBt as a simple

and inexpensive coupling reagent. Except for the coupling of three

racemization sensitive histidine residues which was carried out at room

temperature the synthesis was achieved under controlled microwave

conditions at 86 °C. ChemMatrix resin remained completely stable under

these conditions.4 Finally, Aβ(1–42) was obtained within a 15h overall

processing time in high yield and purity (78% crude yield).3

Apart from peptide synthesis ChemMatrix resin has also been used suc-

cessfully in combinatorial synthesis,5 for the synthesis of oligonucleotide

derivatives,6 PNA,7 asymmetrically substituted phthalocyanines,8 and

peptide hybrids incorporating non-natural chemical residues.9

In summary, ChemMatrix overcomes the challenges of synthesizing

longer and more complex therapeutic peptides. Peptides produced with

ChemMatrix have higher purity and can be obtained with better yields.

Peptides that were hitherto achievable only by ligation or recombinant

techniques can now be synthesized directly on solid support.

For the synthesis of peptide acids, we recommend using the ChemMatrix

with a HMPB anchor as this resin will provide high crude purity and a

recovery yield of 90–95%. The Wang-ChemMatrix will produce similar

crude peptide purity, but the recovery yield is lower (60–70%). HMPB–Ch-

emMatrix resins are also off ered preloaded with the most common amino

acids. A number of protocols for the application of ChemMatrix resin have

been published recently in the literature.10

Features of ChemMatrix Resin

• Exceptional Stability

ChemMatrix resin is made exclusively from primary ether bonds which

are highly chemically stable. No leaching occurs during synthesis and

cleavage.

• High Loading

ChemMatrix resins have a loading of 0.4–0.7 mmol/g.

• Solvent Compatibility

ChemMatrix allows the use of almost any kind of solvent, even water.

High swelling properties of ChemMatrix in water allows high throughput

post-synthetic downstream screening.

• Versatile Choices

ChemMatrix resin is off ered with an extensive range of linkers for

peptide acids, amides and fragments. For peptide synthesis, preloaded

resins are also available for your convenience.

• Demonstrated Superiority

ChemMatrix resin has been fi eld proven for easier and faster develop-

ment of long, complex and hydrophobic peptides. The longer, the more

complex or hydrophobic your peptide is, the more improvement you

will see with ChemMatrix.

• Microwave assisted synthesis

No leaching is observed on microwave synthesizers at 80 °C.

References: (1) García-Martin, F.; Albericio, F. Chem. Today 2008, 26, 29. (2) Frutos, S.;

Tulla-Pucha, J.; Albericio, F.; Giralt, E. Intern. J. of Pept. Res. Ther. 2007, 13, 221. (3) Bacsa, B.;

Bösze, S.; Kappe. C. O. J. Org. Chem. 2010, 75, 2103. (4a) Subiros-Funosas, R.; Acosta, G. A.;

El-Faham, A.; Albericio, F. Tet. Lett. 2009, 50, 6200. (4b) Galanis, A. S.; Albericio, F.; Grøtli,

M. Org. Lett. 2009, 11, 4488. (5) Marani, M.M.; Martínez-Ceron, M. C.; Giudicessi, S. L.; de

Oliveira, E.; Côté S.; Erra-Balsells, R.; Albericio, F.; Cascone, O.; Camperi, S. A. J. Comb. Chem.

2009, 11, 146. (6) Mazzini, S.; García-Martin, F.; Alvira, M.; Aviñó, A.; Manning, B.; Albericio, F.;

Eritja, R. Chem. Biodiv. 2008, 5, 209. (7) Fabani, M. M.; Abreu-Goodger, C.; Williams, D.; Lyons,

P. A.; Torres, A. G.; Smith, K. G. C.; Enright, A. J.; Gait, M. J.; Vigorito., E. Nucl. Acids Res. 2010, 38,

4466. (8) Erdem, S. S.; Nesterova, I. V.; Soper, S. A.; Hammer, R. P. J. Org. Chem. 2008, 73, 5003.

(9) Spengler, J.; Ruíz-Rodríguez, J.; Yraola, F.; Royo, M.; Winter, M.; Burger, K.; Albericio. F. J.

Org. Chem. 2008, 73, 2311. (10) García-Ramos Y.; Paradís-Bas, M.; Tulla-Puchea, J.; Albericio, F.

J. Pept. Science 2010, 16, 675.


12

ChemMatrix resins

NH

OO

NHFmoc

OCH3

OCH3Rink amide CM

NH

OO

HMPB-CMOH

OCH3

NH

O

Trityl-OH CM OH

NH

OO

OHWang-CM

NH

OO

Ramage-CM

NHFmocNH

O

PAL-CM

O

NHFmoc

OCH3

OCH3

H2N OO

O NH2

H2N OO

O NH2

H2N OO

O NH2

n

n

n

68571

727768727741

64191 727776

727792 727784

Aminomethyl CM

ChemMatrix HMPB preloaded resins

NH

OO

O

OCH3

H-Gly-HMPB-CM H-Ala-HMPB-CMO

NH2

NH

OO

O

OCH3

OCH3

NH2

NH

OO

O

OCH3

O

NH2

H-Arg(Pbf)-HMPB-CM

NH

OO

O

OCH3

O

NH2

H-Lys(Boc)-HMPB-CM

NH

OO

O

OCH3

O

NH2

CH3

H-Leu-HMPB-CM

CH3 NH

OO

O

OCH3

O

NH2

CH3

H-Val-HMPB-CM

CH3

H-Phe-HMPB-CM

NH

OO

O

OCH3

O

NH2 NH

OO

O

OCH3

O

H-Pro-HMPB-CM

HN

727806 727822

727849 727865

727814 727830

727857 727873

NH

NHPbf

HNBocHN

For a complete list of ChemMatrix products available from Aldrich

Chemistry, please visit Aldrich.com/chemmatrix

Custom Packaged Reagents (CPR)

To register for an online ordering account or to submit inquiries, visit Discoverycpr.com

Our CPR Service provides a cost eff ective strategy to

procure one to thousands of unique, custom packaged

building blocks and screening compounds for use in

research programs.

CPR is optimized to support several discovery activities:

The chemist looking to identify and procure sets of building blocks for their high • throughput synthetic reactions

The chemical biologist or biologist interested in the diversity of the world’s largest • selection of screening compounds

Customized packaging allows you to receive samples in a ready-to-use format, allowing

you to focus on your research rather than spending time weighing out building blocks or

tracking down vendors.

CPR from Aldrich provides:

Widest selection of building blocks, reagents, and screening compounds through • hundreds of managed vendors worldwide

Internet-based chemical database and procurement functionality• Custom packaging of over 200,000 off -the-shelf products from global sources• Availability and pricing in a single quotation with consolidation of invoicing• Standard or client-supplied custom packaging in vials or plates• Customized labeling, including 1-D or 2-D barcoding to your specifi cations• Normalization of electronic data with shipment including SD fi le generation•


14

OrganometallicsAaron Thornton, Ph.D.Product [email protected]

MIDA Boronates for Suzuki–Miyaura

Cross-Couplings

Professor Martin Burke and coworkers recently prepared retinal using

key MIDA building block BB1 in iterative Suzuki-Miyaura cross coupling

reactions (Scheme 1). The MIDA unit of BB1 is unreactive under these

conditions, allowing for the selective cross-coupling of BB1 with triene

(1). Subsequent hydrolysis of the MIDA unit of (2) followed by a second

Suzuki-Miyaura reaction provided all-trans-retinal.

