An in-mediated tandem reaction of aldehydes with 3-bromo-1-propyne to produce 1-substituted-3-methylene-5-yn-1-ol compounds

Article abstract of DOI:10.1002/ejoc.200700758

A one-pot reaction for the synthesis of 1-substituted-3-methylene-5-yn-1-ol compounds from In-mediated propargylation of aldehydes with 3-bromo-1-propyne was reported. Our studies showed that the propargylic alcohol formed in the reaction was selectively

Full text of DOI:10.1002/ejoc.200700758

FULL PAPER
DOI: 10.1002/ejoc.200700758
An In-Mediated Tandem Reaction of Aldehydes with 3-Bromo-1-propyne To
Produce 1-Substituted-3-methylene-5-yn-1-ol Compounds
Jing-Mei Huang,*[a] Hui-Chao Luo,[a] Zu-Xing Chen,[b] Gui-Chun Yang,[b] and
Teck-Peng Loh*[c]
Keywords: Aldehydes / Alcohols / Alkynes / Indium / Propargylation / Tandem
A one-pot reaction for the synthesis of 1-substituted-3-meth-
ylene-5-yn-1-ol compounds from In-mediated propargylation
of aldehydes with 3-bromo-1-propyne was reported. Our
studies showed that the propargylic alcohol formed in the
reaction was selectively subjected to further propargylation
of the triple bond to afford the Markovnikov addition prod-
ucts in a regiospecific fashion.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
the nature of the organoindium species [InI or InIII] formed
depends on the solvent used. Highly regioselective syntheses
of allenic and homopropargylic alcohols has been achieved
by In-mediated reactions of silicon-substituted propargyl
bromide with aldehydes in THF.[2d] Here we present a
chemo- and regioselective method for the synthesis of 1-
substituted-3-methylene-5-yn-1-ols by the In-mediated tan-
dem reaction of aldehydes with 3-bromo-1-propyne.
Introduction
Organoindium chemistry has attracted considerable
interest.[1] In particular, the reaction of carbonyl com-
pounds with propargylic halides and indium has been ex-
tensively studied because they provide an efficient method
to the syntheses of propargylic and allenic alcohols.[2] Usu-
ally the use of propargyl– and allenyl–metal derivatives re-
sulted in the formation of product mixtures[3] because of
the potential for metallotropic rearrangement between these
two species.[4] Moreover, accessibility of these propargyl
and allenyl nucleophiles is highly substrate dependent.[3–5]
Experimental and theoretical studies[2f] have showed that
Results and Discussion
Recently, while investigating the In-mediated (In powder,
substitution on the propargyl bromide affects the equilib- 2.5 mmol) reaction of hydrocinnamyl aldehyde (1 mmol)
rium between propargyl– and allenyl–metal derivatives, and with 3-bromo-1-propyne (2, 2.5 mmol) in THF (1 mL), we
Scheme 1. Products of propargylation of hydrocinnamyl aldehyde mediated by In in THF.
[a] School of Chemical Science, South China University of
Technology,
consistently detected the formation of product 3a in ad-
dition to allenic alcohol 4a (Scheme 1). No trace of homo-
propargylic alcohol 5a was detected. The structure of 3a
was determined and confirmed by high-resolution mass
spectrometry and 1D NMR (1H and 13C) and 2D NMR
(COSY and HMQC) spectroscopy.
This interesting result prompted us to monitor the pro-
gress of the reaction by using NMR spectroscopy.[6]It was
observed that after 10 min of stirring, all the aldehyde was
consumed with the appearance of a mixture of allenic
alcohol 4a, homopropargylic alcohol 5a and 3a. As the re-
Guangzhou 510640, China
Fax: +86-20-87110622
E-mail: chehjm@scut.edu.cn
[b] Ministry of Education Key Laboratory for the Synthesis
and Application of Organic Functional Molecules, Hubei
University,
Wuhan 430062, China
[c] Division of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
University,
Singapore 639798
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 295–298
