University of Groningen
Monodentate secondary phosphine oxides (SPO's), synthesis and application in
asymmetric catalysis
Jiang, Xiaobin
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Jiang, X. (2004). Monodentate secondary phosphine oxides (SPO's), synthesis and application in
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Chapter 2
Chapter 2
Secondary phosphine oxides (SPO’s)
and nitrile hydrolysis
The first part of this chapter gives an introduction to the synthesis and properties of
secondary phosphine oxides (SPO’s), including their use as ligands in homogeneous
catalysis. The second part describes methods of nitrile hydrolysis. The original aim of the
work, the transition metal catalyzed hydrolysis of nitriles using enantiopure SPO’s as
ligands and the outline of the thesis is introduced.
Contents
2.1 Introduction to secondary phosphine oxides (SPO’s)
18
2.2 Examples of the use of SPO’s as ligands in catalysis
19
2.2.1
Hydroformylation
20
2.2.2
Cross-coupling reaction
21
2.2.3
Asymmetric allylic substitution
21
2.2.4
Nitrile hydrolysis
22
2.3 Introduction to nitrile hydrolysis
22
2.3.1
Classical methods—strong acid or base
23
2.3.2
Enzymatic methods
27
2.3.3
Catalysis with transition metals
29
2.4 Aims and outline of this thesis
33
2.5 References and notes
33
17
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
2.1 Introduction to secondary phosphine oxides (SPO’s)
The name phosphine oxide is derived from the words “phosphine” and “oxygen”, which
means these compounds stem from phosphine compounds upon reacting with molecular
oxygen. This type of compounds can be divided into two classes, depending on the number
of substituents on the phosphorus atom. When there are three substituents, it is called a
tertiary phosphine oxide and when there are two substituents, it is called a secondary
phosphine oxide. It is necessary to point out that the two substituents on the phosphorus
should be carbon. If the two substitutes are oxygen, the compounds are called phosphites
and have different properties compared to the phosphine oxides (Figure 2.1). In this thesis,
only secondary phosphine oxides (SPO’s) are discussed.
O
R1
P
R2
O
R1
R1 O
P
R3
R2 O
H
R2
Secondary phosphine oxide
Tertiary phosphine oxide
O
P
H
Phosphites
Figure 2.1 Structure of phosphine oxides
Secondary phosphine oxides (SPO’s) are also called phosphinous acids or phosphinic acids.
They have been known for many years.1 There is an acidic proton in these compounds;
most of them are not very stable to strong basic conditions, which can lead to the formation
of phosphines or phosphoric acids. They are generally stable towards air and moisture, thus
easy to handle and purify. The compounds can be purified by vacuum distillation or flash
column chromatography (SiO2). Most of them have very high boiling points due to the
presence of hydrogen bonds. At temperatures above 180 oC, SPO’s decompose to the
corresponding phosphoric acids and phosphines in a few minutes even under inert
atmosphere (Scheme 2.1). At room temperature, this process is rather slow. It has been
observed in our lab that storage after 1.5 year at RT * , 80% of t-BuPhPHO
self-disproportionated to the corresponding phosphoric acid as shown in scheme 2.1. At 0
o
C or lower temperatures, this process is quite slow. Thus pure SPO’s should be kept at low
temperatures (below 0 oC at least).
R
R
P OH
2
P
2
R'
R'
O
R
R
P H
H
+
R'
P
R'
O
OH
Scheme 2.1 Self-disproportionation of SPO’s
There is equilibrium between the secondary phosphine oxide form (pentavalent) and the
phosphinite form (trivalent) (Scheme 2.2). There is an energy barrier between these forms.
*
See appendix, RT = room temperature.
18
Chapter 2
For example, when R = t-Bu, R’ = Ph, the calculated energy barrier under vacuum is about
60 kcal/mol.3b At room temperature, the phosphine oxide form is the stable one. Upon
coordination with metal precursors, the phosphinite form is exclusively present in the metal
complexes.2
M
O
R1
R1 P
R2
P
R2
H
M
R1 P
R2
OH
OH
Scheme 2.2 Tautomeric forms of SPO’s and their metal complexes
In principle, when R≠R’, the compound can be chiral, depending on the stability of the
enantiomers. Most SPO’s are easily prepared in one or two steps, and are stable to air and
water at RT. The two enantiomers of t-BuPhPHO are configurationally stable and can be
separated by classical resolution (chiral acids)3 or a 3-steps resolution reported by Haynes
and co-workers 4b (Figure 2.2). In the presence of metal precursors, the two enantiomers are
still stable both in the solution and solid state. They do not racemize under these
conditions.8 Only at high temperatures or strong basic conditions, they can racemize and
decompose easily.
t-Bu
t-Bu
O
O
P
P
H
Ph
H
Ph
R-(+)
S-(-)
Figure 2.2 Enantiomers of t-BuPhPHO
Generally, SPO’s are used as important intermediates for the synthesis of phosphoruscontaining compounds, such as phosphines and tertiary phosphine oxides (Scheme 2.3).4 In
the sequence of reactions leading to these products, the acidic proton is first removed by a
base (such as n-BuLi or LDA at –78 oC) to form anions followed by the addition of
electrophiles to form tertiary phosphine oxides, followed by the reduction to the
corresponding phosphine compounds. In this procedure, the chirality on phosphorus is fully
retained, which means that no racemization happens. In this manner, many achiral and
chiral phosphorus compounds could be synthesized efficiently.4
O
R1
R2
P
H
Base
O
R1
R2
P
R 3X
O
R1
R2
P
R3
Reduction
..
