A facile method for the preparation of bishomopropargylic alcohols from acyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2014.01.144

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 acid chlorides to produce bishomopropargylic alcohols in a single step route and with high regioselectivity and moderate yields.

Full text of DOI:10.1016/j.tetlet.2014.01.144

Tetrahedron Letters 55 (2014) 1894–1897
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile method for the preparation of bishomopropargylic alcohols
from acyl chlorides
⇑
Suhelen Vásquez, Jorge A. Cabezas
Escuela de Química, Universidad de Costa Rica, San José 2060, Costa Rica
a r t i c l e i n f o
a b s t r a c t
Article history:
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 acid chlorides to produce bishomopropargylic alcohols in a single step route and with
high regioselectivity and moderate yields.
Received 3 December 2013
Revised 24 January 2014
Accepted 28 January 2014
Available online 5 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dilithiopropyne
Propargyl bromide lithiation
Homopropargylation
Homopropargyl alcohols
Bishomopropargyl alcohols
The three-carbon homologation, RX ? RCH2C„CH, is a highly
useful transformation, especially in isoprenoid-related synthesis.1
However, this transformation, is often difficult to achieve cleanly
because of the tendency of ambident propargylic nucleophiles,
RC„CCH2M, to produce mixtures of both the allenic and the
acetylenic products2 which are difficult to separate.3
We have previously reported a procedure,4 based on the
controlled lithiation of allene, 1, that produced the operational
equivalent of propargyl dianion, 2, (C3H2Li2, ‘1,3-dilithiopropyne’),
and provided a convenient single-step route to propargylated
derivatives,4 1,5-diynes5 and insect pheromones,5 in excellent
yields and without contamination with allenic derivatives. Based
on this procedure, we later developed a protocol for the highly
efficient transformation of aldehydes and ketones into the
corresponding homopropargylic alcohols6 4 and 5 (Scheme 1).
Although this procedure produces homopropargyl alcohols in
high yields and very good regiochemistry, the high cost of allene,
1, restricts its use. We envisioned that dianion, 2, could be
prepared from the reaction of propargyl bromide, 6, with two
equivalents n-BuLi in the presence of TMEDA. Thus dianion, 2,
obtained from this methodology, reacted with aldehydes or
ketones to afford the corresponding homopropargyl alcohols 4 or
5 in very good yields7 (Scheme 1). Homopropargyl alcohols, 4,
and bishomopropargyl alcohols, 7, are very useful intermediates
in organic synthesis.8
Scheme 1.
Numerous methods for the synthesis of bishomopropargyl
alcohols have been developed, however most of them produce
mixtures of allenic and diacetylenic derivatives and generally they
suffer from poor yields. Reaction of propargyl aluminum reagents
with acyl chlorides gave inseparable mixtures of allenic and diacet-
ylenic alcohols in 41–50% yield.9 Reaction of propargyl magnesium
bromide with aliphatic and aromatic esters10a and with several
3-furanyl propanoates10b gave same mixture of alcohols in 32–85%
and 31–66% yields, respectively. Reaction of same Grignard reagent
with 3-methoxy methylbenzoate produced same mixture of
isomers in 45% yield.10c Brown11 reported a method for the
allenylboration of acetyl chloride and benzoyl chloride, 8, using
B-allenyl-9-BBN, prepared from B-chloro-9-BBN and allenylmagne-
sium bromide. This reaction afforded the corresponding
bishomopropargyl alcohols in 72% and 76% yields respectively,
⇑
Corresponding author. Tel.: +506 2511 4656; fax: +506 2253 5020.
E-mail address: jorge.cabezas@ucr.ac.cr (J.A. Cabezas).
http://dx.doi.org/10.1016/j.tetlet.2014.01.144
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Vásquez, J. A. Cabezas / Tetrahedron Letters 55 (2014) 1894–1897
1895
treatment with TBAF, bishomopropargyl alcohols with good regi-
oselectivities and yields (56–94%). This procedure needs the specific
preparation of the trimethylsilyl reagent, and subsequent liberation
of the terminal alkynes.
We decided to extend our previous studies on the reaction of
1,3-dilithiopropyne, 2, with aldehydes and ketones. Thus, reaction
of 2 with carboxylic acid derivatives would yield the corresponding
bishomopropargyl alcohols, 7, in one-step procedure (Scheme 2).
We wish to report herein a new methodology to obtain bisho-
mopropargyl alcohols, 7, from acyl chlorides, using 1,3-dili-
thiopropyne, 2, in one-pot reaction.