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

1 2

Scheme 1: Iterative Suzuki-Miyaura cross-couplings in the synthesis of

all-trans-retinal.

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

The many advantages of the MIDA boronate platform include air and

moisture stability, stability under anhydrous cross-coupling conditions,

compatibility with a range of common and harsh reagents, solubility

in various organic solvents, silica gel compatibility, and the ability to

undergo slow release cross-couplings.

MIDA Boronates from Aldrich:

BO

N

OOO

H3C

697311

H2CB

O

N

OOO

H3C

698709 700231

B

O

N

O

OO

H3C

B

O

N

O

OO

H3C

H2C

704415

BO

N

OOO

H3C

CH2

707252

H3CB

O

N

O

OO

H3C

S

708828

HC

For complete list of MIDA boronates available from

Aldrich Chemistry, visit Aldrich.com/mida

Slow-Release of Unstable Boronic Acids from

MIDA Boronates

In addition to attenuated reactivity towards anhydrous cross-coupling

conditions, MIDA boronates also possess the capacity for in situ slow-

release of boronic acids under aqueous basic conditions (Scheme 2).

Harnessing this phenomenon, boronic acids that are notoriously unstable

can be eff ectively utilized in cross-coupling when employed as MIDA

boronates. While aqueous solutions of NaOH promote the fast hydrolysis

of MIDA boronates to their corresponding boronic acids, the use of aque-

ous K3PO4 allows for the slow-release of relatively unstable boronic acids,

preventing decomposition of the organometallic species and improving

overall yields for many Suzuki-Miyaura reactions.

Slow Release of Unstable Boronic Acids

Scheme 2: Slow-release of unstable boronic acids from MIDA boronates.

Burke and coworkers examined this slow-release concept by comparing

various freshly prepared boronic acids with their corresponding MIDA

boronates. The study revealed that many boronic acids decompose

signifi cantly via various pathways, including protodeborylation, oxidation,

and polymerization, after just 15 days of benchtop storage under air. On

the other hand, the corresponding MIDA boronates were remarkably

stable, with >95% of each MIDA remaining after ≥60 days of benchtop

storage under air. In addition to complications related to storage, the

overall effi ciency of cross-coupling for these reagents is also impacted

by the nature of the boron unit. For example, while isolated yields are

RB

O

N

OOO R B(OH)2

mild aqueous base (e.g. K3PO4)

Cl R'

Pd-catalyst

R R'

H3C


15Organometallics

generally low to moderate even when freshly-prepared boronic acids are

employed in Suzuki-Miyaura cross-couplings, employing the correspond-

ing MIDA boronate results in excellent yields of the desired cross-coupled

products (Table 1).

RB

O

N

OOO

Ot-Bu

Cl

Pd(OAc)2, SPhos

Ot-Bu

RK3PO4, dioxane:H2O (5:1)

60 °C, 6 h

R B(OH)2 or

1 eq 1 eq

1 mmol

O

BocN

5 >95a

<5 >95

7 >95

R

% remaining after benchtopstorage under air

A B

A (15 days) B (>60 days)

Cross Coupling Isolated Yield (%)

BocN

Ot-Bu

C

C

Ot-Bu

with A with B

68 94

61 90

79 98

Entry

1

2

3

4NN

SO2Ph SO2Ph

<5 >9514 93

across coupling conducted at 100 °C

H3C

Ot-Bu

OOt-Bu

Table 1: Stability and slow-release cross-coupling studies of MIDA boronates vs.

boronic acids.

MIDA Boronates for Classically Challenging

Suzuki-Miyaura Cross-Couplings

The power of this slow-release concept has been further illustrated by

utilizing various MIDA boronates of which the corresponding boronic

acids have historically exhibited challenges with respect to either storage

or use, including 2-heterocyclic, vinyl and cyclopropyl boronic acids.

Because these organoboron species readily decompose through a variety

of pathways, the effi ciency with which their corresponding MIDA bor-

onates may be coupled is particularily noteworthy (Table 2).

RB

O

N

OOO

ClPd(OAc)2, SPhos, K3PO4

dioxane/H2O (5:1), 60 °C, 6 h

Entry

1

2

3

4

BO

N

OOOS

BO

N

OOO

Cl

H3C CH3

CH3

N

NCl

R

R'

R' ClMIDA Isolated Yield (%)Product

H3C CH3

79

97

CH3

N

NS

R R'

BO

N

OOON

Boc98N

Boc

N

O

ClCH3 N

OCH3

BO

N

OOO

N

Cl

NH2

76N NH2

H3C

H3C

H3C

H3C

H3C

Table 2: Slow-release cross-coupling of MIDA boronates with historically challeng-

ing substrates.

2-Pyridinylboronic Acid MIDA Ester as a Stable

2-Pyridinyl Boron Anion Equivalent

The development of a viable air-stable surrogate for the notoriously

unstable 2-pyridinylboronic acid has been a long-standing challenge

in the fi eld of cross-coupling. This motif is ubiquitous in drug-like small

molecules, and therefore of particular importance to the synthetic com-

munity. While 2-pyridinylboronic acid surrogates exist, their use is often

complicated by air- and moisture-sensitivity as well as their somewhat

variable and impure compositions. In contrast, Burke and coworkers

found that 2-pyridinyl MIDA boronate is isolable, benchtop and chroma-

tography stable, and under slow-release conditions can be successfully

coupled with a variety of aryl and heteroaryl chlorides (Table 3).

BO

N

OOON

Cl

Pd2(dba)3, XPhos, K3PO4

DMF/IPA (4:1), 100 °C, 4 h

R

Cu(OAc)2, K2CO3

N R

Entry Cl R Product Isolated Yield (%)

1

2

3

Cl

C

Cl

CN

N

N

Cl

C

CN

N

N

N

72

60

79N

N

719390

H3C

OCH3

OCH3

Table 3: Slow-release cross-coupling of 2-pyridinylboronic acid MIDA ester.

References: (1) Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 131, 17. (2) Knapp, D. M.;

Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.

Pyridinyl MIDA Boronates from Aldrich

BO

N

OO

O

H3C

NH3CO

BO

N

OO

O

H3C

N

723053

723959

BO

N

OOO

H3C

N OCH3

701084

BO

N

OOO

H3C

NH3CO

699845

BO

N

OOO

N

Br

H3C

703370

BO

N

OOO

NCl

H3C

700908

BO

N

OOO

NBr

H3C

702269

BO

N

OO

O

H3C

N

719390

H3C BO

N

OOO

H3C

N

704563

For a complete list of MIDA boronates available from

Aldrich Chemistry, visit Aldrich.com/mida


16

Heterocyclic Organotin Reagents for

Stille Coupling

Stille reactions remain one of the most viable methods for the formation

of C–C bonds in organic chemistry.1 Their use has been highlighted in

various areas, including countless natural product syntheses, material sci-

ence applications, and in numerous synthetic methodology studies. The

coupling of imidazolyl stannane 718793 with heterocycle (4) by process

chemists at Pfi zer was reported in 2003 (Scheme 3).2 This coupling

employed Pd(PPh3)4 as the catalyst and was carried out in 67% isolated

yield. Addition/elimination on the resulting functionalized thienopyri-

dine provided bulk material of the desired VEGFR kinase inhibitor (5). It

is worth noting that of several cross-couplings which were examined,

the Stille coupling employing stannane 718793 was the only reaction

feasible on scales >50g.

