Metal-free catalytic nucleophilic substitution of propargylic alcohols

Article abstract of DOI:10.1002/ejoc.200500960

Organic acids such as PTS efficiently catalyze direct nucleophilic substitutions of the hydroxy groups of propargylic alcohols with a large variety of carbon- and heteroatom-centered nucleophiles. Reactions can be conducted under mild conditions and in air without the need for dried solvents. Reactions on multigram scales are also possible. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500960

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200500960
Metal-Free Catalytic Nucleophilic Substitution of Propargylic Alcohols
Roberto Sanz,*[a] Alberto Martínez,[a] Julia M. Álvarez-Gutiérrez,[a] and Félix Rodríguez*[b]
Dedicated to Professor Steven V. Ley on the occasion of his 60th birthday
Keywords: Aromatic substitution / Homogeneous catalysis / Propargylic alcohols / Nucleophilic substitution / Synthetic
methods
Organic acids such as PTS efficiently catalyze direct nucleo-
philic substitutions of the hydroxy groups of propargylic
alcohols with a large variety of carbon- and heteroatom-cen-
tered nucleophiles. Reactions can be conducted under mild
conditions and in air without the need for dried solvents. Re-
actions on multigram scales are also possible.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Substitution of a hydroxy group in an alcohol by a nu-
cleophile usually requires the transformation of the hydroxy
group into a good leaving group,[1] and the development of
new methods for the direct substitution of alcohols is one
of the most challenging goals in organic chemistry. In par-
Scheme 1. Direct propargylic substitution of alkynols.
ticular, propargylic substitution of hydroxy groups by nu- Results and Discussion
cleophiles is a powerful reaction, as the products obtained
Firmly convinced by the potential of this reaction in or-
in these processes are highly interesting building blocks that
have been widely used in complex natural product synthesis.
The extensive work developed by Nicholas in this area is
particularly noteworthy.[2] However, the fundamental draw-
back of this and other recent related methodologies is that
these processes require the use of stoichiometric amounts
of cobalt or chromium complexes.[3] Very recently, a few
catalytic methodologies for the direct substitution of hy-
droxy groups of propargylic alcohols[4] in the presence of
ruthenium[5] or rhenium[6,7] catalysts have been reported.
The major limitation of these processes is that the metallic
catalysts employed are expensive and/or not easily available.
Furthermore, the reaction is generally limited to terminal
and/or secondary propargylic alcohols in the case of the
ruthenium catalysts[8] and to internal alkynes in the case of
rhenium catalysts. So far, no general method for catalytic
propargylic substitution has been reported (Scheme 1).
ganic synthesis, we initiated a project directed towards the
identification of new catalysts for the direct propargylic
substitution of propargylic alcohols. We thus report here
that simple organic acids such as p-toluenesulfonic acid
monohydrate (PTS) are efficient catalysts of propargylic
substitutions with a large variety of heteroatom- and car-
bon-centered nucleophiles.
Our studies started with the model reaction between alk-
ynol 1a and ethanol as nucleophile (3 equiv.), with screen-
ing of various catalyst systems and use of acetonitrile as
solvent at reflux in all cases. Taking advantage of our ex-
perience in the use of dioxomolybdenum complexes as cata-
lysts[9] and in view of the similarities of these complexes
with the rhenium catalyst used by Toste in related propar-
gylic substitutions,[6] we firstly attempted the reaction in the
presence of 5 mol-% of dichlorodioxomolybdenum com-
plexes (Table 1, Entries 1 and 2). Gratifyingly, the reaction
[a] Área de Química Orgánica, Departamento de Química, Facul- proceeded to completion in 1 h, affording the desired ether
tad de Ciencias, Universidad de Burgos,
2a in quantitative yield. To check the effectiveness of the
Pza. Missael Bañuelos s/n, 09001 Burgos, Spain
catalyst, we ran the reaction in the absence of catalyst, but
no formation of compound 2a was observed after 24 h and
