A new method for the preparation of 1,3-dilithiopropyne: An efficient synthesis of homopropargyl alcohols

Article abstract of DOI:10.1016/S0040-4039(01)01429-0

Controlled dilithiation of propargyl bromide with two equivalents of n-butyllithium, in the presence of TMEDA, produces the operational equivalent of the dianion 1,3-dilithiopropyne. The latter reacts efficiently with aldehydes and ketones to produce homo

Full text of DOI:10.1016/S0040-4039(01)01429-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6819–6822
A new method for the preparation of 1,3-dilithiopropyne:
†
an efficient synthesis of homopropargyl alcohols
Jorge A. Cabezas,* Alb a´ n R. Pereira and Adam Amey
Escuela de Qu ´ı mica, Universidad de Costa Rica, San Jos e´ 2060, Costa Rica
Received 9 July 2001; accepted 3 August 2001
Abstract—Controlled dilithiation of propargyl bromide with two equivalents of n-butyllithium, in the presence of TMEDA,
produces the operational equivalent of the dianion 1,3-dilithiopropyne. The latter reacts efficiently with aldehydes and ketones to
produce homopropargyl alcohols in a single step route and in high yields. © 2001 Elsevier Science Ltd. All rights reserved.
Homopropargyl alcohols are very useful intermediates
in organic synthesis. Their syntheses usually involve
organometallic reagents; however, in most of these
methodologies the regiochemistry of the product is
highly dependent upon steric hindrance, substitution of
the organometallic substrate, solvation and nature of
the metal.
1
reaction of monoanionic propargyl (1) or allenyl (2)
organometallic reagents, with a carbonyl compound.
The major drawback of this methodology comes from
the tendency of such ambident nucleophiles (1, 2) to
produce mixtures of both homopropargylic (3) and
allenic (4) alcohols (Scheme 1).
Allenyllithium reagents, for example, react with
3
aliphatic ketones producing mainly allenic alcohols,
whereas reaction with aromatic carbonyl compounds
gives homopropargylic alcohols in poor yields. Zinc or
Numerous methods for the synthesis of homopropargyl
alcohols have been developed, using different
4
2
magnesium reagents, derived from 2-octynyl bromide
couple with aromatic or aliphatic aldehydes to produce
5
mixtures of allenic and propargylic alcohols.
R
R
M
6
We previously reported that the propargyl dianion 5,
OH
1
obtained from the treatment of allene with two equiva-
lents of n-BuLi, reacted with aldehydes and ketones to
produce homopropargyl alcohols regioselectively.
3
O
1
.
R
R
+
H+
Although this method produces homopropargyl alco-
hols in high yields and very good regiochemistries, the
high cost of allene restricts use of this procedure. To
overcome this difficulty, we have developed a new
procedure for the preparation of 1,3-dilithiopropyne, 5.
We envisioned that 1,3-dilithiopropyne 5 could be pre-
pared from the reaction of propargyl bromide 6 with an
alkyl lithium, thus acid–base reaction of acetylenic pro-
ton of 6, followed by halogen–metal exchange would
produce 5 (Scheme 2). We wish to report that treatment
of propargyl bromide 6 with two equivalents of n-BuLi,
in the presence of TMEDA, produces the operational
equivalent of propargyl dianion 5, that reacts with
aldehydes or ketones to produce the corresponding
homopropargyl alcohols regioselectively in good yields.
2
.
H
H
H
H
H
H
•
•
M
HO
R
R
2
4
Scheme 1.
Keywords: 1,3-dilithiopropyne; homopropargyl alcohols; homo-
propargylation.
*
Corresponding author. Tel.: (506) 207-4656; fax: (506) 253-5020;
e-mail: jcabezas@calzada.equi.ucr.ac.cr
Dedicated to Professor Cam Oehlschlager: Senior Supervisor and
Friend, on the occasion of his 60th birthday.
†
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01429-0

