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VOLUME 11 NUMBER 2 2011
Pd-PEPPSI™-IPent: a new and improved catalyst for cross-coupling.
Catalysis
Organometallics
Building Blocks
Synthetic Reagents
Green Chemistry
Stable Isotopes
Stockroom Reagents
Labware Notes
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ALDRICH
Introduction 3
Aldrich
Haydn Boehm, Ph. D.Global Marketing Manager: Chemical Synthesis
Dear Fellow Chemists,
Welcome to the second edition of Aldrich ChemFiles for 2011, our complimentary quarterly innovation 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.
As well as introducing all the latest innovations across all of our product lines, in 2011 each edition of Aldrich ChemFiles will be themed to a product line. Aldrich ChemFiles Vol. 11, No. 2 will focus on our Catalysis product line, which is very timely as it affords me the opportunity to welcome Dr. Ronaldo Mariz as our new Catalysis Product Manager. In this “Catalysis” issue Ronaldo highlights our latest palladium and nickel catalysts for Negishi, Suzuki, Heck, Sonogashira and Kumada-Corriu-Tamao cross-coupling reactions. Our cover molecule is PEPPSI™-IPent, developed by Prof. Michael Organ, one of several new additions to our portfolio of Pd-PEPPSI catalysts, and illustrates how critically important Pd-catalyzed cross couplings are to the chemical community, a fact reflected by the 2010 Nobel Prize for chemistry being awarded to Prof. Richard Heck, Prof. Ei-ichi Negishi and Prof. Akira Suzuki for their pioneering work in this field.
Aldrich ChemFiles Vol. 11, No. 2 will also introduce the latest innovations across all of our product lines including new MIDA boronates (Organometallics), iodinated building blocks and oxetanes (Building Blocks), new novel oxidants (Synthetic Reagents) and the latest isotope labeled organic molecules (Stable Isotopes). I am also pleased to introduce you to Dr. Pietro Butti, our new Green Chemistry Product Manager, who will discuss how Aldrich is using greener methodologies to produce aromatic azides, which have numerous applications for the synthesis of APIs.
We hope that Aldrich ChemFiles will enable you to expand your research toolbox and advance your chemistry more effectively by implementing the latest innovative synthetic strategies.
Kind regards,
Dr. Haydn Boehm Global Marketing Manager: Chemical Synthesis
Table of ContentsCatalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Synthetic Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Green Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Stable Isotopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Stockroom Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Labware Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Sigma-Aldrich® Corporation6000 N. Teutonia Ave.Milwaukee, WI 53209 USA
Editorial TeamHaydn Boehm, Ph.D.Wesley SmithDean LlanasSharbil J. Firsan, Ph.D.Weimin Qian
Production TeamCynthia SkaggsVincent ClarkChris LeinTom BeckermannChristian HagmannDenise de Voogd
Chemistry TeamAaron Thornton, Ph.D.Daniel Weibel, Ph.D.Josephine Nakhla, Ph.D.Ronaldo Mariz, Ph.D.Pietro Butti, Ph.D.Mark Redlich, Ph.D.Troy Ryba, Ph.D.Todd Halkoski Paula FreemantleMike Willis
Aldrich ChemFiles SubscriptionsTo request your FREE subscription to Aldrich ChemFiles visit aldrich.com/chemfiles or contact your local Sigma-Aldrich office (see back cover).
Aldrich ChemFiles OnlineAldrich ChemFiles is also available in PDF format at aldrich.com/chemfiles.
Aldrich Chemistry ProductsAldrich brand products are sold through Sigma-Aldrich, Inc.Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product for its particular use. See reverse side of invoice or packing slip for addi-tional terms and conditions of sale. All prices are subject to change without notice.
To Place Orders or Contact Customer/ Technical ServicesContact your local Sigma-Aldrich office (see back cover).
Aldrich ChemFiles (ISSN 1933–9658) is a publication of Aldrich Chemical Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. © 2011 Sigma-Aldrich Co.
Volume 11, Number 2
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
4
CatalysisRonaldo Mariz, Ph.D.Product [email protected]
Nickamine: Nickel catalyst for Sonogashira and Kumada-Corriu-Tamao (KCT) coupling•Versatile nickel catalyst
•Excellent functional group tolerance
Sonogashira couplingOne of the most widely used methods for introducing the alkynyl moiety in organic substrates is the coupling of an electrophile and a terminal alkyne normally mediated by a palladium catalyst in the presence of copper as co-catalyst. Recently Xile Hu and co-workers reported the use of the nickel catalyst Nickamine (728551) as a versatile alternative to palladium for the Sonogashira coupling (Scheme 1).1
Scheme 1: Nickel catalyzed Sonogashira coupling of non-activated alkyl halides.
Loadings of 5 mol% of the nickel catalyst enabled the coupling of non-activated alkyl iodides with several terminal alkynes. Alkyl bromides and even chlorides in the presence of NaI and n-Bu4NI as additives respectively, were equally effective. It is noteworthy that the catalyst overcomes problems associated with β-H elimination (undesired side reaction) and operates with excellent functional group tolerance for both coupling partners.
Kumada-Corriu-Tamao (KCT) couplingHu and co-workers have also shown that Nickamine can be successfully employed in the cross-coupling of non-activated alkyl halides and Gri-gnard reagents (Scheme 2).2,3 Despite the reactive nature of the organo-metallic coupling partner many functional groups were tolerated in the protocols applied. The Kumada-Corriu-Tamao coupling permitted access to a variety of functionalized aryl, heteroaryl and alkyl compounds.
Scheme 2: KCT coupling of non-activated alkyl halides and Grignard reagents.
Orthogonal FunctionalizationExploiting the versatility of the catalyst, Hu and co-workers demonstrated that it is possible to make use of both Sonogashira and KCT protocols, as well as the difference in reactivity of the alkyl-X bonds, allowing orthogo-nal functionalization of substrates with multiple reactive sites (Scheme 3).
Scheme 3: Orthogonal functionalization of substrates.
XAlkyl HC R+
5 mol% (728551)3 mol% CuI
(20 mol% NaI for X = Br) (20 mol% n-Bu4NI for X = Cl)
X = I, Br, Cl 1.3 equiv.1.4 equiv. Cs2CO31,4-dioxane, 16 h100°C (X = I, Br)140°C (X = Cl)
Alkyl R
H3C
CH3
Cl
X = I, 84%
O
On-C4H9
X = Br, 76%
EtO
O OTMS
X = I, 73%
NCH3 Ph
X = Cl, 75%
CN
PhPh n-C6H13
X = Cl, 66%X = Cl, 73%
O
AcO
X1R1 R2 MgX2+
3 mol% (728551)30 mol% TMEDA or O-TMEDA
THF, r.t., 1 h
X1 = I, Br
orDMA, -35°C, 0.5 h
R2R1
R2 = aryl, heteroarylor alkyl; X = I, Br, Cl
Et2N
O n-C4H9
78%
NO
O
H3CCH3
CH3
86%
OBr
CH3H3C
89%
N(SiMe3)2
92%
N
OCH3
SCl
62%
NNNC
H3C
74%
N
N
O
OO
CH3
CH3
86%
N
OO
CH3
86%
CH3
Br Cl4
HC n-C6H13
5 mol% (728551)Sonogashira protocol
n-C6H13
5
Cl
MeO
MgCl
HC Si(i-Pr)3
5 mol% (728551)Sonogashira protocol n-C6H13
5
(i-Pr)3Si
Cl3 mol% (728551)
KCT protocol
Br5
Cl
MeO
HC n-C6H13
5 mol% (728551)Sonogashira protocol
5
MeO
n-C6H13
69%
86%
EtO2C
MgCl
I Cl3 mol% (728551)
KCT protocol
2
Cl
EtO2C
HC n-C6H13
5 mol% (728551)Sonogashira protocol
2
EtO2C
n-C6H13
77%
I Cl3 mol% (728551)
KCT protocol
2
ClHC
5 mol% (728551)Sonogashira protocol
73%
NNH3C
MgI
NNH3C
Ph
2
NNH3C
Ph
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
5Catalysis
References: (1) Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 12078. (2) Vechorkin, O.; Proust, V.; Hu, X. L. J. Am. Chem. Soc. 2009, 131, 9756. (3) Vechorkin, O.; Hu, X. L. Angew. Chem., Int. Ed. 2009, 48, 2937.