the starting material was recovered unchanged (Table 1, En-
try 3). These positive findings tempted us to try the catalytic
reaction with other Lewis acids such as InCl3, AlCl3, and
CeCl3 (5 mol-%) (Table 1, Entries 4–6). In the first case we
found complete conversion into the ether 2a in 1 h. With
Fax: +34-947258831
E-mail: rsd@ubu.es
[b] Instituto Universitario de Química Organometálica “Enrique
Moles”, Unidad Asociada al C.S.I.C., Universidad de Oviedo,
c/ Julián Clavería 8, 33006 Oviedo, Spain
Fax: +34-985103446
E-mail: frodriguez@uniovi.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 1383–1386
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1383

R. Sanz, A. Martínez, J. M. Álvarez-Gutiérrez, F. Rodríguez
SHORT COMMUNICATION
use of 5 mol-% of AlCl3 the reaction had, after 24 h, given sponding oxidized ketone, along with 53% of the starting
a mixture of ether 2a and starting material 1a (80:20 ratio alkynol 1a (Table 1, Entry 6). All these encouraging results
1
determined by H NMR analysis of the crude product of led us to consider the possibility of using simple organic
the reaction; Table 1, Entry 5). With CeCl3·7H2O, after 36 h acids as catalysts. Evidently, if this process proceeded it
the reaction had produced 34% of 2a and 12% of the corre- would be a significant advance as it would avoid the use of
potentially toxic metallic species. To our delight, when we
performed the above reaction in the presence of PTS (p-
Table 1. Catalyst screening for ethyl etherification.[a]
toluenesulfonic acid monohydrate) or CSA (camphorsul-
fonic acid) (5 mol-%) as catalysts, the reactions cleanly af-
forded the propargylic ether 2a in short times and in essen-
tially quantitative yields (Table 1, Entries 7–9). Moreover,
dilute HCl (10 mol-%) also catalyzes this transformation
(Table 1, Entry 10). It should be remarked that, in these
mol-% cata-
lyst
Entry Catalyst
t [h]
%2a[b]
cases, the reaction is tolerant of air and moisture and so
can be conducted in an open flask and with direct use of
solvent without any previous drying treatment.
1
2
3
MoO2Cl2(dmf)2
MoO2Cl2(dmso)2
–
1
1
24
1
24
36
1
4
1
4
5
5
–
5
5
5
5
5
5
Ͼ95
Ͼ95
0
Ͼ95
80
In order to check the scope of this process, we performed
a set of experiments with several propargylic alcohols 1 and
different heteroatom-centered nucleophiles, such as
alcohols, thiols, amines, and amides in the presence of PTS
(5 mol-%) as catalyst (Table 2).[10] Starting from alkynols
1a–c, each containing an internal alkyne group, the reac-
tions gave the expected substitution compounds 2 in high
yields and short reaction times (ca. 1 h). We have applied
this methodology to the synthesis of propargylic ethers (En-
tries 1–3, 6–10 and 12–14), thioethers (Entries 4 and 15),
4
5
6
7
InCl3
AlCl3
CeCl3·7H2O
PTS
34
Ͼ95
Ͼ95[c]
Ͼ95
Ͼ95
8
9
PTS
CSA
10
HCl, 1M
10
[a] Reaction conditions: MeCN, 80 °C, EtOH (3 equiv.). [b] Yields
were determined by 1H NMR or GC-MS analysis of the crude
reaction mixture. [c] Run at room temp.
Table 2. Propargylic substitution of alkynols 1 with heteroatom nucleophiles.[a]
Entry
Alkynol
R1
Ph
R2
H
R3
Ph
R4XH
Product
Yield (%)[b]
1
2
3
4
5
6
7
8
1a
EtOH
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
76
74
80
67
75
78
PhCH2OH
CH2=CHCH2OH
CH3(CH2)11SH
PhSO2NH2
MeOH
CH2=CHCH2OH
MeOCH2CH2OH
(–)menthol
CHϵCCH2OH
4-NO2C6H4NH2
EtOH
CH2=CHCH2OH
ClCH2CH2OH
CH3(CH2)11SH
PhSO2NH2
EtOH
CH3(CH2)11SH
MeOH
1b
3-MeOC6H4
H
Ph
76
9
60[c]
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2j
2k
2l
73
81
75
63
83
66
1c
1d
Ph
Ph
H
H
Bu
H
2m
2n
2o
2p
2q
2r
2s
2t
58[d]
52[d]
75[e]
90[f]
86
1e
1f
1g
2-naphthyl
Ph
Me
H
Me
Me
H
Ph
Ph
EtOH
EtOH
CH3(CH2)11SH
EtOH
2u
2v
2w
70
1h
Ph
Ph
Ph
75[f][g]
[a] General reaction conditions: 3 equiv. of nucleophile in MeCN at reflux for 1 hour. [b] Isolated yields after chromatography based on
starting alkynol 1. [c] Obtained as a ca. 2:1 mixture of diastereoisomers. [d] 24 h were required for complete conversions. Small amounts
(Ͻ15%) of bis(1-phenylprop-2-ynyl) ether and cinnamaldehyde were also isolated. [e] 4 h were required for complete conversion. Small
amounts (Ͻ10%) of bis[1-(2-naphthyl)prop-2-ynyl] ether were also isolated. [f] Run at room temp. [g] A 10% yield of β-phenylchalcone
was also isolated.
