Practical synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides via conventional and decarboxylative copper-free Sonogashira coupling reactions

Article abstract of DOI:10.3762/bjoc.10.36

Two efficient protocols for the palladium-catalyzed synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides in the absence of copper were developed. A simple catalytic system consisting of Pd(OAc)2 and P(p-tol)3 using DBU as the base and THF as the solvent was found to be highly effective for the coupling reaction of 2-methyl-3-butyn-2-ol (4) with a wide range of aryl bromides in good to excellent yields. Analogously, the synthesis of aryl-2-methyl-3-butyn-2-ols was performed also through the decarboxylative coupling reaction of 4-hydroxy-4-methyl-2-pentynoic acid with aryl bromides, using a catalyst containing Pd(OAc)2 in combination with SPhos or XPhos in the presence of tetra-n-butylammonium fluoride (TBAF) as the base and THF as the solvent. Therefore, new efficient approaches to the synthesis of terminal acetylenes from widely available aryl bromides rather than expensive iodides and using 4 or propiolic acid rather than TMS-acetylene as inexpensive alkyne sources are described.

Full text of DOI:10.3762/bjoc.10.36

Practical synthesis of aryl-2-methyl-3-butyn-2-ols
from aryl bromides via conventional and
decarboxylative copper-free
Sonogashira coupling reactions
Andrea Caporale*1, Stefano Tartaggia1, Andrea Castellin2
and Ottorino De Lucchi1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 384–393.
1Dipartimento di Scienze Molecolari e Nanosistemi – Università Ca'
Foscari Venezia, Dorsoduro 2137, I-30123 Venice, Italy and 2F.I.S. –
Fabbrica Italiana Sintetici S.p.A., Alte di Montecchio Maggiore
(Vicenza), Viale Milano 26, I-36075 Vicenza, Italy
doi:10.3762/bjoc.10.36
Received: 18 November 2013
Accepted: 10 January 2014
Published: 12 February 2014
Email:
Andrea Caporale* - caporaleandrea74@gmail.com
Associate Editor: K. Itami
* Corresponding author
© 2014 Caporale et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkynes; decarboxylative couplings; Erlotinib; palladium; propiolic acid
Abstract
Two efficient protocols for the palladium-catalyzed synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides in the absence of
copper were developed. A simple catalytic system consisting of Pd(OAc)2 and P(p-tol)3 using DBU as the base and THF as the
solvent was found to be highly effective for the coupling reaction of 2-methyl-3-butyn-2-ol (4) with a wide range of aryl bromides
in good to excellent yields. Analogously, the synthesis of aryl-2-methyl-3-butyn-2-ols was performed also through the decarboxy-
lative coupling reaction of 4-hydroxy-4-methyl-2-pentynoic acid with aryl bromides, using a catalyst containing Pd(OAc)2 in
combination with SPhos or XPhos in the presence of tetra-n-butylammonium fluoride (TBAF) as the base and THF as the solvent.
Therefore, new efficient approaches to the synthesis of terminal acetylenes from widely available aryl bromides rather than expen-
sive iodides and using 4 or propiolic acid rather than TMS-acetylene as inexpensive alkyne sources are described.
Introduction
The Sonogashira coupling reaction of aryl or alkenyl halides The Sonogashira coupling reaction is usually carried out under
with terminal acetylenes is the most straightforward method for Pd/Cu catalysis, in which the palladium has the function to
the preparation of substituted alkynes [1-6], which are exten- promote the cross-coupling of an aryl fragment, added via
sively used as building blocks in a great number of applications oxidative addition of the corresponding halide, with an alkynyl
including the synthesis of pharmaceuticals [7-9], natural prod- residue to provide a disubstituted acetylene after reductive elim-
ucts and organic functional materials [10-13].
ination. The activated acetylide species for the coupling process
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Beilstein J. Org. Chem. 2014, 10, 384–393.
is generated from the reaction of a terminal alkyne with copper couplings have been reported in the recent literature [47-65].
in the presence of a base and is transferred on the palladium site The convenience in using propiolic acid as the alkyne source in
via transmetallation.
