The lithiation reactivity and selectivity of differentially branched alkyldiphenylphosphine oxides - A simple and versatile approach to ortho-functionalized arylphosphine oxides

Article abstract of DOI:10.1002/adsc.201400861

Alkyldiphenylphosphine oxides typically undergo α-deprotonation with alkyllithium reagents. Here, the lithiation of differentially branched alkyldiphenylphosphine oxides was investigated and a diverse, but predictable reactivity was found. γ-Branched deri

Full text of DOI:10.1002/adsc.201400861

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DOI: 10.1002/adsc.201400861
The Lithiation Reactivity and Selectivity of Differentially
Branched Alkyldiphenylphosphine Oxides – A Simple and
Versatile Approach to ortho-Functionalized Arylphosphine
Oxides
a
b
a,
ˇ
Shraddha G. Mahamulkar, Ivana Cꢀsarovꢁ, and Ullrich Jahn *
a
ˇ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nꢁmestꢀ 2,
16610 Prague 6, Czech Republic
E-mail: jahn@uochb.cas.cz
b
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030/8, 12843 Prague 2,
Czech Republic
Received: August 31, 2014; Revised: November 24, 2014; Published online: March 4, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400861.
ꢀ
Abstract: Alkyldiphenylphosphine oxides typically to functionalization and C C bond forming reac-
undergo a-deprotonation with alkyllithium reagents. tions, thus providing a convenient approach to new
Here, the lithiation of differentially branched alkyl- phosphine oxides and phosphine-borane complexes,
diphenylphosphine oxides was investigated and a di- which have a good potential for an approach to new
verse, but predictable reactivity was found. g- ligands for catalysis.
Branched derivatives undergo selective directed
ortho-metalation (DoM) using butyllithium and
TMEDA as an additive. With decreasing degree of Keywords: lithiation; nucleophilic substitution; orga-
g-branching a-lithiation becomes predominant. The nolithium reagents; phosphine oxides; phosphine-
ortho-phosphinoyllithium intermediates are subject borane complexes
Introduction
(oxides) by deprotonation and subsequent reaction
with electrophiles[4,12] are the most important methods
Phosphines and phosphine oxides are important com- for the preparation of (chiral) phosphine (oxide)s. Di-
pound classes in many areas of organic chemistry, cat- rected ortho-metalation (DoM)[13] of arylphosphine
alysis, and material sciences.[1] Phosphines are undis- oxides can in principle also be used to introduce func-
putedly the most important class of ligands in modern tionality, but has been employed only for substrates
metal catalysis research[2] but they are becoming more bearing no acidic hydrogen atoms in aliphatic sub-
and more important as Lewis basic nucleophilic orga- stituents.[14]
nocatalysts.[3] Whereas achiral phosphines have been
It is common wisdom that deprotonation of alkyl-
previously predominately applied, P-chiral derivatives aryl-substituted carbonyl compounds, sulfones, sulfox-
have become the focus of research more recently. ides and also phosphine oxides A takes place at the
Phosphine oxides are equally important. They serve thermodynamically most acidic a-position leading to
on one hand as stable precursors for the often oxida- a-lithiated intermediates B (Scheme 1). Recent work
tion-labile phosphines, on the other hand they are in our group demonstrated that a,g-branched alkyl
also applied as reagents in Wittig–Horner reactions,[4] phenyl sulfones undergo selective DoM even in the
as ligands[5] and Lewis bases.[6]
presence of a significantly more acidic a-proton. The
Nucleophilic substitution reactions using phospho- resulting aryllithiums rearrange subsequently on
rus nucleophiles or electrophiles,[7] transition metal- warming to the a-carbanion.[15] We hypothesized that
catalyzed phosphinoylation of aryl halides,[7,8] radical[9] branched alkyldiarylphosphine oxides A may behave
or transition metal-catalyzed[10] additions to alkenes, similarly and that this represents an attractive and
Michael-type additions to vinylphosphine oxides[11] simple approach to aryl-functionalized phosphine
and the a-functionalization of alkylphosphine oxides via ortho-phosphinoylphenyllithium intermedi-
Adv. Synth. Catal. 2015, 357, 793 – 799
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Shraddha G. Mahamulkar et al.
