A convenient negishi protocol for the synthesis of glycosylated oligo(ethynylene)s

Article abstract of DOI:10.1021/ol801807a

(Chemical Equation Presented) A convenient and efficient sp-sp carbon heterocoupling protocol based on the Negishi reaction was developed, in which the required zinc diacetylide was generated from 1,4-bis(trimethylsilyl) butadiyne in situ and reacted with a bromoacetylene in apolar solvent mixtures. The method has been applied to the synthesis of unsymmetric glycosylated and symmetric diglycosylated oligo(ethynylene)s up to the octa(ethynylene).

Full text of DOI:10.1021/ol801807a

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4525-4528
A Convenient Negishi Protocol for the
Synthesis of Glycosylated Oligo(ethynylene)s
Tobias N. Hoheisel and Holger Frauenrath*
ETH Zu¨rich, Department of Materials, Wolfgang-Pauli-Str. 10, HCI H515,
8093 Zu¨rich, Switzerland
frauenrath@mat.ethz.ch
Received August 4, 2008
ABSTRACT
A convenient and efficient sp-sp carbon heterocoupling protocol based on the Negishi reaction was developed, in which the required zinc
diacetylide was generated from 1,4-bis(trimethylsilyl)butadiyne in situ and reacted with a bromoacetylene in apolar solvent mixtures. The
method has been applied to the synthesis of unsymmetric glycosylated and symmetric diglycosylated oligo(ethynylene)s up to the
octa(ethynylene).
Oligo(ethynylene)s are intriguing targets both because of their
nonlinear optical properties and as model compounds for the
hitherto unknown carbon allotrope carbyne.1-8 While most
investigations to date have focused on stable derivatives,
research in our own group aims at exploiting their inherent
reactivity in order to use amphiphilic oligo(ethynylene)s as
energy-rich molecular precursors for hierarchically structured
carbon materials.
Chodkiewicz10 and the homocoupling reaction under Hay
conditions.11 While the former protocol has been applied in the
synthesis of unsymmetric tri-, tetra-, and pentaynes,6,12-15 the
latter is often used as a final step and has allowed for the
construction of molecules up to the hexadecayne.6,15-17
Other synthetic pathways toward unsymmetric molecules
have transferred typical Pd-catalyzed sp-sp2 cross-coupling
protocols to sp-sp carbon coupling reactions. For example,
conditions analogous to the Sonogashira-Hagihara reaction18
have proved to be very useful and were applied in the
synthesis of oligo(ethynylene)s by several research
groups.19-23 The Negishi reaction, on the other hand, found
Although several protocols for the preparation and elongation
of oligo(ethynylene)s exist,9 the most commonly used methods
remain the heterocoupling protocol according to Cadiot and
(1) Szafert, S.; Gladysz, J. A. Chem. ReV. 2003, 103, 4175–4205
(2) Dembinski, R.; Bartik, T.; Bartik, B.; Jaeger, M.; Gladysz, J. A.
J. Am. Chem. Soc. 2000, 122, 810–822
(3) Diederich, F. Nature 1994, 369, 199–207
.
.
(10) Chodkiewicz, W.; Cadiot, P. Compt. Rend. 1955, 241, 1055–1057.
(11) Hay, A. S. J. Org. Chem. 1962, 27, 3320–3321.
.
(4) Lagow, R. J.; Kampa, J. J.; Wei, H.-C.; Battle, S. L.; Genge, J. W.;
Laude, D. A.; Harper, C. J.; Bau, R.; Stevens, R. C.; Haw, J. F.; Munson,
(12) Bohlmann, F.; Herbst, P.; Gleinig, H. Chem. Ber. 1961, 94, 948–
957
.
E. Science 1995, 267, 362–367
(5) Schermann, G.; Grosser, T.; Hampel, F.; Hirsch, A. Chem.sEur. J.
1997, 3, 1105–1112
(6) Gibtner, T.; Hampel, F.; Gisselbrecht, J.-P.; Hirsch, A. Chem.sEur.
.
(13) Eastmond, R.; Walton, D. R. M. Tetrahedron 1972, 28, 4591–4599
(14) Okada, S.; Hayamizu, K.; Matsuda, H.; Masaki, A.; Nakanishi, H.
Bull. Chem. Soc. Jpn. 1991, 64, 857–863
(15) Bartik, T.; Bartik, B.; Brady, M.; Dembinski, R.; Gladysz, J. A.