R1
R2
P
R3
Scheme 2.3 SPO’s as intermediates for the synthesis of phosphines
19
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
2.2 Examples of the use of SPO’s as ligands in catalysis
The platinum and palladium complexes of SPO’s have been reported and have found some
applications in catalytic reactions.2,5-9 The platinum complexes C4.15 and C4.2 were made
from Pt(PPh3)4 with excess Me2PHO and Ph2PHO, respectively. The Pt(0) species was
oxidized to Pt(II) by SPO’s in situ. The driving force of this reaction might be the poor
solubility of these complexes in most organic solvents (Scheme 2.4). For details see chapter
4.
R
Pt(PPh3)4 +
R
R R
R
P
P
H
Pt
OH
O P H
R R
O
O
P
Tol., RT
H
R
R=Me, L3.1
R=Ph, L3.2
R=Me, C4.1
R=Ph, C4.2
Scheme 2.4 The synthesis of platinum and SPO’s complexes
The palladium SPO complexes C2.1, C2.2 and C2.3 were made from Pd(COD)Cl2 and
(t-Bu)2PHO with different metal/ligand ratios in 1,4-dioxane (Scheme 2.5). The structures
of these three complexes were elucidated by X-ray analysis. They have been used
successfully in catalytic cross-coupling reactions. 7
t-Bu
H
Pd(COD)Cl2
+
(t-Bu)2PHO
t-Bu
O
P
O
P
Cl
HO
t-Bu
Cl
P
Pd
Cl
C2.2
O
Pd
Cl
P
t-Bu
t-Bu
t-Bu
P
OH
t-Bu
t-Bu
H
O
t-Bu t-Bu
C2.1
RT
t-Bu
t-Bu
P
Pd
t-Bu
1,4-dioxane
t-Bu
OH
P
Cl
Cl
Cl
Pd
Pd
t-Bu
Cl
P
t-Bu
HO
C2.3
Scheme 2.5 The synthesis of palladium and (t-Bu)2PHO complexes
All these complexes with SPO’s are stable towards air and moisture, thus easy to handle.
They have proven to be effective catalysts in the following catalytic reactions.
2.2.1 Hydroformylation reaction6
Complexes based on platinum and Ph2POH (C4.2) or other SPO’s have been used as
20
Chapter 2
catalysts in hydroformylation reaction of terminal and internal alkenes in 1990. The
products found were mainly linear aldehyde (>90%). The reaction intermediates were
characterized by NMR and X-ray analysis.
2.2.2 Cross-coupling reaction7
Dimeric and monomeric palladium complexes C2.1-C2.3 with (t-Bu)2POH as ligand have
been used in various C-C cross-coupling reactions such as Heck,7a, f Kumada,7b, c, e Suzuki,
7d, e
Negishi7d and Stille7f reactions with chlorobenzene or substituted chlorobenzene as
substrates (Scheme 2.6). Chlorobenzene is normally not active in cross-coupling reactions
when palladium is used in combination with triarylphosphine ligands. Catalyst C2.1-C2.3
were also found to be active in various C-N7e, f and C-S7d, e, f bond formation reactions with
chlorobenzene as substrate. The nucleophiles in all these reactions can be olefins,7a, f
boronic acids,7d, e amines,7e, f thiols,7d, e, f organozinc 7d, tin7f and Grignard reagents7b, c, e. The
isolated yields are quite good in most cases (approx. 80%). A sulfur analogue of SPO,
(t-Bu)2PHS has also been used as ligand in the nickel- catalyzed Kumada reaction.7b
Cl
X
NaOt-Bu, toluene
+ Nucleophiles
R'
C2.1-C2.3
R
R
X = C, N, S
Nucleophiles = amines, thiols, boronic acids, organic zinc, tin and Grignard reagents
Cl
R'
NaOt-Bu, toluene
+ R'
C2.1-C2.3
R
R
Scheme 2.6 Palladium SPO complex catalyzed cross-coupling reactions
2.2.3 Asymmetric allylic substitution
Recently, Dai and co-workers 8 reported the palladium catalyzed asymmetric allylic
substitution with enantiopure t-BuPhPHO as ligand (Scheme 2.9). The catalyst derived
from [Pd(C3H5)Cl]2 induced the highest e.e. up to 80%. The use of NaOAc led to better
e.e.’s compared to KOAc and LiOAc. The bridged dimeric palladium complex C2.4 was
isolated and characterized by X-ray analysis.8
t-Bu
Cl
Cl
Pd(COD)Cl2 +
P
Ph
O
H
(R)-(+)-L3.4
HO
Ph
Pd
Cl
P
Ph
P
Pd
OH
Cl
t-Bu
C2.4
21
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
[Pd(C3H5)Cl]2
(R)-(+)-L3.4
Pd/L = 1/2
5 mol%
OAc
COOMe
MeOOC
3 eqs. of BSA
Cat. NaOAc
3 eqs. of dimethyl malonate
*
e.e. up to 80%
Scheme 2.9 Palladium catalyzed asymmetric allylic substitution
2.2.4 Catalytic nitrile hydrolysis9
The platinum complexes of Me2POH and Ph2PHO, C4.1 and C4.2, have proven to be
highly active catalysts in nitrile hydrolysis under neutral conditions. Details can be found in
the following paragraph 2.3.3.
