An acetylene zipper - Sonogashira reaction sequence for the efficient synthesis of conjugated arylalkadiynols

Article abstract of DOI:10.1016/j.tetlet.2013.02.066

We describe a new approach to the preparation of unsymmetrical arylalkadiynols, which is based on the isomerization of readily available internal alkadiynols into their terminal isomers followed by Sonogashira cross-coupling. The influence of the reaction conditions on the efficiency of the 'acetylene zipper' of alkadiynols is investigated. Unstable terminal diynols are used without isolation in Pd/Cu-catalyzed cross-couplings with iodoarenes bearing either electron-withdrawing or electron-donating substituents.

Full text of DOI:10.1016/j.tetlet.2013.02.066

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An acetylene zipper—Sonogashira reaction sequence for the efficient
synthesis of conjugated arylalkadiynols
Alexandra E. Kulyashova a, Viktor N. Sorokoumov a, Vladimir V. Popik b, Irina A. Balova a,
⇑
a Saint-Petersburg State University, 26 Universitetskij pr., Peterhoff, St. Petersburg 198504, Russia
b Department of Chemistry, University of Georgia, Athens, GA 30602, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a new approach to the preparation of unsymmetrical arylalkadiynols, which is based on the
isomerization of readily available internal alkadiynols into their terminal isomers followed by Sonogash-
ira cross-coupling. The influence of the reaction conditions on the efficiency of the ‘acetylene zipper’ of
alkadiynols is investigated. Unstable terminal diynols are used without isolation in Pd/Cu-catalyzed
cross-couplings with iodoarenes bearing either electron-withdrawing or electron-donating substituents.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 13 September 2012
Revised 1 February 2013
Accepted 20 February 2013
Available online xxxx
Keywords:
Diacetylene zipper
Terminal alkadiynols
Sonogashira cross-coupling
Arylalkadiynols
A significant number of natural products contain a diacetylenic
moiety. These diacetylenes display a broad spectrum of interesting
biological properties.1 In addition, diacetylenes, especially unsym-
metrical examples, represent important building blocks in organic
synthesis,2 in particular for the preparation of enynes2c and fused
heterocycles,2e as well as in supramolecular chemistry,3 biochem-
istry, and materials science.2d,4 Since the development of the Cad-
iot–Chodkiewicz heterocoupling5 of 1-haloalk-1-ynes with
terminal alkynes, this approach and its modifications,6 including
Pd-catalyzed transformations,6a,7 remain a popular method for
the synthesis of unsymmetrical diacetylenes. Another general ap-
proach to these structures is based on the selective desilylation
of 1,4-bis(trimethylsilyl)buta-1,3-diyne followed by alkylation
and/or cross-coupling reactions.8,9 Alternative methods allowing
access to an expanded collection of functionalized unsymmetrical
diynes and polyynes have been also proposed. For example, the
four-step synthesis of unsymmetrical 1-aryl(hetaryl/vinyl)-buta-
1,3-diynes using Fritsch–Buttenberg–Wiechell10 rearrangement of
the corresponding ethynyl substituted 1,1-dibromoolefins was de-
scribed by Tykwinski et al.11 We have previously reported a conve-
nient synthesis of 1-aryl(hetaryl)-alka-1,3-diynes by Sonogashira12
cross-coupling of alka-1,3-diynes. The latter were generated from
internal isomers via ‘diacetylene zipper’ reactions using lithium
2-aminoethylamide (LAETA) as a ‘super base’.13
iyne systems fused to heterocyclic cores,14 we have extended this
approach to the synthesis of arylalkadiynols. While the Sonogash-
ira cross-coupling is a very popular procedure for the alkynylation
of aryl or vinyl halides,15 terminal diacetylenes are rarely em-
ployed in this reaction, mainly due to their poor availability and
low stability. Terminal conjugated diacetylenes bearing a hydroxyl
group at the opposite end of the molecule are even more versatile
synthetic intermediates, as they can be utilized for the synthesis of
macrocyclic enediynes.14d,e Herein, we report the efficient prepara-
tion of arylalkadiynols using a sequential ‘acetylene zipper’ reac-
tion—Sonagashira coupling procedure. This method allows us to
avoid isolation of very unstable terminal alkadiynols.
Internal diacetylenic alcohols 3 and 4 were prepared in two-
steps from commercially available terminal acetylenes 1a,b and
propargyl alcohol (for primary alkadiynols 3a,b) or 2-methylbut-
3-yn-2-ol (for tertiary alcohol 4b) (Scheme 1).