the synthesis of symmetrical and unsymmetrical diary-
lacetylenes resides not only in its low cost, but also in the possi-
In order to improve the efficacy of the reaction, several variants bility to carry out a conventional and a decarboxylative Sono-
have been introduced to perform efficiently this reaction with gashira coupling reaction in sequence at the two sp carbons with
regard to synthetic and industrial aspects, including protocols in two different aryl halides. Therefore a disubstituted alkyne can
aqueous media [14-17], amine-free [18] or solvent-free condi- be obtained in a one-pot protocol with a considerable reduction
tions [19]. Moreover efficient reusable Pd catalysts [20-24] and of synthetic and purification steps with respect to traditional
even palladium-free methodologies [25-27] were developed. procedures [51,52,62]. Instead, when looking to the preparation
Copper-free reaction protocols [28-41] are highly promising for of terminal alkynes from propiolic acid derivatives, the
industrial applications as the presence of copper could lead to Cu-catalyzed protodecarboxylation of alkynoic acids [67,68] or
the formation of diyne byproducts, causing an irreversible loss the Pd-catalyzed decarboxylation of allyl propiolates [69] have
of precious material, and complicates the recycling of the palla- been reported, but these methods are limited to a narrow class
dium catalyst since the two metals are difficult to separate.
of substrates and are not well suited for the preparation of aryl
alkynes. More recently an optimized protocol for the synthesis
Sonogashira reactions can be used for the syntheses of terminal of terminal arylalkynes from propiolic acid has been reported
alkynes from aryl halides through the coupling with an alkyne by Lee, in which the Pd-catalyzed coupling of propiolic acid
source such as trimethylsilylacetylene (TMSA) or 2-methyl-3- with an aryl iodide is followed by the addition of the Cu-cata-
butyn-2-ol (4) in presence of a Cu/Pd bimetallic catalyst, fol- lyst, which promotes the protodecarboxylation of the arylpropi-
lowed by the basic cleavage of the protecting group [42-46]. olic acid intermediate to the desired alkyne in good yields [70].
Terminal alkynes are often used as starting materials for the
synthesis of disubstituted acetylenes through a second coupling Acetylenic compounds and Sonogashira coupling reactions
process with another aryl halide.
have found many applications in the synthesis of pharmaceu-
tical substances. During the investigation about a possible alter-
Decarboxylative couplings have also been reported as an effi- native preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol
cient synthetic tool for the synthesis of disubstituted alkynes. In (2a) to improve a key-step in the synthesis of Erlotinib, an
fact, the use of propiolic acid as an alkyne source has opened important anticancer pharmaceutical intermediate [71] and a
new possibilities in the synthesis of acetylenic compounds, promising anti-Alzheimer [72], we found that the Pd/Cu-
since many examples leading to diaryl- (sp–sp2 coupling), catalyzed Sonogashira coupling reaction of 3-bromoaniline (1a)
benzyl- (sp–sp3 coupling) and diaryl diacetylenes (sp–sp with 4 is the actual industrial process for the synthesis of 2a in
coupling) in addition to examples of carbon-heteroatom high yield [73-75] (Scheme 1).
Scheme 1: Conventional (from the left) and decarboxylative (from the right) Pd-catalyzed Sonogashira coupling reactions for the preparation of 4-(3-
aminophenyl)-2-methyl-3-butin-2-ol (2a), which is used as an intermediate for the synthesis of Erlotinib hydrochloride (3).
385

Beilstein J. Org. Chem. 2014, 10, 384–393.
However, when the reaction is performed at industrial scale the presence of TBAF (tetrabutylammonium fluoride) as the base.
presence of copper creates several problems in particular during After using different solvents, we found that THF provided the
the purification step. Moreover, the use of copper in Sono- best results with regard to toluene and more polar media such as
gashira reactions should be avoidable because of unwanted side DMF, affording the product in 61% yield (Table 1, entries 1–3).
homo-couplings of the acetylenic substrate, causing an irre- The use of inorganic bases as well as common organic amines,
versible loss of precious starting material. Therefore, the typically employed in conventional Pd/Cu Sonogashira
Pd-catalyzed coupling reaction of 4 or a propiolic acid deriva- coupling protocols, resulted in poor yields of our desired prod-
tive with 3-bromoaniline, in order to approach the synthesis of uct (Table 1, entries 4–6). Piperidine, which has been reported
3-aminophenylacetylene without the use of copper, would be to efficiently perform copper-free coupling reactions of 4 with
highly desiderable [76].
