Highly selective synthetic method for 1,6-diols bearing enyne functions: Development of 3,6-dianion reagent of 1,2-hexadien-4-yne using 1,6-dibromo-2,4-hexadiyne and indium

Article abstract of DOI:10.1002/adsc.200700309

The reaction of aldehydes and ketones with an organoindium reagent generated in situ from indium and 2,6-dibromo-2,4-hexadiyne in the presence of lithium iodide in tetrahydrofuran (THF) selectively produced 1,6-diols linked to an allenyne unit with comple

Full text of DOI:10.1002/adsc.200700309

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DOI: 10.1002/adsc.200700309
Highly Selective Synthetic Method for 1,6-Diols Bearing Enyne
Functions: Development of 3,6-Dianion Reagent of 1,2-Hexadien-
4-yne Using 1,6-Dibromo-2,4-hexadiyne and Indium
Sundae Kim,a Kooyeon Lee,a Dong Seomoon,a and Phil Ho Leea,*
a
Department of Chemistry, Kangwon National University, Chunchon 200-701, Republic of Korea
Fax : (+82)-33-253-7582; e-mail: phlee@kangwon.ac.kr
Received: June 26, 2007
Abstract: The reaction of aldehydes and ketones
with an organoindium reagent generated in situ
from indium and 1,6-dibromo-2,4-hexadiyne in the
presence of lithium iodide in tetrahydrofuran
(THF) selectively produced 1,6-diols linked to an
allenyne unit with complete regioselectivity and
chemoselectivity through 1,2-hexadien-4-yn-3,6-yla-
tion, indicating that the organoindium acted as the
3,6-dianion reagent of 1,2-hexadien-4-yne.
ketones through contemporary propargylation and al-
lenylation in one-pot leading to an allenyne-1,6-diol
has been published. As part of our continuing effort
to expand the synthetic utility of indium, we now
report highly selective 1,2-hexadien-4-yn-3,6-ylation
using
1,6-dibromo-2,4-hexadiyne
and
indium
(Scheme 1).
Keywords: 1,6-dibromo-2,4-hexadiyne; 1,6-diols;
enynes; 1,2-hexadien-4-yn-3,6-ylation; indium
Scheme 1. Indium-mediated reaction of carbonyl compounds
with 1,6-dibromo-2,4-hexadiyne.
Indium has emerged as a useful metal in organic syn-
thesis because of its intriguing chemical properties of
reactivity, selectivity, and low toxicity.[1] On the basis
Our initial study focused on the reactions of benzal-
of these properties of indium, efficient indium-medi- dehyde with organoindium generated in situ from 1,6-
ated organic reactions have been developed and ap- dibromo-2,4-hexadiyne[10] and indium. The results are
plied in environment-friendly organic reactions.[1] summarized in Table 1. Of the reaction conditions ex-
Their first synthetic applications have been found in amined, the best results were obtained with 1.0 equiv.
allylation reactions of carbonyl compounds and their of benzaldehyde, 0.55 equivs. of 1,6-dibromo-2,4-hexa-
derivatives under aqueous and anhydrous Barbier diyne, and 1.1 equivs. of indium in the presence of
conditions.[2] In addition, a range of indium-mediated 1.1 equivs. of lithium iodide in THF at 258C for 1 h
processes have been found to be useful for Reformat- under a nitrogen atmosphere, producing selectively
sky reactions,[3] Michael addition reactions,[4] cross- 1,6-diphenyl-2-vinylidenehex-3-yne-1,6-diol (3a) in
coupling reactions,[5] allylic substitution reactions,[6] 86% yield through 1,2-hexadien-4-yn-3,6-ylation from
and addition of organoindium reagents to carbon- contemporary propargylation and allenylation with
carbon multiple bonds and nitriles.[7] Indium has now complete regioselectivity (entry 10). Surprisingly,
demonstrated itself as the metal of choice for per- there are no traces of 1,8-diphenyl-octa-3,5-diyne-1,8-
forming many of these reactions. A variety of in situ diol (3b) and 1,4-diphenyl-2,3-divinylidene-butane-
generated allylindiums, propargylindiums, and alleny- 1,4-diol (3c) through 2,4-hexadiyn-1,6-ylation and
lindiums are of considerable value for regioselective 1,2,4,5-hexatetraen-3,4-ylation, respectively, and 3d,
and stereoselective allylation, propargylation, and al- 3e and 3f formed in these reactions (Figure 1). The
lenylation to various carbonyl and imine compounds, 1H and 13C NMR spectra of 3a are consistent with a
leading to the corresponding alcohols[8] and amines.[9] 1,6-diol structure possessing an allenyl as well as an
Although many examples of the indium-mediated al- alkynyl group. The sp and sp2 resonances (400 MHz)
lylation and propargylation of simple carbonyl com- of the allenyl group appear at 212.0 ppm (Ca) and
pounds have been reported,[8] as far as we are aware, 91.5 ppm (Cb), respectively. The sp resonance
no 1,2-hexadien-4-yn-3,6-ylation onto aldehydes and (400 MHz) of alkynyl group appears at 79.8 ppm (Cc)
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Sundae Kim et al.
