Vol. 9, No.

Catalysis

Features include:
Asymmetric Synthesis
Metal and Phosphine
Mediated Transformations
(AtaPhos)2PdCl2, a non-proprietary catalyst for N-Heterocyclic Carbenes
Suzuki-Miyaura cross-coupling reactions
Metal Organic Frameworks
(MOFs)
Catalytic Deprotection with
DEPRO™ Catalyst Kit
 $

Introduction Vol. 9 No. 2

The development of efficient and versatile catalysts for use in asymmetric
synthesis and cross-coupling has allowed chemists to achieve unrivaled and Aldrich Chemical Co., Inc.
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Introduction

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 $

Asymmetric Synthesis Ph

Asymmetric Epoxidation of Allylic Alcohols O

Ph
N
O
The catalytic asymmetric epoxidation of olefins has become the O
V (OiPr)
reaction of choice to generate diverse chiral building blocks used in N
Ph
the synthesis of natural products and biologically active molecules. O
The development of catalysts based on bis(hydroxamic acid) ligands for Ph
R2 (1 mol%) R2
the vanadium-catalyzed asymmetric epoxidation of allylic alcohols was
R1 OH R1 OH
based on a desire to reduce the deceleration effect observed in some TBHP (70% aq), CH2Cl2 O
cases in related epoxidations with hydroxamic acid ligands. -20 °C, 48 h

The deceleration observed was predicted to be a result of the Ph CH3 Ph

formation of inactive species, which were formed from the binding Ph OH Ph OH H OH OH
of more than one ligand to the metal. It was predicted that since O O O O

Asymmetric Synthesis
the bidentate ligand (bis(hydroxamic acid)) would be chelating to the 91%, 97% ee 84%, 97% ee 73%, 95% ee 79%, 95% ee
(0 °C)
metal, this deceleration effect could be resolved. Additionally, it was
hypothesized that a larger R group would prevent the carbonyl oxygen Scheme 1
coordination to the metal by favoring a conformation in which the
carbonyl group was directed towards the cyclohexane (Figure 1). Thus,
Ph
an ideal catalyst system was designed via control of the coordination O
Ph
number as well as the steric environment.
N
O
The use of bis(hydroxamic acid) based ligands in combination with O
V (OiPr)
N
VO(O-iPr)3 proved effective in the efficient asymmetric epoxidation
Ph
of various allylic alcohols (Scheme 1). Using only 1 mol% of the O
Ph
catalyst, Yamamoto and co-workers demonstrated a variety of allylic (1 mol%)
alcohols could be converted to the enantiopure epoxides with excellent OH OH O
OH
TBHP (70% aq), CH2Cl2 +
enantioselectivity. Ph Ph
0 °C Ph
This methodology was also applied in the kinetic resolution of allylic 1 51% conversion
racemic 95% ee 93% ee
alcohol 1, which resulted in high enantioselectivities of the epoxy
alcohol as well as the allylic alcohol (Scheme 2).1 Scheme 2

Asymmetric Epoxidation of Homoallylic Alcohols VO(O-iPr)3 (1 mol%)

Ligand (2 mol%)
R3 R3
While there are various efficient catalytic systems for the asymmetric R2 CHP (1.5 eq), toluene R2
epoxidation of allylic alcohols, the extension to homoallylic alcohols OH
rt, 24 h O
OH
R1 R1
had not been demonstrated. While the catalytic system reported
above allowed for the desired transformations, the enantioselectivities O O O O
achieved were a major limitation. After tuning the ligand, Zhang and n-C2H5 OH n-C6H13 OH n-C3H7 OH n-C5H11 OH
Yamamoto discovered that the (2,4,6-triethyl)-substituted biphenyl
bis(hydroxamic acid) ligand (2) provided the desired epoxide products 85%, 93% ee 92%, 98% ee 90%, 97% ee 90%, 99% ee
(from trans olefin) (from trans olefin) (from cis olefin) (from cis olefin)
in excellent yields and enantioselectivities (Scheme 3). In addition, the
kinetic resolution of substrate 3 was facilitated by the same catalyst O
R
system to afford excellent enantioselectivities of both the chiral
N
homoallylic alcohol as well as the epoxidation product (Scheme 4).2 Ligand =
OH
OH
N
R
O
O R Et
N
OH R= Et
OH
N Et
O R 2
Scheme 3
Figure 1

VO(O-iPr)3 (0.5 mol%)

Ligand 2 (1 mol%)
O
HO CHP (0.7 eq), toluene HO + HO
R rt, 30 h R
R
3

R = C2H5 R = C2H5
95% ee, 51% yield 95% ee, 48% yield

R = C4H9 R = C4H9
96% ee, 51% yield 96% ee, 48% yield

Scheme 4

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Asymmetric Transfer Hydrogenation

The use of transfer hydrogenation to reduce alkenes, carboxyl groups,
ketones, or imines has become very popular. Hashiguchi et al. reported N 4 (0.5 mol%) NH
the asymmetric transfer hydrogenation of ketones using a catalyst
CH3 HCO2H-Et3N (5:2), DMF
system comprised of ruthenium complexed with a chiral diamine N
H 28 °C, 5 h N CH3
H
ligand (RuCl(p-cymene)[(S,S)-Ts-DPEN], Scheme 5).3 Subsequently,
this methodology was extended to include transfer hydrogenation 86%, 97% ee

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, Scheme 7
with slight variations in the catalyst-ligand composition and/or solvent,
leading to excellent yields and enantioselectivities of the functionalized O OH
amine heterocycles.4
Asymmetric Synthesis

CH3 4 (0.5 mol%) CH3

Matsumura and co-workers also accomplished the asymmetric transfer IPA, 28 °C, 20 h
hydrogenation of α,β-acetylenic ketones using the RuCl(p-cymene) >99%, 97% ee
[(R,R)-Ts-DPEN] catalyst system. As shown in Scheme 8, the reduction
to the propargylic alcohols occurs selectively without any competitive O OH
reaction with the alkynes.5 4 (0.5 mol%)
n-C5H11
n-C5H11
(H3C)3Si IPA, 28 °C, 15 h (H3C)3Si

Asymmetric Ketone Hydrogenation 98%, 99% ee

Mikami and co-workers reported an asymmetric ketone

hydrogenation that utilizes an achiral benzophenone ligand Scheme 8
(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
PPh2
observed with the benzophenone-based catalyst are superior to those Cl
observed with BINAP-based catalytic systems. When the hydrogenation O Ru
Cl DMFn
of 1’-acetonaphthone was examined with 2,2’-bis(diphenylphosphino) PPh2
benzhydrol as the ligand in place of benzophenone, the O (0.4 mol%) OH
enantioselectivity observed was lower than that observed with (S,S)-DPEN (0.4 mol%)
R R
2,2’-bis(diphenylphosphino)benzophenone) (Table 1).6 H2 (15 atm), KOH (1.0 mol%), IPA
rt, 4 h
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. entry Ketone Product ee (%)
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. O OH
2006, 8, 1517. 1 99

O OH
2 98

SO2 O OH
N
3 92
Ru
N Cl
H2 4 OH
O O OH
(0.5 mol%) CH3
CH3 4 91
IPA, KOH Cl
Cl rt, 19 h
95%, 93% ee
O OH
Scheme 5
5 90

H3CO H3CO
4 (0.4 mol%)
Table 1
N NH
H3CO HCO2H-Et3N (5:2), CH3CN H3CO
CH3 28 °C, 3 h CH3
>99%, 95% ee

Scheme 6

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(1R,2R)-N,N′-Dihydroxy-N,N′-bis(diphenyl­acetyl)-1,2- 8 (1R,2R)-N,N′-Dihydroxy-N,N′-bis(3,3,3-tri­phenyl­- 8
cyclo­hexane­di­amine, 97% pro­pionyl)-1,2-cyclo­hexane­di­amine, 95%
(1R,2R)-N,N′-Dihydroxy-N,N′-bis(diphenyl­acetyl)-cyclo­ Ph (1R,2R)-N,N′-Dihydroxy-N,N′-bis(tri­phenyl­pro­pionyl)- O
Ph
Ph
hexane-1,2-di­amine; (R)-CBHA-DPA; (1R,2R)-N,N′-1,2-cyclo­ O
Ph
cyclo­hexane-1,2-di­amine; N,N′-(1R,2R)-1,2-cyclo­hexane­ Ph
N
hexane­diylbis[N-hydroxy-α-phenyl-ben­zene­acet­amide] N diylbis[N-hydroxy-β,β-diphenyl­ben­zene­propan­amide]; OH
OH OH
[860036‑16‑4] OH
(R)-CBHA-TPP N Ph
N
C34H34N2O4 [860036‑29‑9] O
Ph
Ph Ph
FW 534.64 O C48H46N2O4
Ph
FW 714.89
mp.................................................................................. 200 to 205 °C mp.................................................................................. 217 to 221 °C
[α] 22
D +90.0°, c = 1 in chloroform
D +14.0°, c = 1 in chloroform
[α] 22
700592-50MG 50 mg 700541-50MG 50 mg

