Winding up alkynes: A Pd-catalyzed tandem-domino reaction to chiral biphenyls

Article abstract of DOI:10.1002/chem.201200175

Wrap it up! An intramolecular Pd-catalyzed tandem-domino process leading to highly sterically encumbered biphenyls is reported. The chirality of the newly formed axis is induced by the configuration of the carbohydrate backbone. Copyright

Full text of DOI:10.1002/chem.201200175

DOI: 10.1002/chem.201200175
Winding up Alkynes: A Pd-Catalyzed Tandem-Domino Reaction to Chiral
Biphenyls
Markus Leibeling and Daniel B. Werz*[a]
Dedicated to Professor Lutz F. Tietze on the occasion of his 70th birthday
The formation of biphenyls has comprised a pivotal part
À
of C C coupling chemistry since the seminal work of Ull-
mann in 1901.[1] The transformation using copper powder
and aryl halides affords symmetrical biaryls and copper
halide. Even sterically highly encumbered o,o,o’,o’-tetrasub-
stituted biaryls have been accessed using this old, but power-
ful synthetic procedure.[2] Studies with smaller chiral auxilia-
ries chelating the copper have led to a significant atropose-
lection and have been applied in various natural product
syntheses.[3] Other methods to obtain o,o,o’,o’-tetrasubstitut-
ed biphenyls include oxidative couplings of highly function-
alized phenol derivatives—a process that is similar to bio-
chemical pathways furnishing biaryl-containing natural
products.[4]
Modern techniques to reach biaryl cores rely on Pd-cata-
À
lyzed Suzuki–Miyaura couplings to form the central C C
bond.[5,6] To couple sterically demanding substrates such as
1 and 2 is a particularly challenging issue. Tuning of steric
and electronic properties of the ligands (e.g., 3) proved to
be necessary for a successful outcome (Scheme 1a).[7] Meth-
ods to generate chiral biaryl systems include enantioselec-
Scheme 1. (a) Suzuki–Miyaura coupling and (b) Ir-catalyzed [2+2+2]-cy-
clotrimerization to access o,o,o’,o’-tetrasubstituted biphenyls. The newly
formed bonds are highlighted in bold.
tive couplings employing chiral ligands; however, notewor-
thy are also diastereoselective procedures in which planar
chirality (e.g., induced by Cr(CO)3 complexes) or central
chirality (e.g., induced by sulfoxides) is translated into the
axial chirality of a biaryl axis.[8]
cobalt and iridium catalysts have emerged as indispensable
tools (Scheme 1b).[9,10]
Recently, we investigated a Pd-catalyzed domino process
to access carbohydrate-derived chromans and isochro-
mans.[11] The benzene annulation took place in such a way
that oxidative addition of the catalytic Pd species into the
Another approach for the construction of biaryl systems
takes a central diyne unit as starting point. Each of the two
carbon–carbon triple bonds (e.g., of 5) is reacted in a metal-
catalyzed [2+2+2]-type cycloaddition (Scheme 1b) with an
alkyne (e.g., 6) or a nitrile.[9] In the former case chiral bi-
phenyls such as 8 are formed, whereas the latter case gives
2,2’-bipyridines. The major difference to the above-men-
tioned coupling reactions is the construction of the aromatic
À
C Br bond of a bromo-olefin was followed by two subse-
quent carbopalladation steps and terminated by a cyclization
step. This highly reliable, simple, and robust approach for
the intra- and intermolecular annulation of persubstituted
benzenes through a Pd-catalyzed domino reaction served as
starting point when we sought for multiple carbopalladation
processes leading to sterically encumbered biphenyls.
À
core instead of the formation of the linking C C bond be-
tween the arene units. For these cyclotrimerization reactions,
[a] Dipl.-Chem. M. Leibeling, Dr. D. B. Werz
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstr. 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399476
We intended to check our notion whether the same
domino reactions might take place on both sides of a linear
C2 symmetric molecule. According to the nomenclature de-
veloped by Tietze, two domino processes at separate parts
of the molecule are denominated as tandem-domino reac-
tions.[12,13] In our case, the final cyclisation step of the
E-mail: dwerz@gwdg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200175.
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Chem. Eur. J. 2012, 18, 6138 – 6141

