Practical synthesis of ynolate anions: Naphthalene-catalyzed reductive lithiation of α,α-dibromo esters

Article abstract of DOI:10.1016/S0040-4039(01)01799-3

Reductive lithiation of α,α-dibromo esters using lithium naphthalenide afforded ester dianions leading to ynolate anions in good yields. Naphthalene-catalyzed reductive lithiation was also accomplished. This is a convenient, economical and practical method for the preparation of ynolate anions.

Full text of DOI:10.1016/S0040-4039(01)01799-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8357–8360
Practical synthesis of ynolate anions: naphthalene-catalyzed
reductive lithiation of a,a-dibromo esters
Mitsuru Shindo,a,b,* Ryoko Koretsune,a Wakako Yokota,a Kotaro Itohb and Kozo Shishidoa
aInstitute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan
bConversion and Control by Advanced Chemistry, PRESTO, JST, Japan
Received 29 August 2001; revised 25 September 2001; accepted 26 September 2001
Abstract—Reductive lithiation of a,a-dibromo esters using lithium naphthalenide afforded ester dianions leading to ynolate anions
in good yields. Naphthalene-catalyzed reductive lithiation was also accomplished. This is a convenient, economical and practical
method for the preparation of ynolate anions. © 2001 Elsevier Science Ltd. All rights reserved.
Ynolate anions (3) act not only as carbanions forming
a carbonꢀcarbon bond but also as ketene anion equiva-
lents.1 They are therefore expected to undergo unique
reaction sequences; however, because of the difficulty of
their preparation,1 their chemistry has not been exten-
sively studied. We have developed a novel methodology
for the generation of ynolate anions via cleavage of
ester dianions (2) prepared from readily available a,a-
dibromo esters (1) (Scheme 1),2 and have demonstrated
their use as multifunctional carbanions.3 Although this
synthetic method is simple and convenient, the tert-
butyllithium used in the lithium–halogen exchange is
somewhat expensive and should be carefully handled. If
a safer and more economical method could be devel-
oped, it would be useful, especially for large scale
reactions. In this communication, we describe a practi-
cal synthesis of ynolate anions, utilizing the naphtha-
lene-catalyzed reductive lithiation of a,a-dibromo
esters.
exchange via n- or tert-butyllithium.5 One of the most
frequently used arene species in the preparation of the
radical anion is naphthalene.6 To evaluate the efficiency
of the generation of lithium ynolates, olefination of
benzophenone was selected, since this reaction is known
to afford the olefin (4) in excellent yields.3a,3f
In the first trial, a deep green THF solution (0.4 M) of
lithium naphthalenide (LN), prepared by lithium metal
and an equimolar amount of naphthalene in THF at
room temperature, was added dropwise via syringe to a
colorless THF solution of the dibromo ester (1a) at
−78°C.
Li+
LN:
Reductive lithiation of alkyl halides via radical anions4
is an important method for the preparation of alkyl-
lithium compounds as well as lithium–halogen
After the LN solution (8.3 mL, ca. 3.3 equiv.) was
added dropwise over 15 min, the reaction mixture
turned deep green. At this stage, 1a was completely
O
EtOLi
tert-BuLi
(4 eq)
R
CO2H
Ph
R
CO2Et
R
OLi
Ph
Ph
R
OLi
Br Br
Li
OEt
0 ˚C, 0.5 h
-78 ˚C, 3 h
Ph
rt
ester dianions (2)
ynolate anions (3)
1
4
Scheme 1.
Keywords: ynolate anion; radical anion; catalytic reductive lithiation; lithium naphthalenide.