For a list of Nickel catalysts available from Aldrich Chemistry, visit Aldrich.com/nickel
Frech Pdcat: Piperidinaminophosphine Pincer Palladium catalyst for Suzuki, Heck and Sonogashira coupling •Palladium catalyst for Suziki, Heck and Sonogashira coupling at
ppm levels
Suzuki couplingThe cross-coupling of aryl halides and organoboron nucleophiles is established as one of the most common methods to construct C–C bonds in biaryl frameworks. The Frech group at The University of Zurich has developed a highly active piperidinaminophosphine pincer palladium complex (727733) capable of performing the Suzuki reaction at loadings as low as 0.05 mol% (Scheme 1).1 The catalyst effectively coupled a wide range of aryl bromides and boronic acids/potassium trifluoroborates with very good functional group tolerance under air atmosphere.
Scheme 1: Palladium pincer complex for Suzuki cross-coupling under air atmosphere.
Heck reaction and Sonogashira couplingWhile Frech’s catalyst demonstrates high activity with just 0.05 mol% for the Suzuki coupling, its performance in both Heck reaction and Sonogashira coupling requires even lower amounts of the metal complex. Excellent yields were obtained at ppm levels (not greater than 50 in most cases) reaching turnover numbers of up to 49000 TON for the Heck reaction (Scheme 2)2 and 20000 TON for the Sonogashira coupling (Scheme 3).3
Scheme 2: Heck reaction catalyzed by ppm amounts of Frech catalyst.
Scheme 3: Sonogashira coupling catalyzed by ppm amounts of Frech catalyst.
References: (1) a) Bolliger, J. L.; Blacque, O.; Frech, C. M. Angew. Chem. Int. Ed. 2007, 46, 6514. b) Bolliger, J. L.; Frech, C. M. Adv. Synth. Catal. 2010, 352, 1075. (2) Bolliger, J. L.; Blacque, O.; Frech, C. M. Chem. Eur. J. 2008, 14, 7969. (3) Bolliger, J. L.; Frech, C. M. Adv. Synth. Catal. 2009, 351, 891.
For a list of homogeneous palladium catalysts available from Aldrich Chemistry, visit Aldrich.com/palladium
Ar Br + Ar' B0.05 mol% (727733)
K2CO3, n-BuOH/H2O (9:1)100°C, air atmosphereB = B(OH)2
or BF3K
Ar Ar'
O
O
98%, 1 h
O
OH3C CH3
99%, 1 h
SO
H
91%, 2 h
N
OMe
95%, 8 h
CH3
O
CH3OMe
O
OH
CH3
CH3
H3C
69%, 4 h
CH3HNO
CH3
89%, 6 h
H2N
92%, 4 h
SCH3
81%, 6 h
OMe
CH3
N
OCH3
CH3MeO
O
MeO
O n-C4H9
N
CH3
Ar Br +50 ppm (727733)
K2CO3, DMF140°C, 2.5 to 12 h
97%
H2C R RAr
98% 99%
99% 100%
Ar I +K3PO4, ethylene glicol
140°C, 0.25 to 4 h
Ar' Ar
CH3
CH3CH3
MeO
100%
H2N
100%
HC
OMe
OMe
96%
Ar'
CH3
CH3CH3
N
100%
S
OMe100%
NN
H3C
CH3
CH3
96%
50 ppm (727733)
N
NMe2
NMe2
Ni Cl Nickamine
728551
Nickamine 728551
HN
HN
P
P
Pd Cl
NN
NN
Frech Catalyst
727733
Frech Catalyst 727733
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
6
Cinchona Based Thiourea Organocatalysts •Effective organocatalysts for conjugated additions
Catalysis by purely organic small molecules has emerged as a powerful tool in the field of asymmetric synthesis. Among the plethora of chiral organocatalysts developed so far, cinchona alkaloid-based motifs constitute one of the most popular choices. Recent studies have shown cinchona based thiourea (690384, 690600 and 690481), readily accessed from the corresponding amines (713228, 713201 and 713236), as promising organocatalysts. Important features in these types of catalysts are the configuration at C9 as well as the level of saturation at the pendant chain of the bicyclic moiety, found to affect dramatically the performance for a given reaction.1 For instance, Soós reported enantiose-lectivities of up to 94% in the 1,4-addition of nitroalkanes to Michael acceptors using thiourea 690384 as the most suitable for this specific transformation. The methodology was used to accomplish the selective synthesis of (R)-rolipram, an antidepressant agent (Scheme 1).2
Scheme 1: Thiourea organocatalyzed 1,4-addition of nitromethane to α,β-unsaturated N-acylpyrroles and application in the synthesis of (R)-rolipram.
References: (1) McCooey, S.; Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367. (2) Vakulya, B.; Varga, S.; Soós, T. J. Org. Chem. 2008, 73, 3475.
R N
O
R = alkyl, aryl
N
MeO
NH3C
HHN
HN
S
CF3
CF3
10-30 mol%
25 - 50°C, neat
MeNO2
+
R N
OO2N
N
OO2N
MeOO
78%, 93% ee
N
OO2N
54%, 94%ee
N
OO2N
O
81%, 93%ee
N
OO2N
MeO
90%, 93%ee
N
OO2N
Cl
88%, 89%ee
N
OO2N
93%, 94%ee
aq. MeOH
heating
OO2N
MeOO
OCH3 H2/Pd
MeOO
NHO
(R)-rolipram
For a list of cinchona-based catalysts available from Aldrich Chemistry, visit Aldrich.com/cinchona-alkaloids
690384
713228
N
MeO
NH3C
HHN
HN
S
CF3
CF3
N
MeO
NH3C
H NH2
690481
713201
N
MeO
NH2C
HHN
HN
S
CF3
CF3
N
MeO
NH2C
H NH2
.3 HCl .3 HCl
690600
713236
N
MeO
N
H2C
H
H2N
N
MeO
N
H2C
H
NHS
NH
F3C
F3C
.3 HCl
690384
713228
690600
713236
690481
713201
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
7Catalysis
PEPPSI™-IPent: A New and Improved Catalyst for Negishi CouplingPd-Catalyzed cross-coupling reactions are of the utmost importance to chemistry. From the production of pharmaceutical agents to synthetic polymer synthesis, these reactions have proven to be truly versatile for the selective construction of C-C bonds. Within this class of reactions, the coupling of an organozinc nucleophile with a suitable halogenated electrophile, the Negishi reaction, has proven to be particularly useful. Supporting this, the Nobel Prize in chemistry was awarded to Prof. Ei-ichi Negishi, Akira Suzuki, and Richard Heck for their contributions to the field in 2010.