(1S,2S)-N,N′-Dihydroxy-N,N′-bis(diphenyl­acetyl)-

Asymmetric Synthesis 
8 (1S,2S)-N,N′-Dihydroxy-N,N′-bis(3,3,3-tri­phenyl­- 8
1,2-cyclo­hexane­di­amine, 97% pro­pionyl)-1,2-cyclo­hexane­di­amine, 95%
(1S,2S)-N,N′-Dihydroxy-N,N′-bis(diphenyl­acetyl)-cyclo­ Ph
(1S,2S)-N,N′-Dihydroxy-N,N′-bis(tri­phenyl­pro­pionyl)- Ph
O O
hexane-1,2-di­amine; (S)-CBHA-DPA; (1S,2S)-N,N′-1,2-cyclo­ Ph cyclo­hexane-1,2-di­amine; (S)-CBHA-TPP; N,N′-(1S,2S)- Ph
N Ph
hexane­diylbis[N-hydroxy-α-phenyl-ben­zene­acet­amide] N
OH 1,2-cyclo­hexane­diylbis[N-hydroxy-β,β-diphenyl­ben­zene­ OH
C34H34N2O4 OH propan­amide] N
OH
Ph
N
FW 534.64 Ph C48H46N2O4 Ph
O O
Ph
Ph FW 714.89
mp.................................................................................. 217 to 221 °C
mp.................................................................................. 199 to 204 °C
[α] 22
D −14.0°, c = 1 in chloroform
D -79.0°, c = 1 in chloroform
[α] 22
700533-50MG 50 mg
700576-50MG 50 mg
Vanadium(V) oxytriiso­prop­oxide
(1R,2R)-N,N′-Dihydroxy-N,N′-bis(bis(3,5-dimethyl- 8
­phenyl)acetyl)-1,2-cyclo­hexane­di­amine, 97% Tri­iso­pro­poxy­vanadium(V) oxide; Vanadium(V) tris­iso­ CH3
O
CH3

(1R,2R)-N,N′-Dihydroxy-N,N′-bis(3,5-dimethyl­ H3C CH3

prop­oxide oxide H3C O V O CH3

diphenyl­acetyl)-cyclo­hexane-di­amine; [5588‑84‑1] O CH3

(R)-CBHA-DMDA; N,N′-(1R,2R)-1,2-cyclo­ Beil. 1,IV,1242 CH3

CH3
hexane­diylbis[α-(3,5-dimethyl­phenyl)-N-hydroxy-
O C9H21O4V
3,5-dimethyl-ben­zene­acet­amide] N
FW 244.20
OH liquid
CH3
[860036‑27‑7] CH3
OH
C42H50N2O4 N bp............................................................................80-82 °C/2 mmHg
FW 646.86 density......................................................................1.035 g/mL, 25 °C
O CH3
n 20
D
............................................................................................. 1.479
H3C CH3 404926-1G 1 g
mp.............................................................................194 to 199 °C (D) 404926-10G 10 g

[α] 22
D +76.0°, c = 1 in chloroform tert-Butyl hydro­peroxide solution
700584-50MG 50 mg
TBHP H3C O
OH
[75‑91‑2] H3C CH3
(1S,2S)-N,N′-Dihydroxy-N,N′-bis(bis(3,5-dimethyl­phenyl) 8
Merck 13,1569; Beil. 1,IV,1616
acetyl)-1,2-cyclo­hexane­di­amine, 97%
C4H10O2
(1S,2S)-N,N′-Dihydroxy-N,N′-bis(3,5-dimethyl­ H3C CH3
FW 90.12
diphenyl­acetyl)-cyclo­hexane-di­amine;  5.0-6.0 M in nonane
(S)-CBHA-DMDA; N,N′-(1S,2S)-1,2-cyclo­ CH3
O water.............................................................................................<4%
hexane­diylbis[α-(3,5-dimethyl­phenyl)-N-hydroxy-
3,5-dimethyl­ben­zene­acet­amide] N density......................................................................0.817 g/mL, 25 °C
OH
CH3
C42H50N2O4 CH3 n 20 ............................................................................................. 1.399
OH D
FW 646.86 N
418064-50ML 50 mL
O CH3
Cumene hydro­peroxide, 80%
α,α-Dimethyl­benzyl hydro­peroxide H3C CH3
H3C CH3 OH
[80‑15‑9] O
mp.................................................................................. 186 to 190 °C Beil. 6,IV,3221
[α] 22
D −76°, c = 1 in chloroform
C9H12O2
700568-50MG 50 mg
FW 152.19
bp........................................................................100-101 °C/8 mmHg
vd......................................................................................... 5.4 (vs air)
vp.........................................................................<0.03 mmHg (20 °C)
 technical grade
density........................................................................1.03 g/mL, 25 °C
n 20
D ........................................................................................... 1.5210

247502-5G 5 g
247502-100G 100 g
247502-500G 500 g

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 $

RuCl(p-cymene)[(R,R)-Ts-DPEN] 8 DPBP-bidentate phos­phine, 95% 8

[N-[(1R,2R)-2-(Amino-κN)-1,2-diphenyl­ CH3 2,2′ Bis(diphenyl­phos­phino)benzo­phen­one Ph
P
Ph Ph
P
Ph
H3C O
ethyl]-4-methyl­ben­zene­sulfo­namidato-κN] CH3 [845821‑92‑3]
chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methyl­ O Ru Cl C37H28OP2
H3C S N NH2
ethyl)ben­zene]-ruthe­nium O
FW 550.57
[192139‑92‑7] Ph Ph
C31H35ClN2O2RuS mp.................................................................................. 152 to 156 °C
FW 636.21 692344-100MG 100 mg
mp............................................................................................. 215 °C 692344-500MG 500 mg
[α] 20
D −12°, c = 1 in chloroform
Dichloro(mesit­ylene)ruthe­nium(II) dimer, 95% 8
703907-100MG 100 mg
Di-μ-chloro­dichloro­bis[(1,2,3,4,5,6-η)-1,3,5- H3C
CH3
703907-500MG 500 mg
tri­methyl­ben­zene]di­ruthe­nium; Ruthe­nium(II)
Cl Cl
chloride mesit­ylene dimer
Asymmetric Synthesis

RuCl(p-cymene)[(S,S)-Ts-DPEN] 8 H3C Ru Ru CH3

[52462‑31‑4] Cl Cl
[N-[(1S,2S)-2-(Amino-κN)-1,2-diphenyl­ CH3
H3C C18H24Cl4Ru2 CH3
ethyl]-4-methyl­ben­zene­sulfo­namidato-κN] CH3 H3C
Ru Cl
FW 584.34
chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methyl­ O
H3C S N NH2
ethyl)ben­zene]-ruthe­nium O mp........................................................................................... >300 °C
[192139‑90‑5] Ph Ph
C31H35ClN2O2RuS 701769-100MG 100 mg
FW 636.21 701769-500MG 500 mg

mp........................................................................................... >175 °C Bis(norbor­na­diene)rhodium(I) tri­fluoro­meth­ane­- 8

[α] 20
D +104°, c = 0.45 in chloroform sulfo­nate, 97%
703915-100MG 100 mg [178397‑71‑2] O
703915-500MG 500 mg C15H16F3O3RhS Rh+ F3C S O
O
FW 436.25

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

701610-250MG 250 mg
701610-1G 1 g

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 $

Metal and Phosphine Mediated

Transformations
Se Pd Se
Pincer Ligands Cl
(5 mol%)
Functionalized allyl boronates are useful building blocks in natural R OH + [B(OH)2]2
DMSO/MeOH
R B(OH)2

product synthesis. Olsson et al. reported the use of a palladium 40-60 °C, 16-24 h
pincer complex in combination with diboronic acid for the boronation KHF2
of readily available allylic alcohols. Under mild conditions, a variety
of allylic alcohols were reacted with 5 mol% catalyst to yield the
R BF3K
corresponding boronic acids, which were converted to the more
stable trifluoroborate salt derivatives in good yields. Considering the O
widely available nature of allylic alcohols, the mildness of the reaction

Metal and Phosphine Mediated Transformations

BF3K C3H7 BF3K O BF3K
conditions, and the potential utility in natural product as well as fine
chemical synthesis, this conversion of the typically difficult-to-substitute 92% 94%
COOMe
77%

alcohol moiety into a functionalized alkylboronate is a remarkably

efficient method for the preparation of these reagents (Scheme 1). BF3K
BF3K
The authors suggest the diboronic acid is behaving as a Lewis acid 92% 82%
(Scheme 2); however, since it is not as strong a Lewis acid as alkyl- or Scheme 1
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 Me
group.1 O H2O
R OH + MeOH H H -MeOH B(OH)2
B
R O O H R O OH
+ [B(OH)2]2 B
HO B(OH)2

