Diphenylphosphinoyl-mediated synthesis of ketones

Article abstract of DOI:10.1039/b606873a

α-Diphenylphosphinoyl ketones are selectively and sequentially alkylated at the α-position. Double lithiation and selective alkylation occurs at the less stabilised γ-position. Dephosphinoylation of the alkylation products gives ketones. Mono-alkylation is selective, highly crystalline intermediates are formed and a one-pot strategy is possible. The method is ideally suited for the preparation of acid-sensitive ketones. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606873a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Diphenylphosphinoyl-mediated synthesis of ketones†
David J. Fox,* Daniel Sejer Pedersen and Stuart Warren
Received 15th May 2006, Accepted 21st June 2006
First published as an Advance Article on the web 6th July 2006
DOI: 10.1039/b606873a
a-Diphenylphosphinoyl ketones are selectively and sequentially alkylated at the a-position. Double
lithiation and selective alkylation occurs at the less stabilised c-position. Dephosphinoylation of the
alkylation products gives ketones. Mono-alkylation is selective, highly crystalline intermediates are
formed and a one-pot strategy is possible. The method is ideally suited for the preparation of
acid-sensitive ketones.
The two-step synthesis of ketones via the addition of a carbon-
centred nucleophile to a carboxylic acid, or equivalent, followed
by enolate generation and reaction with electrophiles is one of the
most important reaction sequences in synthetic chemistry. Gener-
ally, the addition of organolithium reagents to simple carboxylate
esters or acyl chlorides is complicated by the tendency of the
nucleophile to react with the ketone generated if the tetrahedral
intermediate decomposes during the reaction.1 Grignard reagents
do react with acid chlorides at low temperature to make ketones
selectively.2 It is possible to acylate other organometallic species
with acid chlorides and thioesters via a C–Cl or C–S bond
insertion mechanism: magnesium,3–5 copper,6–8 tin,9 and zinc10,11
organometallics selectively produce ketones, often with palladium
catalysis. Alternatively, good yields of ketone can be ensured by
trapping12,13 or by stabilisation of the tetrahedral intermediate
through chelation of the metal to the leaving group (Weinreb
amides,14 or thiopyridyl esters15) or the nucleophile. Sulfoxides,
sulfones and sulfonamides,16 sulfinamides,17 phosphinates and
thiophosphinates,17 and phosphine oxides18,19 are good chelating
groups for hard metal ions and also act as electron-withdrawing
groups (EWGs) in the generation of carbon nucleophiles by
deprotonation. In the reactions of these stabilised anions over-
addition is rarely observed (Scheme 1).
observed in the alkylations of simple lithium enolates with alkyl
halides are not always high.20 The use of other metal counterions
(e.g. boron,21 tin,22,23 zinc,24 or manganese25–27) or masked ketone
equivalents such as hydrazones28,29 can give synthetically useful
yields of alkylated products but many of these methods still
require the use of strong bases and/or low temperatures and
the difficult drying of metal salts for transmetallation. Alter-
natively, the activation of ketones with electron-withdrawing
groups allows milder and regioselective enolate generation. In
particular, b-keto-esters,30,31 b-keto-sulfoxides,32 b-keto-sulfones,33
b-keto-phosphonates34 and b-keto-phosphine oxides35 can all be
alkylated (Scheme 1). In these cases the bases used in the alkylation
are weaker than the lithium amide bases needed for the alkylation
of unactivated ketones or hydrazones. The activating ester,30,31
sulfoxide, sulfone, sulfonamide,16 sulfinamide,17 phosphonate,36 or
phosphine oxide35 groups canbe removed withavarietyofreagents
to give simple ketones (Scheme 1). The use of a phosphine oxide
as an auxiliary activating group is of particular benefit because
b-keto-diphenylphosphine oxides are easy to make, are highly
crystalline and are not hydroscopic.
The diphenylphosphinoyl group can facilitate carbon–carbon
bond formation and then be removed to give olefins37 and
cyclopropanes.38 Both cases involve an intramolecular oxygen
nucleophile and a carbon leaving group from phosphorus. The
removal of the phosphinoyl group may also occur with an
intermolecular nucleophile as long as the leaving group ability
is maintained. This suggestion prompted the first experiment: the
treatment of b-keto-phosphine oxide38 3e [Scheme 2, eqn. (1)] with
aqueous sodium hydroxide in ethanol, similar conditions to those
reported for the analogous intramolecular phosphoryl transfer
[Scheme 2, eqn. (2)].39
Scheme 1 Ketone synthesis: (i) acylation; (ii) alkylation; (iii) deprotec-
tion. X = OR; M = Li, Na, K; EWG = CO2R, S(O)R, SO2R, S(O)NR2,
SO2NR2, PO(OR)2, P(O)R2.
