Masked β-, γ- and δ-lithium ester enolates: Useful reagents in organic synthesis

Article abstract of DOI:10.1016/S0040-4039(00)02172-9

The reaction of ω-chloro orthoesters 1 with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5% molar) in the presence of different electrophiles [Bu^tCHO, PhCHO, (CH₂)₅CO, Et₂CO, PhCOMe, PhCH=NPh, Me₃SiCl] in THF at -78°C leads, after hydrolysis and acid-catalysed methanolysis, to functionalised methyl esters 2. In the case of chlorotrimethylsilane, hydroxyethyl esters 2′ are isolated. The reaction is also applied to bicyclic orthoesters 3: whereas β-chloro derivatives and carbonyl compounds gives directly γ-lactones 4 after hydrolysis, the corresponding γ-chloro derivative affords the expected methyl esters after methanolysis.

Full text of DOI:10.1016/S0040-4039(00)02172-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1029–1032
Masked b-, g- and d-lithium ester enolates: useful reagents in
organic synthesis†
Isidro M. Pastor and Miguel Yus*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
Received 18 October 2000; accepted 23 November 2000
Abstract—The reaction of v-chloro orthoesters 1 with lithium and a catalytic amount of 4,4%-di-tert-butylbiphenyl (DTBB, 5%
molar) in the presence of different electrophiles [ButCHO, PhCHO, (CH2)5CO, Et2CO, PhCOMe, PhCHꢀNPh, Me3SiCl] in THF
at −78°C leads, after hydrolysis and acid-catalysed methanolysis, to functionalised methyl esters 2. In the case of chlorotrimethyl-
silane, hydroxyethyl esters 2% are isolated. The reaction is also applied to bicyclic orthoesters 3: whereas b-chloro derivatives and
carbonyl compounds gives directly g-lactones 4 after hydrolysis, the corresponding g-chloro derivative affords the expected methyl
esters after methanolysis. © 2001 Elsevier Science Ltd. All rights reserved.
compounds, being generated in all cases by chlorine–
lithium exchange.7
Normal metal enolates I (a-enolates) are important
intermediates in synthetic organic chemistry mainly in
reactions with carbonyl compounds, which afford
aldol-type products having 1,3-functionality.1 However,
higher-order metal enolates II (b-, g-, d-,… enolates)
are far more difficult to use because they have a ten-
dency to decompose spontaneously to give metal
cycloalcoholates III. Intermediates of the type II would
be interesting from a synthetic point of view because
reacting with carbonyl compounds as electrophiles they
could generate 1,4-, 1,5-, 1,6-,… functionality (1,4- and
1,6-difunctionalised compounds being ‘umpolung’
products2), which is not easily available using conven-
tional methodologies. Among different possibilities
concerning either the metal or n in synthons of the type
II, lithium derivatives (Met=Li) and homoenolates (b-
enolates: n=1) are the most studied intermediates
described in the literature.3 In general, the methodolo-
gies involving lithium homoenolates use either pro-
tected carbonyl compounds4 or functionalised
allyllithium systems3b and they are prepared by depro-
tonation,3b chlorine–lithium exchange4,5 or tin–lithium
transmetallation.6 Very few reports can be found in the
literature for g- or d-enolates derived from carbonyl
In the last few years we have been using an arene-
catalysed lithiation8–11 for the preparation of very reac-
tive organolithium compounds under very mild reaction
conditions: this methodology allowed us to develop
new procedures for preparing organolithium com-
pounds from non-halogenated materials,12 function-
alised organolithium compounds13 from chlorinated
materials14 or heterocyclic precursors,15 and polylithium
synthons.16 In this paper, we apply the mentioned
methodology, arene-catalysed lithiation, for the genera-
tion of masked high order (b-, g- and d-) ester enolates
by chlorine–lithium exchange.