Scheme 2

1,3-Bis[(phenyl­seleno)methyl]ben­zene, 97% 8 [1,3-Phenylene­bis(methyl­ene)]bis(dicyclo­pentyl­- 8

[239448‑30‑7] phos­phine), 95%
C20H18Se2 Se Se 1,3-Bis(dicyclo­pentyl­phos­phino­methyl)ben­zene
FW 416.28 [255874‑48‑7] P P
C28H44P2
mp...................................................................................... 38 to 42 °C FW 442.60

684376-250MG 250 mg mp...................................................................................... 30 to 34 °C

684376-1G 1 g
680451-100MG 100 mg
680451-500MG 500 mg

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 $

Direct Arylation of Heterocycles

BF4
Lewis and co-workers have recently disclosed a highly functional-group P
compatible Rh-catalyzed C-H bond activation for the rapid synthesis of H
(15 mol%)
functionalized heterocycles. The method relies on the use of rhodium Br
H
N
N [RhCl(cod)]2 (5 mol%)
complexed with (Z)-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, + R
X (iPr)2N(iBu), THF X
which behaves as a chelating ligand, addressing the sometimes R
µW, 200 °C, 2 h
slow arylations that occur due to dehydrogenation leading to aryl
halide hydrohalogenation or reduction. This ligand is used as the N
F
tetrafluoroborate salt, which allows easy handling and storage and, N NH N O

when combined with the rhodium precatalyst, provides a highly robust O N Et

H
and efficient catalytic system, in many cases performing arylations that N
55% H 74%
were not possible using traditional catalytic methods. The scope of the 75%
reaction was examined and a variety of heterocycles were successfully
Metal and Phosphine Mediated Transformations

arylated including benzimidazoles, benzoxazoles, benzothiazoles, as

N N
well as bisarylimidazoles, with a variety of functionalized aryl bromides S NHAc
(sulfinyl-, chloro-, acetamide-, hydroxy-, and amino-containing N
H
N
H
functionalities were suitable coupling partners) (Scheme 3).2
93% 85%
Scheme 3

(Z)-1-tert-Butyl-2,3,6,7-tetra­hydro-1H-phos­phepi­nium 8 Chloro­bis(cyclo­octene)rhodium(I),dimer, 98%

tetra­fluoro­borate [12279‑09‑3]
Ellman ligand C32H56Cl2Rh2 Cl
P t-Bu BF4-
C10H20BF4P H
FW 717.50 Rh Rh

FW 258.04 Cl

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

mp.................................................................................... 190 °C (dec.)
 kanata purity
302473-100MG 100 mg
695688-100MG 100 mg
302473-250MG 250 mg
695688-500MG 500 mg
302473-500MG 500 mg
Chloro(1,5-cyclo­octa­diene)rhodium(I) dimer, 98% 302473-1G 1 g

Di-μ-chloro­bis[(1,2,5,6-η)-1,5-cyclo­octa­diene]
Cl
dirhodium; Bis(1,5-cyclo­octa­diene)dirhodium(I) Rh Rh
di­chloride; 1,5-Cyclo­octa­diene­rhodium(I) Cl
chloride dimer; Rhodium(I) chloride
1,5-Cyclo­octa­diene com­plex dimer
[12092‑47‑6]
C16H24Cl2Rh2
FW 493.08
mp.................................................................................... 243 °C (dec.)
227951-500MG 500 mg
227951-5G 5 g

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Air-Stable Trialkylphosphine for Morita-Baylis

Hillman Reactions
N
The use of amines and phosphines in nucleophilic catalysis is well-
precedented; however, arguably one of the severe limitations with N N
O P OH
respect to exploiting the more nucleophilic, yet less basic, phosphine CO2R
+ (20 mol%) CO2R
in this regard is its air sensitivity. This is especially true for the most Ar H
r.t., 5-19 h
Ar

nucleophilic of this class, the trialkylphosphines. While utilization

of these difficult-to-handle phosphines as their trifluoroborate salts Ar R Yield (%)
has provided an excellent solution to handling limitations, there are 4-NO2C6H4 Et 91
circumstances where the use of base is not necessary or possible. He
2-F-4-ClC6H3 Et 60
and co-workers have demonstrated the use of the known cage-like,
2-pyridyl
air-stable trialkylphosphine, 1,3,5-triaza-7-phosphaadamantane (PTA), Et 59

in organocatalysis, and specifically in the Morita-Baylis-Hillman (MBH) 2-NO2C6H4 n-Bu 93

Metal and Phosphine Mediated Transformations

reaction (Table 1). Traditionally, MBH reactions are conducted using Table 1
DABCO®, but slow reaction rates often hamper its utility. The authors’
use of PTA has addressed some of these difficulties, utilizing mild and N N
environmentally friendly conditions, to provide the desired products N
N
N N N N
in good to excellent yields. In addition, the use of PTA is also proving CO2Et P H2O
N N
N N P
successful in historically challenging cases, such as MBH reactions P
+ P
+ EtOH
using acrylate as the electrophile. + OH
EtO O EtO O CO2−
The authors also presented reasonable evidence implicating the 1 2 3
phosphorus-bound Michael adduct 1 by preparation of species 3 via
reaction of PTA with ethyl acrylate in THF-H2O (Scheme 4). Not only Scheme 4
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-phos­pha­ada­man­tane, 97% 8
1,3,5-Triaza-7-phos­pha­tri­cyclo[3.3.1.13.7]decane; PTA; NSC N
266642 N N
[53597‑69‑6] P

C6H12N3P
FW 157.15
mp.................................................................................. 244 to 250 °C
695467-500MG 500 mg
695467-2G 2 g

CH3
Hydroformylation P
Ph

H3C O
Despite a long-standing belief that formyl groups cannot be generated O CH3
O
at quaternary carbon centers via hydroformylation, Clarke and Roff CH3
CHO
(1 mol%)
have developed a method utilizing 1,3,5,7-tetramethyl-6-phenyl-2,4,8- NC(H2C)2 CO2Me NC(H2C)2 CO2Me
[Rh(acac)(CO)2] (0.2%)
trioxa-6-phosphaadamantane, an air-stable phosphane ligand, which 50 °C, 50 bar, 70 h
inhibited hydrogenation and provided excellent levels of regioselectivity Scheme 5
(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.

1,3,5,7-Tetra­methyl-6-phenyl-2,4,8-tri­oxa-6- 8
phos­pha­adamante, 97%
me
CgPPh; 1,3,5,7-Tetra­methyl-8-phenyl-2,4,6- CH3
Ph
tri­oxa-8-phos­pha­tri­cyclo[3.3.1.13,7]decane P
O
[97739‑46‑3] H3C
O CH3
C16H21O3P O
CH3
FW 292.31
mp.................................................................................. 106 to 111 °C
695459-100MG 100 mg
695459-500MG 500 mg
695459-2G 2 g

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com. 9
 $

Amination of Aryl Halides

Chlorophosphines CH3
P
The 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 X
(2 mol%)
R1 [(π-allyl)PdCl]2 (0.5 mol%) R1
chlorides with various amines can be notoriously difficult, usually NH + R3 N
requiring bulky phosphines to achieve reasonable yields. However, the R2 NaO-t-Bu, toluene R2 R3
100 °C, 3 h
scope of amination reactions using these bulkier phosphines is still
somewhat limited with respect to the variety of aryl chlorides that can entry X Product Yield (%)

be employed. To address this limitation, Ackermann et al. synthesized

O
a diaminophosphine ligand, which, when used with Pd(dba)2, afforded
good yields for the catalytic amination of a wide variety of aryl 1 Br N O 97
Metal and Phosphine Mediated Transformations

chlorides with different primary and secondary amines (Scheme 6).5

BRIDP Catalysts O O
Researchers at Takasago developed two phosphine-based ligands
O
for the Buchwald-Hartwig amination reaction with successful results 2 Br
O
for the cross-coupling of a wide array of amines and aryl halides. N 91
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. H3C

The development of a new ligand for efficient amination of a variety 3 Cl N

80
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 CH3
4 Cl
secondary amines.6a N

After the report of Cy-vBRIDP incorporating a vinyl-based phosphine 98

ligand, Suzuki and co-workers reported another amination ligand

(cBRIDP) for use with more challenging coupling partners such as the CH3 H
reaction of aryl chlorides with primary and secondary amines.2 The N
5 Cl 95
vinyl component was replaced with a methylcyclopropane moiety and
the cyclohexyl groups were replaced with t-butyl functionalities (the H3C

cyclohexyl version of this was also developed, Cy-cBRIDP). Improved

Table 2
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 entry X Product Yield (%)
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 1 Cl 82
coupling between 2,4,6-trichlorobenzene and carbazole, yielding N CH3

sterically congested products in good yields (Scheme 8).6b

2 Cl N 94a

Cl
P
N N

(10 mol%) H
3 Cl N CH3 95a
Pd(dba)2 (5 mol%) N
Cl + NH2 1
R R2
R1 R2 NaOtBu, toluene, 105 °C

a
H OMe H H xylene in place of toluene, 120 °C, 3 h
N N N
Table 3
97% 93% 87%
Scheme 6
CH3
P
CH3

