Base-catalyzed ethanolysis of α-diethoxyphosphoryl-γ-lactones: A facile synthesis of cyclopropanecarboxylates

Article abstract of DOI:10.1055/s-2005-917116

A range of alkyl- and alkenylcyclopropanecarboxylic acid ethyl esters has been stereoselectively prepared by treatment of substituted α- diethoxyphosphoryl-γ-lactones with sodium ethoxide in tetrahydrofuran. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917116

2648
LETTER
Base-Catalyzed Ethanolysis of a-Diethoxyphosphoryl-g-lactones:
A Facile Synthesis of Cyclopropanecarboxylates
S
ynthesis of Cyclo
e
propanecar
n
boxylates ryk Krawczyk,* Katarzyna Wꢀsek, Jacek Kꢁdzia
Institute of Organic Chemistry, Technical University of Łódꢂ, ꢃeromskiego 116, 90-924 Łódꢂ, Poland
Fax +48(42)6365530; E-mail: henkrawc@p.lodz.pl
Received 28 July 2005
which are next converted in a usual way into cyclopropyl
ketones.2 Another attractive possibility is represented by
Michael addition of sterically hindered (alkoxycarbonyl-
methylene)triphenylphosphoranes to g-hydroxyenones.3
The adducts possessing (3-hydroxypropyl)triphenylphos-
phonium subunits undergo spontaneous transformation
into substituted cyclopropanecarboxylates.
Abstract: A range of alkyl- and alkenylcyclopropanecarboxylic
acid ethyl esters has been stereoselectively prepared by treatment of
substituted a-diethoxyphosphoryl-g-lactones with sodium ethoxide
in tetrahydrofuran.
Key words: Wittig-type cyclopropanation, g-lactones, alkylation,
cyclopropanecarboxylates, stereoselective synthesis
It is known that alkoxides attack g-lactones at the carbonyl
group causing oxygen–acyl cleavage.4 We reasoned that a
similar type of reaction with a-phosphoryl-g-lactones 5
would provide 2-phosphoryl-4-oxyalkanoate anions 6 and
that it could constitute an initial step of a new method for
construction of a cyclopropane ring (Scheme 2).
The reaction of Wittig and Horner–Wadsworth–Emmons
reagents bearing alkoxycarbonyl groups at the a-carbon
atom with epoxides is commonly known as operationally
simple and in general effective synthetic approach to
cyclopropanecarboxylates.1
The mechanism of this type of cyclopropanation, in
particular that with the phosphonoacetate carboanion 1, is
well recognized.1d,e Its initial step has been proved to
involve the carboanion promoted epoxide ring-opening to
produce 3-oxypropylphosphonates 2 which are subse-
quently converted into the corresponding phosphates 3 by
1,4-migration of phosphoryl functionality from the carbon
to the oxygen atom. Further g-elimination of phosphoric
acid elements from the latter results in cyclopropane ring
closure (Scheme 1).
O
R2
O
R2
R3
R4
P(OEt)2
R1
R3 R4
CO2R
RONa
O
R3
P(OEt)2
R1
O
R4
CO2R
R2
R1
O
5
4
6
Scheme 2
We believed that this approach would be an attractive
alternative to those already reported and that it would
enable effective synthesis of differently substituted cyclo-
propanecarboxylates 4.
O
O
(EtO)2P
CO2Et
O
(EtO)2P
O
The starting unsubstituted a-phosphoryl-g-lactone 5a and
its g-methyl homologue 5b were obtained by using the
routine two-step procedure which involved bromination
of commercially available g-lactones 7a and 7b5 followed
by the Arbuzov reaction of the bromides 8a and 8b with
triethylphosphite (Scheme 3).6
1
EtO2C
R
R
2
EtO2C
H
R
H
+
4
EtO2C
OP(O)(OEt)2
O
R
3
O
P(OEt)2
O
Scheme 1
Br
P(OEt)2
a
b
R4
O
O
R4
O
R4
O
O
Several successful attempts have been made to find
alternative sources of the oxyanions structurally related to
the intermediates 2. It has been demonstrated that base-
promoted intramolecular trans-acylation of readily syn-
thesized 3-acyloxypropyldiphenylphosphine oxides gives
the desired a-diphenylphosphinoyl-g-hydroxy ketones,
O
7a,b
5a, 7a, 8a R4 = H
5b, 7b, 8b R4 = Me
8a (65%)
8b (60%)
5a (88%)
5b (84%)
Scheme 3 Reagents and conditions: (a) Br2, PBr3 (cat.), 100 °C, 25
h; (b) P(OEt)3, 140 °C, 5 h.
