Chemoselective addition of in situ prepared lithium alkynyl borates to aldehydes: a practical and transition metal free approach toward the synthesis of propargylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.01.011

A convenient synthesis of functionalized propargylic alcohols arising from the 1,2-addition of lithium alkynyl-trimethyl borate onto aldehydes under transition metal free mild conditions is reported. The reaction tolerates a wide range of functional groups, is highly chemoselective and the propargylic alcohols are isolated in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.01.011

Tetrahedron Letters 51 (2010) 1386–1389
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoselective addition of in situ prepared lithium alkynyl borates to
aldehydes: a practical and transition metal free approach toward the
synthesis of propargylic alcohols
a,
Irene Notar Francesco a,b, Antoine Renier a, Alain Wagner b, , Françoise Colobert
*
*
a Laboratoire de stéréochimie, UMR CNRS 7509, Université de Strasbourg (E.C.P.M.), 25 Rue Becquerel, 67087 Strasbourg Cedex 2, France
b Novalix-Pharma, Boulevard Sébastien Brant, BP 30170, F-67405, Illkirch Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of functionalized propargylic alcohols arising from the 1,2-addition of lithium
alkynyl-trimethyl borate onto aldehydes under transition metal free mild conditions is reported. The
reaction tolerates a wide range of functional groups, is highly chemoselective and the propargylic alco-
hols are isolated in good to excellent yields.
Received 23 November 2009
Revised 21 December 2009
Accepted 6 January 2010
Available online 11 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lithium alkynyl borate
Aldehyde
Propargylic alcohol
1. Introduction
fully used in the addition to aldehydes and ketones as isolated B-
alkynyl-9-BBN derivatives.14
Propargylic alcohols are versatile building blocks in the synthe-
sis of many natural products and pharmaceuticals.1,2 Over the past
few decades many methods to obtain propargylic alcohols have
been presented. Most of them involved alkynylmetals in nucleo-
philic addition to carbonyl compounds. The alkynyl lithium or
magnesium reagents generally employed in such processes are
typically prepared from acetylene derivatives and organolithium3
or organomagnesium4 bases. However such strong basic and
nucleophile reagents are often incompatible with a large range of
functional groups. Recent efforts on this subject have led to the
use of less reactive but highly efficient alkynylmetals involving
metal species such as Cs,5 Zn,6 In,7 Rh,8 Ag,9 Cu,10 Ga,11 Ce,12 V,13
B,14 and Ti,15 to a large extent in catalytic enantioselective proce-
dures with aldehydes and ketones.
Although many significant results have been achieved in this
field, the development of new procedures, allowing for a better
compatibility between the reactivity of nucleophilic species and
the substitution pattern of carbonyl compounds and alkynes, have
still a considerable interest.
Because of their mildness, large availability, and ready prepara-
tion,16 alkynyl borates have been extensively used in organic syn-
thesis. We recently described their use in Pd-catalyzed Suzuki
coupling with aromatic halides.17–19 They also have been success-
In this Letter, we describe the use of in situ prepared lithium
alkynyltrimethyl borate in the metal-free 1,2-addition to alde-
hydes as an efficient and selective straightforward way to synthe-
size propargylic alcohols. This reaction is in agreement of
functional-group tolerance, environmental sustainability, and
economy, factors that are in constant demand nowadays. Processes
that do not require any transition metal catalyst are of great inter-
est because it avoids the elimination of traces of metal in the final
compound.
2. Results and discussion
In an initial approach we chose to study the reaction of 1-octyne
with benzaldehyde. Hence, the metallation of 1-octyne with
1 equiv of BuLi in THF at À78 °C during 1 h afforded the lithium
1-octynyl intermediate which was treated with 1.35 equiv of trim-
ethylborate in THF at À78 °C. Two hours are normally sufficient to
convert the alkynyl lithium in alkynyl borate derivative as con-
firmed by 11B NMR20 spectra. Addition by cannula of the in situ
prepared lithium octynyl trimethyl borate to the aldehyde in THF
at room temperature afforded after 1 h at reflux the desired cou-
pling product in 98% yield. In the same reaction conditions methyl
benzoate is completely unreactive in evidence of absence of lith-
ium 1-octynyl intermediate (Scheme 1).