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Eur. J. Org. Chem. 2006, 1383–1386

Metal-Free Catalytic Nucleophilic Substitution of Propargylic Alcohols
SHORT COMMUNICATION
amines (Entry 11), and amides (Entries 5 and 16). To our an attractive alternative for the construction of sp3–sp3 car-
delight, the reactions also proceeded effectively with ter- bon–carbon bonds without use of any metallic catalyst.
minal alkynols (1d, 1e), though significantly longer reaction
We then examined the propargylation of alkynols 1 with
times (4–24 hours) were required for complete conversions. aromatic and heteroaromatic compounds. We were pleased
This methodology is not limited to secondary benzylic sub- to find that the presence of 5 mol% of PTS efficiently cata-
strates, as shown by the reactions between tertiary alcohols lyzed the aromatic propargylation (Scheme 3). The reaction
1f or 1g and ethanol or dodecanethiol (Entries 20–22). proceeded efficiently with electron-rich arenes such as 1,3,5-
Interestingly, the reactivity of highly activated tertiary alkyn- trimethoxybenzene, affording compounds 4. Propargylation
ols such as 1h is complicated by the competing Meyer– of phenol took place without observation of any O-alkyl-
Schuster rearrangement[11] and isolation of ether 2w re- ation competitive process and through the para position,[15]
quired strict control of the temperature (RT), the reaction giving rise to p-substituted phenols 5. Heteroaromatic com-
time (30 min), and neutralization prior to the purification pounds such as furan and N-methylindole could also be
step (Entry 23).[12] Moreover, when the starting material propargylated with complete regioselectivity through the
was enantiomerically enriched propargylic alcohol 1a use of this catalytic system to provide functionalized hetero-
(94% ee)[13] the corresponding ethyl ether 2a was obtained cycles 6–7.
in a racemic form. All these results seem to indicate that
the reaction proceeds through the formation of a stabilized tal approach could be applied to multigram synthesis, 6.8 g
carbonium intermediate.[14]
Finally, in order to check whether this simple experimen-
of 2f (80% isolated yield) were easily prepared in one batch
The reactions described above for the metal-free catalytic from 8.1 g (34 mmol) of alkynol 1b.[16] This experiment
synthesis of heteroatom-substituted propargylic compounds demonstrates that the method is also of interest for the
undoubtedly represent a significant achievement as they preparation of at least moderate amounts of these interest-
provide a competitive method to the known strategies for ing compounds in a practicable manner.
the synthesis of these kinds of compounds. From the point
of view of organic synthesis, however, a major challenge is
the creation of new carbon–carbon bonds. With this idea in
mind, we turned our attention to the achievement of direct
Conclusions
In summary, we have found that simple organic acids cat-
alyze the direct propargylic substitution of hydroxy groups
by a range of heteroatom- and carbon-centered nucleo-
philes.[17] The reaction is tolerant of air and moisture and
gives water as the only byproduct. This metal-free strategy
represents a clean, environmentally friendly, and syntheti-
cally competitive alternative to the already established use
of metal complexes. We have also demonstrated that this
method is amenable to large scale synthesis. As the reaction
implies the use of very simple starting materials and cata-
lysts, and since the products obtained are of great interest,
this methodology may be expected to find wide application
in organic synthesis.[18] Current studies are being directed
to investigation of the reaction’s scope, mechanism, limita-
propargylic substitution of hydroxy groups with carbon-
centered nucleophiles. We first tried allyltrimethylsilane as
nucleophile and were pleased to find that the reaction took
place efficiently, affording the corresponding 1,5-enynes 3
in good yields (Scheme 2). This catalytic reaction provides
Scheme 2. Propargylation of alkynols 1 with allyltrimethylsilane.
Scheme 3. Propargylation of alkynols 1 with aromatic and heteroaromatic compounds.
Eur. J. Org. Chem. 2006, 1383–1386
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1385

R. Sanz, A. Martínez, J. M. Álvarez-Gutiérrez, F. Rodríguez
SHORT COMMUNICATION
Smith, L. A. Young, F. D. Toste, Org. Lett. 2004, 6, 1325–1327;
d) R. V. Ohri, A. T. Radosevich, K. J. Hrovat, C. Musich, D.
Huang, T. R. Holman, F. D. Toste, Org. Lett. 2005, 7, 2501–
2504.
tions, and applicability to the synthesis of some natural
products, together with the development of an asymmetric
version.