Angew. Chem., Int. Ed. 1996, 35, 414–417
(16) Eastmond, R.; Johnson, T. R.; Walton, D. R. M. Tetrahedron 1972,
28, 4601–4616
(17) Johnson, T. R.; Walton, D. R. M. Tetrahedron 1972, 28, 5221–
.
.
.
J. 2002, 8, 408–432
.
.
(7) Eisler, S.; Slepkov, A. D.; Elliott, E.; Luu, T.; McDonald, R.;
Hegmann, F. A.; Tykwinski, R. R. J. Am. Chem. Soc. 2005, 127, 2666–
.
2676
.
(8) Luu, T.; Elliott, E.; Slepkov, A. D.; Eisler, S.; McDonald, R.;
Hegmann, F. A.; Tykwinski, R. R. Org. Lett. 2005, 7, 51–54
5236.
.
(18) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
(9) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632–2657.
4467–4470.
(19) Wityak, J.; Chan, J. B. Synth. Commun. 1991, 21, 977–979
.
10.1021/ol801807a CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

Scheme 1
.
Model Reaction for the Optimization of the
Table 1. Results of (A) the Sonogashira-type and (B) the
Negishi-type Coupling Reactions in the Synthesis of 3
Heterocoupling Reactions Analogous to the Sonogashira and
Negishi Protocolsa
entry
methoda
X (1)
Y (2)
conditionsc
yieldd (%)
1
2
A
A
A
A
A
A
A
A
B
B
B
B
B
B
H
H
H
H
H
H
I
Br
I
I
I
I
a
b
a
b
c
d
a
a
e
f
g
g
h
i
23
14
33
35
34
22
16
7
23
30
40
26
48
80
I
3
Br
4
Br
5
Br
6
Br
7
H
8
H
9
TMSb
TMSb
TMSb
TMSb
TMSb
TMSb
10
11
12
13
14
Br
Br
Br
a Sonogashira-type couplings (method A) and Negishi-type couplings
(method B). b In the case of the Negishi couplings, the Zn-organyl was generated
from bis(trimethylsilyl)butadiyne 2d in situ by addition of MeLi·LiBr, followed
by ZnCl2 in THF; the obtained reaction mixture was then applied in the actual
heterocoupling reaction. c Reaction conditions and reagents: (a) 2 mol % of
PdCl2(PPh3)2, 10 mol % of CuI, DIPA, THF, 0 °C; (b) 2 mol % of Pd(PPh3)4,
10 mol % of CuI, DIPA, THF, 0 °C; (c) 5 mol % of PdCl2(PPh3)2, 10 mol %
of CuI, DIPA, THF, 0 °C; (d) 3 mol % of Pd2dba3, 2.5 mol % of CuI, 0.2
equiv of LiI, 2.8 equiv of 1,2,2,5,5-pentamethylpiperidine, DMSO, rt; (e) 5
mol % of Pd(PPh3)4, THF, rt; (f) 5 mol % of PdCl2(dppf)·DCM, THF, 0 °C;
(g) 5 mol % of PdCl2(dppf)·DCM, THF/toluene (3:7 v/v), rt; (h) 5 mol % of
aFor detailed experimental conditions and yields, see Table 1.
entry into the synthesis of oligoynes by way of dehydroha-
logenation of ꢀ-haloenynes.24-26 However, the typical
Negishi conditions have rarely been directly applied to sp-sp
carbon cross-coupling reactions.27-29 Commonly observed
side products in all the heterocoupling protocols mentioned
above are the homocoupling and the so-called selfcoupling
products, which are formally derived from the mutual
reaction of two terminal alkynes or two haloacetylenes,
respectively. Tykwinski and co-workers devoted considerable
effort to circumvent this problem and developed an alterna-
tive method for the synthesis of oligo(ethynylene)s based
on the Fritsch-Buttenberg-Wiechel (FBW) rearrange-
ment.7,8,30,31
In the present investigation, we developed a convenient and
efficient sp-sp heterocoupling protocol on the basis of the
Negishi reaction as a mild and copper-free alternative to existing
protocols. For this purpose, different conditions analogous to
the Sonogashira and Negishi coupling reactions were tested,
varying the haloacetylene, the Pd catalyst, the solvent, and the
reaction temperature. The generation of a zinc diacetylide from
a stable trimethylsilyldiacetylene in situ, and its reaction with
a bromoacetylene in an apolar solvent cleanly furnished the
desired heterocoupling product in high yields. The optimized
PdCl2(dppf)·DCM, THF/toluene (3:7 v/v), 50 °C; (i) 10 mol
% of
PdCl2(dppf)·DCM, THF/toluene (3:7 v/v), 0 °C. d Isolated yield of the hetero-
coupling product 3.
conditions were then used in the synthesis of carbohydrate-
substituted oligo(ethynylene)s up to the octa(ethynylene) as
potential amphiphilic, molecular precursors for a conversion into
carbon materials.
