74220 chemfiles 10.3 v5

Volume 10, Number 3 • 2010

Aldrich

Asymmetric Synthesis

Catalysis

Chemical Biology

Organometallics

Building Blocks

Synthetic Reagents

Stockroom Reagents

Labware Notes

XtalFluor-E®, A New Deoxofl uorination Reagent

74220 ChemFiles 10.3_v5.indd 174220 ChemFiles 10.3_v5.indd 1 8/19/2010 10:17:12 AM8/19/2010 10:17:12 AM

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Prof. Carolyn R. Bertozzi (UC, Berkeley) Copper-Free Click Chemistry: Bioorthogonal Reagents for Tagging Azides

Prof. James L. Leighton (Columbia U.) Powerful and Versatile Silicon Lewis Acids for Asymmetric Chemical Synthesis

Prof. A. Stephen K. Hashmi (Heidelberg U.) Gold-Catalyzed Addition of X–H Bonds to C–C Multiple Bonds

Prof. Vladimir Gevorgyan (UI, Chicago) Copper-, Silver-, and Gold-Catalyzed Migratory Cyclizations toward Heterocycles

Prof. Bruce H. Lipshutz (UC, Santa Barbara) Micellar Catalysis Enabled Cross-Couplings in Water at Room Temperature:

New Applications and a Second-Generation Technology

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3

Intro

du

ction

Volume 10, Number 3

Sigma-Aldrich Corporation

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

Editorial Team

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Wesley Smith

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Production Team

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Chemistry Team

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Josephine Nakhla, Ph.D.

Matthias Junkers, Ph.D.

Mark Redlich, Ph.D.

Troy Ryba, Ph.D.

Todd Halkoski

Paula Freemantle

Mike Willis

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AldrichIntroduction

Haydn Boehm, Ph. D.

Global Marketing Manager: Chemical Synthesis

[email protected]

Welcome to the third edition of the new Aldrich

ChemFiles, our FREE quarterly newsletter written by

our experts from Product Management and R&D.

Our aim is to keep you informed of the new Aldrich

Chemistry products that facilitate the latest research

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as our new Synthetic Reagents Product Manager. Aldrich ChemFiles 10.3 will

also introduce our new Buchwald Precatalysts (Catalysis), Leighton Reagents

(Asymmetric Synthesis), Trifluoroborates (Organometallic Reagents), and PEG

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We hope that Aldrich ChemFiles will enable you to expand your research

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Kind Regards

Haydn Boehm, Ph.D.

Table of Contents

Asymmetric SynthesisLeighton’s Chiral Allyation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Asymmetric Epoxidation using Shi catalyst. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

CatalysisAir-Stable Precatalysts for Amination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

N-Arylation of Aryl Mesylates and Monoarylation of Primary Amines

using BrettPhos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Chemical BiologyNew Polyethylene Glycol Building Blocks for PEGylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Organometallic ReagentsHeterocyclic Organotin Reagents for Stille Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

New Method for Stannylation of Cyclopropenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Building BlocksThiazoles and Imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Synthetic ReagentsXtalFluor-E® and XtalFluor-M®: Convenient, Crystalline

Deoxofluorination Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Stockroom ReagentsThe New Aldrich Sure/Seal™ System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Labware Notes Improved NMR Tubes from Sigma-Aldrich . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22


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

The reaction scope of these silacycles was extended to a practical

method for the enantioselective synthesis of tertiary carbinamines

based on the addition of this chiral allylsilane reagent to a

structurally diverse array of ketone-derived benzoylhydrazones

(Scheme 3).4 While many methods for the synthesis of quaternary

α-amino acids have been published, far fewer reports have dealt

with the synthesis of tertiary carbinamines.

N

OSi

CH3H3C

CH2

Cl

R1

N

R2

NHBz

+R1 CH2

R2 NHNHBzCHCl3

24 h

Ph CH2

H3C NHNHBz

86%; 90% ee

Ph CH2

H3CO2C NHNHBz

76%; 93% ee

Ph CH2

i-Pr NHNHBz

80%; 97% ee

CH2

H3C NHNHBz

70%; 90% ee

2-Thienyl c-Hex CH2

H3C NHNHBz

78%; 94% ee

706671

Scheme 3: Practical synthesis of tertiary carbinamines by enantioselective

allylation of ketone-derived benzoylhydrazones

The free amines are easily accessed in good yields by subjecting

the diff erent hydrazones to reduction with SmI2 (409340).

References: (1) Leighton, J. L. Aldrichimica Acta 2010, 43, 3. (2) Kinnaird, J. W. A.;

Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920. (3)

Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946. (4) Berger, R.; Rabbat,

P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596. (5) Berger, R.; Duff , K.;

Leighton, J. L., J. Am. Chem. Soc. 2004, 126, 5686.

Leighton’s Strained Silacycle

Allylation Reagents

For more information on the applications of the Leighton

silacycle reagents, please see Professor Leighton’s recent

review in Aldrichimica Acta 2010, Vol. 43, No. 1 or visit

aldrich.com/allylation

Asy

mm

etr

ic S

ynth

esi

s

Asymmetric SynthesisDaniel Weibel, Ph.D.

European Market Segment

Manager, Chemistry

[email protected]

Leighton’s Chiral Allylation

Reagents

The asymmetric allylation of carbonyl

compounds remains one of the most important and fundamental

addition reactions for the synthesis of optically active chiral

building blocks homoallylic alcohols.

In 2002, Leighton and co-workers developed strained silacycle

compounds as versatile reagents for the practical enantioselective

allylation of aldehydes.1

A newly developed chiral auxiliary based on the cyclohexane-1,2-

diamine scaff old successfully allylated a broad range of aldehydes

highly enantioselectively (Scheme 1).2

704725

NSi

N

CH2

Cl

Br

Br

R H

O

R

OH

CH2+

CH2Cl2

-10°C, 20 h

OH

CH2

OH

CH2

OH

CH2

OH

CH2

F3C

OH

CH2n-PrTBDMSO

61%; 98% ee

OH

CH2

CH3

H3C

80%; 96% ee

69%; 98% ee 62%; 96% ee 75%; 96% ee

71%; 95% ee

Scheme 1: Leighton’s silacycle reagent for the enantioselective allylation

of aldehydes

The development of practical enantioselective syntheses of chiral

amines is of great importance to synthetic organic and medicinal

chemists. In 2003, Leighton and co-workers successfully used a

pseudoephedrine-derived, fi ve-membered-ring strained silacycle

reagent for the enantioselective allylation of acylhydrazones

(Scheme 2).3

Ph

N

H

NHAc

+ Ph

NHNHAc

CH2

CH2Cl2

10°C, 16 h

80%; 98% ee (recryst.)

N

OSi

CH3H3C

CH2

Cl

706671

Scheme 2: Practical, enantioselective allylation of acylhydrazones using

strained silacycles

NSi

N

CH2

Cl

4-Br-C6H4

4-Br-C6H4

N

OSi

CH3H3C

CH2

ClN

OSi

CH3H3C

Cl

NSi

N

CH2

Cl

4-Br-C6H4

4-Br-C6H4

704725 719056 720380

705098

N

OSi

CH3H3C

CH2

Cl

N

OSi

CH3H3C

Cl

706671 729647


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

Asymmetric Epoxidation Using Shi Catalyst

Catalytic asymmetric epoxidation of alkenes has been the focus

of many research eff orts over the past two decades, the best

known methods probably being those developed by Sharpless1

and Jacobsen-Katsuki.2 Shi has also developed a very effi cient

method for asymmetric epoxidation, using a ketone-derived

organocatalyst based on D-fructose (F0127).3 This organocatalyst

is able to epoxidize trans alkenes and certain cis alkenes with good

to excellent yields and selectivities. More recently, Shi has achieved

excellent results using hydrogen peroxide as an oxidant instead

of OXONE® (228036), which allows a signifi cant reduction in the

amount of additional salts introduced and solvent used in the

reaction (Scheme 4).4

CH3 CH3O

O

O

O

O

O

OH3C

H3C

CH3CH3

H2O2, CH3CN, 0°C; 12h

93%; 92%ee

520160(15mol%)

Scheme 4: Enantioselective epoxidation of trans alkenes using

Shi organocatalyst

Other groups have used Shi’s methodology in pursuit of a

number of unique structural moieties. For example, McDonald

and co-workers recently reported a robust and selective synthesis

of 2-amino-3,5-diols that employs the Shi epoxidation in a

key step (Scheme 5).5 These 2-amino-3,5-diols are 1-deoxy-

5-hydroxysphingosine analogues, which show promise as

anticancer agents.