While numerous advances have been made concerning the Negishi reaction, difficulties still remain for the coupling of sterically demanding substrates. To address this issue, efforts have focused on the development of new, more reactive catalysts for cross-coupling. It has been shown that monoligated Pd-N-heterocyclic carbene (Pd-NHC) complexes, with considerable steric bulk around the metal center, are reactive enough to couple even the most sterically demanding substrates, albeit at elevated temperatures. In an attempt to improve this reaction even further, the group of Prof. Michael Organ has developed a new and improved catalyst for cross-coupling at room temperature, Pd-PEPPSI-IPent (Figure 1).
Figure 1: Pd-PEPPSI-IPent.
Building upon their previous work, Organ and coworkers have developed a powerful catalyst for the cross-coupling of a wide range of organozinc reagents (generated in situ) with various sterically demanding aryl electro-philes at room temperature (Table 1).
Table 1: Pd-PEPPSI-IPent catalyzed Negishi cross-coupling.
In addition to simple biaryl systems, Pd-PEPPSI-IPent may also be used to construct an impressive array of heterobiaryl compounds bearing various functional groups and/or congested steric bulk, all in excellent yields under the mildest conditions reported to date (Table 2).
Table 2: Heterobiaryl synthesis with Pd-PEPPSI-IPent.
Further displaying the power of Pd-PEPPSI-IPent for Negishi cross-cou-pling, the Organ group has also shown that this catalyst can effectively couple sterically demanding substrates at temperatures as low as 0°C (Figure 2). This finding solidifies Pd-PEPPSI-IPent as a truly unique and highly active catalyst for Negishi cross-coupling.
MgBr Pd-PEPPSI-IPentZnCl2, RT
ZnX Ar-X Ar
RT
Ar
X = Cl, Br
Yield %
Cl
Product
90
Cl80
Br97
TBSOTBSO
OBnBr
BnO
87
(Met)Ar Pd-PEPPSI-IPentZnCl2, MetAr-X, RT
Ar
X = Cl, Br
Yield %Product
98
61
quant
79
ZnX
NN
NBr
N
NBoc
NBoc
Br
BrS
NNCl
PhN
N
Ph
OEtO2C
Ar-(Met)ArN N
PdCl ClN
Cl
Pd-PEPPSI-IPent732117
Pd-PEPPSI-IPent 732117
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
8
Figure 2: Pd-PEPPSI-IPent catalyzed Negishi coupling at 0°C.
Pd-PEPPSI™ Catalysts for Cross-CouplingWhile Pd-catalyzed cross-coupling reactions have proven to be critically important to the chemical community, one dilemma often encountered by chemists is not knowing which Pd-catalyst will be most effective for their desired application. Few catalysts exhibit activity across a wide range of substrates and reaction conditions. While Pd(PPh3)4 has developed into one of the most general and commonly used catalysts for cross-coupling, this complex often suffers from poor stability upon storage, as well as the need to handle under inert atmosphere. To address this, the group of Prof. Michael Organ has developed Pd-PEPPSI-IPr as a highly effective and versatile catalyst for cross-coupling (Figure 3).
Figure 3: Pd-PEPPSI-IPr structural features.
Pd-PEPPSI-IPr has been shown to conduct a truly wide range of cross-coupling reactions, including Negishi couplings to form sp2-sp2, sp2-sp3, and even sp3-sp3 connections (Figure 4).
Figure 4: Pd-PEPPSI-IPr for cross-coupling.
In addition to Negishi cross-coupling, Pd-PEPPSI-IPr is also useful for Suzuki and Kumada couplings, as well as Buchwald-Hartwig aminations (Figure 5).
Figure 5: Pd-PEPPSI-IPr for Suzuki, Kumada, and Buchwald-Hartwig couplings.
Reference: Kantchev, E.A.B.; O’Brien, C.J.; Organ, M.G. Pd-N-Heterocyclic Carbene (NHC) Catalysts for Cross-Coupling Reactions. Aldrichimica Acta 2006, 39, 97–111.
Pd-PEPPSI Catalysts from Aldrich
MgBrPd-PEPPSI-IPent
ZnCl2, RT
ZnX
0 oC
Cl
MgBrPd-PEPPSI-IPent
ZnCl2, RT
ZnX
0 oC
Cl
90% yield
80% yield
N N
PdCl ClN
Cl
Pd-PEPPSI- IPr669032
Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation
Bulky IPr substituent affects transmetallation and reductive elimination steps
3-Chloropyridyl ligand improves stability and creates a well-defined catalyst structure
Strongly σ-donating NHC ligand binds tightly to Pd-center preventing dissociation in solution and improving overall performance
Pd-PEPPSI-iPr (1 mol %)
60 oC, 2 h+
SBrZnSN
N
Br
Ph NN
Ph89% yield
sp2 - sp2 coupling:
Pd-PEPPSI-iPr (1 mol %)
RT, 2 h+N
98% yield
sp2 - sp3 coupling:
BrZnO
OEt
Cl O
OEtN
Pd-PEPPSI-iPr (1 mol %)
RT, 2 h+
86% yield
sp3 - sp3 coupling:
Br
O
OZnBr
O
O
Suzuki coupling:
Kumada coupling:
Buchwald-Hartwig amination:
N N
PdCl ClN
Cl669032
N N
PdCl ClN
Cl674702
N N
PdCl ClN
Cl692263
l 0.4 CuI
N N
PdCl ClN
Cl
677256
l 2 CuI
N N
PdCl ClN
Cl
732117
669032 674702
677256
692263
732117
Need a MolarMatic™ Measuring Cylindersfor your Acid/Base solutions?
©2011 Sigma-Aldrich Co. All rights reserved. SIGMA-ALDRICH and ALDRICH are registered trademarks of Sigma-Aldrich Biotechnology L.P., an affiliate of Sigma-Aldrich Co. MolarMatic is a trademark of Sigma-Aldrich Biotechnology, L.P., an affiliate of Sigma-Aldrich Co.
Aldrich MolarMatic Measuring Cylinder
Our MolarMatic graduated measuring cylinder allows you to add concentrated acid to the desired molarity line. Simply pour the measured acid into one liter of water, and your 1 M, 2 M, or 3 M solution is prepared.
• No calculations
• No struggling for the correct cylinder
Convenient Dual-Scale Graduated Cylinder• Class A, 350-mL cylinders
• Graduated in 5.0-mL increments; calibrated "to deliver"
• 1 to 3 molar scale on opposite side
• Eliminates repetitive molar calculations and potential errors
• Set contains one of each cylinder in plastic storage case
Acid Type Cat. No.
Acetic acid Z683728
Hydrochloric acid Z683736
Nitric acid Z683744
Sulfuric acid Z683752
Set of four Z683760
Save time. Add Aldrich.Aldrich.com/molarmatic
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10
Me
MeMe MeB(OH)2
BO
N
O OBr
BB1
BO
N
O O
Me
Me
Me Me
Pd(OAc)2, SPhos, K3PO4
23 °C, 78%toluene
1. aq. NaOH, THF, 23 °C
2.