[7] After the submission of this paper, a related gold-catalyzed re-
action appeared see: M. Georgy, V. Boucard, J.-C. Campagne,
J. Am. Chem. Soc. 2005, 127, 14180–14181.
Experimental Section
[8] The ruthenium-catalyzed propargylic substitutions are believed
to proceed via allenylidene complex intermediates and so ter-
minal alkynes are required. For an interesting mechanistic
study, see: a) S. C. Ammal, N. Yoshikai, Y. Inada, Y. Nishibay-
ashi, E. Nakamura, J. Am. Chem. Soc. 2005, 127, 9428–9438.
However, a few examples involving the reactions of internal
alkynes have been reported: b) Y. Inada, Y. Nishibayashi, M.
Hidai, S. Uemura, J. Am. Chem. Soc. 2002, 124, 15172–15173;
c) Y. Nishibayashi, Y. Inada, M. Yoshikawa, M. Hidai, S. Ue-
mura, Angew. Chem. 2003, 115, 1533–1536; Angew. Chem. Int.
Ed. 2003, 42, 1495–1498; d) E. Bustelo, P. H. Dixneuf, Adv.
Synth. Catal. 2005, 347, 393–397.
General Procedure for PTS-Catalyzed Nucleophilic Substitutions of
Alkynols 1: A flask was charged with alkynol 1 (1 mmol), MeCN
(analytical grade, 5 mL) and the nucleophile (3 mmol for hetero-
atom nucleophiles and allyltrimethylsilane and 1.5 mmol for aro-
matics). PTS (5 mol-%) was added and the flask was heated at
80 °C. Reaction mixtures were maintained at reflux until comple-
tion as judged by TLC or GC-MS analysis of the mixture. The
solvent was removed under reduced pressure and the residue was
then purified by column chromatography (silica gel; hexane/ethyl
acetate), affording the corresponding product.
[9] a) R. Sanz, R. Aguado, M. R. Pedrosa, F. J. Arnáiz, Synthesis
2002, 856–858; b) R. Sanz, J. Escribano, R. Aguado, M. R.
Pedrosa, F. J. Arnáiz, Synthesis 2004, 1629–1632; c) R. Sanz, J.
Escribano, Y. Fernández, R. Aguado, M. R. Pedrosa, F. J. Ar-
náiz, Synlett 2005, 1389–1392.
[10] Although the reactions were conducted with 3 equiv. of the
corresponding nucleophile and 5 mol-% of PTS in acetonitrile
at reflux, we have observed that the reaction also takes place
at room temperature, with the catalyst loading decreased to
1 mol-% and with use of only 1 equiv. of nucleophile. Under
these conditions longer reaction times were required for com-
plete conversions.
[11] The Meyer–Schuster rearrangement usually needs strong acids
or metals as catalysts and elevated temperatures: a) S. Swanina-
than, K. V. Narayanan, Chem. Rev. 1971, 71, 429–438; b) C. Y.
Lorber, J. A. Osborn, Tetrahedron Lett. 1996, 37, 853–856; c)
T. Suzuki, M. Tokunaga, Y. Wakatsuki, Tetrahedron Lett. 2002,
43, 7531–7533.
Supporting Information (for details see the footnote on the first
page of this article): Experimental procedures and spectroscopic
data for all compounds and copies of the NMR spectra of the
crude product obtained from the multigram reaction between 1b
and methanol.
Acknowledgments
We gratefully thank the Ministerio de Educación y Ciencia and
FEDER (CTQ2004-08077-C02-02/BQU) for financial support.
A. M. thanks the Universidad de Burgos for a predoctoral fellow-
ship. F. R. and J. M. A. G. are grateful to the Ministerio de Educa-
ción y Ciencia of Spain (“Ramón y Cajal” contracts).
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[12]
Use of longer reaction times at room temp. (48 h) resulted in
complete conversion of the initially formed ether 2w to the cor-
responding rearranged α,β-unsaturated carbonyl derivative
(Meyer–Schuster rearrangement).
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[15] PPTS-catalyzed propargylation of phenols and naphthols re-
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[16] 1H and 13C NMR spectra of the crude product obtained from
this multigram reaction are included in the Supporting Infor-
mation.
[17] Other nucleophiles used in related works, such as diphenyl-
phosphane oxide or enol silyl ethers, are being studied in our
laboratories; a full detailed account will be provided in due
course.
[18] For a patent on the direct propargylic substitution in the pres-
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[3] T. J. Müller, Eur. J. Org. Chem. 2001, 2021–2033.
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Received: December 8, 2005
Published Online: January 26, 2006
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Eur. J. Org. Chem. 2006, 1383–1386