15058708 Chemfiles Vol 9 No 2 Catalysis

Catalysis

Vol. 9, No. 2

(AtaPhos)2PdCl2, a non-proprietary catalyst for Suzuki-Miyaura cross-coupling reactions

Features include:

Asymmetric Synthesis

Metal and Phosphine Mediated Transformations

N-Heterocyclic Carbenes

Metal Organic Frameworks (MOFs)

Catalytic Deprotection with DEPRO™ Catalyst Kit

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Intr

oduc

tion

Vol. 9 No. 2

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About Our Cover

Josephine NakhlaProduct Manager

IntroductionThe development of efficient and versatile catalysts for use in asymmetric synthesis and cross-coupling has allowed chemists to achieve unrivaled and unprecedented transformations in excellent yields and selectivities and has essentially transformed the way complex molecule synthesis is approached. The first part of this ChemFile highlights our newest catalysts and their applications in asymmetric synthesis and cross-coupling. Our recently introduced N-heterocyclic carbenes are also discussed, with references to their application in a plethora of transformations. The second part of this ChemFile details our Metal Organic Frameworks (MOFs) product offering and their applications (for example, Heck reactions), as well as the new DEPRO™ Catalyst Kit for catalytic deprotection.

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The cover graphic represents the three-dimensional structure of (AtaPhos)2PdCl2, a non-proprietary catalyst for Suzuki-Miyaura cross-coupling reactions, which has been demonstrated to be broadly effective in historically challenging couplings. The palladium is represented in red, the phosphines in yellow, the chlorides in blue, and the nitrogen in green. The hydrogen atoms have been omitted for clarity.

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Asym

metric Synthesis

Asymmetric SynthesisAsymmetric Epoxidation of Allylic AlcoholsThe catalytic asymmetric epoxidation of olefins has become the reaction of choice to generate diverse chiral building blocks used in the synthesis of natural products and biologically active molecules. The development of catalysts based on bis(hydroxamic acid) ligands for the vanadium-catalyzed asymmetric epoxidation of allylic alcohols was based on a desire to reduce the deceleration effect observed in some cases in related epoxidations with hydroxamic acid ligands. The deceleration observed was predicted to be a result of the formation of inactive species, which were formed from the binding of more than one ligand to the metal. It was predicted that since the bidentate ligand (bis(hydroxamic acid)) would be chelating to the metal, this deceleration effect could be resolved. Additionally, it was hypothesized that a larger R group would prevent the carbonyl oxygen coordination to the metal by favoring a conformation in which the carbonyl group was directed towards the cyclohexane (Figure 1). Thus, an ideal catalyst system was designed via control of the coordination number as well as the steric environment.

The use of bis(hydroxamic acid) based ligands in combination with VO(O-iPr)3 proved effective in the efficient asymmetric epoxidation of various allylic alcohols (Scheme 1). Using only 1 mol% of the catalyst, Yamamoto and co-workers demonstrated a variety of allylic alcohols could be converted to the enantiopure epoxides with excellent enantioselectivity.

This methodology was also applied in the kinetic resolution of allylic alcohol 1, which resulted in high enantioselectivities of the epoxy alcohol as well as the allylic alcohol (Scheme 2).1

Asymmetric Epoxidation of Homoallylic AlcoholsWhile there are various efficient catalytic systems for the asymmetric epoxidation of allylic alcohols, the extension to homoallylic alcohols had not been demonstrated. While the catalytic system reported above allowed for the desired transformations, the enantioselectivities achieved were a major limitation. After tuning the ligand, Zhang and Yamamoto discovered that the (2,4,6-triethyl)-substituted biphenyl bis(hydroxamic acid) ligand (2) provided the desired epoxide products in excellent yields and enantioselectivities (Scheme 3). In addition, the kinetic resolution of substrate 3 was facilitated by the same catalyst system to afford excellent enantioselectivities of both the chiral homoallylic alcohol as well as the epoxidation product (Scheme 4).2

N

NOHOH

O

O R

R

Figure 1

N

NOO

O

O

Ph

Ph

Ph

Ph

OHR1R2 (1 mol%)

TBHP (70% aq), CH2Cl2OHR1

R2

O

OHPhPh

O

91%, 97% ee

OHPhCH3

O

84%, 97% ee

OHHPh

O

73%, 95% ee

OHO

79%, 95% ee

V (OiPr)

-20 °C, 48 h

(0 °C)

Scheme 1

N

NOO

O

O

Ph

Ph

Ph

Ph

OH(1 mol%)

TBHP (70% aq), CH2Cl2

V (OiPr)

Ph 0 °C

racemic

OH

Ph

95% ee

O

Ph

OH+

1 51% conversion 93% ee

Scheme 2

N

NOHOH

O

O

R2R3

rt, 24 h

85%, 93% ee (from trans olefin)

OHR1

VO(O-iPr)3 (1 mol%)

R

R

R =

Et

Et

Et

Ligand (2 mol%)

CHP (1.5 eq), toluene R2R3

OHR1O

92%, 98% ee (from trans olefin)

90%, 97% ee (from cis olefin)

90%, 99% ee (from cis olefin)

Ligand =

2

O

n-C2H5 OH

O

n-C6H13 OH

O

n-C3H7 OH

O

n-C5H11 OH

Scheme 3

HO

rt, 30 h

VO(O-iPr)3 (0.5 mol%)Ligand 2 (1 mol%)

CHP (0.7 eq), toluene

3

RHO

RHO

R

O+

R = C2H595% ee, 51% yield




Scheme 4

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Asy

mm

etric

Syn

thes

is

Cl

CH3

OCH3

OH

Cl

(0.5 mol%)

IPA, KOHrt, 19 h

95%, 93% ee

NH2

NSO2

RuCl

4

Scheme 5

N

CH3

H3CO

H3CO

NH

CH3

H3CO

H3CO4 (0.4 mol%)

HCO2H-Et3N (5:2), CH3CN28 °C, 3 h

>99%, 95% ee

Scheme 6

4 (0.5 mol%)

HCO2H-Et3N (5:2), DMF28 °C, 5 h

NH

N

CH3 NH

NH

CH3

86%, 97% ee

Scheme 7

4 (0.5 mol%)

IPA, 28 °C, 20 h

>99%, 97% ee

n-C5H11

OH

98%, 99% ee

CH3

O OH

CH3

(H3C)3Sin-C5H11

O

(H3C)3Si

4 (0.5 mol%)

IPA, 28 °C, 15 h

Scheme 8

R

O

(S,S)-DPEN (0.4 mol%)

H2 (15 atm), KOH (1.0 mol%), IPArt, 4 h

R

OH

Ketoneentry ee (%)

4

3

2

1

5

O

O

O

O

O

99

98

92

91

90

Product

OH

OH

OH

OH

OH

O

PPh2

PPh2

RuCl

Cl DMFn

(0.4 mol%)

Table 1

Asymmetric Transfer HydrogenationThe use of transfer hydrogenation to reduce alkenes, carboxyl groups, ketones, or imines has become very popular. Hashiguchi et al. reported the asymmetric transfer hydrogenation of ketones using a catalyst system comprised of ruthenium complexed with a chiral diamine ligand (RuCl(p-cymene)[(S,S)-Ts-DPEN], Scheme 5).3 Subsequently, this methodology was extended to include transfer hydrogenation of imines with low catalyst loadings, good yields, and excellent enantioselectivities of the desired products observed (Schemes 6 and 7). A variety of imines were subjected to these reaction conditions, with slight variations in the catalyst-ligand composition and/or solvent, leading to excellent yields and enantioselectivities of the functionalized amine heterocycles.4

Matsumura and co-workers also accomplished the asymmetric transfer hydrogenation of α,β-acetylenic ketones using the RuCl(p-cymene)[(R,R)-Ts-DPEN] catalyst system. As shown in Scheme 8, the reduction to the propargylic alcohols occurs selectively without any competitive reaction with the alkynes.5

Asymmetric Ketone HydrogenationMikami and co-workers reported an asymmetric ketone hydrogenation that utilizes an achiral benzophenone ligand (2,2’-bis(diphenylphosphino)benzophenone, DPBP) chelated to a ruthenium catalyst, followed by addition of (1S,2S)-(-)1,2-diphenylethylenediamine (S,S-DPEN). The levels of enantioselectivity observed with the benzophenone-based catalyst are superior to those observed with BINAP-based catalytic systems. When the hydrogenation of 1’-acetonaphthone was examined with 2,2’-bis(diphenylphosphino)benzhydrol as the ligand in place of benzophenone, the enantioselectivity observed was lower than that observed with 2,2’-bis(diphenylphosphino)benzophenone) (Table 1).6

References: (1) Zhang, W. et al. Angew. Chem., Int. Ed. 2005, 44, 4389. (2) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286. (3) Hashiguchi, S. et al. J. Am. Chem. Soc. 1995, 117, 7562. (4) Uematsu, N. et al. J. Am. Chem. Soc. 1996, 118, 4916. (5) Matsumura, K. et al. J. Am. Chem. Soc. 1997, 119, 8738. (6) Mikami, K. et al. Org. Lett. 2006, 8, 1517.