2.3 Introduction to nitrile hydrolysis
The hydrolysis of nitriles to amides and carboxylic acids are very important
transformations in organic chemistry.10 Many industrial examples are known, such as the
hydrolysis of amino nitriles to amino acids, 11 acrylonitrile to acrylamide and acetone
cyanohydrin to the corresponding amide,12 en route to methyl methacrylate. Only using
specific conditions, it is possible to stop the hydrolysis at the amide stage. Frequently used
methods for nitrile hydrolysis to amides use strong acid (96% H2SO4)13 or base (50% KOH
/t-BuOH).14 However, in general, selective hydrolysis of nitriles to amides is troublesome
and yields are reasonable at best due to two reasons:
(1) It is difficult to stop the hydrolysis at the amide stage and further hydrolysis to the
carboxylic acid often takes place, as the rate constant of amide hydrolysis is usually larger
than that for nitrile hydrolysis, especially under dilute acidic or basic conditions. However,
in concentrated acid or base the relationship is reversed (Scheme 2.10).15
R CN + H2 O
slow
R
O
NH2 fast
R
O
OH
Scheme 2.10 Nitrile hydrolysis
(2) Since the nitrile group is not very reactive, harsh conditions using strong acids or bases
at high temperatures are generally required, which precludes the presence of acid or base
sensitive functional groups.
In addition to strong base or acid, enzymes and transition metal catalysts are also used to
convert a variety of nitriles to amides. With enzymes, asymmetric hydrolysis or dynamic
kinetic resolution of nitriles is possible. Below these three different are reviewed.
22
Chapter 2
2.3.1. Classical methods --- Strong acid or base
This is one of the most frequently used general methods present in the literature. In order to
activate nitrile groups, strong inorganic acid/alkaline base and high temperatures are
normally needed. Yields range from poor to good depending on the substrates and
conditions. As stoichiometric amounts of acid or base are used, large amounts of salts are
formed after work-up, which is neither economic nor environmental friendly. As mentioned
above, chemoselective hydrolysis to amides is a problem. Using concentrated acid or base
like 96% H2SO4 or 50% KOH / t-BuOH, it is possible to control the nitrile hydrolysis to
amides selectively to some extent. Nitriles vary greatly in their ease of hydrolysis; sterically
hindered nitriles are extremely difficult to hydrolyze. Some examples are presented below:
(1) Basic conditions:
(a) 50% KOH in t-BuOH or other alcoholic solutions14a
With 50% KOH in boiling t-BuOH solution, some nitriles can be hydrolyzed to amides
selectively. The scope of substrates is rather broad and yields range from 54% to 90% (R=
phenyl, benzyl, t-butyl) with long reaction times (up to 20 h) (Scheme 2.11).
Nitriles can also be converted to substituted amides via a tandem reaction. The nitriles are
first hydrolyzed to primary amides and subsequently alkylated with an alkyl halide to
provide the substituted amide. In this case, the alkyl-substituents can be R1 = benzyl, n-Pr;
R2 = Me, n-Pr. The yields range from 52% to 78% (Scheme 2.11).14b
KOH
RCN
t-BuOH
1h
O
RCONH2
R2X, 4 h
R
NHR2
Scheme 2.11 Nitrile hydrolysis with 50% KOH in t-BuOH
In these procedures, 50% KOH has to be used in refluxing t-BuOH, which excludes the
presence of most other functional groups. NaOH also can be used as base in this reaction.
Other alcohols such as ethanol, 2-propanol, n-BuOH could also be used as solvents.
