In situ generation of ylides for tandem oxidation-olefination reactions of unactivated diols

Article abstract of DOI:10.1055/s-2008-1042799

An efficient desymmetrization of diols is achieved using phosphonium salts which undergo deprotonation in the presence of a hindered amine base and manganese dioxide to produce α,β-unsaturated hydroxy esters in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042799

LETTER
649
In Situ Generation of Ylides for Tandem Oxidation–Olefination Reactions of
Unactivated Diols
In
situGeneration
a
of
Y
lides vid J. Phillips, Andrew E. Graham*
School of Engineering, Swansea University, Singleton Park, Swansea, SA2 8PP, UK
Fax +44(1792)295747; E-mail: A.E.Graham@swan.ac.uk
Received 20 September 2007
olefination processes for the generation of ylides from a
Abstract: An efficient desymmetrization of diols is achieved using
phosphonium salts which undergo deprotonation in the presence of
a hindered amine base and manganese dioxide to produce a,b-un-
saturated hydroxy esters in good yields.
range of phosphonium salts and phosphonates in the pres-
ence of manganese dioxide, however, this methodology is
limited when unactivated alcohols are employed.6 In these
cases, poor yields of product are produced even after ex-
tended reaction times at reflux temperatures. We observed
in our desymmetrization studies that unactivated diols un-
derwent tandem oxidation-olefination reactions with sur-
prising efficiency and were intrigued to discover whether
this was also the case when the ylide is generated in situ.
Key words: diol desymmetrization, in situ ylide generation, a,b-
unsaturated hydroxy esters, lactone formation
The development of tandem preparative procedures,
where a number of transformations are carried out in a
one-pot process, offers significant advantages such as a
reduction in the number of synthetic steps and the subse-
quent improvement in efficiency.1 There has been consid-
erable recent attention in the development of such tandem
sequences,2 in particular for the direct transformation of
alcohols to olefins using Wittig chemistry. The Wittig re-
action remains one of the most effective synthetic meth-
ods for the introduction of a double bond, however, its
utility is limited when applied to carbonyl compounds that
are difficult to isolate due to their instability, toxicity, or
volatility. The application of tandem oxidation-olefina-
tion circumvents these shortcomings and a range of oxi-
dizing reagents have been employed.3 We recently
reported a highly efficient desymmetrization of unactivat-
ed diols using a manganese dioxide mediated oxidation-
Wittig homologation process that produces a,b-unsaturat-
ed hydroxy esters in high yields.4 We have now extended
these studies to demonstrate that the desymmetrization
process proceeds to give a,b-unsaturated hydroxy esters
in tandem oxidation-olefination processes in which the
ylides are generated in situ from the corresponding phos-
phonium salts or phosphonates and an excess of a hin-
dered amine base.
We initially investigated the deprotonation of phosphoni-
um salt 1 (Ph3P+CH2CO2EtBr-) and phosphonate 2
[EtO2P(O)CH2CO2Et] with a range of bases in the pres-
ence of butane-1,4-diol and an excess of manganese diox-
ide. Disappointingly, our initial studies using inorganic
bases, such as lithium hydroxide, or strong organic bases,
such as TBD and MTBD, with phosphonium salt 1 pro-
vided only moderate yields of 3 even after extended reac-
tion times. We were therefore highly gratified to observe
that reactions utilizing triethylamine or DBU in dichlo-
romethane proceeded to give the a,b-unsaturated hydroxy
ester 3 in good yields (Table 1).
Reactions of phosphonate 2 with both inorganic and or-
ganic bases under a variety of conditions,7 and with a
range of additives, provided only moderate yields of prod-
uct even when a large excess of reagents and protracted
Table 1 Tandem Oxidation–Olefination Reactions of Phosphonium
Salts and Phosphonates with Butane-1,4-diol
MnO2 (20 equiv)
HO
HO
CO2Et
OH
1 or 2 (2.6 equiv)
3
base (3 equiv)
Entry Conditions
Time (h) Yield (%)
The utilization of the guanidine bases TBD (1,5,7-triaza-
bicyclo[4.4.0]dec-5-ene) and MTBD (7-methyl-1,5,7-tri-
azabicyclo[4.4.0]dec-5-ene) as promoters for the Wittig
and Horner-Wadsworth-Emmons reactions has recently
been demonstrated and provides potential improvements
in efficiency.5 Furthermore, these promoters are highly at-
tractive due to their ease of handling and the mildness of
the reaction conditions employed. Subsequently, both
MTBD and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
have been successfully employed in tandem oxidation-
1
2
3
4
5
6
7
8
1, LiOH, 4 Å MS, CH2Cl2, r.t.