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Asym

metric Synthesis

(1R,2R)-N,N′-Dihydroxy-N,N′-bis(diphenyl acetyl)-1,2- 8

cyclo hexane di amine, 97%(1R,2R)-N,N′-Dihydroxy-N,N′-bis(diphenyl acetyl)-cyclo-hexane-1,2-di amine; (R)-CBHA-DPA; (1R,2R)-N,N′-1,2-cyclo-hexane diylbis[N-hydroxy-α-phenyl-ben zene acet amide] [860036-16-4]C34H34N2O4 FW 534.64

N

N

OH

O

OH

OPh

Ph

Ph

Ph

mp ................................................................................. 200 to 205 °C[α]22

D +90.0°, c = 1 in chloroform

700592-50MG 50 mg

(1S,2S)-N,N′-Dihydroxy-N,N′-bis(diphenyl acetyl)- 8

1,2-cyclo hexane di amine, 97%(1S,2S)-N,N′-Dihydroxy-N,N′-bis(diphenyl acetyl)-cyclo-hexane-1,2-di amine; (S)-CBHA-DPA; (1S,2S)-N,N′-1,2-cyclo-hexane diylbis[N-hydroxy-α-phenyl-ben zene acet amide] C34H34N2O4 FW 534.64

N

N

OH

O

OH

OPh

Ph

Ph

Ph

mp ................................................................................. 199 to 204 °C[α]22

D -79.0°, c = 1 in chloroform

700576-50MG 50 mg

(1R,2R)-N,N′-Dihydroxy-N,N′-bis(bis(3,5-dimethyl- 8

phenyl)acetyl)-1,2-cyclo hexane di amine, 97%(1R,2R)-N,N′-Dihydroxy-N,N′-bis(3,5-dimethyl-diphenyl acetyl)-cyclo hexane-di amine; (R)-CBHA-DMDA; N,N′-(1R,2R)-1,2-cyclo-hexane diylbis[α-(3,5-dimethyl phenyl)-N-hydroxy-3,5-dimethyl-ben zene acet amide][860036-27-7]C42H50N2O4

FW 646.86

N

N

OH

O

OH

O

CH3

CH3

H3C

CH3H3C

CH3

CH3

CH3

mp ............................................................................194 to 199 °C (D)[α] 22


700584-50MG 50 mg

(1S,2S)-N,N′-Dihydroxy-N,N′-bis(bis(3,5-dimethyl phenyl) 8

acetyl)-1,2-cyclo hexane di amine, 97%(1S,2S)-N,N′-Dihydroxy-N,N′-bis(3,5-dimethyl-diphenyl acetyl)-cyclo hexane-di amine; (S)-CBHA-DMDA; N,N′-(1S,2S)-1,2-cyclo-hexane diylbis[α-(3,5-dimethyl phenyl)-N-hydroxy- 3,5-dimethyl ben zene acet amide]C42H50N2O4

FW 646.86

N

N

OH

O

OH

O

CH3

CH3

H3C

CH3H3C

CH3

CH3

CH3

mp ................................................................................. 186 to 190 °C[α] 22

D −76°, c = 1 in chloroform

700568-50MG 50 mg

(1R,2R)-N,N′-Dihydroxy-N,N′-bis(3,3,3-tri phenyl - 8

pro pionyl)-1,2-cyclo hexane di amine, 95%(1R,2R)-N,N′-Dihydroxy-N,N′-bis(tri phenyl pro pionyl)-cyclo hexane-1,2-di amine; N,N′-(1R,2R)-1,2-cyclo hexane-diylbis[N-hydroxy-β,β-diphenyl ben zene propan amide]; (R)-CBHA-TPP[860036-29-9]C48H46N2O4

FW 714.89

N

N

OH

O

OH

O

PhPh

Ph

PhPh

Ph

mp ................................................................................. 217 to 221 °C[α] 22


700541-50MG 50 mg

(1S,2S)-N,N′-Dihydroxy-N,N′-bis(3,3,3-tri phenyl - 8

pro pionyl)-1,2-cyclo hexane di amine, 95%

(1S,2S)-N,N′-Dihydroxy-N,N′-bis(tri phenyl pro pionyl)- cyclo hexane-1,2-di amine; (S)-CBHA-TPP; N,N′-(1S,2S)-1,2-cyclo hexane diylbis[N-hydroxy-β,β-diphenyl ben zene-propan amide]C48H46N2O4

FW 714.89

N

N

OH

O

OH

O

PhPh

Ph

PhPh

Ph

mp ................................................................................. 217 to 221 °C[α] 22

D −14.0°, c = 1 in chloroform

700533-50MG 50 mg

Vanadium(V) oxytriiso prop oxide

Tri iso pro poxy vanadium(V) oxide; Vanadium(V) tris iso-prop oxide oxide[5588-84-1]Beil. 1,IV,1242C9H21O4VFW 244.20

VO

OOO

CH3H3CCH3

CH3 CH3

CH3

liquid

bp............................................................................80-82 °C/2 mmHg

density .....................................................................1.035 g/mL, 25 °C

n 20D ............................................................................................ 1.479

404926-1G 1 g

404926-10G 10 g

tert-Butyl hydro peroxide solution

TBHP[75-91-2]Merck 13,1569; Beil. 1,IV,1616C4H10O2

FW 90.12

H3C OOH

H3C CH3

5.0-6.0 M in nonane

water ............................................................................................<4%

density .....................................................................0.817 g/mL, 25 °C

n 20D

............................................................................................ 1.399

418064-50ML 50 mL

Cumene hydro peroxide, 80%α,α-Dimethyl benzyl hydro peroxide[80-15-9]Beil. 6,IV,3221C9H12O2

FW 152.19

O

CH3H3COH

bp........................................................................100-101 °C/8 mmHgvd ........................................................................................ 5.4 (vs air)vp ........................................................................<0.03 mmHg (20 °C)

technical grade

density .......................................................................1.03 g/mL, 25 °C

n 20D .......................................................................................... 1.5210

247502-5G 5 g

247502-100G 100 g

247502-500G 500 g


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sigma-aldrich.com6

Asy

mm

etric

Syn

thes

is

RuCl(p-cymene)[(R,R)-Ts-DPEN] 8

[N-[(1R,2R)-2-(Amino-κN)-1,2-diphenyl-ethyl]-4-methyl ben zene sulfo namidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methyl-ethyl)ben zene]-ruthe nium[192139-92-7]C31H35ClN2O2RuSFW 636.21

PhPh

NH2

RuNH3C

H3CCH3

CH3

Cl

SO

O

mp ............................................................................................ 215 °C[α] 20

D −12°, c = 1 in chloroform

703907-100MG 100 mg

703907-500MG 500 mg

RuCl(p-cymene)[(S,S)-Ts-DPEN] 8

[N-[(1S,2S)-2-(Amino-κN)-1,2-diphenyl-ethyl]-4-methyl ben zene sulfo namidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methyl-ethyl)ben zene]-ruthe nium[192139-90-5]C31H35ClN2O2RuSFW 636.21

PhPh

NH2

RuNH3C

H3CCH3

CH3

Cl

SO

O

mp .......................................................................................... >175 °C[α] 20

D +104°, c = 0.45 in chloroform

703915-100MG 100 mg

703915-500MG 500 mg

DPBP-bidentate phos phine, 95% 8

2,2′ Bis(diphenyl phos phino)benzo phen one[845821-92-3]C37H28OP2

FW 550.57

PP OPh Ph Ph Ph

mp ................................................................................. 152 to 156 °C

692344-100MG 100 mg

692344-500MG 500 mg

Dichloro(mesit ylene)ruthe nium(II) dimer, 95% 8

Di-μ-chloro dichloro bis[(1,2,3,4,5,6-η)-1,3,5-tri methyl ben zene]di ruthe nium; Ruthe nium(II) chloride mesit ylene dimer[52462-31-4]C18H24Cl4Ru2

FW 584.34

RuCl

ClRu

CH3

H3C

Cl

Cl

H3C

H3CCH3

CH3

mp .......................................................................................... >300 °C

701769-100MG 100 mg

701769-500MG 500 mg

Bis(norbor na diene)rhodium(I) tri fluoro meth ane - 8

sulfo nate, 97%[178397-71-2]C15H16F3O3RhSFW 436.25

Rh+ F3C SO

OO

mp ................................................................................. 119 to 121 °C

701610-250MG 250 mg

701610-1G 1 g

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$


Metal and Phosphine M

ediated Transformations

Metal and Phosphine Mediated TransformationsPincer LigandsFunctionalized allyl boronates are useful building blocks in natural product synthesis. Olsson et al. reported the use of a palladium pincer complex in combination with diboronic acid for the boronation of readily available allylic alcohols. Under mild conditions, a variety of allylic alcohols were reacted with 5 mol% catalyst to yield the corresponding boronic acids, which were converted to the more stable trifluoroborate salt derivatives in good yields. Considering the widely available nature of allylic alcohols, the mildness of the reaction conditions, and the potential utility in natural product as well as fine chemical synthesis, this conversion of the typically difficult-to-substitute alcohol moiety into a functionalized alkylboronate is a remarkably efficient method for the preparation of these reagents (Scheme 1).

The authors suggest the diboronic acid is behaving as a Lewis acid (Scheme 2); however, since it is not as strong a Lewis acid as alkyl- or haloboranes, they suggest participation by a MeOH molecule. The six-membered transition state facilitates esterification of the boronic acid and consequently converts the hydroxyl moiety into a better leaving group.1

R OH [B(OH)2]2+

Se SePdCl

DMSO/MeOHR B(OH)2

R BF3K

KHF2

BF3K

92%

C3H7 BF3K

94%

BF3KO

O

77%

BF3K

COOMe

BF3K

92% 82%

40-60 °C, 16-24 h

(5 mol%)

Scheme 1

R OH

[B(OH)2]2

+ MeOH

R O

HOMe

H

OB

HO B(OH)2

R OB

B(OH)2

OH

H2O-MeOH

+ H

Scheme 2

1,3-Bis[(phenyl seleno)methyl]ben zene, 97% 8

[239448-30-7]C20H18Se2

FW 416.28SeSe

mp ..................................................................................... 38 to 42 °C

684376-250MG 250 mg

684376-1G 1 g

[1,3-Phenylene bis(methyl ene)]bis(dicyclo pentyl - 8

phos phine), 95%1,3-Bis(dicyclo pentyl phos phino methyl)ben zene [255874-48-7]C28H44P2

FW 442.60

PP

mp ..................................................................................... 30 to 34 °C

680451-100MG 100 mg

680451-500MG 500 mg




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sigma-aldrich.com8

Met

al a

nd P

hosp

hine

Med

iate

d Tr

ansf

orm

atio

ns

Direct Arylation of HeterocyclesLewis and co-workers have recently disclosed a highly functional-group compatible Rh-catalyzed C-H bond activation for the rapid synthesis of functionalized heterocycles. The method relies on the use of rhodium complexed with (Z)-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, which behaves as a chelating ligand, addressing the sometimes slow arylations that occur due to dehydrogenation leading to aryl halide hydrohalogenation or reduction. This ligand is used as the tetrafluoroborate salt, which allows easy handling and storage and, when combined with the rhodium precatalyst, provides a highly robust and efficient catalytic system, in many cases performing arylations that were not possible using traditional catalytic methods. The scope of the reaction was examined and a variety of heterocycles were successfully arylated including benzimidazoles, benzoxazoles, benzothiazoles, as well as bisarylimidazoles, with a variety of functionalized aryl bromides (sulfinyl-, chloro-, acetamide-, hydroxy-, and amino-containing functionalities were suitable coupling partners) (Scheme 3).2