N

Cl

SI

N

N

CH3

SnBu3

718793Pd(PPh3)4 (5 mol%)

DMF, 95 C40 h, 67%

N

Cl

S

N

NH3C

N

NH

S

N

NH3C

HN

H3C

NH2

HN

H3C

t-BuOH/DCE100 C

52%4 5

Scheme 3: Stille reaction in the preparation of VEGFR kinase inhibitors (5).

References: (1) Mascitti, Vincent. Stille coupling. Name Reactions for Homologations 2009,

(Pt. 1), 133–162. (2) Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.;

Munchhof, M. J.; Marx, M. A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Proc. Res.

Dev. 2003, 7, 676.

Organotin Reagents from Aldrich:

683930 719366

678333 698598

SBu3Sn SnBu3

SBu3Sn N

H3C

Bu3Sn

NBu3Sn N

Bu3Sn

718807

719730 706868 707031

706981

N

N

Cl Cl

Bu3Sn

N

NBu3Sn

N

NBu3Sn

Cl

N

N

OCH3Bu3Sn

ONBu3Sn

OCH2CH3

O

707813 717630

638617 642541 706965

NN

CH3

Bu3Sn

N

N

CH3

Bu3Sn

O

N

Bu3Sn S

N

Bu3Sn

S

NSnBu3

Br

675679 719501 718793

NCH3

Bu3SnN

N

CH3

Bu3Sn

N

N

CH3

Bu3Sn

717703

For a complete list of Organotin Reagents available from

Aldrich Chemistry, visit Aldrich.com/organotin

Selective 1,2-Additions with LaCl3·2LiCl

While the 1,2-addition of Grignard reagents to ketones is undoubtedly

a powerful transformation, oftentimes selectivity issues arising from

competitive alpha-deprotonation detract from the use of these reagents.

Various methods have been developed to address this shortcoming,

including the use of CeCl3 and other Lewis acidic salts. However, because

of the heterogeneous nature of these reagents, it is often diffi cult to

obtain adequate selectivity. With this in mind, the lab of Professor Paul

Knochel has shown that LaCl3•2LiCl (703559) may be used to attenuate

the basicity of Grignard reagents, in turn preventing competitive enoliza-

tion side reactions while leading to a powerful method for the selective

1,2-addition of Grignard reagents to ketones. In addition to enolizable

ketones, even sterically hindered ketones, as well as Michael acceptors

and unactivated imines can undergo 1,2-additions selectively to provide

the desired addition products (Table 4).1

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

withno additives

a

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

703559

LaCl3 2LiCl•

R1

Table 4: LaCl3•2LiCl mediated addition to ketones.


17Organometallics

Subsequent to these initial studies with LaCl3•2LiCl, Knochel and cowork-

ers reported that sub-stoichiometric quantities of the lanthanide salt are

suffi cient to promote the desired 1,2-addition, as demonstrated by the

addition of i-PrMgCl•LiCl to unactivated imines (Scheme 4). This protocol

is amenable to the use of alkyl, aryl, and heteroaryl Grignard reagents.2

OMe

N

Ph

•+

LaCl3 2LiCl•

(10 mol%)

THF, rt, 12h

OMe

HN

Ph i-Pr

84%i-PrMgCl LiCl

Scheme 4: 1,2-Addition of organomagnesium reagents in the presence of catalytic

LaCl3•2LiCl.

Advantages of LaCl3•2LiCl:

No pretreatment procedures necessary• Easy handling of reagents and reaction setup• Homogeneous reaction conditions • Improved selectivity and reactivity providing better yields and • decreased reaction times

References: (1) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 497. (2)

Metzger, A.; Gavryushin, A.; Knochel, P. SynLett 2009, 1433.

For a complete list of selective metallation reagents available from

Aldrich Chemistry, visit Aldrich.com/metallations

Chiral Silacycles for Enantioselective

Allylation and Crotylation Reactions

The asymmetric allylation and crotylation of aldehydes and other carbo-

nyl compounds remains one of the most fundamental reactions for the

construction of chiral building blocks. While numerous methods for this

challenging task have been examined previously, including the use of

chiral auxiliaries, chiral reagents and catalytic systems, still today a truly

convenient and broadly reaching method remains elusive. With this goal

in mind, the group of Professor James Leighton has developed a versatile

system that has proven to be uniquely eff ective. Leighton and co-workers

have harnessed the power of strained silacycles for use as allylation re-

agents without the need for any further catalysts or reagents (Scheme 5).

OSi

N

Cl

Me

OSi

N

Cl

Me

Ph

Me

Ph

Me

NSi

N

Cl

H

H

Br

Br

NSi

N

Cl

H

H

Br

Br

Scheme 5: Leighton’s chiral allyl silanes.

These bench-stable and non-toxic reagents undergo enantioselective ad-

dition to a range of carbonyl compounds, including aldehydes, ketones,

and hydrazones1 (Table 5). Notably, all of these reactions are carried out at

convenient reaction temperatures without the need for external activat-

ing reagents, thereby simplifying reaction set-up and manipulation.

OSi

N

Cl

Me

Ph

Me

706671

+O

R H R

OH

R T (oC) yield % e.e. %

-10

-10

-10

80

59

84

81

78

88

OSi

N

Cl

Me

Ph

Me

+N

R R' R

NHBzR' NHNHBz

706671R' T (oC) yield % e.e. %

CH3-10

-10

-10

80

59

84

81

78

88

R

CO2Me

CH3

Table 5: Enantioselective allylation of various aldehydes and hydrazones with

706671.

In addition to enantioselective allylation reactions, Leighton and

co-workers have extended this concept to the enantioselective crotyla-

tion of carbonyl compounds2 (Table 6). Importantly, these diamine

derived silacycles are bench-stable crystalline solids, providing the added

benefi t of simple reaction setup and purifi cation.

NSi

N

Cl

H

H

Br

Br

CH3

+O

R H

R

OH

CH3

R

OH

CH3

R yield % e.e. %

H3C

CH3

BnO

NSi

N

Cl

H

H

Br

Br

CH3

or or

B

A

Silane product

AB

AB

AB

1

2

12

12

12

8381

9798

7071

9697

8283

9699

AB

12

6752

9594

DBU

CH2Cl2, 0 oC

Table 6: Enantioselective crotylation of aldehydes.

References: (1) (a) Kinnaird, J. W. H.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J.Am.

Chem. Soc. 2002, 124, 7920. (b) Berger, R.; Duff , K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126,

5686. (2) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 23, 4375.


18

Chiral Allyl and Crotylsilanes:

For a complete list of allylation reagents available from

Aldrich Chemistry, visit Aldrich.com/allylations

Selective Metalations using i-PrMgCl·LiCl and

s-BuMgCl·LiCl

While halogen-metal exchange reactions are among the most common

methods for preparing reactive organometallic reagents, Li-halogen

exchange reactions typically require low temperatures and off er limited

compatibility with other functionalities. On the other hand, Mg-halogen

exchange reactions require higher temperatures and are often prone to

elimination side reactions. To address these issues, Knochel and cowork-

ers have found that the use of salt additives increase both the rate and

the effi ciency of this Mg-halogen exchange reaction. The most eff ec-

tive reagents are generated with R-MgCl (R = i-Pr, s-Butyl) and 1.0 equiv

of LiCl. The increased reactivity of these aptly named TurboGrignards

may be due to the breakup of polymeric aggregates known to exist in

classical solutions of Grignard reagents. TurboGrignards allow for the

conversion of a variety of functionalized and highly sensitive substrates,

including those containing CO2R, CN, OMe, and halogen moieties, to

their corresponding functionalized organometallic derivatives. While rate

enhancements are observed with TurboGrignards, this increased reactiv-

ity 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 7).1

OSi

N

Cl

Me

706671

OSi

N

Cl

Me

719056

Ph

Me

Ph

Me

NSi

N

Cl

705098

H

H

Br

Br

NSi

N

Cl

704725

H

H

Br

Br

NSi

N

Cl

733075

H

H

Br

Br

NSi

N

Cl

733199

H

H

Br

Br

CH3CH3

Br

FG

MgCl LiCl

FG

•

(TurboGrignard)

FG = CO2R', CN, OMe, 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 7: Aryl/heteroaryl Grignard reagents prepared using i-PrMgCl·LiCl and reac-

tions with electrophiles.