Further investigations showed that oxygenated, polar solvents
such as THF and DME, which are equally effective in terms of
* Corresponding authors. Tel.: +33 3 90 24 27 44; fax: +33 3 90 24 42 (F.C.).
E-mail address: fcolober@chimie.u-strasbg.fr (F. Colobert).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.011

I. Notar Francesco et al. / Tetrahedron Letters 51 (2010) 1386–1389
1387
Scheme 1. Differences in the chemical behavior of lithium alkynyl borate with respect to benzaldehyde and benzoic ester.
conversion rates and reaction times, are the most suitable to our
purposes. In a typical experiment a solution of lithium alkynyl-tri-
methyl borate, formed in situ after the addition of B(OMe)3 on the
corresponding alkynyl lithium at À78 °C in THF, is added to a solu-
tion of the desired aldehyde at room temperature. The temperature
is increased to reflux and the aldehyde consumption is monitored
by TLC (1–4 h are normally sufficient). This protocol was also dem-
onstrated to work among different alkyne species and a wide series
of aldehyde partners. Results obtained with 1-octyne are listed in
Table 1.21
with literature observations, with an electron-donating substituent
on the aromatic ring (Table 1, entry 11), only 47% yield of the
isolated adduct was obtained as expected in reason of a lower
reactivity of the aldehyde toward the carbonyl addition. It has to
be noticed that aromatic aldehydes bearing electron-donating sub-
stituent are rarely used in those kind of organic processes.
In order to evaluate the scope of the reaction also in regard to
the electronic properties of the starting alkyne further tests have
been performed. The results with phenylacetylene in association
with several aldehydes are presented in Table 2.
Good to excellent results were obtained in the coupling reaction
between lithium octynyl trimethyl borate and aliphatic or aro-
matic aldehydes. Coupling with activated aromatic aldehydes in
the presence of electron-withdrawing substituents on the aromatic
moiety led in high yields to the corresponding propargylic alcohols
(Table 1, entries 5–8). In cases of entries 6 and 8, 3 equiv of alkynyl
borate salt has been used because no reaction occurred under nor-
mal conditions. One explanation could be the coordination of the
oxygens of the nitro- or ester groups to the boron species. Very
interesting are the cases in entries 7 and 8 showing that when
the 4-acetyl- and 4-methylcarboxylate-benzaldehyde are used,
the coupling reaction occurred exclusively on the aldehyde giving
in good yield the corresponding products as a proof of the com-
plete chemoselectivity of this method. We also performed the
addition with aromatic aldehydes substituted in ortho or para
position with halide atom (Table 1, entries 9 and 10) giving in sat-
isfactory yields the related propargylic alcohols. In accordance
In a general extent we observed that phenylacetylene gave
good to excellent results with various aldehydes suggesting that
electronic properties of the borate intermediate also play a key
role. The i-butyraldehyde gave the best result (Table 2, entry 2)
among the aliphatic aldehydes that have been used (Table 2,
entries 1–4). With aromatic aldehydes excellent results were
obtained and, to our delight, with electron-donating groups such
as a methoxy on the phenyl ring (Table 2, entries 10 and 11) 75%
and 98% yields were achieved for ortho and para position, respec-
tively, despite to their inactivating function. On the contrary the
4-cyano benzaldehyde (Table 2, entry 6) gave only 65% yield. Aro-
matic aldehydes with halogenated substituent also showed a great
reactivity, allowing high yields (Table 3, entries 7–9) especially in
the case of a fluorine which gave the addition product in nearly
quantitative yield.
