A new method for the preparation of 1,5-diynes. Synthesis of (4E,6Z,10Z)-4,6,10-hexadecatrien-1-ol, the pheromone component of the cocoa pod borer moth Conopomorpha cramerella

Article abstract of DOI:10.1021/jo048019y

(Figure Presented) A new method for the synthesis of 1,5-diynes, from the reaction of 1,3-dilithiopropyne and propargyl chlorides, was developed. This new methodology was used to prepare (4E,6Z,10Z)-4,6,10-hexadecatrien-1-ol, one of the pheromone componen

Full text of DOI:10.1021/jo048019y

A New Method for the Preparation of 1,5-Diynes. Synthesis of
(4E,6Z,10Z)-4,6,10-Hexadecatrien-1-ol, the Pheromone Component
of the Cocoa Pod Borer Moth Conopomorpha cramerella
Alba´n R. Pereira and Jorge A. Cabezas*
Escuela de Quı´mica, Universidad de Costa Rica, San Jose´, 2060, Costa Rica
jcabezas@cariari.ucr.ac.cr
Received November 6, 2004
A new method for the synthesis of 1,5-diynes, from the reaction of 1,3-dilithiopropyne and propargyl
chlorides, was developed. This new methodology was used to prepare (4E,6Z,10Z)-4,6,10-hexa-
decatrien-1-ol, one of the pheromone components of the cocoa pod borer moth Conopomorpha
cramerella, in 51% overall yield.
Introduction
An attractive alternative for the synthesis of 1,5-diynes
is a three-carbon homologation (propagylation) of prop-
argyl halides. Negishi and co-workers reported6 the
preparation of 1,5-enynes in good yields, from the cou-
pling reaction of 1,3-dilithio-3-thiophenylpropyne (pre-
pared from 3-thiophenyl-1-propyne and n-BuLi) with
allylic bromides, followed by reductive elimination (Li/
NH3(l)) of the thiophene group. Although this procedure
allows the preparation of 1,5-enynes in good yields, it is
incompatible with groups sensitive to the lithium reduc-
tion conditions such as disubstituted acetylenes, thus its
application in the preparation of 1,5-diynes is restricted.
We have previously reported an easy preparation of
1,3-dilithiopropyne 1 (also known as propargylide), from
allene, and its regioselective reaction with allylic halides7
and carbonyl compounds,8 and recently we reported a
new preparation of this dianion 1, from propargyl bro-
mide9 (Scheme 1). We envisioned that regioselective
reaction of this dianion (1) with propargyl halides (2)
could represent an easy access to 1,5-diynes (3), according
to Scheme 1. Thus, we are reporting herein an efficient,
one-pot reaction for the preparation of 1,5-diynes, from
the coupling of 1,3-dilithiopropyne 1, with propargyl
halides. We applied this new methodology to develop an
efficient synthesis of (4E,6Z,10Z)-4,6,10-hexadecatrien-
1,5-Unsaturated compounds such as 1,5-dienes are
widely spread in nature and many of them have impor-
tant biological activity. It is possible to find these
structural units in terpenoids,1 juvenile hormones,2 and
insect pheromones.3 Many methods for the synthesis of
1,5-dienes have been reported.4 Attractive synthetic
precursors of (Z,Z)-1,5-dienes are the corresponding 1,5-
diynes.
Some methods for the preparation of functionalized 1,5-
diynes have been reported; however, they are cumber-
some.5 Dai and co-workers reported5c,d the synthesis of
some functionalized 1,5-diynes from the palladium-
catalyzed reaction of (Z)-2-bromocinnamaldehyde with
terminal acetylenes to obtain the corresponding 2-alkynyl
cinnamaldehyde, which upon reaction with lithium acetyl-
ides afforded the functionalized 1,5-diyne-3-ol. This
method required the preparation of the starting material
(Z)-2-bromocinnamaldehyde.
(1) Negishi, E.; Rand, C. L.; Jadhav, K. P. J. Org. Chem. 1981, 46,
5041.