Cl (2 mol%) N
P
[(π-allyl)PdCl]2 (0.5 mol%)
Cl + 3 eq N H N
NaO-t-Bu, xylene
Cl N
120 °C, 3 h
(4 mol%)
Pd(OAc)2 (1 mol%)
NH + Br N
NaO-t-Bu, toluene
100 °C, 3 h 67%
97%
Scheme 7
Scheme 8

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 $

2-Chloro-1,3-bis(2,6-diiso­pro­pyl­phenyl)-1,3,2-diaza­- 8 Cy-vBRIDP 8
phos­pho­li­dine Dicyclo­hexyl(1-methyl-2,2-diphenyl­vinyl)
[314730‑65‑9] i-Pr i-Pr phos­phine; 2-(Dicyclo­hexyl­phos­phino)-1,1- CH3
C26H38ClN2P N N
diphenyl-1-pro­pene
P
FW 445.02 P [384842‑24‑4]
Cl i-Pr
i-Pr C27H35P
mp.................................................................................. 212 to 220 °C FW 390.54
694207-250MG 250 mg
mp.................................................................................. 124 to 130 °C
694207-1G 1 g 702943-100MG 100 mg
702943-500MG 500 mg
Cy-cBRIDP 8
1-(Dicyclo­hexyl­phos­phino)-2,2-Diphenyl-
1-methyl­cyclo­propane; Dicyclo­hexyl(2,2- CH3

Metal and Phosphine Mediated Transformations

diphenyl-1-methyl-1-cyclo­pro­pyl)phos­phine
P
C28H37P
FW 404.57

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

702951-100MG 100 mg
702951-500MG 500 mg

Ferrocenyl Based Ligands and Catalysts 1,1′-Bis(di-tert-butyl­phos­phino)ferro­cene 8

Hartwig and co-workers have reported the use of the electron-rich [84680‑95‑5] t-Bu
C26H44FeP2 P
and bulky ligand 1,1’-bis(di-tert-butylphosphino)ferrocene for the t-Bu
Fe
amination of aryl halides and for the first amination of aryl tosylates. FW 474.42 t-Bu
P
The amination of various amines with aryl chlorides, iodides, and t-Bu
tosylates was effected using this novel ligand in combination with a
mp...................................................................................... 73 to 75 °C
palladium source affording the coupled products in excellent yield.
This ligand is exceptionally effective and, though the electron density 695149-250MG 250 mg
on the metal helps accelerate the oxidative addition (a necessity for 695149-1G 1 g
unactivated aryl chlorides), the electron-richness does not negatively
1,1′-Bis(di-tert-butyl­phos­phino)ferro­cene palladium 8
impact the reductive elimination since the steric bulk associated with
this ligand facilitates this last step of the catalytic cycle (Table 4).7 di­chloride, 98%
References: (5) Ackermann, L. et al. Angew. Chem., Int. Ed. 2006, 45, 7627. (6) (a) Suzuki,
[95408‑45‑0] t-Bu t-Bu
P
K. et al. Adv. Synth. Catal. 2007, 349, 2089. (b) Suzuki, K. et al. Adv. Synth. Catal. 2008, C26H44Cl2FeP2Pd Cl
350, 652. (7) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. FW 651.75 Fe Pd
Cl
P
t-Bu
t-Bu

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

t-Bu
701602-250MG 250 mg
P
t-Bu 701602-1G 1 g
Fe
t-Bu
P 1,1′-Bis(di-iso­propyl­phos­phino)ferro­cene palladium 8
t-Bu (1-2 mol%)
HNR2 + ArylX HNR2 di­chloride, 98%
Pd source, rt or ∆, 7-24 h
[215788‑65‑1] CH3 CH
3
entry Amine ArylX Product Yield (%) Conditions H3C
C22H36Cl2FeP2Pd CH3
P
H3CO H3CO
FW 595.64 Cl
Fe Pd
1 mol% Pd(OAc) Cl
1 HN O 81
Cl N O 100 °C, 10h P
CH3
H3C
CH3 CH3
1 mol% Pd(OAc)
2 HN H3C Cl H3C N 85 mp.................................................................................. 282 to 287 °C
100 °C, 12h

702005-250MG 250 mg
Cl H
N 702005-1G 1 g
NH2Bu Bu 1 mol% Pd(dba)
3 57
110 °C, 24h
CH3 CH3 1,1′-Bis(di-cyclo­hexyl­phos­phino)ferro­cene palladium 8
di­chloride, 98%
4 NH2Ph NC NC 79
2 mol% Pd(dba)2 [917511‑90‑1]
OTs N Ph 110 °C, 16h
H C34H52Cl2FeP2Pd
FW 755.90 P
Cl
CH3 CH3 Pd
1 mol% Pd(dba)2 Fe
NH2Bu Bu Cl
5 49
H3C I H3C NH rt, 7h P

Table 4

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

701998-250MG 250 mg
701998-1G 1 g

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 $

New Catalysts for Suzuki Coupling

Suzuki Coupling of Alkyl Chlorides (H3C)2N
Cl
P Pd P N(CH3)2
Gonzalez-Bobes and Fu reported the use of NiCl2•glyme in the Cl

presence of prolinol in the previously unprecedented Suzuki reactions Ar X

(1 mol%)
of unactivated secondary alkyl chlorides. Both primary, secondary, cyclic + Ar Ar'
K2CO3, toluene−water, reflux, 12 h
and acyclic alkyl chlorides can be utilized in this transformation, as well Ar' B(OH)2
as electron-rich and electron-poor arylboronic acids (Table 5).8
entry X Product Yield (%)
Non-Proprietary Catalysts for Cross-Coupling NH2

Great strides have been made in the development of catalysts for 1 Cl 93

N
cross-coupling chemistry, particularly for Suzuki-Miyaura reactions. H3C
The cross-coupling reaction of heteroaryl halides is of particular NH2
Metal and Phosphine Mediated Transformations

interest to the pharmaceutical industry since many biologically active 2 Cl 92

CF3
compounds are accessed through use of the Suzuki-Miyaura reaction. N
However, the efficient coupling of five-membered heteroaryl halides
NH2
or six-membered heteroaryl chlorides bearing heteroatom substituents
3 Cl 93
with boronic acids has not been well-developed. Catalysts are thought OCH3
to form inactive complexes with many of these types of substrates, N

and thus, they typically require high catalyst loadings in order to

H2N H3 C
achieve good yields.
4 Cl CH3 98
The Guram group at Amgen has recently communicated the N
development of an air-stable palladium complex, (AtaPhos)2PdCl2, for H3 C

Suzuki-Miyaura cross-coupling reactions (Table 6). The catalyst was

very effective at coupling a wide variety of substrates with arylboronic 5 Cl
N OCH3
95
N
acids, including amino-substituted 2-chloropyridines and five- H3CS
membered heteroaryl halides. The products are observed in excellent
yields and high turnover numbers (up to 10,000 TON) are typically N CN
6 Cl 94
achieved.9 N
H3CS

References: (8) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360. (9) (a) H3C
Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727. (b) Singer, R. A. et al. Synthesis 2003,
7 Cl N 99
1727. (c) Guram, A. S. et al. Org. Lett. 2006, 8, 1787.
N
H3CS H3C

H3CO
NiCl2 •glyme (6 mol%)
Ralkyl Cl + (HO)2B R1 Ralkyl R1 8 Cl N OCH3 98
prolinol (12 mol%) N
KHMDS (2 equiv) H3CO
i-PrOH, 60 °C

entry Alkyl Chloride Arylboronic acid Yield (%) 9 Cl H3CO OCH3 97

N N

1 Cl B(OH)2 80

10 Cl CH3 96
S
Cl
2 Me H3C B(OH)2 74
Me
CH3
N
11 Br OCH3 93
Cl N
3 F B(OH)2 46a H3C
CH3
OTBS

CH3
4 O Cl F3 C B(OH)2 79 N
12 Br F 95
N
H3C
aYield of trans isomer CH3

Table 5 Table 6

Nickel(II) chloride ethylene glycol dimethyl ether 8 Bis[(dicyclo­hexyl)(4-dimethyl­amino­phenyl)phos­- 8

com­plex, 98% phine] palladium(II) chloride
NiCl2 glyme CH3 (A-caPhos)2 PdCl2
[29046‑78‑4] O Cl C40H64Cl2N2P2Pd
Ni Cl H3C Cl CH3
C4H10O2 · Cl2Ni O FW 812.22 N P Pd P N
CH3 H3C Cl CH3
FW 219.72
mp........................................................................................... >300 °C
696668-1G 1 g 692913-250MG 250 mg
696668-5G 5 g 692913-1G 1 g