23 °C, 66%
Me
Me
Me Me Me H
OBr
Me
O
H
Pd(OAc)2, SPhos, K3PO4, THF
703478
H3C
H3C
O
O
all-trans-retinal
1
OrganometallicsAaron Thornton, Ph.D.Product [email protected]
The Utility of MIDA BoronatesOver the past three years Aldrich Chemistry has introduced the MIDA boronates as a powerful new class of boronic acid surrogates that can be used for Suzuki-Miyaura cross-coupling reactions. These useful reagents were developed by the group of Prof. Martin Burke at the University of Illinois, and their work has illustrated the utility of MIDA boronates in the context of both methodological studies and the realm of total synthesis. In doing this, the Burke group has shown that the MIDA boronate plat-form possesses a number of advantages over their classical boronic acid and boronate ester counterparts (Figure 1).
Figure 1: The advantages of MIDA boronates.
Due to these unique features and advantages, three distinct applications for the MIDA boronates have been disclosed.
Applications of MIDA Boronates
•Iterative cross-coupling
•Advanced building block synthesis
•Slow-release cross-coupling
Importantly, all three of these applications represent unique opportuni-ties for chemists that could not be accomplished with other organo-boron species prior to these reagents.
Iterative Cross-Coupling with MIDA BoronatesMIDA boronates have proven to be unreactive under classical non-aque-ous cross-coupling conditions. This unique reactivity difference allows for the use of MIDA boronates in iterative cross-coupling sequences. This technique was recently used by the Burke group in their synthesis of all-trans-retinal (Scheme 1). In this synthesis MIDA boronate BB1,
containing both electrophilic (vinyl-halide) and nucleophilic (MIDA boronate) moieties was successfully cross-coupled in an iterative fashion. Because of the enhanced stability of the MIDA boronate moiety, BB1 was efficiently coupled with triene boronic acid 1 in 78% yield. Following this, hydrolysis of the MIDA unit with aqueous NaOH revealed the organo- boron species that was subsequently coupled in a second Suzuki reac-tion, yielding all-trans-retinal in a highly efficient manner.
Scheme 1: Iterative cross-coupling of MIDA boronate BB1 in the synthesis of all-trans-retinal.
MIDA Boronates for Iterative Cross-Coupling
BO
N
O OBrBB1
703478
H3C
O BO
N
O OBu3Sn
704873
H3C
O
BO
N
O O
702269
H3C
O
NBr
BO
N
O O
H3C
O
N
Br
703370
BO
N
OOO
H3C
701092
SBr
BO
N
O O
704997
H3C
O
BHO
OH
BO
N
O O
698156
H3C
OB
O
N
O O
698040
H3C
O
IBr
BB1 703478 704873
702269
704997
703370
698156
701092
698040
RB
O
N
OO
O
H3C
R = (hetero)aryl, alkenyl, alkynyl, alkyl
MIDA Boronates
•Air, moisture and chromatographically stable
•Compatable with a range of common and harsh reagents and reaction conditions
•Solubility in various commonly used organic solvents
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
11Organometallics
BO
N
O OO
O
H
697494
N O
O
Bn
n-Bu2BOTfB
O
N
O OO
OHO
O N
O
BnCH3
O
EtO P(OEt)2
O
NaH, DMF
BO
N
O OO
EtO
O
BO
N
O OO
I
CrCl2, CHI3
H2O2, MeOHEt3N, DCM
THF:dioxane
79%
71%
88%
OH3C
H3C
H3C
H3C
H3C
Advanced Building Block Synthesis Using MIDA BoronatesThe Burke group has shown that a diverse range of reactions can be car-ried out while keeping the MIDA group intact due to its enhanced stabil-ity. For example, asymmetric aldol reactions, Horner-Wadsworth-Emmons and Takai olefinations, as well as a range of other reactions can all be carried out in the presence of the MIDA unit in good yields with excellent selectivity (Scheme 2).
Scheme 2: Advanced building block synthesis with MIDA boronates.
MIDA Boronates for Building Block Synthesis
Slow-Release Cross-Coupling of MIDA BoronatesIn addition to iterative cross-coupling and building block synthesis, MIDA boronates have also been shown to undergo the in situ slow-release of boronic acids under aqueous basic conditions (Scheme 3). Harnessing the power of this phenomenon, boronic acids that are notoriously un-stable can now be effectively utilized when employed as MIDA boronates. The slow-release of sensitive boronic acids can be achieved using mildly basic aqueous K3PO4. This slow-release concept prevents decomposition of the precursor organometallic species and in many cases improves the overall yield of the Suzuki-Miyaura reaction.
Scheme 3: Slow-release of unstable boronic acids from MIDA boronates.
This concept is exemplified by the development of 2-pyridinylboronic acid MIDA ester as a viable 2-pyridinylboron anion equivalent. 2-Pyridinylboronic acids and esters have been developed in the past, but due to their air and moisture sensitivity, cross-coupling with these reagents is often low-yielding and almost always inefficient. Now, via this slow-release methodology, the Suzuki coupling of 2-pyridinylboronic acid MIDA ester with a wide range of aryl- and heteroaryl chlorides is predictable and high-yielding (Scheme 4).
Scheme 4: Suzuki-Miyaura cross-coupling of 2-pyridinylboronic acid MIDA ester.
Sensitive Organo-Boron Species Ideal for Slow-Release Cross-Coupling
To view our complete line of MIDA boronates, visit Aldrich.com/mida
RB
O
N
O OO R B(OH)2
mild aqueous base (e.g. K3PO4) Cl R'
Pd-catalyst
R R'
MIDA-Boronate
H3C
Slow-Release Suzuki Coupling
BO
N
O OON
ClPd2(dba)3, XPhos, K3PO4
DMF/IPA (4:1), 100 °C, 4 h
R
Cu(OAc)2, K2CO3
N R
Entry Cl R Product Isolated Yield (%)
1
2
3
Cl
Cl
CN
N
N
Cl
CN
N
N
N
72
60
79N
N
719390
H3C
O
CH3
O
CH3
BO
N
O OO
H3C
704415
BO
N
O OO
O
H
697494
H3C
BO
N
O OO
721573
H3C
O
BO
N
OOO
H3C
704547
SH
O
BO
N
O OO
698008
H3C
OH
BO
N
O OO
698210
H3C
H
O
704415
704547
697494
698008
721573
698210B
O
N
OOO
H3C
NMeOBO
N
OOO
H3C
N
723053723959
BO
N
O OO
H3C
700908
BO
N
O OO
H3C
702269
BO
N
OOO
H3C
N
719390
H3C
BO
N
OOO
H3C
733539
NBoc
719390
700908
723959
702269
723053
733539
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
12
Building BlocksMark RedlichProduct [email protected]
Iodinated Building Blocks •Ease the purification of coupling reactions 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. Iodinated substrates are often preferred to the brominated analog, due to cleaner reactions. They are also handy precursors for the formation of organolithium, organozinc or organomagnesium reagents. Sigma-Aldrich is pleased to offer these useful building blocks for your research.
