First Evidence for the Use of Organosilver Compounds in Pd-Catalyzed Coupling Reactions; A Mechanistic Rationale for the Pd/ Ag-Catalyzed Enyne Synthesis?

Article abstract of DOI:10.1021/ol015830b

(matrix presented) Silver acetylides have been prepared and used in Pd-catalyzed coupling reactions. Enynes have thus been obtained in good yields. This work demonstrates that organosilver compounds could enter the Pd catalytic cycle; it also supports the

Full text of DOI:10.1021/ol015830b

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1661-1664
First Evidence for the Use of
Organosilver Compounds in
Pd-Catalyzed Coupling Reactions; A
Mechanistic Rationale for the Pd/
Ag-Catalyzed Enyne Synthesis?
Sandra Dillinger, Philippe Bertus,† and Patrick Pale*
Laboratoire de synthe`se et re´actiVite´ organique, associe´ au CNRS, Institut Le Bel,
UniVersite´ L. Pasteur, 4 rue B. Pascal, 67000 Strasbourg, France
ppale@chimie.u-strasbg.fr
Received March 13, 2001
ABSTRACT
Silver acetylides have been prepared and used in Pd-catalyzed coupling reactions. Enynes have thus been obtained in good yields. This work
demonstrates that organosilver compounds could enter the Pd catalytic cycle; it also supports the role of silver acetylides as intermediates
in the new Pd/Ag-catalyzed coupling reaction.
In connection with the synthesis of enyne natural products,1,2
especially those bearing ene- and dienediyne moiety such
as NCS-Chrom3 and related members,4,5 we are currently
investigating coupling reactions. We recently demonstrated
that a new set of catalysts based on silver and palladium
complexes is efficient for the coupling of sensitive vinyl
triflates and acetylenes.6,7 To get a better understanding of
this new coupling reaction, we looked for the formation of
intermediates in this process. In this communication, we
present preliminary results that demonstrate that silver
acetylides could be such intermediates. As shown here, silver
acetylides can indeed react with in situ formed vinyl-
palladium species, yielding substituted enynes.
Sp-sp2 coupling reactions, the so-called Sonogashira-
Linstrumelle reaction, require palladium as catalyst and
copper as a cocatalyst.8 Our use of silver ion as cocatalyst
(4) N1999A2: (a) Ishii, M.; Ando, T.; Kajiura, T.; Kameyama, T.; Nihey,
Y. Jpn. Kokai Tokkyo Koho JP 07291955; Chem. Abstr. 1996, 124,
115564h. (b) Ando, T.; Ishii, M.; Kajiura, T.; Kameyama, T.; Miwa, K.;
Sugiura, Y. Tetrahedron Lett. 1998, 39, 6495-6498. Kedarcidine: (c)
Hofstead, S. J.; Matson, J. A.; Malacko, A. R.; Marquard, H. J. Antibiot.
1992, 45, 1250-1254. (d) Leet, J. E.; Schroeder, D. R.; Hofstead, S. J.;
Golik, J.; Colson, K. L.; Huang, S.; Klohr, S. E.; Doyle, T. W.; Matson, J.
A. J. Am. Chem. Soc. 1992, 114, 7946-7948. C-1027: (e) Zhen, Y.-S.;
Ming, X.-Y.; Yu, B.; Otani, T.; Saito, H.; Yamada, Y. J. Antibiot. 1989,
42, 1294-1298. (f) Yoshida, K.-I.; Minami, Y.; Azuma, R.; Saeki, M.;
Otani, T. Tetrahedron Lett. 1993, 34, 2637-2640. Maduropeptine: (g)
Hanada, M.; Ohkuma, H.; Yonemoto, T.; Tomita, K.; Ohbayashi, M.;
Kamei, H.; Miyaki, T.; Konishi, M. M.; Kawaguchi, H.; Forenza, S. J.
Antibiot. 1991, 44, 403-414. (h) Schroeder, D. R.; Colson, K. L.; Klohr,
S. E.; Zein, N.; Langley, D. R.; Lee, M.; Matson, J. A.; Doyle, T. W. J.
Am. Chem. Soc. 1994, 116, 9351-9352.
(5) For recent reviews dealing with the synthesis of such compounds,
see: (a) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry;
Stang, P. J., Diederich, F., Eds; VCH: Weinheim, 1995; pp 203-283. (b)
Lhermitte, H.; Grierson, D. S. Contemp. Org. Synth. 1996, 41-63 and 93-
124. (c) Grissom, J. W.; Gunawardena, G. U.; Klingberg, D.; Huang, D.
Tetrahedron 1996, 52, 6453-6518.
(6) (a) Bertus, P.; Pale, P. Tetrahedron Lett. 1996, 37, 2019-2022. (b)
Bertus, P.; Pale, P. Tetrahedron Lett. 1997, 38, 8193-8196.
(7) Bertus, P.; Pale, P. J. Organomet. Chem. 1998, 567, 173-180.
† Present address: Laboratoire des re´actions se´lectives et applications,
associe´ au CNRS, Universite´ de Reims-Champagne Ardenne, BP 1039,
51687 Reims, France.
(1) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1992, 33, 5355-
5358. Dalla, V.; Pale, P. Tetrahedron Lett. 1994, 35, 3525-3528.
(2) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron 1993, 49, 5225-
5236.
(3) (a) Ishida, N.; Miyazaki, K.; Kumagai, K. M.; Rikimura, M. J.
Antibiot. 1965, 18, 68-76. (b) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.;
Furihata, K.; Otake, N.; Ishida, N. Tetrahedron Lett. 1985, 26, 331-334.
10.1021/ol015830b CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/28/2001