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 $

(4-(N,N-Dimethyl­amino)phenyl)di-tert-butyl phos­phine, 95% Bis(di-tert-butyl(4-dimethyl­amino­phenyl)phos­phine)-

A-taPhos t-Bu dichloro­palladium(II)
C16H28NP P
t-Bu (A-taPhos)2PdCl2 H3C t-Bu Cl t-Bu CH3
FW 265.37 H3C
N [887919‑35‑9] N P Pd P N
H3C t-Bu Cl t-Bu CH3
CH3 C32H56Cl2N2P2Pd
mp...................................................................................... 57 to 61 °C FW 708.07
678740-1G 1 g
677264-1G 1 g
678740-5G 5 g
Bis[di-(tert-butyl)(4-tri­fluoro­methyl­phenyl)phos­phine] 8
palladium(II) chloride
C30H44Cl2F6P2Pd t-Bu Cl t-Bu
FW 757.93 F3C P Pd P CF3
t-Bu Cl t-Bu

Metal and Phosphine Mediated Transformations

mp........................................................................................ 230 °C (D)
692921-250MG 250 mg
692921-1G 1 g

Accelerate Chiral Separation with

ChiroSolv Kits
®

The ChiroSolv Kit Advantage

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ChiroSolv Resolving Kits for ChiroSolv Resolving Kits for
for more information.
Liquid Racemates Solid Racemates
681431 Acid Series 1 698881 Acid Series 1
681423 Acid Series 2 699527 Acid Series 2
681415 Acid Series 3 698873 Acid Series 3
699217 Acid Series 4 699225 Acid Series 4
681407 Base Series 1 699233 Base Series 1
681393 Base Series 2 698938 Base Series 2
681377 Base Series 3 698946 Base Series 3
699241 Base Series 4 698954 Base Series 4

ChiroSolv is a registered trademark of ChiroSolve, Inc.

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 $

Gold Catalysis
The 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 O O
P
to accelerate this important class of reactions. Since gold catalysts can O
Au Cl

be considered as metallic sources of H+, several research groups have MeO2C CO2Me MeO2C CO2Me
successfully demonstrated the utility of Au(I) catalysts for Friedel-Crafts-
(3-10 mol%)
type reactions. Tarselli and Gagne recently reported an efficient and
functional-group-tolerant method for the cyclization of 4-allenyl arenes AgSbF6 (5 mol%) R
0.2M CH2Cl2
to afford benzocycles in the presence of chloro(triphenylphosphite) R
6-16 h
gold. The reaction was generally amenable with electron-rich arenes,
CO2Me CO2Me
but heterocyclic aromatic compounds with coordinating abilities such as CO2Me
MeO2C MeO2C
MeO2C CO2Me
MeO2C
triazoles, isoxazoles, and oxazoles led to catalyst poisoning. On the other
Metal and Phosphine Mediated Transformations

MeO
hand, the reaction was tolerant of functional groups and moieties such N
as ethers, acetals, and pyrroles (Scheme 9).10 MeO O
OMe O
Echavarren and co-workers used a Au(I) catalyst to effect the
transformation of substrate 4 to 5. This reaction proceeds through a 79% 59% 93% 87%

5-exo-dig cyclization followed by trapping with MeOH (Scheme 10).11

Scheme 9
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
t-Bu Au N C CH3
1,6-enynes. Using the electron-rich Au(I)-phosphite based catalyst below P
(6), the authors reacted 1,6-enynes with arenes and heteroarenes to t-Bu SbF6-
afford carbocycles. This reaction occurs via 5-exo-dig cyclization to afford
a cyclopropyl metal carbene species, which upon reaction with the
MeO2C (2 mol%) MeO2C
nucleophile affords the carbocyclic product (Table 7).12
MeO2C
MeO2C AgSbF6 (2 mol%)
References: (10) Tarselli, M. A.; Gagne, M. R. J. Org. Chem. 2008, 73, 2439. (11) Nieto- MeOH, 23 °C
4 0.25 h 5 OMe
Oberhuber, C. et al. Chem.-Eur. J. 2006, 12, 1677. (12) Amijs, C. H. M. et al. J. Org. Chem.
2008, 73, 7721. 91%

Scheme 10

t-Bu

t-Bu t-Bu
O O
P
t-Bu AuCl
O
t-Bu
t-Bu
6
Z + NuH (5 mol%) Z
R2
1 AgSbF6 (5 mol%) R1
R
CH2Cl2 H Nu
R2
T (°C),
entry enyne NuH product % yield
time (h)

NC
NC
1 Z = NTs, R1=Ph, R2 = H 23, 48 49
N Z NH
H
H Ph

MeO
MeO
2 1 2 -50, 5 63
Z = C(CO2Me)2, R = R = Me
N Z NH
H
H

MeO OMe MeO

Z OMe
3 Z = C(SO2Ph)2, R1 = R2 = Me -50, 1 60

OMe H
OMe

4 Z = C(CO2Me)2, R1 = Ph, R2 = H 23, 1 Z NH 71

N
H
H Ph
Table 7

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 $

Chloro(tri­phenyl­phos­phite)gold, 97% 8 Bis(3,5-di-tert-butyl-4-methoxy­phenyl)chloro­phos­phine 8

C18H15AuClO3P [212713‑08‑1] Cl
FW 542.70 C30H46ClO2P t-Bu P t-Bu

O O FW 505.11 H3CO OCH3

P
Au Cl
O t-Bu t-Bu

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

mp.................................................................................... 97 to 102 °C  kanata purity
701505-250MG 250 mg 694703-100MG 100 mg
701505-1G 1 g 694703-500MG 500 mg

(Aceto­nitrile)[(2-biphenyl)di-tert-butyl­phos­phine] 8 Bis(3,5-dimethyl­phenyl)chloro­phos­phine 8
gold(I) hexa­fluoro­anti­monate [74289‑57‑9] Cl

Metal and Phosphine Mediated Transformations

C16H18ClP H3C P CH3
[866641‑66‑9] t-Bu Au N C CH3
C22H30AuF6NPSb P
t-Bu
FW 276.74
SbF6-
FW 772.17 CH3 CH3

density......................................................................1.102 g/mL, 25 °C
mp.............................................................................198 to 203 °C (D) n 20
D ............................................................................................. 1.606

697575-250MG 250 mg 695165-100MG 100 mg

697575-1G 1 g 695165-500MG 500 mg

Chloro[tris(2,4-di-tert-butyl­phenyl)phos­phite]gold 8
[Tris(2,4-di-tert-butyl­phenyl)phos­phite]gold t-Bu
chloride
New Ligands
[915299‑24‑0] t-Bu t-Bu Di-tert-butyl­cyclo­hexyl­phos­phine, 95% 8
C42H63AuClO3P O O
P [436865‑11‑1] H3C
FW 879.34 Au Cl H3C CH3
t-Bu
O C14H29P
P CH3
t-Bu
FW 228.35
H3C CH3
t-Bu

mp.................................................................................. 200 to 202 °C density......................................................................0.889 g/mL, 25 °C

n 20
D ............................................................................................. 1.506
699616-500MG 500 mg
698288-500MG 500 mg

Dicyclo­hexyl-(2,6-diiso­pro­pyl­phenyl)phos­phine, 97% 8
New Phosphine Precursors C24H39P
Bis(3,5-di-tert-butyl-4-methoxy­phenyl)phos­phine 8
FW 358.54 i-Pr i-Pr
P
C30H47O2P t-Bu
H
P t-Bu
FW 470.67
H3CO OCH3 mp.................................................................................... 96 to 100 °C
t-Bu t-Bu
698814-250MG 250 mg
mp.................................................................................. 114 to 119 °C
698814-1G 1 g
 kanata purity
Tri­iso­propyl­phos­pho­nium tetra­fluoro­borate, 97% 8
694673-100MG 100 mg [121099‑07‑8] H3C CH3
694673-500MG 500 mg C9H22BF4P H
H3C P CH3 BF4-
Bis(3,5-di(tri­fluoro­methyl)phenyl)phos­phine 8 FW 248.05 CH3 CH3

[166172‑69‑6] F3C
H
P CF3 698466-500MG 500 mg
C16H7F12P
FW 458.18 2-(2-(Diphenyl­phos­phino)ethyl)pyri­dine 8
CF3 CF3 [10150‑27‑3]
mp...................................................................................... 69 to 73 °C C19H18NP N P
Ph
FW 291.33 Ph
 kanata purity
mp...................................................................................... 58 to 62 °C
695335-100MG 100 mg
695335-500MG 500 mg  kanata purity
695599-100MG 100 mg
Bis(3,5-di(tri­fluoro­methyl)phenyl)chloro­phos­phine 8
695599-500MG 500 mg
[142421‑57‑6] Cl
C16H6ClF12P F3C P CF3

