Chemfiles Vol. 10, No. 4

Aldrich
Volume 10, Number 4 • 2010
Asymmetric Synthesis
Catalysis
Chemical Biology
Organometallics
Fe(S,S-PDP) - an electrophilic iron catalyst for site-selective C-H oxidation
Building Blocks
Synthetic Reagents
Stockroom Reagents
Labware Notes
Chemistry Services
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Introduction
Haydn Boehm, Ph. D.
Volume 10, Number 4 Global Marketing Manager: Chemical Synthesis
haydn.boehm@sial.com
Introduction
Sigma-Aldrich Corporation Dear Chemists
6000 N. Teutonia Ave.
Firstly I would like to offer congratulations from all
Milwaukee, WI 53209, USA
of us here at Sigma-Aldrich to Prof. Richard Heck
Editorial Team of the University of Delaware in Newark, US, Prof.
Haydn Boehm, Ph.D. Ei-ichi Negishi of Purdue University, US, and Prof.
Wesley Smith
Akira Suzuki of Hokkaido University in Japan, who were awarded the 2010
Dean Llanas
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Production Team
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Carrie Spear the world.
Chris Lein Indeed this news has proven very timely as Prof. Negishi was our second speaker
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Josephine Nakhla, Ph.D.
Matthias Junkers, Ph.D. The cover molecule of our fourth edition of the new Aldrich ChemFiles is
Mark Redlich, Ph.D. Fe(S,S-PDP), which was originally reported by Prof. Christina White, and is now
Troy Ryba, Ph.D. available from Aldrich Chemistry as part of our chiral 2,2’-bipyrrolidines portfolio
Todd Halkoski
Paula Freemantle
(Asymmetric Synthesis). In Aldrich ChemFiles 10.4 we also introduce the latest
Mike Willis building blocks for chemical biology (Chemical Biology), PEMB for reductive
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Technical Services Table of Contents
Please contact your local Sigma-Aldrich office (see back cover).
Asymmetric Synthesis ...............................................................................................................................4
Aldrich ChemFiles (ISSN 1933–9658) is a publication of Aldrich Chemical Catalysis ................................................................................................................................................................6
Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. © 2010 Chemical Biology ....................................................................................................................................... 10
Sigma-Aldrich Co. Organometallic Reagents.................................................................................................................... 12
Building Blocks ............................................................................................................................................ 14
Synthetic Reagents ................................................................................................................................... 16
Stockroom Reagents ............................................................................................................................... 18
Labware Notes.............................................................................................................................................. 20
Chemistry Services ................................................................................................................................... 22

On the basis of this set of selectivity rules the preferential oxidation
Asymmetric Synthesis of the electron-rich and sterically unencumbered tertiary C–H
Daniel Weibel, Ph.D. European Market
bond at C-10 of antimalarial tetracyclic compound (+)-artemisinin
Segment Manager, Chemistry (361593) was predicted. In addition to the site selectivity issue
posed in this substrate, a chemoselectivity challenge is present
daniel.weibel@sial.com in the form of a sensitive endoperoxide moiety known to be
prone to Fe(II)-mediated cleavage.3 (+)-10β-Hydroxyartemisinin

Chiral 2,2’-Bipyrrolidines was generated in diastereomerically pure form as the major
C2-symmetrical, chiral 2,2’-bipyrrolidines product in 54% yield (after recycling of artemisinin). Interestingly,
have recently emerged as interesting (+)-artemisinin (361593) has previously been transformed
structural chiral motifs in a number of enzymatically with microbial cultures of Cunninghamella echinulata
ligands for asymmetric transformations to 10β-hydroxyartemisinin in 47% yield with substantially longer
(Figure 1). When the two nitrogen atoms function either in a reaction times and a 10-fold lower volume throughput.3 The ability
bidentate chelate ligand or are covalently bonded to another of the simple, small molecule iron catalyst Fe(S,S-PDP) (730459)
atom, the two pyrrolidines adopted a stair-like structure, which with broad substrate scope to achieve P-450-like tailoring enzyme
creates a highly asymmetric environment. selectivities is remarkable.
H3C OH
H H H H CH3 H2O2
H H
H H
O O
N N N N H3C H3C
H H H H N N O O
O O
OH OH H H N
O H O H
HO2C HO2C CH3 N 2 NCCH3 CH3
CO2H CO2H 1.5• HO2C CO2H Fe (SbF6 )2
O O
OH OH
(+)-artemisinin N NCCH3 54%
N
688622 688746 712116
730459
Figure 1. Commercially available chiral 2,2’-bipyrrolidines.
Prof. Denmark has exploited this feature in the development of a Scheme 2: Selective aliphatic iron-catalyzed C–H oxidation
highly selective catalyst for asymmetric allylations.1 The addition of
Recently, Prof. White reported the same bulky, electrophilic
allylic trichlorosilanes to unsaturated aldehydes can be catalyzed
iron catalyst is capable of site-selective oxidation of isolated,
by chiral bisphosphoramide derived from 2,2’-bipyrrolidine (for the
unactivated secondary C–H bonds to afford mono-oxygenated
corresponding chiral bisphosphoramide catalyst derived from
products in preparatively useful yields without the use of directing
N,N′-dimethyl-1,1′-binaphthyldiamine, (715549) to give homo-
or activating groups (Scheme 3).4
allylic alcohols with excellent diastereo- and enantioselectivities
(Scheme 1). 730459 (15 mol %)
AcOH (1.5 eq) O
H H
EWG H2O2 (3.6 eq) EWG
n CH3 n CH3
H H CH3CN, rt, 30 min H H
H N O O N H O O O O O O CH3 O
P (CH2)5 P
H N N N N H CH3
CH3 CH3 H3CO CH3 H3CO H3CO CH3 H3CO CH3
O CH3
1. (5-10 mol %) 50% 51% 54% 43%
O Hunig's base, -78°C OH
R1 SiCl3
+
R H 2. NaHCO3, KF R CH2
R2 R1 R2 Scheme 3: Selective iron-catalyzed methylene oxidation
OH OH OH OH
In 2008, Prof. Lawrence Que developed an iron catalyst bearing
R CH2 R CH2 R CH2 R CH2
CH3 CH3 H3C CH3 the optically active 6-Me2-BPBP ((R,R)-1,1’-bis(6-methyl-2-
84-92%
80-88% ee
57-83% 54-91% 70-89%
88-96% ee
pyridinylmethyl)-2,2’-bipyrrolidine) ligand (712337) for asymmetric
anti/syn: 99/1 anti/syn: >95/5
81-86% ee (anti) 88-95% ee (syn) olefin dihydroxylation.5 This complex is hitherto one of the most
effective reported to date achieving up to 97% enantiomeric
Scheme 1: Highly selective asymmetric allylic allylations using a bisphos-
phoramide organocatalyst excess of the syn-diol product from cis-disubstituted olefins
(Scheme 4). These ee values are comparable to those obtained
In 2007, Prof. Christina White reported on an iron-based small with the osmium-based AD α or β mixes (392758 or 392766).
molecule catalyst Fe(S,S-PDP) (730459) bearing the (S,S)-1,1’-bis(2- These results demonstrate for the first time that a synthetic
pyridinylmethyl)-2,2’-bipyrrolidine (712361) moiety as chelating nonheme iron catalyst can approach the high enantioselectivity
ligand that uses hydrogen peroxide to oxidize a broad range of found in syn-dihydroxylating enzymatic systems.
substrates.1 Predictable selectivity is achieved solely on the basis
of the electronic and steric properties of the C–H bonds, without
the need for directing groups. This type of general and predictable
reactivity stands to enable aliphatic C–H oxidation as a method for
streamlining complex molecule synthesis (Scheme 2).
4 sigma-aldrich.com TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit aldrich.com/chemicalsynthesis.