* Corresponding author. Tel./fax: +81-88-633-7294; e-mail: shindo@ph2.tokushima-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01799-3

8358
M. Shindo et al. / Tetrahedron Letters 42 (2001) 8357–8360
converted into the monoanion (5a).† The same amount
(8.3 mL, ca. 3.3 equiv.) of LN solution was added
dropwise over 15 min at −78°C. The deep green reaction
mixture was then warmed to 0°C and was stirred for 30
min. After addition of several drops (ca 0.18 equiv.) of
1,2-dibromoethane to quench the excess radical anion, a
THF solution of benzophenone (1.2 equiv. based on the
dibromo ester)‡ was added at room temperature. The
mixture was stirred for an additional 30 min before
work-up. The desired olefin (4a) was isolated in 82%
yield, demonstrating that the ynolate anion (3a) was
generated in good yield via the radical anion method. It
also illustrates that the first lithiation furnishing 5a was
very fast while the second giving the dianion (2a) was
relatively slow. In this method, an excess of LN was
required, probably due to air contamination during the
transfer of the LN solution via syringe (Scheme 2).
Next, we examined the addition of a,a-dibromo ester to
the LN solution (Scheme 3). To the LN solution (ca. 4.8
mmol) was added the dibromo ester (1.0 mmol) at −78°C.
After stirring for 30 min, the reaction was allowed to
warm to 0°C and was stirred for an additional 30 min.
After addition of 1,2-dibromoethane, benzophenone (1.2
mmol) was added at room temperature. The desired
olefin (4a) was isolated in 84% yield (Table 1, entry 1).
In both methods, the efficiency of generation of ynolates
is extremely high. However, more than 5 equiv. of
naphthalene must be removed after the reaction,
although it can be recovered.
To solve this problem, naphthalene-catalyzed reductive
lithiation7 of a,a-dibromo esters was examined (Table 1).
Using 42 mol% (based on lithium) of naphthalene, the
reaction gave 4a in 72% yield, although it took 3.5
LN
(ca. 3.3 eq)
LN
(ca. 3.3 eq)
Bu CO2Et
Bu
Bu
Li
OLi
OLi
Br Br
OEt
Br
OEt
-78 ˚C
15 min
-78 ˚C
15 min
1a
5a
2a
BrCH2CH2Br
O
EtOLi
Bu
Ph
CO2H
Ph
Ph
Ph
Bu
OLi
0 ˚C, 0.5 h
rt, 30 min
3a
4a
82%
Scheme 2.
O
Ph
(1.2 eq)
Ph
Bu
Ph
CO2H
Ph
naphthalene
Conditions
Bu CO2Et
Br Br
+
Bu
OLi
Li
0 ˚C
30 min
rt, 30 min
(4.8 eq)
4a
Scheme 3.
Table 1. Naphthalene-catalyzed reductive lithiation of a,a-dibromo esters leading to ynolate anions
Entry
Naphthalene (mol%)a
Preparation time of LN (min)b
Conditions
Yield (%)c
1
2
3
4
5
6
7
104
42
21
21
10
5
80
40
15
15
15
15
15
−78°C, 30 min
−78°C, 3.5 h
84
72
73
65
78
79
68
−78°C, 20 min; −50°C, 2.0 h
−50°C, 2 h
−78°C, 40 min; −50°C, 2.5 h
−78°C, 30 min; −50°C, 4 h
−78°C, 1.5 h; −50°C, 7.5 h
2.6
a Based on lithium metal.
b Lithium (4.8 mmol) and naphthalene in THF (13 mL) were stirred at room temperature.
c Based on dibromo ester.
† At this stage, Darzen’s product (6) was isolated if the reaction mixture was treated with benzophenone at room temperature.
EtO2C
O
Ph
Bu
6
Ph
‡ To estimate the efficiency of the synthesis, a small excess of the electrophile was used.

M. Shindo et al. / Tetrahedron Letters 42 (2001) 8357–8360
8359
O
naphthalene
Ph
R
CO2H
Ph
Ph
R
CO2Et
+
R
OLi
Li
Br Br
(1.3 eq)
0 ˚C
30 min
rt, 30 min
Ph
Conditions
(6.2 eq)
4
Scheme 4.