1, TBD, CH2Cl2, r.t.
24
24
24
24
24
24
24
8
33
28
61
65
19
0
1, Et3N, CH2Cl2, r.t.
1, DBU, CH2Cl2, r.t.
2, DBU, LiCl (4 equiv), CH2Cl2, r.t.
2, MTBD, CH2Cl2, r.t.
2, TBD, CH2Cl2, r.t.
20
37a
SYNLETT 2008, No. 5, pp 0649–0652
x
x.
x
x.
2
0
0
8
2, LiOH, 4 Å MS, reflux, THF
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042799; Art ID: D29807ST
© Georg Thieme Verlag Stuttgart · New York
a Reaction contains 30% of the corresponding lactone product.

650
D. J. Phillips, A. E. Graham
LETTER
reaction times were employed. In a number of cases, the the reaction conditions. This is insufficient to trap all of
yield of 3 was limited by the production of significant the carbonyl intermediate, either in its cyclic or acylic
quantities of lactone produced in a competing oxidative form10 as the olefin product, which instead undergoes a
cyclization process. This lactone has been reported to un- second oxidation process to give the lactone which is un-
dergo polymerization in the presence of catalytic quanti- reactive toward the ylide.11 Thus, the low yields of prod-
ties of strong bases such as TBD.8 We were surprised that uct observed in reactions utilizing extended reaction times
there is little information on the use of manganese dioxide or elevated temperatures can also be explained by the ox-
for the oxidative cyclization of diols to lactones, given idation reaction being favored over the olefination reac-
that this methodology would provide a potentially mild tion.
and simple alternative to current methodologies.9 In addi-
tion, the generation of the lactol intermediate provides a
potential explanation for the selectivity observed in the
desymmetrization process. In order to clarify this point,
we undertook the oxidative cyclization of symmetrical,
unactivated diols to assess the efficiency of this process
(Table 2).
We next considered the oxidation-olefination reaction of
a range of simple, unactivated diols which underwent ef-
ficient desymmetrization with the phosphonium salts 1
and 4 [Ph3P+CH(CH3)CO2EtBr-] to produce the corre-
sponding a,b-unsaturated hydroxy esters in good yield
(Table 3).
Table 3 Synthesis of a,b-Unsaturated Hydroxy Esters from Phos-
phonium Salts
Table 2 Manganese Dioxide Mediated Lactone Formation
Entry Diola
Productb
Yield (%)c
MnO2 (20 equiv), CH2Cl2,
r.t., 24 h
CO2Et
HO
HO
OH
n
n
1 or 4 (2.6 equiv)
DBU (3 equiv)
R
1
2
0
HO
OH
O
O
R = H or Me
Entry Diol
Producta,b
Yield
(%)c
72
74
OH
HO
HO
O
O
O
1
HO
OH
68
65
65
81
69d
3
4
HO
CO2Et
OH
OH
O
O
2
HO
HO
HO
OH
CO2Et
CO2Et
81
0
3
4
5
HO
HO
HO
HO
HO
OH
OH
O
5
OH
HO
HO
CO2Et
CO2Et
O
O
OH
a All diols were used as supplied.
a Reactions using Aldrich 10 mm MnO2.
b Reactions produced ca. 5% Z-isomer.
c Reactions produced ca. 5% diester.
d Reaction at reflux.
b All compounds gave satisfactory spectroscopic data.
c Reactions in CHCl3 at reflux for 24 h using 20 equiv of MnO2.