Chiral 2,2’-Bipyrrolidines
N CH3
N 2 OTf H H H H
H H H
Fe
H
N OTf N N N N N N
H H H H H H
N CH3 OH OH
HO2C HO2C
CO2H CO2H 1.5• HO2C CO2H
2 mol % OH OH OH
35% H2O2 (10 eq)
R' R' ∗
R ∗ R'
CH3CN, rt, 20 min 688622 688746 712116
OH
OH OH OH O H H H H
∗ ∗ CH3 ∗ ∗ N
H3C ∗ CH3 H3C ∗ H3C OH H3C ∗ O CH3
N NCCH3 N N N N
OH OH OH OH 2
H
Fe (SbF6 )2
97% ee 96% ee 78% ee 76% ee H
N NCCH3 N N N N
N
• 4HCl • 4HCl
Scheme 4: Iron-catalyzed asymmetric olefin cis-dihydroxylation
References (1) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488. (2) Chen, M. 730459 712353 712361
S.; White, M. C. Science 2007, 318, 783. (3) Zhan, J.; Guo, H.; Dai, J.; Zhang, Y.; Guo, D.
Tetrahedron Lett. 2002, 43, 4519. (4) Chen, M. S.; White, M. C. Science 2010, 327, 566. H H H H
(5) Suzuki, K.; Oldenburg, P. D.; Que, L, Jr. Angew. Chem. Int. Ed. 2008, 47, 1887.
N N N N
N N N N
CH3 H3C CH3 H3C

• 4HCl • 4HCl
712337 712345
For a complete list of bipyrrolidines available from Aldrich

Chemistry, please visit aldrich.com/bipyrrolidines
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Catalysis +
P Au NCCH3 SbF6
Market Segment Manager
Organometallics & Catalysis R3 (2 mol %)
H3CO2C H3CO2C
H3CO2C
josephine.nakhla@sial.com H3CO2C CH2Cl2, rt
Catalysis
R3
H R1
R2 R2
R1
Alkyne Hydration H3CO2C H3CO2C

H3CO2C
H3CO2C H3CO2C
The hydration of alkynes has been R3
H3CO2C
CN NO2
H CH 3 H H
Ph H
extensively studied for more than
100 years. This reaction allows access
74% 58%
to various carbonyl derivatives from alkyne precursors. Nolan 78%
and coworkers reported alkyne hydration using a gold catalyst.
Nolan, a pioneer in the use of N-heterocyclic carbenes (NHCs)
O P AuCl
as ligands in various catalytic transformations with different
3
metals, developed conditions employing a gold-NHC complex (5 mol %) R
AgSbF6 (5 mol %) R
and silver hexafluoroantimonate for the hydration of alkynes R
R CH2Cl2, rt
(Scheme 1). It is important to note that an acid is not needed for
this transformation and the reaction was feasible at low catalyst PhO2S O
HO
loadings (10 ppm). PhO2S
94% 56%
N N
Scheme 2: Intramolecular cycloaddition of 1,3-enynes with alkenes
Au
Cl Reference (1) Nieto-Oberhuber, C.; Pèrez-Galán, P.; Herrero-Gómez, E.; Lauterbach,
(0.01 mol %) T.; Rodriguez, C.; López, S.; Bour, C.; Rosellón, A.; Cárdenas, D. J.; Echavarren, A. M. J.
O
AgSbF6
R1 R2 R1
R2 Am. Chem. Soc. 2008, 130, 269.
1,4-Dioxane/H2O (2:1)
120 °C, 18 h
O O O Propargyl Claisen Rearrangement