Table 1. Dialkylation of methyl diphenylphosphine oxide.[a]
ꢀ
R X
Entry
Base
2 [%]
3 [%]
1
2
3
4
n-BuLi
n-BuLi
n-BuLi
TMSCH2Cl
BnBr
TMSCl
EtI
c 5
d –
e 7
f –
c 82
d 87
e 75
f 95
Scheme 1. Metalation regioselectivity of phosphine oxides.
[b]
–
[a]
ates C, which may subsequently serve as ligands or
Lewis bases.
We report here that g-branched alkyldiphenylphos-
phine oxides display a unique and distinct metalation
behavior toward organolithium compounds. We show
that DoM indeed takes place, but compared to sul-
Reaction conditions: 4 (1.0 mmol), LDA (1.3 mmol), elec-
trophile (1.3 mmol) in THF at ꢀ788C, addition of n-BuLi
(1.2 mmol) and electrophile (1.3 mmol).
[b]
LDA (2.6 mmol) and EtI (2.6 mmol).
fones, phosphine oxides show a more diverse reactivi- used at once the reaction stopped after some time
ty, which is strongly dependent on the reaction condi- and a mixture of phosphine oxides 2 and 3 was isolat-
tions and the presence of additives. Optimized condi- ed in reduced yield. However, 3f could be obtained in
tions allow for the efficient preparation of diverse good yield by a double alkylation using 2.6 equiv. of
new aryl-functionalized alkyl(diaryl)phosphine oxides LDA and ethyl iodide (Table 1, entry 4).
in good yields with high ortho/a-selectivities.
The metalation selectivity of alkyldiphenylphos-
phine oxides 3a–f was initially investigated by using
butyllithium and different additives and solvents fol-
lowed by deuteration or silylation (Scheme 3). Phos-
phine oxides 3a and 3c underwent selective DoM
Results and Discussion
Branched alkyldiphenylphosphine oxides 3 were pre-
pared using two methodologies. a,g,g-Branched alkyl-
diphenylphosphine oxides 3a and 3b were synthesized
in two steps (Scheme 2). An oxidative substitution of
triphenylphosphine with isoamyl bromide in the pres-
ence of NaOH, gave isopentyldiphenylphosphine
oxide 2a,[16] which was deprotonated by LDA and the
resulting a-phosphinoylalkyllithium was alkylated by
isobutyl or ethyl iodide to give differentially branched
phosphine oxides 3a and 3b in 72% and 96% yield,
respectively.
The branched phosphine oxides 3c–e were prepared
by a one-pot dialkylation of commercially available
methyldiphenylphosphine oxide 4 (Table 1, entries 1–
3). Initial deprotonation by LDA and alkylation gave
the intermediates 2c–e, which were again deprotonat-
ed by regenerating LDA by addition of BuLi followed
by addition of another batch of alkyl halide or
TMSCl providing phosphine oxides 3c–e in good
yields. When 2.6 equiv. of LDA and electrophile were
Scheme 3. The divergent reactivity of branched phosphine
oxides toward butyllithium in the presence of different addi-
tives and solvents.
Scheme 2. Synthesis of branched phosphine oxides with iso-
propyl group(s).
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Lithiation Reactivity and Selectivity of Branched Alkyldiphenylphosphine Oxides
Table 2. DoM/electrophilic substitution of g,g’-dibranched
phosphine oxides 3a and 3c.[a]
with BuLi in the presence of TMEDA in toluene as
the solvent despite the presence of the a-proton as
determined by the isolation of 5a and 5c after deuter-
ation of the reaction mixture with D2O at low temper-
ature. LDA was in contrast unreactive as a base (see
the Supporting Information). Unsymmetrical 3b
having only one g-branch gave a mixture of 5b and 6b
in a 1:1 ratio.