(2) Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis; John
Wiley & Sons: New York, 1989, p 146.
(3) Henrick, C. A. Tetrahedron 1977, 33, 1845.
(4) (a) Axelrod, E.; Milne, G. M.; van Tamelen, E. E. J. Am. Chem.
Soc. 1970, 92 (7), 2139. (b) Dumond, Y.; Negishi, E. J. Am. Chem. Soc.
1999, 121, 11223.
(6) Negishi, E.; Rand, C. L.; Jadhav, K. P. J. Org. Chem. 1981, 46,
5041.
(5) (a) Gleiter, R.; Haberhauer, G.; Irngartinger, H.; Oeser, T.;
Rominger, F. Organometallics 1999, 18, 3615. (b) Cao, X. P.; Chan, T.
L.; Chow, H. F. Tetrahedron Lett. 1996, 37, 1049. (c) Dai, W. M.; Fong,
K. C.; Danjo, H.; Nishimoto, S. Angew. Chem., Int. Ed. Engl. 1996, 35,
779. (d) Dai, W. M.; Fong, K. C. Tetrahedron Lett. 1996, 37, 8413.
(7) Hooz, J.; Cabezas, J.; Musmanni, S.; Calzada, J. Org. Synth.
1990, 69, 120.
(8) Cabezas, J. A.; Alvarez, L. X. Tetrahedron Lett. 1998, 39, 3935.
(9) Cabezas, J. A.; Pereira, A. R.; Amey, A. Tetrahedron Lett. 2001,
42, 6819.
10.1021/jo048019y CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/08/2005
2594
J. Org. Chem. 2005, 70, 2594-2597

Preparation of 1,5-Diynes
SCHEME 1. Synthesis of 1,5-Undecadiyne 3
SCHEME 2. Synthesis of Functionalized
1,5-Diynes
TABLE 1. Reaction of 1 with 2 (see Scheme 1) under
Different Reaction Conditions
concn of
1 (mol/L)
1:2
ratio
% yield
of 3
entry
methoda
ably 1,3-dilithipropyne (1), formed (Cn ∼ 0.34 mol/L), and
it was reacted with 1-chloro-2-octyne (2) and stirred at
room temperature for 12 h. After the usual workup and
purification by column chromatography, 1,5-undecadiyne
3 was obtained in 27% yield (Table 1, entry 2). In this
experiment a significant amount of unreacted starting
material 2 was detected (70% by 1H NMR), thus the
molar ratio between dianion 1 and halide 2 was increased
from 1.7 to 2.4; in this case the yield of diyne 3 increased
to 71% (Table 1, entry 3). When the reaction was repeated
increasing the molar concentration of 1,3-dilithiopropyne
(1), from 0.34 M to 0.48 M, diyne 3 was isolated in 81%
yield with a very high purity (Table 1, entry 4). In this
case all the starting material 2 was consumed.
1
2
3
4
A
B
B
B
0.33
0.34
0.34
0.48
2.1
1.7
2.4
2.4
8b
27c
71c
81c
a Method of preparation of 1 (Scheme 1): (A) propargyl bromide
+ n-BuLi (TMEDA);9 (B) allene + n-BuLi.7 b Calculated by 1H
NMR. c Percent yield of chromatographically isolated compound.
1-ol (13), one of the pheromone components of the cocoa
pod borer moth Conopomorpha cramerella.
Results and Discussion
To show the versatility of this new methodology, diynes
5 and 7 were prepared (Scheme 2). Reaction of 1,3-
dilithiopropyne (1) with 3-chloro-1-phenylpropyne (4),
under the same optimized conditions described before
(Table 1, entry 4), afforded, after protonolysis, 1-phenyl-
1,5-hexadiyne (5) in 70% isolated yield (Scheme 2).