FW 492.63
CF3 CF3
New Palladium Complexes
mp...................................................................................... 25 to 29 °C (1,3-Bis(diphenyl­phos­phino)propane)palladium(II) 8
 kanata purity chloride
Dichloro[1,3-bis(diphenyl­phos­phino)propane] Ph
694746-100MG 100 mg P Ph
palladium(II)
694746-500MG 500 mg Pd Cl
[59831‑02‑6] P
Ph Ph Cl
C27H26Cl2P2Pd
FW 589.77
696676-500MG 500 mg
696676-2G 2 g

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 $

(2-Butenyl)chloro­palladium dimer, ≥97% 8 Palladium(II)[1,3-bis(diphenyl­phos­phino)propane]- 8

Bis[(1,2,3-η)-2-buten-1-yl]di-μ-chloro­di- CH3 bis(benzo­nitrile)-bis-tetra­fluoro­borate
palladiumdi-π-crotylpalladium chloride; Cl
Pd
H2C
[Pd(dppp)(PhCN)2](BF4)2 F
Pd Ph
Di-2-butenyl­dipal­ladium di­chloride; CH2 Cl [175079‑12‑6] F B F
Ph
F
Dichloro­bis(1-methyl­allyl)dipal­ladium CH3 C41H36B2F8N2P2Pd Pd2+ N
Ph
P
[12081‑22‑0] FW 898.71 Ph Ph N F
C8H14Cl2Pd2 F B F
Ph F
FW 393.94
696617-250MG 250 mg
mp.................................................................................. 133 to 140 °C
700045-250MG 250 mg
700045-1G 1 g
N-Heterocyclic Carbenes

N-Heterocyclic Carbenes
Enyne Cyclizations
Echavarren 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 N N

in combination with AgSbF6, the major product resulted from 5-exo- Au

dig cyclization to afford a cyclopropyl metal carbene species, which Cl
OAc (3 mol%)
upon reaction with the nucleophile afforded the carbocyclic product AgBF4 (2 mol%)
OAc

(see previous section). On the other hand, when the carbene-based R1 R2 R1 4 R2

3 µW, DCE, 80 °C
Au-complex was used, the cyclopropyl derivative was observed as the 12 min
major product.1
OAc OAc OAc
Rearrangement of Allylic Acetates OAc

Marion and co-workers reported the first rearrangement of allylic

97% 87% 88% 98%
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,
Scheme 2
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
Au
Overman, Henry, and Hartwig for analogous allylic rearrangments with 3
O O O O O O -Au
4
Hg and Pd (cyclization-induced rearrangement-Scheme 3).2 R1 Au R1 R1Au
Au

N-Heterocyclic Carbene-Copper Complexes

Scheme 3
N-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 Ts N N
new metal complexes for catalysis. Nolan and co-workers are among O
Ar CO2Me
the pioneers in the use of NHC ligands for catalysis and they have O
Ts R1
reported the use of Cu-NHCs for a variety of catalytic transformations. R1 R2
O N
R1
Conjugate reduction of a,ß-unsaturated ketones and esters, the R 1
R2 Ar H R2
NC
hydrosilylation of ketones, the cyclopropanation of terminal alkenes, +
R2
as well as olefinations, carbene transfer reactions, aziridination of CO2Me O
R1
olefins, and methylenation of aldehydes (Scheme 4) are among some EtO
examples of the uses of Cu-NHC complexes (specifically (IPr)CuCl) in O
R2 O
modern catalysis. Finally, these catalysts are air- and moisture-stable, OSiR3 R1 R2 N N EtO
R1
and they can be used as precursors to synthesize more air-sensitive R1 R2 R3SiH Cu R2
complexes.3
Cl

SnBu3
R1
R1 + N2 CO2R R1 R2
N N +
+ N2 CO2Et PhI NTs
Au
Cl Ts
2 CO2R CO2Et N
(5 mol%) SnBu3 R2
O O R1
COPh R1 R1
COPh
TsN TsN
Ph Ph
TsN COPh COPh
Ph AgSbF6 (5 mol%) +
Ph
1 CH2Cl2, 0.5 h
H
H Ph Scheme 4
99% (98:2)

with [Tris(2,4-di-tert-butylphenyl)phosphite]gold chloride/

AgSbF6, 91% (5:95)

Scheme 1

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 $

Nolan and co-workers have described the use of the Cu-Imes carbene
complex 5 in the olefination of aldehydes (and ketones) in the
N N
presence of PPh3, i-PrOH, and TMSCHN2. While similar olefinations
have been reported using Wilkinson’s catalyst, the Cu-alternative offers Cu
Cl
a more economical solution. The functional group compatibility is quite 5
good, allowing for the formation of functionalized aliphatic olefins, (5 mol%)
O
dienes, and styrenes containing nitro (notoriously deleterious to these TMSCHN2 (1.4 eq)

types of reactions), trifluoromethyl, amino, and ester functionalities as R H

i-PrOH (1.1 eq), PPh3 (1.1 eq)/THF R H
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 O
reactions under slightly modified reaction conditions (Scheme 6).4 H3CO O
72% 82% 88%
References: (1) Amijs, C. H. M. et al. J. Org. Chem. 2008, 73, 7721. (2) Marion, N. et al.

N-Heterocyclic Carbenes
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. Boc
N
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,
74% 88%
S.; Nolan, S. P. Aldrichimica Acta 2008, 41, 43. (4) Lebel, H. et al. J. Org. Chem. 2007,
72, 144.
Scheme 5

i-Pr i-Pr
1,3-Bis(2,4,6-tri­methyl­phenyl)imidazol-2-yl­idene gold(I) 8
N N
chloride, 95%
Cu
Chloro[1,3-bis(2,4,6-tri­methyl­phenyl)imidazol- CH3 H3C i-Pr
Cl
i-Pr

2-yl­idene] gold(I) H 3C N N CH3 6

C21H24AuClN2 (5 mol%)
CH3 Au H3C O TMSCHN2 (2.0 eq)
FW 536.85 Cl R1 R2 PPh3 (1.2 eq), i-PrOH (12 eq), /THF R1 R2
mp........................................................................................... >300 °C
696501-100MG 100 mg
696501-500MG 500 mg OTBS
Ph t-Bu
O2N
Chloro[1,3-bis(2,6-diiso­pro­pyl­phenyl)imidazol-2-yl- 8 78% 92% 73%
­idene]gold(I)
1,3-Bis(2,6-diiso­pro­pyl­phenyl-imidazol-2-yl­idene)gold(I) i-Pr
chloride CO2Et
N
[852445‑83‑1] i-Pr
68% 93%
C27H36AuClN2 N AuCl
i-Pr i-Pr
FW 621.01 Scheme 6

mp............................................................................................. 298 °C
696277-100MG 100 mg
696277-500MG 500 mg

[1,3-Bis(2,6-diiso­pro­pyl­phenyl)imidazol-2-yl­idene] 8
copper(I) chloride
[578743‑87‑0] i-Pr
C27H36ClCuN2
N
FW 487.59 i-Pr

N CuCl
i-Pr i-Pr

mp........................................................................................... >300 °C
696307-250MG 250 mg
696307-1G 1 g

Bis[1,3-bis(2,4,6-tri­methyl­phenyl)imidazol-2-yl­idene] 8
copper(I) tetra­fluoro­borate
C42H48BCuF4N4 CH3 CH3
FW 759.21
CH3
H3C H3C CH3
N N
Cu BF4-
N N
H3C CH3 CH3
H3C

CH3 CH3

696242-250MG 250 mg
696242-1G 1 g

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 $

Bis(1,3-bis(2,6-diiso­pro­pyl­phenyl)imidazol-2-yl­idene) 8 1,3-Dimethyl­imida­zolium-2-carboxy­late, 97% 8

copper(I) tetra­fluoro­borate 1,3-Bis(methyl)imida­zolium-2-carboxy­late CH3
N
[886061‑48‑9] [536755‑29‑0] O
i-Pr
C54H72BCuF4N4 C6H8N2O2 N
CH3 O
FW 927.53 N i-Pr FW 140.14
N mp.................................................................................. 221 to 225 °C
CuBF4
i-Pr i-Pr
668400-1G 1 g
668400-5G 5 g
2

mp........................................................................................... >300 °C 1,3-Bis(2,4,6-tri­methyl­phenyl)-4,5-dihydro­imida­zolium 8

696250-100MG 100 mg
tetra­fluoro­borate, 95%
696250-500MG 500 mg SIMes-HBF4; 4,5-Dihydro-1,3-bis(2,4,6-tri­methyl­phenyl)- CH3
1H-imida­zolium tetra­fluoro­borate(1-); 4,5-Dihydro- H3C
N-Heterocyclic Carbenes