Neither bromination of the lactone 7b nor phosphoryl-
ation of the bromolactone 8b occurred stereoselectively.
Thus, the prepared a-phosphoryl-g-substituted-g-lactone
SYNLETT 2005, No. 17, pp 2648–2652
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917116; Art ID: G24105ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5

LETTER
Synthesis of Cyclopropanecarboxylates
2649
Table 1 Alkylation of Lactones 5a,b
Entry
Substrate
Alkylating agent R1X
CH2=CHCH2Br
Producta
9a
Yield (%)b
1
2
3
4
5
6
7
5a
5a
5a
5a
5b
5b
5b
67
73
74
75
83
92
70
(E)-PhCH=CHCH2Br
PhCH2Br
9b
9c
(E)-(EtO)2P(O)CH=CHCH2Br
CH2=CHCH2Br
9d
9e (85:15)c
9f (85:15)c
9g (85:15)c
PhCH2Br
(E)-(EtO)2P(O)CH=CHCH2Br
a All new compounds were characterized by IR, 1H NMR, 13C NMR and 31P NMR spectroscopy.
b Yield of isolated, purified product.
c Diastereoisomeric ratio taken from 31P NMR spectrum.
5b was a mixture of trans and cis isomers with close to a dimethyl-a-diethoxyphosphoryl-g-lactone (11b), which
1:1 ratio. Attempted separation of particular components we intended to use as a starting material for the prepara-
of this mixture was unsuccessful. a-Substituted and a,g- tion of ethyl trans-chrysanthemate, could be obtained in a
disubstituted a-phosphoryl-g-lactones 9a–d and 9e–g satisfactory yield, solely when the lactone 10 was sub-
were synthesized by alkylation of enolates derived from jected to the reaction with a large excess of 2-methyl-1-
the lactones 5a and 5b with selected allyl and benzyl propenylmagnesium bromide in THF solution for a pro-
bromides, respectively. No reaction was observed with longed time and decreased temperature (Table 2).9
simple alkyl iodides in similar conditions (Scheme 4,
A series of preliminary experiments enabled us to find
optimal conditions for the proposed cyclopropanation
Table 1).7
reaction. The most satisfactory results were achieved by
O
O
heating the lactone substrates 9a–g and 11a,b with
equimolar amount of sodium ethoxide in a mixture of
THF and ethanol (100:2) for a few hours (Table 3).10
P(OEt)2
P(OEt)2
R1
a,b
R4
O
R4
O
O
O
Table 2 Synthesis of Adducts 11a,b
5a,b
9a–g
O
O
Scheme 4 Reagents and conditions: (a) LDA (1 equiv), THF,
P(OEt)2
P(OEt)2
R2
–78 °C, 0.5 h; (b) R1X, –78 °C, 1 h, then r.t., 20 h.
a or b
O
O
O
O
The products of substitution 9e–g were formed as a mix-
ture of inseparable cis and trans diastereoisomers. Their
ratios were determined by 31P NMR and are shown in
Table 1. The spectroscopic data did not allow us to assign
the relative configuration to particular stereoisomers.
However, in any case stereochemistry of 9e–g was of no
importance since chirality at their a-carbon atoms was
expected to be lost in further transformation.
10
11a,b
Entry R2MgBr
Product
11a
Yield (%)
1
2
CH3(CH2)3MgBra
86
65
(CH3)2C=CHMgBrb
11b
Reaction conditions: (a) R2MgBr (2 equiv), Et2O, 0 °C, 3 h; (b)
R2MgBr (5 equiv), THF, –15 °C, 72 h.