O

O

O

O

O

OH3C

H3C

CH3CH3

H2O2CH3CN:EtOH:CH2Cl2

520160(30 mol%)H3C

C13H27

O

Ot-Bu

O

H3CC13H27

O

Ot-Bu

O

O

90%; dr=12:1

H3CC13H27

OHOH

NH2

1-deoxy-5-hydroxysphingosine analogue

Scheme 5: Selective route to sphingosine derivatives using Shi’s epoxidation

organocatalyst

A recent example of the use of the Shi catalyst is the synthesis

of chiral thiosulfonate derivatives. Chiral sulfi nyl derivatives

have been of interest for the past three decades.6 This interest

stemmed from the use of these molecules as chiral controllers in

asymmetric synthesis, as chiral ligands and as Lewis bases. Khiar

et al. reported a new method to synthesize enantiomerically pure,

Asym

me

tric Synth

esis

functionalized, sterically demanding thiosulfonates.7 Investigating

several catalysts for the oxidation of disulfi des, diesters and

diethers, Khiar et al. determined that a particular chiral pyranone

derived from D-glucose, the Shi catalyst, yielded the best yields

and stereoselectivities. Using the Shi catalyst in combination with

oxone in acetonitrile and dimethoxymethane, the authors reported

up to 89% yield and up to 96% ee for the oxidation of disulfi des

(Scheme 6).

SS

Et EtBzO

Et EtOBz S

SEt Et

BzO

Et EtOBz

O

89%; 93%ee

OxoneCH3CN:CH2Cl2

O

O

O

O

O

OH3C

H3C

CH3CH3

520160(30 mol%)

Scheme 6: Enantioselective disulfi de oxidation using Shi catalyst

References: (1) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis

(2nd Ed.); Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 6A. (2) Jacobsen, E. N.

In Catalytic Asymmetric Synthesis (1st Ed.); Ojima, I., Ed.; VCH: New York, 1993;

Chapter 4.2. (3) (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (b) Frohn, M.; Shi, Y.

Synthesis 2000, 1979. (c) Wang, Z.-X. et al. J. Am. Chem. Soc. 1997, 119, 11224.

(d) Tu, Y. et al. J. Am. Chem. Soc. 1996, 118, 9806. (4) Shu, L.; Shi, Y. Tetrahedron

2001, 57, 5213. (5) Wiseman, J. M. et al. Org. Lett. 2005, 7, 3155. (6) Fernandez, I;

Khiar, N. Chem. Rev. 2003, 95, 1717. (7) Khiar, N. et al. Org. Lett. 2007, 9, 1255.

Expoxidation Catalyst

For more information on Aldrich Chemistry's Expoxidation

Catalyst portfolio, please visit aldrich.com/epoxidation

O

O

O

O

O

OH3C

H3C

CH3CH3

520160

O

O

O

O

O

OCH3

CH3

H3CH3C

O

O

O

H3CH3C

NO

O

CH3

O

H

H

718653 693456



Cat

alys

is

CatalysisJosephine Nakhla, Ph.D.

Market Segment Manager

Organometallics & Catalysis

[email protected]

Palladium(II) Acetate,

Recrystallized

It has been demonstrated that in some

applications recrystallized palladium(II) acetate (Pd(OAc)2) performs

better than typical grades. White and Overman have both

independently demonstrated that in some applications a particular

grade of Pd(OAc)2 is necessary. In particular, the preparation of the

White catalyst as well as the preparation of the COP catalysts, [COP-

OAc]2 and [COP-Cl]2, by Overman successfully employ and require

recrystallized Pd(OAc)2.

Figure 1: Recrystallized palladium(II) acetate (Pd(OAc)2)

References: Anderson, C. E.; Kirsch, S. F.; Overman, L. E.; Richards, C. J.; Watson, M. P. Org. Synth., 2007, 84, 148.

For more information on our catalysts,

visit aldrich.com/catalysis

Cationic Palladium Complex, [Pd(dppp)

(PhCN)2](BF4)2

Cationic palladium(II) complexes are utilized in a variety of

reactions. [Pd(dppp)(PhCN)2](BF4)2 (696617) was shown to catalyze

the hetero Diels-Alder reaction of dienes with aldehydes. The

reaction yields substituted 5,6-dihydro-2H-pyrans without the use

of Lewis acids (Scheme 1). The reaction is believed to proceed

through a stepwise mechanism.

O

PhH[Pd(dppp)(PhCN)2](BF4)2

O

Ph

67%

CHCl3, 50°C, 20h696617

Scheme 1: Cationic palladium complex in hetero Diels-Alder reaction

References: (1) Oi, S.; Kashlwagi, K.; Terada, E.; Ohuehi, K.; lnoue, Y. Tetrahedron

Lett. 1996, 37, 6351. (2) Davies, J. A.; Hartley, F. R.; Murray, S. G. J. Chem. Soc. Dalton

Trans. 1980, 2246.

For more information on Aldrich Chemistry's catalyst

portfolio, please visit aldrich.com/catalysis

Air-Stable Precatalysts for Amination

C–N bond forming cross-couplings typically require a palladium

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 yet

air- and moisture-stable precatalysts, which, under the standard

reaction conditions, form the active monoligated Pd-species. These

precatalysts (704954, 704946, 707589, 708739) are exceptionally

effi cient even under challenging conditions, such as coupling

electron-poor anilines with deactivated aryl chlorides. The catalyst

precursors also off er other advantages including low catalyst

loadings and short reaction times.

NH2

+

ClR

K2CO3, t-BuOH, 1 h, 110 °C

HN

EtO2COCH3

86%

HN

NC

OCH3

OCH3

HN

O2N n-Bu

1 mol%

99% 97%

704954EWG

HN

EWG R

HN

i-Pr

i-Pr CHO90%

(with 707589)

Scheme 2: Buchwald precatalysts in N-arylations of electron-poor amines

with electron-rich aryl chlorides

R1R2NH+

ClR3

NaOt-Bu, dioxane, 10 min, 100 °C

HN CF3

96%

HN H

N

93% 96%

704954 (0.1 mol%), XPhos (0.1 mol%)NR1R2

R3

H3COF

H3C

CH3 H3C

CH3

Scheme 3: Buchwald precatalysts in N-arylations with low

catalyst loadings

Buchwald Precatalysts

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

For more information on our Buchwald catalyst and ligand

portfolio, visit aldrich.com/buchwald

PdNH2Cl

i-Pr

i-Pr

i-Pr

PCy2

704954

(from XPhos)

PdNH2Cl

PCy2OMe

OMe

PdNH2Cl

PCy2Oi-Pr

Oi-Pr

704946

(from SPhos)

707589

(from RuPhos)

PdNH2Cl

i-Pr

i-Pr

i-Pr

P t-Bu2

708739

(from t-BuXphos)



N-Arylation of Aryl Mesylates and

Monoarylation of Primary Amines

Using BrettPhos

Buchwald and coworkers recently reported the use of a

catalyst system comprised of the highly effi cient ligand

2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-

1,1′-biphenyl (718742) (BrettPhos) and a palladium precatalyst

(also containing the BrettPhos moiety) for the N-arylation of

aryl mesylates with aryl amines (Scheme 4). Aryl mesylates

constitute an important class of organic electrophiles due to

their reasonable atom economy, cheap cost, and high stability.

