Copper-free synthesis of skipped diynes via cross-coupling reactions of alkynylalanes with propargylic electrophiles

Article abstract of DOI:10.1021/ol0623769

Alkynylalanes provide a new, copper-free route to skipped diynes when combined with propargylic electrophiles bearing an aluminum-complexing leaving group. The reaction is mild, efficient, and, in contrast to copper-mediated methods, highly regioselective

Full text of DOI:10.1021/ol0623769

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5629-5632
Copper-Free Synthesis of Skipped
Diynes via Cross-Coupling Reactions of
Alkynylalanes with Propargylic
Electrophiles
Jilali Kessabi, Renaud Beaudegnies, Pierre M. J. Jung, Benjamin Martin,
Florian Montel, and Sebastian Wendeborn*
SYNGENTA Crop Protection AG, Research Chemistry, CH-4002 Basel, Switzerland
sebastian.wendeborn@syngenta.com
Received September 27, 2006
ABSTRACT
Alkynylalanes provide a new, copper-free route to skipped diynes when combined with propargylic electrophiles bearing an aluminum-complexing
leaving group. The reaction is mild, efficient, and, in contrast to copper-mediated methods, highly regioselective.
Extensive research attention has rendered traditionally cop-
intermediates and target molecules for natural product
synthesis,7 as well as attractive synthons for construction of
novel organic molecules8 and coordination complexes.9 The
principle approaches to such skipped diynes involve cross-
coupling copper-acetylides with propargylic electrophiles.10
The requisite acetylenic copper species is usually generated
in situ using stoichiometric amounts of copper(I) in the
presence of a weak base such as potassium carbonate.
Alternatively, catalytic quantities of copper(I) suffice when
preformed magnesium-acetylides are employed as coupling
partners.8,11
per-mediated Csp-Csp1 and Csp-Csp 2 cross-coupling reactions
2
into copper-free3 and, recently, even into entirely transition-
metal-free procedures.4
3
Less focus has been placed on Csp-Csp cross-coupling
reactions,5 and typically these methods still rely on generation
of a copper-acetylide which reacts with an electrophilic halide
or sulfonates.6
Our interest lies in methylene-bridged 1,4-diynes (com-
monly referred to as skipped diynes) which are valuable
(1) (a) Glaser, C. Ber. 1869, 2, 422. (b) Eglinton, G.; Galbraith, A. R.
Chem. Ind. 1956, 737. (c) Hay, A. S. J. Org. Chem. 1960, 25, 1275. (d)
Chodkeiwicz, W.; Cadiot, P. C. R. Soc. Fr. 1955, 241, 1055.
(2) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(3) (a) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (b) For
copper-free Sonogashira coupling, see: Soheili, A.; Albaneze-Walker, J.;
Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191.
(4) (a) Jan, J.; Wang, L. Synth. Commun. 2005, 35, 2333. (b) Leadbeater,
N. E.; Marco, M.; Tominack, B. J. Org. Lett. 2003, 5, 3919.
(5) It should be noted that in particular advances have been made in the
use of tris(alkynyl)indiums with benzyl bromide catalyzed by Cl2Pd(dppf)
(Perez, J.; Perez-Sestelo, L.; Sarandeses, A. J. Am. Chem. Soc. 2001, 123,
4155.) and in the use of alkynylboron dichlorides with benzyl, benzylallyl,
and benzylpropargyl secondary alcohols (Kabalka, G. W.; Yao, M.-L.;
Borella, S. Org. Lett. 2006, 8, 879.).
Although widely employed, this copper-mediated cross-
coupling approach to 1,4-diynes can suffer from a number
of limitations. First, the yield of the desired coupled product
1 can be reduced due to competitive formation of regioiso-
(7) (a) Durand, S.; Parrain, J.-L.; Santelli, M. J. Chem. Soc., Perkin Trans.
1 2000, 253. (b) Tedeschi, C.; Saccavini, C.; Maurette, L.; Soleilhavoup,
M.; Chauvin, R. J. Organomet. Chem. 2003, 670, 151.