X

N Br

R+

PH

BF4

[RhCl(cod)]2 (5 mol%)

(iPr)2N(iBu), THFµW, 200 °C, 2 h

X

HN

R

NH

N

74%

NH

NS

93%

NH

NNHAc

85%

O

EtO

N

55%NH

NH

NF

75%

(15 mol%)

Scheme 3

(Z)-1-tert-Butyl-2,3,6,7-tetra hydro-1H-phos phepi nium 8

tetra fluoro borateEllman ligandC10H20BF4PFW 258.04

P t-BuH

BF4-

mp ................................................................................. 243 to 264 °C

kanata purity

695688-100MG 100 mg

695688-500MG 500 mg

Chloro(1,5-cyclo octa diene)rhodium(I) dimer, 98%Di-μ-chloro bis[(1,2,5,6-η)-1,5-cyclo octa diene]dirhodium; Bis(1,5-cyclo octa diene)dirhodium(I) di chloride; 1,5-Cyclo octa diene rhodium(I) chloride dimer; Rhodium(I) chloride 1,5-Cyclo octa diene com plex dimer[12092-47-6]C16H24Cl2Rh2

FW 493.08

RhCl

RhCl

mp ...................................................................................243 °C (dec.)

227951-500MG 500 mg

227951-5G 5 g

Chloro bis(cyclo octene)rhodium(I),dimer, 98%[12279-09-3]C32H56Cl2Rh2

FW 717.50 Rh

Cl

Rh

Cl

mp ...................................................................................190 °C (dec.)

302473-100MG 100 mg

302473-250MG 250 mg

302473-500MG 500 mg

302473-1G 1 g

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Ar H

O

+CO2R

Ar

OHCO2R

N N

N

P

(20 mol%)

r.t., 5-19 h

Ar Yield (%)

4-NO2C6H4 91

2-pyridyl

R

Et

Et

Et

60

59

2-NO2C6H4 n-Bu 93

2-F-4-ClC6H3

Table 1

N N

N

P

CO2Et+

N N

N

P

EtO O

N N

N

P

EtO O

H2O

+ OH

N N

N

P

CO2−

+ EtOH

1 2 3

Scheme 4

Air-Stable Trialkylphosphine for Morita-Baylis Hillman ReactionsThe use of amines and phosphines in nucleophilic catalysis is well-precedented; however, arguably one of the severe limitations with respect to exploiting the more nucleophilic, yet less basic, phosphine in this regard is its air sensitivity. This is especially true for the most nucleophilic of this class, the trialkylphosphines. While utilization of these difficult-to-handle phosphines as their trifluoroborate salts has provided an excellent solution to handling limitations, there are circumstances where the use of base is not necessary or possible. He and co-workers have demonstrated the use of the known cage-like, air-stable trialkylphosphine, 1,3,5-triaza-7-phosphaadamantane (PTA), in organocatalysis, and specifically in the Morita-Baylis-Hillman (MBH) reaction (Table 1). Traditionally, MBH reactions are conducted using DABCO®, but slow reaction rates often hamper its utility. The authors’ use of PTA has addressed some of these difficulties, utilizing mild and environmentally friendly conditions, to provide the desired products in good to excellent yields. In addition, the use of PTA is also proving successful in historically challenging cases, such as MBH reactions using acrylate as the electrophile.

The authors also presented reasonable evidence implicating the phosphorus-bound Michael adduct 1 by preparation of species 3 via reaction of PTA with ethyl acrylate in THF-H2O (Scheme 4). Not only does formation of adduct 3 substantiate organocatalysis through the Michael adduct, but it also proves that the tertiary alkyl phosphine is behaving as the organocatalyst and not the nitrogen.3

1,3,5-Triaza-7-phos pha ada man tane, 97% 8

1,3,5-Triaza-7-phos pha tri cyclo[3.3.1.13.7]decane; PTA; NSC 266642[53597-69-6]C6H12N3PFW 157.15

N N

N

P

mp ................................................................................. 244 to 250 °C

695467-500MG 500 mg

695467-2G 2 g

HydroformylationDespite a long-standing belief that formyl groups cannot be generated at quaternary carbon centers via hydroformylation, Clarke and Roff have developed a method utilizing 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, an air-stable phosphane ligand, which inhibited hydrogenation and provided excellent levels of regioselectivity (for quaternary versus linear regioisomer) (Scheme 5).4

References: (1) Olsson, V. J. et al. J. Am. Chem. Soc. 2006, 128, 4588. (2) Lewis, J. C. et al. J. Am. Chem. Soc. 2008, 130, 2493. (3) He, Z. et al. Adv. Synth. Catal. 2006, 348, 413. (4) Clarke, M. L.; Roff, G. J. Chem.-Eur. J. 2006, 12, 7978.

NC(H2C)2 CO2Me [Rh(acac)(CO)2] (0.2%)

OO

PO

CH3

CH3

CH3

H3C

Ph

(1 mol%)

50 °C, 50 bar, 70 h

NC(H2C)2 CO2Me

CHO

Scheme 5

1,3,5,7-Tetra methyl-6-phenyl-2,4,8-tri oxa-6- 8

phos pha adamante, 97%meCgPPh; 1,3,5,7-Tetra methyl-8-phenyl-2,4,6-tri oxa-8-phos pha tri cyclo[3.3.1.13,7]decane[97739-46-3]C16H21O3PFW 292.31

OO

PO

CH3

CH3

CH3

H3C

Ph

mp ................................................................................. 106 to 111 °C

695459-100MG 100 mg

695459-500MG 500 mg

695459-2G 2 g









$

sigma-aldrich.com10

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Amination of Aryl Halides

ChlorophosphinesThe Buchwald-Hartwig amination reaction, or the coupling between an aryl halide and an amine, is extremely important in various areas of both academic and industrial research. The amination of aryl chlorides with various amines can be notoriously difficult, usually requiring bulky phosphines to achieve reasonable yields. However, the scope of amination reactions using these bulkier phosphines is still somewhat limited with respect to the variety of aryl chlorides that can be employed. To address this limitation, Ackermann et al. synthesized a diaminophosphine ligand, which, when used with Pd(dba)2, afforded good yields for the catalytic amination of a wide variety of aryl chlorides with different primary and secondary amines (Scheme 6).5

BRIDP CatalystsResearchers at Takasago developed two phosphine-based ligands for the Buchwald-Hartwig amination reaction with successful results for the cross-coupling of a wide array of amines and aryl halides. These ligands exhibit several noteworthy advantages, with regard to efficiency and turnover numbers, as well as the ability to access biaryls substituted with a nitrogen atom.

The development of a new ligand for efficient amination of a variety of aryl halides focused on optimizing the sterics and electronics and ultimately resulted in the development of a phosphine-based ligand consisting of two phenyl groups connected to a dicyclohexylphoshinylpropylidene (Cy-vBRIDP (Scheme 7)). N-Arylation using Cy-vBRIDP was exceptionally effective with aryl bromides and secondary amines.6a

After the report of Cy-vBRIDP incorporating a vinyl-based phosphine ligand, Suzuki and co-workers reported another amination ligand (cBRIDP) for use with more challenging coupling partners such as the reaction of aryl chlorides with primary and secondary amines.2 The vinyl component was replaced with a methylcyclopropane moiety and the cyclohexyl groups were replaced with t-butyl functionalities (the cyclohexyl version of this was also developed, Cy-cBRIDP). Improved catalytic activity was demonstrated with cBRIDP, with loadings as low as 0.2 mol% achieved and generating a variety of tertiary amines in good-to-excellent yields. In addition, cBRIDP proved to be a highly general ligand, facilitating couplings with different electron-poor and electron-rich aryl bromides and chlorides (Table 2 and Table 3). Additionally, sterically hindered couplings were effected such as the coupling between 2,4,6-trichlorobenzene and carbazole, yielding sterically congested products in good yields (Scheme 8).6b

Cl

R1

+ NH2

R2

NP

N

Cl

(10 mol%)Pd(dba)2 (5 mol%)

NaOtBu, toluene, 105 °C

NH

R1 R2

NH

97%

NHOMe

93%

NH

87%

Scheme 6

+Pd(OAc)2 (1 mol%)

NBrNH

CH3

P

97%

(4 mol%)

100 °C, 3 hNaO-t-Bu, toluene

Scheme 7

NHR2

R1

R3X

+ NR3

R1

R2

Br

Cl

Cl

Cl

N O

O

N

H3C

N

CH3

HN

H3C

CH3

97

91

80

98

95

ProductX Yield (%)

P

CH3

[(π-allyl)PdCl]2 (0.5 mol%)

NaO-t-Bu, toluene

(2 mol%)

entry

1

3

4

BrN

OO

O

O2

100 °C, 3 h

5

Table 2

Cl

Cl

N

N

94a

82

ProductX Yield (%)

Cl N 95aCH3

entry

1

2

3

CH3

axylene in place of toluene, 120 °C, 3 h

Table 3

Cl

Cl

Cl

HN3 eq+

P

CH3

[(π-allyl)PdCl]2 (0.5 mol%)

NaO-t-Bu, xylene

N

N

N

67%

(2 mol%)

120 °C, 3 h

Scheme 8



$




2-Chloro-1,3-bis(2,6-diiso pro pyl phenyl)-1,3,2-diaza - 8

phos pho li dine[314730-65-9]C26H38ClN2PFW 445.02

NP

N

i-Pr

i-Pr i-Pr

i-Pr

Cl

mp ................................................................................. 212 to 220 °C

694207-250MG 250 mg

694207-1G 1 g

Cy-cBRIDP 8

1-(Dicyclo hexyl phos phino)-2,2-Diphenyl-1-methyl cyclo propane; Dicyclo hexyl(2,2-diphenyl-1-methyl-1-cyclo pro pyl)phos phine C28H37PFW 404.57