The case of TMS substituent, that turns to be useful for further
functionalization, was also explored (Table 3) but we observed the
Table 1
1,2-Addition of in situ formed lithium 1-octynyl-trimethyl borate to aliphatic and aromatic aldehydesa
Entry
R
Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5
n-C5H11
i-Pr
t-Bu
p-(CN)C6H4
p-(NO2)C6H4
p-(COMe)C6H4
p-(CO2Me)C6H4
p-(Br)C6H4
o-(F)C6H4
p-(OMe)C6H4
98
65
65
99
97
62
68
75
61
68
47
c
c
10
11
a
Unless otherwise stated, reactions were run under argon by using a commercially available 1.6 M nBuLi solution in hexane with the following molar ratios: 1-octyne/
nBuLi/B(OMe)3/aldehyde = 1.3:1.3:1.35:1.
b
Isolated yields after chromatography.
3 equiv of lithium octynyl trimethyl borate.
c

1388
I. Notar Francesco et al. / Tetrahedron Letters 51 (2010) 1386–1389
Table 2
1,2-Addition of in situ formed lithium phenylethynyl-trimethyl borate to aliphatic and aromatic aldehydesa
Entry
R
Yieldb (%)
1
2
3
4
5
6
7
8
9
n-C5H11
i-Pr
t-Bu
Cyclohexyl
C6H5
p-(CN)C6H4
o-(F)C6H4
o-(Cl)C6H4
p-(Br)C6H4
o-(OMe)C6H4
p-(OMe)C6H4
77
91
87
71
88
65
95
65
71
75
98
10
11
a
Unless otherwise stated, reactions were run under argon by using a commercially available 1.6 M nBuLi solution in hexane with the following molar ratios: phenyl
acetylene/nBuLi/B(OMe)3/aldehyde = 1.3:1.3:1.35:1.
b
Isolated yields after chromatography.
Table 3
1,2-Addition of in situ formed lithium trimethylsilylethynyl-trimethyl borate to aliphatic and aromatic aldehydesa
Entry
R
Yieldb (%) A (A + B)c
1
2
3
4
5
6
7
t-Bu
1-Pentenyl
C6H5
p-(OMe)C6H4
mm’p-(OMe)3C6H2
p-(CO2Me)C6H4
p-(COMe)C6H4
89 (95)c
87
54
56
(81)c
43 (83)c,d
48 (99)c
a
Unless otherwise stated, reactions were run under argon by using a commercially available 1.6 M nBuLi solution in hexane with the following molar ratios: TMS-
acetylene/nBuLi/B(OMe)3/aldehyde = 1.3:1.3:1.35:1.
b
Isolated yields after chromatography.
Yield of compound A + B.
3 equiv of lithium octynyl trimethyl borate.
c
d
formation of a product which corresponds to the deprotected prop-
argylic alcohol. Excellent yields were reached with aliphatic alde-
hydes as pivalaldehyde and n-hexanal with only 6% of the
deprotected triple bond in the case of pivalaldehyde (Table 3, en-
tries 1 and 2). Benzaldehyde and p-anisaldehyde are quite equally
effective giving 54% and 56%, respectively, of the propargylic alco-
hol (Table 3, entries 3 and 4). Surprisingly with 3,4,5-trimethoxy-
benzaldehyde, 81% of the byproduct without TMS was obtained
and when the 4-acetyl and the 4-methylcarboxylate benzaldehyde
are used, an equal mixture of coupling products with and without
TMS is obtained in excellent yields (Table 3, entries 6 and 7). The
deprotection of the triple bond is probably caused by two different
factors. The excess of the lithiated ate complex, as well as the hydro-
lysis during the work up, could affect the amount of the deprotected
alcohol as confirmed by TLC. Such process seems to be independent
from the electronic properties of starting materials.
from simple and cheap precursors. Further studies on an asymmet-
ric version are currently under investigation.