(b) H2O2 in alkali solution16
H2O2 in dilute aqueous alkali can also be used to hydrolyze nitriles to the amides and finally
to the acids.17 This procedure can be stopped at the amide stage by using different alkaline
conditions with H2O2 in aqueous ethanol.16a Compared to method a (50% KOH in refluxing
t-BuOH), the reaction conditions are much milder. In this case, R can be c-hexyl, c-pentyl,
PhCH2CH2, PhCH=CH, p-NO2-C6H4-CMe2 with yields exceeding 80% (Scheme 2.12).
The effective species is thought to be HO2-, which is a much stronger nucleophile than
hydroxide ion (α-effect nucleophile).
23
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
This reaction can also be performed in DCM with the help of a phase transfer catalyst
(n-Bu4NHSO4) and excess H2O2. In this case, R can be phenyl, Ph(CH2)3, c-hexyl, c-pentyl,
(E)-PhCH=CHCH2 with yields exceeding 80% (Scheme 2.12).18
NaOH, aq. EtOH
RCN
H2O2 (2 eq.),
50oC
RCONH2
n-Bu4 NHSO4 / CH2 Cl2
RCN
20% aq.
HO-
/ excess H2 O2
RCONH2
Scheme 2.12 Nitrile hydrolysis with H2O2 and alkali
More recently, a simple and versatile procedure was reported by Katritzky and coworkers19
who used a combination of 30% H2O2 / K2CO3 / DMSO at 0 oC to obtain high yields of pure
amides. This is one of the most effective methods reported in the literature. The substituted
group R can be phenyl, 4-ClC6H4, 2-pyridyl, 2-MeOC6H4CH2, n-octyl, PhCH2CH2,
4-MeO2CC6H4, etc. The reaction is very fast (5-30 min) and high yields are obtained in the
range of 65% to 99% (Scheme 2.13). However, we found that this procedure fails for
sterically hindered nitriles like tertiary nitriles.
RCN
30% H2 O2 , 0 o C
RCONH2
DMSO / K2 CO 3
Scheme 2.13 The hydrolysis of nitriles to amides with H2O2/K2CO3 in DMSO
A method based on a combination of urea / H2O2 / K2CO3 was also reported providing
reasonable yields of amides (50-60%).20
(2) Acidic conditions:
(a) H2SO4 or other inorganic acids
This is an often-used method to hydrolyze nitriles to amides. Aqueous H2SO4 (75%),21
aqueous H2SO4 (70%) in acetic acid22 or 96% H2SO4 13 at temperatures of 60-150 oC can be
used to hydrolyze nitriles to amides effectively without significant further hydrolysis to the
acids. A long reaction time is normally required to give reasonable yields. Quite large
amounts of side products are often found in this reaction due to the harsh conditions. After
basic work-up, amides are obtained with yields in the range from poor (18%) to excellent
(90%) depending on the substrate and conditions (Scheme 2.14). Other strong acids like
HCl can also be used. Some sterically hindered nitriles such as tertiary nitriles can be
hydrolyzed to the corresponding amides with this method. Even formamide can be prepared
in this way from HCN. In the presence of a tertiary alcohol like t-BuOH or the related
olefins (2-methyl-1-propene), mono-substituted amides are produced (Ritter reaction).23
24
Chapter 2
CN
R
O
RCN + H2 O
96% H2 SO4
NH2
R
S
Thiocyanate
O
O
t-BuOH
R
N
H
NH2
R
S
Thiocarbamate
Scheme 2.14 Nitriles to amides with 96% H2SO4
Thiocyanates can be viewed as a special kind of nitrile with a sulfur atom attached to the
cyano group. These compounds can be hydrolyzed to the corresponding thiocarbamate by
concentrated H2SO4 in high yields.24 For example, when R is phenyl, the isolated yield of
the thiocarbamate is 87%. In the presence of alcohols (MeOH, EtOH, etc), mono
N-alkylated thiocarbamates are obtained in high yields similar as in the Ritter reaction
(Scheme 2.14).
(b) Formic acid or formic acid and HCl (HBr)
Formic acid can hydrolyze nitriles to amides at high temperature (180-250 oC) in a silver
(Ag) or tantalum (Ta) vessel. The disadvantages of this reaction are high temperature and
the use of the expensive vessels. The reason why good yields of amides are only obtained in
tantalum or silver vessels is not clear. R can be c-hexyl, 3-Cl-C6H4, 2-Me-C6H3, 1-naphthyl
with yields exceeding 87% (Scheme 2.15).25
With the combination of formic acid and HCl or HBr, the reaction temperature can be as
low as 40 oC and there is no need for a silver or tantalum vessel. R can be c-hexyl, phenyl,
4-Me-C6H3, benzyl, 2-OH-C3H6 with yields exceeding 85% (Scheme 2.15).26
HCO2 H, 180-250o C
RCONH2
RCN
Ta or Ag vessel, 2 h
HCO2H / HCl
RCN
40oC
RCONH2
Scheme 2.15 Nitrile hydrolysis to amides with formic acids
(c) TiCl4 and glacial acetic acid27
This method was developed for the hydrolysis of carbohydrate derived nitriles. The
reaction is performed at 0 oC with the yields approx. 80%. R are different carbohydrate
moieties. No epimerization was found on the stereogenic centers of the sugar units (Scheme
2.16).