Advantages of TurboGrignards:

Increased functional group compatibility• Mild reaction conditions• Minimal side reactions• Allows for the large-scale production of reactive • Grignard reagents

References: (1) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.

(2) P. Knochel, E P 1582 524 A1.

TurboGrignard Reagents from Aldrich:

For more information on these new reagents, visit

Aldrich.com/metalations

Sold in collaboration with

H3C

CH3

MgCl.LiCl

656984

H3CCH3

MgCl.LiCl

703486


19Organometallics

Organotrifl uoroborates as Coupling Partners in Suzuki-Miyaura ReactionsSuzuki-Miyaura cross-coupling reactions are some of the most common

methods for the formation of C–C bonds in organic chemistry. The use of

organotrifl uoroborate salts as boronic acid surrogates has lead to signifi -

cant advancement in the fi eld of Suzuki-Miyaura reactions. Trifl uorobo-

rates exhibit excellent functional group tolerance and stability towards

common reagents, in turn leading to a truly versatile class of reagents.1, 2

Our platform of trifl uoroborate salts is continually growing, with new

product introductions occurring regularly.

Benefi ts of Organotrifl uoroborates:

Stable tetracoordinate species• Less prone to protodeboronation• Air-and moisture-stable•

Potassium Vinyltrifl uoroborate as a Versatile Dianion PrecursorMolander and co-workers have developed a powerful strategy for the

production of a unique 1,2-dianion equivalent using potassium vinyl-

trifl uoroborate.1 This useful organotrifl uoroborate undergoes selective

hydroboration with 9-BBN to generate (3), a 1,2-dianion equivalent that

can then undergo a variety of selective transformations (Scheme 6).

BF3K

Potassium vinyltrifluoroborate

655228

BF3KB

9-BBN

3

Scheme 6: Hydroborated intermediate (3) as a 1,2-dianion equivalent.

This versatile 1,2-dianion equivalent undergoes sequential Suzuki-Miyaura

cross-coupling with a range of organic electrophiles, including aryl-,

heteroaryl-, and alkenyl halides (Table 8).

BF3K

1.) 9-BBN2.) Pd(OAc)2, DavePhos, KF,

3.) RuPhos, K2CO3,toluene/H2O

R' Br

R'' Br

R''R'

R'-Br R''-Br yield %

OMe

MeO BrN

Br OMe82

OMe

MeO Br

SCl O

H

84

O ClO

H

N

NBr

60

Br

OMe

MeO Br

74

Me

MeBr

N

Br OMe80

Me

OMe

MeO

N

OMe

OMe

MeOS

H

O

OMe

MeO

Me

Me

Me

N

OMe

N

NO

H

O

Table 8: Sequential Suzuki-Miyaura cross-couplings to build molecular complexity

from potassium vinyltrifl uoroborate.

References: Molander. G. A.; Sandrock, D. L. Org. Lett. 2009, 11, 2369.

Alkenyl Potassium Trifl uoroborates from Aldrich:

BF3K

655228

BF3K

684937

BF3K

723916

BF3K

720682

BF3K

683590

BF3K

720933

BF3K

720747

Br

CH3

CH3

H3C

H3CO

CH3

H3CCH3

CH3

H3C


20

Ni-Catalyzed Cross-Coupling of

Heteroaryltrifl uoroborates with Unactivated

Alkyl Halides

Recently the lab of Professor Gary Molander disclosed a method for the

eff ective cross-coupling of air and moisture stable heteroaryltrifl uo-

roborates with unactivated alkyl halides.3 While previous methods for

this same transformation have been developed, still today a number of

shortcomings remain. Most notable is the need for excess organoboron

coupling partner, and the limited scope of organoboron reagents that

can be used for this transformation (generally restricted to aryl boronic

acids only). To address these issues, Molander has taken advantage of

the increased stability of organotrifl uoroborates as well as the increased

reactivity of Ni catalysts. Under the optimized conditions a range of

heteroaryltrifl uoroborates can be coupled effi ciently with both alkyl

bromides and iodides (Table 9).

OBF3K

or

N

BF3K+ Alkyl X

OAlkyl

or

N

Alkyl

NiBr2.glyme (10 mol %)

bathophenanthroline (10 mol %)LiHMDS (3 eq), s-BuOH

A

B

Alkyl-X

BnOBr

O

O

Br

ICl

Br

Br

I

Alkyl-Xyield % yield %

A, 80B, 76

A, 76B, 78

A, 84B, 63

A, 67B, 68

A, 63B, 68

A, 60B, 71

(X = Br, I)

Table 9: Cross-coupling of 2-benzofuranyl- and 4-pyridinyltrifl uoroborates with

various alkyl halides.

References: (1) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.

(2) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49. (3) Molander, G. A.;

Argintaru, O. A.; Aron, I.; Dreher, S. D. Org. Lett. 2010, 24, 5783.

NNH

BF3K

711144

N

NKF3B

711098

N

BF3K

711101

SH3C CH3

BF3K

711136

NO

NKF3B

706116

NBr

BF3K

717517

NF

BF3K

717487

SBF3K

717509

NN

722588

O

KF3B

NBoc

BF3K

719420

Heteroaryltrifl uoroborates from Aldrich:

For a complete list of organotrifl uoroborates available from Aldrich

Chemistry, visit Aldrich.com/tfb

Materials ScienceMaterials Science

Nano-layers of metals, semiconducting and dielectric materials are

crucial components of modern electronic devices, high-effi ciency

solar panels, memory systems, computer chips and a broad variety of

high-performance tools.

The technique of choice for depositing nano-fi lms on various surfaces

is Atomic Layer Deposition (ALD), which uses consecutive chemical

reactions on a material’s surface to create nanostructures with

predetermined thickness and chemical composition (Figure 1).

Aldrich Materials Science off ers high-quality precursors for ALD safely

packaged in steel cylinders suitable for use with a variety of

deposition systems.

We continue to expand our portfolio of ALD precursors to include

new materials. For an updated list of our deposition precursors, please

visit aldrich.com/ald

Precursors for Atomic Layer DepositionHigh-Tech Solutions for Your Research Needs

(a)

(b)

Figure 1. Schematic of the ALD method based on sequential, self-limiting

surface reactions.

For additional vapor deposition precursors prepacked in cylinders, please contact us by email at [email protected]

Precursors Packaged for Deposition Systems

Atomic

No. Description Molecular Formula Form Prod. No.