Conjugate addition of Grignard reagents to a,b-unsaturat-
ed a-phosphoryl-g-lactones has recently paved a con-
venient way to their trans-b-substituted and saturated
homologues.8 Using similar procedure and treating
routinely prepared lactone 10 with n-butylmagnesium
bromide in diethyl ether solution in the presence of copper
iodide, we obtained trans-b-butyl-g,g-dimethyl-a-di-
ethoxyphosphoryl-g-lactone (11a), the first of potential
precursors of trisubstituted cyclopropanecarboxylates.
Synthesis of second lactone possessing the same substitu-
tion pattern required considerable modification of stan-
dard protocol. The trans-b-(2-methyl-1-propenyl)-g,g-
The cyclopropanecarboxylates 12,11 22 and 2312 were ob-
tained as trans isomers exclusively. The cis stereochemis-
try of compounds 18 and 19 was unequivocally assigned
on the basis of NOE experiments. It is likely that configu-
ration of 1-unsubstituted cyclopropanecarboxylates 12,
22, 23 results from the final equilibration of their enolates
while configuration of 1-substituted cyclopropanecarbox-
ylates 18 and 19 arises rather from kinetically controlled
ring closure. The formation of 1-alkenylphosphonates 16
and 20 was accompanied by their isomerization to the
corresponding 2-alkenylphosphonates 17 and 21. Thus,
Synlett 2005, No. 17, 2648–2652 © Thieme Stuttgart · New York

2650
H. Krawczyk et al.
LETTER
Table 3 Formation of Cyclopropanecarboxylates from Lactones 5a, 9a–g and 11a,b
Entry
1
Starting lactone
Time (h)
8
Producta
Yield (%)
56
CO2Et
O
P(OEt)2
Me
12
O
Me
O
5b
O
CO2Et
P(OEt)2
2
3
4
5
10
6
60
75
65
60
13
14
15
O
O
9a
CO2Et
O
Ph
P(OEt)2
Ph
O
O
9b
O
CO2Et
Ph
P(OEt)2
Ph
8
O
O
O
9c
O
O
O
CO2Et
CO2Et
O
P(OEt)2
P(OEt)2
P(OEt)2
P(OEt)2
4
16
17
O
9d
16:17 = 13:87
CO2Et
O
Me
P(OEt)2
6
7
Me
10
10
10
8
85
42
70
65
72
Me
Me
Me Me
O
O
22
11a
Me
O
Me
CO2Et
P(OEt)2
Me
Me
Me
Me
Me Me
CO2Et
O
O
23
11b
O
P(OEt)2
Me
8
18 cis:trans = 10:1
O
Me
O
9e 85:15
CO2Et
Ph
O
Me
P(OEt)2
Ph
9
19
O
Me
O
9f
O
O
O
CO2Et
CO2Et
O
P(OEt)2
P(OEt)2
P(OEt)2
Me
Me
P(OEt)2
10
4
20
21
O
Me
O
9g
20:21 = 0:100
21 cis:trans = 84:16
a Reaction conditions: THF, EtONa (1 equiv)/EtOH, r.t., then reflux.
Synlett 2005, No. 17, 2648–2652 © Thieme Stuttgart · New York

LETTER
Synthesis of Cyclopropanecarboxylates
2651
Spectroscopic Data for 3-Benzyl-3-diethoxyphosphoryl-
5-methyltetrahydrofuran-2-one (9f).
the cyclopropanation product of 9d was isolated as a
mixture of 16 and 17 in a ratio 13:87. Under the same con-
ditions the vinylphosphonate 20 isomerized fully to the
corresponding 2-alkenyl derivative 21. The product was
obtained as a mixture of cis/trans-isomers in a ratio 84:16.