In many cases the regioselective generation of enolates from
near-symmetrical ketones can be problematic, and the yields
Cambridge University, University Chemical Laboratory, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: djf34@cam.ac.uk
† Electronic supplementary information (ESI) available: experimental and
analytical details for all compounds. See DOI: 10.1039/b606873a.
Scheme 2 Reagents and conditions: NaOH, H2O, EtOH: (i) reflux;
(ii) 60 ◦C.
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This reaction produced ketone 5a cleanly and in high yield,
with the sodium diphenylphosphinate by-product easily removed
by aqueous base. Taken in conjunction with the acylation18,19
and alkylation reactions, this promised to be a simple, powerful
and general ketone synthesis (Scheme 3).
A series of b-keto-phosphine oxides was synthesised by the
method of Warren and Torr (Table 1).19 With the exception of
entries 5 and 9, all these b-keto-phosphine oxides are known
compounds prepared by a similar method. Typically, these re-
actions never go to completion. However, it is usually simple to
separate unreacted starting material from the product by column
chromatography or crystallisation. Bartoli et al. have developed
conditions that improve the yield of the acylation of phosphine
oxides by using an excess of base and acylating agent.40 However,
as it is simple to separate starting material from product, the less
wasteful Warren procedure, which employs stoichiometric base
and acylating agent, was used.
Selective mono-alkylation is difficult with, for example, tra-
ditional acetoacetate chemistry in particular with reactive elec-
trophiles such as allylic halides. We hoped that our method would
provide a more reliable method for this purpose. As can be seen
from Table 2, selective mono-alkylation occurs in good yields with
sodium methoxide as base and activated electrophiles at room
temperature. Despite their reactivity and base sensitivity, even a-
bromo esters and ketones react only once in high yield (entries
6 and 7). Most reactions are complete within a few hours and
products are easily isolated by column chromatography.
Scheme 3 (i) Acylation; (ii) alkylation; (iii) dephosphinoylation.
Table 1 Acylation of phosphine oxides 1 (Scheme 3)a
The alkylation products are generally highly crystalline due to
the diphenylphosphinoyl group making it possible to crystallise
the product directly from the crude reaction mixture. This is
particularly useful when the reactions are performed on a large
scale. Owing to the moderate reactivity of b-keto-phosphine oxides
towards very reactive electrophiles, we suspected that they would
be unreactive towards less reactive alkyl halides. Attempts at
alkylating methyl ketone 2a (Table 2, entry 13) and phenyl ketone
2d (entry 9) with an alkyl iodide showed that the nature of the
enolate nucleophile has a strong influence on the reaction outcome.
Whereas, phenyl ketone 2d produces the desired mono-alkylated
product in good yield no reaction occurs with methyl ketone
2a. The same trend is observed with alkyl bromides (Table 2,
entries 8 and 14) which give only low conversions even at elevated
temperature. The alkylation reactions of methyl ketone 2a and
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
Me
Me
Me
Et
i-Pr
Ph
Furan-2-yl
PhCH2CH2
Me
Et
2a41
2b19
2c42
2d19
2e
52
46
49
77
76
69
62
63
65
74
2f43
3a19
3b19
3c
i-Pr
Ph
10
3d44
a Conditions: THF, −78 ◦C, n-BuLi (1.05 equiv.), methyl ester (1.1 equiv.)
except for entries 1, 6 and 7 where the ethyl ester was used.
