CeCl3-mediated addition of acetylenic bis-lithium salts to aldehydes and ketones: An efficient route to bis-substituted alkyne diols

Article abstract of DOI:10.1016/j.tetlet.2017.07.094

An efficient, chemoselective protocol to access propargylic diols via a CeCl₃-mediated addition reaction is reported. Propargylic alcohols were transformed into the corresponding acetylenic bis-lithium salt intermediates, which react with aldehydes and ketones in the presence of dry CeCl₃ to furnish the corresponding bis-substituted alkyne diols. This protocol does not involve protection-deprotection or transmetallation steps, and allows the use of poorly reactive or highly enolizable substrates.

Full text of DOI:10.1016/j.tetlet.2017.07.094

Accepted Manuscript
CeCl3-mediated addition of acetylenic bis-lithium salts to aldehydes and ke-
tones: an efficient route to bis-substituted alkyne diols
Jefferson Luiz Princival, Jeiely Gomes Ferreira
PII:
S0040-4039(17)30963-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.094
TETL 49176
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
24 May 2017
24 July 2017
28 July 2017
Please cite this article as: Princival, J.L., Ferreira, J.G., CeCl3-mediated addition of acetylenic bis-lithium salts to
aldehydes and ketones: an efficient route to bis-substituted alkyne diols, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.07.094
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Graphical Abstract
CeCl3-mediated addition of acetylenic bis-
lithium salts to aldehydes and ketones: an
efficient route to bis-substituted alkyne diols
Leave this area blank for abstract info.
Jefferson Luiz Princival* and Jeiely Gomes Ferreira

Tetrahedron Letters
Tetrahedron Letters
journal homepage: www.els evier.com
CeCl3-mediated addition of acetylenic bis-lithium salts to aldehydes and ketones: an
efficient route to bis-substituted alkyne diols
Jefferson Luiz Princivala* and Jeiely Gomes Ferreiraa
a Laboratório de Catálise Orgânica, Departamento de Química Fundamental, Universidade Federal de Pernambuco, Recife-PE (Brazil)
Av. Jornalista Anibal Fernandes s/n - Cidade Universitária - CEP 50740-560 / Tel.:+55 (81) 2126-7463. princivalj@yahoo.com.br
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient, chemoselective protocol to access propargylic diols via a CeCl3-mediated addition
reaction is reported. Propargylic alcohols were transformed into the corresponding acetylenic
bis-lithium salt intermediates, which react with aldehydes and ketones in the presence of dry
CeCl3 to furnish the corresponding bis-substituted alkyne diols. This protocol does not involve
protection-deprotection or transmetallation steps, and allows the use of poorly reactive or highly
enolizable substrates.
Received in revised form
Accepted
Available online
Keywords:
Lanthanide
2017 Elsevier Ltd. All rights reserved
.
Bis-lithium salt
Propargylic diols
Organometallic
1,2-Addition
Acetylenic diols are interesting functionalities which are
found as subunits in a wide range of bioactive metabolites.[1]
Among the reported methods for their preparation, a common
synthetic strategy is the alkynylation reaction of ketones or
aldehydes with protected propargylic alcohols. Although the
conversion of propargylic alcohols into their respective ethers
can be a straightforward transformation, at least two additional
synthetic operations are required (Scheme 1).
reporting their reactivity with carbonyl compounds showing
satisfactory results have been reported.
We became interested in developing a general process to
synthesize internal propargylic diols by evaluating the reactivity
of alkynyic bis-lithium salt intermediates in the presence of
cerium(III) (Scheme 1).
The protection-deprotection and bis-lithium salt routes are
summarized in Scheme 1.
In many cases, bis-lithium salts can be directly used, wherein
the alkoxy group is considered as a non-nucleophilic site.
However, for this purpose the reactive bis-organometallic reagent
must be compatible with sensitive functional groups e.g.
enolizable carbonyl containing compounds. In order to avoid
unwanted side-reactions, these reagents can be transmetallated
into other derivatives. An example, is the use of CeCl3 for the
preparation of organocerium reagents, which possess both very
low basicity and excellent nucleophilicity.
After the pioneering work developed by Imamoto and co-
workers,[2] these reagents have been applied for efficient
carbonyl addition reactions in which organomagnesium and/or
organolithium reagents initially failed to provide the desired
alcohols in acceptable yields.[3]
In many reported methods for the preparation of bis-
functionalized organocerium reagents, the treatment of an
organolithium or organomagnesium reagent with one2,[4] or two
equivalents[5] of dry CeCl3 is commonly required. However we
recently observed[6] that the presence of catalytic dry CeCl3 (10
mol%) in the alkynylation of aldehydes considerably increased
the yield of the addition products.
Scheme 1. Preparation of propargylic diols.
Despite the preparation of bis-lithium intermediates being
well known, to the best of our knowledge no general method
Initially, the preparation of alkynylic bis-lithium salts was
achieved via direct deprotonation of propargylic alcohols using
two equivalents of n-BuLi at -78 °C (Scheme 2). After generating