P

CH3

mp ................................................................................. 115 to 122 °C

702951-100MG 100 mg

702951-500MG 500 mg

Cy-vBRIDP 8

Dicyclo hexyl(1-methyl-2,2-diphenyl vinyl)phos phine; 2-(Dicyclo hexyl phos phino)-1,1-diphenyl-1-pro pene[384842-24-4]C27H35PFW 390.54

P

CH3

mp ................................................................................. 124 to 130 °C

702943-100MG 100 mg

702943-500MG 500 mg

Ferrocenyl Based Ligands and CatalystsHartwig and co-workers have reported the use of the electron-rich and bulky ligand 1,1’-bis(di-tert-butylphosphino)ferrocene for the amination of aryl halides and for the first amination of aryl tosylates. The amination of various amines with aryl chlorides, iodides, and tosylates was effected using this novel ligand in combination with a palladium source affording the coupled products in excellent yield.This ligand is exceptionally effective and, though the electron density on the metal helps accelerate the oxidative addition (a necessity for unactivated aryl chlorides), the electron-richness does not negatively impact the reductive elimination since the steric bulk associated with this ligand facilitates this last step of the catalytic cycle (Table 4).7

References: (5) Ackermann, L. et al. Angew. Chem., Int. Ed. 2006, 45, 7627. (6) (a) Suzuki, K. et al. Adv. Synth. Catal. 2007, 349, 2089. (b) Suzuki, K. et al. Adv. Synth. Catal. 2008, 350, 652. (7) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369.

HN H3C Cl H3C N

NH2Bu

CH3

Cl

CH3

HN

Bu

NH2Ph NC OTs NC NH

Ph

HN OCl N O

H3CO H3CO

ArylXAmine Productentry Yield (%)

NH2BuIH3C

CH3

NHH3C

CH3Bu

4

3

2

1

5

81

85

79

49

57

1 mol% Pd(OAc)100 °C, 10h

Conditions

1 mol% Pd(OAc)100 °C, 12h

1 mol% Pd(dba)110 °C, 24h

1 mol% Pd(dba)2rt, 7h

2 mol% Pd(dba)2110 °C, 16h

HNR2 ArylX+

Fe

P

Pt-Bu

t-Bu

t-Bu

t-Bu

(1-2 mol%)

Pd source, rt or ∆, 7-24 hHNR2

Table 4

1,1′-Bis(di-tert-butyl phos phino)ferro cene 8

[84680-95-5]C26H44FeP2

FW 474.42 Fe

P

Pt-Bu

t-Bu

t-Bu

t-Bu

mp ..................................................................................... 73 to 75 °C

695149-250MG 250 mg

695149-1G 1 g

1,1′-Bis(di-tert-butyl phos phino)ferro cene palladium 8

di chloride, 98%[95408-45-0]C26H44Cl2FeP2PdFW 651.75 Fe

P

P

t-But-Bu

t-But-Bu

PdCl

Cl

mp ................................................................................. 203 to 208 °C

701602-250MG 250 mg

701602-1G 1 g

1,1′-Bis(di-isopropylphosphino)ferrocenepalladium 8

di chloride, 98%[215788-65-1]C22H36Cl2FeP2PdFW 595.64

Fe

P

P

PdCl

Cl

CH3

CH3

CH3

CH3H3CCH3

H3CCH3

mp ................................................................................. 282 to 287 °C

702005-250MG 250 mg

702005-1G 1 g

1,1′-Bis(di-cyclohexylphosphino)ferrocenepalladium 8

di chloride, 98%[917511-90-1]C34H52Cl2FeP2PdFW 755.90

Fe

P

P

PdCl

Cl

mp ................................................................................. 294 to 300 °C

701998-250MG 250 mg

701998-1G 1 g


















$

sigma-aldrich.com12

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New Catalysts for Suzuki Coupling

Suzuki Coupling of Alkyl ChloridesGonzalez-Bobes and Fu reported the use of NiCl2•glyme in the presence of prolinol in the previously unprecedented Suzuki reactions of unactivated secondary alkyl chlorides. Both primary, secondary, cyclic and acyclic alkyl chlorides can be utilized in this transformation, as well as electron-rich and electron-poor arylboronic acids (Table 5).8

Non-Proprietary Catalysts for Cross-CouplingGreat strides have been made in the development of catalysts for cross-coupling chemistry, particularly for Suzuki-Miyaura reactions. The cross-coupling reaction of heteroaryl halides is of particular interest to the pharmaceutical industry since many biologically active compounds are accessed through use of the Suzuki-Miyaura reaction. However, the efficient coupling of five-membered heteroaryl halides or six-membered heteroaryl chlorides bearing heteroatom substituents with boronic acids has not been well-developed. Catalysts are thought to form inactive complexes with many of these types of substrates, and thus, they typically require high catalyst loadings in order to achieve good yields.

The Guram group at Amgen has recently communicated the development of an air-stable palladium complex, (AtaPhos)2PdCl2, for Suzuki-Miyaura cross-coupling reactions (Table 6). The catalyst was very effective at coupling a wide variety of substrates with arylboronic acids, including amino-substituted 2-chloropyridines and five-membered heteroaryl halides. The products are observed in excellent yields and high turnover numbers (up to 10,000 TON) are typically achieved.9

References: (8) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360. (9) (a) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727. (b) Singer, R. A. et al. Synthesis 2003, 1727. (c) Guram, A. S. et al. Org. Lett. 2006, 8, 1787.

Ralkyl Cl + (HO)2B R1NiCl2 glyme (6 mol%)

prolinol (12 mol%)KHMDS (2 equiv)

i-PrOH, 60 °C

•Ralkyl R1

Arylboronic acidAlkyl Chloride Yield (%)entry

Cl

MeMe

Cl

Cl

OTBS

O Cl

B(OH)2

B(OH)2H3C

B(OH)2F

B(OH)2F3C 79

46a

74

80

4

3

2

1

aYield of trans isomer

Table 5

ProductXentry Yield (%)

4

3

2

1

5

Cl

Cl

Cl

Cl

Cl

Cl

Cl

6

7

N

NH2

H3C

N

NH2

CF3

N

NH2

OCH3

NCH3

H2N H3C

H3C

NN

H3CS

OCH3

NN

H3CS

CN

NN

H3CS H3C

H3C

93

92

93

98

95

94

99

Ar X

+ Ar Ar'

B(OH)2Ar'

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

Cl

K2CO3, toluene−water, reflux, 12 h

(1 mol%)

Cl

Br

Br

Cl

Cl

8

9

10

11

12

NN

H3CO

H3CO

OCH3

N NH3CO OCH3

CH3S

NN

H3C

CH3

CH3

OCH3

NN

H3C

CH3

CH3

F

98

97

96

93

95

Table 6

Nickel(II) chloride ethylene glycol dimethyl ether 8

com plex, 98%NiCl2 glyme[29046-78-4]C4H10O2 · Cl2NiFW 219.72

O

ONi

CH3

CH3

Cl

Cl

mp .......................................................................................... >300 °C

696668-1G 1 g

696668-5G 5 g

Bis[(dicyclo hexyl)(4-dimethyl amino phenyl)phos - 8

phine] palladium(II) chloride(A-caPhos)2 PdCl2C40H64Cl2N2P2PdFW 812.22 P PdN

H3C

H3CP N

CH3

CH3Cl

Cl

692913-250MG 250 mg

692913-1G 1 g







$




(4-(N,N-Dimethyl amino)phenyl)di-tert-butyl phos phine, 95%A-taPhosC16H28NPFW 265.37

NH3C

CH3

Pt-Bu

t-Bu

mp ..................................................................................... 57 to 61 °C

677264-1G 1 g

Bis[di-(tert-butyl)(4-tri fluoro methyl phenyl)phos phine] 8

palladium(II) chlorideC30H44Cl2F6P2PdFW 757.93 Pd PP

Cl

Cl

t-Bu

t-Bu t-Bu

t-BuCF3F3C

mp .......................................................................................230 °C (D)

692921-250MG 250 mg

692921-1G 1 g

Bis(di-tert-butyl(4-dimethyl amino phenyl)phos phine)-dichloro palladium(II)(A-taPhos)2PdCl2[887919-35-9]C32H56Cl2N2P2PdFW 708.07

P Pd PCl

ClNN

H3C

H3C CH3

CH3t-Bu t-Bu

t-Bu t-Bu

678740-1G 1 g

678740-5G 5 g

sigma-aldrich.com

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Sigma-Aldrich® is pleased to partner with ChiroSolve, Inc. to offer a series of ready-to-use, disposable kits for chiral resolution of both solid and liquid racemates. These kits allow scientists to quickly screen calibrated quantities of resolving agents and solvents against a racemate to find the optimum combination, as well as optimize reaction conditions in order to separate a racemic mixture into its constituent enantiomers. The kits’ high throughput format allows scientists to identify the optimum resolution process within 24 hours that might otherwise take over 2 months.

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681431 Acid Series 1681423 Acid Series 2681415 Acid Series 3699217 Acid Series 4681407 Base Series 1681393 Base Series 2681377 Base Series 3699241 Base Series 4

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698881 Acid Series 1699527 Acid Series 2698873 Acid Series 3699225 Acid Series 4699233 Base Series 1698938 Base Series 2698946 Base Series 3698954 Base Series 4

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sigma-aldrich.com14

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Gold CatalysisThe Friedel-Crafts reaction is well-documented in organic chemistry; however, one major limitation is the common use of strong acids. There have been studies on the use of stoichiometric and catalytic metals to accelerate this important class of reactions. Since gold catalysts can be considered as metallic sources of H+, several research groups have successfully demonstrated the utility of Au(I) catalysts for Friedel-Crafts-type reactions. Tarselli and Gagne recently reported an efficient and functional-group-tolerant method for the cyclization of 4-allenyl arenes to afford benzocycles in the presence of chloro(triphenylphosphite)gold. The reaction was generally amenable with electron-rich arenes, but heterocyclic aromatic compounds with coordinating abilities such as triazoles, isoxazoles, and oxazoles led to catalyst poisoning. On the other hand, the reaction was tolerant of functional groups and moieties such as ethers, acetals, and pyrroles (Scheme 9).10

Echavarren and co-workers used a Au(I) catalyst to effect the transformation of substrate 4 to 5. This reaction proceeds through a 5-exo-dig cyclization followed by trapping with MeOH (Scheme 10).11

Echavarren and co-workers have also reported the intermolecular addition reactions of nucleophiles, including electron-rich arenes and heteroarenes, allylsilanes, and 1,3-dicarbonyl compounds to 1,5- and 1,6-enynes. Using the electron-rich Au(I)-phosphite based catalyst below (6), the authors reacted 1,6-enynes with arenes and heteroarenes to afford carbocycles. This reaction occurs via 5-exo-dig cyclization to afford a cyclopropyl metal carbene species, which upon reaction with the nucleophile affords the carbocyclic product (Table 7).12

References: (10) Tarselli, M. A.; Gagne, M. R. J. Org. Chem. 2008, 73, 2439. (11) Nieto-Oberhuber, C. et al. Chem.-Eur. J. 2006, 12, 1677. (12) Amijs, C. H. M. et al. J. Org. Chem. 2008, 73, 7721.