Phosphine oxides 3d–f bearing benzylic groups
(3d), branching in the closer b-position (3e) or no ad-
ditional branching (3f) undergo predominately a-de-
protonation and provided a-deuterated phosphine
oxides 6d–f both in toluene or THF. However, a sub-
stitution reaction at phosphorus surprisingly compet-
ed with a-deprotonation providing butylphosphine
oxides 7d and 7f to a non-negligible extent, whereas
the a,a-disilylated derivative 3e furnished exclusively
the a-deuterated compound 6e.
ꢀ
Entry E X
R
10
[%]
11
3a, c
[%] [%][b]
ꢀ
1
2
3
4
5
6
7
8
TMS Cl
TMSCH2
TMSCH2
TMSCH2
a 74
b 67
c 73
d 76
e 85
f 82
5
–
–
3
5
6
–
–
–
ꢀ
PhS SPh
16
15
8
–
4
ꢀ
Cl p-Ts
Br C2H4Br TMSCH2
ꢀ
ꢀ
I C2H4I
TMSCH2
TMSCH2
(CH3)2CHCH2 g 66
(CH3)2CHCH2 h 77
ꢀ
Bu3Sn Cl
ꢀ
TMS Cl
31
21
ꢀ
I C2H4I
[a]
Reaction conditions: 3a or 3c (0.5 mmol), n-BuLi
(0.65 mmol), TMEDA (0.65 mmol), electrophile (for
amounts, see the Supporting Information) in toluene
(3.0 mL) at ꢀ788C.
The DoM selectivtiy was lost on switching the sol-
vent in the metalation reaction of 3c to THF. The
ortho-deuterated compound 5c was isolated only in
62% yield and the a-monodeuterated butylphosphine
oxide 7c resulting from replacement of a phenyl
group in 3c was formed in 33% yield. Remarkably, no
[b]
Recovered 3a, c.
deuteration at the aryl units was observed in 7c, but with several typical electrophiles provided compounds
deprotonation at the newly introduced butyl group 10a–h in good yields (Table 2, entries 1–8). Small
becomes the most facile process. When 2.2 equiva- amounts of substitution products 11 were detected as
lents of BuLi in THF and 6 equivalents of HMPA was side products (entries 1 and 4–6). This reflects the se-
used instead of TMEDA the substitution reaction at lectivity observed in the DoM-deuteration experiment
phosphorus becomes the exclusive pathway furnishing
phosphine oxide 8c in 58% yield together with 42%
ꢀ
Table 3. C C bond formation reactions of ortho-phosphin-
A
recovered 3c.[17] To learn more about the relative fa-
oylphenyllithiums with aldehydes and ketones.[a]
cility of these competing reaction channels chlorotri-
methylsilane was added to a similar reaction per-
formed in toluene with HMPA as an additive, which
led to exclusive isolation of the a-silylated phosphine
oxide 9c in 55% yield. These results and the not ob-
served otherwise facile formation of the ortho-silylat-
ed products 10a, g (vide infra, Table 2, entries 1 and
7) show that nucleophilic substitution at phosphorus
is faster than both DoM or a-deprotonation in the
presence of HMPA and that the subsequent deproto-
nation at the newly generated acidic butyl group pre-
dominates in the sequence under these conditions.
The generated ortho-phosphinoylphenyllithium in-
termediates are highly stable toward ortho!a trans-
metalation. This represents a significant difference
compared to the previously studied sulfones.[15]
Whereas ortho-sulfonylphenyllithiums transmetalate
between ꢀ40 and ꢀ208C to the corresponding a-carb-
Entry
3
R1
R2 12 [%]
(dr)[b]
13
3a, c
[%] [%][c]
1
2
3
4
5
6
7
8
9
c
c
c
c
c
c
c
c
a
a
Ph
H
H
H
H
H
a 63 (3:1)
11
11
–
5
–
6
–
–
–
–
4
25
11
–
4-BrC6H4
n-C5H11
CH3CH=CH
PhCH=CH
Ph
b 72 (1:1)
c 71 (1:1)
d 81 (2.4:1)
e 90 (1:1)
Ph f 74 (ꢀ)
Ph g 71 (1.9:1)
h 65 (ꢀ)
7
Fc
14
32
9
-(CH2)5-
Ph
CH3CH=CH
H
H
i 84 (1.3:1)
j 77 (3.3:1)
10
–
17
ACHTUNGTRENNUNGanions, their phosphinoyl analogs are stable up to
room temperature and show no tendency at all to
transmetalation.