polycyclic aryl bromides [77], gave only 17% yield with our
substrate (Table 1, entry 6). Instead, a decisive increase of the
Although many examples of copper-free Sonogashira reactions yield was observed by replacing TBAF with DBU, which
between aryl halides and terminal alkynes for the synthesis of furnished product 2a in 84% yield (Table 1, entry 7). A further
disubstituted acetylenes have been reported in the literature [9], improvement was found by modifying the catalyst with
few specific protocols for 4 were presented [77-79]. Successful different ligands (Table 1, entries 7–11). In fact, changing of
copper free synthesis of 4-aryl-2-methyl-3-butyn-2-ols from PPh3 with P(p-tol)3 allowed to obtain 2a in 89% yield (Table 1,
aryl bromides have been performed by carrying out the reaction entry 9), whereas other monodentate or chelating phosphines
in piperidine as the solvent [39,78] or by using aminophos- displayed a lower efficiency. Pd sources other than Pd(OAc)2
phines [18] as well as phenanthryl imidazolium carbenes as the were also used but did not show positive effects.
catalyst ligands [79]. A more practical methodology has been
reported by Shirakawa in which a Pd(OAc)2/PPh3 catalyst
Table 1: Synthesis of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol-from
system in DMSO and in the presence of K3PO4 as the base was
able to couple aryl bromides with terminal alkynes, including a
couple of examples with 2-methyl-3-butyn-2-ol, in moderate
yield [35]. Two simple reaction protocols for the copper-free
coupling of 4 have been also reported for iodo nitroxides [30]
and cyclopropyl iodides [29].
3-bomoaniline and 2-methyl-3-butyn-2-ol.a
Herein, we present two practical and very efficient synthetic
methods for the preparation of aryl-2-methyl-3-butyn-2-ols
from aryl bromides via Pd-catalyzed conventional and decar-
boxylative coupling reactions by using 4 or 4-hydroxy-4-
methyl-2-pentynoic acid as the alkyne sources and without the
use of copper. These methods have been optimized for the syn-
thesis of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol, which has
never been prepared through a Cu-free coupling process and
which is also a pharmaceutical intermediate for Erlotinib.
Entry Solvent
Base
Ligand
Yield (%)
1
toluene
THF
DMF
THF
THF
THF
THF
THF
THF
THF
THF
TBAF
TBAF
TBAF
K2CO3
NEt3
PPh3
PPh3
PPh3
PPh3
PPh3
32
61
9
2
3
4
14
5
5
6
piperidine PPh3
17
84
75
89
45
50
7
DBU
DBU
DBU
DBU
DBU
PPh3
8
P(p-FC6H4)3
P(p-tol)3
P(o-tol)3
dppe
The present work provides also a more detailed description
about the coupling process and a more extended rection scope
that was not included in a previous patent application by our
group, in which the decarboxylative coupling reaction for the
synthesis of intermediate 2a has been firstly described [76].
9
10
11
aReaction conditions: 1a (1.0 mmol), 4 (1.2 mmol), Pd(OAc)2
(0.03 mmol), ligand (6 mol %), base (3 equiv), 6 h, 80 °C. Yields were
determined by GC using tetradecane as an internal standard.
Results and Discussion
In order to perform efficiently the palladium-catalyzed coupling
reaction between 3-bromoaniline (1a) and 4 to give 2-methyl-4-
(3-aminophenyl)-3-butyn-2-ol (2a) (Table 1), we screened Having thus found an optimized method for the cooper free
different bases, solvents and ligands in the absence of copper. palladium-catalyzed coupling of 3-bromoaniline (1a) with
We firstly examined the coupling reaction using a catalytic 2-methylbut-3-yn-2-ol (4), we next examined wherever this
system based on palladium acetate and triphenylphosphine in protocol could be applied to a more general class of substrates.
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Beilstein J. Org. Chem. 2014, 10, 384–393.
As stated in Table 2, good to excellent yields were obtained by Bromobenzenes bearing a methyl groups in the ortho, meta and
using different aryl bromides including electron-rich, electron- para positions gave the corresponding products in similar good
poor, sterically crowded and heterocyclic derivatives. More- yields. Thus, the reaction can be applied to a wide substrate
over, the coupling reaction seems to be very efficient and selec- range witnessing the attractiveness and the generality of this
tive with regard to different functional groups placed on the aryl protocol. It is also worth noting that these conditions are also
bromide, including acetamido, dimethylamino, methoxy, highly practical and well suited to scale-up the reaction, since
chloro, fluoro, trifluoromethyl, nitro, methoxycarbonyl and inexpensive 4 can be efficiently coupled with aryl bromides
cyano groups. Bromonaphthalene (1j) and 3-bromopyridine instead of iodides by using common solvents and ligands for the
(1n) reacted smoothly.
palladium catalyst.