Reactions of butane-1,4-diol and pentane-1,5-diol in
dichloromethane at room temperature in the presence of
manganese dioxide gave moderate amounts of the lac-
tones, in addition to considerable quantities of the corre-
sponding lactols. Reactions in chloroform at reflux
temperatures gave improved yields of the lactones, al-
though considerable quantities of these products were ob-
tained at room temperature after extended reaction times.
Reactions of propane-1,3-diol and hexane-1,6-diol, how-
ever, gave no lactol or lactone products and starting mate-
rial was recovered unchanged. It would appear from these
studies that it is unlikely that the desymmetrization pro-
cess proceeds through a lactol intermediate, given that we
have previously demonstrated that these diols undergo
tandem oxidation-olefination efficiently to produce the
corresponding a,b-unsaturated hydroxy ester products.4 It
would also appear that the oxidation-olefination reac-
tions involving the phosphonate 2 are limited in their effi-
ciency due to the low quantities of ylide generated under
We also considered the synthesis of the corresponding di-
enyl diesters using the sequential PCC oxidation-Wittig
process we previously reported.4 Reactions involving
DBU and phosphonium salts 1, 4, or
5
(Ph3P+CH2CO2MeBr–) in the presence of silica-supported
PCC produced both symmetrical and unsymmetrical di-
enyl diesters in good yields (Table 4). Using this ap-
proach, it was also possible to generate unsaturated
products derived from unstable Wittig reagents, although
yields did not exceed 20% in the cases studied to date.12
In summary, we have demonstrated that the desymmetri-
zation of unactivated diols proceeds to give a,b-unsaturat-
ed hydroxy esters in good yields in reactions where the
ylide is generated in situ from the corresponding phospho-
nium salt and an amine base. Low yields of a,b-unsaturat-
ed hydroxy esters are produced in reactions utilizing
phosphonates but are limited by a competing oxidative cy-
Synlett 2008, No. 5, 649–652 © Thieme Stuttgart · New York

LETTER
In Situ Generation of Ylides
651
Table 4 PCC-Mediated Synthesis of Dienyl Diesters from Phosphonium Salts
PCC (2 equiv), CH2Cl2, r.t.,
24 h, imidazole (2 equiv)
R1
HO
CO2Et
R2O2C
CO2Et
n
n
1, 4 or 5 (2.6 equiv)
DBU (3 equiv)
1 = H or Me R2 = Me or Et
n = 2 or 3
R
Entry
1
Reactant
Product
Yield (%)a
CO2Et
83
73
EtO2C
HO
CO2Et
CO2Et
CO2Et
2
EtO2C
HO
CO2Et
CO2Et
3
4
MeO2C
84
78
HO
HO
CO2Et
EtO2C
EtO2C
CO2Et
HO
5
61
CO2Et
CO2Et
a Reactions produced ca. 5% E,Z-isomer.
[M + H]+, 133 [M + NH4]+. HRMS (CI, NH3): m/z calcd for
clization of the diol to the lactone. Finally, a,b-unsaturat-
ed hydroxy esters are converted into the corresponding
dienyl esters in a sequential reaction sequence utilizing
PCC as the oxidant in the presence of DBU and phospho-
nium salts.
C6H11O2: 115.0754 [M + H]+; found: 115.0754 [M + H]+.