Structural integrity of each isomerization product was
IR (film): 1764, 1256 cm–1. 1H NMR (250 MHz, CDCl3):
d = 1.22 (d, 3JHH = 6.2 Hz, 3 H, major), 1.25 (d, 3JHH = 5.5
Hz, 3 H, minor), 1.39 (td, 3JHH = 7.0 Hz, 4JPH = 0.6 Hz, 3 H,
major + minor), 1.40 (td, 3JHH = 7.0 Hz, 4JPH = 0.5 Hz, 3 H,
major + minor), 2.32 (dd, 3JPH = 13.7 Hz, 3JHH = 8.5 Hz, 1 H,
major + minor), 2.40 (d, 3JHH = 8.5 Hz, 1 H, major + minor),
2.94 (dd, 2JHH = 13.8 Hz, 3JPH = 9.7 Hz, 1 H, minor), 2.97
(dd, 2JHH = 13.4 Hz, 3JPH = 9.2 Hz, 1 H, major), 3.29 (dq,
3JHH = 8.5 Hz, 3JHH = 6.2 Hz, 1 H, major + minor), 3.52 (dd,
2JHH = 13.4 Hz, 3JPH = 6.0 Hz, 1 H, major), 3.60 (dd,
2JHH = 13.4 Hz, 3JPH = 5.7 Hz, 1 H, minor), 4.20–4.36 (m, 4
1
verified by H NMR and 31P NMR analysis. Base-cata-
lyzed isomerization of 1-alkenylphosphonates to the cor-
responding 2-alkenylphosphonates had been previously
reported.13
In summary, we have shown that a-diethoxyphosphoryl-
g-lactones are versatile starting materials for the prepara-
tion of cyclopropanecarboxylates. The described syn-
thesis offers a convenient approach to multisubstituted
cyclopropanecarboxylates equivalent to that of a conven-
tional Wittig-type cyclopropanation.
H, major + minor), 7.16–7.30 (m, 5 H, major + minor). 13
C
NMR (62.9 MHz, CDCl3): d = 16.20 (2 d, 3JPC = 5.9 Hz),
21.12 (s), 35.46 (d, 2JPC = 2.0 Hz), 38.20 (d, 2JPC = 3.0 Hz),
51.30 (d, 1JPC = 145.6 Hz), 63.02 (d, 2JPC = 7.2 Hz), 63.50 (d,
2JPC = 6.9 Hz), 74.36 (d, 3JPC = 8.3 Hz), 127.39 (s), 128.58
(s), 129.62 (s), 135.02 (d, 3JPC = 15.9 Hz), 174.77 (d,
2JPC = 5.7 Hz). 31P NMR (101 MHz, CDCl3): d = 23.86
(minor), 24.14 (major). Anal. Calcd for C16H23O5P: C,
58.89; H, 7.10. Found: C, 59.02; H, 7.05.
References
(8) (a) Janecki, T.; Kuꢄ, A.; Krawczyk, H.; Błaszczyk, E. Synlett
2000, 611. (b) Janecki, T.; Błaszczyk, E. Synthesis 2001,
403.
(9) General Procedure for the Preparation of trans-3-
Diethoxyphosphoryl-5,5-dimethyl-4-(2-methylprop-1-
enyl)tetrahydrofuran-2-one (11b).
(1) (a) Denney, D. B.; Boskin, M. J. J. Am. Chem. Soc. 1959, 81,
6330. (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem.
Soc. 1961, 83, 1733. (c) Denney, D. B.; Vill, J. J.; Boskin,
M. J. J. Am. Chem. Soc. 1962, 84, 3944. (d) Tömösközi, I.
Tetrahedron 1963, 19, 1969. (e) Izydore, R. A.; Ghirardelli,
R. G. J. Org. Chem. 1973, 38, 1790. (f) Baboulene, M.;
Sturtz, G. Phosphorus 1973, 2, 195. (g) Fitzsimmons, B. J.;
Fraser-Reid, B. Tetrahedron 1984, 40, 1279. (h) Petter, R.
C. Tetrahedron Lett. 1989, 30, 399. (i) Petter, R. C.;
Banerjee, S.; Englard, S. J. Org. Chem. 1990, 55, 3088.