Table 2: Copper-free palladium-catalyzed coupling of 2-methylbut-3-yn-2-ol (4) with aryl bromides.a
Entry
ArBr 1
Product 2
Yield Entry
(%)
ArBr 1
Product 2
Yield
(%)
1
86
10
95
1j
1a
2j
2a
2
3
95
73
11
12
96
96
1b
1c
1k
2b
2c
2k
1l
2l
4
5
89
70
13
14
89
84
1m
1d
1e
2m
2d
2e
1n
2n
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Beilstein J. Org. Chem. 2014, 10, 384–393.
Table 2: Copper-free palladium-catalyzed coupling of 2-methylbut-3-yn-2-ol (4) with aryl bromides.a (continued)
6
7
80
89
15
77
1f
1o
1p
1q
2f
2o
2p
16
17
72
92
1g
1h
1i
2g
2h
2i
8
9
87
94
2q
aReaction conditions: 1a–q (1.0 mmol), 2-methylbut-3-yn-2-ol (4) (1.2 mmol), Pd(OAc)2 (3 mol %), P(p-tol)3 (6 mol %), DBU (3 mmol), 80 °C, 6 h.
Yields refer to isolated products.
The copper-free synthesis of 4-aryl-2-methyl-3-butyn-2-ols was with the reported data, tetrabutylammonium fluoride (TBAF)
also approached through a decarboxylative coupling reaction in [64,66] was found to be able to promote the decarboxylative
which a derivative of propiolic acid (5) was used as the alkyne coupling at 80 °C (Table 3, entry 5) whereas Cs2CO3 [63], CsF
source. In order to prevent the possible double coupling process or organic amines were less effective in promoting this reaction
due to the high reactivity of the terminal C(sp)-H, the protec- (Table 3, entries 1–4).
tion of the acetylenic proton of 5 was necessary. Analogously to
acetylene [80,81], the protection of propiolic acid with acetone The use of bulky electron-rich biarylphosphines as ligands for
was carried out in presence of an excess of KOH (6.0 equiv) at the palladium catalyst seems also to play a crucial role in
room temperature (Scheme 2).
promoting the coupling reaction. In fact, SPhos (Table 3, entry
5) resulted the best ligand with respect to XPhos (Table 3, entry
7), whereas other simple monodentate phosphines, such as
Pt-Bu3 or PPh3, seem not to be able to promote efficiently the
reaction (data not shown). The change of the Pd source to
Pd2(dba)3 led to a further increase of the yield up to 89%
(Table 3, entry 8), while other precursors decreased the perfor-
mances of the system. Concerning the solvent media, similar
yields were obtained using THF or NMP (Table 3, entries 5 and
6), but when toluene or dioxane were used, the yields were not
satisfactory.
Scheme 2: Protection of propiolic acid with acetone.
The screening of the optimal palladium catalyst for the
Pd-catalyzed coupling reaction of 3-bromoaniline with With an optimized system for the coupling of 6 with
4-hydroxy-4-methyl-2-pentynoic acid (6) was studied by using m-bromoaniline in hand, we next investigated the scope of the
different bases, ligands and Pd sources (Table 3). In accordance reaction (Table 4).
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Beilstein J. Org. Chem. 2014, 10, 384–393.
Table 3: Palladium-catalyzed coupling reaction of 4-hydroxy-4-methyl-2-pentynoic acid and m-bromoaniline.a
Entry
Solvent
Base
Pd
Ligand
Yield (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
NMP
THF
THF
THF
Cs2CO3
CsF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
(PdallylCl)2
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
XPhos
SPhos
SPhos
5
7
NH(iPr)2
DBU
4
42
80
76
55
89
79
TBAF
TBAF
TBAF
TBAF
TBAF
aReaction conditions: 1a (0.5 mmol), 6 (0.63 mmol), Pd source (5 mol %), ligand (7.5 mol %), base (3 equiv), 14 h, 80 °C. Yields were determined by
GC using tetradecane as an internal standard.