Table 2. Olefination of benzophenone via ynolate anions
Thus, the naphthalene-catalyzed reductive lithiation of
dibromo esters leading to the practical synthesis of
ynolate anions was successful.
generated by catalytic reductive lithiationa
Entry
R
Conditions
Yield (%)
To examine the generality of this process, several kinds
of ynolate anions were synthesized (Scheme 4, Table 2).
In these reactions, a slight excess of ynolate anions to
benzophenone was used. As shown in Table 2, alkyl-
substituted ynolate anions were efficiently synthesized
to afford the desired olefins (4) in excellent yields
(entries 1–6).8 The reaction on a 10 mmol scale also
afforded the product in good yield (entry 2), demon-
strating that this method is suitable for large scale
reactions. In the case of the phenyl substituted ynolate
anion, only a moderate yield was obtained (entry 7),
while at lower temperatures, the yield was improved to
94%, as shown in entry 8.
1
Me
−78°C, 45 min; −50°C, 89
3 h
2b
3
Me
−78°C, 50 min; −50°C, 78c
3 h
Bu
−78°C, 30 min; −50°C, 89
3 h
−78°C, 25 min; −50°C, 99
3 h
−78°C, 30 min; −50°C, 94
3 h
−78°C, 15 min; −50°C, 85
3 h
4
iPr
5
PhCH2CH2
tert-Bu
Ph
6
7
−78°C, 25 min; −50°C, 72
3 h
8
Ph
−100°C, 1.5 h; −78°C,
3 h
94
This process was applied to the tandem reaction which
we developed. The tandem [2+2] cycloaddition–Dieck-
mann condensation3c afforded the cyclohexenone (7) in
excellent yield (Scheme 5).
a Unless otherwise noted, 1 mmol of benzophenone was employed. In
all cases, 10 mol% of naphthalene was used. The typical procedure
was described in Ref. 8.
b 10 mmol scale.
In conclusion, we have developed a highly efficient
synthetic method for the generation of ynolate anions
via naphthalene-catalyzed reductive lithiation of a,a-
dibromo esters. Compared with the previous methods,
ours is not only safe and economical, but also general
and convenient, allowing advances and wide use of
ynolate anions.
c Benzophenone was recovered in 19%.
h to complete the reductive lithiation (entry 2). Encour-
aged by these results, we continued to search for the
optimum conditions for more efficient catalytic reac-
tions. When 21 mol% of naphthalene was used, the
colorless reaction mixture changed to deep green at
−78°C. The change in color indicated the completion of
the first lithiation. After the reaction mixture stirred at
−50°C for 2 h, the desired product was obtained in 73%
yield (entry 3). However, the reaction, which was car-
ried out at −50°C from the beginning, gave lower yields
(entry 4), probably due to undesired reactions between
the unreacted dibromo ester (1a) and the lithium eno-
late 5a. Satisfactory yields were successfully obtained in
the range of 2.6–10 mol% of naphthalene (entries 5–7).
Acknowledgements
This research was partially supported by a Grant in Aid
for Scientific Research on Priority Areas (A) ‘Exploita-
tion of Multi-Element Cyclic Molecules’ from the Min-
istry of Education, Culture, Sports, Science and
Technology, Japan, and the Asahi Glass Foundation.
O
O
naphthalene
(0.75 eq)
Me
O
CO2Et
Me CO2Et
Me
Ph
+
Li
O
Br Br
(1.5 eq)
-78 ˚C, 30 min;
-50 ˚C, 2.5 h;
0 ˚C, 30 min
-78 ˚C, 2 h
OLi
Ph
(7.5 eq)
O
SiO2
Me
97%
benzene
reflux
Ph
7
Scheme 5.

8360
M. Shindo et al. / Tetrahedron Letters 42 (2001) 8357–8360
4. For reviews, see: (a) Holy, N. J. Chem. Rev. 1974, 74,
References
243–277; (b) Cohen, T.; Bhupathy, M. Acc. Chem. Res.
1989, 22, 152–161. See also Ref. 7.