The reaction of compounds 1 with an excess of lithium
powder (1:5 molar ratio) and a catalytic amount of
4,4%-di-tert-butylbiphenyl (DTBB, 1:0.1 molar ratio, 5%
molar) in the presence of different electrophiles [E=
ButCHO, PhCHO, (CH2)5CO, Et2CO, PhCOMe,
PhCHꢀNPh, Me3SiCl] (Barbier-type conditions17) in
THF at −78°C for 30 min led, after hydrolysis with
phosphate buffer (pH:7) and final p-toluenesulfonic
Keywords: chlorine–lithium exchange; functionalised esters; g-lactones; DTBB-catalysed lithiation.
* Corresponding author. Fax: +34 965 903549; e-mail: yus@ua.es
†
This paper is warmly dedicated to Professor Rafael Uso´n on the occasion of his 75th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02172-9

1030
I. M. Pastor, M. Yus / Tetrahedron Letters 42 (2001) 1029–1032
Table 1. Preparation of compounds 2 from chloro orthoesters 1
Entry
Starting material
Electrophile E
Product 2a
No.
n
X
Yield (%)b
Rfc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
ButCHO
PhCHO
(CH2)5CO
Et2CO
PhCOMe
PhCHꢀNPh
Me3SiCl
ButCHO
PhCHO
(CH2)5CO
Et2CO
PhCOMe
PhCHꢀNPh
Me3SiCl
2aa
2ab
2ac
2ad
2ae
2af
3
3
3
3
3
3
3
4
4
4
4
4
4
4
ButCHOH
PhCHOH
(CH2)5COH
Et2COH
58
0.31
0.20
0.29
0.24
0.23
0.46
0.25
0.28
0.24
0.25
0.24
0.18
0.49
0.28
63 (54)d (47)e
59
51
52
57
40
62
66
56
52
49
54
47
PhC(OH)Me
PhCHNHPh
Me3Si
2%agf
2ba
2bb
2bc
2bd
2be
2bf
ButCHOH
PhCHOH
(CH2)5COH
Et2COH
PhC(OH)Me
PhCHNHPh
Me3Si
2%bgf
a All compounds 2 were ]95% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C
NMR, and MS).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting chloro orthoester 1.
c Silica gel, hexane/ethyl acetate: 5/1.
d Yield corresponding to the reaction at 0°C.
e Yield corresponding to the two-step reaction.
f The corresponding hydroxyethyl ester 2% was isolated (see text).
Scheme 1. (i) Li, DTBB (5% molar), E=ButCHO, PhCHO, (CH2)5CO, Et2CO, PhCOMe, PhCHꢀNPh, Me3SiCl, THF, −78°C,
30 min; (ii) phosphate buffer (pH:7), −78 to 20°C, ca. 15 min; (iii) MeOH, PTSA (cat.), 20°C, overnight.
acid (PTSA)-catalysed methanolysis, to the correspond-
ing functionalised methyl esters 218 (Scheme 1 and
Table 1). When the same process was carried out at 0°C
or in a two-step reaction (Grignard-type conditions),
lower yields were obtained (Table 1, entry 2 and foot-
notes d and e, respectively). On the other hand, a
different result was observed when using chloro-
trimethylsilane: in this case silylated hydroxyethylesters
2% were the only reaction products isolated (Table 1,
entries 7 and 14, and footnote f).
The application of the reaction shown in Scheme 1
to the corresponding b-derivatives (1, n=2) was not
possible because we could not prepare the starting
material in a pure form following the same methodol-
ogy: a ca. 1:1 inseparable mixture of the expected
product and the corresponding a,b-unsaturated or-
thoester (resulting from a dehydrochlorination process)
was obtained.
In order to overcome the former problem, the bicyclic
orthoester 3a was prepared and submitted to the same
reaction conditions as for compounds 1 [E=R1R2CO:
ButCHO, PhCHO, Et2CO, (CH2)5CO, PhCOMe]. After
controlled hydrolysis and final treatment with a cata-
From a mechanistic point of view, intermediates IV and
V are probably involved in the process before the last
tandem hydrolysis–methanolysis treatment. The gener-
ation of compounds 2% can be explained by the an-
chimeric assistance of the silicon atom in the hydrolysis
step through the intermediate VI.