Table 4: Palladium catalyzed coupling of 4-hydroxy-4-methyl-2-pentynoic acid (6) with aryl bromides.a
Entry
ArBr 1
Product 2
Yield (%) Entry
ArBr 1
Product 2
Yield (%)
1
79 (86)b
7
72
1h
1a
2h
2a
2
80
8c
68
1i
1b
2i
2b
3
69
9
53
1j
1d
2j
2d
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Table 4: Palladium catalyzed coupling of 4-hydroxy-4-methyl-2-pentynoic acid (6) with aryl bromides.a (continued)
4
5
6
56
78
82
10c
11c
12c
25
61
80
1e
1k
1n
2e
2k
2n
1f
2f
1g
1o
2g
2o
aReaction conditions: 1 (0.5 mmol), 4-hydroxy-4-methyl-2-pentynoic acid (6) (0.63 mmol), Pd(OAc)2 (5 mol %), SPhos (7.5 mol %), TBAF·3H2O
(1.5 mmol), 80 °C, 14 h. Yields refer to isolated products. bPd2(dba)3 was used instead of Pd(OAc)2. c4-Hydroxy-4-methyl-2-pentynoic acid (1 mmol)
and XPhos instead of SPhos were used.
A variety of aryl bromides bearing electron-rich, electron- from protected terminal alkyne even under such mild condi-
neutral and electron-poor substituents were coupled with tions and therefore, the terminal alkyne generated in situ
4-hydroxy-4-methyl-2-pentynoic acid (6) affording the corres- couples with another molecule of the starting aryl bromide to
ponding products in good yields. As can be seen from the exam- provide the symmetrical acetylene.
ples listed in Table 4 several functional groups were tolerated
including acetamido, methoxy and nitro groups. The reaction Finally, it is worth noting that the preparation of product 2a has
has been applied also to heterocyclic and polycyclic aryl bro- been also reported through the acid hydrolysis of the acetamido
mides.
group of 2b or by the reduction of the nitro group of 2o [76],
however the direct coupling of 3-bromoaniline with 4 or 6
A little modification with respect to 3-bromoaniline (1a) was clearly remains the most efficient approach to the synthesis of
necessary in order to successfully apply the protocol to all 3-ethynylaniline.
substrates used for the synthesis of 4-aryl-2-methyl-3-butyn-2-
ols through the decarboxylative coupling approach. In fact, Conclusion
electron rich aryl bromides reacted smoothly with 6 when using Two simple and efficient protocols for the preparation of aryl-2-
a system containing Pd(OAc)2/SPhos as the catalyst [82], methyl-3-butyn-2-ols from aryl bromides, which are inexpen-
TBAF as the base in THF as solvent. The corresponding sive intermediates for the preparation of terminal alkynes, have
alkynes were therefore obtained in good yields (60–80% range), been described. A copper-free, palladium catalyst generated
especially for those substrates bearing methyl, methoxy and from Pd(OAc)2 and P(p-tol)3 allowed the coupling of aryl bro-
amino groups (Table 4, entries 1–8). However, in the case of mides with 4 in THF. The use of DBU as the base seems to play
bromobenzene and aryl bromides bearing electron withdrawing a crucial role to efficiently perform this coupling reaction on a
groups, the corresponding products were obtained with satisfac- wide scope of substrates without the use of copper. Moreover,
tory yields only when using 2 equiv of 4 with respect to the sub- the palladium-catalyzed decarboxylative coupling reaction of
strate and replacing SPhos with XPhos as ligand for the palla- 4-hydroxy-4-methyl-2-pentynoic acid with aryl bromides for
dium catalyst (Table 4, entries 9–12). In these cases we the preparation of aryl-2-methyl-3-butyn-2-ols has been investi-
observed also the formation of the symmetrical diarylacetylene gated. The decarboxylative coupling was carried out by using a
as byproduct derived from the starting aryl bromides in a 2–5% catalyst generated in situ from Pd(OAc)2 and a bulky electron-
yield range. Likely, the acetone protecting group is cleaved rich phospine, such as SPhos or XPhos, in THF as the solvent
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Beilstein J. Org. Chem. 2014, 10, 384–393.
and in presence of TBAF as the base. By approaching the syn- with alternating vacuum and nitrogen cycles, a degassed solu-
thesis of aryl-2-methyl-3-butyn-2-ols through decarboxylative tion of TBAF∙3H2O (0.47 g, 1.5 mmol) in THF (3 mL) was
coupling reactions of 4-hydroxy-4-methyl-2-pentynoic acid, we added. Aryl bromides 1a,b, 1d–h and 1j (0.5 mmol) were added
found a good compatibility with differently substituted aryl bro- via syringe (solid aryl bromides were added as solution in
mides.
degassed THF) and the mixture was stirred at 80 °C for 14 h.