1,3-Bis(2,4,6-tri­methyl­phenyl)-1,3-dihydro-2H-imidazol- 8 1,3-dimesityl-1H-imida­zolium tetra­fluoro­borate;

2-yl­idene, 97% 4,5-Dihydro-1,3-dimesitylimida­zolium tetra­fluoro­borate N CH3

1,3-Bis(2,4,6-tri­methyl­phenyl)imidazol-2-yl­idene CH3 [245679‑18‑9] N BF4-

[141556‑42‑5] C21H27BF4N2 H3C CH3

H3 C
C21H24N2 FW 394.26
N CH3
FW 304.43 CH3
N
H3C CH3 mp.................................................................................. 290 to 296 °C
693545-1G 1 g
CH3 693545-5G 5 g
mp............................................................................................. 140 °C 1,3-Bis(2,6-diiso­pro­pyl­phenyl)-4,5-dihydro­imida­zolium 8
696188-250MG 250 mg tetra­fluoro­borate, 95%
696188-1G 1 g SIPr-HBF4; 4,5-Dihydro-1,3-bis(2,6-diiso­pro­pyl­ i-Pr
phenyl)imida­zolium tetra­fluoro­borate;
1,3-Bis(2,6-diiso­pro­pyl­phenyl)-1,3-dihydro-2H-imida- 8 N+
N,N′-Bis(2,6-diiso­pro­pyl­phenyl)dihydro­imida­zolium
zol-2-yl­idene, 97% i-Pr BF4-
tetra­fluoro­borate N
1,3-Bis(2,6-diiso­pro­pyl­phenyl)imidazol-2-yl­idene i-Pr
[282109‑83‑5]
i-Pr i-Pr

[244187‑81‑3] C27H39BF4N2
N
C27H36N2 i-Pr FW 478.42
FW 388.59 N
mp................................................................................................ >300
i-Pr i-Pr

693553-1G 1 g
693553-5G 5 g
mp.................................................................................. 213 to 217 °C
696196-250MG 250 mg
1,3-Di-tert-butyl­imidazoli­nium tetra­fluoro­borate, 95%
696196-1G 1 g 1,3-Bis(tert-butyl)-4,5-dihydro-1H-imida­zolium tetra­fluoro­ t-Bu
N+
borate; N,N′-Bis(tert-butyl)dihydro­imida­zolium tetra­fluoro­ BF4-
1,3-Dicyclo­hexyl­imida­zolium tetrafluoroborate salt, 97% borate N
t-Bu
[286014‑38‑8] [137581‑21‑6]
C15H25BF4N2 C11H23N2 · BF4
FW 320.18 N FW 270.12
N BF4- 659991-1G 1 g
659991-5G 5 g

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

1,3-Bis(1-adamantyl)imidazoli­nium tetra­fluoro­borate, 97%
N,N′-(1-Adamantyl)-4,5-dihydro­imida­zolium tetra­fluoro­
666181-250MG 250 mg borate
666181-1G 1 g C23H35N2 · BF4 N
BF4
666181-5G 5 g FW 426.34 N

1,3-Di-tert-butyl­imida­zolium tetra­fluoro­borate, 97%

N,N′-Bis(tert-butyl)imida­zolium tetra­fluoro­borate; t-Bu
N+
1,3-Bis(tert-butyl)-imidazol-2-ylidi­nium tetra­fluoro­borate BF4- mp........................................................................................... >300 °C
[263163‑17‑3] N
t-Bu 660027-1G 1 g
C11H21N2 · BF4
FW 268.10 1-(1-Adamantyl)-3-(2,4,6-tri­methyl­phenyl)imidazoli­nium
mp.................................................................................. 157 to 198 °C chloride
659983-1G 1 g 1-(1-Adamantyl)-3-(2,4,6-tri­methyl­phenyl)-4,5- CH3

659983-5G 5 g dihydro­imida­zolium chloride H3C

N N
C22H31ClN2
1,3-Bis(1-adamantyl)imida­zolium tetra­fluoro­borate, 97% FW 358.95 CH3 Cl

N,N′-(Adamantyl)imida­zolium tetra­fluoro­borate; 1,3-Bis(tri­ mp.................................................................................. 263 to 280 °C

cyclo[3.3.1.13,7]dec-1-yl)-1H-imida­zolium tetra­fluoro­borate
665029-100MG 100 mg
[286014‑42‑4] N
665029-500MG 500 mg
C23H33BF4N2 N BF4-
FW 424.33

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

660035-1G 1 g

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 $

Metal Organic Frameworks (MOFs)
Stephen Caskey, Ph.D.
Scientist, New Product Research
Sigma-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
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

Metal Organic Frameworks (MOFs)

materials known. Most porous MOFs reported to date are microporous Mesoporous Mater. 2004, 73, 81. (7) Park, K. S. et al. Proc. Nat. Acad. Sci. U.S.A. 2006,
(pore diameters of less than 2 nm) as defined by IUPAC based on the 103, 10180. (8) Banerjee, R. et al. Science 2008, 319, 939. (9) Hwang, Y. K. et al. Angew.
type of gas sorption isotherm the material displays; however, there Chem., Int. Ed. 2008, 47, 4144.
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
Organic Linkers
over zeolites in the prospect of predictable alteration of organic units
O O
to provide tailored materials for given applications. For example, the CH3
O O
length of the organic linker often defines the size of resulting pores of
N N
a given material. Furthermore, functionalization of the organic unit can O O O O
provide predictably functionalized pores. O O
BDC BTC mIM
Aldrich is pleased to offer MOFs under the tradename BasoliteTM. These from terephthalic from trimesic acid from 2-
acid methylimidazole
materials (Figure 1) provide a good selection of different pore shapes Metal Ions
and sizes, different metals (Al, Cu, Fe, and Zn) and different organic Al3+
BasoliteTM A100
688738
linkers (BDC, BTC, mIM).
Cu2+ BasoliteTM C300
688614
HKUST-1 (Basolite™ C300) Fe3+ BasoliteTM F300
690872
Zn2+ BasoliteTM Z1200
HKUST-1 is a copper-based MOF that was first reported in 1999 691348
by Williams and co-workers.1 Blue cubic crystals are formed under
solvothermal conditions. Under these conditions, CuII paddlewheel Figure 1
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
Figure 2
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 OO OO OO OO
proposed to have been achieved by size selectivity.3 The best known H2O Cu Cu OH2 Evacuation
Cu Cu
-H2O
example of size selective catalysis using a MOF was reported in JACS OO OO OO OO

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 Scheme 1
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 O
+ Me3SiCN
MOF catalyst Me3SiO CN

catalyzed by several different zeolites as well as HKUST-1 (Basolite™ Ar H CH2Cl2 Ar H

C300, 688614).6
Scheme 2
ZIFs
O Pd on MOF O
New MOF materials termed zeolitic imidazolate frameworks (ZIFs) I +
OH DMA
are generated from metal ions and imidazolate anions.7 The bonding 120 °C OH
angles of the imidazolate are thought to mimic the bonding angles 5h ≥ 95% conversion
about Si-O bonds found in zeolites; thus, ZIFs and zeolites tend to Scheme 3
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

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 $

Basolite™ A100 8 Trimesic acid, 95%

Alu­mi­num tere­phthal­ate; MIL 53 Ben­zene-1,3,5-tri­carboxy­lic acid O OH

C8H5AlO5 [554‑95‑0]
FW 208.10 Beil. 9,IV,3747 O O
C9H6O6
bulk density............................................................................0.4 g/cm3 OH OH
FW 210.14
BET surf. area.............................................................. 1100-1500 m2/g mp........................................................................................... >300 °C
particle size distribution................................................31.55 μm (D50) acetic acid.....................................................................................<5%
688738-10G 10 g
482749-100G 100 g
688738-100G 100 g
482749-500G 500 g
688738-500G 500 g
Tere­phthal­ic acid, 98%
Basolite™ C 300 8
Ben­zene-1,4-dicarboxy­lic acid O
Metal Organic Frameworks (MOFs)

Copper ben­zene-1,3,5-tri­carboxy­late; Cu-BTC MOF [100‑21‑0] OH

C18H6Cu3O12 Merck 13,9238; Beil. 9,IV,3301 HO
FW 604.87 C8H6O4 O
bulk density..........................................................................0.35 g/cm3 FW 166.13
BET surf. area.............................................................. 1500-2100 m2/g mp........................................................................................... >300 °C
particle size distribution................................................15.96 μm (D50) vp.........................................................................<0.01 mmHg (20 °C)
ait............................................................................................... 925 °F
688614-10G 10 g
688614-100G 100 g 185361-5G 5 g
688614-500G 500 g 185361-100G 100 g
185361-500G 500 g
Basolite™ Z1200 8
2,6-Naph­thalene­dicarboxy­lic acid, 99%
2-Methyl­imid­azole zinc salt; ZIF 8
[59061‑53‑9] [1141‑38‑4] O