New Iodinated Building Blocks
N N
I
714364
O
CH3
HOI
722057
N
I
722170
O
H
H3COI
722278
N Cl
CH3
I
724092
N Cl
ClI
730564
CH3
INO2
730742
N
I
731412
N3
I
779059
N Cl
NH2I
720372
N Cl
II
724084
N
IBr
O
OH
729639
Oxetanes •Oxetanes can improve the pharmokinetic profile and stability of a
target molecule when replacing a gem-dimethyl or a carbonyl unit Oxetanes are the closest homologs to epoxides, but historically have received far less attention than their three-membered-ringed breth-ren. However, oxetanes are receiving increasing attention as attractive modules for drug discovery, largely due to a recent series of reports from Rogers-Evans, Carreira and coworkers. They have shown how oxetanes can perform as surrogates for carbonyl groups,1 how certain proper-ties of a target molecule are improved when an oxetane unit replaces a gem-dimethyl unit2 and also how the use of oxetane-containing scaffolds can be employed as alternatives to unstable 1,3-heteroatom substituted cyclohexanes.3
Furthermore, oxetanes are critical moieties in drug-like and various bio-logically active molecules such as the natural product paclitaxel, or Taxol®, and docetaxel, its synthetic analog (Figure 1).4 Other oxetane-containing natural products such as Merrilactone A (Figure 2)5 and the β-amino acid oxetin (Figure 3) have demonstrated therapeutic potential.6 Brubaker and coworkers have also recently demonstrated the use of oxetan-3-tert-butylsulfinimine, L500429 as a common synthetic intermediate for the preparation of 3-substituted-3-aminooxetanes (Scheme 1).7
Figure 1: Paclitaxel (Taxol®) and Docetaxel
Figure 2: Merrilactone A
Figure 3: β-Amino Acid Oxetin
OHOAc
OHO
OHObz
O
O
OHPh
R2NHR1O
Paclitaxel: R1 = Ac, R2 = BzDocetaxel: R1 = H, R2 = Boc
OO
O
O
O
HO
O
NH2O
OH
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
13Building Blocks
N NH
N
NH2
729469
N
S
Cl
728780
O
N
N
Cl
Cl
Cl
728772
H
O
CH
725021
S
BrO
OH
732214
S
Br CN
731315
NBoc
731293
NH
N
CH3Br
730769
F
F
FBr
730475
N
N
CF3
730025
F
BrF
F
729973
For a complete list of available oxetanes, visit Aldrich.com/oxetane
Other New Building Blocks
O
O CH3
O
L500046
O
NS
t-Bu
O
L500429
HN
O
HOOH
O
O• ½
L500496
NH
O
L500534
New Oxetanes
For a comprehensive list of Building Blocks, visit Aldrich.com/bb
References: (1) Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47, 4512. (2) (a) Wuitschik, G. et al. Angew. Chem. Int. Ed. 2006, 45, 7736. (b) Wuitschik, G. et al. J. Med. Chem. 2010, 53, 3227. (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. (7) Hamzik, P. J.; Brubaker, J. D. Org. Lett. 2010, 12, 1116.
Other New Building Blocks Cont'd
BrNH2
O
OH
724920
S
NH2
H2N
724904
OOH
Br
724882
ON
Br
724637
H2C C NH
Boc
724513
N
S Cl
Cl
H
O
724300
NN
Br
O
723940
NH
N
Br
723924
OH
CH3
Br
722480
Br
F
F
722472
O
Br
722456
NOH
Br
722049
NHH3CO
O
OH
722014
S
Br
H
O
716553
OH
O
Br OH
716421
O
O F
F
Br
714542
NN
SH3C Br
711381
725005
NH
N
H2N
O
NS
t-Bu
O
R-Li
O
RHN
SO
t-Bu
62 - 98% O
OS+
MeMe
CH2-
83%N
SO
t-Bu Nu
O
HN
SO
t-Bu
70 - 98%
Nu
L500429
O
NS
t-Bu
O
Scheme 1: Synthesis of Substituted 3-Aminooxetanes
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
14
Synthetic ReagentsTroy Ryba, Ph.D.Product [email protected]
Ferrate (VI) Chemistry and Application Summary: A New and Novel Oxidant from Ferratec, LLC*•One of the strongest known oxidants
•Green oxidant
•Cost-effective, small scale and large
Although discovered in the 1700s, potassium ferrate (VI) K2FeO4 (723835) has largely remained an academic curiosity due to the absence of a scalable production process for stable, high purity, chlorine-free, ferrate (VI) salts. However, a commercial process now exists to enable efficient production for specialty and niche applications.
Ferrate is not only more active than conventional commodity disinfec-tants such as chlorine, permanganate, ozone, monopersulfate, chromic acid and hydrogen peroxide, but it also circumvents the hazardous side products of these chemistries.
* We would like to acknowledge Ferratec, LLC for providing this article.
Ferrate Thermodynamic Oxidizing PowerFerrate has one of the highest standard reduction potentials known, 0.7–2.2 volts. As with many oxidants, there is a pH dependence to the observed standard half-cell potential (E°) values of ferrate (VI) due to a fundamental change in the overall chemical reactions involved. Reduction potential of oxo ions are lowest at high pHs, and greatest at low pHs. For ferrate (VI), this pH dependence is understood using the following reactions:
Basic SolutionFeO4
= + 3e- + 3H2O = 5 OH- + FeOOH E° = 0.77 V
Acid Solution (pH 1.7–7.0)FeO4
= + 3e- + 5H+ = 2 H2O + FeOOH E° ~ 1 V
Acid Solution (pH <1.7) FeO4
= + 3e- + 8H+ = 4 H2O + Fe3+ E° = 2.2
At neutral pH values the intermediate protonated species HFeO4- exists
and the reduction potential is about one volt (see below). FeOOH precipitate due to the exceptionally broad pH window for this highly insoluble solid (> pH 1.7 to > 10% NaOH) is a valuable trait for water purification. Therefore, neutral and lower pH values can be used to increase the kinetic and thermodynamic aggressiveness of ferrate (VI) for oxidation and disinfection, while maintaining excellent coagulant properties of the FeOOH product.
In line with the well-established reactivity of oxo ions in general, the protonation of the ferrate (VI) ion strongly enhances its reactivity.
FeO4= + H+ = HFeO4
- pKa1 = 7.8
HFeO4- + H+ = H2FeO4 pKa2 = 3.2
Potassium Ferrate (723835) is also an extremely “green” chemical. When dissolved, K2FeO4 completely converts to innocuous minerals: potassium bicarbonate, iron flocs & rust (Fe2O3), and oxygen. Furthermore, the FeOOH flocs collected from the water purification or chemical production process are not toxic. The large body of experience of FeOOH/Fe2O3-encapsulated contaminants (such as toxic metal ions, phosphate, arsenate, biological cell mass, etc.) indicates that such contaminants are not leachable by the EPA’s TCLP test.
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
15Synthetic Reagents
Some Applications for Potassium Ferrate•Water Treatment — provides acid neutralization capacity, coagulation
and flocculation, precipitation of P and As, disinfection, clarification, taste and odor removal, replenishment of DO, reduction in TOC, BOD, COD, and trace toxic metal ion removal. Its disinfection range includes algae, protozoans, viruses, and bacteria.
• Soil remediation (heavy metals, organics)
• Disinfection of medical equipment
• Sanitization of food
•Sorbent for odor control (phenolics, mercaptans, hydrogen sulfide, sulfur dioxide, aldehydes, rancid acids, etc.)