Table 2 Selective mono-alkylation of b-keto-phosphine oxides 2 (Scheme 3)
Entry
2 R2
Alkylating agent R1–X
Product (methoda)
Yield (%)
=
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-Furanyl
Me
Me
Me
(E)-PhCH CHCH2Br
3e (a)
3e (b)
3f (a)
3g (a)
3h (a)
3i (a)
3j (a)
3k (c)
3l (c)
3m (a)
3n (a)
3o (a)
3p (d)
3q (e)
3r (a)
3s (a)
99
97
85
74
75
=
(E)-PhCH CHCH2Cl
=
(Z)-PhCH CHCH2Br
=
CH2 CHCH2Br
PhCH2Br
PhC(O)CH2Br
BrCH2CO2t-Bu
PhCH2CH2Br
CH3(CH2)11I
86
84
<17b
71
=
(E)-PhCH CHCH2Br
83
87
=
(E)-PhCH CHCH2Br
PhCH2Br
72
CH3(CH2)11I
MeO2C(CH2)10Br
0b
Et
<10b
95
=
PhCH2CH2
(E)-PhCH CHCH2Br
=
CH2 CHCH2Br
82
a Conditions: (a) NaOMe (1.1 equiv.), R1–X (1.2 equiv.), THF; (b) as in (a) with NaI (1 equiv.) added; (c) NaH (1.1 equiv.), R1–X (1.2 equiv.), DMF,
80 ◦C; (d) NaH (1.1 equiv.), R1–X (1.2 equiv.), DMF; (e) as in (c) with NaI (1 equiv.) added. b Conversion by NMR.
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Table 3 Alkylation of 2a and 2d with butyl halides
Yield (%)b
3t 3u
Entry
Bu–X
Methoda/◦C
1
2
3
4
5
6
7
BuCl
BuBr
BuBr
BuBr
BuBr
BuBr
BuI
a,b,c,d (RT/60)
a,b,c,d (RT)
a (60)
b (60)
c (60)
d (60)
a (RT)
0
<14
0
20
23
41
5
0
<4
4
35
42
49
4
Scheme 4 Reagents and conditions: i) NaOMe, THF, (E)-cinnamyl
bromide; ii) NaH, DMF, (E)-cinnamyl bromide, 80 ◦C; iii) NaH, DMF,
1,4-diiodobutane.
8
9
10
BuI
BuI
BuI
c (RT)
a (60)
c (60)
73
24
67
39
1
57
us to perform a number of experiments with alkyl ketones (entries
4–7) that all produced the dialkylated products 4 in moderate to
good yields.
To establish if it was possible to do a double alkylation of phenyl
ketones, we made the second alkylation intramolecular producing
cyclic phenyl ketone 4g (Scheme 4), giving the product in moderate
yield.
a Conditions: (a) NaOMe (1.1 equiv.), THF, Bu–X (1.1 equiv.), 20 h;
(b) as in (a) with NaI (20 mol%) added; (c) NaH (1.1 equiv.), DMF, Bu–X
(1.1 equiv.), 20 h; (d) as in (c) with NaI (20 mol%) added. b Conversion by
NMR; RT = room temperature.
phenyl ketone 2d were investigated further using butyl chloride,
bromide and iodide as electrophiles, and NaOMe/THF and
NaH/DMF as base (with and without added sodium iodide)
at room temperature and at 60 ◦C (Table 3). All reactions were
examined by NMR after 20 h. Butyl chloride was completely
inert under all the studied conditions (entry 1) and butyl bromide
gave hardly any conversion at room temperature and only poor
conversion at elevated temperature (entries 2–6). The addition of
sodium iodide did not have any significant effect on conversion
rates. Only butyl iodide gave conversions that could be considered
useful from a synthetic point of view when sodium hydride in
DMF was employed (entries 8 and 10). Both the methyl ketone 2a
and phenyl ketone 2d gave good conversions.
Introduction of a second substituent at the a-position of mono-
alkylated b-keto-phosphine oxides 3 might be difficult due to the
complete absence of dialkylatedside-products previously(Table 2).
As foreseen, the first attempt at alkylating a phenyl ketone failed to
give any product (Scheme 4). However, when the same reaction was
attempted with methyl ketone 3a, and sodium hydride in DMF,
the dialkylated product was obtained in a good yield (Table 4,
entry 2) and when sodium methoxide in THF was employed the
product was obtained in excellent yield (entry 3). This prompted
Using phosphine oxide 3e as a model compound, a number
of different dephosphinoylation conditions were examined: (a)
sodium hydroxide in refluxing water and ethanol; (b) potassium
hydroxide in refluxing methanol; (c) sodium methoxide in refluxing
methanol; (d) potassium fluoride in refluxing water and ethanol;
(e) potassium carbonate in refluxing water and ethanol. With the
exception of potassium fluoride (Table 5, entry 5), all of these de-
phosphinoylation conditions resulted in conversion to the desired
ketone in excellent yield. In many instances, the ‘crude’ reaction
product 6 was analytically pure. It is noteworthy that the acetal-
protected phosphine oxide 5i (entry 14) was dephosphinoylated in
good yield, demonstrating that this method is ideally suited for
the synthesis of acid-sensitive ketones. Moreover, (Z)-alkene 5k
(entry 16) did not isomerise to the (E)-isomer under the reaction
conditions, and furan 5m (entry 18) was stable giving a good yield
of ketone.