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Table 1. Optimization of indium-mediated reaction of benzaldehyde with 1,6-di-
bromo-2,4-hexadiyne.[a]
[a]
Reactions were carried out under Grignard-type condition unless otherwise
noted. Reaction was quenched with H2O.
Additive (1.1 equivs.) was used.
Isolated yield.
Recovery yield of 2.
Recovery yield of 1a.
Reaction was quenched with 10% HCl.
Diastereomeric ratio=1:1.
Reaction was carried out under Barbier-type conditions.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
THF (0.2M solution, 86%) was the better than
DMF (60%) (entry 10 vs. 12). The quenching of the
reaction mixture using 10% HCl is highly essential
for good results due to the solubility of indium salts
(entry 4 vs. 6). The use of indium in less than 1.0–
1.1 equivs. and 1,6-dibromo-2,4-hexadiyne in more
than 0.55 equivs. resulted in lower yields. Lithium
iodide as an additive is critically important for excel-
lent yields (entry 8 vs. 9 vs. 10). 1,6-Diiodo-2,4-hexa-
1
diyne was detected in part in the H NMR spectrum
after treatment with lithium iodide in THF, indicating
that iodide substituted bromide in 1,6-dibromo-2,4-
hexadiyne and then, the corresponding iodide reacted
smoothly with indium to produce the organoindium
reagent.
Figure 1. Possible isomeric products from the indium-medi-
ated reaction of benzaldehyde with 1,6-dibromo-2,4-hexa-
diyne.
and 94.5 ppm (Cd), respectively, indicating that com-
pound 3a was produced selectively.
To demonstrate the efficiency and scope of the
present method, we applied this reaction system to a
The diastereomeric ratio (1:1) of 3a was determined variety of aldehydes and ketones to obtain 2-vinylid-
by NMR interpretation of the MTPA diester (4) ob- enehex-3-yne-1,6-diol derivatives. The results are sum-
tained from the reaction of 3a with (S)-MTPA-Cl in marized in Table 2.[11] Under the optimized conditions,
69% yield [Eq. (1)].[11]
aliphatic aldehydes such as acetaldehyde, butyralde-
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Highly Selective Synthetic Method for 1,6-Diols Bearing Enyne Functions
COMMUNICATIONS
Table 2. Indium-mediated reaction of carbonyl compounds with 1,6-dibromo-2,4-hexadiyne.[a]
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[a]
In (1.1 equivs.), LiI (1.1 equivs.), and 2 (0.55 equivs.) were used.
Diastereomeric ratio=1:1.
In (2.2 equivs.), LiI (2.2 equivs.), and 2 (1.1 equivs.) were used.
Reaction was carried out at 08C.