(8) Such as pericyclynes: Maurette, L.; Godard, C.; Frau, S.; Lepetit,
C.; Soleilhavoup, M.; Chauvin, R. Chem.-Eur. J. 2001, 7, 1165.
(9) Cobalt complexes and ruthenium complexes have been described:
(a) Guo, R.; Green, J. R. Chem. Commun. 1999, 2503. (b) Cabeza, J. A.;
Grepioni, F.; Moreno, M.; Riera, V. Organometallics 2000, 19, 5424.
(10) For these types of couplings and a few copper-free references, see
ref 7 and references cited therein.
(6) For a general review, see: Normant, J. F. Synthesis 1972, 63.
10.1021/ol0623769 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/04/2006

meric alkynylallenes 2 which result from an undesired
nucleophilic attack by the acetylenic copper species at the
triple bond (SN2′) rather than at the sp3 carbon of the
electrophile (pathways A and B, respectively, in Scheme 1).
the Csp-aluminum σ bond, as well as the propargylic
Csp -leaving group bond, as a consequence of the proposed
complexation shown in Scheme 2.
3
Scheme 2. 1,4-Diynes via Mutual Activation of Alkynylalanes
and Propargylic Electrophiles
Scheme 1. Competitive Reactions Involved in the Formation
of 1,4-Skipped Diynes 1
In analogy, Hooz et al.15 also invoke such aluminum
complexes to explain the different regioselective outcomes
of alkynylalane additions to R,â-unsaturated endo- and
exocyclic ketones as shown in Scheme 3.
In turn, these allenic products are prone to polymerization.
Second, undesired isomerization of the 1,4-diyne 1 to the
corresponding allenes and eventually the 1,3-isomer is pos-
sible even under the weakly basic conditions, thus lowering
the yield and complicating the isolation of the skipped
diynes.12 Finally, the acetylenic copper species can be prone
to oxidative homocoupling (pathway C, Scheme 1).13
During the course of our work devoted to alternative
approaches to skipped 1,4-diynes which address the afore-
mentioned limitations of copper(I)-mediated couplings, we
have recently reported a method obviating the use of base
which employs a bimetallic silicon-copper system.14 Herein,
we present the first use of alkynylalanes for the preparation
of methylene-bridged 1,4-diynes via their cross-coupling with
Scheme 3. Regioselectivity of the Addition of Alkynylalane
to R,â-Unsaturated Ketones
The alkynylalane adds to give the 1,4-Michael addition
product in acyclic systems, but in conformationally restricted
systems such as cyclohexenylethanone and cyclohexenone,
only the R,â-unsaturated ketone which is able to adopt a
cisoid conformation in the transition state complex leads to
a 1,4-Michael adduct.16
A differentiation should be made between these types of
mutual complexation couplings and those between alanes and
allylic,17 benzylic,18 and tertiary19 electrophiles considered
to proceed by a cationic SN1 mechanism which, through a
lack of stabilization (as well as a lack of regioisomers),20
would be implausible here.
For the preparation of our base-sensitive diynes (vide
supra), it was preferable to avoid the use of strongly basic
transmetalation methods (alkynyl-alkali metal-Al exchange)
commonly applied for the generation of the requisite alky-
nylalane species21 (pathway A in Scheme 4).
3
a selection of propargylic electrophiles. This novel Csp-Csp
bond-forming reaction relies on the sole use of a mono-
metallic aluminum-alkynyl species and thereby circumvents
the ubiquitous need for copper in such cross-coupling
reactions.
The origin of this work rests on the expectation that if an
alkynylalane is generated in the presence of a propargylic
electrophile capable of complexing with the Lewis acid
aluminum species a coupling reaction could ensue and lead
to the formation of a skipped diyne. The successful trans-
fer of the alkynyl residue would rely in part on weakening
(11) (a) Brandsma, L. Synthesis of Acetylenes, Allenes and Cumulenes;
Elsevier: Amsterdam, 2003 and references therein. (b) Jeffery, T.; Guenot,
S.; Linstrumelle, G. Tetrahedron Lett. 1992, 33, 5757. (c) Hansen, T. V.;
Stenstrom, Y. Tetrahedron: Asymmetry 2001, 12, 1407. (d) Spinella, A.;
Caruso, T.; Martino, M.; Sessa, C. Synlett 2001, 1971. (e) For an
exception: Padmanabhan, S.; Nicholas, K. M. Tetrahedron Lett. 1983, 24,
2239.