COMMUNICATION
Scheme 2. Synthesis of disubstituted tetra-alkynes 13a–f starting from octa-2,7-diyn-1-ol (9a) or nona-2,8-diyn-1-ol (9b). [a] Glc=glucose. [b] Gal=gal-
actose.
second domino reaction would generate a chiral axis in a dia-
stereoselective process.
We started our investigation of the anticipated tandem-
domino sequence with the propano-tethered, isopropyli-
dene-protected glucal derivative 13a (Scheme 3). Unfortu-
nately, we observed the desired biphenyl in only poor yield
(30%) and without any diastereoselectivity of the resulting
chiral axis (diastereomeric ratio (d.r.)=1:1) to the desired
biphenyl. By employing substrate 13b with butano-tethers
between the triple bonds, both the yield and diastereoselec-
tivity could be slightly improved (38%, d.r.=4:1). Changing
the protecting group to the benzylidene acetal also im-
proved the yield and the selectivity for both cases. Biphenyl
14c was obtained in 41% yield and with a d.r. of 2:1. How-
ever, the improvement in the case of the butano-tethered bi-
phenyl 14d was significantly higher; the product was ob-
tained in 60% yield and a diastereoselectivity of 10:1. En-
couraged by these results, we examined the synthesis of bi-
The starting materials are easily obtained by using a facile
synthetic strategy starting from 1,6-heptadiyne or 1,7-octa-
diyne (Scheme 2). After the conversion to the respective
propargylic alcohol 9,[14] easily obtained by the reaction of
the monolithiated species with paraformaldehyde a copper-
mediated Glaser–Hay coupling[15] by using atmospheric
oxygen as oxidant results in the corresponding linear tetra-
alkyne 10a and 10b in very good yields (84 and 86%, re-
spectively). The two hydroxyl functionalities were converted
into the iodides by a twofold Mukaiyama redox condensa-
tion reaction using iodine, triphenylphosphine, and imida-
zole. With the iodides as appropriate leaving groups in
hand, the attachment of the tetra-alkyne chain to the carbo-
hydrate derivatives was accomplished by a SN2 reaction. As
reaction partners, the suitably protected 2-bromoglycals
12[11a] with a free hydroxyl group at C3 were employed for
this step. To investigate the stereochemical and steric influ-
ences, two different 2-bromoglucals 12a and 12b (with iso-
propylidene and benzylidene protecting groups, respective-
ly) and one 2-bromogalactal 12c were used. Due to difficul-
ties in preparing the 4,6-isopropylidene-protected bromoga-
lactal we focused on the benzylidene protection in the latter
case. Each of the three bromoglycals was combined with
both the hexadecatetrayne 11a and the octadecatetrayne
11b to afford in total six different precursors 13a–13 f.
Next, we explored different reaction conditions for the
anticipated tandem-domino process itself. The first attempts
to use similar conditions as in the case of the intramolecular
carbohydrate-derived chroman and isochroman formation
were in vain. To our delight, it was possible to adjust the
catalytic system we already developed for the intermolecu-
lar version of the chroman and isochroman formation. Opti-
mal reaction conditions included the use of tetrakis(triphe-
nylphosphine) palladium (20 mol%) as palladium source,
triACHTUNGTRENNUNG
(tert)butylphosphonium tetrafluoroborate (Fuꢃs salt)[16]
(40 mol%) as additional electron-rich and sterically encum-
bered ligand, and di-isopropylamine (8.0 equiv) as base in
a mixture consisting of N,N-dimethylformamide, acetoni-
trile, and N-methylpyrrolidone (8:8:1) at 1208C.
Scheme 3. Tandem-domino reaction and corresponding deprotection to
highly substituted chiral biphenyls. [a] Hydrolysis was performed for 15a
and 15b. [b] Hydrogenolysis was performed for 15c and 15d, respective-
ly.
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www.chemeurj.org
6139