Scheme 2.
without contamination with the allenic isomer. Unfortunately, this
method needs a two-step preparation of the reagent and an oxida-
tive work-up to furnish the tertiary alcohols. Oestreich12 reacted
c
-trimethylsilyl propargyl zinc bromide with esters to prepare, after
Table 1
Conversion of acid chlorides into different bishomopropargylic alcohols
Entry
Substrate
E2
Product(s)a
Isolated yield (%)
57
O
OH
Cl
1
H3O+
8
9
O
O
OH
OH
Cl
Cl
2
3
4
H3O+
H3O+
H3O+
65
57
60
10
11
12
13
O
OH
Cl
Cl
Cl
14
15
O
OH
H3O+
H3O+
55b
33b
Cl
5
6
16
17
O
OH
H
O
19
20
O
SiMe3
SiMe3
O
SiMe3
O
SiMe3
Cl
Cl
Cl
Cl
(83 :17)
7
ClSi(CH3)3
53
14
SiMe3
21
OH
22
O
Cl
8
9
CH3I
47
10
23
O
OH
Cl
Cl
OH
(CH2O)n
44c
HO
8
8
24
O
O
N
O
HO
H
10
23
O
H
25
26
a
b
c
All products gave satisfactory spectroscopic characteristics 1H NMR (400 MHz) and 13C NMR (100 MHz).
Yield after isomerization through a ‘zipper’ reaction.
2-Butyn-1-ol (by-product obtained by reaction of excess of 1,3-dilithiopropyne with paraformaldehyde) was removed by Kugelrohr distillation and the residue was
purified by column chromatography using silica gel.

1896
S. Vásquez, J. A. Cabezas / Tetrahedron Letters 55 (2014) 1894–1897
Preliminary reactions at À78 °C, of dianion 2, (prepared from
Reaction of 2, with ethyl chloroformate did not result in a clean
reaction, instead many unidentified by-products were obtained.
However when the reaction was performed with ethylformate,
19, 1,6-heptadiyn-4-ol, 20, was obtained in 33% yield15 (Table 1,
entry 6).
propargyl bromide, 6, and n-BuLi in the presence of TMEDA,
Scheme 1) with carboxylic esters failed to produce the desired bis-
homopropargylic alcohols, 7, cleanly and in good yield. However
when a cold (À78 °C) ethereal solution of 2, was reacted with
benzoyl chloride, 8, the corresponding alcohol 4-phenyl-1,6-hepta-
diyn-4-ol, 9, was obtained in 57% yield (Table 1, entry 1). Reaction
of 2, with several aromatic acyl chlorides produced the
corresponding 1,6-heptadiyne-4-ols in moderate yields without
contamination with allenic alcohols (Table 1, entries 1–4).
When 1,3-dilithiopropyne, 2, was reacted with hexanoyl chlo-
ride, 16, a mixture (1:1) of the diacetylenic (17) and allenic (18)
alcohols was obtained (Scheme 3). Increasing the polarity of the
reaction (ether:THF, or higher amounts of TMEDA), increased the
amount of allene derivative 18.
One feature of this methodology is the fact that dianion, 2, can
be reacted selectively with two different electrophiles, first at the
‘soft’ propargyl position and later at the ‘hard’ acetylide anion.
Thus an ethereal solution of dianion 2, was treated with b-naphthyl
chloride, 10, as the first electrophile and then with methyl iodide
as the second electrophile (E2). In this case, 5-(b-naphthyl)-2,7-
nonadiyn-5-ol, 23, was obtained in 47% overall yield (Table 1, entry
8). The triol, 5-phenyl-2,7-nonadiyn-1,5,9-triol, 24, was obtained
in 44% yield, after treating 1,3-dilithiopropyne, 2, sequentially with
benzoyl chloride, 8, and paraformaldehyde (Table 1, entry 9).
Treatment of 2, with p-chlorobenzoyl chloride, 14, and trimethyl-
silyl chloride produced a mixture of the silated products 21 and
22 (Table 1, entry 7).
Interestingly, sequential addition of benzoyl chloride, 8, and N-
formylmorpholine, 25, to 1,3-dilthiopropyne, 2, produced the
highly functionalized hydroxy aldehyde, 26, in 23% isolated yield
in one-pot reaction (Table 1, entry 10). In all cases shown in Table 1,
viscous reaction mixtures were obtained from which the bishomo-
propargyl alcohol was the major product and only isomer obtained
(except in entries 5 and 6). The target compounds were easily puri-
fied by column chromatography.