The synthetic applicability of the aryllithium inter-
mediates generated by DoM of 3a and 3c was investi-
gated in detail. Metalation by n-BuLi/TMEDA in tol-
uene at ꢀ788C for 30 min and subsequent treatment
[a]
Reaction conditions: 3a or 3c (0.5 mmol), n-BuLi
(0.65 mmol), TMEDA (0.65 mmol), aldehyde or ketone
(for amounts, see the Supporting Information) in toluene
(3.0 mL) at ꢀ788C.
[b]
[c]
1
Determined by H NMR.
Recovered 3a, c.
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Shraddha G. Mahamulkar et al.
Figure 1. X-Ray crystal structures of compounds 3c, 10a, and the major diastereomers of 12d and 12g. The displacement el-
lipsoids are drawn at 30% probability level.
of 3c (vide supra). Moreover, some starting material the addition in these examples remained however
was recovered (entries 2–4 and 6–8). The methodolo- low.
gy is especially suited to provide precursors, which
can be in the future applied as electrophiles or tive configuration of the major diastereomers of addi-
nucleophiles in subsequent cross-coupling reactions tion products 12d and 12g were proven by X-ray crys-
(entries 4, 5, 8 and 1, 6, 7, respectively), thus allowing tallography (Figure 1).[19] In structure 3c (and also in
further diversification.[18]
10a, 12d and 12g) an ortho-hydrogen atom is in plane
The structure of compounds 3c, 10a, and the rela-
ACHTUNGTRENNUNG
ꢀ
Phosphine oxides 3a, c easily engaged in C C bond with the oxygen atom, thus probably facilitating DoM
formation reactions by nucleophilic addition to car- over deprotonation of the antiperiplanar a-proton,
bonyl compounds after DoM (Table 3). Aromatic, ali- provided the solution conformation of the sterically
phatic, and a,b-unsaturated aldehydes reacted in good crowded compounds is similar. The structures of 12d
yields giving functionalized phosphine oxides 12a–e, i, and 12g are dominated by an intramolecular hydro-
j (entries 1–5, 9 and 10). Even ketones were applica- gen bond between the hydroxy and phosphine oxide
ble as substrates (entries 6–8). Sometimes small groups. Based on the unequivocal determination of
amounts of substitution/addition products 13 were de- the configuration of the major diastereomers of 12d
tected (entries 1, 2, 4, 6). The diastereoselectivity of and 12g, the configuration of the major diastereomers
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Lithiation Reactivity and Selectivity of Branched Alkyldiphenylphosphine Oxides
Table 4. Divergent Wittig–Horner reactions of 3d and 3f.[a]
Table 6. Reduction of alcohols 12a, f, i.[a]
Entry
Substrate
R
R1
R2
17 [%]
Entry
3
R1
Product
Yield [%]
1
2
3
12a
12f
12i
TMSCH2
TMSCH2
(CH3)2CHCH2
Ph
Ph
Ph
H
Ph
H
a 85
b 86
c 83
1
2
3
4
d
d
f
Ph
C11H23
Ph
14a
14b
15a
15b
50
44
69
50
[a]
Reaction conditions: 12a, f,
(0.0023 mmol), PMHS (0.345 mmol) in dry MeOH
i (0.115 mmol), PdCl2
f
C5H11
(2.0 mL) at 408C.
[a]
Reaction conditions: 3d or 3f (1.0 mmol), n-BuLi
(1.3 mmol), TMEDA (1.3 mmol), aldehyde (1.3 mmol) in
toluene (6.0 mL) at ꢀ788C.