It was also possible to apply the method to the synthesis of
deuterium labelled ketones by performing the dephosphinoyla-
tion in deuterated solvents. For example, ketones 5n and 5o
(Scheme 5) were synthesised in good yield by treating the respective
b-keto-phosphine oxides with sodium deuteroxide in refluxing
deuterium oxide and ethanol-d.1
Table 4 Alkylation of b-keto-phosphine oxides 3 (Scheme 3)
Starting material 3
Entry
R1
R2
Alkylating agent R3–X
Product (methoda)
Yield (%)
=
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Ph
Me
Me
Et
i-Pr
Me
(CH2)2Ph
Ph
(E)-PhCH CHCH2Br
4a (a,b)
4b (c)
4b (a)
4c (a)
4d (a)
4e (a)
4f (a)
0
72
97
81
80
54
87
46
=
(E)-PhCH CHCH2Br
=
(E)-PhCH CHCH2Br
=
(E)-PhCH CHCH2Br
=
(E)-PhCH CHCH2Br
=
=
(E)-PhCH CHCH2
CH2 CHCH2Br
=
=
(E)-PhCH CHCH2
(CH3)C CHCH2Br
ICH2CH2CH2CH2I
H
4g (d)
a Conditions: (a) NaOMe, R3–X, THF, 20 ◦C; (b) NaH, R3–X, DMF, 80 ◦C; (c) NaH, R3–X, DMF, 20 ◦C; (d) NaH (2.2 equiv.), R3–X (1.2 equiv.), DMF.
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Table 5 Dephosphinoylation of phosphine oxides 3 and 4 (Scheme 3)
Starting material 3/4
Entry
R1
R2
R3
Product (methoda)
Yield (%)
=
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
(E)-PhCH CHCH2
5a (a)
5a (b)
5a (c)
5a (d)
5a (e)
5b (a)
5b (c)
5c (a)
5d (a)
5e (a)
5f (a)
5g (a)
5h (a)
5i (b)
99
96
=
(E)-PhCH CHCH2
=
(E)-PhCH CHCH2
95
(E)-PhCH CHCH2
>95b
0
=
=
(E)-PhCH CHCH2
=
(E)-PhCH CHCH2
92
95
86
96
78
68
=
(E)-PhCH CHCH2
PhCH2
PhCH2
=
CH2 CHCH2
CH3(CH2)11
PhC(O)CH2
t-BuOC(O)CH2
67
77c
82
=
15
16
17
H
H
H
PhCH2CH2
Ph
(E)-PhCH CHCH2
5j (b)
5k (a)
5l (a)
81
93
78
=
(Z)-PhCH CHCH2
=
CH2 CHCH2
=
18
19
20
21
22
23
H
Furan-2-yl
Me
Et
i-Pr
Me
(E)-PhCH CHCH2
5m (b)
6a (a)
6b (a)
6c (a)
6d (b)
6e (a)
72
96
91
97
71
80
=
Me
Me
Me
(E)-PhCH CHCH2
=
(E)-PhCH CHCH2
=
(E)-PhCH CHCH2
=
=
CH2 CHCH2
(CH3)2C CHCH2
(E)-PhCH CHCH2
=
=
PhCH2CH2
(E)-PhCH CHCH2
a Conditions: (a) 4 M aq. NaOH, EtOH, reflux; (b) KOH (10 equiv.), MeOH, reflux; (c) K2CO3 (10 equiv.), H2O, EtOH, reflux; (d) NaOMe (10 equiv.),
MeOH, reflux; (e) KF (10 equiv.), H2O, EtOH, reflux. b Conversion by NMR with Ph2P(O)OMe as the other product. c The carboxylic acid was obtained.