MeO2C CO2Me MeO2C CO2Me

(3-10 mol%)

OP

O

OAu Cl

AgSbF6 (5 mol%)0.2M CH2Cl2

6-16 h

N

MeO2C CO2MeMeO2C CO2Me

MeO

MeO

OMe

59%79%

MeO2C CO2Me

OO

93%

MeO2C CO2Me

87%

R

R

Scheme 9

MeO2C

MeO2CMeO2C

MeO2C

OMe

t-BuP

t-Bu N C CH3Au

SbF6-

(2 mol%)

AgSbF6 (2 mol%)MeOH, 23 °C

4 50.25 h

91%

Scheme 10

Z

R2R1

+ NuH Z

H

R2

R1

Nu

PAuCl

O

O Ot-Bu

t-Bu

t-Bu

t-Bu

t-But-Bu

(5 mol%)

AgSbF6 (5 mol%)

CH2Cl2

6

entry enyne NuH T (°C),time (h) product % yield

Z = C(CO2Me)2, R1 = Ph, R2 = H

Z = NTs, R1=Ph, R2 = H

Z = C(CO2Me)2, R1 = R2 = Me

Z = C(SO2Ph)2, R1 = R2 = Me

NH

NC

Z

H Ph

NH

NC

NH

MeO

Z

H

NH

MeO

MeO OMe

OMe

Z

H

MeO

OMe

OMe

NH

Z

H Ph

NH

1

2

3

4

23, 48

-50, 5

-50, 1

23, 1

49

63

60

71

Table 7



$




Chloro(tri phenyl phos phite)gold, 97% 8

C18H15AuClO3PFW 542.70

OP

O

OAu Cl

mp ................................................................................... 97 to 102 °C

701505-250MG 250 mg

701505-1G 1 g

(Aceto nitrile)[(2-biphenyl)di-tert-butyl phos phine] 8

gold(I) hexa fluoro anti monate[866641-66-9]C22H30AuF6NPSbFW 772.17

t-BuP

t-Bu N C CH3Au

SbF6-

mp ............................................................................198 to 203 °C (D)

697575-250MG 250 mg

697575-1G 1 g

Chloro[tris(2,4-di-tert-butyl phenyl)phos phite]gold 8

[Tris(2,4-di-tert-butyl phenyl)phos phite]gold chloride[915299-24-0]C42H63AuClO3PFW 879.34

OP

O

OAu Cl

t-Bu

t-Bu

t-Bu

t-Bu

t-But-Bu

mp ................................................................................. 200 to 202 °C

699616-500MG 500 mg

New Phosphine Precursors

Bis(3,5-di-tert-butyl-4-methoxy phenyl)phos phine 8

C30H47O2PFW 470.67

HP

t-Bu t-BuH3CO

t-But-Bu

OCH3

mp ................................................................................. 114 to 119 °C

kanata purity

694673-100MG 100 mg

694673-500MG 500 mg

Bis(3,5-di(tri fluoro methyl)phenyl)phos phine 8

[166172-69-6]C16H7F12PFW 458.18

HPF3C

CF3 CF3

CF3

mp ..................................................................................... 69 to 73 °C

kanata purity

695335-100MG 100 mg

695335-500MG 500 mg

Bis(3,5-di(tri fluoro methyl)phenyl)chloro phos phine 8

[142421-57-6]C16H6ClF12PFW 492.63

PCl

CF3 CF3

CF3F3C

mp ..................................................................................... 25 to 29 °C

kanata purity

694746-100MG 100 mg

694746-500MG 500 mg

Bis(3,5-di-tert-butyl-4-methoxy phenyl)chloro phos phine 8

[212713-08-1]C30H46ClO2PFW 505.11

PCl

t-Bu

t-BuH3CO

t-Bu

t-Bu

OCH3

mp ................................................................................. 116 to 120 °C

kanata purity

694703-100MG 100 mg

694703-500MG 500 mg

Bis(3,5-dimethyl phenyl)chloro phos phine 8

[74289-57-9]C16H18ClPFW 276.74

P

CH3

H3C CH3

CH3

Cl

density .....................................................................1.102 g/mL, 25 °C

n 20D ............................................................................................ 1.606

695165-100MG 100 mg

695165-500MG 500 mg

New Ligands

Di-tert-butyl cyclo hexyl phos phine, 95% 8

[436865-11-1]C14H29PFW 228.35

P

CH3H3CH3C

CH3

CH3H3C

density .....................................................................0.889 g/mL, 25 °C

n 20D ............................................................................................ 1.506

698288-500MG 500 mg

Dicyclo hexyl-(2,6-diiso pro pyl phenyl)phos phine, 97% 8

C24H39PFW 358.54

P

i-Pri-Pr

mp ................................................................................... 96 to 100 °C

698814-250MG 250 mg

698814-1G 1 g

Tri iso propyl phos pho nium tetra fluoro borate, 97% 8

[121099-07-8]C9H22BF4PFW 248.05

PH3C

CH3

CH3H3C

CH3

CH3H

BF4-

698466-500MG 500 mg

2-(2-(Diphenyl phos phino)ethyl)pyri dine 8

[10150-27-3]C19H18NPFW 291.33

N PPh

Ph

mp ..................................................................................... 58 to 62 °C

kanata purity

695599-100MG 100 mg

695599-500MG 500 mg

New Palladium Complexes

(1,3-Bis(diphenyl phos phino)propane)palladium(II) 8

chlorideDichloro[1,3-bis(diphenyl phos phino)propane]palladium(II)[59831-02-6]C27H26Cl2P2PdFW 589.77

PPdPPh

Ph

Ph PhCl

Cl

696676-500MG 500 mg

696676-2G 2 g



























$

sigma-aldrich.com16

N-H

eter

ocyc

lic C

arbe

nes

(2-Butenyl)chloropalladiumdimer,≥97% 8

Bis[(1,2,3-η)-2-buten-1-yl]di-μ-chloro di- palladiumdi-π-crotylpalladium chloride; Di-2-butenyl dipal ladium di chloride; Dichloro bis(1-methyl allyl)dipal ladium[12081-22-0]C8H14Cl2Pd2

FW 393.94

CH2

CH3

PdCl

PdCl H2C

CH3

mp ................................................................................. 133 to 140 °C

700045-250MG 250 mg

700045-1G 1 g

Palladium(II)[1,3-bis(diphenyl phos phino)propane]- 8

bis(benzo nitrile)-bis-tetra fluoro borate[Pd(dppp)(PhCN)2](BF4)2[175079-12-6]C41H36B2F8N2P2PdFW 898.71 P

PhPh

Ph PhN

N Ph

Ph

Pd2+

BF

F FF

BF

F FF

696617-250MG 250 mg

N-Heterocyclic CarbenesEnyne CyclizationsEchavarren and co-workers have also demonstrated the utility of Au-NHCs in the reactions of 1,6-enynes. They determined that the outcome of the cyclization of 1,6-enyne 1 (Scheme 1) was dependent on the ligand coordinated to the metal. When 2 was used in combination with AgSbF6, the major product resulted from 5-exo-dig cyclization to afford a cyclopropyl metal carbene species, which upon reaction with the nucleophile afforded the carbocyclic product (see previous section). On the other hand, when the carbene-based Au-complex was used, the cyclopropyl derivative was observed as the major product.1

Rearrangement of Allylic AcetatesMarion and co-workers reported the first rearrangement of allylic acetates using a gold catalyst ligated to an N-heterocyclic carbene ligand. A bulky ligand bound to the gold catalyst proved imperative to this approach. The catalyst system was found to be highly versatile, providing a variety of rearranged primary oxo derivatives in good yield, either under thermal or microwave conditions (Scheme 2). In addition, the scope was found to be quite broad for a wide variety of allylic acetates. The authors propose a mechanism akin to that described by Overman, Henry, and Hartwig for analogous allylic rearrangments with Hg and Pd (cyclization-induced rearrangement-Scheme 3).2

N-Heterocyclic Carbene-Copper ComplexesN-heterocyclic carbene ligands have proven very popular in the last 20 years. The electronic and steric modularity associated with the resulting complexes have made NHCs obvious candidates when designing new metal complexes for catalysis. Nolan and co-workers are among the pioneers in the use of NHC ligands for catalysis and they have reported the use of Cu-NHCs for a variety of catalytic transformations. Conjugate reduction of a,ß-unsaturated ketones and esters, the hydrosilylation of ketones, the cyclopropanation of terminal alkenes, as well as olefinations, carbene transfer reactions, aziridination of olefins, and methylenation of aldehydes (Scheme 4) are among some examples of the uses of Cu-NHC complexes (specifically (IPr)CuCl) in modern catalysis. Finally, these catalysts are air- and moisture-stable, and they can be used as precursors to synthesize more air-sensitive complexes.3

TsN

Ph

TsN

H Ph

(5 mol%)

AgSbF6 (5 mol%)CH2Cl2, 0.5 h

N N

AuCl

COPh

COPhTsN

H

COPh

COPhPh

+

99% (98:2)