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action progressed, the amount of 5a decreased as the summarized in Table 2. In most cases, the reaction pro-
amount of 3a increased, whereas the amount of allenic ceeded smoothly to afford desired products 3 in moderate-
alcohol remained unchanged. These results showed that the to-good yields.
initially formed homopropargylic alcohol was slowly con-
verted into 3a in the presence of an excess amount of pro-
pargylic bromide and indium (Scheme 2).
Table 2. InBr3-catalyzed tandem reaction of different aldehydes
with 3-bromo-1-propyne.
Scheme 2. The reaction pathway for the formation of 3a.
Because of the potential usefulness of 1-substituted-3-
methylene-5-yn-1-ol compounds (3a) in organic synthesis,
our studies were further directed to improve the yield of 3a.
A variety of solvents were screened, and the reaction done
in THF was found to afford the product with the highest
yield of 50%. In contrast, 3a was obtained in only 15%
yield when toluene was used as the solvent. All other sol-
vents screened (ether, methanol, DMF, dichloromethane
and water) suppressed the formation of 3a completely. Sev-
[a] Reaction conditions: aldehyde (1 mmol), propargyl bromide
eral Lewis acids were also screened with THF as the solvent (2.5 mmol), In (powder, 2.5 mmol), InBr3 (0.1 mmol), THF (1 mL),
0 °C to r.t., 15 h. [b] Isolated yield.
to investigate the impact on the reaction (Table 1), and it
was found that with the InBr3 catalyst, the yield of 3a in-
creased to 65%. Further optimization by carrying out the
With both the aliphatic and aromatic aldehydes, further
reaction at lower temperature (0 °C) increased the product
propargylation was selective on the triple bonds and pro-
yield to 70%.
duced Markovnikov addition products 3. One can rational-
ize that the reaction is similar to the reported allylindation
of alkynes with allylindium,[7] and it was demonstrated that
Table 1. Impact of Lewis acids on the tandem propargylation of
aldehyde.[a]
Markovnikov addition products were selectively produced
by allylindation of alkynes with allylindium. The authors
suggested the reaction occurred by initial indium acetylide
formation followed by the addition of one equivalent of al-
lylindium across the triple bond. Our results also suggested
a similar pathway.
The propargylation of 3 did not proceed further even
with an excess amount of propargylic indium. This result
was consistent with a previous report by Chan et al.[2b] Our
result also implied that the hydroxy group facilitated the
propargylation of triple bonds.
Attention is drawn to the fact that the subsequent pro-
pargylation to form 3 occurred preferentially with 5 that
bears the alkyne moiety rather than 4 that bears the allenic
group. This result was different from the recently reported
observation by Chan.[2b] They found that when methyl-sub-
stituted propargyl bromide (1-bromo-2-butyne) was used,
further allenation on the allenic alcohol was observed. To
demonstrate that further propargylation was not favoured
Entry
Lewis Acid
Yield of 3a+4a [%] (ratio of 3a/4a)[b]
1
2
3
4
5
6
7
8
–
66 (76:24)
66 (76:24)
34 (70:30)
37 (71:29)
77 (76:24)
84 (77:23)
71 (76:24)
85 (82:18)
La(OTf)3
Yb(OTf)3
In(OTf)3
InCl3
InBr3
InI3
InBr3
[c]
[a] Reaction conditions (unless otherwise stated): aldehyde
(1 mmol), propargyl bromide (2.5 mmol), In (powder, 2.5 mmol),
Lewis acid (0.1 mmol), THF (1 mL), r.t., 15 h. [b] Isolated yield.
[c] Mixing was initially carried out at 0 °C.
The optimized reaction conditions with propargyl bro- on allenic alcohol in our reaction system, we carried out a
mide 2 were extended to other aldehydes. The results are reaction by using a preformed mixture of allenic alcohol
296
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Eur. J. Org. Chem. 2008, 295–298