(12) (a) Mel’nikova, V. I.; Pivnitskii, K. K. Zh. Neorg. Khim. 1990, 26,
78. (b) Mathai, I. M.; Taniguchi, H.; Miller, S. I. J. Am. Chem. Soc. 1967,
89, 115. (c) Hungerford, N. L.; Kitching, W. J. Chem. Soc., Perkin Trans.
1 1998, 1839.
(13) (a) Trost, B. M.; Fleming, I. ComprehensiVe Organic Synthesis;
Pergamon: Oxford, 1991; Vol. 5, p 1543. (b) Bohlmann, F.; Schoenowsky,
H.; Inhoffen, E.; Grau, G. Chem. Ber. 1964, 97, 794.
(14) Montel, F.; Beaudegnies, R.; Kessabi, J.; Martin, B.; Muller, E.;
Wendeborn, S.; Jung, P. M. J. Org. Lett. 2006, 8, 1905.
(15) Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320.
(16) This limitation can be overcome indirectly by employing a nickel
catalyst: (a) Schwartz, J.; Carr, D. B.; Hansen, R. T.; Dayrit., F. M. J.
Org. Chem. 1980, 45, 3053. (b) Kwak., Y.-S.; Corey, E. J. Org. Lett. 2004,
6, 3385.
(17) (a) Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc. 1986, 108, 1098.
(b) Gallina, C. Tetrahedron Lett. 1985, 26, 519.
(18) Miller, D. B. J. Org. Chem. 1966, 31, 908.
(19) Negishi, E.; Baba, S. J. Am. Chem. Soc. 1975, 97, 7385.
(20) Flemming, S.; Kabbara, J.; Nickisch, K.; Westermann, J.; Mohr, J.
Synlett 1995, 183.
5630
Org. Lett., Vol. 8, No. 24, 2006

On the basis of this result, we rationalized that a more
suitable electrophilic coupling partner could be that which
possesses a group with the ability to complex the alkynyl-
aluminum species but which would be less subject to un-
desirable nucleophilic attack. One such candidate is propargyl
carbonate which upon reaction with phenylethynylalane led
to the desired skipped diyne product in 15% yield (entry
3),24,25 encouraging our further investigation.
Scheme 4. Approaches to Alkynylalanes
Our attention was drawn toward the incorporation of non-
carbonyl-based propargylic functionalities, such as phos-
phates and phosphinates, known for their inertness toward
nucleophilic attack at the phosphorus-oxygen double bond.
Initially, coupling of the easily prepared propargyl dieth-
ylphosphate with 2 equiv of phenylethynylalane led to a clean
reaction according to GC and 1H NMR analysis of the crude
material. Our desired skipped diyne 1 had been generated
for the first time not only in high isolated yield (79%, entry
4) but also free from the regioisomeric alkynylallene.
Attempts to carry out the reaction of propargyl phosphates
with just 1 equiv of the alkynylalane resulted in absolutely
no consumption of the electrophile even in the presence of
different Lewis acids (ZnCl2, ZnI2, Al(OiPr)3, Al(OiBu)3).
In addition, the cross-coupling reactions of the corresponding
readily available diphenylphosphate and diphenylphosphinate
with phenylethynylalane were similarly regioselective and
equally effective (entries 5 and 6, respectively).