F
Toste and coworkers reported the use of the gold catalyst
H3CO [(Ph3PAu)3O]BF4 for the rapid two-step, one-pot sequence of a
88% 97% 72%
Claisen rearrangement of a propargyl vinyl ether followed by a
O O reduction of the resulting aldehyde functionality to provide a
O
variety of homoallenic alcohols. The reactions are generally high
76% 95%
yielding and the robust catalyst system is able to induce almost
complete chirality transfer (in most cases, ee’s were >90%). Low
Scheme 1: Hydration of alkynes using gold-NHC complex catalyst loadings (1 mol %) and substitution at the alkyne is well
Reference (1) Marion, N.; Ramón, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448.
tolerated generating the desired allenes in high yields (Scheme 3).
Reference (1) Sherry, B. S.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
Intramolecular Cycloaddition of 1,3-Enynes
BF4
with Alkenes
O
PPh3
Echavarren and co-workers employed a crystalline gold complex Au
Au Au
containing either the o-biphenyl phosphine ligand JohnPhos, Ph3P PPh3
(1 mol %) OH
or a bulky aryl ether phosphine under mild conditions to effect R1 O CH2Cl2, rt;
R3 •
the [4+2] cycloaddition of 1,3-enynes with olefins. A family of bi- NaBH4, MeOH, rt R1 R3
and tricyclic scaffolds were prepared in good yields (Scheme 2). OH OH OH
Both electron-withdrawing and electron-donating groups were • • •

H
tolerated on the aryl moiety. PivO
F3C
78% 81% 86%
Scheme 3: Preparation of homoallenic alcohols via Claisen rearrangement/

reduction sequence

Gold Catalysts from Sigma-Aldrich
AuCl
Au N C CH3 AuCl
CH3
t-Bu P t-Bu P t-Bu P t-Bu
P AuCl H3C P AuCl
SbF6-
CH3
Catalysis
697575 254037 715050 679771 404217
i-Pr i-Pr
AuCl
H3C P CH3
H3C i-Pr
N N AuCl
P S AuCl P AuCl
CH3 H3C i-Pr
H3C i-Pr Au i-Pr
Cl
i-Pr
288225 420727 696277 687510 702749
O
P PPh3 BF4−
Au NaAuCl4 • 2H2O AuBr3 AuCl
1/ CH C H Au Au
O Au O 2 3 6 5 Ph3P PPh3
F3C S N S CF3
O O
677922 665142 298174 398470 481130
AuCl3 • AuCl3
N
334049 677876
Silver Salt Additives

O CF3
S O
O O
S OAg
Ag N AgSbF6 AgBF4 AgPF6 F3C S OAg
O
S O O
O H3C
CF3
668001 176427 227730 208361 227722 176435
For a complete list of Gold Catalysts available from Aldrich Chemistry, please visit aldrich.com/gold

Aldrich® Chemistry Webinars
Zirconium-catalyzed Asymmetric
Carboalumination of Alkenes (ZACA Reaction)
Your speaker for this Aldrich To watch a recording of this webinar, please visit
sponsored webinar is:
aldrich.com/ ZACAwebinar
Overview: Many, if not the majority, of the organic compounds that are of interest and
importance to mankind are chiral or optically active. Until recently, the major route to
such chiral compounds and biocatalysts was the biosynthesis performed by nature,
which employed enzymes as synthetic tools. Slowly but surely, other methods have
emerged and their significance was predicted to increase significantly during the 21st
century, when W. Knowles, R. Noyori, and K. B. Sharpless were awarded the 2001 Nobel
Prize for their pioneering research using non-biological asymmetric methods for C–H
and C–O bond formation.
What about the all-important C–C bond formation for asymmetric organic skeleton
Ei-ichi Negishi, Ph.D.
formation? This webinar introduces the discovery, development and application
H. C. Brown Distinguished
of the ZACA reaction, and showcases how its efficient, selective, potentially green
Professor of Chemistry
and economical syntheses of biologically and medicinally important chiral organic
Purdue University
compounds can benefit mankind.
Co-Winner of 2010
Nobel Prize in Chemistry R2
i) R23Al, Cat. (-)-(NMI)2ZrCl2
1 OH
R ii) O2 R1
Areas covered in the webinar:
R2 = Me, 68–92% yield, 70–90% ee
• Discovery and development of the ZACA (-)-(NMI)2ZrCl2=
R2 = Et, 56–90% yield, 85–95% ee
reaction R2 = Higher primary alkyl groups,
ZrCl2
2 74–85% yield, 90–95% ee
• Its application to efficient and selective
synthesis of chiral natural products
• Synthesis of vitamins (E, K, etc.) and other To view previous and future webinars, please visit aldrich.com/cheminars
compounds of dietary and medicinal interest
Hosted by:
Who should attend:
• Organic Chemists
• Medicinal Chemists
• Anyone involved in research in academic or
corporate labs
©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.

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Proline Analogs
Chemical Biology Proline is a non-polar, natural amino acid that forms a tertiary
Matthias Junkers, Ph.D.
Product Manager
amide when incorporated into peptides. Thus, it is the only
proteinogenic amino acid that does not act as a hydrogen bond
matthias.junkers@sial.com donor in a peptide chain. Proline is known as a classical breaker
Chemical Biology
of both the α-helical and β-sheet secondary structures in proteins