25
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
RCN
TiCl4
RCONH2
Glacial acetic acid, 0oC
Scheme 2.16 Nitrile hydrolysis to amides with TiCl4
(3) Miscellaneous
(a) BF3*Et2O
It was found that some specific tertiary nitriles can be hydrolyzed with BF3*Et2O in
methanol under mild conditions. No racemization was found with respect to the stereogenic
center when using enantiopure nitriles. Yields are approx. 70%, although the scope of this
procedure has not been established yet (Scheme 2.17).28
CN
O
S
BF3.OEt2
O
H2N
O
S
n-Bu Tol
MeOH, 78%
n-Bu Tol
Scheme 2.17 Nitrile hydrolysis with BF3*Et2O
(b) Aqueous borax (Na2B4O7)29
The hydrolysis of aldehyde cyanohydrins to α-hydroxyamides can be achieved by treatment
with aqueous borax or alkaline borates at 80 oC (Scheme 2.18). The reaction is finished in
1-8 h under basic conditions (pH 9-11).
CN
R
OH
O
aq. Na2B4O7 (borax)
80 oC
NH2
R
OH
Scheme 2.18 Cyanohydrin hydrolysis with aqueous borax
Results are shown in table 2.1. In some cases, the yields could be increased by the addition
of KCN.
Table 2.1 Results of α-cyanohydrin hydrolysis with aq. borium reagents
Borate
NaB(OH)4
Borax (Na2B4O7)
Borax
KB(OH)4
Borax
Borax
Borax
26
R
H
n-hexyl
Me
Me
Ph
i-Pr
MeSCH2CH2
Yield (%)
39
67
72
75
73
86
79
Chapter 2
(c) MnO2 on SiO230
Some nitriles can be hydrolyzed to amides with MnO2 on a SiO2 support, which is prepared
by treating SiO2 with Mn(SO4)2 and aqueous KMnO4. The reaction is performed in
refluxing n-octane for 48 h and isolated yields range from 35% (R = benzyl) to 83% (R =
t-Bu).
(d) Active Al2O3
A combination of active Al2O3 and KF in refluxing t-BuOH can be used to hydrolyze some
nitriles to amides. Yields range from 10% to 98% depending on the substrate.31 Another
combination of active Al2O3 and CF3SO3H can also be applied in this process at 60 oC with
yields in the range of 18%-92%.32 For example, when R is t-Bu, the isolated yield is 87%
(Scheme 2.19).
RCN
KF / Al 2 O 3 / t-BuOH
reflux
Al2 O 3 / CF 3 SO 3 H
RCN
RCONH 2
60 o C
to 100
oC
RCONH 2
Scheme 2.19 Nitrile hydrolysis to amides with active Al2O3
(e) Silane reagents
Some silyl reagents can hydrolyze nitriles to amides. For example, when t-BuCN (R= t-Bu)
is treated with potassium trimethylsilanoate in refluxing toluene for 16 h, trimethyl
acetamide is isolated in 32% yield as a side-product.33 With the use of dimethylphenyl
silane lithium salt, following by the addition of 3 M aq. HCl, some nitriles can be
hydrolyzed to the amides with the yields ranging from 10% to 95%.34
2.3.2. Enzymatic methods35
Enzymes are known that can convert nitriles to amides or acids in an asymmetric 35, 39-45 or
non-asymmetric 36 way depending on the substrates and enzymes. The enzymes used in the
hydrolysis of nitriles are called “nitrile hydrolases”. They can be divided into two classes.
The first one, nitrile hydratases (NHase) catalyzes the hydrolysis of a nitrile to the
corresponding amide, which is then converted by an amidase to the acid and ammonia. The
second class is called “nitrilases”; it catalyzes the direct hydrolysis of a nitrile to the
corresponding acid and ammonia (Scheme 2.20).
R
R
CN
CN
+H2 O
Nitrile hydratase
(NHase)
+2H2 O
Nitrilase
R
COOH + NH3
+H2 O
R
CONH2
Amidase
R
COOH + NH3
Scheme 2.20 Two pathways for nitrile hydrolysis by enzymes
27
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
By the use of nitrile hydratases, some non-chiral aliphatic nitriles like acrylonitrile and
hetero-aromatic nitriles with base or acid sensitive groups can be successfully hydrolyzed
to the corresponding amides.36 Two examples of industrial processes based on the use of
nitrile hydratases illustrate the successful application in the hydrolysis of nitriles to the
corresponding amides. The first is the hydrolysis of acrylonitrile to acrylamide (Nitto)37 and
the second the hydrolysis of 3-cyanopyridine to nicotinic acid (Lonza).37, 38
Other examples are the dynamic kinetic resolution of racemic nitriles such as 2.1 (with
pseudomonas putida 5B)39 and 2.2 (with agrobacterium tumefaciens d3)40 to enantiopure
amides 2.3 and 2.4, respectively, in approx. 30-40% conversions with e.e. > 90% (Scheme
2.21).