We therefore opted for a salt-free method recently reported
by Micouin22 which involves treating terminal alkynes with
trimethylaluminum in the presence of only catalytic amounts
of triethylamine (pathway B, Scheme 4). For our purposes,
the alkynylalane of phenyl acetylene was prepared according
to Micouin’s conditions22 and employed as a model substrate
for coupling with numerous propargyl electrophiles. The
coupling procedure is straightforward and simply involves
dropwise addition of the phenylethynylalane to the electro-
phile in dichloromethane at 0 °C or at room temperature.23
The outcomes of these reactions are reported in Table 1. Our
Table 1. Cross-Coupling Reaction of Phenylethynylalane with
Propargylic Electrophiles: The Effect of the Leaving Groupa
An added improvement for the preparation of methylene-
bridged diynes such as 1 came from the observation that
inexpensive propargylic methyl- and tolyl-sulfonates were
even better partners in this novel alkynylalane-mediated
cross-coupling because they led to the highest yields of the
skipped diyne (cf. entries 7-10 vs entries 4-6). Advanta-
geously, just stoichiometric amounts of alkynylalane were
required when the mesylate was used as the coupling partner
(entry 8). Furthermore, the propargylic sulfonatesswhether
derived from terminal or internal acetylenesswere found to
be as reactive at lower temperatures (-30 °C for the mesylate
and 0 °C for the tosylate) as they were at room temperature.
equiv of
alane
temp time yield of 1b
entry
X
R′
Et rt
rt
Et rt
(°C)
(h)
(%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
2
2
2
2
2
2
1
2
2
2
2
2
2
OAc
OAc
-
-
12
8
10
8
2
0.5
1
-
-
d
H
OCOOMe
15
79
85
80
92
88
96
85
OPO(OEt)2 Et 0-rt
OPO(OPh)2 Et rt
OPO(Ph)2
OSO2Me
OSO2Me
OSO2pTol
OSO2pTol
Cl
Et rt
Et
H
Et
H
0
0
0
0
2
d
Et rt
Et rt
-
15
-
-
-
Particularly noteworthy is the high yield of the regiose-
lective reaction between the terminal propargylic sulfonates
and the alkynylalane (entries 8 and 10) because literature
precedent,26 as well as our own experiences,27 has shown
that SN2′ attack predominates on terminal propargylic elec-
trophiles when the nucleophilic coupling partner is an
alkynyl-copper (presumably resulting in allene formation and
subsequent polymerization).
d
I
-
-
-
d
OMe
H
rt
Et rt
d
OCH2OMe
a Reaction conditions:23 PhCtCAlMe2 in (CH2Cl2)/heptane (1 M) was
added to the electrophile in CH2Cl2, and the reaction was followed by GC.
b Isolated yields. c Major isolated component is a result of a double addition
to the carbonyl of the acetate providing PhCtCC(OH)(CH3)CtCPh.
d Recovery of phenylacetylene after a hydrolytic quench and slow degrada-
tion of the propargylic electrophile.
Of consideration is that electrophiles which possess a
chloride, iodide, methoxy, or methoxymethyl substituent at
the propargylic position did not cross-couple with the
alkynylalane under these conditions. Upon extended reaction
times, only inseparable mixtures were generated in each
first attempt at generating the 1,4-diyne using pent-2-ynyl
acetate as a coupling partner led to an undesired double 1,2-
addition to the carbonyl group of the ester function (entry
1, Table 1).
(21) (a) Shinoda, M.; Iseki, K.; Oguri, T.; Hayasi, Y.; Yamada, S.;
Shibasaki, M. Tetrahedron Lett. 1986, 27, 87. (b) Fried, J.; Sih, J. C.
Tetrahedron Lett. 1973, 14, 3899. (c) Fried, J.; Lin, C.; Ford, S. H.
Tetrahedron Lett. 1969, 10, 1379. (d) Ben-Efraim, D. A.; Sondheimer, F.
Tetrahedron 1969, 25, 2823.
(22) (a) Feuvrie, C.; Blanchet, J.; Bonin, M.; Micouin, L. Org. Lett. 2004,
6, 2333. (b) Wang, B.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6, 3481.
(23) See Supporting Information for experimental procedure.
(24) The corresponding N,N-dimethyl carbamate behaved similarly
according to GC analysis.
(25) The GC and NMR of this product are identical to those of the
coupling product prepared by traditional copper chemistry (see ref 23).