In addition, BrettPhos was found to be an eff ective ligand in

the unprecedented monoarylation of primary amines with aryl

chlorides at exceptionally low loadings (Scheme 5).

ArOMs + H2NAr'

PdNH2Cl

i-Pr

i-Pr

PCy2 OCH3

i-Pr OCH3

1 mol%

1 mol% BrettPhos (718742)

K2CO3, t-BuOH, 110 °C, 16 h

ArN(H)Ar'

HN

N

CH3

CH399%

HN

H3CO

CO2Et

90%

H3CO

OCH3

HN

CO2Et

84%CO2Et

i-Pr

i-Pr

PCy2 OCH3

i-Pr OCH3

Scheme 4: Use of BrettPhos in the N-arylation of aryl mesylates

with aryl amines

ArCl + H2NR

PdNH2Cl

i-Pr

i-Pr

PCy2 OCH3

i-Pr OCH30.01-0.05 mol%

0.01-0.05 mol% BrettPhos (718742)

NaOt-Bu, Bu2O, 80-110 °C, 1 h

ArN(H)R

i-Pr

i-Pr

PCy2 OCH3

i-Pr OCH3

N(H)Hex

OMe

N(H)Bn

90%88%

HNH3C

CH3

CF3

97%

Scheme 5: Use of BrettPhos in the monoarylation of aryl chlorides and

primary amines

2-(Dicyclohexylphosphino)3,6-dimethoxy-

2′,4′,6′-triisopropyl-1,1′-biphenyl

Reference: (1) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.

Soc. 2008, 130, 13552.

i-Pr

i-Pr

PCy2 OCH3

i-Pr OCH3

718742

718742

Non-Proprietary Catalysts for

Cross-Coupling

The cross-coupling reaction of heteroaryl halides is of particular

interest to the pharmaceutical industry since many biologically

active compounds are accessed through use of the Suzuki-Miyaura

reaction. However, the effi cient coupling of fi ve-membered

heteroaryl halides or six-membered heteroaryl chlorides bearing

heteroatom substituents with boronic acids has not been well-

developed. Catalysts are thought to form inactive complexes with

many of these types of substrates, and thus, they typically require

high catalyst loadings in order to achieve good yields. The Guram

group at Amgen has recently communicated the development of

an air-stable palladium complex, (AtaPhos)2PdCl2, for Suzuki-Miyaura

cross-coupling reactions. The catalyst was very eff ective at coupling

a wide range of substrates with arylboronic acids, including amino-

substituted 2-chloropyridines and fi ve-membered heteroaryl

halides. The products are observed in excellent yields and high

turnover numbers (up to 10,000 TON) are typically achieved. A

series of new PdCl2{PR2(Ph-R’)}2 catalysts were developed with

various reactivities.

Productentry Yield (%)

2

1

3

N

NH2

H3C

NCH3

H2N H3C

H3C

NN

H3CS

OCH3

93

98

95

Ar Cl

+ Ar Ar'

B(OH)2Ar'

(H3C)2N P N(CH3)2PPdCl

Cl

K2CO3, toluene−water, reflux, 12 h

(1 mol%)

Scheme 6: Air-stable palladium complex, (AtaPhos)2PdCl2, for Suzuki-Miyaura

cross-coupling

Cross-Coupling Catalyst

References: (1) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727. (2) Singer, R. A.

et al. Synthesis 2003, 1727. (3) Guram, A. S. et al. Org. Lett. 2006, 8, 1787.

For more information on our cross-coupling catalysts

portfolio, please visit aldrich.com/catalysis

Catalysis


Cl

678740


Cl

F3C P CF3PPdCl

Cl

692913

692921



Ch

em

ical

Bio

log

y [email protected]

New Polyethylene Glycol

Building Blocks for

PEGylation

Circulatory half-life is a key success

factor for new drugs. In this respect, modifi cation of potential

candidates ranging from non-peptidic small molecules to peptides

and proteins, antibody fragments, aptamers, and saccharides or

oligonucleotides with polyethylene glycol chains (commonly

referred to as PEGylation or PEG-ing) off ers numerous advantages.

PEGylation is considered one of the most successful techniques

to enhance the therapeutic and biotechnological potential of

peptides and proteins.1 PEGs are non-toxic, non-immunogenic,

non-antigenic, highly soluble in water, and FDA approved.2 The

PEGylated conjugates show a decreased degradation by metabolic

enzymes and a reduction or elimination of protein immunogenicity

as the PEG coating prevents the approach or recognition by

proteolytic enzymes and antibodies. (Scheme 1) Furthermore,

PEGylation may favorably alter drug distribution in the organism.3

While PEGylation may improve the pharmacokinetic properties of a

drug, the drug’s main activity is predominantly preserved.4

Since the fi rst therapeutic PEG-protein conjugate (PEG-adenosine

deaminase) had been approved by the FDA in 1990, a large

number of new PEGylated drugs was introduced to the market

Chemical BiologyMatthias Junkers, Ph.D.

Product Manager

representing a multi-billion dollar business.2 Table 1 summarizes a

selection of FDA approved PEG conjugates including therapeutic

peptides, proteins, small molecules, oligonucleotides, and

antibodies:

Year Disease PEG conjugate Tradename

1990 Severe combined immunodefi ciency disease (SCID)

PEG-adenosine deaminase Oncaspar®

1994 Acute lymphoblastic leukemia

PEG-asparaginase Adagen®

2000 Hepatitis C PEG-interferon α2β PEG-Intron®

2002 Hepatitis C PEG-interferon α2a5 Pegasys®

2002 Treating of neutropenia during chemotherapy

PEG-G-CSF (pegfi lgrastim) Neulasta®

2002 Acromegaly PEG-growth hormone receptor antagonist, pegvisomant6

Somavert®

2004 Age-related macular degeneration

Branched PEG-anti-VEGF aptamer, Pegaptanib (oligonucleotide PEG conjugate)7

Macugen®

2005 Ovarian cancer, Karposi’s sarcoma, AIDS related cancer

Pegylated liposome-encapsuled doxorubicin (small molecule drug)8

Doxil®, Caelyx®

2008 Crohn’s disease PEGylated fab fragment of humanized anti-tumor necrosis factor (monoclonar antibody), certolizumab pegol9

Cimzia®

Table 1: Examples of FDA approved therapeutic PEG conjugates

More recently, researchers have enforced strategies that utilize

releasable PEGs in order to control protein release rates.10 Usually a

trigger moiety is introduced between protein and PEG that can be

cleaved enzymatically or by aqueous hydrolysis.