R
R
H2O
R'
CN
R'
pseudomonas putida 5B or
agrobacterium tumefaciens d3
R=Cl, R’= i-Pr, 2.1
R=H, R’= Et, 2.2
O
NH2
2.3
2.4
Scheme 2.21 Kinetic resolution of nitriles with enzymes
Next to the examples mentioned above, the hydration of achiral di-nitriles such as 2.5 to 2.6
has proven a particularly attractive strategy for obtaining chiral synthons (Scheme 2.22).41
Enantioselectivities are normally very high (up to >99%).
CN
CN
R
2.5
CONH2
H2O
rhodococcus sp. CGMCC0497
R'
R
R' = CN, COOH
2.6
Scheme 2.22 Asymmetric hydrolysis of di-nitriles
Frequently used enzymes in the asymmetric hydrolysis or dynamic kinetic resolution of
nitriles are obtained from rhodococcus rhodochrous IFO15564 Nhase;41a-b rhodococcus sp.
N-771;42 rhodococcus sp. R-312;43 pseudomonas putida 5B; agrobacterium tumefaciens
d3; bacillus pallidus Dac521; 44 rhodococcus sp. DSM11397; 45 rhodococcus sp.
CGMCC0497 41f etc. Among these enzymes, bacillus pallidus Dac521 is a special one. It is
thermostable and only works with aliphatic nitriles like acetonitrile and acrylonitrile,
whereas for cyclic, hydroxy nitriles, di-nitriles or aromatic nitriles, no conversions are
found.
Thiocyanate hydrolase, isolated from thiobacillus thioparus THI115, can catalyze the
hydrolysis of thiocyanate to thiocarbamate and finally to carbonyl sulfide (Scheme 2.23).46
However, it does not work with other nitriles such as acetonitrile and propionitrile.
28
Chapter 2
-
+H2 O
S
CN
-
O
S
+H2 O
NH2 -NH 3
-
O
S
OH
+H2 O
-OH
-
S
C
O
Scheme 2.23 The hydrolysis of thiocyanate with thiocyanate hydrolase
In spite of many successful examples summarized above, there are still some disadvantages
associated with enzyme- catalyzed nitrile hydrolysis. Most enzymes are quite sensitive to
the structural variation of nitriles and reaction conditions. Slow reactions and low
conversion are also problems associated with enzymatic methods, whereas sometimes
reproducibility is a problem.
2.3.3. Catalysis with transition metals
(1) Heterogeneous catalysts47
(a) “Reduced Cu”48
Nitriles can be hydrolyzed to amides under neutral conditions by the use of a black copper
powder prepared from CuSO4 and NaBH4 in aqueous NaOH solution. Yields are in the
range of 50-95% depending on the substrates. The active catalyst is a reduced Cu(0) species.
The structure of this catalyst is unknown.
(b) Zeolites and metal oxides49
NaY zeolite can catalyze the hydrolysis of nitriles to amides. It is found that only aromatic
nitriles can be hydrolyzed, whereas aliphatic nitriles do not react. Yields are not high
(30-40%).50 A mechanistic study of this transformation has been performed using Zn2+
zeolite.51
Some metal oxides can also catalyze this transformation. For example, MnO2, CuO, Co3O4
are found to be active and selective for the hydrolysis of acrylonitrile to acrylamide,
although yields (<20%) are too low for any synthetic application. 49
(c) Supported metals
It is found that some metals like Cu, Ni, Ag, Pd supported on poly (4-vinylpyridine), zeolite
X, zeolite Y, SiO2, Celite, TiO2, γ-Al2O3, ZnO or a MgO surface can catalyze the hydrolysis
of nitriles, such as acrylonitrile to acrylamide.52 Among them, the combination of Cu on
MgO surface is the most active catalyst. However, compared to other methods, the yields
are rather low (20-50%).
(2) Homogeneous catalysts53
Homogeneous catalysts have also been used in the hydrolysis of nitriles to amides and
29
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
proved to be much more effective and selective than heterogeneous catalysts.
For an efficient homogeneous catalyst there are three basic requirements:
1. There should be site (s) that can accommodate the substrates and bring them in close
proximity to the metal center.
2. Bond formation between the substrate(s) and catalyst can occur.
3. The newly formed complexes between the products and the catalyst can be released so
that the catalytic cycle can be repeated.
Some catalysts are not effective for nitrile hydrolysis, due to strong binding of the amides to
the catalysts, which makes it difficult for the product to be released, thus blocking the
catalytic cycle.54
Below are summarized successful catalysts used in the hydrolysis of nitriles.
