Abstract
Thesis title: Copper catalyzed phosphorous-carbon bond formation: Application
to the synthesis of tertiary phosphine boranes
This thesis deals with a) preparation of scalemic tertiary phosphine
boranes with copper catalyst b) design and synthesis of phosphine-phosphinite
ligands, and their application to asymmetric allylic alkylation with palladium
complexes c) di-μ-hydroxy-bis(N,N,N’,N’-tetramethylenediamine)copper(ll)chloride [Cu(OH).TMEDA]2Cl2 catalyzed tandem phosphorous-carbon
bond formation-oxyfunctionalization leading to the efficient synthesis of phenacyl
containing tertiary phosphine-boranes. Accordingly, the thesis divided into four
chapters.
Chapter I: General introduction and literature review
Chapter I provide an up to date coverage of fascinating synthesis of scalemic tertiary phosphine boranes,
and their use in design and development of asymmetric catalysis using in combination with different
metals. This chapter mainly devoted to P (III) phosphines and derivatives (with P-N, P-O and other
bonds). Additionally, some P (V) compounds (oxides and sulfides) are also discussed as the
intermediates in phosphine synthesis. The following division is used for synthetic methods: 1.
Preparation by resolution of racemic or diastereomeric mixtures which was further sub-titled as a)
chemical resolution by means of cyclometallated palladium compounds, and b) chemical resolution by
use of menthol as chiral auxiliaries 2. Preparation by asymmetric synthesis: in this, we have covered a)
use of ephedrine and other heterobifunctional auxiliaries, b) use of sparteine and related compounds, c)
Use of sparteine for the dynamic resolution of racemic phosphine-boranes. 3. Preparation via asymmetric
catalysis. Finally, deoxygenation of phosphine oxides and deboranation of phosphine-boranes were
discussed.
Chapter II: Stereocontrolled copper Iodide catalyzed phosphorus- carbon bond
formation: An efficient synthesis of Scalamic tertiary phosphineboranes
This chapter describes a mild and efficient protocol for phosphorus-carbon bond formation using
sub-stiochiometric amounts of copper iodide as a catalyst. A series of sterically and electronically divergent
phosphineboranes were subjected to coupling reactions and the corresponding products were obtained in
high yields with retention of configuration. The reaction proceeded under non-basic conditions thus avoiding
base-catalyzed recemization.
The racemic phenylmethlphosphine borane (±)-1(1equiv.) ethyl diazoacetate 2 (1.5 equiv.), and a catalytic
amount of CuI (5 mole %) in CH3CN stirring at ambient temperature. After 4 hours the product (±)-3 was
isolated in 92% yield (Scheme 1). A control reaction conducted without CuI was unsuccessful. In order to
increase the efficiency of the reaction, various sets of parameters were examined such as solvents, amount
of base and catalyst (i.e. copper source) have been evaluated by selecting methylphenylphosphine borane
(±)-1 and ethyldiazo ester 2 as substrates.
BH3
P H
CH3
( ) -1
O
BH3
OEt
CuI (5 mole%)
CH3CN, 4h, rt
N2
2
P
CH3
O
OEt
( )-3
yield: 92%
Scheme 1
In certain instances of metal catalyzed cross-coupling reactions with variations in solvent polarity leads to
retention or inversion of the resulting product. In the light of these observations, we intend to check
whether the copper catalyzed reaction proceeds with retention or inversion of configuration at
phosphorus.
Accordingly,
(Rp)-tert-butylphenylphosphine-borane
(Rp)-4
was
reacted
with
ethyl
diazoacetate 2 in the presence of 5-mole% CuI in acetonitrile at ambient temperature. The product (Rp)- 5
was isolated in 80% yield (Scheme 2).
BH3
BH3
P
H
+ 2
O
CuI (5mole%)
CH3CN, rt, 4h
P
OEt
(Rp)-5
yield:80%
(Rp)-4
Scheme 2
Determination of absolute configuration:
In order to find out the absolute configuration of phosphorus atom, compound (Rp)-5 was converted to
known compound (Rp)-8 using hydrolysis then followed by decarboxylation (Scheme 3).
BH3
CuI (5 mole%)
(Rp)-4 + 2
ee = 99%
BH3
O
P
OEt +
CH3CN, 4h, rt
P
Retention
inversion
(Rp)-5 yield:80%
(Rp)-5
O
OEt
KOH
MeOH, 2h, rt
BH3
BH3
O
P
CH3
(Rp)-7
ee = 99.5%
Xylene
reflux, 1h
P
OH
(Rp)-6
yield: 75%
Scheme 3
The compound (Rp)-7 was conformed by 1H NMR. A doublet obtained at δ 1.08(J = 15Hz) integrating for
nine protons assigned for P-tBu protons. A doublet arising due to P-CH3 appeared at δ 1.55 integrating
for three protons and the aromatic proton appeared at δ 7.35-7.81as multiplet integrating for five protons.
Based on this information the structure found to be (Rp)-7. The optical rotation of (Rp)-7 [α]25D – 8.1 oC
was compared to that of know compound [α]25D – 8.2 oC and was found to be identical, indicating the
retention of configurat- ion during the process.
In conclusion, we have developed a base-free phosphorous-carbon bond forming reaction in the
presence of a copper catalyst. The source of coupling catalyst is low cost commercially available benchtop chemical. The loading of the catalyst in the reaction is sub-stoichiometric amount i.e. only 5 mol%. It is
also noteworthy that the substrates are combined in a 1:1 ratio and no traces of self coupled diazo
compound such as fumarate or maleate side products were observed. The reaction proceeded under
non-basic conditions thus avoiding base catalyzed racemization. To the best of our knowledge this is the
first copper-mediated carbon-phosphorus bond formation protocol maintaining complete stereospeficity of
the phosphorus center.