O

O

O

O

O

O

O

O

O

O

O

O

OO

O

O

O

O

O

O

O

O

O

O

OO

O

O

OO

O

Bioactive Molecule

//

size increaseleads to reducedrenal filtration

decreased accessibility

for proteolytic enzymes

and antibodies

PEG hydrophilicityimproves solubility

Scheme 1: PEGylation may improve the properties of drug candidates



Ch

em

ical Bio

log

y

Further important applications of functionalized polyethylene

glycols apart from drug discovery are:

Introduction of solubilizing handles in SPPS• 11

Soluble polymer supports for Peptide Synthesis• 12

Soluble polymer supports for Organic Synthesis• 13

Introduction of hydrophilic amino acids in Peptide Synthesis• 14

Preparation of PEG-coated surfaces• 15

Linking of macromolecules to surfaces• 16

Preparation of PEG-cofactor adducts for biorectors• 17

Aldrich is proud to off er the most comprehensive portfolio

of PEG reagents on the market with molecular weights up to

20 kDa for effi cient PEGylations. Numerous homobifunctionalized,

heterobifunctionalized, and mono-methoxy endcapped

monofunctionalized PEG’s are available in high quality and

monodispersity. We provide polyethylene glycols activated for

the most widely used conjugation techniques to primary amines

or thiols. The amino groups (e.g. lysine) of proteins and peptides

are the preferred choice for PEG conjugation by alkylation or

713783 (MW 2000) 713791 (MW 1000) 712558 (MW 750)

712469 (MW 10000) 712582

HN

OO

HN

On

O

OO

OO

ON

O

O

HN

OO

HN

On

O

OO

OO

ON

O

O

NO

OCH3

O

O n

NO

OCH3

O

O n

NHN

O

O OO

4

O

ON

O

O

712507 (MW 3000)

712515 (MW 3000) 712523 (MW5000) 712590

712604

HN

OOH

nO

S

HN

OO

nO

HSOH

OHN

OO

nO

HSOH

O

H3COO

OO

N3

H3COO

N3

11

726249 726176 (MW 2000)

726168 (MW 10000)

H3COO

N3

19

H3COO

N3

n

H3COO

N3

n

For a complete list of PEGylation available from Aldrich Chemistry please visit aldrich.com/PEGylation

acylation. Alkylation maintains a positively charged amine,

whereas acylation yields a neutral amide linkage. Acylation

can be realized most conveniently with N-hydroxysuccinimide

(NHS) activated carboxylated PEGs. Azide functionalized PEGs

allow the application of Staudinger ligation and Huisgen dipolar

cycloaddition techniques. The introduction of diff erent protecting

groups leads to extremely useful macromolecular cross-linking

agents and spacers. All common target moieties can be specifi cally

addressed with the appropriate functionalized PEG linker. Please

fi nd a collection of our most recent additions to our portfolio

of PEGylation products below, and visit us on the web for a full

product listing.

References: (1) Freitas, D. SciTopics 2010, April 14th, from www.scitopics.com/PEGylation.html. (2) Veronese, F. M.; Pasut, G. Drug Discovery Today. 2005, 21, 1451. (3) Veronese, F. M. Biomaterials 2001, 22, 405. (4) Veronese, F. M. Bio Drugs 2008, 22, 315. (5) Bailon, P. et al. Bioconjug. Chem. 2001, 12, 195. (6) Trainer, P. J. N. Eng. J. Med. 2000, 342, 1171. (7) The EyeTech Study Group Retina 2002, 22, 143. (8) Pasut, G.; Guiotto, A.; Veronese, F. M. Exp. Opin. Ther. Pat. 2004, 14, 859. (9) Chapman, A. P. Adv. Drug Deliv. Rev. 2002, 54, 531. (10) Zhao, H.; Yang, K.; Martinez., A. et al. Bioconjug. Chem. 2006, 17, 341. (11) Seitz, O.; Kunz, H. J. Org. Chem. 1997, 62, 813. (12) Pillai V. N. R.; Mutter, M. J. Org. Chem. 1980, 45, 5364. (13) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489. (14) Koskinen, A. M. P. et al. Bioorg. Med. Chem. Lett. 1995, 5, 573. (15) Harris, J. M. et al. J. Polym. Sci. Polym. Chem. Ed. 1984, 22, 341. (16) Andreadis, J. D.; Chrisey, L. A. Nucleic Acids Res. 2000, 28 (2), e5. (17) Okada, H.; Urabe, I. Meth. Enzymol. 1987, 136, 34.

New PEG linkers

(average molecular weight of polymers in brackets)



Org

ano

me

talli

cs [email protected]

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. Their use has been highlighted in various areas,

including countless elegant natural product syntheses, material

science, and in synthetic methodology. The use of 1-Methyl-5-

(tributylstannyl)imidazole (718793) by process chemists at Pfi zer

in a Stille reaction was reported in 2003. The coupling employed

iodothienopyridine as the electrophile in the presence of Pd(PPh3)4

as the catalyst. Addition-elimination on the resulting functionalized

thienopyridine provided bulk material of the desired VEGFR kinase

inhibitor. It is worth noting that of several cross-couplings which

were examined, the Stille coupling was the only reaction feasible

on scales >50 g.

OrganometallicsJosephine Nakhla, Ph.D.


Organometallics & Catalysis

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%

Scheme 1: Stille reaction in preparation of VEGFR kinase inhibitor

Organotin Reagents from Aldrich

717703 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

For a complete list of organotin reagents from Aldrich

Chemistry, please visit aldrich.com/organotin

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.



Org

ano

me

tallics

New Method for Stannylation

of Cyclopropenes

Due to the wide utility of the cyclopropene ring, methods

for the synthesis of highly substituted cyclopropenes are of

broad interest to the scientifi c community. Methods to prepare

functionalized cyclopropenes currently include preparation of

the cyclopropenyllithium species and subsequent treatment with

a trialkyltin chloride, which is then followed by a Stille coupling.

However, the obvious limitation to this method is that the

cyclopropene ring cannot possess base-sensitive functionalities,

which can promote side reactions such as ring opening and

formation of stabilized anions. Recently, Lam and coworkers

developed a method employing Bu3SnCF2CF3 (711063), which in

the presence of stoichiometric KF, allowed for the mild stannylation

of otherwise sensitive functionalized cyclopropenes (Scheme 2).

These building blocks were further elaborated in a Stille reaction

to provide highly functionalized tetrasubstituted cyclopropenes

(Scheme 3). A protocol was developed by which the stannylation

and Stille coupling were conducted in one-pot, further facilitating

access to these useful building blocks.

R3

CO2R2R1

711063

Bu3SnCF3

FF

KF, DMF, 40 °C

R1 CO2R2

R3Bu3Sn

Scheme 2: Stannylation of cyclopropenes using Bu3SnCF2CF3

R1 CO2R2

R3Bu3Sn Pd2(dba)3 (2.5 mol%)

Ph3As (10 mol%)

THF

R1 CO2R2

R3R4

R4 X

MeO2C CO2Me

Ph

O2N 91%

MeO2C CO2Me

Ph

87%

MeO2C

MeO2C CO2Me

n-BuPh

78%O

CO2Me

n-Bu

61%S

O2N

Scheme 3: Preparation of tetrasubstituted cyclopropenes

Tributyl(perfl uoroethyl)stannane

CF3

FF

Bu3Sn

711063

Reference: Fordyce, E. A. F.; Luebbers, T.; Lam, H. W. Org. Lett. 2008, 10, 3993.

For a complete list of organotin reagents from Aldrich

Chemistry, please visit aldrich.com/organotin

Method for Introducing Sulfur Linkages

Matzger and co-workers developed a useful method for

the introduction of sulfur linkages using Bu3SnSSnBu3 in the

preparation of oligothienoacenes. Historically, the preparation

of these molecules has been limited and not feasible for

longer chain thienoacenes. The low solubility and problematic

isolation both contribute to the challenges associated with

preparing oligothienoacenes. The synthesis of these molecules

in the Matzger lab begins with the introduction of the TIPS

group through Li-Br exchange of the precursor dibromide and

addition of TIPS-Cl. The bromine at the 2-position was treated

with LDA to provide the 3-bromo-substitued isomer. The use

of Bu3SnSSnBu3 in a Pd-catalyzed coupling with 2 equivalents

of the 3-bromo-substituted precursor provided the thio-linked

thienoacene. Incorporating the sulfur linkage typically involves

metalation followed by reaction with bis(phenylsulfonyl)sulfi de,

which often leads to linking at the two- and three-position rather

than the 3,3-position. Oxidative ring closure and deprotection

yields the fi nal oligothienoacene (Scheme 4). The TIPS groups

are strategically placed to avoid competing deprotonation at the

2-position when conducting the oxidative ring closure.