In search of a suitable method for the synthesis of unsym-
metric oligo(ethynylene)s, the FBW rearrangement was dis-
carded because the conditions did not appear to be compatible
with the presence of peracetylated glycosyl residues, and all
attempts using the Cadiot-Chodkiewicz reaction had previously
failed in our hands. Therefore, we decided to explore conditions
analogous to both the Sonogashira and the Negishi coupling
reactions, using the preparation of the glycosylated tri(ethy-
nylene) 3 as a model reaction (Scheme 1, Table 1).
The Sonogashira-type reactions were carried out in tetrahy-
drofuran (THF) using different Pd catalysts, CuI as the
cocatalyst, and an amine base (Table 1). However, none of these
reactions furnished acceptable results. For example, the reaction
of propargyl ꢀ-D-glucopyranoside 1a and 1-iodo-4-trimethyl-
silylbutadiyne 2c employing PdCl2(PPh3)2, CuI, and diisopro-
pylamine (DIPA) yielded 23% of the desired tri(ethynylene) 3
(entry 1). With Pd(PPh3)4 as the catalyst, the yield was even
lower (entry 2). By comparison, reactions starting from 1-bromo-
4-trimethylsilylbutadiyne 2b furnished higher yields (entries 3
and 4), and the reaction with Pd(PPh3)4 as the catalyst resulted
in the overall highest yield of 35% achieved with the Pd/Cu-
promoted cross-coupling reactions. Increasing the catalyst
concentration did not have a significant effect (entry 5), and,
(20) Cai, C.; Vasella, A. HelV. Chim. Acta 1995, 78, 2053–2064
(21) Lopez, S.; Fernandez-Trillo, F.; Castedo, L.; Saa, C. Org. Lett. 2003,
5, 3725–3728.
(22) Kim, S.; Kim, S.; Lee, T.; Ko, H.; Kim, D. Org. Lett. 2004, 6,
3601–3604.
(23) Ding, L.; Olesik, S. V. Nano Lett. 2004, 4, 2271–2276.
(24) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem.
.
1984, 49, 2629–2632
(25) Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687–3689
(26) Metay, E.; Hu, Q.; Negishi, E.-I. Org. Lett. 2006, 8, 5773–5776
(27) Negishi, E.-i.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org.
Lett. 2003, 5, 1597–1600
.
.
.
.
(28) Negishi, E.-I.; Anastasia, L. Chem. ReV. 2003, 103, 1979–2017
.
(29) Tykwinski and co-workers also performed a transmetalation of the
lithium intermediate obtained via the FBW rearrangement into a zinc organyl
in situ and coupled the latter to aryl halides as well as, in one example,
(30) Morisaki, Y.; Luu, T.; Tykwinski, R. R. Org. Lett. 2006, 8, 689–
692.
(31) Luu, T.; Morisaki, Y.; Cunningham, N.; Tykwinski, R. R. J. Org.
Chem. 2007, 72, 9622–9629.
4-(2-iodoethynyl)toluene; see refs 30 and 31
.
4526
Org. Lett., Vol. 10, No. 20, 2008

Scheme 2
.
Slow Reductive Elimination and a Reversible
Scheme 3. Preparation of a Glycosylated Tetra(ethynylene) Using
the Optimized Reaction Conditions Based on the Negishi Protocol
Transmetalation in the Negishi Coupling May Explain the
Observed Side Products, the Role of the Solvent, and the
Advantageous Use of Bromoacetylenes
applying reaction conditions developed by Cai and Vasella,20
the desired product 3 was obtained in a disappointing yield
(entry 6). Despite the more acceptable results, the use of 2b is
unattractive since it is an unstable liquid which, reportedly, tends
to explode upon heating,32 rendering its purification dangerous.