Chapter III: Design and synthesis of phosphine–phosphinite ligands: Applications
towards Palladium-catalyzed asymmetric allylic alkylation
Optically active phosphine ligands have played a significant role in transsion metal ligand catalyzed
asymmetric reaction, although numerous chiral phosphine ligand have been reported so far, the
development of novel and highly efficient chiral ligand is still an important research subject in the field of
asymmetric catalysis.
In this chapter we have discussed our results about new class of phosphine-phosphinite ligands and
their facile synthesis using previous methodology. An important feature of this ligand is that a bulky alkyl
groups such tert-butly group and smallest alky-group (methyl) is bond to phosphorous atom. The twophenyl groups are attached to the phosphinite bond. These ligands are stable in air for a specified period
and can be handling without special precautions. We investigated the chirality inducing ability of the
novel chiral phosphine-phosphinite ligands for the palladium-catalyzed asymmetric allylic alkylation using
1, 3- diphenyl-2-propenyl acetate with dimethylmalonate as standard substrates. The corresponding
alkylated product was obtained with good yield and with acceptable level of enantioselectivity.
BH3
2
BH3
CuI(5mol%)
P H
CH3CN, rt, 4h
R
O
P
R
BH3
LAH
OEt 0 0C-rt, 5h
P
R
11
10
(Rp)-4 R = tBu
(Rp)- 8R = CH3
(Sp)-9 R = Omenthoxy
OH
yield: 85%, 95%ee
yield: 85%, 99% ee
Ph2PCl
rt, 6h
DCM
Et3N
BH3
Et2NH
P
R
(Rp)-13 R = tBu
(Rp)-14R = CH3
(Sp)-15 R = Omenthoxy
O P Ph
Ph
60 0C, 5h
yield: 75%, 95%ee
P
O P Ph
R
Ph
12
yield: 70%, 95%ee
L
Ph
Ph
OAc
16
1 mol%CH2 (CO2Me)2, 17
0.5 mol%[Pd(C3H5)Cl]2, L
2 equi.BSA, CH2Cl2
Ph
* Ph
CH(CO2Me)2
18
yield: 80%, >85% ee
K3P04, rt, 12h
Scheme 4
ChapterIV: Di-μ-hydroxy-bis(N,N,N’,N’-tetramethylnediamine)-copper (ll) chloride
[Cu(OH).TMEDA]2Cl2 Catalyzed Tandem Phosphorous-Carbon bond formation
Oxyfunctionalization: Efficient Synthesis of Phenacyl Tertiary PhosphineBoranes.
This chapter deals a novel [Cu(OH).TMEDA]2Cl2 catalyzed tandem phosphorous-carbon bond formation
and oxyfunctionalization. This novel process resulted in rapid synthesis of a series of sterically and
electronically divergent phenacyl tertiary phosphine-boranes.
The reaction of secondary phosphine-borane (1.2 equiv.) and phenyl acetylene (1equiv.) in the presence
of 10mol% of Cu-TMEDA in acetonitrile, stirring at ambient temperature resulted in the phenacyl
containing tertiary phosphine-borane 24 in 40% yield. A control reaction conducted without CuI was
unsuccessful. Various Cu catalyst precursors were screened in order to increase the yield of product 24.
A probable mechanism also proposed.
BH3
P
H
R1
10mol%
[Cu(OH).TMEDA]2Cl2
20mol% Et3N
BH3
O
P
R1
Ph 23
CH3CN, rt, 6h
(±)-19 R1 = Me
(±)-20 R1 = tBu
(±)-21 R1 = Ph
(±)-22 R1 =OMenthoxy
24 R1 = tBu
Scheme 5
Under identical conditions, we examined the reaction of phosphine-boranes (±)-19, (±)-20 (±)-21 and (±)22, with Michael acceptor such as methyl propiolate. 25. In all case
-addition products were
isolated. Significantly, reaction of (±)-19, (±)-20, (±)-21 and (±)-22, with 25 gave E-selective products 26,
27, 28 and 29 respectively (Scheme 6).
BH3
P
H
R1
10mol%
[Cu(OH).TMEDA]2Cl2
20mol% Et3N
CO2Me 25
BH3
P
R1
CH3CN, rt, 1h
(±)-19 R1 = Me
(±)-20 R1 = tBu
(±)-21 R1 = Ph
(±)-22 R1 =OMenthoxy
O
OCH3
(E)-26 R1 = Me; 95%
(E)-27 R1 = tBu: 90%
(E)-28 R1 = Ph; 92%
(E)-29 R1 =OMenthoxy; 80%
Scheme 6
A fast and efficient hydrophosphination-oxidation reaction was brought about using activated alkenes.
Thus, phosphine-boranes (±)-20 were allowed to react with styrene 30 under the same set of conditions
resulting in phenacyl tertiary phosphine-borane 24 in 85% isolated yield. The
compound 24 matches with original compound previously isolated.
1HNMR
spectra of
BH3
P
H
R1
(±)-20
10mol%
[Cu(OH).TMEDA]2Cl2
20mol% Et3N
Ph 30
CH3CN, rt
BH3
O
P
R1
24
R1 = tBu
Scheme 7
In conclusion, we have succeeded in developing a di-μ-hydroxy-bis(N,N,N’,N’-tetramethylenediamine)copper(II)chloride, [Cu(OH).TMEDA]2Cl2 catalyzed tandem phosphorous- carbon bond formationoxyfunctionalization protocol for the synthesis of series of sterically and electronically divergent penacyl
tertiary phosphine-boranes. Not only aryl terminal acetylenes were successfully oxidized but also a fast
and efficient hydrophosphination-oxidation reaction was brought about using activated alkenes such as
substituted styrenes.