SBr

S Br

SBr

S TIPS

S

S TIPSBr

S

S

TIPS S

S

S TIPS

S

S

1) BuLi/THF

2) TIPSCl

LDATHF80%

Bu3SnSSnBu3

Pd(PPh3)4toluene

95%

85%

S

S

S

720585

Scheme 4: Preparation of oligothienoacenes using Bu3SnSSnBu3 to

introduce sulfur linkage

Reference: Zhang, X.; Cote´, A. P.; Matzger, A. J. J. Am. Chem. Soc. 2005,

127, 10502.

Bis(tributyltin)sulfi de

S SnSnH3C

H3C

H3C

CH3

CH3

CH3

720585



Org

ano

me

talli

cs

For a complete list of Trifl uoroborates available from Aldrich Chemistry, please visit aldrich.com/tfb

Reference: Molander, G.A.; Ellis, N. Acc. Chem Res. 2007, 40, 275.

711144 711098 711101 717517 717487

NNH

BF3K

N

NKF3B

N

BF3K

NBr

BF3K

NF

BF3K

722588 706116 711136 717509 719420

NN

O

KF3B

NO

NKF3B

SH3C CH3

BF3K

SBF3K

NBoc

BF3K

721654 718572 715212

BF3K

N

OH3C

CH3

BF3K

NH

BF3KH3C

New Trifluoroborates from Aldrich

Organotrifluoroborates as Coupling

Partners in Suzuki-Miyaura Reactions

Suzuki-Miyaura cross-coupling reactions are some of the most

common methods for the formation of C–C bonds in organic

chemistry. The use of some boronic acids is complicated by their

instability and their propensity for trimerization. The advent of

boronic acid surrogates such as trifl uoroborates has transformed

the fi eld, allowing for shelf-storage and usability of otherwise

unstable boronic acids. Trifl uoroborates exhibit excellent

functional group tolerance and stability towards common

reagents, which has also lead to their widespread use. Our

platform of trifl uoroborate salts is continually growing, with new

product introductions occurring regularly. Some of our recent

additions are listed below.

Benefi ts of Trifl uoroborates:

Stable tetracoordinate species• Less prone to protodeboronation• Prepared from inexpensive KHF• 2

Air and moisture-stable• Easily purifi ed via recrystallization, precipitation,• or Soxhlet extraction

Materials ScienceMaterials Science

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Aldrich Cheminars™ Presents

MIDA Boronate Building Blocks:Towards a General Platform for Small Molecule Synthesis

Your host for this Aldrich

sponsored webinar:

Martin Burke, Ph.D.

Assistant Professor of Chemistry,

University of Illinois

at Urbana-Champaign, U.S.A.

Moderator:

Mitch Jacoby, Ph.D.

Senior Editor, C&EN

This Aldrich Cheminar discusses the many physical and chemical features of

MIDA boronates that underlie their widespread utility, including:

� Ease of preparation, purifi cation, and storage and minimized environmental impact

� Reversibly attenuated boronic acid reactivity that enables small molecule synthesis via

iterative cross-coupling

� Capacity for slow-release cross-coupling that transforms even notoriously unstable

2-heterocyclic, vinyl, and cyclopropyl subunits into air-stable and highly eff ective

cross-coupling partners

� Compatibility with a wide range of common reaction conditions which enables the

multistep synthesis of structurally complex boronic acids from simple B-containing

starting materials

To view this Aldrich Cheminar, and to register for future Cheminars, please

visit aldrich.com/cheminars

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For more information on MIDA boronates, please visit aldrich.com/MIDA

©2010 Sigma-Aldrich Co. All rights reserved. Sigma-Aldrich and Aldrich are trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P.

Hosted by:



N

S CH3

O

EtO

716308

O

S

N

N

S

OEt

O

NN

S

S

N

N

S

NS

OEtO

AcO

O

NH

CH3

O

1

7 linear steps, 16% overall yield

Scheme 1: Ethyl 2-methylthiazole-4-carboxaldehyde as a starter for pyridine-

thiazole structure 1

Thiazoles can also serve as a protected formyl group that can be

liberated in the late stages of a complex natural product synthesis.5

While thiazoles are prevalent in a wide range of bioactive natural

products, the imidazole ring occurs largely in the context of the

natural amino acid histidine. In addition, the imidazole ring has

appeared as a component of unnatural cyclic peptides,6 and used

as an ester isostere in peptidomimetic studies.7 However, the

applications of imidazole are not limited to the realm of peptides

and peptidomimetics. They are present in the large family of

bromopyrrole-imidazole alkaloids isolated from marine sponges

based on the common metabolite oroidin (Figure 3) that feature

signifi cant biological activities.1 The imidazole ring is also present in

the pilocarpine alkaloids, as well as potential therapuetic agents for

thrombosis, cancer, and infl ammatory diseases.8

HN

O

NH

N

NH

NH2Br

Br

Figure 3: Structure of Oroidin

New Thiazoles

For a complete list of thiazoles available from

Aldrich Chemsitry, please visit aldrich.com/thiazole

Bu

ildin

g B

lock

s

[email protected]

Thiazoles and Imidazoles

Thiazoles and imidazoles have been

frequently discovered as a vital

component of novel and structurally

diverse natural products that exhibit

a wide variety of biological activities. The exceptional range

of antitumor, antiviral, and antibiotic activities, as well as their

presence in peptides, or ability to bind to proteins, DNA, and RNA,

has directed numerous synthetic studies and new applications of

these azole heterocycles.

The thiazole ring has been identifi ed as a central feature of myriad

natural products, perhaps the best known being the epothilones

(Figure 1). These are antitumor agents that display improved

potency against Taxol-resistant tumor cell lines, and variants of

epothilone B in particular have been pursued by several major

pharmaceutical companies.1

O

O

HO

O OH O

R

N

S X

epothilone A: R = H; X = Hepothilone B: R = Me; X = Hepothilone E: R = H; X = OHepothilone F: R = Me; X = OH

O

HO

O OH O

N

S

R

epothilone C: R = Hepothilone D: R = Me

Figure 1: Structure of Epothilones A–F

Additionally, thiazoles are frequently cropping up in peptide

research. For example, the pseudopeptide dolastatin 10 (Figure 2)

is an exceptionally potent antineoplastic agent,2 and other

thiazole-containing marine cyclic peptides have demonstrated

signifi cant cytotoxicity.3 A recent report demonstrates the use

of ethyl 2-methylthiazole-4-carboxaldehyde (716308) as a

starting material to the pyridine-thiazole structure 1 (Scheme 1),

a protected form of the core cluster of thiopeptide antibiotics

micrococcin P1-P2, thiocillin I, and YM266183.4

H3CN

HN

NN

CH3 O

O

CH3 O O O

CH3 HN

O

N

S

Figure 2: Structure of Dolastatin 10

Building BlocksMark Redlich, Ph.D.