Water packaged for use in deposition systems

H2O liquid 697125

13 Trimethylaluminum (CH3)3Al liquid 663301

14 (3-Aminopropyl)triethoxysilane H2N(CH2)3Si(OC2H5)3 liquid 706493

14 Silicon tetrachloride SiCl4 liquid 688509

14 Tris(tert-butoxy)silanol ((CH3)3CO)3SiOH solid 697281

14 Tris(tert-pentoxy)silanol (CH3CH2C(CH3)2O)3SiOH liquid 697303

22 Tetrakis(diethylamido)titanium(IV) [(C2H5)2N]4Ti liquid 725536

22 Tetrakis(dimethylamido)titanium(IV)

[(CH3)2N]4Ti liquid 669008

22 Titanium tetrachloride TiCl4 liquid 697079

22 Titanium(IV) isopropoxide Ti[OCH(CH3)2]4 liquid 687502

30 Diethylzinc (C2H5)2Zn liquid 668729

31 Triethylgallium (C3H2)3Ga liquid 730726

31 Trimethylgallium Ga(CH3)3 liquid 730734

39 Tris[N,N-bis(trimethylsilyl)amide]yttrium

[[(CH3)3Si]2N]3Y solid 702021

40 Bis(methyl-η5-cyclo-pentadienyl)methoxymethylzirconium

Zr(CH3C5H4)2CH3OCH3 liquid 725471

Atomic

No. Description Molecular Formula Form Prod. No.

40 Tetrakis(dimethylamido)zirconium(IV)

[(CH3)2N]4Zr solid 669016

40 Tetrakis(ethylmethylamido)zirconium(IV)

C12H32N4Zr liquid 725528

44 Bis(ethylcyclopentadienyl)ruthenium(II)

C7H9RuC7H9 liquid 679798

72 Bis(methyl-η5-cyclopentadienyl) dimethylhafnium

Hf[C5H4(CH3)]2(CH3)2 solid 725501

72 Bis(methyl-η5-cyclopentadienyl)methoxymethylhafnium

HfCH3(OCH3)[C5H4(CH3)]2 liquid 725498

72 Tetrakis(dimethylamido)hafnium(IV)

[(CH3)2N]4Hf low-melting solid

666610

72 Tetrakis(ethylmethylamido)hafnium(IV)

[(CH3)(C2H5)N]4Hf liquid 725544

73 Tris(diethylamido)(tert-butylimido)tantalum(V)

(CH3)3CNTa(N(C2H5)2)3 liquid 668990

74 Bis(tert-butylimino) bis(dimethylamino)tungsten(VI)

((CH3)3CN)2W(N(CH3)2)2 liquid 668885

78 Trimethyl(methylcyclo-pentadienyl)platinum(IV)

C5H4CH3Pt(CH3)3 low-melting solid

697540


22

Indoles and Indole Isosteres

Substituted indoles have frequently been referred to as “privileged struc-

tures” since they are capable of binding to multiple receptors with high

affi nity, and thus have applications across a wide range of therapeutic

areas.1 However, recent publications often demonstrate the need for a

researcher to attenuate or amplify the activity of their target compound

without altering the steric bulk of the structure; thus, isosteres of the in-

dole ring have proven very valuable to synthetic and medicinal chemists.

The azaindole and indazole moieties diff er only by the addition of an

extra ring nitrogen, and thus exhibit excellent potential as bioisosteres

of the indole ring system. Although more rare in nature, interest in these

structures has surged over the past decade and they comprise essential

subunits in many pharmaceutically relevant compounds.2,3 Indazoles

have been widely reported to display signifi cant activity as antifungals,

anti-infl ammatory agents, antiarrhythmic agents, analgesics, and nitric

oxide synthase inhibitors.2a Of the various azaindoles, 7-azaindoles are of

particular interest because of their ability to mimic purines in their roles

as hydrogen-bonding partners. Similarly, imidazopyridines have proven

eff ective as purine mimics in several recent studies.4

When two ring nitrogens are added to the indole subunit, it results in

7-deazapurines, an important class of compounds found in a wide vari-

ety of biological niches. Various ribonucleosides containing 7-deazapu-

rines demonstrate a broad spectrum of biological activity, even at

nanomolar concentrations.5

Aldrich is pleased to off er a wide variety of these useful building blocks

for your research.

New Indoles

For a complete list of indoles from Aldrich Chemistry, visit

Aldrich.com/indole

NH

H2N

NH

H3CO

F3CNH

CH3

HO

NH

Br O

OCH3

NH

H3CO

733040 723789 716529

724718 724378

Building BlocksMark RedlichProduct [email protected]

New Azaindoles

For a complete list of azaindoles available from

Aldrich Chemistry, visit Aldrich.com/azaindole

New Indazoles

For a complete list of indazoles available from

Aldrich Chemistry, visit Aldrich.com/indazole

New Imidazopyridines

685755 721050 732141

N

N

NH2

N

N

Br

NN

Br

For a complete list of imidazopyridines available from

Aldrich Chemistry, visit Aldrich.com/imidazopyridine

New Purines and Deazapurines

For a complete list of purines and deazapurines available from Aldrich

Chemistry, visit Aldrich.com/purine

NH

N

Br

N

NH

H3CO N

NH

OSiH3CCH3

CH3

732168 707953 723770

NNH

Br

NN

CH3

Br

717525 717215

722332 717592

N

N NH

NH2

N

N N

HN

NH2

Cl


23Building Blocks

Thiazoles

Thiazoles have been frequently discovered as a vital component of novel

and structurally diverse natural products that exhibit a wide variety of

biological activities. Their presence in peptides, their ability to bind to

proteins, DNA, and RNA, as well as the exceptional range of antitumor,

antiviral, and antibiotic activities of thiazole-containing compounds have

directed numerous synthetic studies and new applications. The thiazole

ring has been identifi ed as a central feature of myriad natural products,

and synthetic variants have been pursued by pharmaceutical companies

due to their signifi cant activity.6

Additionally, thiazoles are important features of various peptides and

pseudopeptides that function as potent antineoplastic agents,7 or have

demonstrated signifi cant cytotoxicity or antibiotic properties.8 Thiazoles

can also serve as a protected formyl group that can be liberated in the

late stages of a complex natural product synthesis.9

New Thiazoles

For a complete list of thiazoles available from

Aldrich Chemistry, visit Aldrich.com/thiazole

Other New Building Blocks

N

S NH

Boc N

S Br

t-BuN

S NH2

H3C

O

HO

N

SH3C NH2

BrN

S

BrOH3C

O N

723649 724122 722375

717851 717258

718076

729442

725293

723282

722316

722340

722464

721530

722359

OHCl Br

BocN

HN

BocCH3

O

OO

CH3

O

OCH3 O OH

O

NH

O

O CH3

O

NH

NO CH3

O

NN

CH3

CH3

O

HO

NN

OH

O

CH3

H3C

724890 722367 724149

NH2

NH2

NOH

OH

H3CO NH2

SO

OCl

Cl NO2

Other New Building Blocks — cont'd

For a comprehensive list of Building Blocks available form Aldrich

Chemistry, visit Aldrich.com/bb

References: (1) Horton, D. A. et al. Chem. Rev. 2003, 103, 893 and references therein.

(2) Recent reviews of indazoles: a) Schmidt, A. et al. Eur. J. Org. Chem. 2008, 4073. (b)

Cerecetto, H. et al. Mini-Rev. Med. Chem. 2005, 5, 869. (c) Stadlbauer, W.; Camp, N. In

Science of Synthesis: Houben-Weyl Methods of Molecular Transformations; Bellus, D., Ley,

S. V., Noyori, R., Regitz, M., Schaumann, E., Shinkai, E., Thomas, E. J., Trost, B. M., Reider, P.

J., Eds.; Thieme: Stuttgart, Germany, 2002; Vol. 12, p 227. (3) Recent reviews of azaindoles:

(a) Popowycz, F. et al. Tetrahedron 2007, 63, 1031. (b) Popowycz, F. et al. Tetrahedron

2007, 63, 8689. (c) Song, J. J. et al. Chem. Soc. Rev. 2007, 36, 1120. (4) Huang, W.-S. et al.