D. B. Werz and M. Leibeling
phenyls with a galactal-derived backbone. Due to the orien-
tation of all hydroxyls to the same side of the six-membered
ring, even higher diastereoselectivities should be expected
during this substrate-controlled process. Indeed, the antici-
pated products 14e and 14 f were obtained in good yields
(66 and 60%, respectively) and only one single diastereoiso-
mer was formed. Converted to a single reaction step, such
a yield means about 92% yield in every bond-forming trans-
formation.
The cleavage of the protecting groups furnished the free
hydroxyl functionalities of the native carbohydrate back-
bone. Palladium hydroxide on carbon (Pearlmanꢃs cata-
lyst)[17] under atmospheric hydrogen pressure cleaved the
benzylidene protecting group of the galactal-derived biphen-
yls 14e–14 f. The removal of the benzylidene-acetal in 14c–
14d proved to be a challenging task and could not be
achieved by employing Pd(OH)2/C. We found that acidic re-
action conditions (by using trifluoroacetic acid) accom-
plished the hydrolysis of the acetals in moderate yield.[18] It
is noteworthy that biphenyl 15b was obtained as a single
diastereoisomer after deprotection, although the protected
biphenyl was used as a diastereomeric mixture of 10:1.
Therefore we assume that the minor diastereoisomer is de-
composed by the harsh reaction conditions.
substituents point to each other and force strong steric re-
pulsion. On the other hand, the Ra configuration would
result in a less-hindered arrangement. The bulky phenyl
groups do not face each other showing almost no interac-
tion.
In conclusion, we have developed a Pd-catalyzed tandem-
domino approach for the synthesis of highly substituted bi-
phenyls. Two independent sequences consisting of a twofold
carbopalladation and cyclization led to the desired products.
Six carbon–carbon bonds, six rings, and one chiral axis are
formed in one step. In several cases the axial chirality be-
tween both newly formed benzene units could be adjusted
with high diastereomeric ratios. The stereogenic information
is induced by the stereochemistry of the carbohydrate back-
bone and can further be increased by the use of bulky pro-
tecting groups. Such a Pd-catalyzed approach using tetra-
AHCTUNGTREGaNNNU lkynes and terminal bromo-olefins might become a valuable
tool for the preparation of complex biaryls.
Experimental Section
General procedure: The alkynylated bromoglycal 13 (0.10 mmol,
1.0 equiv) was dissolved in a mixture of DMF/MeCN/NMP (5.0 mL,
5.0 mL, 0.6 mL). [PdACTHNUTRGNEUNG(PPh3)4] (20 mmol, 0.2 equiv), [(tBu)3PH]BF4
For the mechanism of the domino transformation we pro-
(40 mmol, 0.4 equiv) and diisopropylamine (0.80 mmol, 8.0 equiv) were
then added. The reaction was stirred in a microwave reactor for 2 h at
1208C. The absorption level was set to “very high” and the prestirring
time to 10 s. The reaction was stopped by the addition of brine. The
aqueous layer was extracted three times with EtOAc. The combined or-
ganic layers were washed with water and brine, and dried over Na2SO4.
The solvent was removed by rotary evaporation and the residue was puri-
fied by silica gel column chromatography (pentane/EtOAc) to afford bi-
phenyl 14 as a colorless to slightly yellow solid.
pose a similar one as suggested in our previous work.[11] The
domino sequence is initiated by an oxidative addition of the
0
À
Pd into the C Br bond. Two subsequent carbopalladation
reactions then lead to the formation of two rings and
a 1,3,5-triene. The final cyclisation step affords the benzene
unit and can be regarded either as disrotatory electrocyclic
À
6p-electron ring-closure or as C H activation. A second cas-
cade, independent from the first one, leads to the biphenyl
in the same manner. Therefore, the process should be re-
garded as a tandem-domino reaction.
Our results show that the diastereoselectivity is controlled
by the length of the tethering unit, the protecting group and,
most importantly, the stereochemistry of the carbohydrate
itself. Larger tethers as well as sterically more demanding
protecting groups favour the formation of a single diastereo-
isomer. This effect is further enhanced by employing galac-
tose-derived compounds, in which larger substituents point
into the same direction. The assumption that the formation
of the chiral axis is controlled by steric effects is depicted in
Figure 1. We suggest that the Sa configuration of the chiral
axis would cause a disfavoured arrangement. Both phenyl
Acknowledgements
We are grateful to the Deutsche Forschungsgemeinschaft (Emmy Noeth-
er Fellowship to D.B.W.), the Fonds der Chemischen Industrie (Dozen-
tenstipendium to D.B.W.) and the State of Lower Saxony (Ph.D. Fellow-
ship of the CaSuS Program to M. L.). Furthermore, we thank Prof. Dr.
Lutz F. Tietze for helpful discussions and generous support of our work.
Keywords: biphenyls · carbohydrates · chromans · domino
reaction · palladium
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A Pd-Catalyzed Tandem-Domino Reaction to Chiral Biphenyls
COMMUNICATION
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Received: January 16, 2012
Published online: April 16, 2012
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