Ph Ph

O O

with [Tris(2,4-di-tert-butylphenyl)phosphite]gold chloride/AgSbF6, 91% (5:95)

2

1

Scheme 1

R1

OAc

N N

AuCl

(3 mol%)AgBF4 (2 mol%)

R1

OAc

OAc

97%

OAc

88%

OAc

87%

OAc

98%

R2R2

3 µW, DCE, 80 °C

12 min

4

Scheme 2

O O

R1 Au

O O

R1

Au

O O

R1Au

3Au -Au

4

Scheme 3

N N

CuCl

R1

CO2Et

O

EtO

R2

R1OSiR3

R2R1

O

EtO

R2

R1

R1

O

R2R1

R2R1

O

R2R1

N2 CO2Et+

R1

CO2R

R1 N2 CO2R+

SnBu3

SnBu3

R1

R2

NTs+ PhI

N

R1

R2

Ts

R3SiH

O

R1

R2

O

R1

R2

NTs

Ar H

+NC

CO2Me

N NTs

Ar CO2Me

Scheme 4



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N-H

eterocyclic Carbenes

Nolan and co-workers have described the use of the Cu-Imes carbene complex 5 in the olefination of aldehydes (and ketones) in the presence of PPh3, i-PrOH, and TMSCHN2. While similar olefinations have been reported using Wilkinson’s catalyst, the Cu-alternative offers a more economical solution. The functional group compatibility is quite good, allowing for the formation of functionalized aliphatic olefins, dienes, and styrenes containing nitro (notoriously deleterious to these types of reactions), trifluoromethyl, amino, and ester functionalities as well as for heteroaromatic olefins substituted with pyridine, pyrrole, and indole derivatives (Scheme 5). The isopropyl-derived carbene complex 6 was also demonstrated to be quite useful in these types of reactions under slightly modified reaction conditions (Scheme 6).4

References: (1) Amijs, C. H. M. et al. J. Org. Chem. 2008, 73, 7721. (2) Marion, N. et al. Org. Lett. 2007, 9, 2653. (3) (a) Díez-González, S. et al. Organometallics, 2006, 25, 2355. (b) Díez-González, S.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 349. (c) Jurkauskas, V. et al. Org. Lett. 2003, 5, 2417. (d) Lebel, H. et al. J. Org. Chem. 2007, 72, 144. (e) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054. (f) Fructos, M. R. et al. J. Am. Chem. Soc. 2004, 126, 10846. (g) Kaur H. et al. Organometallics 2004, 23, 1157. (h) Díez-González, S.; Nolan, S. P. Aldrichimica Acta 2008, 41, 43. (4) Lebel, H. et al. J. Org. Chem. 2007, 72, 144.

1,3-Bis(2,4,6-tri methyl phenyl)imidazol-2-yl idene gold(I) 8

chloride, 95%Chloro[1,3-bis(2,4,6-tri methyl phenyl)imidazol-2-yl idene] gold(I)C21H24AuClN2

FW 536.85

N N

CH3

CH3

H3C

H3C

CH3H3C

AuCl

mp .......................................................................................... >300 °C

696501-100MG 100 mg

696501-500MG 500 mg

Chloro[1,3-bis(2,6-diiso pro pyl phenyl)imidazol-2-yl- 8

idene]gold(I)1,3-Bis(2,6-diiso pro pyl phenyl-imidazol-2-yl idene)gold(I) chloride[852445-83-1]C27H36AuClN2

FW 621.01

N

N

i-Pri-Pr

i-Pr

i-Pr

AuCl

mp ............................................................................................ 298 °C

696277-100MG 100 mg

696277-500MG 500 mg

[1,3-Bis(2,6-diiso pro pyl phenyl)imidazol-2-yl idene] 8

copper(I) chloride[578743-87-0]C27H36ClCuN2

FW 487.59 N

N CuCl

i-Pr

i-Pr

i-Pr

i-Pr

mp .......................................................................................... >300 °C

696307-250MG 250 mg

696307-1G 1 g

Bis[1,3-bis(2,4,6-tri methyl phenyl)imidazol-2-yl idene] 8

copper(I) tetra fluoro borateC42H48BCuF4N4

FW 759.21

N

NCu

N

N

H3C CH3 CH3H3C

H3C CH3H3CCH3

CH3 CH3

CH3CH3

BF4-

696242-250MG 250 mg

696242-1G 1 g

R H

O

R H

(5 mol%)

N N

CuCl

72%

H3CO

82%

O

O

88%

74%

NBoc

88%

TMSCHN2 (1.4 eq)

i-PrOH (1.1 eq), PPh3 (1.1 eq)/THF

5

Scheme 5

R1 R2

O

R1 R2

(5 mol%)

N N

CuCl

i-Pr

i-Pr

i-Pr

i-Pr

PhOTBS

78%

TMSCHN2 (2.0 eq)

PPh3 (1.2 eq), i-PrOH (12 eq), /THF

68%

CO2Et

93%

O2Nt-Bu

92% 73%

6

Scheme 6












$

sigma-aldrich.com18

N-H

eter

ocyc

lic C

arbe

nes

1,3-Dimethyl imida zolium-2-carboxy late, 97% 8

1,3-Bis(methyl)imida zolium-2-carboxy late [536755-29-0]C6H8N2O2

FW 140.14

N

NO

O

CH3

CH3

mp ................................................................................. 221 to 225 °C

668400-1G 1 g

668400-5G 5 g

1,3-Bis(2,4,6-tri methyl phenyl)-4,5-dihydro imida zolium 8

tetra fluoro borate, 95%SIMes-HBF4; 4,5-Dihydro-1,3-bis(2,4,6-tri methyl phenyl)-1H-imida zolium tetra fluoro borate(1-); 4,5-Dihydro-1,3-dimesityl-1H-imida zolium tetra fluoro borate; 4,5-Dihydro-1,3-dimesitylimida zolium tetra fluoro borate[245679-18-9]C21H27BF4N2

FW 394.26

N

N

CH3H3C

H3C

CH3

BF4-

CH3

CH3

mp ................................................................................. 290 to 296 °C

693545-1G 1 g

693545-5G 5 g

1,3-Bis(2,6-diiso pro pyl phenyl)-4,5-dihydro imida zolium 8

tetra fluoro borate, 95%SIPr-HBF4; 4,5-Dihydro-1,3-bis(2,6-diiso pro pyl-phenyl)imida zolium tetra fluoro borate; N,N′-Bis(2,6-diiso pro pyl phenyl)dihydro imida zolium tetra fluoro borate[282109-83-5]C27H39BF4N2

FW 478.42

i-Pr

i-Pr

i-Pr

i-Pr

BF4-

N+

N

mp ............................................................................................... >300

693553-1G 1 g

693553-5G 5 g

1,3-Di-tert-butyl imidazoli nium tetra fluoro borate, 95%1,3-Bis(tert-butyl)-4,5-dihydro-1H-imida zolium tetra fluoro-borate; N,N′-Bis(tert-butyl)dihydro imida zolium tetra fluoro-borate[137581-21-6]C11H23N2 · BF4

FW 270.12

t-Bu

t-Bu

BF4-

N+

N

659991-1G 1 g

659991-5G 5 g

1,3-Bis(1-adamantyl)imidazoli nium tetra fluoro borate, 97%N,N′-(1-Adamantyl)-4,5-dihydro imida zolium tetra fluoro-borateC23H35N2 · BF4 FW 426.34 N

NBF4

mp .......................................................................................... >300 °C

660027-1G 1 g

1-(1-Adamantyl)-3-(2,4,6-tri methyl phenyl)imidazoli niumchloride1-(1-Adamantyl)-3-(2,4,6-tri methyl phenyl)-4,5-dihydro imida zolium chlorideC22H31ClN2

FW 358.95

NN

CH3

H3C

CH3

Cl

mp ................................................................................. 263 to 280 °C

665029-100MG 100 mg

665029-500MG 500 mg

Bis(1,3-bis(2,6-diiso pro pyl phenyl)imidazol-2-yl idene) 8

copper(I) tetra fluoro borate[886061-48-9]C54H72BCuF4N4

FW 927.53 N

NCuBF4i-Pr

i-Pr

i-Pr

i-Pr

2

mp .......................................................................................... >300 °C

696250-100MG 100 mg

696250-500MG 500 mg

1,3-Bis(2,4,6-tri methyl phenyl)-1,3-dihydro-2H-imidazol- 8

2-yl idene, 97%1,3-Bis(2,4,6-tri methyl phenyl)imidazol-2-yl idene[141556-42-5]C21H24N2

FW 304.43

H3C

N

N

H3C

CH3

CH3

CH3

CH3

mp ............................................................................................ 140 °C

696188-250MG 250 mg

696188-1G 1 g

1,3-Bis(2,6-diiso pro pyl phenyl)-1,3-dihydro-2H-imida- 8

zol-2-yl idene, 97%1,3-Bis(2,6-diiso pro pyl phenyl)imidazol-2-yl idene[244187-81-3]C27H36N2

FW 388.59i-Pr

i-Pr

i-Pr

i-Pr

N

N

mp ................................................................................. 213 to 217 °C

696196-250MG 250 mg

696196-1G 1 g

1,3-Dicyclo hexyl imida zolium tetrafluoroborate salt, 97%[286014-38-8]C15H25BF4N2

FW 320.18N

N

BF4-

mp ................................................................................. 171 to 175 °C

666181-250MG 250 mg

666181-1G 1 g

666181-5G 5 g

1,3-Di-tert-butyl imida zolium tetra fluoro borate, 97%N,N′-Bis(tert-butyl)imida zolium tetra fluoro borate; 1,3-Bis(tert-butyl)-imidazol-2-ylidi nium tetra fluoro borate[263163-17-3]C11H21N2 · BF4

FW 268.10

t-Bu

t-Bu

BF4-

N+

N

mp ................................................................................. 157 to 198 °C

659983-1G 1 g

659983-5G 5 g

1,3-Bis(1-adamantyl)imida zolium tetra fluoro borate, 97%N,N′-(Adamantyl)imida zolium tetra fluoro borate; 1,3-Bis(tri-cyclo[3.3.1.13,7]dec-1-yl)-1H-imida zolium tetra fluoro borate[286014-42-4]C23H33BF4N2

FW 424.33N

N

BF4-

mp ................................................................................. 277 to 282 °C

660035-1G 1 g


























$


Metal O

rganic Framew

orks (MO

Fs)

Metal Organic Frameworks (MOFs)Stephen Caskey, Ph.D.Scientist, New Product ResearchSigma-Aldrich Corporation

Metal-organic frameworks (MOFs) are a relatively new class of porous, crystalline materials with a broad range of applications. MOFs are composed of metal ions or clusters, which act as the joints, bound by multidirectional organic ligands, which act as linkers in the network structure. These networks can be 1-D, 2-D, or 3-D extended, periodic structures. The joints and linkers assemble in such a way that regular arrays are formed resulting in robust (often porous) materials analogous to zeolites. MOFs are the highest reported surface area materials known. Most porous MOFs reported to date are microporous (pore diameters of less than 2 nm) as defined by IUPAC based on the type of gas sorption isotherm the material displays; however, there have been a limited number of recent examples of demonstrated mesoporous (pore diameters of 2-50 nm) MOF materials. Besides much greater internal surface areas, MOFs offer significant advantages over zeolites in the prospect of predictable alteration of organic units to provide tailored materials for given applications. For example, the length of the organic linker often defines the size of resulting pores of a given material. Furthermore, functionalization of the organic unit can provide predictably functionalized pores.