An In-Mediated Tandem Reaction of Aldehydes with 3-Bromo-1-propyne
Figure 1. NMR study on the chemoselectivity of subsequent propargylation.
(4a) and propargylic alcohol 5a[8] for further propar-
Conclusions
gylation, which was mediated by indium in THF, with an
excess amount of propargylic bromide 2 (2.5 equiv.).[9] The
result was consistent with our initial observation on the di-
rect propargylation on aldehydes; the propargylation of 5a
occurred smoothly to produce 3a and the reaction was com-
plete in 15 h (Figure 1). Most importantly, 4a remained un-
changed in the reaction, thus confirming our initial pro-
posal. However, the reason for the different selectivity is
still, at present, not fully understood.
A chemo- and regioselective method was developed for
the synthesis of 1-substituted-3-methylene-5-yn-1-ols by the
In-mediated tandem reaction of aldehydes with 3-bromo-1-
propyne. Further studies to expand the scope of this reac-
tion and its application to the synthesis of complex mole-
cules are in progress.
Our results also showed that further reaction on the tri-
ple bond was highly regioselective; only the propargylation
product was produced and no allenylation product was col-
lected. This can be best interpreted by the equilibrium be-
tween propargyl and allenyl metal intermediates. Studies by
Chan et al.[2f] showed that in the parent propargyl/allenyl
indium system, the equilibrium is in favour of the allenylin-
dium species. Hence, in our reaction, when the parent bro-
mide (3-bromo-1-propyne) was used, further propar-
gylation occurred and a product with a terminal triple bond
was collected. Studies also showed that with methyl substi-
tution on the propargyl bromide, the equilibrium is in fav-
our of the propargyl species. Thus, as reported by Chan’s
group, further reaction on the triple bond producing a ter-
minal allenic product (allenylation product) was observed
when methyl-substituted propargyl bromide was used.[2b]
It is worthy to note that under the current reaction con-
ditions, the obtained products were different than the ones
obtained in the presence of the chiral promoter cinchon-
idine, as previously reported by our group.[2c] Further reac-
tion at the triple bond to produce 1-substituted-3-methyl-
ene-5-yn-1-ol was not observed in the presence of cinchonid-
ine, and we suggested that this was due to the deactivation
of the allenylindium species through the formation of al-
lenyl indium–cinchonidine complexes.
Experimental Section
Illustrative Experimental Procedure
Synthesis of 3a: Propargyl bromide (2; 0.22 mL. 2.5 mmol) was
added to a mixture of In (powder, 285 mg, 2.5 mmol), hydrocinna-
myl aldehyde (1a; 0.12 mL, 1 mmol) and InBr3 (35 mg, 0.1 mmol)
in THF (1 mL) at 0 °C. The resulting mixture was warmed to room
temperature and stirred for 15 h. The reaction was quenched by
the addition of water (0.5 mL), and the mixture was extracted with
diethyl ether (3ϫ10 mL). The organic layer was combined and
washed with brine and dried with anhydrous MgSO4. Evaporation
of the solvent followed by purification by silica gel chromatography
gave a mixture of 3a and 4a as an oil (3a, 150 mg, 70%). FTIR
(KBr, neat): ν = 3310, 2117, 1680, 1602, 1494, 1454 cm–1. 1H NMR
˜
(500 MHz, CDCl3, 25 °C): δ = 7.34–7.21 (m, 5 H, Ph), 5.28 (d, J
= 1.5 Hz, 1 H, =CHH), 5.01 (s, 1 H, =CHH), 3.84–3.79 (m, 1 H,
CHOH), 2.97 (br. s, 2 H, HCCCH2), 2.89–2.81 (m, 1 H, PhCHH),
2.79–2.70 (m, 1 H, PhCHH), 2.37 (dd, J = 3.7, 14.1 Hz, 1 H,
CHOHCHHC=C), 2.25 (dd,
J
=
6.0, 14.1 Hz,
1
H,
CHOHCHHC=C), 2.19 (t, J = 2.5 Hz, 1 H, CCH), 1.83–1.80 (m,
2 H, PhCH2CH2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
142.0, 140.8, 128.5, 128.4, 125.9, 114.6, 81.2, 71.2, 68.6, 44.0, 38.8,
32.1, 26.0 ppm. HRMS (EI): calcd. for C15H18O [M]+ 214.1352;
found 214.1344.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for 3a–g.
Eur. J. Org. Chem. 2008, 295–298
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J.-M. Huang, H.-C. Luo, Z.-X. Chen, G.-C. Yang, T.-P. Loh
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Acknowledgments
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The project was sponsored by the Ministry of Education Key Labo-
ratory for the Synthesis and Application of Organic Functional
Molecules (Hubei University), Nanyang Technological University,
Singapore and the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry of China.
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mide (2; 0.44 mL, 5 mmol) was added to the mixture of In
(powder, 570 mg, 5 mmol), hydrocinnamyl aldehyde (1a;
0.24 mL, 2 mmol) in THF (2 mL) at room temperature. The
resulting mixture was stirred at this temperature and an aliquot
(0.1 mL) of the reaction mixture was taken out by syringe at
each time when the reaction was run for 10 min, 30 min, 1 h,
2.5 h and 15 h. Each portion of reaction mixture was quenched
by adding water (0.1 mL), and the mixture was extracted with
diethyl ether (5 mL). The organic layer was washed with brine
and dried with anhydrous MgSO4. The solvent was evaporated,
and the residue was subjected to NMR analysis.
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[8] The ratio of 5a/4a was 1:2, and the mixture was obtained from
the In-mediated coupling of hydrocinnamyl aldehyde with pro-
pargylic bromide in water. See ref.[2a]
[9] The experimental procedure for the NMR study was similar to
that in ref.[6] An aliquot (0.1 mL) of the reaction mixture was
taken out by syringe at each time when the reaction was run
for 6 h and 15 h. Each portion of the reaction mixture was
quenched by adding water (0.1 mL), and the mixture was ex-
tracted with diethyl ether (5 mL). The organic layer was washed
with brine and dried with anhydrous MgSO4. The solvent was
evaporated, and the residue was subjected to NMR analysis.
Received: August 16, 2007
Published Online: November 12, 2007
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Eur. J. Org. Chem. 2008, 295–298