Product Manager

723452 714801720534

N

S Cl

N

S NH2NC

N

S ClNC

717029 717231703311

N

S Si

Br

CH3

CH3

CH3N

S CH3

O

HN

S NH2

716308 708178

N

S CH3

O

O

721522

N

SNH2

719617

N

S Br

717428

N

S

H3C

CH3

O

O S

N O

Cl



New Iodinated Building Blocks

Iodine-containing substrates are valuable building blocks for

a diverse array of synthetic methodologies. They have the

ability to participate in various cross-coupling reactions for the

generation of carbon–carbon, carbon–nitrogen, and carbon–

oxygen bonds. Often iodinated substrates are preferred to the

brominated analogs, due to cleaner reactions. They are also handy

precursors for the formation of organolithium, organozinc, or

organomagnesium reagents. Sigma-Aldrich is pleased to off er

these useful building blocks for your research.

Bu

ildin

g B

locks

New Imidazoles and Benzimidazoles

For a complete list of Imidazole available from

Aldrich Chemistry, please visit aldrich.com/imidazole

For a complete list of Benzimidazoles available from

Aldrich Chemistry, please visit aldrich.com/benzimidazole

724114 721069 714828720003

N

ClI

N

ICl

ClN

I

Cl

O2N

N

I

Cl

H2N

720054 722596 717584723290

N

NO2

Cl

I

N Cl

I O

H

N CH3

O

OHI

N Cl

I O

OH

707260 720879 713457708364

N

Br

I

N

I

I

NN

I

I

713449 716286 717800716405

OI

N HCH3

H3C

I

OO

OH

H3COI

O

OH

I OH

sigma-aldrich.com

Custom Packaged Reagents from Sigma-Aldrich puts high throughput back into your chemistry!

When projects demand custom arrays of reagents, DiscoveryCPR can meet the challenge.

To register for an online ordering

account or to submit inquiries:

DiscoveryCPR.comDiscoveryCPR

The Standard in Reagent Management for

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• Internet-based reagent database

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718211 711292

711284

711276

N

NCH3

SO

OCl

N

NCH3

Br

N

NCH3

Br

O

H

N

NCH3

Br

Br

716537 715794

709166703826

N

NHO

H3CO

H3CO

ON

N

H2N

CH3

NH

N

OH

O

NH

NBr

709697

NH

N

OHO



Other New Building Blocks

NCSNH2

CN

• HClCl

OCH3

NH

• HCl Br

BrH3C O OH

OO O

FF

709352 717037 717444 721581 714461 711403

NH2

NH

BocOH

HO F

OH

NH2Br Br

OH

OH3C

NH2

OH

O

H3CO H2N

NH2

NOH

709700 722677 708356 716413 721506 722189

NH

OH

O

• HCl

O O

ClCl

O O

BrBrN

O

O

HO N

OHO

O

N

OO

O

715581 719242 719226 718343 722111 720763

N

N

OH

BrBr

N

N

Br

HO

N

N

NFmoc

OH

ONH

HN

CF3

N

N NH

NH2

709670 709735 716022 706477 716324 722332

N

N N

HN

NH2

Cl

NBoc

NBoc

O

NH2O

ClO

OH

717592 720690 719706 716448 709913 715204

Br

OOH O

OH

Br

720062 720097

Bu

ildin

g B

lock

s

References: (1) Jin, Z. Nat. Prod. Rep., 2005, 22, 196. (2) Pettit, G. R. et al. J. Am. Chem. Soc. 1987, 109, 6883. (3) (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. (4) Aulakh, V. S.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 5750.

(5) Dondoni, A.; Marra, A. Chem. Rev. 2004, 104, 2557. (6) Haberhauer, G.; Rominger, F. Eur. J. Org. Chem. 2003, 3209. (7) Dhanak, D. et al. Bioorg. Med. Chem. Lett.

2001, 11, 1445 (8) (a) Appleby, I. et al. Org. Lett 2005, 7, 1931. (b) Allerton, C. M. N. et al. W.O. Pat. Appl. 2002014285, 2002; Chem. Abstr. 2002, 136, 184120.

For a complete list of Building Blocks available from Aldrich Chemsitry, please visit aldrich.com/chemprod


Request your copy of our NMR Solvents Brochure ataldrich.com/nmrbrochure

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Aldrich NMR Solvents

Aldrich provides solvents of the highest quality to meet therigorous demands for NMR-based research and analyses.

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Highly deuterated solvents• Anhydrous solvents• D• 2O Extra (99.994 atom % D)

“Special HOH” solvents• Customized mixtures•

Extensive packaging options• Variety of TMS concentrations• NMR Reference standards•



Syn

the

tic

Re

age

nts

[email protected]

XtalFluor-E® and

XtalFluor-M®: Convenient,

Crystalline Deoxofluorination

Reagents

Figure 1: Structures of the new deoxofl uorination reagents, XtalFluor-E

(719439) and XtalFluor-M (719447).

The introduction of fl uorine into the framework of an organic

molecule is an important synthetic transformation. Historically,

though, this transformation has been fraught with technical

challenges when using traditional fl uorination reagents such

DAST and Deoxo-Fluor®. In particular, the chemical practitioner

has been forced to weigh the benefi ts of these once best-in-class

reagents against the disadvantages of their stringent handling

and safety requirements.

DBU, Et3N 3HF, or* promoters:

R OH

XtalFluor-E or -M

+ promoter *substrates products

R H

O

R R

O

R OH

O

RS

O

CH3

R F

R H

R R

R F

O

RS F

F F

F F

O

OHRO

RO

RORO O

FRO

RO

RORO

Et3N 2HF

Substrate Scope

Synthetic ReagentsTroy Ryba, Ph.D.

Product Manager

N SF2H3C

H3CBF4

XtalFluor-E

N SF2 BF4

XtalFluor-M

O

XtalFluors

719447719439

XtalFluor-E

XtalFluor-M

DAST

Deoxo-Fluor 60 o C

60 o C

119 o C

141 o C

Accelerated Rate Calorimetry (ARC)

(higher temperature = more stable)

®

®

Scheme 1: Generic substrate scope of XtalFluor-mediated deoxofl uorination.

With the recent introduction of XtalFluor-E and XtalFluor-M by

Couturier and coworkers, however, many of the issues surrounding

the safety and handling requirements of traditional fl uorination

reagents are no longer of concern.2 XtalFluors, as their name

intimates, are crystalline deoxofl uorination reagents amenable

to short-term handling open to the atmosphere. The substrate

and reactivity profi les of the XtalFluors are also comparable to the

traditional deoxofl uorination reagents (Scheme 1): alcohols are

converted to the corresponding alkyl fl uorides, aldehydes and

ketones to the geminal-difl uorides, carboxylic acids to the acyl

fl uorides, sulfoxides to the fl uoromethyl thioethers and hemiacetal

sugars to the corresponding glycosyl fl uoride donors.

An intrinsic property of the XtalFluors is that they do not generate

free HF under anhydrous reaction conditions. While the mechanism

is still under investigation, it is thought that the XtalFluors activate

the C–O bond without concomitant fl uoride release. Only upon

subsequent exposure to a promoter such as DBU, Et3N ∙ 3HF, or

Et3N ∙ 2HF, does fl uoride attack the activated carbon atom. The

chemical effi ciency of the deoxofl uorination is high. As can be

noted in Scheme 2, generally, if DAST or Deoxo-Fluor work, so too

should the XtalFluors (Scheme 2).

The stability of the XtalFluors has also been investigated by

Accelerated Rate Calorimetry (ARC). These studies have shown that

the XtalFluors have greater thermal stability than DAST or Deoxo-

Fluor (Table 1). This may be of particular practical interest when

considering reagents to utilize for scale-up routes.

Table 1: Accelerated Rate Calorimetry (ARC) data comparisons indicating a

higher thermal stability of the XtalFluors.