5. (a) Jones, R. G.; Gilman, H. In Organic Reactions;
Adams, R., Ed.; John Wiley & Sons: New York, 1951;
Vol. 6, pp. 339–366; (b) Wakefield, B. J. In Organolithium
Methods; Academic Press: London, 1988.
1. For synthetic methods, see: (a) Schollkopf, U.; Hoppe, I.
Angew. Chem., Int. Ed. Engl. 1975, 14, 765, Hoppe, I.;
Schollkopf, U. Liebigs Ann. Chem. 1979, 219–226; (b)
Woodbury, R. P.; Long, N. R.; Rathke, M. W. J. Org.
Chem. 1978, 43, 376; (c) Kowalski, C. J.; Fields, K. W. J.
Am. Chem. Soc. 1982, 104, 7321–7323; (d) Stang, P. J.;
Roberts, K. A. J. Am. Chem. Soc. 1986, 108, 7125–7127;
(e) Julia, M.; Saint-Jalmes, V. P.; Verpeaux, J. N. Synlett
1993, 233–234; (f) Satoh, T.; Mizu, Y.; Hayashi, Y.;
Yamakawa, K. Tetrahedron Lett. 1994, 35, 133–134; (g)
Chiang, Y.; Kresge, A. J.; Popik, V. V. J. Am. Chem. Soc.
1995, 117, 9165–9171; (h) Kai, H.; Iwamoto, K.; Chatani,
N.; Murai, S. J. Am. Chem. Soc. 1996, 118, 7634–7635.
For reviews, see: (i) Shindo, M. Chem. Soc. Rev. 1998, 27,
367–374; (j) Shindo, M. J. Syn. Org. Chem. Jpn. 2000, 58,
1155–1166; (k) Shindo, M. Yakugaku Zasshi 2000, 120,
1233–1246.
6. For other arenes, see: (a) Freeman, P. K.; Hutchinson, L.
L. Tetrahedron Lett. 1976, 1849–1852; Freeman, P. K.;
Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–1930; (b)
Cohen, T.; Matz, J. R. Synth. Commun. 1980, 6, 311–317.
7. (a) Yus, M.; Ramon, D. J. J. Chem. Soc., Chem. Commun.
1991, 398–400; (b) Yus, M.; Herrera, R. P.; Guijarro, A.
Tetrahedron Lett. 2001, 42, 3455–3458; (c) For reviews,
see: Yus, M. Chem. Soc. Rev. 1996, 155–161; Ramon, D.
J.; Yus, M. Eur. J. Org. Chem. 2000, 225–237.
8. Typical procedure: To the LN solution, prepared by reac-
tion of naphthalene (0.65 mmol) and lithium (6.2 mmol) in
THF (13 mL) for 15 min, was added a THF solution (2
mL) of the dibromo ester (1.0 mmol) at −78°C. After
stirring for 45 min at −78°C and for 3 h at −50°C, the
reaction was allowed to warm to 0°C and was stirred for
an additional 30 min. After the addition of 1,2-dibro-
moethane (ca. 0.15 mmol), benzophenone (1.0 mmol) was
added at room temperature. The solution was stirred again
for 30 min before work-up. The reaction was diluted with
ether and extracted with aqueous NaOH solution. The
aqueous layer was then acidified and extracted with ether.
The organic layer was concentrated to afford the almost
pure product.
2. (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433–4436; (b)
Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54,
2411–2422.
3. (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett.
1998, 39, 4857–4860; (b) Shindo, M.; Oya, S.; Sato, Y.;
Shishido, K. Heterocycles 1998, 49, 113–116; (c) Shindo,
M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121,
6507–6508; (d) Shindo, M.; Oya, S.; Murakami, R.; Sato,
Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 5943–5946; (e)
Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.; Shishido, K.
Tetrahedron Lett. 2000, 41, 5947–5950; (f) Shindo, M.;
Sato, Y.; Shishido, K. J. Org. Chem. 2000, 65, 5443–5445.