Coupling reactions of propargylide 1 are highly regio-
selective. Depending on the “hardness” of the electrophile,
it is possible to react 1,3-dilithiopropyne (1) selectively
by its sp3 or sp carbon, or through the sp2 carbon of the
rearranged allene species.8,9 To show the selectivity of
this methodology, functionalized diyne 7 was prepared
(Scheme 2). Thus, dianion 1 was reacted with 1-chloro-
2-undecadiyne 6 followed by addition of paraformalde-
hyde to obtain, after the usual workup and column
chromatography purification, 2,6-pentadecadiyne-1-ol (7)
in 55% yield and in a one-pot reaction.
We decided to apply this new methodology to the
synthesis of (4E,6Z,10Z)-hexadecatrien-1ol (13), one of
the pheromone components of the cocoa pod borer moth
Conopomorpha cramerella. This insect constitutes the
most serious pest of cocoa plantations in Southeast Asia.12
Its life cycle starts when the eggs are laid on the pod
surface of the cocoa plantations (this cycle lasts for 2-7
days), and once in the larva stage, it tunnels the pod
surface until it reaches the sclerotic layer of the husk,
where it feeds, causing scarification and sticking of the
beans. Damage to the funicles of pods results in beans
that are malformed and under sized, significantly reduc-
Preliminary reactions involved treatment, at -78 °C,
of 1-chloro-2-octyne (2) with 1,3-dilithiopropyne (1), which
was prepared by the treatment of propargyl bromide with
2 equiv of n-butyllithium in the presence of TMEDA9
1
(Scheme 1). In this case, H NMR analysis of the crude
reaction mixture showed the presence of traces of the
expected product 1,5-undecadiyne (3) (Table 1, entry 1),
and several unidentified byproducts, including allene
derivatives, whose formation might have been favored
by the presence of TMEDA. It has been reported that
when alkylation (with n-heptyl iodide) of metalated allene
(from allene and n-butyllithium) is performed in a polar
coordinating media such as THF and TMEDA, a mixture
of the corresponding substituted allene and acetylene
products (1.2:1 ratio) is obtained in poor yields,10 and as
the polarity of the solvent increases the allene derivative
is favored at the expense of the corresponding acetylene
product. It is also known that coordinating agents such
as ethylenediamine diminish the reactivity of carbanions
as lithium acetylide.11 Because of these results, the
reaction was next undertaken in a less polar solvent
system, and 1,3-dilithiopropyne (1) was prepared by the
reaction of allene and n-butyllithium in a solvent mixture
of ether:hexanes (1:1) as previously reported.7 Thus,
allene was treated with n-BuLi (0.7 equiv) at -78 °C,
and the reaction mixture was allowed to warm to -15
°C, at which temperature a heavy precipitate, presum-
(10) Calzada, J. G. Ph.D. Thesis, The University of Alberta, Canada,
1974, p 8.
(11) Stowell, J. C. Carbanions in Organic Synthesis; John Willey &
Sons: New York, 1979; p 78.
(12) Beevor, P. S.; Cork, A.; Hall, D. R.; Nesbitt, B. F.; Day, R. K.;
Mumford, J. D. J. Chem. Ecol. 1986, 12, 1.
J. Org. Chem, Vol. 70, No. 7, 2005 2595

Pereira and Cabezas
SCHEME 3. Synthesis of
(4E,6Z,10Z)-4,6,10-Hexadecatrien-1-ol (13)
Using this sequence, the trienol 13 was stereospecifically
synthesized in 4 steps and with an overall yield of 51%.
Alternatively, product 11 was prepared by the Sono-
gashira’s palladium cross coupling reaction17 between (E)-
5-bromo-4-pentenyl tert-butyldimethylsilyl ether (14) and
1,5-undecadiyne 3 (previously prepared, Scheme 1), using
copper(I) as catalyst,18 in 94% yield (Scheme 3). Vinyl
bromide 14 was stereospecifically prepared by hydrozir-
conation of 4-pentynyl tert-butyldimethylsilyl ether (9)
with Schwartz’s reagent followed by treatment with NBS.
With this alternative route, trienol 13 was obtained in
45% overall yield.