Fluorination Reagents

For a complete list of fl uorination reagents available from Aldrich Chemistry, please visit aldrich.com/fl uoro

DBU, Et3N 3HF, or* promoters:

XtalFluor-E or -M+ promoter*substrates

Specific Examples

products

OH

S

O

CH3

F

CH3

OH

OH

N (R)(R)OH

O

BnO

O OH

OBnBnOOBn

BnO

OH

entry

1

2

3

4

5

6

7

8

9

O

O

EtO2C

N OO

BnO

11

CH3

F

F

N (S)(S)

FO

BnO

O F

OBnBnOOBn

BnO

S F

F

F

EtO2C

FF

NO

BnO

FF

F

76 %

72 %

85 %

68 %

96 %

90 %

72 %

75 %

79 %

96 %

% yield

10 OH

O

F

O

89 %

Et3N 2HF

Synth

etic R

eag

en

ts

719439 719447 338915235253

N SF2H3C

H3CBF4 N SF2 BF4O N SF3ON SF3

H3C

H3C

344648 494119

392715439479

Et3N 3HF N SF3

CH3O

CH3O

NS

F

SPh Ph

O O O O

N

N

F

Cl

2 BF4

28625 439312 184225323659

N

N

N

F

FFNH3C CH3

CH3

F BF4

N

H F

N

F CF3SO3−

Scheme 2: Specifi c examples of deoxofl uorination with XtalFluor-E or XtalFluor-M.

References: (1) Beaulieu, F. et al. Org. Lett. 2009, 11, 5050. (2) L’Heureux, A. et al. J. Org. Chem. 2010, 75, 3401. (3) Haufe, G. J. Prakt. Chem. 1996, 338 , 99. (4) McClinton,

M. A. Aldrichimica Acta 1995, 28, 31. (5) Gatner, K. Pol. J. Chem. 1993, 67, 1155. (6) Franz, R. J. Fluorine Chem., 1980, 15, 423.



Sto

ckro

om

Re

age

nts

Stockroom ReagentsTodd Halkoski


[email protected]

The New Aldrich

Sure/Seal™ System

The Ideal Solution for Anhydrous and Air-Sensitive Reagents

As the leader in air-sensitive chemistry, Sigma-Aldrich carries by

far the largest breadth of anhydrous solvents and air-sensitive

reagents to service the research market. Our traditional Sure/Seal

is now undergoing major improvements. During the upcoming

months, you will begin experiencing the value of these new

design improvements.

New Crimp Cap Design

Increased puncture area by 4x to accommodate multiple • punctures

Crimp cap helps maintain product quality by providing an• air-tight system

New Plug Style

Maximimizes surface area contact with the bottle to prevent • moisture and oxygen entry

More than 50% thicker than competing brands•

For additional testing documentation on how the New

Aldrich Sure/Seal performs, visit aldrich.com/sureseal

New Elastomer Liner

Provides • outstanding resealing properties

Secondary resin layer ensures resistance to chemicals• Outperforms competing seals with respect to moisture uptake•

Aldrich Sure/Seal Karl Fischer

Analysis Results

Utilizes a coulometric titration method to measure the rate of

moisture uptake. To determine the effectiveness of the liner’s seals

and closure design, a five-week study was conducted.

Comprehensive testing confi rms the New Aldrich Sure/Seal outperforms

other products on the market by maintaining low water absorption even

after multiple punctures.

Unpunctured 4 Punctures

Unpunctured 4 Punctures

New Aldrich Sure/Seal System

Competitor A System

New Aldrich Sure/Seal Previous Aldrich Sure/Seal

Methanol

0

50

100

150

200

250

300

350

400

450

500

0 1 2 3 4 5

Mo

istu

re G

ain

(p

pm

)

Aldrich Sure/Seal: ~8.3 ppm

Competitor A: ~86.2 ppm

Average Weekly Gain

Time (weeks)



Stockro

om

Re

age

nts

New Aldrich Sure/Seal Chemicals Now

Available from United States locations

Below you will find the inventory for these products are using

the new Sure/Seal design.

Solvents

Cat. No.Available sizeswith New Design Product Name

401765 100 mL, 1 L,6 × 1 L, 2 L

Benzene, Anhydrous, 99.8%

305197 All Unit Sizes Benzyl alcohol, anhydrous, 99.8%

281549 All Unit Sizes 1-Butanol anhydrous, 99.8%

471712 All Unit Sizes tert-Butanol, anhydrous, 99.5+%

284513 All Unit Sizes Chlorobenzene, anhydrous, 99.8%

372978 All Unit Sizes Chloroform, anhydrous, ≥99%, contains amylenes as stabilizer

288306 1 L, 2 L, 100 mL Chloroform, anhydrous, ≥99%, contains 0.5–1.0% ethanol as stabilizer