Our initial efforts were focused on the optimization of the con-
ditions for the crucial prototropic isomerization of internal alkadiy-
R
H
R
OH
Cu+
Br2, KOH
R
H
Br
2a,b
R
n
n
n
H3C
H3C
H3C
OH
79−88%
64−77%
In connection with our investigations on the cyclizations of
functionalized buta-1,3-diynylarenes with the aim to obtain ened-
1a,b
3a,b, 4b
3 R = H,
n = 2 (a),
n = 3 (b)
4
R = CH3
⇑
Corresponding author. Tel.: +7 812 428 6733; fax: +7 812 428 6733.
E-mail address: balova.irina@chem.spbu.ru (I.A. Balova).
Scheme 1. Synthesis of internal alkadiynols 3 and 4.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.066
Please cite this article in press as: Kulyashova, A. E.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.02.066

2
A. E. Kulyashova et al. / Tetrahedron Letters xxx (2013) xxx–xxx
R R
R R
OH
n+1
R
1. LAETA
2. H2O
OH
+
R
H
n-1
n
H3C
H3C
OH
5b
3a,b, 4b
6a,b, 7b
3 R = H,
6 R = H,
4 R = CH3,
5 R = CH3,
n = 3 (b)
7 R = CH3,
n = 2 (a), n = 3 (b)
n = 2 (a), n = 3 (b)
Scheme 2. Isomerization of the internal alkadiynols.
nols (Scheme 2). Since terminal diynes decompose significantly
during isolation, 1H NMR spectroscopy was employed for analysis
of the products (see Supplementary data). Isomerization of tertiary
alcohol 4b under conditions previously described for alkadiynes,13
in THF with a four-fold excess of LAETA (Table 1, entry 1) did not
give the expected terminal isomer 7b. NMR data indicated that
the conjugated system of triple bonds had shifted only by one po-
sition giving the isomer 5b, isolated in a good yield. Formation of
homopropargylic isomers was previously observed for acetylene
alcohols16a and explained by their higher thermodynamic stability
under ‘acetylene zipper’ conditions.16b In contrast to alkadiynes,
alcohols 3 and 4 are deprotonated by LAETA to give alkoxide ions
and can form aggregates.17 Taking into account that diamines were
usually used as solvents for ‘acetylene zipper’ reactions of alky-
nols,16a,18 we hypothesized that employing ethylenediamine
(EDA) as a co-solvent might help to enhance the yield of the isom-
erization. Indeed, the desired terminal diacetylene 7b appeared in
the reaction mixture when EDA was used (Table 1, entry 2). A two-
fold increase in the amount of EDA led to no significant change in
the ratio of isomers 5b and 7b (Table 1, entry 3).
The best result was obtained when a 1:2 mixture of EDA/THF
was used. Under these conditions, conversion of the internal
diacetylene into the terminal isomer was complete and the desired
diynol 7b was obtained as the major product (Table 1, entry 4).
This observation indicates that the presence of EDA in the solvent
mixture was crucial for the success of the diynol ‘zipper’ reaction. It
was previously known that organolithium reagents as well as N-
lithiated species such as amides adopt oligomeric structures, and
additives are often used to enhance their reactivity. In particular,
the addition of amines promotes the breakdown of agglomerates
of organolithium compounds.19 Apparently, an excess of EDA is
necessary for achieving decomposition of LAETA–alkoxide aggre-
gates, which leads to an increase in the efficiency of triple bond
isomerization. Under optimized conditions, isomerization of pri-
mary alkadiynols 3a,b gave only terminal isomers 6a,b (Table 1,
entries 5 and 6). Reducing the concentration of amide from 1.4 to
1.2 M did not affect the outcome of the reaction, and only the ter-
minal isomer 6a was observed in the reaction mixture after 10 min
(Table 1, entry 7). Also, it should be mentioned that retro-Favorsky
reaction (elimination of acetone from dimethylpropargyl alcohols
with release of terminal alkadiynes) did not occur under the given
conditions.