In conclusion, we reported herein a new procedure for
the preparation of 1,5-diynes and functionalized deriva-
tives in good yields. This new method allowed us to
developed a new synthesis of (4E,6Z,10Z)-hexadecatrien-
1-ol (13), one of the pheromone components of the cocoa
pod borer moth Conopomorpha cramerella, in only 4 steps
and with higher overall yield (51%) than those previously
reported.12,14
Experimental Section
Typical Procedure for the Synthesis of 1,5-Diynes.
Preparation of 1,5-Undecadiyne (3).19 A dry 250-mL three-
necked flask equipped with a magnetic stirring bar, a pressure-
equalizing addition funnel, and a dry ice condenser was
charged with 50 mL of dry ethyl ether and 20 mL of dry
hexanes and cooled to -78 °C. On a separate assembly, allene
gas (density at -40 °C ) 0.67 g/mL) from a compressed gas
cylinder was condensed into a 10 mL graduated cylinder
(cooled to -40 °C) equipped with a 14/20 standard taper joint
attached to a Claisen adapter, a bubbler, and a dry ice
condenser. After 9.0 mL (150 mmol) of allene had been
collected, the adapter, bubbler, and condenser were removed
and the graduated cylinder was capped with a rubber septum,
the cooling bath was removed from the graduated cylinder,
and allene was distilled into the reaction flask, using a double
tipped needle. n-BuLi in hexanes (45.6 mL, 110 mmol) was
added dropwise, from the addition funnel in 30 min, to the
reaction flask and the reaction mixture was allowed to warm
to -15 °C, where a white precipitate was formed and stirred
at this temperature for 15 min. After this time, the reaction
was cooled to -78 °C, 1-chloro-2-octyne (2; 3.3 g, 22.8 mmol)
in ether (10 mL) was added, and the reaction mixture was
allowed to warm to room temperature overnight. The mixture
was added over ice, extracted with ether (3 × 30 mL), and dried
(MgSO4). After the desiccant was removed, the solvent was
distilled using a Vigreaux column and the residue was purified
by column chromathography, using hexane as eluent. The
column chromatography fractions were concentrated by distil-
lation using a 10 cm Vigreaux column to obtain 2.73 g (18.4
mmol) of diyne 3 (81% yield). 1H NMR (CDCl3, 400 MHz) δ
0.90 (t, 3H, J ) 7.4 Hz), 1.26-1.40 (m, 4H), 1.48 (tt, 2H, J )
7.4, 7.4 Hz), 2.00 (t, 1H, J ) 2.0 Hz), 2.14 (tt, 2H, J ) 2.0, 7.4
Hz), 2.38 (m, 4H); 13C NMR (CDCl3, 100.6 MHz) δ 14.5, 19.1,
19.4, 19.6, 22.7, 29.1, 31.4, 69.3, 78.4, 81.9, 83.4; IR (film) 3306,
ing quality and thus the value of processed beans.
Feeding in pods also causes them to yellow or ripen
unevenly and prematurely, confusing ripeness standards
for harvesting.13 Losses can be in excess of 50% of the
crop.12
In 1985 Beevor and co-workers12 isolated, identified,
and synthesized the pheromone components of Conopo-
morpha cramerella. Here, a very long, nonstereospecific
synthesis was used. Later, in 1992, Yen and co-workers14
reported a shorter synthesis for this compound, in eight
steps and with an overall yield of 32%.
We considered that the crucial step for the synthesis
of trienol 13 is the stereospecific formation of the bond
between carbons 5 and 6, thus we decided to perform this
synthesis coupling two unit fragments with 5 and 11
carbon atoms (Scheme 3). Our synthesis started with the
commercially available 4-pentyn-1-ol (8) (5 carbon unit),
which was treated with tert-butyldimethylsilyl chloride
to obtain the corresponding silyl ether 9, in quantitative
yield.15 The silyl ether 9 was hydroborated with di-
siamylborane, followed by sequential treatment with
1-lithio-1,5-undecadiyne (10) (11 carbon unit; from 1,5-
undecadiyne 3 and n-BuLi), iodine at -78 °C, and sodium
hydroxide to afford stereospecifically the coupling product
11 in 86% yield.16 Hydroboration of triple bonds of 11,
with disiamylborane at -20 °C, followed by treatment
with acetic acid produced the corresponding triene 12,
in 60%, which upon treatment with Bu4NF gave the
desired (4E,6Z,10Z)-hexadecatrien-1-ol (13) quantita-
tively and with a very high stereochemical purity (>99%).