New Building Blocks for and peptides, and it plays a crucial role in protein folding. Synthetic
proline derivatives, mimetics and analogs offer further options to
Chemical Biology tune the biological, pharmaceutical, or physicochemical properties
Modern automated synthesis protocols of peptides and proteins.
allow the fast and efficient production of
biopolymers like peptides and even proteins, or oligonucleotides. In recent years proline derivatives and analogs have also found
In recent years, even the automated synthesis of complex increasing popularity as organocatalysts in asymmetric synthesis.4
carbohydrates has been described.1 Automated synthesis
procedures build the bridge to Chemical Biology. It does not CH
O H2C O
require a fully trained chemist to perform automated synthesis. HC
O N
Even groups with a primary focus on biology research can utilize OH N OH
N Boc Boc
synthesizers to produce primers, test molecules, probes, etc., Boc
OH
quickly and efficiently. On the other hand, chemistry benefits 711985 711977 717045
equally from automated procedures. Synthesis challenges that
used to take weeks or months can today be completed in a matter O F O
of hours or a few days accelerating research tremendously. Fast N
N OCH3 OH
and efficient synthesis is only possible if all necessary tools are H Boc
readily available. Sigma-Aldrich is proud to offer a leading choice of 712884 717010
tools and building blocks for advancing science in the "omics" era
(genomics, proteomics, glycomics, metabolomics – to name just Unsaturated Amino Acids
a few). This issue of Aldrich ChemFiles highlights some examples of
recent additions to our portfolio. Recent developments in Chemical Biology research have increased
the demand of amino acid building blocks with unsaturated side
chains. Alkyne moieties can be used in bioorthogonal synthesis
Beta Amino Acids
strategies to form hybrid structures, introduce chemical probes into
Although they are less abundant than their α-analogues, biomolecules, or link large fragments with each other. The most
β-amino acids occur in nature both in free form and bound to prominent technique relies on the Huisgen dipolar cycloaddition
peptides. Oligomers composed exclusively of β-amino acids reaction between an azide and an alkyne.
(so-called β-peptides) might be the most thoroughly investigated
peptidomimetics. Besides being remarkably stable to metabolism, Olefin moieties open amino acids and peptides to metathesis
exhibiting slow microbial degradation, and inherently stable to reactions and a full range of other bioorthogonal synthesis routes.
proteases and peptidases, they fold into well-ordered secondary Olefin metathesis is a key to the production of hydrocarbon
structures consisting of helices, turns, and sheets. In this respect, stapled peptides.5 Stapled peptides are currently in discussion as
the most intriguing effects have been observed when β2-amino a new class of superpotent drugs or magical bullets promising
acids are present in the β-peptide backbone.2 A whole new to make peptide α-helices more potent and cell permeable by
“world” has emerged from the design of fascinating new peptidic locking them in the most active conformation.6
macromolecules from β- and γ-homologated proteinogenic amino
References: (1) Timmer, M.S.M.; Adibekian, A.; Seeberger, P.H. Angew. Chem. Int. Ed.
acids and other components. Sigma-Aldrich has a history as a 2005, 44, 7605. (2) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206. (2) Seebach, D.;
leading supplier of β3-amino acids. Now, the portfolio of β2-amino Beck, A.K.; Bierbaum, D.J. Chem. Biodiv. 2004, 1, 1111. (4) (a) Vignola, N.; List, B. J. Am.
acids is significantly increased with members that had not yet been Chem. Soc. 2003, 125, 450. (b) Dalko, P.I.; Moisan, L.; Angew. Chem. Int. Ed. 2004, 43,
5138. (5) Walensky, L.D. et al. Science 2004, 305, 1466. (6) Kritzer, A.K. Nature Chemi-
available commercially. cal Biology 2010, 6, 566.

New Amino Acid Building Blocks Monosaccharides
N3 N3
CH3 O CH3 O O OH O O
HO OH
H3C OH H3C O O CH3 O
H3C OH H2N OH HO
• HCl • HCl O CH3
H2N NH2 O
NH2 NH2 OH • 2HBr HO
O
Chemical Biology
714135 714143 714119 714216 714224 725978
OH N3
O O
H O O
N OH O O
H2N OH Boc OH O O
Boc H3C H3C O O
O N O O
OH H H3C O CH3 H3C O CH3
OH
H3C H3C H
713821 OH OH
714127 713856
712167 712736 725862
O O
H
N OH O CH3 OH OAc N3
Boc OH
O N Boc O AcO O N3 HO O
N OBn OAc OH
Boc H OH
OBn OCH3 CN
OBn OAc OH
713848 713724 713813
712140 712817 712752
O O Boc
OH OH
NH For a complete list of building blocks available from Aldrich
N
Boc
N
Boc O Chemistry, please visit aldrich.com/chemprod
H H O
713864 713872 713473
O O O
Boc H2N
NH OH H2N OCH3 O
H3C CH3
• HCl
• HCl
670243 726273 726354
O O O
HC
H2N OH OH HC OH
HN HN HN
Boc Boc Boc
726230 712221 714240
O
NH2 O
HC OH • HCl
HN HC OH
Boc
714232 711926

New Boronic Acids and Boronate Esters—
Organometallics cont'd
H3C CH3
Organometallics & Catalysis CH3 H3C
CH3
H3C CH3 H3C
O O O H3C O
josephine.nakhla@sial.com B H3C
Organometallics
B H3C B N
N O
H3 C O N
O
H3C CH3 N N
N H
N
H3C H CH3
Suzuki Coupling
716251 716227 715557
The cross-coupling of organoborons with
organic electrophiles in the presence of H3C CH3 CH3
CH3 H3C
a palladium catalyst (Scheme 1), is one H3C CH3 H 3C
O H3C O
O O H3C
B B
of the most widely utilized methods for C–C bond formation in H3C O
B N H3C O N
S
CN
transition metal chemistry. Organoboron reagents are readily N N
N
N Cl
prepared or are commercially available, relatively non-toxic, and do
not react with common functional groups. Several new product 718920 715476 715565
additions to our boron portfolio are highlighted below. H3C CH
H3C 3
H 3C O H3C
H3C O
B O N H3C
PdLn O H3C B O B
R1 X + R2 BY2 R1 R2 + BY2X N
N O
N H3C N
CH3 O N
R1 = aryl, heteroaryl, alkenyl O
R2 = aryl, heteroaryl, alkenyl, alkyl H3C CH3
X = Cl, Br, I, OTf
H3C
B N 724270 718823 716243
BYn = Y=(OH)2, F3K, O or
B O O
O O
(MIDA) O
B
O
Scheme 1: The Suzuki reaction
718491
Reference: Wolfe, J. P.; Nakhla, J. S. The Suzuki Reaction. Name Reactions for
Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 163–184.
For a complete list of boron reagents available from Aldrich
Chemistry, please visit aldrich.com/boron
New Boronic Acids and Boronate Esters
OH OH OH Stille Coupling
B B Br B
HO HO N OH
N The cross-coupling of organotins with organic electrophiles in the
N N NH2 N
H presence of a transition-metal catalyst (Scheme 2), remains one
706256 706221 686816 of the most viable methods for the formation of C–C bonds in
organic chemistry, particularly with heterocyclic nucleophiles. The
HO
OH OH
B OH Stille reaction, like other commonly used cross-couplings, has been
B B
OH OH
CH3 employed in methodology development, countless elegant natural
Br N H3C O N S
O product syntheses, and in materials science.
666556 718815 701939
M(0)
R1 X + R2 Sn(alkyl)3 R 1 R2 + X Sn(alkyl)3
OH HO OH
B
N B • HCl • HCl R1 = aryl, heteroaryl, alkenyl, acyl, benzyl, alkyl
HO HO
B N N N
R2 = aryl, heteroaryl, alkenyl, alkynyl, allyl, benzyl, alkyl
H
OH N N X = Cl, Br, I, OTf
H H
720828 715409 709379