Starting materials 1 were prepared in 70–80% yield
from the corresponding v-chloronitriles by an acid-
catalysed methanolysis followed by ketalysation with
ethyleneglycol.19
Scheme 2. (i) Li, DTBB (5% molar), R1R2CO=ButCHO,
PhCHO, (CH2)5CO, Et2CO, PhCOMe, THF, −78°C, 30 min;
(ii) phosphate buffer (pH:7), −78 to 20°C, ca. 15 min; (iii)
PTSA (cat.), 20°C, overnight.

I. M. Pastor, M. Yus / Tetrahedron Letters 42 (2001) 1029–1032
Table 2. Preparation of compounds 4 from chloro orthoester 3a
1031
Entry
Carbonyl compound (E)
Product 4a
R2
No.
R1
Yield (%)b
Rfc
1
2
3
4
5
ButCHO
PhCHO
(CH2)5CO
Et2CO
4a
4b
4c
4d
4e
But
Ph
H
H
45
0.37
0.36
0.48
0.39
0.35
43 (<5)d
(CH2)5
39
38
37
Et
Ph
Et
Me
PhCOMe
a All compounds 2 were ]96% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C
NMR, and MS).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting chloro orthoester 3a.
c Silica gel, hexane/ethyl acetate: 9/1.
d Yield corresponding to the reaction at 0°C.
lytic amount of PTSA, the corresponding g-lactones 4
were obtained (Scheme 2 and Table 3). For compound
3a it is better not to perform the methanolysis in the
last step of the process in order to avoid the generation
of a mixture of the lactone 4 and the corresponding
methyl ester. In the case of performing the reaction at
Scheme 3. (i) Li, DTBB (5% molar), E=ButCHO, PhCHO,
PhCOMe, THF, 0°C, 30 min; (ii) phosphate buffer (pH:7),
0 to 20°C, ca. 15 min; (iii) MeOH, PTSA (cat.), 20°C,
overnight.
higher temperature (0°C), lower yields are obtained
(Table 2, entry 2 and footnote d).
Of course, the process described in Scheme 2 can be
applied to the corresponding g-derivatives. Thus, when
compound 3b was allowed to react under the conditions
shown in Scheme 1, but at 0°C, the expected com-
pounds 2 were isolated (Scheme 3 and Table 3). In this
case, the reaction at lower temperature (−78°C)
afforded poorer yield (Table 3, entry 2 and footnote d).
The participation of intermediates VII and VIII was
demonstrated by performing the corresponding
deuterolysis with deuterium oxide instead of the hydrol-
ysis: deuterated compound 5 was isolated in 87% yield
and 85% deuterium incorporation.
3-hydroxymethyl-3-methyloxetane and boron trifl-
uoride etherate.20
Finally, we can conclude that the methodology de-
scribed in this paper is a reasonable entry to b-, g-, and
d-lithio carboxylic acid synthons by DTBB-catalysed
chlorine–lithium exchange. The reaction of these inter-
mediates with different electrophiles, mainly carbonyl
Starting materials 3 were prepared by successive treat-
ment of the corresponding v-chloro acyl chlorides with
compounds, allows the remote functionalisation of car-
boxylic acids.
Table 3. Preparation of compounds 2 from chloro orthoester 3b
Entry
Carbonyl compound (E)
Product 2a
No.
X
Yield (%)b
Rfc
1
2
3
ButCHO
PhCHO
PhCOMe
2aa
2ab
2ae
ButCHOH
PhCHOH
PhC(OH)Me
38
0.31
0.20
0.23
41 (30)d (37)e
37
a All compounds 2 were ]95% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C
NMR, and MS).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting chloro orthoester 3b.
c Silica gel, hexane/ethyl acetate: 5/1.
d Yield corresponding to the reaction at −78°C.
e Yield corresponding to the two-step process.

1032
I. M. Pastor, M. Yus / Tetrahedron Letters 42 (2001) 1029–1032
8. First account: Ramo´n, D. J.; Yus, M. J. Chem. Soc.,
Acknowledgements
Chem. Commun. 1991, 398–400.