2957, 2930, 2860, 2121, 1434, 1338, 1260, 1111, 727, 637 cm-1
;
MS m/e (rel intensity) 148 (M+, 0.1), 147 (M+ - H, 0.7), 133
(5), 120 (2), 199 (11), 117 (4), 109 (15), 105 (31), 91 (100), 79
(17), 77 (16), 67 (22), 65 (13), 55 (10), 53 (9), 52 (7), 51 (7).
Anal. Calcd for C11H16: C, 89.12; H, 10.88. Found: C, 87.24;
H, 11.33.
(17) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(13) Management of the Cocoa Pod Borer; The Malaysian Plant
Protection Society: Kuala Lumpur, 1987; p 4.
(14) Yen, Y.; Lin, S.; Suen, M. Synth. Commun. 1992, 22, 1567.
(15) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190.
(16) Negishi, E.; Lew, G.; Yoshida, T. J. Chem. Soc., Chem. Commun.
1973, 874.
(18) Ratovelama, V.; Linstrumelle, G. Synth. Commun. 1981, 11,
917.
(19) The preparation of 1,5-undecadiyne (3) already has been
described: (a) Ward, J. P.; van Dorp, D. A. Recl. Trav. Chim. Pays-
Bas 1966, 85, 117. (b) Gunstone, F. D.; Lie Ken Jie, M. Chem. Phys.
Lipids 1970, 1.
2596 J. Org. Chem., Vol. 70, No. 7, 2005

Preparation of 1,5-Diynes
(E)-4-Hexadecen-6,10-diynyl tert-Butyldimethylsilyl
Ether (11): Procedure A (from 9). BH3‚THF (1 M solution,
5 mL, 5 mmol) was added into a 50 mL dry flask, cooled to 0
°C and under nitrogen. 2-Methyl-2-butene (2 M solution, 5 mL,
10 mmol) was added dropwise and the solution was stirred at
this temperature for 1 h. After this time, the flask was cooled
to -30 °C and a THF solution (5 mL) of 4-pentynyl tert-
butyldimethylsilyl ether (9; 0.99 g, 5 mmol) was added
dropwise, and the mixture was allowed to warm to 0 °C and
stirred at this temperature for 1 h. After this time the reaction
mixture was cooled to -78 °C and treated with a THF solution
of 1-lithio-1,5-undecadiyne (10) [prepared at -50 °C, from 1,5-
undecadiyne (3; 0.741 g, 5 mmol) and n-BuLi (2.65 M, 1.9 mL,
5 mmol) in 7 mL of THF]. The mixture was allowed to warm
from -78 °C to -50 °C and stirred at this temperature for 1.5
h. The mixture was cooled to -78 °C and a THF solution (10
mL) of I2 (1.3 g, 5 mmol) was added and the solution was
allowed to warm to 0 °C in 2.5 h. The mixture was treated
with NaOH (3 M, 2 mL) and H2O2 (30%, 2 mL), stirred for 15
min, and extracted with ether (3 × 25 mL), and the organic
extracts were washed with NaHSO3 and dried (Na2SO4). The
crude was purified by column chromathography, using Al2O3
as the stationary phase and mixtures of ether:hexane as
eluant, to obtain 1.68 g of the product (86% yield).