•Surface finishing of metals for corrosion protection, especially iron, aluminum, aluminum alloys, stainless steels, and zinc
• Chemical synthesis oxidation reagents
• Chemical and biological warfare agent decontamination
•Diesel and military fuel desulfurization. Achieves > 99% removal of total S and even removes the recalcitrant hindered alkylbenzothiophenes.
Comparison of Ferrate(VI) with other Disinfection Systems
Disinfection System
Toxic Gas? Biocidal Activity Against Corrosive?
Forms DBPs
Reduces TOCs
Can Promote
Distribution Biofilm
Formation?
Provides Coagulation
and Flocculation?
Provides Easily
Contolled Residual
Disinfectant?
Can Form
Odors?UV Light
Sensitive?
Can be Applied During
Clarification?
Oxidative Strength
(Disinfection Power)
Very Sensitive to Feed Water
Quality
Bacteria?Pathogenic Protozoans? Viruses?
Cl2/NaOCl/ Ca(OCl)2
YES YES NO — YES Yes (incl. THMs and
HAAs)
YES NO NO DIFFICULT Yes — NO HIGH YES
NH2Cl YES WEAK NO — YES Yes (incl. NDMA)
— YES NO YES YES, (NHCl2, NCl3)
— NO LOWEST —
ClO2 YES — SOMETIMES — YES Yes (incl. ClO2
- & ClO3
-)
— NO NO DIFFICULT — YES NO LOW —
O3 YES YES YES — YES Yes (incl. Bromate
and bromoform
THM in feed waters
with Br-)
YES NO NO NO — — NO VERY HIGH —
UV (254nm)
NO YES YES — NO — — NO NO NA — NA NO — YES
Ferrate(VI) NO YES YES YES NO None known (no THMs and
HAAs. Tests with Br- still
needed)
YES NO YES NA NO — YES VERY HIGH NO
•Cathodic material for batteries. Ferrate(VI) is a 3 or even 4 electron/mole donor. Depending on other battery components, it may be possible to use ferrate(VI) to produce a primary or secondary battery that can be disposed of as a nonhazardous waste. The very high and tunable half cell potential of ferrate(VI) reduction appears to offer the opportunity of new “super iron” battery technology.
Broad Spectrum and Potent Antimicrobial ActivityLaboratory test results illustrating the disinfection of B. anthracis While the mechanisms for biocidal action by ferrate have not yet been extensively studied, test data show ferrate (VI) ion is a promising broad spectrum biocide: at 25 ppm ferrate(VI) ion, Cryptosporidium spores are disintegrated into fragments with at least a log 4 reduction in viable spores; 1 ppm is effective against pathogenic microorganisms such as E. Coli, total fecal Coli forms and others.
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
16
Aromatic Azides: Synthesis in a Microstructured Continuous Flow System•Microreactors improve reaction mixing, heat exchange, and safety
•Solvated azides improve reaction safety Since the seminal work of Peter Griess in the 19th century,1,2 organic azides, thanks to their intriguing nature, attracted the interest of various chemists over the years.3 Today this kind of compound has found applications in a variety of fields.4-9 Organic azides were found to be involved in a number of processes for the synthesis of active compounds10,11 (Scheme 1) and many of these compounds are available in the Aldrich Chemistry portfolio.12
Scheme 1: Solid phase, microreaction-assisted synthesis of rac-oxomaritidine.11
The process (Scheme 2) involves a Sandmeyer reaction on an aromatic amine compound, followed by treatment of the resulting diazonium salt intermediate with an aqueous solution of sodium azide to produce the desired aromatic azide in high yields.
Scheme 2: General method for the synthesis of aromatic azides.
To overcome the lack of aromatic azide products on the chemistry mar-ket, Aldrich Chemistry has developed a safe, robust and universal method for the synthesis of aromatic azides using microreaction technologies (Scheme 3).
Continuous flow microreactors have various advantages over larger scale batch processes, especially for the synthesis of highly reactive com-pounds such as the organic azides.
Green ChemistryPietro Butti, Ph.D.Product [email protected]
Scheme 3: Reaction equipment set-up for the synthesis of the aromatic azides.
•High surface-to-volume ratio and the absence of heat and mass transport limitations.
•Opportunity to directly transpose reaction conditions from a small scale to a large scale process.
•Closed system combined with small hold-up volumes offers an intrinsically safe environment for chemicals prone to explosive decomposition.12
Using the Microreactor Explorer Kit (19979), all unstable compounds are kept in solution during the entire process, preventing accumulation of labile intermediates or products.
Applying the concept of flow chemistry, the safe preparation of a variety of high purity organic azides has been achieved.
At Aldrich Chemistry, we are committed to the safety of our customers. Therefore, all compounds are offered as a convenient and safe 0.25-0.5M solution in tert-butyl methyl ether.
For a complete list of organic azides available from Aldrich Chemistry, visit Aldrich.com
Microreactorand RTU
Mixing Unit
1
Mixing Unit
2
ExtractionUnit
NH3Cl
RNaNO2
(aq.)(aq.)
N3
R
OrganicSolvent NaN3(aq.)
Org. Phase
H2O phase
NH2 N2Cl N3NaNO2(aq.)HCl (aq.) NaN3 (aq.)
R- N2
RR
N3
HO
O
OMeMeO
Solid Phase Chemistry
+N
O
MeO
MeOH
Microreaction Technology
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
17
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
1
To discover Microreactor Technology & Flow Chemistry
Microreactor Explorer Kit
19979-1KT
Microreactor Explorer Kit
Our all-in-one solution allows you to explore innovative newtechnologies right away at a highly attractive price:
• Improve product profiles, purities and yields of your products
• Perform scale-independent synthesis from mg to kg in a single day
• Control highly exothermic reactions
• Handle unstable or hazardous materials (even explosives) safely
• Minimize the time frame for process development
Improve safety and cost. Add Aldrich.
Aldrich.com/mrt
Green Chemistry
ortho-Substituted aromatic azides
meta-Substituted aromatic azides
para-Substituted aromatic azides
References: (1) Griess P. Philos. Trans. R. Soc. London 1864, 13, 377. (2) Griess, P. Justus Liebigs Ann. Chem. 1865, 135, 131. (3) Scriven E. F. V.; Turnbull K. Chem. Rev. 1988, 88, 297–368. (4) Bräse, S. Gil, C. Knepper K., Zimmermann V. Angewandte Chemie International Edition 2005, 44, 5188–5240. (5) Scriven, E.F.V.;Turnbull K. Chem. Rev. 1988, 88, 297–368. (6) Baskin, J.M.; Bertozzi, C.R. QSAR Comb.Sci. 2007, 26, 1211–1219. (7) Meldal, M.; Tornøe, C.W. Chem.Rev., 2008, 108, 2952–3015. (8) Wamhoffa, H.; Richardta, G.; Stöbena, S. Adv. Heterocycl. Chem. 1995, 64, 159–249. (9) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G., deLosSantos J.M. Tetrahedron 2007, 63, 523–575. (10) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–1137. (11) Baxendale, I. R.; Deeley, J.; Griffiths-Jones C. M.; Ley S. V. Saaby, S.; Tranmer G. K. Chem. Commun. 2006, 2566–2568. (12) (a) Junkers, M. Sigma-Aldrich ChemFiles 2008, 8, 2. (b) Delville, M.M.E.; Nieuwland P.J.; Janssena, P.; Koch, K. vanHesta J.C.M., Rutjesa F.P.J.T. Chem. Eng. J. 2010, doi:10.1016/j.cej.2010.08.087.