Typical Procedure for the PCC-Mediated Synthesis of Dienyl
Diesters: (E,E)-Octa-2,6-dienedioic Acid Diethyl Ester
A mixture of (E)-6-hydroxyhex-2-enoic acid ethyl ester (3, 146 mg,
0.92 mmol) and PCC (2 equiv, 0.40 g, 1.84 mmol, ground with 2
weight equiv of silica, 0.80 g) was stirred for 4 h at r.t. in CH2Cl2
(50 mL). Imidazole (2 equiv, 0.13 g, 1.84 mmol) was added and the
reaction mixture stirred for a further 1 h. The addition of (ethoxy-
carbonylmethylene)triphenylphosphosphonium bromide 1 (2.6
equiv, 1.05 g, 2.39 mmol) and DBU (3 equiv, 0.42 g, 2.76 mmol)
was followed by 19 h of stirring. At this time, the silica-supported
PCC was removed by filtration through a Celite pad, which was
then washed with additional CH2Cl2 (2 × 50 mL). The solvent was
then removed to give an orange–brown oil which was purified by
column chromatography (hexane → 10% EtOAc-hexane) to give
the title compound (174 mg, 83%) as a colorless oil. IR (film/neat):
Typical Procedure for the Desymmetrization of Diols by in Situ
Generation of the Wittig Reagent: (E)-5-Hydroxypent-2-enoic
Acid Ethyl Ester
A mixture of propane-1,3-diol (142 mg, 1.87 mmol), (ethoxycarbo-
nylmethylene)triphenylphosphonium bromide 1 (2.6 equiv, 2.09 g,
4.86 mmol), DBU (3 equiv, 0.89 g, 5.61 mmol) and MnO2 (20
equiv, 3.26 g, 37.4 mmol) in CH2Cl2 (50 mL) was stirred for 24 h at
r.t. At this time, the MnO2 was removed by filtration through a
Celite pad, which was then washed with additional CH2Cl2 (2 × 10
mL). The solvent was then removed to give an orange oil which was
purified by column chromatography (hexane → 20% EtOAc-hex-
ane) to give the title compound (177 mg, 68%) as a colorless oil. IR
1
nmax = 2982, 1714, 1654, 1368, 1265, 1095 cm–1. H NMR (400
MHz, CDCl3): d = 1.28 (6 H, t, J = 7 Hz), 2.35-2.40 (4 H, m), 4.18
(4 H, q, J = 7 Hz), 5.84 (2 H, d, J = 16 Hz), 6.90-6.95 (2 H, m). 13
C
1
(film/neat): nmax = 3422, 1714, 1653, 1267, 1162, 1038 cm-1. H
NMR (100 MHz, CDCl3): d = 166.7, 147.3, 123.0, 60.7, 30.8, 14.6.
MS (CI, NH3): m/z = 244 [M + NH4]+, 227 [M + H]+. HRMS (CI,
NH3): m/z calcd for C12H22O4N: 244.1543 [M + NH4]+; found:
244.1542 [M + NH4]+.
NMR (400 MHz, CDCl3): d = 1.25 (3 H, t, J = 7 Hz), 2.20 (1 H, br
s, OH), 2.46 (2 H, dq, J = 7, 1 Hz), 3.76 (2 H, t, J = 7 Hz), 4.20 (2
H, q, J = 7 Hz), 5.91 (1 H, dt, J = 16, 1 Hz), 6.95 (1 H, dt, J = 16, 7
Hz). 13C NMR (100 MHz, CDCl3): d = 166.9, 145.8, 123.9, 61.3,
60.8, 35.8, 14.6. MS (ES, NH3): m/z = 162 [M + NH4]+, 145 [M +
H]+. HRMS (ES, NH3): m/z calcd for C7H16O3N: 162.1125 [M +
NH4]+; found: 162.1124 [M + NH4]+.
Acknowledgment
These studies have enjoyed generous financial support from the En-
gineering and Physical Sciences Research Council (D.J.P.). The au-
thors thank the EPSRC National Mass Spectrometry Service,
University of Wales Swansea, UK and Mr. Nathan Welsh for his in-
valuable assistance and thoughtful insights.
Typical Procedure for the Oxidative Cyclization of Diols:
4-Methyltetrahydropyran-2-one
A mixture of 3-methylpentane-1,5-diol (243 mg, 2.06 mmol),
MnO2 (20 equiv, 3.58 g, 41.2 mmol) in CHCl3 (10 mL) was stirred
at reflux for 24 h. At this time, the manganese dioxide was removed
by filtration through a Celite pad, which was then washed with ad-
ditional CHCl3 (2 × 10 mL) The solvent was then removed to give
the title compound (190 mg, 81%) as a colorless oil. IR (neat):
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Synlett 2008, No. 5, 649–652 © Thieme Stuttgart · New York

652
D. J. Phillips, A. E. Graham
LETTER
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