J. Med. Chem. 2010, 53, 4701. (b) Buckley, G. M. et al. Bioorg. Med. Chem. Lett. 2008, 18,

3656. (c) Buckley, G. M. et al. Bioorg. Med. Chem. Lett. 2008, 18, 3291. (5) (a) Suhadolnik,

R. J. Pyrrolopyrimidine Nucleosides in Nucleoside Antibiotics; Wiley-Interscience: New York,

1970; 298 and references therein. (b) Kasai, H. et al. Biochemistry 1975, 14, 4198. (c) Nauš,

P. et al. J. Med. Chem. 2010, 53, 460. (6) Jin, Z. Nat. Prod. Rep., 2005, 22, 196. (7) Pettit, G. R.

et al. J. Am. Chem. Soc. 1987, 109, 6883. (8) (a) Davidson, B. S. Chem. Rev. 1993, 93, 1771.

(b) Fusetani, N.; Matsunaga, S. Chem. Rev. 1993, 93, 1793. (c) Wipf, P. Chem. Rev. 1995, 95,

2115. (d) Aulakh, V. S.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 5750. (9) Dondoni, A.; Marra,

A. Chem. Rev. 2004, 104, 2557.

722073

722022

725048

720321

715646

720844

720917

714372

724165

697966

719722

730343

O

H

OHNO2

H3CO

N

HN

CH3

BocN

OO

CH3

CH3

N

O H

Boc

NN

N

ClON CH3

O

H

NN

NH2

N

NCl

ClN

N

Br

Br Br

N

N

Cl

NH2

O2N

N

N

CF3O

H3CO

ClN

N

S

NH2

727598

724254

722243

694770

722251

724157

O

NNH2

O

NH3CO

F

SO

OCl

O

O

OH

SO

OClCl


24

Cross-Couplings in Water

Conducting transition metal-catalyzed cross-coupling chemistry in water

instead of organic solvent has a number of potential benefi ts in terms of

cost, environmental impact, safety, and impurity profi les. Increasing focus

on the “green-ness” of chemical processes has further promoted recent

developments in this fi eld. The actual means of implementing reactions

in water, however, especially at room temperature and for water-insolu-

ble organic substrates, has not always been clear. One solution that has

been applied to a broad range of transition metal-catalyzed processes is

the use of small amounts of a nanomicelle-forming amphiphile in water,

which provides a lipophilic medium in which cross-coupling reactions

can take place.

Micellar Catalysis

Beginning in 2008, Lipshutz et al. published a series of papers demon-

strating the viability of surfactant promoted, transition metal-catalyzed

chemistry in water at room temperature. Using a variety of commercially

available surfactants, a number of palladium- and ruthenium-catalyzed

processes were found to be amenable to mild, room temperature reac-

tions in water. Products can be recovered from the aqueous phase using

standard extraction procedures and in high isolated yields.

Synthetic ReagentsTroy Ryba, Ph.D.Product [email protected]

TPGS–750–M: Second Generation Amphiphile for Organometallic Chemistry in Water @ RT

TPGS–750–M: A Second Generation

Amphiphile

Lipshutz and co-workers have recently developed a second

generation technology to their original PTS-enabling surfactant based

on a polyoxyethanyl-α-tocopheryl succinate derivative, TPGS-750-M

(733857) (Figure 1). This designer surfactant is composed of a lipophilic

α-tocopherol moiety and a hydrophilic PEG-750-M chain, joined by an

inexpensive succinic acid linker, and spontaneously forms micelles upon

dissolution in water. The balance and composition of TPGS-750-M’s

lipophilic and hydrophilic components has been tailored to promote a

broader array of chemistry in water more effi ciently than that seen in PTS.

Furthermore, this new, more practical surfactant can be readily substi-

tuted for older amphiphiles, usually with equal or greater

effi ciency in terms of both yield and reaction times.

Figure 1: TPGS–750–M.

O

O

3

OO

OO

OMe

16

*Special thanks to Professor Bruce Lipshutz, Zarko V. Boskovic and Alex R. Abela of

University of California, Santa Barbara for contributing this article on TPGS-750-M.


25Synthetic Reagents

Olefi n Metathesis

Employing the second generation Grubbs catalyst (2 mol %) a variety of

lypophillic substrates successfully undergo ring-closing or cross-meta-

thesis in water at room temperature to produce high isolated yields of the

desired products (Scheme 1). Reactions were conducted in 2.5% TPGS-

750-M/water, with yields equal to or slightly better than those performed

using various other surfactant-water combinations.

O

OOTBS

Grubbs-2 (2 mol %)

2.5% TPGS-750-M, water22 oC, 12 hOTBS

O

O

91%

NTs

Grubbs-2 (2 mol %)

2.5% TPGS-750-M, water22 oC, 12 hN

Ts88%

Scheme 1: Selected olefi n metathesis.

Pd-Catalyzed Cross-Coupling Reactions

A variety of widely used palladium-catalyzed cross-coupling reactions can

now be run under mild room temperature conditions in water with TPGS-

750-M, using a variety of commercially available palladium complexes

and ligands. These transformations, including Suzuki-Miyaura, Sono-

gashira, Buchwald-Hartwig aminations, and Heck, are amongst the most

heavily used bond forming reactions, both industrially and academically

(Scheme 2).

Scheme 2: Selected Pd-catalyzed cross coupling reactions.

Operationally extremely simple Suzuki-Miyaura reactions using micellar

catalysis and bis(di-tert-butylphosphino)ferrocene palladium chloride

complex provide access to highly sterically congested substrates at room

temperature using triethylamine as base.

B(OH)2

OMeBr

OMe

88%

Br

99%

Br NH2HN

93%

+

+

+

2 mol % Pd(dtbpf)Cl2Et3N (3 equiv)

2% TPGS-750-M, water20 °C, 24 h

KOH (1.5 equiv) 2% TPGS-750-M, water

22 oC, 19 h

[(allyl)PdCl]2 (0.5 mol %)

Takasago's cBRIDP (2 mol %)

3% TPGS-750-M, water 22 oC, 21 h

PdCl2(CH3CN)2 (1 mol %)X-Phos (2.5 mol %)

Et3N (2 eq.)

OMeI

OMe

95%

+ 5% TPGS-750-M, water

22 oC, 12 h

(PtBu3)2Pd (2 mol %)

Et3N (3 equiv)

Sonogashira reactions and Buchwald-Hartwig aminations are also

amenable to reaction in water with TPGS-750-M using the palladium

chloride/X-Phos combination in the former, and allyl palladium chlo-

ride/cBRIDP in the latter (Figure 2).

Figure 2: Selected ligand examples.

Heck cross-couplings with aryl iodides can be successfully performed

using Pd(P(t-Bu)3)2 as the palladium source in the bulk aqueous environ-

ment containing TPGS-750-M (5 wt. %), obviating the need for high

temperatures commonly associated with Heck reactions.

Zinc-mediated Negishi-like couplings between aryl and alkyl

halides can be performed in aqueous TPGS-750-M (Scheme 3).