(a) Rh(I) complexes55
The rhodium complex trans-[Rh(OH)(CO)(PPh3)2] and the complex made in situ from
[Rh(COD)Cl]2 and TPPTS56 have been used as catalysts in the hydrolysis of nitriles to
amides.
(b) Cu(II),60a-b Ni(II),60a-b Zn(II),60a-b, 57 Fe(II),60a Ru(III)59g, Rh(III)59g , Ir(III)58 & Co(III)
complexes
Some nitriles with additional coordination sites such as 2-cyanopyridine, 2-cyano-1,10phenanthroline can be hydrolyzed to amides using Cu(II),60a-b Ni(II),60a-b Zn(II)60a-b, 57 and
Co(III),60e-f, 59 Ru(III),60g Ir(III) and Rh(III) complexes under basic conditions.60
(c) Ru(II)-complex
[Ru(II)(tpy)(bpy)](PF6)2 was used to hydrolyze benzyl nitrile to benzyl amide under basic
conditions (tpy = 2,2': 6',2"-terpyridine). The active species is thought to be [Ru(tpy)(bpy)
(OH)]+.61 Another Ru(II) catalyst, [RuH2(PPh3)4] 62was reported for the preparation of Nalkylated amides from nitriles and amines at 160 oC in DME. [(NH3)5RuCl]Cl2 63 can be
used stoichiometrically in the hydrolysis of some nitriles to amides.
(d) [MeCp)2Mo(OH)(H2O)]+ complex64
A new molybdenum-based catalyst for nitrile hydrolysis has been developed recently,
which shows quite high activities in the hydrolysis of a variety of simple nitriles and nitriles
with functional groups.
(e) Pd (II) complexes
PdCl2 can be used stiochiometrically to hydrolyze nitriles to amides.65 Pd (II) complexes
such as cis-[PdL(H2O)2]2+ (L = En, Met-OMe, dtcol, dien, H2O); 66 [PdCl(OH)(bipy)
(H2O)]; 67 a combination of [K2PdCl4] / bipy / NaOH68 and a di-nuclear palladium complex,
30
Chapter 2
[C23H29N4O2SPd2] 69 have been used for the hydrolysis of nitriles to amides under basic
conditions. The structures of these ligands are depicted in figure 2.3. Most of the
Pd-complexes have been used in kinetic studies of the nitrile hydrolysis process.
O
NH2
NH2
H
N
NH2
En
O
Pd Pd
N
N
N
N
S
NH2
dien
[C23H29N4O2SPd2]
CH3OOC
P
NH2
O
H
S
phospholane (C4H8POH) Met-OMe
HO
S
N
H
NH
HN
S
dtcol
H
N
cyclen
Figure 2.3 Structure of some ligands and
a bis-Pd complex used in metal catalyzed hydrolysis
En=ethane-1,2-diamine; Met-OMe=methionine methyl ester; dtcol=1,5-dithia-cyclo-octan
-3-ol; dien=diethylenetriamine; cyclen=1,4,7,11-tetraazacyclododecane; C4H8POH= phospholane; bipy =2,2’-bipyridine; TPPTS = triphenylphosphine trisulfonate.
(f) Pt (II) and Pt (0) complexes
The platinum catalysts such as trans-[PtH(H2O)(PR3)2X] (R = Me, Et; X = OH, Cl) are able
to hydrolyze simple nitriles to amides under basic conditions. 70 Other Pt(0) complexes such
as [PtC6H8(PPh3)2],55a [Pt(PEt3)3], [Pt(PiPr3)3] and [PtP(c-C6H11)3] show much lower
activities under similar conditions.71
A breakthrough in this field has been made by Parkins and co-workers who developed a
Pt(II) complex, [PtH(PMe2OH)(PMe2O)2H] which can catalyze the hydrolysis of various
nitriles to amides with high activities under neutral conditions. The applied secondary
phosphine oxide ligands (SPO’s) are possibly involved in the hydrolysis reaction by
intramolecular nucleophilic attack on the coordinated nitrile. 9
A comparison of most homogeneous catalysts for the hydrolysis of nitriles is listed in table
2.2.