excess of the terminal acetylenes due to competitive Glaser homo-
coupling in the presence of Cu(I) salts.15 Additionally, we found
that complete conversion of the more reactive iodoarene 8 re-
quired three equivalents of the starting internal alcohol 4, appar-
ently due to the low stability of terminal alkadiynols. The
Sonogashira cross-coupling reaction was complete in five hours,
giving product 13b in good yield (Table 2, entry 1). As expected,
the reaction of terminal alcohol 7 with 2-iodothioanisole (9) pro-
ceeded slowly, and was accompanied by significant polymeriza-
tion. 2-(Methylsulfanylphenyl)nona-5,7-diyn-1-ol (14b) was
isolated in moderate yield after 24 h (Table 2, entry 2). In the case
of primary alcohol 3b, a fivefold excess of diacetylene over iodoare-
nes 8 and 9 was used, and the reactions led to the desired arylalk-
adiynols 15b and 16b in similar yields (entries 3 and 4).
Next, we attempted the synthesis of arylalkadiynols bearing
amino groups at the ortho-position relative to the diacetylene moi-
ety. While it is known that Sonogashira coupling proceeds faster
with electron-poor aryl halides, we were surprised to observe no
conversion of starting iodide 10 containing a dimethylamino group
(Table 2, entry 5). However when the DIPA–DMF21 system was em-
ployed instead of conventional Et3N–THF for the cross-coupling,
product 17b was formed in a satisfactory yield (Table 2, entry 6).
The yield of arylalkadiynol 16b was also improved by using the
DIPA–DMF system (entry 7). An increase in the yield was obtained
by reducing the LAETA concentration during the first step of the
procedure. When the ‘diacetylene zipper’ of diynols 3a,b was per-
formed under the conditions of entry 7 (Table 1), the target aryl-
diynols 16a,b 18a, and 19a were obtained in very good yields
(Table 2, entries 8–11).22 It was also found that these conditions al-
lowed for the reduction of the amount of starting internal alcohol
from 5 to 3.5 equiv, and for the scale-up of the synthesis to 7.5 g of
diynols 3 without any loss of efficiency.
In summary, we have developed an efficient two-step protocol
for the preparation of arylalkadiynols. This approach employs the
prototropic isomerization of internal diacetylenic alcohols fol-
lowed by Sonogashira cross-coupling of the terminal isomers with
iodoarenes. The optimized conditions described here allow the
preparation of arylalkadiynols bearing either electron-withdraw-
Table 1
Isomerization of alkadiynols 3 and 4 (see Scheme 2)a
With an efficient method for the preparation of terminal diacet-
ylenes in hand, we turned our attention to the optimization of the
prototropic isomerization–Sonogashira cross-coupling sequence.
The ‘zipper’ reaction was conducted under the conditions of entry
4 in Table 1. The reaction mixtures were quenched with water to
decompose the lithium diacetylides, and were extracted with
Et2O. Solutions of alkadiynols 6, 7 were used in the coupling step
without further purification. Aryl iodides 8–12, with either elec-
tron-withdrawing or electron-donating substituents, or both, were
used in the second step to test the scope and limitations of this ap-
proach with respect to the preparation of arylalkadiynols
(Scheme 3, Table 2). Since tertiary alcohol 7 is more stable than pri-
mary analogs 6, we employed the former in the initial experiments.
Pd/Cu-catalyzed cross-coupling is usually carried out with an
Entry
Alkadiynol
EDA:THF (v/v)
Ratio of isomers (by 1H NMR)b
1
2
3
4
5
6
7
4b
4b
4b
4b
3b
3a
3a
0:1
1:8
1:3.5
1:2
1:2
1:2
1:2
5bc /—
5b/7b (1:1)
5b/7b (1:1)
7b
6b
6a
6a
a
Reaction conditions: 15–25 °C, 10 min, ratio LAETA: 3(4) was 4:1;
cLAETA = 1.38 M for entries 1–6, for entry 7 cLAETA = 1.20 M.
b
The ratio of isomeric alcohols was determined by the relative intensity of the
characteristic signals in the 1H NMR spectra: d 1.97 (terminal proton of isomer 7b
„CH) and d 2.42 (methylene group of isomer 5b „CH2C(CH3)2OH).
c
Isolated in 86% yield.
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A. E. Kulyashova et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
ArI
R R
OH
Y
R R
OH
n+1
1. LAETA
2. H2O
R
8 12
−
R
H
n+1
n
Pd0/Cu+1
32−87%
H3C
OH
x
6a,b 7b
3a,b, 4b
13 19
−
6
3
R = H,
R = H,
7
4
R = CH3,
R = CH3,
a
b
)
a
b
n = 2 ( ), n = 3 (
n = 2 ( ), n = 3 (
)
Scheme 3. Synthesis of arylalkadiynols by sequential ‘diacetylene zipper reactions’ of alkadiynols 3 and 4 and Pd/Cu-catalyzed cross-coupling (see Table 2).