Under these conditions, typically highly moisture sensitive organozinc

halides are formed in situ from an alkyl halide and zinc dust, and react

with an aryl halide under palladium catalysis. With the aid of a surfac-

tant and a stabilizing ligand for RZnX, such as tetramethylethylenedi-

amine (TMEDA), this entire process takes place in water, leading to a

variety of primary and secondary alkyl-substituted aromatics. The choice

of catalyst is crucial for the success of the reaction; Pd(Amphos)2Cl2

(Bis(di-tert-butyl (4-dimethylaminophenyl)phosphine) palladium(II)

chloride) was found to be the optimal catalyst.

Scheme 3: Selected Negishi-like cross-coupling example.

C–H Activation Reactions

Cationic palladium in combination with stoichiometric oxidant benzo-

quinone and silver nitrate successfully catalyzes ortho-functionalization

of a variety of aryl acetamides in water at room temperature using this

amphiphile (Scheme 4).

Scheme 4: Selected C–H activation reaction.

Reference: Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59.

For more information on TPGS–750–M, visit

Aldrich.com/tpgs750m

i-Pr

i-Pr

PCy2

i-PrMe

P(t-Bu)2Ph

Ph

X-Phos cBRIDP

685151638064

Br

Br

EtO2CEtO2C

0.5% Pd(Amphos)2Cl2TMEDA (1 equiv)Zn dust (3 equiv)

2% TPGS-750-M, water, rt

80%

+

[Pd(MeCN)4](BF4)2 (10 mol %)BQ, AgNO3

OMe

HN

CO2n-Bu

2% TPGS-750-M, water, rt

HN

O

OMe

O

On-Bu

H

O+

83%


26

Stable Isotope Labeled

Reagents from ISOTEC®

Stable isotope containing compounds are used in a variety of applica-

tions including tracers in clinical studies,1 labeled amino acids for use in

protein quantifi cation2 and standards for metabolic research.3 Historically,

the introduction of stable isotopes has been a diffi cult, time consum-

ing and costly process requiring the specialized skill of a stable isotope

chemist. The reagents below were designed to introduce stable isotopes

using standard chemical procedures.

13C Labeled Olefi nation Reagents

The 13C labeled olefi nation reagents4 were developed to simplify the

labeling process by providing a set of substrates ready to be incorpo-

rated into precedented chemical syntheses.5 These olefi nation reagents

provide access to a fi xed 13C label within the alkene as well as site-vari-

able deuterium incorporation (Scheme 1). This methodology effi ciently

provides a densely labeled compound ready for further functionalization.

PhS

13CH2

O O

K2CO3, CH2OH2O/DMSO

1. K2CO3H2O/DMSO

2. RI, 3. R'CHO

K2CO3, CD2OH2O/DMSO

K2CO3, CD2OD2O/DMSO

K2CO3, CH2OD2O/DMSO

PhS

13CH

O O

CH2

PhS

13C

O O

R

R'

PhS

13C

O O

DD

PhS

13C

O O

CH2

D

PhS

13CH

O O

DD

P

O

OEt

OEt

D

Scheme 1: Olefi nation reagents labeling strategies.

The availability of all three sulfur oxidation states allows control of the

reaction conditions including base type and strength as well as access to

a preferred sulfur removal strategy.6 By providing access to mild reaction

conditions, fewer compatibility issues arise between reaction conditions,

olefi nation reagent and substrate.

New 13C Labeled Olefi nation Reagents

715832 715816715824

PhS

13CH2

O O

P

O

OEt

OEtPhS

13CH2

O

P

O

OEt

OEtPhS

13CH2

P

O

OEt

OEt

Stable IsotopesLisa Roth, Ph.D.Product [email protected]

D and/or 13C Labeled 1,3–Dithiane Unlabeled 1,3–Dithiane is a versatile reagent able to act as an acyl anion

equivalent when submitted to Corey-Seebach reaction conditions.7

This well known chemistry can also be carried out when 1,3–Dithiane

is labeled at the 2 position providing labeled and protected aldehydes,

ketones, α-hydroxyketones, 1,2–diketones and α-keto acid derivatives.

Deprotection can be facilitated using standard methods to give the

appropriately labeled substrates (Scheme 2).8

Scheme 2: 1,3–Dithiane for the introduction of D and/or 13C.

New Labeled D and/or 13C 1,3–Dithiane

S

13CS

716111S

13CS D

D

716073

HH

References: (1) Brown, L. D.; Cheung, A.; Harwood, J. E. F.; Battaglia, F. C.; J. Nut. 2009,

139, 1649. (2) Hanke, S.; Besir, H.; Oesterhelt, D.; Mann, M.; J. Proteome. Res. 2008, 7, 1118.

(3) Li, C.; Hill, R.W.; Jones, A. D.; J. Chrom. B 2010, 878, 1809. (4) Licensed from Highlands

Stable Isotopes Corp. (5) a) Capela, R.; Oliveira, R.; Gonçalves, L. M.; Domingos, A; Gut, J.;

Rosenthal, P. J.; Lopes, F.; Moreira, R.; Biorg. Med. Chem. Lett. 2009, 19, 3229. (b) Verissimo,

E.; Berry, N.; Gibbons, P.; Cristiano, M. L. S.; Rosenthal, P. J.; Gut, J.; Ward, S. A.; O’Neill, P. M.;

Biorg. Med. Chem. Lett. 2008, 18, 4210. (6) a) Beye, G. E.; Ward, D. E.; J. Am. Chem. Soc. 2010,

132, 7210. (b) Pellissier, H.; Tetrahedron 2006, 62, 5559. (7) a) Seebach, D.; Corey, E. J.; J. Org.

Chem. 1975, 40, 231. (b) Mundy, P. B.; Ellerd, M. G.; Favaloro, F. G., Jr.; Name Reactions and

Reagents in Organic Synthesis, 2nd ed.; Wiley & Sons: New York, 2005; p 186, 745. (8) Wutz, P.

G. M.; Greene, T. W.; Protection for the Carbonyl Group, Greene’s Protective Groups in Organic

Synthesis, 4th ed.; Wiley & Sons: New York, 2007; p 482.

For more information on these products avaliable from

Aldrich Chemistry, visit Aldrich.com/sinext

or contact:

Stable Isotope Technical Services

Phone: (937) 859-1808

(800) 448-9760 (US and Canada)

Fax: (937) 859-4878

E-mail: [email protected]

S

13CS R

R

O13C

R'R R13C

R'

O OH

R13C R'

O

OR

13C OHO

O

R = H or D

For more information on our

Greener Alternatives, Programs

and Services, visit

sigma-aldrich.com/green

Greener Alternatives

Check out our Web portal to find out about

our Greener Products and Programs

Unlock a smarter, greener laboratory

Visit our Greener Alternatives Web portal at sigma-aldrich.com/green to learn how you can

reduce your lab’s environmental impact–without compromising the quality of your data

or research. Come see how Sigma-Aldrich® is meeting the research community’s needs

for products and services which can signifi cantly lessen environmental impact. Put our

commitment to environmental sustainability to work in your lab.

Greener ProductsBrowse greener alternatives.

Programs and ServicesDiscover solutions designed to reduce the environmental impact of your lab.

Learning CenterResources and links to information on environmental sustainability.


28

Aldrich NMR Solvents

Challenge 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 pas-

sionate about providing this high level of quality to our customers and

work continuously to meet these requirements. We off er the widest

range of NMR solvents with the highest isotopic enrichment available

along with excellent chemical purity. We consistently review and im-

prove our methods for solvent purifi cation 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.

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 Surface

1. 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 prepara-tion setup may be adequate.

How to Avoid Sources of Impurities and Chemical Residues

1. 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 Residue

1. 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 Evaporation

1. 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

Stockroom ReagentsTodd HalkoskiMarket Segment [email protected]

Aldrich also off ers 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 eff orts. We

also off er 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.