10c–e into the corresponding phosphines, which were
not stable to air and were thus converted in situ to
of all other compounds 12 can be assigned on the the corresponding phosphine-borane complexes 16a–f
basis of their 1H and 13C NMR chemical shifts.
(Table 5).[21]
The Wittig–Horner reaction as the most important
Since the nucleophilic addition to aldehydes gives
application for a-phosphinoylalkyllithiums[4] was diastereomeric mixtures and to check the stability and
briefly tested for substrates 3d and 3f amenable to a- robustness of the obtained phosphine oxides towards
deprotonation to demonstrate their applicability functional group modification, the selective reductive
(Table 4). Benzylated phosphine oxide 3d gave trisub- removal of the hydroxy group in selected adducts 12a,
stituted alkenes 14a, b directly after deprotonation by f, and i was performed (Table 6). Optimized condi-
n-BuLi/TMEDA and reaction with benzaldehyde or tions using 2 mol% PdCl2 as a catalyst and poly(me-
dodecanal between ꢀ78–08C (entries 1 and 2), where- thylhydrosiloxane) (PMHS) as the reducing agent[22]
as the ethylated phosphine oxide 3f provided b-hy- gave ortho-benzylic phosphine oxides 17a–c in good
droxy phosphine oxides 15a, b under identical condi- yields. No reduction of the phosphine oxide unit was
tions (entries 3 and 4).
observed under these conditions.
As a prerequisite to obtain new potential phosphine
ligands the reduction of the phosphine oxide unit to
the phosphine-borane complexes was studied.[20] The Conclusions
trichlorosilane/diethylamine system proved to be most
reliable to transform phosphine oxides 3a, c, f and In summary, g,g’-branched phosphine oxides undergo
selective DoM even in the presence of more acidic a-
protons. The resulting aryllithiums are stable up to
room temperature and can be functionalized by di-
Table 5. Reduction of tertiary phosphine oxides.[a]
verse electrophiles. From all these reactions, P-chiral
but so far racemic phosphine oxides result. These
compounds can be reduced to the corresponding
phosphine-borane complexes, whereas hydroxylated
phosphine oxides can be selectively deoxygenated at
the benzylic position furnishing (ortho-benzylphenyl)-
phosphine oxides. The metalation of phosphine oxides
is strongly dependent on the conditions. In the pres-
ence of HMPA a selective substitution of a phenyl
group by butyllithium took place, which leads to an-
other class of P-chiral compounds. Current efforts are
directed toward devising asymmetric approaches to
phosphine oxides.[23] The potential of the resulting op-
tically enriched compounds in asymmetric transfor-
mations, such as cross-coupling reactions, or as Lewis
bases will be explored. Investigations along these
lines are ongoing in these laboratories.
Entry
Substrate
R1
R2
16 [%]
1
2
3
4
5
6
3a
3c
3f
10c
10d
10e
(CH3)2CHCH2
TMSCH2
CH3CH2
TMSCH2
TMSCH2
TMSCH2
H
H
H
Cl
Br
I
a 81
b 62
c 62
d 62
e 62
f 64
[a]
Reaction conditions: 3a, c, f, 10c–e (0.5 mmol), Et2NH
(2.10 mmol), HSiCl3 (1.94 mmol) in toluene (3.0 mL) at
1208C. After completion addition of BH3·THF
(1.0 mmol).
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Shraddha G. Mahamulkar et al.
action mixture for 5–8 h and monitoring by TLC, the bora-
ne·THF complex (0.250 mL, 1.0 mmol) was added. The reac-
tion mixture was stirred for 45 min and quenched by addi-
tion of MeOH (5.0 mL). After concentration under reduced
pressure the residue was purified by flash column chroma-
tography.
