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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
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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
Haydn Boehm, Ph.D.
Wesley Smith
Dean Llanas
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Production Team
Cynthia Skaggs
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Chris Lein
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Denise de Voogd
Chemistry Team
Daniel Weibel, Ph.D.
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
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
methodologies and trends, and allow you to access key starting materials and
reagents more efficiently.
Our cover molecule, XtalFluor-E®, affords us the opportunity to introduce a new
line of fluorinating reagents, and also gives us the chance to introduce Troy Ryba
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
Linkers (Chemical Biology).
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
74220 ChemFiles 10.3_v5.indd 374220 ChemFiles 10.3_v5.indd 3 8/19/2010 10:17:22 AM8/19/2010 10:17:22 AM
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
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
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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
74220 ChemFiles 10.3_v5.indd 574220 ChemFiles 10.3_v5.indd 5 8/19/2010 10:17:26 AM8/19/2010 10:17:26 AM
6 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
Cat
alys
is
CatalysisJosephine Nakhla, Ph.D.
Market Segment Manager
Organometallics & Catalysis
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)
74220 ChemFiles 10.3_v5.indd 674220 ChemFiles 10.3_v5.indd 6 8/19/2010 10:17:27 AM8/19/2010 10:17:27 AM
7Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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
(H3C)2N P N(CH3)2PPdCl
Cl
678740
(H3C)2N P N(CH3)2PPdCl
Cl
F3C P CF3PPdCl
Cl
692913
692921
74220 ChemFiles 10.3_v5.indd 774220 ChemFiles 10.3_v5.indd 7 8/19/2010 10:17:30 AM8/19/2010 10:17:30 AM
8 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
Ch
em
ical
Bio
log
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
74220 ChemFiles 10.3_v5.indd 874220 ChemFiles 10.3_v5.indd 8 8/19/2010 10:17:31 AM8/19/2010 10:17:31 AM
9Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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)
74220 ChemFiles 10.3_v5.indd 974220 ChemFiles 10.3_v5.indd 9 8/19/2010 10:17:32 AM8/19/2010 10:17:32 AM
10 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
Org
ano
me
talli
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.
Market Segment Manager
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.
74220 ChemFiles 10.3_v5.indd 1074220 ChemFiles 10.3_v5.indd 10 8/19/2010 10:17:34 AM8/19/2010 10:17:34 AM
11Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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
74220 ChemFiles 10.3_v5.indd 1174220 ChemFiles 10.3_v5.indd 11 8/19/2010 10:17:35 AM8/19/2010 10:17:35 AM
12 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
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
sigma-aldrich.com
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Alternative Energy Web Portal: aldrich.com/renewable
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Materials for Renewable and Alternative Energy SolutionsSolar Energy Conversion (Organic, Crystalline and Thin Film Photovoltaics)• Hydrogen Economy • Supercapacitors/Advanced Batteries• Alternative Fuels•
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74220 ChemFiles 10.3_v5.indd 1274220 ChemFiles 10.3_v5.indd 12 8/19/2010 10:17:36 AM8/19/2010 10:17:36 AM
sigma-aldrich.com
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
Register FREE at cenwebinars.stream57.com/midaboronate
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:
74220 ChemFiles 10.3_v5.indd 1374220 ChemFiles 10.3_v5.indd 13 8/19/2010 10:17:55 AM8/19/2010 10:17:55 AM
14 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
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
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
74220 ChemFiles 10.3_v5.indd 1474220 ChemFiles 10.3_v5.indd 14 8/19/2010 10:18:12 AM8/19/2010 10:18:12 AM
15Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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
Medicinal Chemistry and Organic Synthesis
• Internet-based reagent database
and procurement
• Powerful batch-search and
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• Determine price and availability from
your desktop
• From micromoles to grams
• Quick 48-hour turnaround time for
compounds and building blocks
• Reduce waste; eliminate on-site stocking
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• Specify vial type and labeling
requirements, including bar-coding
• No minimum order required
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Let DiscoveryCPR Put High Throughput Back in Your Operation!
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
74220 ChemFiles 10.3_v5.indd 1574220 ChemFiles 10.3_v5.indd 15 8/19/2010 10:18:13 AM8/19/2010 10:18:13 AM
16 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
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
74220 ChemFiles 10.3_v5.indd 1674220 ChemFiles 10.3_v5.indd 16 8/19/2010 10:18:21 AM8/19/2010 10:18:21 AM
Request your copy of our NMR Solvents Brochure ataldrich.com/nmrbrochure
sigma-aldrich.com
Unsurpassed Quality for Peak Performance
Aldrich NMR Solvents
Aldrich provides solvents of the highest quality to meet therigorous demands for NMR-based research and analyses.
For additional information, visit aldrich.com/nmr
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•
74220 ChemFiles 10.3_v5.indd 1774220 ChemFiles 10.3_v5.indd 17 8/19/2010 10:18:22 AM8/19/2010 10:18:22 AM
18 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
Syn
the
tic
Re
age
nts
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.
74220 ChemFiles 10.3_v5.indd 1874220 ChemFiles 10.3_v5.indd 18 8/19/2010 10:18:32 AM8/19/2010 10:18:32 AM
19Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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.
74220 ChemFiles 10.3_v5.indd 1974220 ChemFiles 10.3_v5.indd 19 8/19/2010 10:18:33 AM8/19/2010 10:18:33 AM
20 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
Sto
ckro
om
Re
age
nts
Stockroom ReagentsTodd Halkoski
Market Segment Manager
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)
74220 ChemFiles 10.3_v5.indd 2074220 ChemFiles 10.3_v5.indd 20 8/19/2010 10:18:35 AM8/19/2010 10:18:35 AM
21Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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
Cat. No.Available sizeswith New Design Product Name
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
Cat. No.Available sizeswith New Design Product Name
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
Cat. No.Available sizeswith New Design Product Name
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
Cat. No.Available sizeswith New Design Product Name
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)
74220 ChemFiles 10.3_v5.indd 2174220 ChemFiles 10.3_v5.indd 21 8/19/2010 10:19:05 AM8/19/2010 10:19:05 AM
22 TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.sigma-aldrich.com
Lab
war
e N
ote
s
Labware NotesPaula Freemantle
Product Manager
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
74220 ChemFiles 10.3_v5.indd 2274220 ChemFiles 10.3_v5.indd 22 8/19/2010 10:19:12 AM8/19/2010 10:19:12 AM
23Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
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
74220 ChemFiles 10.3_v5.indd 2374220 ChemFiles 10.3_v5.indd 23 8/19/2010 10:19:15 AM8/19/2010 10:19:15 AM
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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
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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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