Scheme 2: The Stille reaction
OH OH
N
B Br B
OH
Reference: Mascitti, Vincent. Stille coupling. Name Reactions for Homologations.
OH
HO
B N Boc John Wiley & Sons, Inc. (2009), (Pt. 1), 133–162.
CH3 N N
OH H
O OH
720798 717681 718785
OH O
O 2N B OH
OH H O B
OH
HO O
B
O2N
O OH OH
721042 717622 720771

Organotin Reagents from Aldrich Organozincs
H3C CH3
H3C ZnBr
S
N ZnBr N ZnBr
Bu3Sn SnBu3 Bu3Sn
S Bu3Sn
680982 680966 499382
Organometallics
717703 683930 719366
ZnI
F ZnI
ZnBr
Bu3Sn Bu3Sn N N
F
Bu3Sn N N Cl N Cl O
710261 710296 630411

678333 698598 718807
ZnBr
ZnBr
O ZnBr
O
Bu3Sn Bu3Sn Bu3Sn N OCH3
N N
710318 710326 710288
N N Cl N
Br S H3C S
719730 706868 707031 ZnBr ZnBr
714356 710237
O Bu3Sn
CH3
OCH2CH3 N
N Bu3Sn
N
N For a complete list of organozinc reagents available from
Bu3Sn N
O CH3
Aldrich Chemistry, please visit aldrich.com/zinc
706981 707813 717630
Common Catalysts Employed for
O Bu3Sn S Br N
Cross-Coupling
Bu3Sn
SnBu3
N Pd(OAc)2 Pd2(dba)3 Pd(PPh3)4
N S
520764 328774 216666

638617 642541 706965
Bu3Sn
N
N New Palladium Catalysts from
Bu3Sn N
CH3
N
Bu3Sn N
CH3
Aldrich Chemistry
CH3
675679 719501 718793 CH3

H3C Si CH3 CH3
Pd Pd
Cl H2C
Cl Cl Pd Pd Pd CH2
CH2 Cl
Pd
For a complete list of organotin reagents available from H3C Si CH3 CH3
CH3
Aldrich Chemistry, please visit aldrich.com/organotin
720526 719986 700045 721689
Negishi Coupling Common Ligand or Catalyst Families

The cross-coupling of organozincs with organic electrophiles in t-Bu
O
the presence of a transition-metal catalyst (Scheme 3), is widely P
t-Bu
Fe O P(t-bu)3
utilized due to the mild, yet reactive nature of organozinc halides. Ph Ph
Ph Ph PCy2
Ph
NiLn or PdLn
R 1 X1 + R2 Zn X2 R1 R2 + ZnX1X2 570958
675784 675709
Hartwig Guram Fu
R1 = aryl, alkenyl, acyl
R2 = aryl, heteroaryl, alkenyl, allyl, benzyl, homoallyl, homopropargyl H3C CH3
X1 = Cl, Br, I, OTf CH3 H3C
X2 = Cl, Br, I
N N
Pt-Bu2
Scheme 3: The Negishi reaction CH3 H3C
H3C Pd CH3
Cl
Reference: Yet, Larry. Negishi Cross-Coupling Reaction. Name Reactions for
Homologations. John Wiley & Sons, Inc. (2009), (Pt. 1), 70–99.
638439 709042
Buchwald Nolan
For a complete list of catalysts available from Aldrich
Chemistry, please visit aldrich.com/catalysis

Building Blocks R2HN
Ph
O
O
R1O O OH
Mark Redlich, Ph.D. OH O

H
Product Manager OH
OBz OAc
mark.redlich@sial.com Paclitaxel: R1 = Ac, R2 = Bz

Docetaxel: R1 = H, R2 = Boc
Building Blocks
Figure 1: Paclitaxel (Taxol®) and Docetaxel

Oxetanes
O
Oxetanes are the closest homologs to O
HO
epoxides, but historically have received far O O
O
less attention than their three-membered-
ringed brethren. However, oxetanes have received increasing Figure 2: Merrilactone A
exposure as attractive modules for drug discovery, largely due
Br
to a recent series of reports from Rogers-Evans, Carreira, and N
H
coworkers. They have demonstrated the improved physico- and Br
N
N
N
NH2
H H
biochemical properties of a molecular scaffold when an oxetane O
unit replaces a gem-dimethyl unit1 and also reported an oxetane Figure 3: β-Amino Acid Oxetin
ring can function as a surrogate for a carbonyl group.1b,2 More
recently, they have demonstrated the use of 1,6-substituted We are pleased to now offer a wide selection of new oxetane
azaspiro[3.3]heptanes containing an oxetane ring as alternatives to building blocks for a variety of applications in synthetic and
unstable 1,3-heteroatom substituted cyclohexanes.3 In most cases, medicinal chemistry.
3-oxetanone, 731536, was the principal building block employed
by the authors to install the oxetane unit (Scheme 1). New Oxetanes
CN O OH I
O O O
O O NO2
OEt
P
OEt 731536 733296 731560
O
O H
CN O N
H2N OH
O O
SO2Ph
OEt O O
O O
O 731536
O 731579 733091 731544
O
Cl H
O NH
NH
O O
O O
O CH3
731587 731609
O
For a complete list of oxetanes available from Aldrich
Scheme 1: Oxetane Derivatives Synthesized from 3-Oxetanone Chemistry, please visit aldrich.com/oxetane
The presence of the oxetane moiety in drug-like and biologically