In summary, we developed a convenient single-step process to
obtain bishomopropargylic alcohols, from acyl chlorides, in moder-
ate yields. The reaction selectivity of dianion, 2, allows synthesis of
highly functionalized products in one-pot reaction. In spite of the
fact that in some cases overall yields may seem low (e.g. 26,
23%), this highly functionalized products (23, 24, 26) are obtained
in one-pot procedure. In a multiple-step synthesis (e.g. a three-step
synthesis) with good yields, a similar result could be achieved
(65% Â 60% Â 60% = 23% overall yield). We also demonstrated that
if formation of the undesired allenic alcohol shall take place, in the
case of aliphatic acyl chlorides, the yield of the target bishomo-
propargylic alcohol can be further enhanced by subjecting the
reaction crude to the ‘zipper’ reaction conditions.
This result is in agreement with our previous findings6,7 that as
the carbonyl group, of the electrophile species, became ‘harder’
(aromatic vs aliphatic) a significant amount of the allenic deriva-
tive was obtained, presumably as a result of the nucleophilic addi-
tion of the ‘harder’ allenyl carbon of the isomeric form of the
ambident dianion, 2 (Scheme 4).
It has been reported that internal acetylenes can be isomerized
to the corresponding terminal acetylenes through the ‘zipper’ reac-
tion.13 It has been proposed that this isomerization proceeds via a
series of deprotonation allenil-propargyl rearrangements,14 using
potassium 3-aminopropylamide (KAPA) as a base (Scheme 5).
Because an allenic alcohol such as 18 has a similar structure as
the proposed intermediates in this isomerization, it may be plausi-
ble its isomerization to 17, under the ‘zipper’ reaction conditions
(Scheme 5). We were pleased to observe that when the crude reac-
tion mixture, obtained from the reaction of 16 and 2, was treated
with potassium 3-aminopropylamide (KAPA), allenic alcohol, 18,
was completely isomerized to 17 (Scheme 3). After this base treat-
ment, 4-pentyl-1,6-heptadiyn-4-ol, 17, was obtained in 55% overall
yield from hexanoyl chloride, 16 (Table 1, entry 5).
Li
HO
HO
O
2
Li
C
+
Cl
-78o to 0o
16
17
18
•
KAPA
HO
Typical procedure. Preparation of 5-phenyl-2,7-nonadiyne-
1,5,9-triol (24)
A solution16 of dry diethyl ether (7.5 mL), dry hexane (5.0 mL),
and n-BuLi17 in hexane (2.5 mL, 6.2 mmol) was cooled to À78 °C
and TMEDA added (0.25 mL, 1.55 mmol) followed by dropwise
addition of propargyl bromide (0.30 mL, 3.1 mmol) (CAUTION:
highly toxic). The resulting mixture was stirred for 40 min at this
temperature until the formation of a white precipitate. A solution
of benzoyl chloride (0.140 g, 1.0 mmol) in tetrahydrofuran (2.5 mL)
was added dropwise over 10 min and the reaction mixture was al-
lowed to warm to room temperature over 2 h and cooled back to
À78 °C. THF (3.6 mL) was added to this mixture, followed by addi-
tion of paraformaldehyde in one portion (0.444 g, 14.8 mmol). After
stirring the suspension, under nitrogen, for 24 h at room tempera-
ture, the mixture was poured into ice-cold NH4Cl solution, then ex-
tracted with diethyl ether, and the organic extracts dried (Na2SO4).
After evaporation of solvent in vacuo, impurities (2-butyn-1-ol) were
distilled by Kugelrohr and the residue was purified by column chro-
matography with silica gel using ether:hexanes mixtures to obtain
0.110 g (44%) of product.
17
Scheme 3.
"soft" end
"hard" end
Li
H2C
C
C
Li
2
Scheme 4.
N
NH
H
K
H
H
H
R
R=
•
R
H
OH
18
17
Increasing amounts of TMEDA resulted in formation of allenic isomer. Lower
amounts of TMEDA produced lower yields of product.
Scheme 5.

S. Vásquez, J. A. Cabezas / Tetrahedron Letters 55 (2014) 1894–1897
1897
6. Cabezas, J. A.; Alvarez, L. X. Tetrahedron Lett. 1998, 39, 3935.
7. Cabezas, J. A.; Pereira, A. R.; Amey, A. Tetrahedron Lett. 2001, 42, 6819.
Acknowledgments
8. (a) Nicolaou, K.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. Angew.