9. Reviews: (a) Yus, M. Chem. Soc. Rev. 1996, 155–161. (b)
Ramo´n, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225–237
(Microreview).
10. For a polymer supported arene-catalysed version of this
reaction, see: (a) Go´mez, C.; Ruiz, S.; Yus, M. Tetra-
hedron Lett. 1998, 39, 1397–1400. (b) Go´mez, C.; Ruiz,
S.; Yus, M. Tetrahedron 1999, 55, 7017–7026.
This work was generously supported by the DGES (no.
PB97-0133) from the Spanish Ministerio de Educacio´n
y Cultura (MEC). I.M.P. thanks the Generalitat Valen-
ciana for a fellowship.
References
11. Previous contribution on this topic from our laboratory:
Pastor, I. M.; Yus, M. Tetrahedron Lett. 2000, 41, 5335–
5339.
12. (a) Review: Guijarro, D.; Yus, M. Recent Res. Dev. Org.
Chem. 1998, 2, 713–744. (b) Previous contribution on this
topic from our laboratory: Foubelo, F.; Yus, M. Tetra-
hedron Lett. 2000, 41, 5047–5051.
13. Reviews: (a) Na´jera, C.; Yus, M. Trends Org. Chem.
1991, 1, 155–181. (b) Na´jera, C.; Yus, M. Recent Res.
Dev. Org. Chem. 1997, 1, 67–96. (c) Yus, M.; Foubelo, F.
Rev. Heteroat. Chem. 1997, 17, 73–107.
14. Previous contribution on this topic from our laboratory:
Alonso, F.; Falvello, L. R.; Fanwick, P. E.; Lorenzo, E.;
Yus, M. Synthesis 2000, 949–952.
15. (a) Review: Ref. 13c. (b) Previous contribution on this
topic from our laboratory: Falvello, L. R.; Foubelo, F.;
Soler, T.; Yus, M. Tetrahedron: Asymmetry 2000, 11,
2063–2066.
16. (a) Review: Foubelo, F.; Yus, M. Trends Org. Chem.
1998, 7, 1–26. (b) Previous contribution on this topic
from our laboratory: Lorenzo, E.; Alonso, F.; Yus, M.
Tetrahedron 2000, 56, 1745–1757.
17. For reviews on lithiation processes under Barbier-type
reaction conditions, see: (a) Blomberg, C. The Barbier
Reaction and Related One-step Processes; Springer-Ver-
lag: Berlin, 1993. (b) Alonso, F.; Yus, M. Recent Res.
Dev. Org. Chem. 1997, 1, 397–436.
1. For general information see, for instance: (a) Heathcock,
C. H. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I.; Heathcock, C. H., Eds.; Pergamon Press:
Oxford, 1991; Vol. II, pp. 133–179 and 181–238. (b)
Moon Kim, B.; Williams, S. F.; Masamune, S. In Com-
prehensive Organic Synthesis; Trost, B. M.; Fleming, I.;
Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991;
Vol. II, pp. 239–275.
2. For reviews, see: (a) Seebach, D. Angew. Chem., Int. Ed.
Engl. 1979, 18, 239–258. (b) Umpoled Synthons; Hase,
T.-A., Ed.; J. Wiley & Sons: New York, 1987.
3. For reviews on homoenolates, see: (a) Werstiuk, N. H.
Tetrahedron 1983, 39, 205–268. (b) Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1984, 23, 932–948. (c) Stowell, J. C.
Chem. Rev. 1984, 84, 409–435. (d) Kuwajima, I.; Naka-
mura, E. Top. Curr. Chem. 1990, 155, 1–39. (e) Kuwa-
jima, I.; Nakamura, E. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I.; Heathcock, C. H.,
Eds.; Pergamon Press: Oxford, 1991; Vol. II, pp. 441–
473. (f) Crimmins, M. T.; Nantermet, P. G. Org. Prep.
Proc. Int. 1993, 25, 41–81. (g) Ahlbrecht, H.; Beyer, U.