active molecules is nothing new to synthetic and medicinal
chemists. Perhaps the best-known examples of oxetane-containing
drugs are the natural product paclitaxel (Taxol®) and its synthetic
analog docetaxel (Figure 1). Joëlle Dubois and coworkers studied
the effect of the deletion of the oxetane ring in analogs of
docetaxel and found the analogs to be less active than docetaxel
in biological assays.4 Merrilactone A (Figure 2) shows promise as
a nonpeptidal neurotropic agent, 5 and the β-amino acid oxetin
(Figure 3) has demonstrated both herbicidal and antibiotic
activity.6

Halogenated Pyridines Other New Building Blocks
Pyridines continue to be extremely popular building blocks for O
synthetic chemists across a number of disciplines. The pyridine C CH2 H2C C O HC NH2
moiety is found in a wide range of synthetic targets with

applications in catalysis, drug design, molecular recognition, 715018 714992 715190
Building Blocks
and natural product synthesis. Halogenated pyridines in
particular are attractive building blocks for various cross-coupling OH CH3
HC H3C Si NH2
methodologies. Sigma-Aldrich is pleased to offer these useful CH3 NH2 • HCl
CH3
CH3
halogenated pyridines for your research.
723800 720356 686360
I Br Br
NH2 NH2
NH2
N N F N NH2 CH3 H3C

NH2 OCH3 OCH3
722170 722421 720224
721492 721484 724688
OH
Br F3C Cl
NH2 Boc
NH2 HN
N SH N NH2
N Cl H3CO N
CH3 N
714445 H
720895 714488
724661 718084 709662
I I
Cl F Br
Cl I CH3
HN N
N F Boc
N Cl N Cl S N
N H
H2N O
720208 730564 724084
727547 708399 723649
I Br Br
Br Br H3C
CH3 H3CO CH3
H N
N HO N
N OCH3 NH2 N H
N Cl O S F3C
O H O H
722731 724092 707325 716529
722375 723789
O OH Br CH3
Br NH2 I NH2 Br
Cl H3C Si O N
N CH3 N
N Cl N Cl N
N N
N Cl CH3 H
724076 720909 720372 717215 723770 721050
O H3CO
O O
F Br Br
OH OH OH
N Cl N CH3 N OCH3 N
H
697338 717576 725250 724378
For a complete list of halogenated pyridines available from For a complete list of building blocks available from Aldrich
Aldrich Chemistry, please visit aldrich.com/hal-pyr Chemistry, please visit aldrich.com/bb
References: (1) (a) Wuitschik, G. et al. Angew. Chem., Int. Ed. 2006, 45, 7736. (b)
Wuitschik, G. et al. J. Med. Chem. 2010, 53, 3227. (2) Wuitschik, G. et al. Angew.
Chem., Int. Ed. 2008, 47, 4512. (3) Burkhard, J. A. et al. Org. Lett. 2010, 12, 1944.
(4) Deka, V. et al. Org. Lett. 2003, 5, 5031. (5) (a) Birman, V. B.; Danishefsky, S. J. J. Am.
Chem. Soc. 2002, 124, 2080. (b) Huang, J.-M. et al. Tetrahderon Lett. 2000, 41, 6111.
(c) Huang, J.-M. et al. Tetrahderon 2001, 57, 4691. (6) Omura, S. et al. J. Antibiot.
1984, 37, 1324.

Synthetic Reagents Selected Examples
Troy Ryba, Ph.D.

Yield (%) Yield (%)
Product Manager Carbonyl Amine Product MeOH neat
troy.ryba@sial.com
CHO Ph
Synthetic Reagents
PhNH2 N 72 80
H
5-Ethyl-2-methylpyridine CHO Bn
N 87a 92a
borane (PEMB): A New BnNH2
H
Reagent for Reductive

Aminations CHO N
Pr
0b 96
Pr2NH
Pr
PEMB
H
C4H9 CHO PhNH 2 N
C4H9 Ph 92 94
CH3 O H
PhNH2 N
H3C N Ph 92 93
.
BH3
O H
N
5-Ethyl-2-methylpyridine borane (PEMB) BnNH2 Bn 83a 70a
725080
O Ph
HN
Figure 1: Structure of the new reductive amination reagent, PEMB (725080). H3C C3H7 PhNH2 74 94
H3C C3H7
The reaction of a primary amine with an aldehyde or ketone in the
O
presence of an appropriate hydride source provides quick access Bn
BnNH2 HN 84 83
H3C C3H7
to an array of secondary amines. Critical to the success of this
H3C C3H7
transformation is the nature of the reducing agent. Highly reactive
hydrides will be intolerant not only with the weak Brönsted acid O HN
Bn
catalysts commonly employed but also with water generated upon 62c 70
CH3 BnNH2 CH3
iminium ion formation.
Useful Applications of PEMB a Isolated as the dialkylammonium acetate

b No reductive ammination product, benzyl alcohol generated
c
Percent conversion in 1 h
R R
O AcOH N 1. PEMB HN
R H R NH2, rt R H 2. workup R H Scheme 2: Selected reductive amination examples run in
methanol and neat.
R R
O AcOH N 1. PEMB HN References: Burkhardt, E. R.; Coleridge, B. M. Tetrahedron Lett. 2008, 49, 5152–5155.
R R R NH2, 50 o C R R 2. workup R R
Scheme 1: Representative transformation conditions for reduction

amination with PEMB.
5-Ethyl-2-methylpyridine (PEMB) exhibits enhanced shelf stability

relative to other amine-boranes for reductive aminations
(Scheme 1). Studies have shown solvolysis is slow (less than 7%
daily) in water/THF or methanol solutions.
Reductive aminations with PEMB can be run in methanol. However,
solvent can be eliminated completely and the reactions can be run
neat, often with better yield than when run in solution (Scheme 2).
Unlike some other hydride reducing agents, two of the three
borane hydrides are utilized and usually an excess of reagent is not
required.