in such coupling reactions was based on the similarities
between silver and copper.6,7,9 We therefore thought that the
mechanism of both processes should be closely related.
Although some steps remain unclear in the Sonogashira-
Linstrumelle reaction, a broad mechanism involving the
formation of copper acetylides and then a transmetalation
with an organopalladium species is usually proposed10 for
the Pd-catalytic cycle (Scheme 1, top, m ) Cu). The copper
formed, copper acetylides are known to enter the palladium
catalytic cycle at the transmetalation step as other organo-
metallics. However, as far as we are aware of, nothing is
known about the ability of silver acetylides to be involved
into the palladium catalytic cycle. To check this assumption,
we prepared several silver acetylides and attempted to have
them react with vinyl triflates in the presence of a palladium
source. Various attempts to obtain the silver derivative of
Scheme 1
Scheme 2
1-hexyne gave white-gray solids,15 the spectroscopic data
of which indeed corresponded to the acetylide. However,
elemental analysis revealed the actual formation of com-
plexes between silver n-butylacetylide and the salt used for
its formation (e.g., 1a, Table 1).16 The use of these complex
silver acetylides did not allow for coupling with vinyl triflates
whatever the conditions used (e.g., Table 1, entries 1 and
2). Using a slight modification of a reported procedure,15
pure silver n-butylacetylide 217,18 was obtained as a stable
gray solid soluble in organic solvents. This acetylide is not
able by itself to induce any coupling reaction with 4-tert-
butylcyclohex-1-enyl triflate (entry 3); however, put in the
presence of Pd(PPh3)4, it underwent a smooth transformation
giving the expected 4-tert-butyl-1-(hex-1′-ynyl)cyclohex-1-
ene 67 (entries 4-7).19
catalytic cycle is far less known.11 On the basis of what is
known and what we learned from silver and alkyne interac-
tions, the steps depicted in Scheme 1 (bottom, m ) Cu or
Ag) can nevertheless be proposed for the Cu- or Ag-catalytic
cycle. Coordination of alkenes or alkynes to silver is well-
known;12 such coordination activates the alkyne toward
nucleophilic addition13 or deprotonation.14
The conversion and the yield of coupling product proved
to be very sensitive to the relative amount of reagents used.
A quantity of 0.1 equiv of Pd(PPh3)4 gave a modest yield
(entry 4) even after prolonged time, while the reaction
became nearly quantitative and exceedingly rapid with 0.5
equiv (entry 5). From the other sources of palladium
In the latter, a zwitterion should be formed, but it would
rapidly rearrange to the more stable silver acetylide. Once
(14) Lewandos, G. S.; Maki, J. W.; Ginnebaugh, J. P. Organometallics
1982, 1, 1700. In situ formed silver acetylides can also be trapped by
halogen; see: Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1984, 23, 727-728.
(15) Travkin, I. J. Gen. Chem. USSR (Engl. Transl.) 1976, 46, 1081.
Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78, 1675-1678.
(16) When 1-hexyne is added to a solution of silver nitrate or triflate in
acetone-water, a solid rapidly appeared, the elemental and spectroscopic
analysis of which corresponded to a mixed silver acetylide-salt complex:
AgNO3‚AgCtCC4H9 or AgOTf‚AgCtCC4H9. The silver acetylide-silver
nitrate has already been isolated; see: Chevastelon, R. C. R. Acad. Sci.
1897, 124, 1364.
(8) Sonogashira, K. In ComprehensiVe Organic Chemistry; Fleming, I.,
Trost, B. M., Eds; Pergamon: Oxford, 1991; Vol. 3, pp 521-549.
(9) The occurrence of copper acetylides has been suggested as in situ
formed intermediates in Sonogashira-Linstrumelle reactions. We thus
looked for less nucleophilic intermediates in order to avoid side reactions
observed with sensitive triflates and acetylenes; see refs 6 and 17.
(10) A simplified version of the Pd-catalytic cycle has been drawn for
convenience. Cationic palladium species having the triflate as counterion
and/or anionic pentacoordinated palladium complexes are probably involved
in this cycle. For more details, see: Amatore, C.; Jutand, A.; Suarez, A. J.
Am. Chem. Soc. 1993, 115, 9631-9641. Jutand, A.; Mosleh, A. Organo-
metallics 1995, 14, 1810-1817.
(17) Bertus, P. the`se de doctorat, Universite´ de Reims-Champagne-
Ardenne, Reims, 1997. General Procedure. Silver nitrate (2.1 equiv) was
suspended in a mixture of water (3 M) and methanol (5 M). To this
suspension kept in the dark was dropwise added an aqueous ammoniac
solution until the solution was homogeneous, and then the alkyne (1 eq)
was added. A white solid rapidly formed, which was filtered off. The solid
was then washed with water and dried under vacuum. The solid so obtained
(85-95% yield) must be preserved from light but is not air sensitive; it is
readily soluble in organic solvents.
(11) To our knowledge, no details are so far available for the mechanism
of the copper catalysis in these reactions.
(12) Noltes, J. G.; Van Koten, G. In ComprehensiVe Organometallic
Chemistry I; Wilkinson, G., Abel, E. W., Stone, F. G. A., Eds; Pergamon:
Oxford, 1982; Vol. 2, p 709. Van Koten, G.; James, S. L. Jastrzebski, J. T.
B. H. In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone,
F. G. A., Wilkinson, G., Eds; Pergamon: Oxford, 1995; Vol. 3, p 57.
(13) (a) Pale, P.; Chuche, J. Tetrahedron Lett. 1987, 28, 6447-6448.
(b) Dalla, V.; Pale, P. Tetrahedron Lett. 1994, 35, 3525-3528. (c) Dalla,
V.; Pale, P. New J. Chem. 1999,23, 803-805. (d) Pale, P.; Chuche, J. Eur.
J. Org. Chem. 2000, 1019-1025.
(18) Selected data for 2: NMR 1H (200 MHz, CDCl3) 0.94 (3H, t, J )
7.2), 1.46 (2H, m), 1.66 (2H, m), 2.48 (2H, t, J ) 7.3); NMR 13C (CDCl3)
13.6 (q); 21.7 (t), 22.4 (t), 31.8 (t), 80.2 (s), 129.9 (s); IR (KBr): 2041,
1458, 1290, 1246, 1103, 1032. Anal. Calcd for C6H9Ag: C, 38.1; H, 4.7.
Found: C, 35.5; H, 4.3; N, 0.5.
1662
Org. Lett., Vol. 3, No. 11, 2001