After cooling to rt the mixture was diluted with water (20 mL)
and extracted with AcOEt (3 × 20 mL). The combined organic
Experimental
All reactions, if not stated otherwise, were performed in oven- extracts were washed with H2O (20 mL), saturated aqueous
dried glassware under an argon atmosphere containing a teflon- NaCl (20 mL), dried over MgSO4 and concentrated in vacuum.
coated stirring bar and a dry septum. Chemicals and solvents The crude product was purified by silica gel chromatography
were either purchased (puriss. p.a.) from commercial suppliers (eluant cyclohexane/Et2O or EtOAc gradient) affording the
or purified by standard techniques. All reactions were moni- corresponding products 2a,b, 2d–h and 2j.
tored by GC using tetradecane as an internal standard. Response
General procedure for the preparation of
factors of the products with regard to tetradecane were obtained
experimentally by analyzing known quantities of the arylalkynes 2i, 2k, 2n and 2o (method C)
substances. GC analyses were carried out using an HP-5 capil- An oven-dried 20 mL Schlenk tube equipped with a magnetic
lary column (phenyl methyl siloxane, 30 m × 320 × 0.25, 100/ stirring bar and a rubber septum was charged with Pd(OAc)2
2.3-30-300/3, 2 min at 50 °C, heating rate 25 °C/min, 3 min at (5.6 mg, 25 µmol), 2-Dicyclohexylphosphino-2′,4′,6′-triiso-
250 °C). Column chromatography was performed with propylbiphenyl (17.9 mg, 37.5 µmol), and 4-hydroxy-4-methyl-
230–400 mesh silica-gel. NMR spectra were obtained on a 2-pentynoic acid (6, 128 mg, 1.00 mmol). After purging the
Bruker AVANCE 300 spectrometer (300 MHz) using CDCl3 as vessel with alternating vacuum and nitrogen cycles, a degassed
solvent, 300 MHz and 75 MHz, respectively. Mass spectral data solution of TBAF∙3H2O (0.47 g, 1.5 mmol) in THF (3 mL) was
were acquired on a Trace GC–MS 2000 ThermoQuest. Melting added. Aryl bromides 1i, 1k, 1n and 1o (0.5 mmol) were added
points were measured on a Büchi 535.
via a syringe (solid aryl bromides were added as solution in
degassed THF) and the mixture was stirred at 80 °C for 14 h.
After cooling to rt the mixture was diluted with water (20 mL)
and extracted with AcOEt (3 × 20 mL). Combined organic
General procedure for the preparation of
arylalkynes 2a–q (method A)
An oven-dried 20 mL Schlenk tube equipped with a magnetic extracts were washed with H2O (20 mL), saturated aqueous
stirring bar and a rubber septum was charged with Pd(OAc)2 NaCl (20 mL), dried over MgSO4 and concentrated in vacuum.
(6.7 mg, 30 µmol) and tri(p-tolyl)phosphine (18.2 mg, The crude product was purified by silica gel chromatography
60 µmol). After purging the vessel with alternating vacuum and (eluant cyclohexane/Et2O or EtOAc gradient) affording the
nitrogen cycles, degassed THF (3 mL), 1,8-diazabicycloundec- corresponding products 2i, 2k, 2n and 2o.
7-ene (450 µL, 3.0 mmol), 2-methylbut-3-yn-2-ol (120 µL,
1.24 mmol) and aryl bromides 1a–q (1 mmol) were added via
Supporting Information
syringe (solid aryl bromides were added as solution in degassed
THF) and the mixture was stirred at 80 °C for 6 h. After cooling
Supporting Information File 1
to rt the mixture was diluted with water (20 mL) and extracted
with AcOEt (3 × 20 mL). The combined organic extracts were
washed with H2O (20 mL), saturated aqueous NaCl (20 mL),
dried over MgSO4 and concentrated in vacuum. The crude
product was purified by silica gel chromatography (eluant
hexane/Et2O gradient) affording the corresponding products
2a–q.
Description of all procedures and characterization data of
all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-36-S1.pdf]
Acknowledgements
We gratefully acknowledge MIUR (Rome) within the national
PRIN framework and FIS for financial support and for the
generous donation of precious materials.
General procedure for the preparation of
arylalkynes 2a,b, 2d–h and 2j (method B)
An oven-dried 20 mL Schlenk tube equipped with a magnetic
stirring bar and a rubber septum was charged with Pd(OAc)2
(5.6 mg, 25 µmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-
biphenyl (15.4 mg, 37.5 µmol) and 4-hydroxy-4-methyl-2-
pentynoic acid (6, 80 mg, 0.63 mmol). After purging the vessel
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