6
820
J. A. Cabezas et al. / Tetrahedron Letters 42 (2001) 6819–6822
soft end
hard end
-
Br
n-BuLi
TMEDA
+
H2C
C
C
Li
Li
6
5
E1: RCOR
HO
LiO
H+
HO
1
. E2
. H+
R
R
R
R
E2
R
R
2
Li
Scheme 2.
Initial reactions where cold (−78°C), ethereal solutions
of 6 were treated with tert-BuLi (3 equivalents) fol-
lowed by treatment with benzophenone 7 and warmed
to room temperature, failed to produce the expected
alcohol 8. Inverse addition of propargyl bromide 6 to
cold (−78°C) solutions of tert-BuLi, followed by reac-
tion with benzophenone 7 gave after protonolysis at
The present procedure provides a convenient single-step
process to obtain homopropargyl alcohols in good
yield. The products reported here were obtained in
similar yields and purities as in our previous proce-
dure. An additional advantage is that the initially-
formed lithium acetylide intermediate (Scheme 2) may
be further reacted, in situ, with a second electrophile
6
(
(
E2) to obtain disubstituted homopropargyl alcohols
Table 1, entries 6, 7, 8).
25°C, the alcohol 8 in 25% yield. It is well known that
the basicity of lithium reagents is increased by strongly
coordinating agents such as hexamethylphosphoramide
Typical procedure. Preparation of 1,1-diphenyl-3-pentyn-
(
HMPA) or tetramethylethylenediamine (TMEDA).
1
, 5-diol (18)
The n-BuLi–TMEDA complex has been used to
remove protons from benzylic, allylic and propargylic
7
8
9
A solution of dry diethyl ether (12.4 mL), dry hexane
positions to form the corresponding carbanions. 1,3-
Dilithiopropyne has been prepared from propyne by
10
(
7.0 mL) and n-BuLi (5.4 mL, 16.4 mmol) was cooled
to −78°C and TMEDA added (0.62 mL, 4.1 mmol),
followed by dropwise addition of propargyl bromide
8
this method. We decided to use this complexed base to
attempt the metal–halogen exchange in 6, thus when 1
(
0.78 mL, 8.2 mmol) (CAUTION: highly toxic) and the
equivalent of propargyl bromide 6 was added to a cold
resulting mixture stirred for 20 minutes at this tempera-
ture. After this time a white precipitate formed. A
solution of benzophenone (0.709 g, 3.90 mmol) in
diethyl ether (5 mL) was added dropwise over 5 min
and the reaction mixture was allowed to warm to room
temperature over 2 h. THF (7 mL) was added to this
mixture, followed by addition of paraformaldehyde in
one portion (0.861 g, 28.7 mmol). After stirring the
mixture, under nitrogen, for 24 h at room temperature,
the resulting suspension was poured into ice cold
(
−78°C) ethereal solution of n-BuLi (2 equivalents) and
TMEDA (0.5 equivalents), followed by treatment with
benzophenone 7 the alcohol 8 was obtained, after pro-
tonolysis, in 96% yield (Table 1, entry 1). To demon-
strate the utility of this procedure, we prepared several
propargyl alcohols by the reaction of anion 5 with some
aldehydes and ketones as shown in Table 1. As in our
6
previous communication, we noted that as the car-
bonyl group became ‘harder’ (aliphatic ketones or alde-
hydes) a significant amount of the allenic derivative was
obtained (Table 1, entry 5), presumably as a result of
the nucleophilic addition of the ‘harder’ allenyl carbon
of the isomeric form of the ambident dianion 5 (Scheme
NH Cl solution, then extracted with ether and the
4
organic extracts dried (Na SO ). After evaporation of
2
4
solvent in vacuo, impurities (2-butyn-1-ol) were distilled
by Kugelrohr and the residue was purified by column
chromatography (silica gel) using ether:hexanes mix-
tures to obtain 0.795 g (82%) of product.
2).
To demonstrate the selectivity of dianion 5, we reacted
it with two different electrophiles, first at the ‘soft’
propargyl position and later at the ‘hard’ acetylide
anion. Thus, an ethereal solution of dianion 5 was
treated with benzophenone as the first electrophile (E1)
and then with paraformaldehyde (E2) (Scheme 2); in
this case 1,1-diphenyl-3-pentyn-1,5-diol was obtained in
Acknowledgements
We wish to thank ‘Consejo Nacional para Investiga-
ciones Cient ´ı ficas y Tecnol o´ gicas’ (CONICIT, Costa
Rica) and Vicerrector ´ı a de Investigaci o´ n (UCR) for
financing this project through a research grant, and
Chem Tica International of Costa Rica for a generous
donation of chemicals.
8
2% yield (Table 1, entry 6). This reaction, between
anion 5 and benzophenone, was repeated using
trimethylsilyl chloride and ethyl chloroformiate as the
second electrophile, and products 19 and 20 were
obtained respectively (Table 1, entries 7 and 8)

J. A. Cabezas et al. / Tetrahedron Letters 42 (2001) 6819–6822
6821
Table 1. Conversion of 1,3-dilithiopropyne into different homopropargyl alcohols
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