Scheme 5 Reagents and conditions: i) NaOD, D2O, EtOD, reflux.
Scheme 6 Reagents and conditions: i) n-BuLi, THF, PhCO2Me, −78 ◦C;
The synthesis and dephosphinoylation of b-keto-phosphine
=
ii) NaOH, H2O, EtOH, reflux; iii) NaOMe, THF, (CH3)2C CHCH2Br.
oxides can also be combined into a one-pot reaction with
no purification of intermediates. As described above, b-keto-
phosphine oxides can be constructed in a number of ways. For
example, phosphine oxide 1a (Scheme 6) was acylated followed by
dephosphinoylation of the crude product 3v to give a moderate
yield of ketone 5p over two steps.
Alternatively, alkylation of b-keto-phosphine oxides can be
accomplished first followed by dephosphinoylation. For example,
phosphine oxide 2d (Scheme 6) was alkylated with prenyl bromide
followed by dephosphinoylation of the crude product 3x to give a
high yield of ketone 5q over two steps.
at the less stabilised c-position. Systematic investigation into the
effect that the substitution pattern of the phosphine oxide has on
the reaction outcome was conducted using cinnamyl bromide as
the electrophile (Table 6). This revealed that increased methylation
at either the a- or c-position reduces the yield of the c-alkylation.
The introduction of one methyl group at either the a- or c-position
reduced the yield by 10–20% (entries 2–4) and the introduction of
methyl groups at both the a- and c-positions reduced the yield by
approximately 40% (Entry 5).
Bis-methylation at the c-position irrespective of the a-
substitution gives only trace amounts of alkylated products 8e
and 8f by NMR (entries 6 and 7). Hence, only one of the
lithiated centres can carry an alkyl group for the reaction to
be synthetically useful (entries 1–3). The synthesised c-alkylated
Alkylation of a-,c-dilithiated b-keto-phosphine oxides can also
lead to the synthesis of interesting ketones.45 The treatment of var-
iously substituted b-keto-phosphine oxides with two equivalents
of LDA produces a dilithium derivative, which selectively reacted
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Table 6 c-Alkylation of dilithiated b-keto-phosphine oxides 6 and dephosphinoylation of products 7
Starting material
Entry
R1
R2
R3
Product (methoda)
Yield 7a–f (%)
Product (methoda)
Yield 8a–d (%)
1
2
3
4
5
6
7
H
Me
H
H
Me
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
7a (a)
7b (a)
7c (a)
7c (b)
7d (a)
7e (a)
7f (a,c)
65
55
45
8a [d (e)]
8b (d)
8c (e)
8c
8d (d)
8e
8f
91 (86)
85
93
—
70
—
—
48
22
<5b
<5b
Me
a Conditions: (a) LDA (2 equiv.), 9 (1 equiv.), THF, −78 ◦C; (b) LDA (2 equiv.), 9 (1 equiv.), THF, −78 to 0 ◦C; (c) LDA (2 equiv.), 9 (1 equiv.), THF,
−78 ◦C to room temperature; (d) 4 M aq. NaOH, EtOH, reflux; (e) KOH (10 equiv.), MeOH, reflux. b Conversion by NMR.
products were easily dephosphinoylated to give ketones in high
yield (Table 6). As a consequence, the same a-,c-disubstituted b-
keto-phosphine oxide 3r can be produced via alkylation in either
order. Comparison of the two routes to b-keto-phosphine oxide
Acknowledgements
D. S. P. would like to thank the Alfred Benzon Foundation,
Cambridge European Trust and the Anglo-Danish Society for
financial support.
3r (Scheme 7) showed that both alkylation yields are higher if the
c-substituent is introduced first.
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=
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to produce b-keto-d-hydroxy phosphine oxides in high yield
(Scheme 8). The double anion equivalent of phosphine oxide 2a
and benzaldehyde gave phosphine oxide 7g in high yield. However,
this compound gave a complex mixture when dephosphinoylation
was attempted.
Scheme 8 Reagents and conditions: i) LDA, THF, PhCHO, −78 ◦C;
ii) KOH, MeOH, reflux.
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Taking the acylation, a- and c-alkylation and dephosphinoy-
lation reaction in conjunction, this method has proved to be a
general, practical method for the synthesis of branched ketones,
which has several advantages over existing methods.
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