Finally, a permutation of the terminal acetylene and haloacety-
lene functionalities resulted in a yield of less than 20% starting
from the 3-iodopropargyl ꢀ-D-glucopyranoside 1c (entry 7) and
decreased even further to an unacceptable 7% in the case of
the 3-bromopropargyl ꢀ-D-glucopyranoside 1b (entry 8).
The side product formation encountered in the Pd/Cu-
promoted cross-coupling reactions turned out to be a serious
issue. Thus, the homocoupling product was formed in large
amounts in all cases and sometimes was the major product,
despite the thorough exclusion of oxygen. Interestingly, the
propargyl ꢀ-D-glucopyranoside 1a was also observed as a side
product in the reactions starting from the halopropargyl ꢀ-D-
glucopyranosides 1b and 1c (entries 7 and 8), indicating that a
reversible scrambling of the halogen substituents may be the
origin of the generally unsatisfactory results (vide infra).
The limited success of the Sonogashira-type cross-coupling
reactions led us to explore the scope of the Negishi protocol as
an alternative because the diminished reactivity of alkynyl zinc
compounds toward ester groups appeared to be compatible with
the use of peracetylated glycosyl residues. Attempts to generate
the essential alkynyl zinc derivative33 2e from 1,4-bis(trimeth-
ylsilyl)butadiyne 2d in situ,29 using MeLi·LiBr in Et2O for a
selective monodesilylation34 followed by addition of ZnCl2 in
THF, revealed that these two steps proceeded with quantitative
conversion within minutes.35 This rendered the Negishi protocol
very attractive because the starting material 1,4-bis(trimethyl-
silyl)butadiyne 2d is a stable crystalline compound, can
straightforwardly be prepared on a 30 g scale, purified by
sublimation, and stored at ambient conditions. The obtained
solution of 4-(trimethylsilyl)butadiynyl zinc chloride 2e in Et2O/
THF was then applied in the actual cross-coupling reaction
following the Negishi protocol. Thus, with 3-iodopropargyl ꢀ-D-
glucopyranoside 1c as the substrate and 5 mol % of Pd(PPh3)4
as the catalyst in THF,27 a yield of 23% of the desired
tri(ethynylene) 3 was achieved (entry 9). The use of
PdCl2(dppf)·DCM as the catalyst increased the yield to 30%
(entry 10) which can be attributed to an accelerated reductive
elimination step. When the same reaction was conducted in less
polar solvent mixtures such as toluene/THF (7:3 v/v), tri(ethy-
nylene) 3 was already obtained in 40% yield (entry 11).36
Comparable reactions starting from the 3-bromopropargyl ꢀ-D-
glucopyranosides 1b proceeded significantly slower but es-
sentially without side product formation (entry 12).37 While
higher reaction temperatures led to increased reaction rates and
substantially improved overall yields (entry 13), various side
products were observed, and the reaction mixture turned black.
Therefore, the reaction was conducted in toluene/THF (7:3
v/v) at 0 °C but with an increased amount of catalyst (entry
14). Under these conditions, the reaction proceeded smoothly
within a reasonable time frame. After 25 h, tri(ethynylene) 3
was isolated in a yield of 80%, and only traces of side products
were observed. This excellent result combined with the con-
venient use of 1,4-bis(trimethylsilyl)butadiyne 2d as the sub-
strate render this protocol a valuable and efficient alternative
to established procedures.
Interestingly, the propargyl ꢀ-D-glucopyranoside 1a was,
again, observed as one of the side products, and even as the
major product when the reaction was conducted in polar
(32) De Graaf, W.; Smits, A.; Boersma, J.; Van Koten, G.; Hoekstra,
W. P. M. Tetrahedron 1988, 44, 6699–6704.
(33) Compound 2e was already reported and used in a Pd-catalyzed
propargylic 1,3-substitution; see: Kleijn, H.; Meijer, J.; Overbeek, G. C.;
Vermeer, P. Recl. TraV. Chim. Pays-Bas 1982, 101, 97.
(34) Holmes, A. B.; Jones, G. E. Tetrahedron Lett. 1980, 21, 3111–
3112.
(36) THF can not be fully replaced as a solvent since it is indispensable
in the preparation of the alkynyl zinc compound.
(37) At room temperature, a yield of 26% was achieved after 23 h
reaction time, but only half of the starting material had reacted.
(35) See the Supporting Information.