Amine Boranes O O
PhNEt2 N Me2NH i-Pr2NEt

N
H3C N N H
CH3 BH3 BH3
BH3
BH3 BH3
BH3 BH3
Synthetic Reagents
654213 179752 179043 262323 180203 180238 253111
t-BuNH2 Et3N Me3N H3N
BH3 BH3 BH3 BH3
197939 178977 178985 287717
For a complete list of Amine Boranes available from Aldrich Chemistry, please visit aldrich.com/amineboranes
Materials Science
Aldrich MOF Constructor

An Easy Way to Design your Own MOF
Metal-Organic Frameworks (MOFs) are porous coordination Aldrich Materials Science is uniquely positioned to assist you in
networks with record-setting surface areas. MOFs are built from constructing your own MOF. Please review our current offering
metal ion clusters connected by organic linker molecules or struts. of organic linkers, high-purity metal salts, and solvents, or request
They are designed for specific applications requiring high surface custom-designed materials to meet your research needs.
area materials.
Organic Linker Molecules for Metal-Organic Frameworks

For a complete list of organic linker molecules for MOFs, please visit aldrich.com/moflinkers
O O O O O
O O O O O
HO OH HO OH OH H2N HO
HO OH OH OH OH
HO OH HO OH OH HO HO HO HO
NH2 OH
O O O O O O O O O
716499 716502 714747 717312 523763 382132 185361

O OH
O O
O
HO OH
OH
O OH
O HN O
N R
N O HO N N OH
O O R=* HO OH HO OH
N N CH3
OH N N N
OH OH H H R R H H O O O O
482749 I202 M50850 706884 719250 715298 686859
High-Purity Metal Salts for Synthesis of Metal-Organic Frameworks

For a complete list of metal salts and other related materials, please visit aldrich.com/ceramics
Zn(NO3)2 • xH 2O Mg(NO3)2 • 6H2O Cu(NO3)2 • 2.5 H2O Al(NO3)3 • 9H2O
230006 203696 467855 229415
Ni(NO3)2 • 6H2O Cu(NO3)2 • xH2O Co(NO3)2 • 6H2O

203874 229636 203106

National Association of Scientific Materials Managers
Stockroom Reagents (NAOSMM)
Todd Halkoski
Sigma-Aldrich is a proud partner of NAOSMM. As an added
Solvents benefit, their members receive savings on a wide range of Sigma-
Aldrich Chemistry products.
Stockroom Reagents
todd.halkoski@sial.com
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We specialize in providing the most comprehensive product New Lab Start-Up Program
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From ACS grade to TraceSELECT® Ultra for the ultra trace analysis
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Easy-to-find site offers monthly savings Nomograph allows you
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on Chemistry, Life Science, Analytical and
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Labware Notes
Paula Freemantle
Product Manager
Labware Notes
labware@sial.com
Distillation Adapter for

On-The-Fly Sampling
Distillation is the most widely used bulk
separation method used in the laboratory
as well as industry. Beyond purification, it is widely used to
characterize complex fluids (such as fuels) through measurement
of the distillation curve, a plot of the boiling temperature against
volume distilled. A common theme in both of these applications is
the desire to understand the composition. In purification, the goal
is to monitor the distillation progress, and in fluid characterization,
one seeks to relate the composition to the temperature data.
The distillate sampling adapter (Figure 1) installed following Figure 1: Distillate sampling adapter.
a condenser or distillation column, can provide this important
capability without the need for cumbersome, expensive and For a complete list of adapters available from Aldrich
often unreliable fraction collectors.1–3 The flow of the distillate Chemistry, please visit aldrich.com/labware
is focused to drop into a 0.05 mL “hammock” that is positioned
directly below the flow path. The sampling port, equipped with Aldrich GC sampling adapter, with vacuum connection
a vacuum tight valve, allows access to the hammock with a and PTFE valve
standard chromatographic syringe, through a septum. To sample Joint size Cat. No.
the distillate, one simply positions the chromatographic syringe, 14/20 Z569895
preferably equipped with a blunt tipped needle, in the well of 24/40 Z569909
the hammock. It is a simple matter to withdraw samples as the 29/32 Z569917
distillation progresses. The sample can then be directly injected Replacement valve septa 33310-U
into the gas chromatograph or spectrometer, or injected into an Septum inserter for valve 33311
autosampler vial for analysis later. Indeed, any analytical technique References: (1) Bruno, T. J., Ott, L.S., Lovestead, T.M., Huber, M.L., The composi-
that is applicable for liquid samples ranging in volume from tion explicit distillation curve technique: relating chemical analysis and physical
properties of complex fluids. J. Chromatogr. 2010, A1217, 2703–2715. (2) Bruno,
1 to 50 microliters can be used to characterize the distillate. T. J., Ott, L.S., Lovestead, T.M., Huber, M.L., Relating complex fluid composition and
thermophysical properties with the advanced distillation curve approach. Chemi-
This adapter has been used for many complex fluid analyses,
cal Eng. Tech. 2010, 33, (3), 363–376. (3) Bruno, T. J., Ott, L.S., Smith, B.L., Lovestead,
including gasolines, diesel fuels, rocket kerosenes, jet fuels, T.M., Complex fluid analysis with the advanced distillation curve approach. Anal.
crude oils, transformer fluids, waste oils and arson accelerants. Chem. 2010, 82, 777–783.
Some of the analytical techniques applied to distillate fraction
analysis include gas chromatography (with mass selective, flame
ionization and chemiluminescence detection), FTIR spectroscopy,
Karl Fischer coulombic titrimetry and refractometry. The ability
to couple quantitative analysis with the distillation opens the
door to thermochemical determinations such as the enthalpy of
combustion of fuels, as a function of distillate cut. The adapter has
also been used to measure corrosivity of crude oil fractions, with a
copper coupon test performed at various distillate cuts.