(2) (a) Wallace, P.; Warren, S. Tetrahedron Lett. 1985, 26,
5713. (b) Wallace, P.; Warren, S. J. Chem. Soc., Perkin
Trans. 1 1988, 2971. (c) Ayrey, P.; Warren, S. Tetrahedron
Lett. 1989, 34, 4581. (d) Nelson, A.; Warren, S. J. Chem.
Soc., Perkin Trans. 1 1999, 3425.
To a stirred solution of 2-methyl-1-propenylmagnesium
bromide (2.04 mL, 20.15 mmol) in THF (5 mL) and catalytic
amount of CuI (0.05 g, 0.26 mmol) a solution of lactone 10
(1.00 g, 4.03 mmol) in THF (5 mL) under argon atmosphere
at –15 °C was added. The reaction mixture was and kept at
this temperature for 72 h. Then the mixture was warmed to
r.t., acidified to pH = 5 with sat. NH4Cl solution and
extracted with CH2Cl2 (4 × 10 mL). Combined extracts were
dried (MgSO4) and evaporated. Crude product was purified
by column chromatography (silica gel, EtOAc–hexane 1:1
for 11a,b).
(3) Avery, T. D.; Fallon, G.; Greatrex, B. W.; Pyke, S. M.;
Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2001, 66,
7955.
Spectroscopic Data.
IR (film): 1764, 1676, 1268 cm–1. 1H NMR (250 MHz,
CDCl3): d = 1.26 (s, 3 H), 1.31 (t, 3JHH = 7.0 Hz, 3 H), 1.37
(t, 3JHH = 7.1 Hz, 3 H), 1.47 (s, 3 H), 1.76 (d, 4JHH = 1.1 Hz,
3 H), 1.79 (d, 4JHH = 1.0 Hz, 3 H), 3.00 (dd, 2JPH = 23.2 Hz,
3JHH = 11.8 Hz, 1 H), 3.64 (ddd, 3JPH = 16.1 Hz, 3JHH = 11.8
Hz, 3JHH = 10.1 Hz, 1 H), 4.13 (dq, 3JPH = 7.1 Hz, 3JHH = 7.1
Hz, 1 H), 4.27 (dq, 3JPH = 7.1 Hz, 3JHH = 7.1 Hz, 1 H), 4.28
(dq, 3JPH = 7.1 Hz, 3JHH = 7.1 Hz, 1 H), 5.03 (ddd,
3JHH = 10.1 Hz, 4JHH = 1.1 Hz, 4JHH = 1.0 Hz, 1 H). 13C NMR
(62.9 MHz, CDCl3): d = 15.88 (d, 3JPC = 6.5 Hz), 16.02 (d,
3JPC = 6.2 Hz), 17.94 (s), 22.45 (s), 25.64 (s), 26.70 (s),
45.11 (d, 1JPC = 151.3 Hz), 46.52 (d, 2JPC = 2.1 Hz), 61.93 (d,
2JPC = 6.7 Hz), 63.05 (d, 2JPC = 6.3 Hz), 86.18 (d, 3JPC = 14.2
Hz), 119.81 (s), 136.90 (s), 170.00 (s). 31P NMR (101 MHz,
CDCl3): d = 21.01. Anal. Calcd for C14H25O5P: C, 55.25; H,
8.28. Found: C, 55.12; H, 8.20.
(4) (a) Reeve, C. D.; Crout, D. H. G.; Cooper, K.; Fray, M. J.
Tetrahedron: Asymmetry 1992, 785. (b) Ohta, A.;
Sawamoto, D.; Jayasundera, K. P.; Kinoshita, H.; Inomata,
K. Chem. Lett. 2000, 492.
(5) Daremon, C.; Rambaud, R. Bull. Soc. Chim. Fr. 1971, 294.
(6) Giaocchino, F.; Bernd, S.; Wilfried, P. Z. Naturforsch., B:
Chem. Sci. 1983, 38, 493.
(7) General Procedure for the Preparation of a-Substituted
and a,g-Disubstituted a-Diethoxyphosphoryl-g-lactones
9a–d and 9e–g.