Table 1. Coupling of Silver Acetylides
investigated, palladium acetate together with triphenylphos-
phine, a mixture known to produce an active zerovalent
palladium species,20 is the only one really effective for this
coupling. Here again, 0.5 equiv of palladium is required to
get an acceptable yield of enyne (entry 6). With Pd(PPh3)4,
changing the solvent dramatically affected the reaction
efficiency. In acetonitrile or ether, the formation of coupling
product was slower although the starting triflate was
consumed in a few hours (entry 7 or 8, respectively). These
variations suggest a rather slow transmetalation step since
the oxidative addition step with vinyl triflates is known to
be a fast process.21
a good yield were observed in the presence of 0.5 equiv of
Pd(PPh3)4 (entry 10). Again, acetonitrile and ether instead
of DMF as solvent decreased the efficiency, although less
dramatically as in the case of 1 (entries 11 and 12).
It is puzzling that one-half of an equivalent of zerovalent
palladium species gives the best results. However, such
amount leads to a silver-palladium ratio of 2 to 1, and it is
interesting to note that the same ratio between silver and
palladium was also found as the best one for optimal results
in the catalytic version.22
Silver acetylides bearing functional groups behave in the
same way. Using the same procedure as for 1-hexyne,
benzylated (Z)-3-methylpent-2-en-4-ynol could be converted
into the corresponding silver acetylide 3. Submitted to the
conditions mentioned above, this acetylide gave the expected
coupling products 8, 9 (entries 13-18). Surprisingly, modest
yields were achieved with either unfunctionalized or func-
tionalized triflates when the reaction was conducted in DMF
(4 or 5; entries 13 and 16, respectively). In ether, quite
different results were obtained depending on the triflate
nature. A very fast and efficient coupling was achieved with
5 (entry 18), while poor yield was obtained with 4 (entry
15). With the silver acetylide 3, acetonitrile proved to be
the best solvent choice, giving coupling products rapidly and
efficiently (entries 14 and 17). These discrepancies may
Similar trends were observed when the same silver
acetylide was reacted with the triflate derived from dimedone
5 (entries 9-12). Almost no reaction occurred in the presence
of 0.1 equiv of Pd(PPh3)4 (entry 9), but a rapid reaction and
(19) General Procedure. To a triflate solution (1 equiv, 0.02 M) kept
under argon and in the dark were successively added tetrakis(triphenyl)
phosphine (0.5 equiv) and the required silver acetylide (1.2 equiv). The
resulting solution rapidly darkened. After the disappearance of one of the
reagents (see Table 1), ether was added, followed by a saturated aqueous
solution of ammonium chloride. The mixture was then filtered, and the
two layers were separated. The aqueous layer was extracted three times
with ether. The combined organic layers were then washed three times with
water, dried with MgSO4, filtered, and concentrated under reduced pressure.
The crude enyne was then purified by chromatography.
(20) Amatore, C.; Jutand, A.; Amine M’Barki, M. Organometallics 1992,
11, 3009-3013.
(21) Stang, P.; Kowalski, M. H.; Schiavelli, M. D.; Longford, D. J. Am.
Chem. Soc. 1989, 111, 3347-3356.
(22) Bertus, P.; Pale, P. Unpublished results, see also refs 6, 7, and 17.
Org. Lett., Vol. 3, No. 11, 2001
1663