Hamilton® Syringe, 700 Series News and Innovation
This syringe is a good choice for use with the sampling adapter. New Aldrich Condenser Design Eliminates Puddling
volume 10 μL, needle size 22s ga (blunt tip) on Equipment
Cat. No. 58380-U Condensate cup catches water that forms on
Labware Notes
the outer surface of the condenser during
use and eliminates puddling on reactor and
equipment. Tubing connects to cup's hose barb
to drain away water automatically.
Z568945 overall H 60 mm, Joint: ST/NS 14/20

Aldrich Distillation Glassware
• Apparatus Z568988 overall H 200 mm, Joint: ST/NS 24/40
• Condensers Z568996 overall H 200 mm, Joint: ST/NS 29/32
• Distilling columns and packings Z569003 overall H 300 mm, Joint: ST/NS 14/20
• Heads Z569038 overall H 300 mm, Joint: ST/NS 29/32

• Traps
For a complete list of condensing products available from
• Glassware kits Aldrich Chemistry, please visit aldrich.com/labware
For a complete list of distillation products available from

Aldrich Chemistry, please visit aldrich.com/labware

• Automatic conformational analysis: Each small molecule ligand
Chemistry Services is flexed, in an energetically directed approach, and re-oriented
Mike Willis thousands of times in the search for potential matches between
Market Segment Manager the ligand and the protein surface.
mike.willis@sial.com
• Speed enables in silico screening of millions of small molecules:
Chemistry Services
3DPL employs a unique and patented derivative field grid to direct

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identified binding site as input for the screening experiment.
products/3DPL.asp
• Entire protein surface may be considered: Each small molecule

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offers the opportunity to identify ligands that would have been
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one or more pre-defined active sites on the protein surface.

The Next Generation of Labeled Synthons
For Improved Site-Specific and Stereospecific Syntheses
Dr. Rodolfo Martinez and his group Some of the most versatile compounds in the collection include the methyl addition
at Highlands Stable Isotopes have reagents of which methyl-13C phenyl sulfide (716081) is a notable example. Methyl
developed a novel set of patented phenyl sulfide has a rich chemistry and, if prepared with carbon and deuterium
stable isotope synthetic reagents. labels in the methyl group, is a versatile labeling precursor easily converted into a
These exclusive reagents facilitate nucleophilic or an electrophilic synthon.
the production of site-specific and
S Cl SO2Cl2 S sec -BuLi S Li
stereospecific labeled compounds. Ph 13
C
H2 or NCS
Ph 13
CH3 Ph 13
C
H2
They also help improve the speed
and quality of the synthesis of Labeled methyl phenyl sulfide can be oxidized, adjusting the pKa and allowing for
labeled materials. These versatile subsequent modifications. A Raney® Ni mediated desulfurization can be used to
reagents include the following remove the sulfur, leaving a labeled methylene group. Alternatively, a 13C-labeled
categories: aldehyde, carboxylic acid, or carboxylic ester can be prepared directly.
O O O
• Protected methyl addition 13

C 13
1. PhSO CH2Li
13
C 1. TFAA
13
C
reagents H13C OR H13C OR
2. H2O
H13C OR
13
Ph 13
• α-Keto amide, acid, and ester H 3C

O
CH
O
S
13
C
CH
LDA
H
13
C
13
CH
precursors H H
R' x
O
• Olefination reagents O O
• Phenyl vinyl compounds H13C

13
C
OR
Raney® Ni
H13C
13
C
OR
• Thioethers and dithioethers O

Ph
S
13
C
13
CH
H213C
13
CH
• Phthalimides and succinimides H R’ R’
To view the Next Generation of O O

Labeled Synthons offered by O
13
H3 C C 13
C
ISOTEC® Stable Isotopes, visit PhS
13
C
OBn
N OBn H13C OR
sigma-aldrich.com/sinext CH3 R 13
CH X = O,S,NR2,SiR 3
X
For additional information,

please email the Stable Isotope O
n = 0-2
O n = 0-2 S
Technical Service Group at 13
CH3
S
13
S CH
isosales@sial.com 13 13 13
H C CH CH2
[13C]Methyl phenyl sulfide
H213C OH
Reference: Martinez, R. A.; Alvarez, M. 716081
A.; Velarde, S. P.; Silks, L. A. P.; Stotter, P. L.;
Schmidt, J. G.; Unkefer, C. J. Large-Scale X Y
Preparation of [13C]-Methyl Phenyl Sulfide O
n = 0-2
O O
13C 13C
from [13C]Methanol by a One-Step Process. S 13
C
13C
Org. Process Res. Dev. 2002, 6, 851. 13

C 13
CH2 H13C OR W 13
CH H13C Z
H2
W,X,Y,Z = H,O,S,NR2,SiR3
H 13
Br CH
13C
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Aldrich

Volume 10, Number 4 • 2010

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O O O Propargyl Claisen Rearrangement

and tricyclic scaffolds were prepared in good yields (Scheme 2). OH OH OH

Both electron-withdrawing and electron-donating groups were • • •

Scheme 3: Preparation of homoallenic alcohols via Claisen rearrangement/

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288225 420727 696277 687510 702749

677922 665142 298174 398470 481130

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668001 176427 227730 208361 227722 176435

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713864 713872 713473

670243 726273 726354

726230 712221 714240

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720828 715409 709379

721042 717622 720771

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680982 680966 499382

710261 710296 630411

520764 328774 216666

675679 719501 718793 CH3

720526 719986 700045 721689

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Useful Applications of PEMB a Isolated as the dialkylammonium acetate

Scheme 1: Representative transformation conditions for reduction