(26) Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis 1993,
65.
(27) Kessabi, J.; Beaudegnies, R.; Jung, P. M. J.; Martin, B.; Montel,
F.; Wendeborn, S., unpublished results.
Org. Lett., Vol. 8, No. 24, 2006
5631

instance from which only phenyl acetylene was identifiable
(entries 11-14), thereby supporting the argument in favor
of the important complexing roles played by the ester,
sulfonyl, and phosphonyl/phosphinyl groups in the cross-
couplings which were successful (entries 3-10). This may
be rationalized by invoking the formation of a favorable six-
membered aluminum-coordinated transition state.28
yielding (77%) and advantageously could be carried out at
temperatures much lower than that required for the phosphate
(0 vs 90 °C). Moreover, the mesylate necessitated a
significantly shorter reaction time compared to the phosphate
(1 vs 73 h) and only required the use of stoichiometric
amounts of the alane which is consistent with what was
previously observed (cf. Table 1, entry 8).
A useful extension of this methodology would be its
application for the preparation of functionalized diynes which
are amenable to further transformations. To this end, the
propargyl alcohol derived ethoxyethyl ether and tert-butyl-
diphenylsilyl ether were selected as precursors to representa-
tive functionalized alkynylalanes (entries 3 and 4, respec-
tively). Although Micouin’s conditions for alkynylalane
preparation failed to provide the requisite nucleophilic
coupling partners in these instances, they were attainable on
treatment with nBuLi and transmetalation with AlMe2Cl at
-35 °C. Their subsequent cross-couplings with the mesylate
derived from pent-2-yn-1-ol were regioselective and afforded
the desired acetal and silyloxy functionalized diynes in
moderate yields (49 and 55%, respectively, Table 2 (R′ )
Et)). In addition, the chloroalkyl-substituted diyne was
successfully prepared as shown in entry 5 via the interme-
diacy of 1-chloro-oct-7-ynylalane, highlighting the chemose-
lective nature of the substitution at the mesylate center rather
than at the chloride during the cross-coupling.
In summary, a novel, copper-free, and regioselective
synthesis of methylene-bridged skipped diynes has been
developed which relies on cross-coupling alkynylalanes with
phosphinate-, phosphate-, or sulfonate-based propargylic
electrophiles capable of mutual complexation with the
nucleophile. The method is efficient and mild and advanta-
geously does not lead to detrimental isomerization of the
base-sensitive skipped diyne because only catalytic amounts
of triethylamine are required for initial preparation of the
alkynylalane.
The preparation of dialkyl-substituted methylene-bridged
diynes was also shown to be possible using this alkynylalane-
mediated cross-coupling as shown in Table 2. First, the use
Table 2. Cross-Coupling Reactions of Functionalized
Alkynylalanes with Propargylic Phosphates and Mesylatesa
alane
temp time yield of 1b
entry
R
(equiv)
X
(°C)
(h)
(%)
1c
2c
3c
n-pentyl
n-pentyl
2
1
2
OPO(OEt)2
OSO2Me
OSO2Me
0-90 73
23
77
49
0-23
1
4
-35-rt
4c
2
1
OSO2Me
OSO2Me
-35-rt
4
7
55
73
5d
Cl(CH2)6
0-23
a The alane was added to the mesylate in toluene.23 b Isolated yields.
c R′ ) ethyl. d R′ ) n-pentyl.
of propargyl phosphate as the electrophilic coupling partner
provided dodeca-3,6-diyne (entry 1) regioselectively, albeit
in low yield (23%). In contrast, the coupling of the
corresponding mesylate (entry 2) was significantly higher
Supporting Information Available: General experimen-
tal data and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) The need for 2 equiv of alkynylalane when employing propargyl
phosphates and phosphinates suggests that the reaction is proceeding via
an alternative mechanism, essentially involving Lewis acid activation prior
to coordination and transfer brought on by the second equivalent of
alkynylalane.
OL0623769
5632
Org. Lett., Vol. 8, No. 24, 2006