[b]
[c]
[d]
[e]
In (3.3 equivs.) and 2 (1.65 equivs.) were used. LiI was not used.
hyde, and cyclohexanecarbaldehyde regioselectively
gave 1,6-diol derivatives linked to the allenyne unit in
78–85% yields (entries 1–3). Treatment of trans-cin-
namaldehyde with 1,6-dibromo-2,4-hexadiyne and
indium produced the desired 1,6-diol compound in
70% yield (entry 5). In the cases of various aromatic
aldehydes, electronic variation on the aromatic sub-
stituents such as chloride, iodide, methoxy, methyl,
nitro, hydroxy, ketone, methoxycarbonyl, and acetoxy
Figure 2. Synthon of the 3,6-dianion of 1,2-hexadien-4-yne.
did not diminish the efficiency and selectivity (en- functional group between the hydroxy groups in good
tries 6–17). It is noteworthy that protection of a hy- to excellent yields with complete regioselectivity and
droxy and ketone group on substrates is not necessary chemoselectivity.
as demonstrated by the reaction of 3-hydroxybenzal-
In summary, we have shown that the reaction of al-
dehyde (entry 14) and 4-acetylbenzaldehyde dehydes and ketones with the organoindium reagent
(entry 15). 2,4,6-Trimethylbenzaldehyde reacted with generated in situ from indium and 1,6-dibromo-2,4-
the 1,6-dianionic indium reagent to afford the desired hexadiyne in the presence of lithium iodide in DMF
product in 82% yield after 34 h due to the steric
produced 1,6-diols linked to allenyne in good to ex-
effect (entry 12). Heteroatoms turned out to be com- cellent yields through 1,2-hexadien-4-yn-3,6-ylation
patible with the employed reaction conditions from contemporary propargylation and allenylation
(entry 18). The reaction worked equally well with ali- with complete regioselectivity and chemoselectivity,
phatic ketones such as 4-phenyl-2-butanone and cy- indicating that 1,6-dibromo-2,4-hexadiyne acted selec-
clohexanone (entries 19 and 20). Reaction of aceto- tively as a synthon of the 3,6-dianion of 1,2-hexadien-
phenone with organoindium gave the 1,6-diol linked 4-yne (Figure 2).
to allenyne in 68% yield (entry 21). All of the above
reactions selectively gave 1,6-diols having an allenyne
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Highly Selective Synthetic Method for 1,6-Diols Bearing Enyne Functions
COMMUNICATIONS
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Experimental Section
Typical Experimental Procedure for 1,2-Hexadien-4-
yn-3,6-ylation
Indium (63.0 mg, 0.55 mmol) and lithium iodide (74 mg,
0.55 mmol) in dry THF (1.5 mL) were slowly added to 1,6-
dibromo-2,4-hexadiyne (65.0 mg, 0.275 mmol) in dry THF
(1 mL) at room temperature under a nitrogen atmosphere.
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Rf =0.3) to give 1,6-diphenyl-2-vinylidenehexa-3-yne-1,6-
diol; yield: 63.0 mg (86%); 1H NMR (400 MHz, CDCl3):
d=7.36–7.25 (m, 10H), 5.21 (s, 1H), 5.10 (s, 2H), 4.75 (t,
J=6.3 Hz, 1H), 2.69 (d, J=6.3 Hz, 2H), 2.27 (s, 2H);
13C NMR (100 MHz, CDCl3) Isomer A: d=212.04, 142.45,
141.33, 128.43, 128.30, 128.01, 127.88, 126.35, 125.69, 94.54,
91.51, 79.76, 75.02, 74.26, 72.31, 30.62; Isomer B: d=
212.04,142.45, 141.33, 128.43, 128.30, 128.01, 127.88, 126.33,
125.69, 94.54, 91.51, 79.76, 75.00, 74.24, 72.31, 30.62; IR
(film): n=3419, 3026, 2921, 2217, 1514, 1043 cmÀ1; HR-MS
(EI): m/z=290.1306, calcd for C20H18O2 (M+): 290.1307.
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Acknowledgements
This work was supported by the Korea Science and Engineering
Foundation (KOSEF) through the National Research Lab. Pro-
gram funded by the Ministry of Science and Technology (No.
M10600000203–06 J0000–20310), by the CMDS at KAIST, by
the Korea Science and Engineering Foundation (KOSEF, R01–
2006–000–11283–0) and by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, Basic
Research Promotion Fund) (KRF-2006–353-C00030). The
NMR and mass data were obtained from the central instrumen-
tal facility in Kangwon National University.
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to 4 to determine the diastereomeric ratio.
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