Experimental Section
Directed ortho-Metalation of g,g’-Dibranched
Phosphine Oxides 3a, c and Functionalization;
General Procedure
n-BuLi (0.41 mL, 0.65 mmol, 1.6M in hexane) was added to
a stirred solution of phosphine oxide 3a (164 mg, 0.5 mmol)
or 3c (194 mg, 0.5 mmol) and TMEDA (0.098 mL,
0.65 mmol) in toluene (3.0 mL) at ꢀ788C. After 30 min at
this temperature, the electrophile (for amounts see the Sup-
porting Information at the individual compounds) was
added at ꢀ788C. The reaction mixture was stirred at ꢀ788C
for 3–4 h, quenched by addition of water and diluted with
an organic solvent (Table 2, for entries 1, 3–6 EtOAc; for
entries 2, 7–8 CH2Cl2). The layers were separated and the
aqueous one was extracted with the respective solvent. The
combined organic fractions were dried over Na2SO4 and
evaporated to give the crude product, which was purified by
flash column chromatography.
Reduction of Alcohols 12; General Procedure
PdCl2 (0.4 mg, 0.0023 mmol) and PMHS (0.021 mL,
0.345 mmol) were added to a solution of the corresponding
hydroxy phosphine oxide 12 (0.115 mmol) in dry MeOH
(2.0 mL). The mixture was stirred at 408C for 1 h. After
completion the reaction mixture was diluted with EtOAc,
filtered through a pad of celite, which was washed with
EtOAc, and evaporated to give the crude product, which
was purified by flash column chromatography.
Acknowledgements
Directed ortho-Metalation of g,g’-Dibranched
Phosphine Oxides 3a, c and their Reaction with
Aldehydes and Ketones; General Procedure
Generous financial support by the Grant Agency of the
Czech Republic (P207/11/1598) and the Institute of Organic
Chemistry and Biochemistry of the Academy of Sciences of
the Czech Republic (RVO:61388963) is gratefully acknowl-
edged. We thank Dr. Radek Pohl (IOCB Prague) for assign-
ing the NMR spectrum of compound 12a.
n-BuLi (0.41 mL, 0.65 mmol, 1.6M in hexane) was added to
a stirred solution of phosphine oxide 3a (164 mg, 0.5 mmol)
or 3c (194 mg, 0.5 mmol) and TMEDA (0.098 mL,
0.65 mmol) in toluene (3 mL) at ꢀ788C. After 30 min at this
temperature, the aldehyde or ketone (for amounts see the
Supporting Information at the individual compounds) was
added at ꢀ788C. The reaction mixture was stirred at ꢀ788C
and quenched by addition of water after 3–4 h. A solvent
was added (Table 3, for entries 1, 3–5 EtOAc; for entries 2,
6–10 CH2Cl2), the layers were separated and the aqueous
one was extracted with the same solvent. The combined or-
ganic fractions were dried over Na2SO4 and evaporated to
give the crude product, which was purified by flash column
chromatography.
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Horner–Wittig Reaction of 3d, f; General Procedure
n-BuLi (0.81 mL, 1.3 mmol, 1.6M in hexane) was added to
a stirred solution of phosphine oxide 3d (396 mg, 1.0 mmol)
or 3f (272 mg, 1.0 mmol) in toluene (6.0 mL) and TMEDA
(0.196 mL, 1.3 mmol) at ꢀ788C. After 30 min at this temper-
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quenched by addition of water after 4 h and 24 h for 14a
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or CH2Cl2 (Table 4, entries 3 and 4), the layers were separat-
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Na2SO4 and evaporated to give the crude product, which
was purified by flash column chromatography.
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Phosphine·Borane Complexes 16; General Procedure
Diethylamine (0.216 mL, 2.10 mmol) was added to a solution
of the corresponding phosphine oxide (0.5 mmol) in toluene
(3.0 mL) and cooled at 08C before dropwise addition of tri-
chlorosilane (0.195 mL, 1.94 mmol). After refluxing the re-
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Adv. Synth. Catal. 2015, 357, 793 – 799

FULL PAPERS
Lithiation Reactivity and Selectivity of Branched Alkyldiphenylphosphine Oxides
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Adv. Synth. Catal. 2015, 357, 793 – 799
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
799