C8H12N4Zn Beil. 9,921 OH

FW 229.60 C12H8O4 HO
FW 216.19 O
bulk density..........................................................................0.35 g/cm3
mp........................................................................................... >300 °C
BET surf. area.............................................................. 1300-1800 m2/g
particle size.......................................................................4.9 μm (D50) 523763-5G 5 g

691348-10G 10 g 2,5-Dihydroxy­tere­phthal­ic acid, 98%

691348-100G 100 g 2,5-Dihydroxy-1,4-ben­zene­dicarboxy­lic acid O
691348-500G 500 g [610‑92‑4] HO
OH
Beil. 10,554 HO
Basolite™ F300 8 OH
C8H6O6 O
Iron 1,3,5-ben­zene­tri­carboxy­late; Fe-BTC FW 198.13
C9H3FeO6
mp........................................................................................... >300 °C
FW 262.96
382132-5G 5 g
bulk density................................................................. 0.16‑0.35 g/cm3
382132-25G 25 g
BET surf. area.............................................................. 1300-1600 m /g 2

1,3,5-Tris(4-carboxy­phenyl)ben­zene, ≥98% 8
690872-10G 10 g
690872-100G 100 g 4,4′,4′′,-Ben­zene-1,3,5-triyl-tris(benzoic acid) O OH

690872-500G 500 g [50446‑44‑1]

C27H18O6
Imid­azole, 99% FW 438.43
1,3-Diaza-2,4-cyclo­penta­diene; Gly­oxal­ine N
[288‑32‑4] N
Merck 13,4935; Beil. 23,V,4,191; Fieser 1,492; 2,220 H HO OH

C3H4N2 O O
FW 68.08 mp.................................................................................. 322 to 327 °C
pKa (25 °C)................................................................................... 6.95  solvent ≤20 wt. %
mp...................................................................................... 88 to 91 °C
686859-1G 1 g
bp............................................................................................. 256 °C
vp..............................................................................<1 mmHg (20 °C)
2-Methyl­imid­azole, 99%
2-Methyl­gly­oxal­ine N
 ReagentPlus® [693‑98‑1] CH3
N
H
I202-1G 1 g Beil. 23,V,5,35
I202-5G 5 g C4H6N2
I202-100G 100 g FW 82.10
I202-500G 500 g mp.................................................................................. 142 to 143 °C
I202-2KG 2 kg bp...................................................................................... 267-268 °C
vp................................................................................<1 mmHg (0 °C)
M50850-100G 100 g
M50850-500G 500 g

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 $

Catalytic Deprotection—DEPRO™
Catalyst Kit/Catalytic Deprotection N-debenzylation with L-(-)-N-Benzyl-α-methylbenzylamine

Robert J. McNair Ph.D, Development Manager, 140

Johnson-Matthey Catalysis
120
Deprotection

H2 Uptake (ml)
100
In the manufacture of pharmaceuticals and fine chemicals there is
often a requirement for a protection strategy to minimize possible 80
side reactions during a synthesis. Small, easily removed protecting
groups (PG), available for a range of functional groups, is highly 60
desired. One such easily removed PG is derived from the facile catalytic
40

Catalytic Deprotection—DEPRO™ Catalyst Kit/Catalytic Deprotection

hydrogenolysis of benzylic groups. An analysis of the published
medicinal chemical routes shows that over 1000 drug syntheses 20
currently use this type of protection. The classic functional groups
requiring protection are alcohols, acids and amines. 0
0 30 60 90 120 150 180
Simple cleavage of these protecting groups is critical. Cleavage by
catalytic hydrogenation can be performed with good selectivity under Time (minutes)
mild conditions using a heterogeneous palladium on carbon (Pd/C)
Ethanol Ethyl Acetate Tetrahydrofuran Acetic Acid
catalyst in the presence of hydrogen gas or a hydrogen transfer agent,
e.g. ammonium formate or isopropanol. Efficient removal depends on Figure 1
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) Presenting...
type PG of amines.

Model Reactions
Two 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.
Sigma-Aldrich’s ChemBlogs
Standard reaction conditions for deprotection of the glucopyranose
sugar were 25oC, 3 bar hydrogen pressure using a 5 weight percent An industry-first for open scientific discussion.
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 Selectivity

The 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 Visit chemblogs.com
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, sigma-aldrich.com
the DEPRO catalysts were found to be more active and selective than
the current Pearlman’s catalyst.

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com. 21
 $

Solvent Effects
Solvent choice is critical for any deprotection reaction. For amine Hydrogenation of N-Benzyl-N-α-methylbenzylamine at 50°C,
deprotection, the free amine products are well known to strongly 3 bar hydrogen pressure with various catalysts in ethanol
adsorb at active sites, inhibiting or even completely poisoning the 45
catalyst. For each of the O-debenzylation and N-debenzylation
reactions a series of commonly employed solvents, THF, ethanol, 40
ethyl acetate, acetic acid, and solvent mixtures were screened under 35

H2 Uptake (mL)
standard reaction conditions using several of the top performing 30
catalysts. Results were in general independent of specific catalyst type.
25
For the O-debenzylation, reaction rates were fastest in THF, slightly
20
slower in ethanol and acetic acid, and slowest in ethyl acetate.
Reaction rates were generally linear with all reactions ultimately 15
producing the completely debenzylated product.
Catalytic Deprotection—DEPRO™ Catalyst Kit/Catalytic Deprotection

10
For the N-debenzylation, reaction rates were fastest in ethanol and 5
slowest in THF (Figure 2). The presence of acid served to prevent 0
catalyst inhibition through protonation of the amine product. 0 30 60 90 120 150 180
Time (min)
Catalyst Design Effects
DEPRO-901 DEPRO-904 DEPRO-905 DEPRO-903
The performance of a Pd/C catalyst is affected by the nature of the DEPRO-906 DEPRO-902 Pearlman's
underlying carbon support, the size and location of the deposited
metal particulates, the active metal precursor, the metal oxidation
Figure 2
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 Deprotection kit I for N-O de­benzyl­ation 8
throughout the support structure (a standard or uniform catalyst).
Deposited metal may be either in a reduced or unreduced form. Deprotection kit I for N-O de­benzyl­ation

For most O-debenzylation and N-debenzylation reactions, eggshell Components

unreduced, and eggshell reduced catalysts perform better than DEPRO-901 5% Pd/C
uniform catalysts. For otherwise equivalent catalysts, the underlying DEPRO-902 10% Pd/C
carbon support can have a large effect on both the initial reaction rate DEPRO-903 5% Pd/C
and selectivity to the desired product. The DEPRO™ catalysts represent DEPRO-904 5% Pd/C
a cross section of these desired properties. DEPRO-905 10% Pd/C
DEPRO-906 10% Pd/C

Summary 703605-1KT 1 kit

Facile 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.

22 sigma-aldrich.com TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.
PTS Amphiphile for Metathesis and
Cross-Coupling in Water
Recently introduced by Professor Bruce Lipshutz of the reaction mixture with EtOAc-hexane or deposition
UC-Santa Barbara, polyoxyethanyl α-tocopheryl sebacate onto a bed of silica gel and elution with EtOAc. In most
(PTS) is a nonionic amphiphile that is proving to be a examples studied, PTS outperformed other non-ionic
versatile “solubilizer” for organic molecules in water.1 amphiphiles such as Triton®-X100 and Brij® 30.
Lipophilic substrates and catalysts can efficiently enter
the micelles formed by PTS in water leading to important O
cross-coupling reactions at room temperature without the O O
H
O
need for a co-solvent. O
4 n

O
To use, one simply places the requisite amount of PTS
(15 wt% in water) into a test tube with a stir bar and PTS (n = ca. 13)
adds the organic substrate(s) and catalyst. Reactions 698717
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

Olefin Cross Metathesis2 Suzuki-Miyaura Coupling4

Bn O CH3 CH3
Bn O
2% Grubbs II O Br B(OH)2
CbzHN Ot-Bu 2 mol % Pd(dtbpf)Cl2 CH3
O Ot-Bu 5 +
CbzHN 5 + 2.5 wt% aq PTS CH3
O Et3N, 2 wt% aq PTS
O CH3 CH3
rt, 12 h 96% rt, 5 h CH3
CH3
E isomer only 85%

Olefin Ring Closing Metathesis3 Heck Coupling5

OCH3
OBn OBn
I 2 mol %
2 mol % Grubbs II Pd(dtbpf)Cl2
+
N O 2.5 wt% aq PTS N O BnO 15 wt% aq PTS BnO
S S
OTBS OCH3 Et3N, rt OTBS
O O rt, 3 h O O H3C N H3C N
Ts Ts
96%
90%
9:1 E/Z

Sonogashira Coupling6

CH3 1 mol % PdCl2(CH3CN)2 CH3

Br 2.5 mol % X-Phos
+
Et3N, 3 wt% aq PTS
CH3 CH3
rt, 23 h
quant.

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.

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