N3
F
779814
N3
Cl
779938
N3
OCH3
778729
N3
I
778516
N3
CH3
778613
779814 779938
778613
778516
778729
FN3
778842
N3Cl
778958
N3I
779059
N3CH3
779164
N3OCH3
779261
N3CO2H
727458
778842
779164
778958
779261
779059
727458
N3
727490
N3
F
779253
N3
Cl
727482
N3
I
779482
N3
CH3
727466
N3
OCH3
727431
N3
Br
779377
N3
OCF3
779709
N3
CO2CH3
779598
727490
779482
779377
779253
727466
779709
727482
727431
779598
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
18
Stable IsotopesLeslie Patterson, Ph.D.Product [email protected]
Stable Isotope Labeled Reagents from ISOTEC®The labeling of organic molecules with stable isotopes, such as 13C, D, 15N, and 18O, is important to many fields including metabolism, proteomics and ADME. To aid in the synthesis of such molecules, The Next Generation of Labeled Synthons has been developed. This line of products contains labeled reagents which were designed to merge seamlessly into a variety of synthetic routes, providing quick and efficient access to stable isotope labeled compounds.
Ethyl N,N-dimethyloxamatesα-Dicarbonyl containing compounds are extremely important in terms of biological relevance as well as synthetic utility.1 Due to their impor-tance, the synthesis of stable isotope labeled α-dicarbonyl compounds is of great value. Synthesizing these types of compounds has been done routinely using labeled diethyl oxalate,2 however this chemistry provides only symmetrically labeled products. To obtain compounds possessing carbonyls differentiated by a 13C label, the challenge greatly increases.3
To address this deficiency in the methodology of stable isotope labeling, the 13C labeled ethyl N,N-dimethyloxamates were designed.4 These re-agents are offered in three different labeling patterns and take advantage of the clear reactivity differences between the ester and amide carbonyls which results in regiospecifically 13C labeled products.
Scheme 1: Pyruvic and Acrylic Acid Syntheses
The utility of these reagents is evident in the efficient, straightforward syntheses of pyruvic and acrylic acids (Scheme 1). One synthetic route and two synthetic steps impressively provide access to these compounds in high yield and isotope enrichment.
New Ethyl N,N-dimethyloxamates
Vinyl Sulfides, Sulfoxides and SulfonesOrganosulfur compounds play an important role in organic chemistry. Due to the multiple strategies available to remove sulfur,5 combined with its presence in biologically relevant molecules,6 many applications benefit from the unique reactivity organosulfur compounds possess.
Vinyl organosulfur compounds are of particular synthetic utility due to the broad range of reactions and conditions with which they are compatible. These reagents are well suited for use as Michael acceptors,7 in various cylclo-addition reactions8 and in Heck vinylations (Scheme 2).9
Scheme 2: Vinyl Organosulfur Capabilities7b,8a,c,9
13C labeled phenyl vinyl sulfide, sulfoxide and sulfone are each offered in three labeling patterns.4 The natural abundance versions of these reagents and their derivatives have seen success in numerous projects including total syntheses of natural products10 and preparation of biologi-cally relevant scaffolds like alkaloids and quinolines.11 With the available literature precedence, as well as convenient labeling patterns, these reagents will fit into any stable isotope labeling project.
H3CN 13C
O
CH3
O
O
730246
CD3MgI
CD3MgI (2eq)
H3CN 13C
CD3
CH3
O
O
H3CN 13C
CD3
CH3
O
OHCD3
HO 13CCD3
O
O
HO 13C
O
CD2
CD3
Pyruvic Acid
Acrylic Acid
H+
H+
S
On
Ph
BrS
On
Ph
O
OCH3
OCH3
O
OCH3OCH3
PhS
N Ph
O
H3CO
NH
SO2Ph
Ph
O
H3CO
Ph
CN
O
OEt
SPh
OO
∗∗EtO
CNPh
O
n=0,1,2
H3CN
13C O
CH3
O
O
H3CN 13C
O
CH3
O
O
H3CN
13C13C
O
CH3
O
O
716065 730246 716057716065 730246 716057
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
19
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
1
ISOTEC® Stable Isotopes has a variety of syntheticreagents ideal for any labeling applicationCommon Laboratory Reagents Acetic acid-13C2 (282022) Benzene-13C6 (423637) Bromoacetic acid-13C2 (283835) Diethyl malonate-2-13C (281859) Ethyl bromoacetate -2-13C (293172) Hydrazine-15N2 monohydrate (492787) Iodomethane-d3 (176036) Methyl-d3-magnesium iodide (293091) Potassium cyanide-13C,15N (490539)
Derivatizing Reagents Acetic anhydride-13C4 (487821) Phenyl-d5 isocyanate (493244) 2-Nitrobenzenesulfenyl chloride-13C6
(640492)
Reducing Reagents Deuterium gas (617474) Diborane-d6 (463140) LiAlD4 (193100) NaBD3CN (190020) NaBD4 (205591)
For a complete listing of stable isotope products, visit Aldrich.com/isotec
For more information please contact:
ISOTEC Stable Isotopes Technical Service
Phone: (800) 448-9760 (US and Canada) (937) 859-1808
Fax: (937) 859-4878
Email: [email protected]
©2011 Sigma-Aldrich Co. All rights reserved. ISOTECH and ALDRICH are registered trademarks of Sigma-Aldrich Biotechnology L.P.,an affiliate of Sigma-Aldrich Co.
Stable Isotopes
New Vinyl Sulfides, Sulfoxides and Sulfones
References: (1) Neveux, M.; Bruneau, C.; Lécolier, S.; Dixneuf, P H. Tetrahedron 1993, 49, 2629. (2) a) Dischino, D.D.; Lee, C.W.; Belema, M.; Zusi, C. J. Label. Cmpds. Radiopharm. 2003, 46, 159. b) Watanabe, M.; Tada, N.; Itoh, K.; Hayashi, N. J. Label. Cmpds. Radiopharm. 1987, 24, 1429. c) Nicolas, C.; Verny, M.; Maurizis, J.-C.; Payard, M.; Faurie, M. J. Label. Cmpds. Radio-pharm. 1986, 23, 837. (3) Yuan, S.-S.; Ajami, A. M. J. Label. Cmpds. Radiopharm. 1984, 21, 735.
(4) Licensed from Highlands Stable Isotopes Corp. (5) a) Beye, G.E.; Ward, D. E. J. Am. Chem. Soc. 2010, 132, 7210. b) Pellissier, H. Tetrahedron 2006, 62, 5559. (6) Capela, R.; Oliveira, R.; Gonçalves, L.M.; Domingos, A; Gut, J.; Rosenthal, P.J.; Lopes, F.; Moreira, R. Biorg. Med. Chem. Lett. 2009, 19, 3229. (7) a) de la Pradilla, R.F.; Tortosa, M.; Lwoff, N.; del Águila, M.A.; Viso, A. J. Org. Chem. 2008, 73, 6716. b) Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4, 2097. (8) a) Gao, S.-Y.; Chittimalla, S.K.; Chuang, G.J.; Liao, C.-C. J. Org. Chem. 2009, 74, 1632. b) Avenoza, A.; Busto, J.H.; Mata, L.; Peregrina, J.M.; Pérez-Fernández, M. Synthesis 2008, 5, 743. c) Llamas, T.; Arrayás, R.G.; Carretero, J.C. Org. Lett. 2006, 8, 1795. (9) Battace, A.; Zair, T.; Doucet, H.; Santelli, M. Synthesis 2006, 20, 3495. (10) Prilezhaeva, E.N. Rus. Chem. Rev. 2000, 69, 367. (11) a) Kouznetsov, V.V. Tetrahedron 2009, 65, 2721. b) Pearson, W.H.; Lee, I.Y.; Mi, Y.; Stoy, P. J. Org. Chem. 2004, 69, 9109.