Org. Lett., Vol. 10, No. 20, 2008
4527

yield. The tri(ethynylene) 3 and the tetra(ethynylene) 7 were
then desilylated using AgNO3 in DCM/MeOH, furnishing the
corresponding terminal acetylenes 8 and 9 (Scheme 4).
Scheme 4. Synthesis of the Symmetric, Diglycosylated
Hexa(ethynylene) and Octa(ethynylene)
Table 2. Selected Optical Properties of the Glycosylated
Oligo(ethynylene)s with n-Conjugated Triple Bonds
compd
n
λmax (nm)
εmax (M-1 cm-1
)
3
7
10
11
3
4
6
8
220
232
287
326
123000
355000
474000
504000
The tri(ethynylene) 8 was isolated in 89% yield and then
subjected to an acetylene homocoupling under Hay conditions,
furnishing the symmetric, diglycosylated hexa(ethynylene) 10
in 51% yield. As the tetra(ethynylene) 9 turned out to be highly
unstable in the solid state, it was directly applied in the following
Hay coupling after removing the silver iodide from the
deprotection reaction with a silica gel filtration. The symmetric
octa(ethynylene) 11 was obtained in 58% yield over two steps.
Both 10 and 11 were stable at room temperature for days, at
least, probably due to the sterically demanding carbohydrate
end groups.
iCompound 11 was synthesized in 58% over two steps, since compound
9 was not isolable.
The UV absorption spectra of the oligo(ethynylene)s 3, 7,
10, and 11 (Figure 1; Table 2) revealed the expected batho-
chromic shifts and hyperchromic effects upon increasing the
number of conjugated triple bonds, as well as a very clearly
resolved vibronic fine structure for the higher oligo(ethynylene)s.
In comparison to other series of oligo(ethynylene)s with
different end groups, such as disilyl16 or diaryl8 derivatives,
the glycosylated CH2O substituents induce significantly smaller
bathochromic shifts with respect to the unsubstituted parent
oligo(ethynylene)s.16
In conclusion, an efficient, convenient, and copper-free sp-sp
heterocoupling protocol based on the Negishi reaction has been
developed for the preparation of unsymmetric oligo(ethy-
nylene)s. The required zinc acetylide was generated from the
corresponding stable trimethylsilyl derivative in situ, and the
use of an apolar solvent and bromoacetylenes furnished the
desired heterocoupling product in high yield. The method was
applied to the synthesis of unsymmetric glycosylated and
symmetric diglycosylated oligo(ethynylene)s up to the octa-
(ethynylene). These compounds are important intermediates in
the envisaged preparation of carbon-rich amphiphiles to be used
as potential molecular precursors for hierarchically structured
carbon materials.
Figure 1. UV spectra of the oligo(ethynylene)s in acetonitrile.
solvents. Taking into account that the utilization of apolar
solvent mixtures and bromoacetylenes as the substrates were
the decisive modifications to achieve high conversions, we
tentatively interpret these findings to result from both a rate-
determining reductive elimination and, more importantly, a
reversible transmetalation (Scheme 2). An equilibrium in the
transmetalation may cause the observed scrambling of the
reactant functionalities. Both the presumed homo- and self-
coupling products may then be formed in heterocoupling
reactions from the substrate mixtures. The use of bromoacety-
lenes in apolar solvents presumably leads to the formation of
less soluble zinc salts and, thus, shifts the transmetalation
equilibrium toward product formation.
The newly developed protocol based on the Negishi cross-
coupling was then applied to the synthesis of higher glycosylated
oligo(ethynylene)s (Scheme 3). Thus, the glycosylated diacety-
lene 5 was converted into the corresponding bromodiacetylene
6 according to a modified literature procedure.22 The Pd-
catalyzed coupling of 6 under the established conditions afforded
the TMS-protected glycosylated tetra(ethynylene) 7 in 45%
Acknowledgment. We thank Dr. Heinz Ru¨egger (ETH
Zu¨rich, Switzerland) for help with NMR spectroscopy as well
as Prof. A. Dieter Schlu¨ter (ETH Zu¨rich, Switzerland) for
his generous support. Funding from ETH Zu¨rich (Projekt
ETH-05 08-2) is gratefully acknowledged.
Supporting Information Available: Additional figures,
experimental procedures, analytical data, and NMR spectra
of all novel compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL801807A
4528
Org. Lett., Vol. 10, No. 20, 2008