Aldrich is pleased to offer MOFs under the tradename BasoliteTM. These materials (Figure 1) provide a good selection of different pore shapes and sizes, different metals (Al, Cu, Fe, and Zn) and different organic linkers (BDC, BTC, mIM).

HKUST-1 (Basolite™ C300)HKUST-1 is a copper-based MOF that was first reported in 1999 by Williams and co-workers.1 Blue cubic crystals are formed under solvothermal conditions. Under these conditions, CuII paddlewheel dimers form readily to act as square-planar building blocks and are linked by the trimesate trianions that act as trigonal-planar building blocks. These crystals are then exchanged into a low boiling solvent and evacuated under vacuum at elevated temperature to generate a porous material. Prior to evacuation, solvent molecules, generally water, fill the axial coordination positions of the CuII-paddlewheels. Once the coordinating ligands are removed under vacuum, the material becomes sensitive toward re-coordination of the ligand such that irreversible decomposition can occur upon exposure to air/moisture (Scheme 1). This is generally true of all Cu-based MOFs, but not necessarily for other metals. If the material is handled properly, the Langmuir surface area of HKUST-1 is ca. 2200 m2/g.2 HKUST-1 has been called several different names such as MOF-199 and Cu-BTC, and Aldrich sells it as Basolite™ C300 (688614).

De Vos has reported the separation of C8-alkylaromatic compounds (p-xylene, m-xylene, and ethylbenzene), which are too close in boiling point to separate by distillation. They investigated HKUST-1 (BasoliteTM C300, 688614), MIL-53(Al) (Basolite™ A100, 688738) and MIL-47(V). MIL-47, a V-based material, was used in this separation, which is proposed to have been achieved by size selectivity.3 The best known example of size selective catalysis using a MOF was reported in JACS in 2008.4 This work was also featured in Chemical & Engineering News.5 A Mn-based tetrazole MOF with BET surface area of ca. 2100 m2/g was shown to act as a size-selective Lewis acid catalyst for the cyanosilylation of carbonyls (Scheme 2). While the size-selection aspect of this work is unprecedented for this reaction, it can be catalyzed by several different zeolites as well as HKUST-1 (Basolite™ C300, 688614).6

ZIFsNew MOF materials termed zeolitic imidazolate frameworks (ZIFs) are generated from metal ions and imidazolate anions.7 The bonding angles of the imidazolate are thought to mimic the bonding angles about Si-O bonds found in zeolites; thus, ZIFs and zeolites tend to form closely related structures. ZIFs involve M-N bonds instead of M-O bonds. The thermal stability of ZIFs are reported to be higher than most MOFs, up to ca. 500 ºC, however, organic components are still present, which limit the stability. Some of the most important ZIFs are

O

OO

O

O

O

OO

O

ON N

CH3

BasoliteTM A100688738

Al3+

Cu2+

Fe3+

Zn2+

BasoliteTM C300688614

BasoliteTM F300690872

BasoliteTM Z1200691348

BTCfrom trimesic acid

mIMfrom 2-

methylimidazole

BDCfrom terephthalic

acid

Organic Linkers

Metal Ions

Figure 1

Figure 2

CuO

O

O

OCuO

O

O

OOH2H2O Cu

O

O

O

OCuO

O

O

O

Evacuation-H2O

Scheme 1

Ar

O

H Ar H

Me3SiO CNMe3SiCN+

MOF catalyst

CH2Cl2

Scheme 2

IPd on MOF

OH

O+

OH

O

DMA120 °C

5 h ≥ 95% conversion

Scheme 3

ZIF-8 (sold by Aldrich under the name Basolite™ Z1200, 691348) and ZIF-69, which is useful for CO2 storage.8 The high thermal stability of ZIFs points to the potential for application as solid supports for catalysis. Several MOFs have already been examined as solid supports, analogous to alumina, silica, or activated carbon, for heterogeneous catalysts to improve surface areas and enhance recyclability. Férey and co-workers recently reported the preparation of Pd-impregrenated MIL-101, a Cr-based MOF, that showed good activity and recyclability for the Heck reaction of iodobenzene with acrylic acid (Scheme 3).9

References: (1) Chui, S. S.-Y. et al. Science 1999, 283, 1148. (2) Wong-Foy, A. G. et al. J. Am. Chem. Soc. 2006, 128, 3494. (3) (a) Alaerts, L. et al. Angew. Chem., Int. Ed. 2007, 46, 4293. (b) Alaerts, L. et al. J. Am. Chem. Soc. 2008, 130, 14170. (c) Finsy, V. et al. J. Am. Chem. Soc. 2008, 130, 7110. (4) Horike, S. et al. J. Am. Chem. Soc. 2008, 130, 5854. (5) Ritter, S. Chem. Eng. News 2008, 86(16), 8. (6) Schlichte, K. et al. Microporous Mesoporous Mater. 2004, 73, 81. (7) Park, K. S. et al. Proc. Nat. Acad. Sci. U.S.A. 2006, 103, 10180. (8) Banerjee, R. et al. Science 2008, 319, 939. (9) Hwang, Y. K. et al. Angew. Chem., Int. Ed. 2008, 47, 4144.




$

sigma-aldrich.com20

Met

al O

rgan

ic F

ram

ewor

ks (M

OFs

)

Basolite™ A100 8

Alu mi num tere phthal ate; MIL 53C8H5AlO5

FW 208.10

bulk density ...........................................................................0.4 g/cm3

BET surf. area .............................................................1100-1500 m2/g

particle size distribution ...............................................31.55 μm (D50)

688738-10G 10 g

688738-100G 100 g

688738-500G 500 g

Basolite™ C 300 8

Copper ben zene-1,3,5-tri carboxy late; Cu-BTC MOFC18H6Cu3O12

FW 604.87

bulk density .........................................................................0.35 g/cm3

BET surf. area .............................................................1500-2100 m2/g

particle size distribution ...............................................15.96 μm (D50)

688614-10G 10 g

688614-100G 100 g

688614-500G 500 g

Basolite™ Z1200 8

2-Methyl imid azole zinc salt; ZIF 8[59061-53-9]C8H12N4ZnFW 229.60

bulk density .........................................................................0.35 g/cm3

BET surf. area .............................................................1300-1800 m2/g

particle size ......................................................................4.9 μm (D50)

691348-10G 10 g

691348-100G 100 g

691348-500G 500 g

Basolite™ F300 8

Iron 1,3,5-ben zene tri carboxy late; Fe-BTCC9H3FeO6

FW 262.96

bulk density ................................................................ 0.16-0.35 g/cm3

BET surf. area .............................................................1300-1600 m2/g

690872-10G 10 g

690872-100G 100 g

690872-500G 500 g

Imid azole, 99%1,3-Diaza-2,4-cyclo penta diene; Gly oxal ine[288-32-4]Merck 13,4935; Beil. 23,V,4,191; Fieser 1,492; 2,220C3H4N2

FW 68.08

NH

N

pKa (25 °C)................................................................................... 6.95

mp ..................................................................................... 88 to 91 °C

bp............................................................................................. 256 °C

vp .............................................................................<1 mmHg (20 °C)

ReagentPlus®

I202-1G 1 g

I202-5G 5 g

I202-100G 100 g

I202-500G 500 g

I202-2KG 2 kg

Trimesic acid, 95%Ben zene-1,3,5-tri carboxy lic acid[554-95-0]Beil. 9,IV,3747C9H6O6

FW 210.14

O

O

O

OH OH

OH

mp .......................................................................................... >300 °C

acetic acid ....................................................................................<5%

482749-100G 100 g

482749-500G 500 g

Tere phthal ic acid, 98%Ben zene-1,4-dicarboxy lic acid[100-21-0]Merck 13,9238; Beil. 9,IV,3301C8H6O4

FW 166.13

OHHO

O

O

mp .......................................................................................... >300 °C

vp ........................................................................<0.01 mmHg (20 °C)

ait .............................................................................................. 925 °F

185361-5G 5 g

185361-100G 100 g

185361-500G 500 g

2,6-Naph thalene dicarboxy lic acid, 99%[1141-38-4]Beil. 9,921C12H8O4

FW 216.19

OHHO

O

O

mp .......................................................................................... >300 °C

523763-5G 5 g

2,5-Dihydroxy tere phthal ic acid, 98%2,5-Dihydroxy-1,4-ben zene dicarboxy lic acid[610-92-4]Beil. 10,554C8H6O6

FW 198.13

OHHO

HO

OH

O

O

mp .......................................................................................... >300 °C

382132-5G 5 g

382132-25G 25 g

1,3,5-Tris(4-carboxyphenyl)benzene,≥98% 8

4,4′,4′′,-Ben zene-1,3,5-triyl-tris(benzoic acid)[50446-44-1]C27H18O6

FW 438.43

OHO

O

HO

O

OH

mp ................................................................................. 322 to 327 °C

solvent≤20wt.%

686859-1G 1 g

2-Methyl imid azole, 99%2-Methyl gly oxal ine[693-98-1]Beil. 23,V,5,35C4H6N2

FW 82.10

N

NH

CH3

mp ................................................................................. 142 to 143 °C

bp...................................................................................... 267-268 °C

vp ...............................................................................<1 mmHg (0 °C)

M50850-100G 100 g

M50850-500G 500 g















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Catalytic D

eprotection—D

EPRO™

Catalyst K

it/Catalytic D

eprotection

Catalytic Deprotection—DEPRO™

Catalyst Kit/Catalytic DeprotectionRobert J. McNair Ph.D, Development Manager, Johnson-Matthey Catalysis

DeprotectionIn the manufacture of pharmaceuticals and fine chemicals there is often a requirement for a protection strategy to minimize possible side reactions during a synthesis. Small, easily removed protecting groups (PG), available for a range of functional groups, is highly desired. One such easily removed PG is derived from the facile catalytic hydrogenolysis of benzylic groups. An analysis of the published medicinal chemical routes shows that over 1000 drug syntheses currently use this type of protection. The classic functional groups requiring protection are alcohols, acids and amines.