Try our NMR Solvents today to see their high quality

for yourself.

For a complete listing of all NMR-related products and information,

visit Aldrich.com/nmr


29Stockroom Reagents

Specialty NMR Solvents

Aldrich off ers a wide range of high purity deuterated solvents for the

NMR community. In addition, we also off er various specialty solvents for

more demanding applications. Whether you need the highest enriched

deuterium oxide available, or solvents with a reduced HOD peak, we

have what you need.

“Special HOH” Solvents

When customers requested NMR solvents with a suppressed HOD peak

we listened, and developed NMR solvents called “Special HOH”. These

solvents have an HOD peak which is less than 1% of the HOH peak, to

minimize potential exchange with an analyte. “Special HOH” solvents also

meet our standard water specifi cation for NMR solvents.

1H-NMR Spectrum of DMSO-d6 “Special HOH”

Anhydrous NMR Solvents

When water content is of paramount concern, try our anhydrous

solvents that contain reduced levels of water.

“Extra” Enriched D2O

With an enrichment of 99.994 atom % D, this is the highest enriched

deuterium oxide available.

For additional information visit us at Aldrich.com/nmr

or contact:

Stable Isotope Technical Services

Phone: (937) 859-1808

(800) 448-9760 (US and Canada)

Fax: (937) 859-4878

E-mail: [email protected]

11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 –0.5ppm

2.5 2.4ppm

3.3ppm

HOH

DMSO-d6 residual peak

HOD

Deuterium oxide, Extra, 99.994 atom % D

613398-10G serum bottle 10 g

613398-50G serum bottle 50 g

Acetonitrile-d3, 99.8 atom % D, Anhydrous (water < 10 ppm)

569550-10X1ML ampule 10 x 1 mL

Benzene-d6, 99.6 atom % D, Anhydrous (water < 10 ppm)

570680-50G glass bottle 50 g

Chloroform-d, 99.8 atom % D, Anhydrous (water < 10 ppm)


Dimethyl sulfoxide-d6, 99.9 atom % D, Anhydrous (water < 50 ppm)




Methanol-d4, 99.8 atom % D, Anhydrous (water < 50 ppm)




Toluene-d8, 99.6 atom % D, Anhydrous (water < 10 ppm)


Acetonitrile-d3, 99.8 atom % D, "Special HOH"




Dimethyl sulfoxide-d6, 99.9 atom % D, "Special HOH"




716731-10x0.75ML ampule 10 x 0.75 mL

716731-10ML serum vial 10 mL

716731-50ML serum vial 50 mL

Data acquired on a Varian 400 MHz instrument.


30

Inert Atmosphere Glove-Boxes

Sigma-Aldrich® off ers a wide range of Plas-Labs™ glove boxes for most

oxygen and moisture-sensitive applications .

The boxes are manufactured with a clear, one piece acrylic top and a

molded base section. Gaskets are double layered for a reliable, airtight

seal. The 8 in. ports with ambidextrous Hypalon® glove with SS O-rings

give easy access to all parts of the glove box. The transparent transfer

chamber has an adjustable vacuum gauge.

Nitrogen Dry Box

The Plas-Labs™ nitrogen Dry Box is a completely enclosed chamber

designed for working in nitrogen, argon and plasma-type atmospheres

and ideal for handling oxygen sensitive materials.

Drying train removal without disturbing internal atmosphere• Two vacuum/pressure pumps to speed purging.• Fluorescent light system with illuminated controls•

Single-station model - Internal H×W×D - 26 in.×41 in.×26 in.

Z562920 AC input 120 V

Z563285 AC input 240 V, Euro plug

Z562939 AC input 240 V, UK plug

Multi-station model - Internal H×W×D - 28 in.×60 in.×38 in.




Labware NotesPaula FreemantleProduct [email protected]

Basic Glove Box

The Plas-Labs Basic glove

boxes are engineered to

fi t general laboratory iso-

lation applications. They

can be easily modifi ed

for specifi c uses and are

very handy for isolating

sensitive research studies

from a hostile exterior

environment.

These economical units are compact, portable, lightweight and

self-contained.

Three tier suspended clear acrylic shelves • White leveling tray for transferring the transfer chamber.• Four purge valves• Multiple electrical outlet strip•

Single-station model - Internal H×W×D - 26 in.×41 in.×28 in.




Multi-station model - Internal H×W×D - 28 in. × 60 in. × 38 in.





31Labware Notes

Eliminating Static

from Glove Boxes

Static in plastic glove boxes

and bags can be a problem in

many applications. The anti-

static ionizer from Plas-Labs™

is an eff ective way to eliminate

all static charges within 36

inches (90 cm) of unit.

Ion balance adjustment• Compact footprint• Virtually maintenance free•

Z563064 120 V

Z563072 240 V, UK plug

Z563323 240 V, Euro plug

For more information about these products or to place an order visit

Aldrich.com

The AtmosBag™

An Economical Solution for ControlledAtmosphere Applications. AtmosBag is a fl exible, infl atable

polyethylene chamber with built-in

gloves that lets you work in a totally

isolated and controlled environ-

ment. Our customers use it for a

wide variety of applications from

providing an emergency isolation environment for inspecting unknown

materials to the transfer of air- and moisture-sensitive materials when

sampling or weighing. AtmosBag even permits weighing operations

inside a fume hood for added safety. Air currents that would interfere with

weighing are eliminated inside of AtmosBag.

Z106089 Two-hand, non-sterile, size L, Tape-seal

Z108405 Four-hand, non-sterile, Tape-seal

Z112828 Two-hand, non-sterile, size M, Tape-seal

Z112836 Two-hand, non-sterile, size S, Tape-seal

Z118354 Two-hand, sterile, size L, Tape-seal

Z118362 Two-hand, sterile, size M, Tape-seal

Z118370 Two-hand, sterile, size S, Tape-seal

Z530204 Two-hand, size S, Zipper-lock

Z530212 Two-hand, size M, Zipper-lock

Z530220 Two-hand, size L, Zipper-lock

Z555525 Four-hand, Zipper-lock

Full details can be found in our Technical Bulletin AL 211 which can be

downloaded from Aldrich.com

NMR Tube Holders

Unbreakable, NMR tube car-

rier provides protection for

the tube and lab personnel

when transporting samples.

The clear, shatter-resistant

polycarbonate case allows

for visual sample identifi ca-

tion and inspection prior

to opening. Natural rubber

plugs on both ends of the

case provide impact absorp-

tion if accidentally dropped. NMR tubes are held securely in place inside

the PC case by the bottom loading rubber plug. Carrier holds one 5 mm

diameter tube, 7 or 8 in. L.

Z567078-5EA

News and Innovation

Chemrus® Disposable Filter Funnels

Convenient and inexpensive, these disposable fi lter funnels have

polypropylene bodies with tapered stems that fi t 7/10 joints with-

out seals. The funnels are available in two styles, Buchner and Hirsch,

and a choice of 10 micron polyethylene frit, Celite, or perforated

plate for use with fi lter paper.

Maximum use temperature is 110 °C. Order vacuum adapters, fi lter

paper, vials and 20–400 to 24–400 vial connector separately not

given below.

Cat. No. Style Filter type Capacity (mL)

Z679798 Buchner PE frit, 10 micron 18



Z679860 Buchner Celite® (0.5g) 18

Z679860 Buchner Celite® (1.5g) 40

Z679836 Hirsch Perforated Plate 20

Z679844 Hirsch Perforated Plate 60

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