References and notes
1. Stang, P. J.; Diederich, F. In Modern Acetylene Chemistry; Stang, P. J., Diederich, F.,
Eds.; VCH: Weinheim, 1995.
2. Brandsma, L. In Preparative Acetylene Chemistry, 2nd ed.; Elsevier: Amsterdam,
1988.
3. Wakefield, B. J. In Organolithium Methods; Academic: London, 1988; p 32.
Chapter 3.
4. Wakefield, B. J. In Organomagnesium Methods in Organic Synthesis; Academic:
London, 1988; pp 46–48. Chapter 3.
5. Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463.
6. Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
7. (a) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org. Lett. 2005, 7,
1363; (b) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 13760.
8. Dhondi, P. K.; Chisholm, J. D. Org. Lett. 2006, 8, 67.
9. Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395.
10. Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901.
11. Jia, X.; Yang, H.; Fang, L.; Zhu, C. Tetrahedron Lett. 2008, 49, 1370.
12. Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233.
13. Hirao, T.; Misu, D.; Agawa, T. Tetrahedron Lett. 1986, 27, 933.
In summary a new, practical, and efficient reaction involving
lithium alkynyltrimethyl borate in the 1,2-addition to aldehydes
is presented. This novel process constitutes a straightforward and
chemoselective protocol to functionalized propargylic alcohols

I. Notar Francesco et al. / Tetrahedron Letters 51 (2010) 1386–1389
1389
14. (a) Brown, H. C.; Molander, G. A.; Singh, S.; Racherla, U. S. J. Org. Chem. 1985, 50,
1577; (b) Lewis, M.-D.; Duffy, J.-P.; Heck, J.-V.; Menes, R. Tetrahedron Lett. 1988,
19, 2279; (c) Evans, J.-C.; Goralsky, C.-T.; Hasha, D.-L. J. Org. Chem. 1992, 57,
2941.
15. (a) Li, H.; Huang, Y.; Jin, W.; Xue, F.; Wan, B. Tetrahedron Lett. 2008, 49, 1686;
(b) Kamble, R. M.; Singh, V. K. Tetrahedron Lett. 2003, 44, 5347; (c) Chen, Z.-C.;
Hui, X.-P.; Yin, C.; Huang, L.-N.; Xu, P.-F.; Yu, X.-X.; Cheng, S.-Y. J. Mol. Catal. A
2007, 269, 179.
16. Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1991, 29, 2631.
17. Castanet, A. S.; Colobert, F.; Schlama, T. Org. Lett. 2000, 2, 3559.
18. Colobert, F.; Castanet, A. S.; Abillard, O. Eur. J. Org. Chem. 2005, 3334.
19. Hernandez Torres, G.; Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2006, 1450.
20. [B(OMe)3]: 11B NMR (CDCl3, 400 MHz, 25 °C) d 19.7 ppm [lithiated 1-octynyl-
trimethyl borate]: 11B NMR (CDCl3, 400 MHz, 25 °C) d 4.3 ppm.
21. Preparation of lithiated 1-octynyl-trimethyl borate and 1,2-addition to
pivalaldehyde (Table 1, entry 4): solution of n-butyllithium (1.6 M in
hexane, 1.3 mmol, 800 L) was slowly added to solution of 1-octyne
L) in THF (7 mL). After 1 h at À78 °C, trimethyl borate
L) was slowly added and the mixture was stirred for further
A
l
a
(1.3 mmol, 192
(1.35 mmol, 150
l
l
2 h. The temperature was raised up to 20 °C during 20 min and the solution
was added by cannula to a solution of pivalaldehyde (1 mmol, 110 L) in THF
l
(1 mL). The reaction was heated under reflux until complete disappearance
of the starting aldehyde (TLC) and allowed to cool to room temperature.
After the addition of water (15 mL) and extraction with ethyl acetate
(3 Â 15 mL), the combined organic phases were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (eluent = cyclohexane/ethyl acetate 98:2).
Yield 99%.