Table 2
Synthesis of arylalkadiynols 13–19 (Scheme 3)20
Entrya
ArI
X
Y
Alkadiynols
R (n)
Base
Solvent
Product (yield %)
(ratio 3,4: ArI)
1
2
3
4
5
6
7
8
9
8
9
8
NO2
SMe
NO2
H
H
H
H
4b (3:1)
4b (3:1)
3b (5:1)
3b (5:1)
3b (5:1)
3b (5:1)
3b (5:1)
3b (3.5:1)
3a (3.5:1)
3a (3.5:1)
3a (3.5:1)
CH3 (3)
CH3 (3)
H (3)
H (3)
H (3)
H (3)
H (3)
H (3)
H (2)
H (2)
H (2)
Et3N
Et3N
Et3N
Et3N
Et3N
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
THF
THF
THF
THF
13b (70)
14b (32)
15b (61)
16b (52)
17b (0)
17b (61)
16b (64)
16b (89)
16a (87)
18a (82)
19a (85)
9
SMe
NMe2
NMe2
SMe
SMe
SMe
NMe2
NH2
10
10
9
9
9
COOMe
COOMe
H
H
H
COOEt
H
THF
DMF
DMF
DMF
DMF
DMF
DMF
10
11
11
12
a
The first step of the sequence was carried out under the conditions of entry 4 (Table 1) for entries 1–7; the conditions of entry 7 (Table 1) were applied for entries 8–11.
DIPA = 1-(2-hydroxypropylamino)propan-2-ol.
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from readily available starting materials.
Acknowledgments
We are thankful to Saint-Petersburg University for Research
Grants (12.38.14.2011, 12.37.128.2011). V.S. acknowledges finan-
cial support from a Grant of the President RF (MR-504.2011.3).
A.K. thanks the University of Georgia for SURO and SPbU for
12.42.315.2012 scholarships.
Supplementary data
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Supplementary data (experimental details, NMR, MS spectra, of
synthesized compounds and copies of NMR spectra)associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.02.066.
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A. E. Kulyashova et al. / Tetrahedron Letters xxx (2013) xxx–xxx
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Supplementary data) and yields refer to those of isolated products.
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22. Procedure for the synthesis of 16a. Under argon, Li (1.48 g, 0.21 mol) was added
gradually to a mixture of dry ethylenediamine (12.80 mL, 0.21 mol + 59.0 mL)
and THF (118.4 mL). The mixture was stirred untill the starting dark blue color
faded and a yellowish suspension of the lithium salt (cLAETA = 1.2 M) was
obtained. Then the mixture was cooled to 16 °C and internal diynol 3a (6.5 g,
0.053 mol) was added dropwise at 16–20 °C (carefully controlled), and the
resulting mixture stirred for 10 min. The mixture was poured onto ice and
extracted with Et2O (3 Â 100 mL). The combined organic layers were washed
with a saturated solution of NH4Cl (1 Â 100 mL), and brine (1 Â 100 mL) and
dried over anhydrous Na2SO4, concentrated (to 1/2 vol) under reduced
pressure and used in the next step.
Under argon, the obtained solution of the terminal diynol 6a was added to a
mixture of iodoarene 9 (3.80 g, 0.015 mol), Pd(PPh3)2Cl2 (0.53 g, 0.76 mmol),
PPh3 (0.40 g, 1.52 mmol) and DIPA (8.08 g, 60.8 mmol) in DMF (80 mL) and
stirred at 40 °C over 30 min. Then CuI (0.2 g, 1.05 mmol) was added and the
mixture was stirred overnight at 40 °C. The mixture was washed with NH4Cl
(2 Â 100 mL), H2O (1 Â 100 mL), and brine (2 Â 100 mL) and extracted with
EtOAc (3 Â 100 mL). The combined organic layers were dried over anhydrous
Na2SO4 and the solvents evaporated. The crude product was purified by flash
chromatography (5:1 hexane/EtOAc, silica gel, Rf = 0.18) to yield 16a (3.23 g,
87%) as a yellow oil.
Please cite this article in press as: Kulyashova, A. E.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.02.066