reflect the difference in coordination ability of each solvent,
which may affect the reactivity of the organosilver species.
These results clearly show that silver acetylides can enter
palladium-catalyzed reactions as various other organo-
metallics do. Such silver organometallics can therefore be
intermediates in the palladium/silver-catalyzed coupling
reaction we already described.6,7 Therefore, the present results
strongly favor a mechanism in which in situ generated silver
acetylides react with organopalladium species in the new Pd/
Ag-catalyzed coupling reaction.6,7
Together with its relevance to mechanistic studies, the
process described here with silver acetylides is interesting
because it cleanly yields to sensitive polyunsaturated com-
pounds. This process can thus be helpful for solving synthetic
problems occurring with complex or sensitive molecules.
Further works are now in progress to delineate further the
in situ formation of silver acetylides and the mechanism of
the Pd/Ag-catalyzed coupling reaction. Expanding the scope
of silver organometallics in coupling reactions is also under
investigations.
Acknowledgment. The authors thank Dr. Thomas
Netscher, Hoffmann-La Roche, for a generous gift of (Z)-
3-methyl pent-2-en-4-ynol. P.B. thanks the Ministe`re de la
Recherche et de la Technologie for a doctoral fellowship.
P.P. thanks the Institut Universitaire de France.
OL015830B
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Org. Lett., Vol. 3, No. 11, 2001