294772 100 mL Decahydronaphthalene, mixture of cis + trans, anhydrous, ≥99%

457116 All Unit Sizes Decane anhydrous, ≥99%

240664 All Unit Sizes 1,2-Dichlorobenzene, anhydrous, 99%

284505 All Unit Sizes 1,2-Dichloroethane anhydrous, 99.8%

270997 100 mL, 1 L,4 × 2 L

Dichloromethane, anhydrous, ≥99.8%, contains 50–150 ppm amylene as stabilizer

296082 All Unit Sizes Diethyl ether, contains 1 ppm BHT as inhibitor, anhydrous, ≥99.7%

271012 100 mL, 12 × 100 mL, 1 L, 2 L

N,N-Dimethylacetamide anhydrous, 99.8%

227056 All Unit Sizes N,N-Dimethylformamide anhydrous, 99.8%

276855 100 mL, 12 × 100 mL, 1 L, 6 × 1 L

Dimethyl sulfoxide, anhydrous, ≥99.9%

297879 All Unit Sizes Dodecane anhydrous, ≥99%

459836 All Unit Sizes Ethanol 200 proof, anhydrous, ≥99.5%

277649 All Unit Sizes Ethanol reagent, anhydrous, denatured

270989 All Unit Sizes Ethyl acetate, anhydrous, 99.8%

324558 100 mL, 1 L, 2 L,6 × 1 L

Ethylene glycol, anhydrous, 99.8%

246654 All Unit Sizes Heptane anhydrous, 99%

296317 All Unit Sizes Hexadecane anhydrous, ≥99%

296090 All Unit Sizes Hexane anhydrous, 95%

227064 All Unit Sizes Hexane, mixture of isomers anhydrous, ≥99%

471402 All Unit Sizes 1-Hexanol, anhydrous, ≥99%

322415 All Unit Sizes Methanol anhydrous, 99.8%

284467 1 L 2-Methoxyethanol, anhydrous, 99.8%

Solvents


277258 100 mL, 1 L 2-Methylbutane, anhydrous, ≥99%

309435 All Unit Sizes 3-Methyl-1-butanol anhydrous, ≥99%

294829 100 mL, 1 L 2-Methyl-1-propanol, anhydrous, 99.5%

296821 All Unit Sizes Nonane anhydrous, ≥99%

296988 All Unit Sizes Octane anhydrous, ≥99%

236705 100 mL, 1 L, 2 L Pentane, anhydrous, 99+%

300314 1 L, 2 L Petroleum ether, anhydrous

279544 All Unit Sizes 1-Propanol anhydrous, 99.7%

278475 All Unit Sizes 2-Propanol anhydrous, 99.5%

371696 All Unit Sizes Tetrachloroethylene, anhydrous, ≥99%

522651 All Unit Sizes 1,2,3,4-Tetrahydronaphthalene, anhydrous, 99%

244511 All Unit Sizes Toluene anhydrous, 99.8%

296104 All Unit Sizes 1,2,4-Trichlorobenzene, anhydrous, ≥99%

304050 All Unit Sizes Triethyl orthoformate, anhydrous, 98%

305472 1 L, 2 L Trimethyl orthoformate, anhydrous, 99.8%

360066 All Unit Sizes 2,2,4-Trimethylpentane, anhydrous, 99.8%

296325 All Unit Sizes m-Xylene, anhydrous, ≥99%

294780 1 L, 2 L o-Xylene, anhydrous, 97%

Kinetic Bases


302120 All Unit Sizes Butyllithium solution, 2.0 M in cyclohexane

195596 All Unit Sizes Sec-Butyllithium solution, 1.4 M in cyclohexane

186171 All Unit Sizes Butyllithium solution 1.6 M in hexanes

230707 All Unit Sizes Butyllithium solution, 2.5 M in hexanes

186198 All Unit Sizes tert- Butyllithium solution, 1.7 M in pentane

561452 25 mL Ethyllithium solution, 0.5 M in benzene: ether

468568 All Unit Sizes Hexyllithium solution, 2.3 M in hexane

529745 100 mL Isopropyllithium solution, 0.7 M in pentane

197343 All Unit Sizes Methyllithium solution, 1.6 M in diethyl ether

277304 100 mL Potassium bis(trimethylsilyl)amide solution, 0.5 M in toluene

297054 All Unit Sizes (Trimethylsilyl)methyllithium solution, 1.0 M in pentane

Lewis Acids


296112 All Unit Sizes Diethylzinc solution, 1.0 M in hexanes

268569 All Unit Sizes Trimethylaluminum solution, 2.0 Min hexanes

198048 100 mL, 800 mL Trimethylaluminum solution, 2.0 Min toluene

Reducing Agents


214949 All Unit Sizes Diisobutylaluminum hydride solution, 1.0 M in cyclohexane

190306 All Unit Sizes Diisobutylaluminum hydride solution, 1.0 M in hexanes

215007 All Unit Sizes Diisobutylaluminum hydride solution, 1.0 M in toluene

Liner Integrity

When using air-sensitive solvents and reagents, liners should not

only seal to maintain product quality, but also consistently hold

form after repeated puncture. The New Aldrich Sure/Seal gives

you the assurance of safety and a quality product.

New Sure/Seal SystemCompetitor A

Toluene Testing—5 Weeks (20 punctures)



Lab

war

e N

ote

s

Labware NotesPaula Freemantle

Product Manager

[email protected]

Improved NMR Tubes from

Sigma-Aldrich

Color coded for easy identification out of the box

Aldrich ColorSpec® NMR tubes are printed with colored bands

at the top of each tube and are supplied with colored caps to

indicate the quality grade of the NMR tube. In addition, each tube

is printed with the MHz rating and a marking spot.

Chemists can easily identify the grade of a ColorSpec® NMR tube

at all stages of its use, from opening the box, filling, storage and

transport to NMR machine, and even after wash and oven drying.

Avoid poor quality spectra or risk of probe damage from mistaking

low grade tubes and using in high frequency instruments.

Aldrich ColorSpec NMR Tubes

Precision tubes (RED color code) are thin wall (0.38 mm)

Type 1, Class A Borosilicate glass, suitable for low or high

temperature work and are precision ground and highly polished

for spinning stability and highest resolution. Thrift tubes (YELLOW

color code) and disposable tubes (BLUE color code) are medium

wall (0.43 mm) Type 1, Class B Borosilicate glass for ambient

temperature, general use.

Disposable/Thrift Precision (Glass)

Material ASTM Type 1 Class B Borosilicate Glass

(commercial name N51A)

ASTM Type 1 Class B Borosilicate Glass

(commercial name Pyrex)

Impact on shimming quality by

paramagnetic impurities1

Medium (>1,200 ppm Fe2O3) Small (400 ppm Fe2O3)

Rapid cooling / heating No Yes, within 120 °C

Max. working temperature Ambient 230 °C

Sample volume repeatability2 10% 0.50%

Cut-off wavelength 320 nm 320 nm

Recommended application 1D NMR experiments with a small organic molecule

(Molecular Weight <1,500) below 600 MHz

Experiments that require critical shimming quality,

for example. High/ultra high field, non-spinning,

multi-dimensional, multi-nuclei, DNP experiments

and studies involving biological samples.

Note 1: Impact on shimming quality varies upon magnetic field strength. Dispoable/Thrift tubes are recommended for 1D low field experiments.

Note 2: Sample volume reproducibility refers to the maximum volume fluctuation when filling different NMR tubes to the same sample height.

This number correlates to the reproducibility of time domain signal amplitude between different runs.

For a complete listing of Aldrich ColorSpec NMR tubes, please visit our website at aldrich.com/colorspec



Labw

are N

ote

s

Aldrich SafetyBarb®NMR tube cleaner

Z558362 and Z558370

Inner PTFE wash tube with Luer connection

prevents NMR tube breakage during the

cleaning process. Detaches for thorough

cleaning or replacement. SafetyBarb vacuum

connection. Washes 3, 5, and 10 mm NMR

tubes in both 7 and 8 in. lengths. Order

replacement SafetyBarb hose connectors

Z547786 (straight) or Z547883 (angled).

Instructions for use:

1. Connect the inner PTFE needle to the stainless steel Luer fitting.

2. Assemble the inner and outer glass washer components using silicone grease.

3. Install tube washer into a 24/40 female jointed flask using silicone grease.

4. Attach the SafetyBarb hose connector to the tube washer.

5. Connect vacuum source to the SafetyBarb hose connector.

6. Place one NMR tube, open end down, over the PTFE needle.

7. Fill the tall tube with desired wash solvent.

8. Turn on vacuum to wash NMR tube.

9. Repeat fill process as necessary until NMR tube is clean.

Aldrich glass combination pH electrodes

Z113441

BNC, double junction, AgCI electrode with Ultra-thin, long stem

for NMR tubes

Aldrich NMR tube labels

Z220574

Self-laminating, vinyl labels with

white, write-on surface resist oil,

water, and solvent. Label wraps

around 5 mm tube for positive

sample identification. Supplied

with 26 labels on a card,

25 cards per pack.

Aldrich Spectral Viewer FT-NMR

Spectral Viewer

products are

electronic reference

books on CD-ROM

that contains

thousands of spectra

from the Aldrich

spectral libraries.

The easy-to-use software is more powerful than a printed book,

allowing text and data field searching and the manipulation,

printing, and exporting of spectra. There are two FT-NMR libraries

available containing over 15,000 compounds in total. The libraries

can be used individually and can be combined to create a single

powerful, electronic reference. Spectral Viewer is expandable so

that when new spectral libraries are released, they can be easily

added to the software. Academic and Network versions

are available.

FT-NMR, standard library

11,800 compounds Z541265

FT-NMR, 2001 supplemental library

3,500 compounds Z538086

For additional Spectral Viewer listings, visit our website at

aldrich.com/spectralviewer


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Biotechnology, L.P. Sigma brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich

publications. Purchaser must determine the suitability of the product(s) for their particular use. Additional terms and conditions may apply. Please see reverse side of the invoice or packing slip.

Xtal-Fluor-E is a registered trademark of OmegaChem, Inc, XtalFluor-M is a registered trademark of OmegaChem, Inc., Sure/Seal is a trademark of Sigma-Aldrich Biotechnology LP and

Sigma-Aldrich Co., Deoxo-Fluor is a registered trademark of Air Products & Chemicals, Inc. and ColorSpec is a registered trademark of Sigma-Aldrich Biotechnology LP and Sigma-Aldrich Co.

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