Simple cleavage of these protecting groups is critical. Cleavage by catalytic hydrogenation can be performed with good selectivity under mild conditions using a heterogeneous palladium on carbon (Pd/C) catalyst in the presence of hydrogen gas or a hydrogen transfer agent, e.g. ammonium formate or isopropanol. Efficient removal depends on selection of the most active and selective catalyst, and an optimized set of reaction conditions. This need has led to the development of a range of more active and selective catalysts with reduced metal loadings designed for O-debenzylation of benzyl protected alcohols and acids, N-debenzylation of amines, amides and Cbz (carbamate) type PG of amines.

Model ReactionsTwo model reactions were selected and investigated; the debenzylation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose, and the debenzylation of N-benzyl N-α-methylbenzylamine.

Standard reaction conditions for deprotection of the glucopyranose sugar were 25oC, 3 bar hydrogen pressure using a 5 weight percent catalyst loading based on substrate (for 5% Pd/C catalysts). Standard reaction conditions for deprotection of the amine were 50oC, 3 bar hydrogen pressure with a 5 weight percent catalyst loading based on substrate (for 5% Pd/C catalysts). Catalysts with higher percent metal loadings were evaluated on an equal metal basis. Screening reactions were carried out in an Argonaut Endeavor™ 8 x 10 ml reactor system. Reactions, products and byproducts were monitored by hydrogen uptake, GC and/or HPLC.

Catalyst Activity and SelectivityThe DEPRO™ 5% Pd/C and 10% Pd/C catalysts were screened under the standard reaction conditions for each reaction along with a current deprotection catalyst standard in the Industry, 20% Pd(OH)2/C Pearlman’s catalyst. For the O-debenzylation, reactions proceeded with complete conversion to the fully debenzylated product. For the N-debenzylation, hydrogenolysis of the less bulky benzyl group occurred with high selectivity in most cases. The reaction rate/hydrogen uptake profile for the N-debenzylation reaction is shown in Figure 1. For both the O-debenzylation and N-debenzylation reactions, the DEPRO catalysts were found to be more active and selective than the current Pearlman’s catalyst.

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0 30 60 90 120 150 180

N-debenzylation with L-(-)-N-Benzyl-α-methylbenzylamine

H2

Upt

ake

(ml)

Time (minutes)

Ethanol Ethyl Acetate Tetrahydrofuran Acetic Acid

Figure 1

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ytic

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Solvent EffectsSolvent choice is critical for any deprotection reaction. For amine deprotection, the free amine products are well known to strongly adsorb at active sites, inhibiting or even completely poisoning the catalyst. For each of the O-debenzylation and N-debenzylation reactions a series of commonly employed solvents, THF, ethanol, ethyl acetate, acetic acid, and solvent mixtures were screened under standard reaction conditions using several of the top performing catalysts. Results were in general independent of specific catalyst type.

For the O-debenzylation, reaction rates were fastest in THF, slightly slower in ethanol and acetic acid, and slowest in ethyl acetate. Reaction rates were generally linear with all reactions ultimately producing the completely debenzylated product.

For the N-debenzylation, reaction rates were fastest in ethanol and slowest in THF (Figure 2). The presence of acid served to prevent catalyst inhibition through protonation of the amine product.

Catalyst Design EffectsThe performance of a Pd/C catalyst is affected by the nature of the underlying carbon support, the size and location of the deposited metal particulates, the active metal precursor, the metal oxidation state and the method of catalyst preparation. Metal particulates can be made to distribute preferentially at the exterior surface of the support (an eggshell or surface loaded catalyst) or be evenly dispersed throughout the support structure (a standard or uniform catalyst). Deposited metal may be either in a reduced or unreduced form.

For most O-debenzylation and N-debenzylation reactions, eggshell unreduced, and eggshell reduced catalysts perform better than uniform catalysts. For otherwise equivalent catalysts, the underlying carbon support can have a large effect on both the initial reaction rate and selectivity to the desired product. The DEPRO™ catalysts represent a cross section of these desired properties.

SummaryFacile cleavage of O-benzyl and N-benzyl protecting groups can be achieved by catalytic hydrogenation using heterogeneous Pd/C catalysts at low temperature and pressure, with low catalyst loadings and low catalyst weight percent metal. The structure of the substrate plays an important role in determining the activity and selectivity of any debenzylation catalyst. It is important to investigate a number of catalyst types for each specific application. A variety of solvents, temperatures, pressures, and catalyst loadings should be evaluated to arrive at an optimized set of reaction conditions.

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DEPRO-901 DEPRO-904 DEPRO-905 DEPRO-903

DEPRO-906 DEPRO-902 Pearlman's

Hydrogenation of N-Benzyl-N-α-methylbenzylamine at 50°C, 3 bar hydrogen pressure with various catalysts in ethanol

H2 U

pta

ke (

mL)

Time (min)

Figure 2

Deprotection kit I for N-O de benzyl ation 8

Deprotection kit I for N-O de benzyl ation

Components

DEPRO-901 5% Pd/C DEPRO-902 10% Pd/C DEPRO-903 5% Pd/C DEPRO-904 5% Pd/C DEPRO-905 10% Pd/C DEPRO-906 10% Pd/C

703605-1KT 1 kit




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Recently introduced by Professor Bruce Lipshutz of UC-Santa Barbara, polyoxyethanyl α-tocopheryl sebacate (PTS) is a nonionic amphiphile that is proving to be a versatile “solubilizer” for organic molecules in water.1 Lipophilic substrates and catalysts can efficiently enter the micelles formed by PTS in water leading to important cross-coupling reactions at room temperature without the need for a co-solvent.

To use, one simply places the requisite amount of PTS (15 wt% in water) into a test tube with a stir bar and adds the organic substrate(s) and catalyst. Reactions are generally complete within 3–24 hours and can be accelerated if needed upon mild heating to 40–50 °C. Work-up is also very simple involving either extraction of

the reaction mixture with EtOAc-hexane or deposition onto a bed of silica gel and elution with EtOAc. In most examples studied, PTS outperformed other non-ionic amphiphiles such as Triton®-X100 and Brij® 30.

PTS (n = ca. 13)698717

O

O

OO

O H4

O

n

+ Ot-Bu

O

CbzHNO

5O

Bn

Ot-Bu

O

96%

2% Grubbs II

rt, 12 h

CbzHNO

5O

Bn

E isomer only

2.5 wt% aq PTS

References: (1) Sold under license from Zymes, LLC. (2) Lipshutz, B. H. et al. Org. Lett. 2008, 10, 1325. (3) Lipshutz, B. H. et al. Adv. Synth. Catal. 2008, 350, 953. (4) (a) Lipshutz, B. H. et al. Org. Lett. 2008, 10, 1333. (b) Lipshutz, B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329. (5) (a) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329. (b) Neither acrylates nor styrenes any longer require 15 wt% PTS/water in coupling to aryl iodides; see Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta, 2008, 41, 59. (6) Lipshutz, B. H. et al. Org. Lett. 2008, 10, 3793.

Triton® and Brij® are registered trademarks of ICI Americas, Inc. and Union Carbide Corporation, respectively.

SN O

O OS

N O

O O

2 mol % Grubbs II

2.5 wt% aq PTS

rt, 3 h

96%

CH3

CH3

Br B(OH)2

CH3

CH3

+CH3

CH3

CH3

CH3

85%

2 mol % Pd(dtbpf)Cl2

Et3N, 2 wt% aq PTS

rt, 5 h

OBn

BnO

I

NTs

H3COTBS

+

OCH3

2 mol %OBn

BnO

NTs

OCH3

H3COTBS

90%9:1 E/Z

Pd(dtbpf)Cl2

Et3N, rt

15 wt% aq PTS

+

1 mol % PdCl2(CH3CN)2

Et3N, 3 wt% aq PTS

rt, 23 h

CH3

Br

CH3

2.5 mol % X-Phos

CH3

CH3

quant.

PTS Amphiphile for Metathesis and Cross-Coupling in Water

Olefin Cross Metathesis2

Olefin Ring Closing Metathesis3

Suzuki-Miyaura Coupling4

Heck Coupling5

Sonogashira Coupling6




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©2009 Sigma-Aldrich Co. All rights reserved. SIGMA, , SAFC, , SIGMA-ALDRICH, ALDRICH, , FLUKA, , and SUPELCO, are trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P. Sigma brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product(s) for their particular use. Additional terms and conditions may apply. Please see reverse side of the invoice or packing slip. Eppendorf® is a registered trademark of Eppendorf-Netheler-Hinz GmbH. Sepharose® is a registered trademark of GE Healthcare. IGEPAL® is a registered trademark of General Dyestuff Corp. Coomassie® is a registered trademark of Imperial Chemical Industries Ltd. ProteoSilver™ is a trademark of Sigma-Aldrich Biotechnology LP and Sigma-Aldrich Co. Basolite™ is a trademark of BASF product. DEPRO™ is a trademark of Johnson-Matthey.

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15058708 Chemfiles Vol 9 No 2 Catalysis

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