A solution of a-diethoxyphosphoryl-g-lactone (5, 17.0
mmol) in THF (10 mL) was added dropwise under argon
atmosphere at –78 °C to a stirred solution of LDA prepared
from BuLi (10.6 mL, 17 mmol) and i-Pr2NH (2.40 mL, 17
mmol) in THF (15 mL). When the addition was completed
the reaction mixture was warmed to –5 °C and stirred for 0.5
h. After this time the mixture was cooled to –78 °C and allyl
bromide (17 mmol) in THF (10 mL) was added. The stirring
was continued for 1 h at this temperature and then the
reaction mixture was warmed to r.t. and stirred for 20 h. The
mixture was acidified to pH = 1 using 1 N HCl solution and
THF was evaporated under reduced pressure. The residue
was extracted with CHCl3 (3 × 15 mL). Combined extracts
were washed with H2O (15 mL) and brine (15 mL), dried
(MgSO4) and evaporated. Crude products were distilled in
vacuum (for 9a–c and 9e,f) or purified by column chromato-
graphy (silica gel, eluent CHCl3–acetone 5:1 for 9d and 9g).
(10) General Procedure for the Preparation of Ethyl
Cyclopropanecarboxylates 12–23.
To a suspension of NaH (0.14 g, 6.0 mmol) and a-diethoxy-
phosphoryl-g-lactone 5b, 9a–g or 11a,b (6.0 mmol) in THF
(15 mL) was added dropwise under argon atmosphere at r.t.
a solution of EtOH (0.40 mL, 6.6 mmol) in THF (5 mL). The
reaction mixture was stirred for 0.5 h and then was heated at
reflux for time given in Table 3. After cooling to r.t. brine (5
mL) was added and THF was evaporated. The residue was
extracted with CH2Cl2 (3 × 15 mL) and dried (Na2SO4).
After evaporation the crude products were purified by
Synlett 2005, No. 17, 2648–2652 © Thieme Stuttgart · New York

2652
H. Krawczyk et al.
LETTER
column chromatography (silica gel, eluent CHCl3–hexane
80:20 for 9a–c and 50:50 for 22, 23 and CHCl3–acetone
90:10 for 16, 17 and 21).
Spectroscopic Data for 1-Benzyl-2-methylcyclopropane-
carboxylic Ethyl Ester (19).
(s), 14.03 (s), 21.76 (s), 22.24 (s), 27.69 (s), 33.26 (s), 60.37
(s), 125.68 (s), 128.00 (s), 128.39 (s), 140.60 (s), 175.25 (s).
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C,
76.89; H, 8.28.
(11) Choi, S.-Y.; Newcomb, M. Tetrahedron 1995, 51, 657.
(12) Rao, A. V. R.; Rao, M. N.; Garyali, K. Synth. Commun.
1984, 14, 557.
(13) (a) Gerber, J. P.; Modro, T. A.; Wagener, C. C. P.; Zwierzak,
A. Heteroat. Chem. 1991, 2, 643. (b) Kiddle, J. J.; Babler, J.
H. J. Org. Chem. 1993, 58, 3572.
IR (film): 1768 cm–1. 1H NMR (250 MHz, CDCl3): d = 0.55
(dd, 3JHH = 6.5 Hz, 3JHH = 4.0 Hz, 1 H), 1.11 (t, 3JHH = 7.0
Hz, 3 H), 1.20 (d, 3JHH = 6.2 Hz, 3 H), 1.51–1.60 (m, 2 H),
2.78 (d, 2JHH = 15.8 Hz, 1 H), 3.21 (d, 2JHH = 15.8 Hz, 1 H),
4.03 (q, 3JHH = 7.0 Hz, 1 H), 4.03 (q, 3JHH = 7.0 Hz, 1 H),
7.16–7.27 (m, 5 H). 13C NMR (62.9 MHz, CDCl3): d = 14.02
Synlett 2005, No. 17, 2648–2652 © Thieme Stuttgart · New York