Synthesis 1999, 365–390. (h) Katritzky, A. R.; Piffl, M.;
Lang, H; Anders, E. Chem. Rev. 1999, 99, 665–722. (i)
For previous contribution on this topic from our labora-
tory, see: Alonso, E.; Ramo´n, D. J.; Yus, M. Tetrahedron
1997, 53, 2641–2652.
18. General procedure for compounds 2: To a dark green
suspension of lithium powder (ca. 70 mg, 10 mmol) and
DTBB (53 mg, 0.2 mmol, 5% molar) in THF (10 ml) was
slowly added (ca. 1 h) a solution of the orthoester 1 (2
mmol) and the corresponding electrophile (2.2 mmol) in
THF (3 ml) at −78°C. After stirring for an additional 30
min, the reaction mixture was hydrolysed with a phos-
phate buffer solution (pH:7, 10 ml) and extracted with
ethyl acetate (3×10 ml). The organic phase was succes-
sively washed with brine (10 ml) and water (10 ml) and
dried with Na2SO4. After evaporation of the solvents (15
Torr), the resulting residue was dissolved in dry methanol
(20 ml). The resulting solution was treated with PTSA (10
mg) and stirred at room temperature overnight. After
adding water (20 ml), the resulting mixture was extracted
with ether (5×10 ml), the organic layer successively
washed with 0.1 M NaOH (2×10 ml) and water (10 ml)
and dried (MgSO4). Evaporation of the solvents (15 Torr)
gave a residue, which was purified by column chromatog-
raphy (silica gel, hexane/ethyl acetate) to yield the pure
title compounds 2.
4. See, for instance: (a) Barluenga, J.; Rubiera, C.; Ferna´n-
dez, J. R.; Yus, M. J. Chem. Soc., Chem. Commun. 1987,
425–426. (b) Barluenga, J.; Ferna´ndez, J. R.; Yus, M. J.
Chem. Soc., Chem. Commun. 1987, 1534–1535. (c) Barlu-
enga, J.; Ferna´ndez, J. R.; Rubiera, C.; Yus, M. J. Chem.
Soc., Perkin Trans. 1 1988, 3113–3117.
5. See, for instance: (a) Caine, D.; Frobese, A. S. Tetra-
hedron 1978, 883–886. (b) Takahaka, H.; Ohkura, E.;
Ikuro, K.; Yamazaki, T. Synth. Commun. 1991, 20, 285–
292.
6. See, for instance: (a) Goswami, R.; Corcoran, D. E.
Tetrahedron Lett. 1982, 23, 1463–1466. (b) Goswami, R.;
Corcoran, D. E. J. Am. Chem. Soc. 1983, 105, 7182–7183.
(c) Nakahira, H.; Ryu, I.; Ikeb.; Kambe, N.; Sonoda, N.
Angew. Chem., Int. Ed. Engl. 1991, 30, 177–179. (d) Ryu,
I.; Nakahira, H.; Ikebe, M.; Sonoda, N.; Yamato, S.-y.;
Komatsu, M. J. Am. Chem. Soc. 2000, 122, 1219–1220.
7. (a) Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1990, 31,
3763–3766. (b) Ramo´n, D. J.; Yus, M. Tetrahedron Lett.
1990, 31, 3767–3770. (c) Ramo´n, D. J.; Yus, M. J. Org.
Chem. 1991, 56, 3825–3831. (d) Ramo´n, D. J.; Yus, M. J.
Org. Chem. 1992, 57, 750–751. (e) Gil, J. F.; Ramo´n, D.
J.; Yus, M. Tetrahedron 1993, 49, 4923–4938. (f) Gil, J.
F.; Ramo´n, D. J.; Yus, M. Tetrahedron 1994, 50, 7307–
7314.
19. (a) Casy, G.; Furber, M.; Richardson, K. A.; Stephenson,
G. R.; Taylor, R. J. K. Tetrahedron 1986, 42, 5849–5856;
(b) Marko´, I. E.; Ates, A. Synlett 1999, 1033–1036.
20. Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571–
5574.
.