Chem. Int. Ed. Engl. 1990, 29, 1064–1067; (b) Kim, Y. H.; Kwon, S. K.; Choi, S. K. J.
Macrom. Sci. Pure Appl. Chem. 1994, A31, 2041–2053; (c) Hanazawa, T.; Sasaki,
K.; Takayama, Y.; Sato, F. J. Org. Chem. 2003, 68, 4980.
9. (a) Gaudemar, M. Ann. Chim. 1956, 1, 161–165; (b) Gaudemar, M. Compt. Rend.
1954, 239, 1303–1305; (c) Driguez, H.; Traynard, J. C. Comptes Rendus des
Seances de l’Academie des Sciences Serie C: Sciences Chimiques. 1968, 267, 497–
499.
We wish to thank CONARE for a research grant through Fondos
de Educación Superior (FEES) and Vicerrectoría de Investigación
(UCR) for financial support.
Supplementary data
10. (a) Plouin, D.; Glénat, R. Bull. Soc. Chim. 1973, 2, 737; (b) Hashmi, A. S. K.;
Hamzié, M.; Rudolph, M.; Ackermann, M.; Rominger, F. Adv. Synth. Catal. 2009,
351, 2469; (c) Hashmi, A. S.; Choi, J. H.; Bats, J. J. Prakt. Chem. 1999, 341.
11. Brown, H. C.; Khire, U.; Gowriswari, N.; Racherla, U. J. Org. Chem. 1995, 60, 544–
549.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
144.
12. (a) Oestreich, M.; Sempere-Culler, F. Chem. Comm. 2004, 692–693; (b)
Oestreich, M.; Sempere-Culler, F.; Machotta, A. B. Angew. Chem., Int. Ed. 2005,
44, 149–152.
References and notes
13. (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891–892; (b) Brown,
C. A.; Yamashita, A. J. Chem. Soc. Chem. Comm. 1976, 959–960.
14. Negishi, E. In Organometallics in Organic Synthesis; John Wiley & Sons: New
York, 1980; Vol. 1,
15. This compound has been synthesized from ethylformate and propargyl
bromide in 37% yield, employing an aluminum-mediated method: Sieburth,
S. M.; Madsen-Duggan, C. B.; Zhang, F. Tetrahedron Lett. 2001, 42, 5155.
16. In the current procedure a solvent ratio (v/v) of diethyl ether–hexanes (1:1)
must to be used in order to obtain 1,3-dilithiopropyne in good yield, as
originally stated.2a,4
1. (a) Corey, E. J.; Achiwa, K. Tetrahederon Lett. 1970, 2245; (b) Corey, E. J.;
Katzenellenbogen, J. A.; Gilman, N. W.; Roman, S. A.; Erickson, B. W. J. Am.
Chem. Soc. 1968, 90, 5618; (c) Johnson, W. S.; Li, T.-T.; Harbert, C. A.; Bartlett, W.
R.; Herrin, T. R.; Staskun, B.; Rich, D. H. J. Am. Chem. Soc. 1970, 92, 4461.
2. (a) Calzada, J. G. Ph.D. Dissertation, University of Alberta, 1974.; (b)
Sondheimer, F.; Wolovsky, R.; Ben-Efraim, D.A. J. Am. Chem. Soc. 1961, 83,
1686. Deming, R. C.; Wulff, C. A. In The Chemistry of Ketenes, Allenes and Related
Compounds, Part 1, Patai, S.; Eds.; Wiley: New York; 1980.; (c) Pearson, N. R.;
Hahn, G.; Zweifel, G. J. Org. Chem. 1982, 47, 3364; (d) Brown, H. B.; Khire, U.;
Gowriswari, N.; Racherla, U. J. Org. Chem. 1995, 60, 544–549.
17. n-BuLi was titrated according to: Watson, S. C.; Eastham, J. F. J. Organomet.
Chem. 1967, 165.
3. Ireland, R. E.; Dawson, M. I.; Lipinski, C. A. Tetrahedron Lett. 1970, 2247.
4. Hooz, J.; Cabezas, J.; Musmanni, S.; Calzada, J. Org. Synth. 1990, 69, 120.
5. Pereira, A. R.; Cabezas, J. A. J. Org. Chem. 2005, 70, 2594.