Tetrahedron Letters
Table 1. CeCl3 mediated reaction of 2b with paraformaldehyde.
the bis-lithiated intermediate 2b, it was captured with
paraformaldehyde in order to obtain diol 4 in only 32% yield
(Table 1, entry 1). Nevertheless, upon the addition of an
equimolar quantity of CeCl3, before the addition of 2b, a slight
increase in the yield of 4 (44 %) was observed (Table 1, entry 7).
In order to find the optimal experimental conditions, the
reaction was tuned using 2b and paraformaldehyde as model
reagents, examining the effect of different amounts of CeCl3
(Scheme 2; Table 1).
Analyzing the results from Table 1, it is possible to infer that
the use of 0.5 equiv. of CeCl3, based on the lanthanide salt, is
optimal, leading to the formation of 4 in 90% yield (Table 1,
Entries 4 and 5).
Entry CeCl3 (equiv.) Temp. (°C) Time (h) Yield 4 (%)
None
0.1
0.3
0.5
0.5
0.5
1.0
1.5
2.0
-78 °C
-40 °C
-40 °C
-40 °C
-78 °C
0 °C
20
4
32
67
82
90
90
35
44
34
30
1
2
3
4
5
6
7
8
9
4
4
4
4
-40 °C
-40 °C
-40 °C
4
4
4
The examined method was expanded to primary and tertiary
propargylic alcohols in order to observe the reactivity of their
respective bis-lithium salts with several aldehydes and ketones
(Table 2).
Scheme 2. Formation of bis-lithium salt 2b and the CeCl3
mediated reaction with paraformaldehyde.
Table 2. CeCl3-mediated alkynylation reaction with aldehydes and ketones
Entry
Propargylic alcohol
Carbonyl compound
Product
Yield (%)b
With
CeCl3
Without
CeCl3
a
Li (67)
Mg (74)[7]
1
94
Li (70)
Mg (60)[8]
2
3
91
1a
1a
Li (75); Lit.
(86)[9]
Mg (n.d.)
100
Li (71); Lit. (78)9
Mg (n.d.)
4
5
100
90
1a
1a
Li (26)
Mg (40)[10]
Li (69); Lit.
(52)[11]
Mg (n.d.)
6
100
1a
1a
Li (71)
Mg (n.d.)
7
8
100
90
Li (32);
Lit.c (85)[12]
Mg (n.d.)
Li (61); Lit.
(96)[13]
Mg (n.d.)
9
1b
90
2

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Li (77)
Mg (80)[14]
10
100
1b
Li (48)
Mg (n.d.)
11
12
91
93
Li (58)
Mg (n.d.)
1c
1c
3a
3d
Li (72); Lit.
(91)[15]
Mg (n.d.)
13
100
Li (43)
Mg (n.d.)
14
15
90
92
3k
3a
Li (51)
Mg (n.d.)
1d
1d
Li (59); Lit.
(91)[16]
Mg (n.d.)
16
17
97
91
3d
3h
Li (30)
Mg (n.d.)
Reagents and conditions: propargylic alcohol (3 mmol), n-BuLi (6.6 mmol), carbonyl (3 mmol), CeCl3 (1.5 mmol), THF, -40 °C.
c
b
aPrepared by stirring the carbonyl with CeCl3 (0.5 equiv.) for 4 h at room temperature; Isolated yield; Lit. procedure propargylic
alcohol (1 mmol); n-BuLi (3 mmol, 1.5 equiv.) and formaldehyde (1.5 mmol, 1.5 equiv.); n.d. (isolated yield not described).
As can be seen in Table 2, all reactions using CeCl3 (0.5
equiv.) as a mediator furnished the desired propargylic diols in
high yields, even when using poorly reactive or readily
enolizable carbonyl compounds.
Compared to the literature, the current method demonstrates
some advantages. For example, when benzaldehyde was reacted
the with bis-lithium salt, compound 10 was obtained in only 52%
yield according to Williams and co-workers,[17] whereas the
present use of CeCl3 furnished 10 in quantitative yield (Entry 6).
Compared with bis-magnesium salts, as described by Zhu and
compound by CeCl3 as a Lewis acid and (b) formation of 21 by
attack of the free alkoxide on the cerium atom, delivering one
equivalent of LiCl. The generation of an intermediate with
enhanced reactivity is supported by the pioneering work
developed by Knochel and co-workers,[20] where the addition of
LiCl to organomagnesium reagents results in the generation of a
more reactive organometallic species. Thus, a plausible proposed
structure for the intermediate, based on the molar quantities of
each reagent, is depicted in Scheme 3.
co-workers,[18] the current approach shows
a substantial
increase in yield when butanal is used. Whereas reaction of the
lithium reagent, mediated by CeCl3, affords 6 in 90% yield, the
use of a Grignard reagent led to the formation of 6 in 60% yield
(Entry 2).
The most notable results were observed using 2-butanone
which led to the formation of 9 in 90% yield when the reaction
was conducted in the presence of CeCl3; almost quantitative
recovery of the ketone was observed when the reaction was
conducted in the absence of the lanthanide salt (Entry 5).
According to the procedure reported by Chobanyan and co-
workers,[19] the reaction using a bis-magnesium salt purpose,
gave the desired product 9 in only 40% yield.
Scheme 3. Plausible proposed intermediates.
In conclusion, we have shown that the current method
represents a simple protocol for the preparation of alkynylic diols
in very high yields without the need for protection/deprotection
steps.
After comparing the literature with the current approach, we
propose that the successful outcome is a result of synergic effects
from the following possible factors; (a) activation of the carbonyl
3

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J.; Slatford, P. A.; Williams, J. M. J. Tetrahedron
Lett. 2007, 48, 5111-5114.
Acknowledgments
The authors thank CNPq, FACEPE, CAPES and INCT-
INAMI for Financial support and UFPE as well as CETENE for
the Infrastructure.
[12] Kinouchi, W.; Saeki, R.; Kawashima, H.;
Kobayashi, Y. Tetrahedron Lett. 2015, 56, 2268-
2268.
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4

Tetrahedron Letters
Highlights
•
•
•
•
Efficient approach for the synthesis of disubstituted
propargylic diols in high yields.
The protocol features no protection/deprotection
steps and broad substrate scope.
The current strategy is based on CeCl3 mediated
addition of bis-lithium salts.
Plausible intermediate for the transformations was
proposed.
5