For more information on these products, visit Aldrich.com/sinext
or contact:
Stable Isotope Technical ServicePhone: (937) 859-1808 (800) 448-9760 (US and Canada) Fax: (937) 859-4878 E-mail: [email protected]
PhS
13C PhS
13C13CH2
PhS 13CH2
PhS
13C
O
PhS 13CH2
O
PhS
13C13CH2
O
PhS
13C
O O
PhS 13CH2
O O
PhS
13C13CH2
O O
715352715379715360
715891715883 715948
715875 716189715867
715360
715883
715875
715379
715948
715867
715352
715891
716189
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit Aldrich.com/chemicalsynthesis.Aldrich.com
20
Stockroom ReagentsTodd HalkoskiMarket Segment Manger Solvents and [email protected]
Sigma-Aldrich® is a leading global supplier and manufacturer of high quality, stockroom and essential research products We specialize in providing the most comprehensive product range and widest selection of purity grades to fulfill your particular application needs.
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The Sigma-Aldrich Pressure-Temperature Nomograph allows you to quickly and easily estimate boiling points at various pressures. Interactive controls simplify calculations to improve the efficiency of your distillation or evaporation process.
Pressure Conversion Tab: Use the built-in Pressure Conversion Calculator to convert among five units of pressure using either numeric values or scientific notation.
Temperature Conversion Tab: Quickly calculate temperature conversions without leaving the Nomograph.
Printable: Need a hard copy to take with you? Simply right-click and select 'print'.
Aldrich.com/nomograph
Need a Molarity Calculator for your Acid/Base solutions?
Aldrich Normality and Molarity Calculator
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22
Labware NotesPaula FreemantleProduct [email protected]
PureSolv™ Micro Solvent Purification SystemEasy Access to Freshly Prepared Anhydrous SolventsMany organic and organometallic reactions require solvents that are free of water and oxygen. Classically, anhydrous solvents are prepared in the laboratory by refluxing the solvent in the presence of an active metal. This is an intrinsically hazardous operation.
The dangers of this method of solvent purification led Professor Robert Grubbs to investigate alternative methods. In collaboration with Dow, Grubbs published a method to remove water from organic solvents using activated alumina. Reference: Organometallics 1996, 15, 1558.
This approach uses dry nitrogen or argon to push solvent at ambient temperature through a column containing the drying agent. Oxygen is removed by bubbling inert gas through the solvent reservoir prior to pushing it through the drying column.
PureSolv Micro is a bench scale, self-contained system that permits the easy dis-pensing of small quan-tities of dry solvent at the turn of a valve. These systems are engineered for safety because they operate at very low pressure, require no electricity, and are bonded and grounded to remove hazards associated with electrostatic discharge.
How PureSolv Micro Works
1. Fill the stainless steel solvent storage reservoir with 4L of HPLC-grade raw solvent.
2. Degas the solvent by connecting the nitrogen line to the reservoir.3. Pressurize the solvent reservoir to push solvent through the drying column. 4. Dry solvent is stored inside the drying column ready for immediate use.5. Attach a collection flask to the dispensing joint.6. Degas the collection flask using vacuum and inert gas cycling.7. Turn the dispense valve to allow solvent to flow into the collection flask.8. Refill the flask with inert gas.9. Your collected solvent is now ready to use.
Flask Joint 24/40 Z568031 with activated PureSolv media column Z568058 with activated molecular sieves Z568023 with activated Alumina column Flask Joint 29/32 Z683981 with activated PureSolv media column Z684007 with activated molecular sieves Z683973 with activated Alumina column
For more information about these products or to place an order, visit Aldrich.com/puresolv
7 Micron Filter
Solvent Dispense Line
Pressure Flex Quick DisconnectLine for Reservoir and Sparging
Quick DisconnectSolvent Flex Line
Solvent Reservoir
Solvent PurifyingColumn
Metering Valve
Swagelok® Value Controls:Dispense Vacuum Gas Purge
to Regulated Gas Supply
to Vacuum Source
Pressure Regulator w/Pressure Relief Valve
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
23Labware Notes
Wrap-It-Ties
One-piece nylon fasteners are self-locking fasteners excellent for:
•Securing rubber septa to glass joints
•Attaching tubing to hose barbs
•Closing plastic bags or drum liners
Simply position the tie around the septum, tubing, or bag, and push the narrow end of the fastener through the locking mechanism until finger tight. Complete the operation by clinching the tie with an installing tool (shown in photo). Ties are easily removed with a slide cutter or similar tool.
Wrap-It-Ties Z256323 Wrap-It Tie set Z105953 Wrap-It Tie L 4 in. Z105961 Wrap-It Tie L 5.6 in. Z256331 Wrap-It Tie L 7 1/2 in. Z256307 Wrap-It Tie tool heavy-duty version Z564850 Wrap-It Tie tool economy version
Aldrich® solvent storage/dispensing flask, septum-inlet, with PTFE inlet valve Designed for use with PureSolv Micro systems. PTFE inlet valve may be closed after filling to isolate dry solvent and to remove flask from PureSolv system and take to different location for use. 100 mL capacity. Use septum Z565695 or Z565679.
Z568538 24/40 Joint Z684457 29/32 joint
For a complete listing of air-sensitive chemicals and solvents and Labware for handling them, visit the Air-Sensitive Products Guide on line at Aldrich.com/airchem
News and Innovation
XploSens PS peroxide detection test stripsZ683108 50 test strips
Xpell™ indicating pellets for peroxides prevention
•Neutralizes peroxides as they form
•Inert to solvents and non-contaminating
•Distinct blue color indicates the absence of peroxide
•No special disposal requirements
•Not for use with THF
Z683094 80 grams treats up to 8 L of solvent
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©2011 Sigma-Aldrich Co. All rights reserved. SIGMA, SAFC, SIGMA-ALDRICH, ALDRICH, SUPELCO, ISOTEC, and TRACESELECT are registered trademarks of Sigma-Aldrich Biotechnology, L.P., an affiliate of Sigma-Aldrich Co. MolarMatic is a trademark of Sigma-Aldrich Biotechnology L.P., an affiliate of Sigma-Aldrich Co. PEPPSI is a trademark of Total Synthesis Ltd. Journal Citation Reports is a registered trademark of Thomson Reuters (Scientific) Inc. Taxol is a registered trademark of Bristol-Myers Squibb Company. iPhone and iPad are registered trademarks of Apple Inc. Supply Rewards is a trademark of Supply Rewards. PureSolv is a trademark of Innovative Technology, Inc. XPell is a trademark of XploSafe LLC. Sigma brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product(s) for their particular use. Additional terms and conditions may apply. Please see reverse side of the invoice or packing slip.
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