Hz), 2.10 (m, 4H), 2.33 (tt, 2H, J ) 6.1, 2.1 Hz), 2.43 (tt, 2H,
J ) 6.5, 1.8 Hz), 3.56 (t, 2H, 6.5 Hz), 5.42 (dtt, 1H, J ) 15.6,
1.8, 1.8 Hz), 6.03 (dt, 1H, J ) 15.6, 7.5 Hz); 13C NMR (CDCl3,
100.6 MHz) δ -5.1, 14.1, 18.4, 18.8, 19.3, 20.2, 22.4, 26.0, 28.8,
29.4, 31.1, 32.0, 62.3, 78.4, 79.8, 81.4, 87.1, 109.8, 143.1; IR
(film) 2956, 2930, 2858, 1463, 1362, 1255, 1104, 954, 836, 776
cm-1; HRMS (EI) mass calcd for C22H38SiO 369.2590, found
369.2588.
(E)-5-Bromo-4-pentenyl tert-Butyldimethylsilyl Ether
(14). A THF solution of acetylene (9; 0.495 g, 2.5 mmol) was
added dropwise to a THF (15 mL) solution of Cp2Zr(H)Cl (1.03
g, 4 mmol), at room temperature under nitrogen, and the
solution was stirred at this temperature for 30 min. After this
time, NBS (0.66 g, 3.75 mmol) was added through a solid
addition funnel20 and stirring was continued for 50 min. The
mixture was quenched by the addition of water, extracted with
ether, and dired (Na2SO4). The solvent was evaporated in
vacuo and the residue purified by column chromatography,
using hexanes, to obtain 0.55 g of 14 (79%). 1H NMR (CDCl3,
400 MHz) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.61 (tt, 2H, J ) 7.2, 6.0
Hz), 2.11 (tdd, 2H, J ) 7.2, 7.2, 1.2 Hz), 3.61 (t, 2H, J ) 6.0
Hz); 13C NMR (CDCl3, 100.6 MHz) δ -5.3, 18.3, 25.9, 29.3,
31.6, 62.0, 104.4, 137.7; HRMS (EI) mass calcd for C11H23SiOBr
279.0780, found 279.0779.
Procedure B (from 14). A benzene solution (3 mL) of (E)-
5-bromo-4-pentenyl tert-butyldimethylsilyl ether (14; 0.279 g,
1 mmol) was added to Pd(PPh3)4 (0.03 g, 0.026 mmol),
previously dissolved in benzene (5 mL), and the resulting
mixture was stirred at room temperature for 30 min. After
this time, the mixture was treated with 1,5-undecadiyne (3;
0.148 g, 1 mmol) dissolved in diethylamine (3 mL), followed
by addition of CuI20 (0.041 g, 0.2 mmol), and the resulting
reaction mixture was stirred at room temperaure overnight.
The crude reaction was treated with NH4Cl solution, extracted
with ether (3 × 25 mL), and dried (Na2SO4). After the solvent
was evaporated in vacuo the product was purified by column
Acknowledgment. We wish to thank Consejo Na-
cional de Investigaciones Cient´ıficas y Tecnolo´gicas
(CONICIT, Costa Rica), The Third World Academy of
Sciences (TWAS, Italy), Florida Ice & Farm Co. (Costa
Rica), and the Universidad de Costa Rica (proyect No.
809-98-229) for financial support of this project through
Research Grants. Also we wish to thank the Chemistry
Department of Universidad de Santiago de Compostela,
Spain, for elemental analysis and high resolution mass
spectra.
1
chromatography to obtain 0.325 g of 11 (94% yield). H NMR
1
Supporting Information Available: Copies of H NMR
(CDCl3, 400 MHz) δ 0.00 (s, 6H), 0.85 (m, 12H), 1.20-1.36 (m,
4H), 1.44 (tt, 2H, J ) 6.1, 6.1 Hz), 1.55 (tt, 2H, J ) 6.9, 6.9
and (or) 13C NMR spectra of all compounds, and experimental
procedures for the preparation of compounds 7, 12, and 13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) CuI (or NBS) was added under nitrogen using a solids addition
funnel: Shriver, D. F.; Drezdon, M. A. The Manipulation of Air-
Sensitive Compounds; John Wiley & Sons: New York, 1986; p 30.
JO048019Y
J. Org. Chem, Vol. 70, No. 7, 2005 2597