31
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
Table 2.2 A comparison of homogeneous catalysts for nitrile hydrolysis a
Catalyst
[PtH(PMe2OH)(PMe2O)2H] 9
[PtH(PPh2OH)(PPh2O)2H] 9
[PtCl(PMe2OH)(PMe2O)2H] 9
[PtCl(PPh2OH)(PPh2O)2H] 9
[PtCl(PMe2Ph)(PMe2O)2H] 9
[PtCl(C4H8POH)(C4H8PO)2H] 9
[Pt(PEt3)3]
Pt[P(c-C6H11)3]
trans-[PtH(H2O)(PMe3)2][OH]
trans-[PtH(H2O)(PMe3)2][OH]
trans-[PtH(H2O)(PEt3)2][OH]
[PtC6H8(PPh3)2]
[Pt(NHCOMe)Ph(PEt3)2]72
PdCl2
[C23H29N4O2SPd2]
Cis-[Pd(En)(H2O)2]2+ 66
Cis-[Pd(Met-OMe)(H2O)2]2+
Cis-[Pd(dtcol)(H2O)2]2+ 66
Cis-[Pd(dien)(H2O)2]2+ 66
[Pd(H2O)4]2+ 66
[PdCl(OH)(bipy)(H2O)]
[K2PdCl4] / bipy / NaOH
[Co(cyclen)(OH2)2]3+
trans-[Rh(OH)(PPh3)2(CO)]
[Rh(COD)Cl]2 / TPPTS / NaOH
[RuH2(PPh3)4]
[(NH3)5RuCl]Cl2
[(MeCp)2Mo(OH)(H2O)]+ 64
Zn(NO3)2 + ketoxime
NaOH
T (oC)
90
90
90
90
90
90
80
80
25
78
78
80
80
60
80
40
40
40
40
40
76
76
40
80
80
160
80
80
80
78
TOF
380
23
488
20
186
90
2.7
26.7
21.5
178.4
69.9
16.7
2.2
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
29.4
8.8
n.r.
50.0
295
n.r.
n.r.
4.8
45 c
0.4
TON
5700
369
1464
100
558
450
54
405
n.r.
6000 b
6000 b
58
102
1c
4000 b
5
5
5
5
5
294
230
10
150
934
30
1c
114
1000 d
1c
(a). TOF (mol/mol of catalyst h), TON (mol/mol of catalyst), in most cases, the nitrile is acetonitrile,
n.r. = not reported. (b). From kinetic experiments under basic condition, TON might be not accurate.
(c). Stoichiometric amount. (d). For p-OCH3C6H4CH2CN.
From this table it can be seen several catalysts are quite active, however, some of the data
(TOF and TON) were obtained from kinetic studies and the selectivity is also a major
problem for functionalized nitriles such as acrylonitrile. Most of the reactions were
performed under basic conditions. It is clear from the table that platinum SPO’s complexes
are the most effective and selective catalysts for the hydrolysis of nitriles to amides under
neutral condition.
32
Chapter 2
2.4 Aims and outline of this thesis
The main goals of the proposed research are the following:
(1) Explore the possibility to affect kinetic resolution of racemic nitriles via their
hydrolysis using chiral platinum SPO complexes.
(2) Explore the possibility to deracemise meso-dinitriles using the same catalysts.
(3) Explore other applications of chiral secondary phosphine oxides as ligands in
asymmetric homogeneous catalysis. Possible reactions are:
a. Hydrogenation
b. Hydroformylation
c. Allylic substitution
d. Epoxide ring-opening
The thesis is composed of the following chapters:
Chapter 1 and 2 are introductory chapters, describing the state-of-the-art in asymmetric
catalysis, asymmetric hydrogenation and methods of nitrile hydrolysis as well as an
introduction to SPO ligands.
Chapter 3 deals with the design and synthesis of racemic and enantiopure SPO’s. In chapter
4, the characterization of platinum SPO’s complexes with the aid of NMR and X-ray
analysis is described. The hydrolysis of various nitriles catalyzed by platinum or palladium
SPO complexes is described and a possible mechanism is discussed.
Chapter 5 describes the applications of enantiopure SPO’s as ligands in iridium- catalyzed
asymmetric imine hydrogenation. Studies on the optimization of several parameters such as
solvents, metal precursors, hydrogen pressure, temperatures, additives, ligands and
substrates are presented.
In chapter 6, the application of SPO’s as ligands in the hydrogenation of α- or
β-dehydroamino acids, N-acetyl enamides, itaconic acids and enol carbamate catalyzed by
rhodium and iridium are described. Optimization of the reaction conditions for different
substrates are also given. A study of applications in asymmetric allylic substitution is also
described.
Chapter 7 draws conclusion on the results of the research presented in this thesis. The future
prospects of SPO’s are also discussed.
2.5 References and notes
1
For general information about secondary phosphine oxides (SPO’s), see: (a). Klein, H. J.
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Chemie (Houben-Weyl), 4 auflage, Muller, E. ed., Band XII/1, Teil 1, Georg Thieme Verlag,
Stuttgart, 1963, p 193. (c). Gallagher, M. J. in The Chemistry of the Organophosphorus
Compounds Vol II, Phosphine Oxides, Sulfides, Selenides and Tellurides, Hartley, F. R. Ed.,
33
Secondary phosphine oxides (SPO’s) and nitrile hydrolysis
Wiley, Chichester, 1992, p 53.
2
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4
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7
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9
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10
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12
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13
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Chapter 2
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