Methods for preparing macrocyclic products by ring-closing...

Details Methods for preparing macrocyclic products by ring-closing... Methods for preparing macrocyclic products by ring-closing...

2000-08-04

2003-02-25

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C540S450000, C540S451000, C540S460000, C546S112000, C546S113000, C546S115000, C546S116000, C546S120000, C514S183000, C514S211070, C514S218000, C514S277000, C514S299000, C514S302000, C514S450000, C514S430000, C514S431000

Reexamination Certificate

active

06525197

ABSTRACT:

The present invention pertains to methods for preparing macrocyclic products having 9 or more ring atoms by a ring-closing metathesis of diyne substrates.
By alkyne metathesis there is understood the mutual transalkylidynation of alkynes according to scheme 1.
Usually, reactions of this type are catalyzed by metal compounds (reviews: Schrock, R. R.
Polyhedron
1995, 14, 3177; Ivin, K. J.; Mol, J. C.
Olefin Metathesis and Metathesis Polymerization
, Academic Press, New York, 1997, p 192-223). Contrary to the metathesis of alkenes, which is a well-established field of research today and has found numerous applications in the preparation of technically important products (reviews: Ivin, K. J.; Mol, J. C.
Olefin Metathesis and Metathesis Polymerization
, Academic Press, New York, 1997; Schuster, M. et al.,
Angew. Chem.
1997, 109, 2125), in organic chemistry the application of the alkyne metathesis is restricted to the preparation of special polymers (Weiss, K. et al.,
Angew. Chem.
1997, 109, 522), the ring-opening polymerization of cycloalkynes (Krouse, S. A. et al.,
Macromolecules
1989, 22, 2569; Zhang, X-P. et al.,
Macromolecules
1994, 27, 4627) and the dimerization or the cross metathesis of acyclic alkynes (Kaneta, N. et al.,
Chem. Lett.
1995, 1055; Sancho, J. et al.,
J. Mol. Cat.
1982, 15, 75; Villemin, D. et al.,
Tetrahedron Lett
1982, 5139). The metatheses of diynes result in polymeric products by acyclic diyne metathesis (Krouse, S. A. et al.,
Macromolecules
1989, 22, 2569) or by cyclopolymerization (Fox, H. H. et al.
J. Am. Chem. Soc.
1994, 116, 2827; Koo, K.-M. et al.,
Macromolecules
1993, 26, 2485).
Both heterogeneous and homogeneous transition metal compounds can be used as catalysts or pre-catalysts for alkyne metatheses. Transition metal alkylidyne complexes and transition metal carbyne complexes which may either be added to the reaction mixtures in isolated form or formed in situ from suitable pre-catalysts are regarded as catalytically active species (Katz, T. J. et al.,
J. Am. Chem. Soc.
1975, 97, 1592). The catalytic activity of transition metal compounds in alkyne metatheses can be increased by the addition of suitable additives such as, e.g., phenol derivatives (Mortreux, A. et al.,
J. Chem. Soc. Chem. Commun.
1974, 786; Mortreux, A. et al.,
J. Mol. Cat.
1977, 2, 73; Villemin, D. et al.,
Tetrahedron Lett.
1982, 5139), aluminium alkyls (Petit, M. et al.,
J. Chem. Soc. Chem. Commun.
1982, 1385), or SiO
2
(Mortreux, A. et al.,
Bull. Soc. Chim. Fr.
1972, 1641; Mortreux, M. et al.
J. Mol. Cat.
1980, 8, 97).
Preferred catalysts or pre-catalysts for alkyne metatheses are Mo(CO)
6
(Mortreux, A. et al.,
J. Chem. Soc. Chem. Commun.
1974, 786; Mortreux, A. et al.,
J. Mol. Cat.
1977, 2, 73; Villemin, D. et al,
Tetrahedron Lett
1982, 5139; Tsonis, C. React.
Kinet. Catal. Lett.
1992, 46, 359), MoO
2
(acac)
2
/Et
3
Al (Petit, M. et al.,
J. Chem. Soc, Chem. Commun.
1982, 1385), MoO
3
/SiO
2
(Mortreux, A. et al.,
Bull. Soc. Chim. Fr.
1972, 1641; Mortreux, M. et al.
J. Mol. Cat.
1980, 8, 97), WoO
3
/SiO
2
(Pennella, F. et al.,
Chem, Commun
1968, 1548), W(≡CCMe
3
)(OR)
3
or Mo(≡CCMe
3
)(OR)
3
[R═CMe
3
, CH(CF
3
)
2
, CMe
2
CF
3
, CMe(CF
3
)
2
, C(CF
3
)
3
, C
6
H
3
Me
2
, C
6
H
3
i-Pr
2
, C
6
H
3
t-Bu
2
] (Review: Schrock, R. R.,
Polyhedron
1995, 14, 3177; Sancho, J. et al.,
J. Mol. Cat.
1982, 15, 75; Weiss, K. in
Carbyne Complexes
[Fischer, H. et al., Eds.], Verlag Chemie, Weinheim, 1988, p 220), Re(≡CCMe
3
)(═NAr)[OCMe(CF
3
)
2
]
2
(Schrock, R. R. et al.,
J. Am. Chem. Soc.
1988, 110, 2686; Weinstock, I. A. et al.,
J. Am. Chem, Soc.
1991, 113, 135), (Me
3
CO)
3
W≡W(OCMe
3
) or (Me
3
CO)
3
Mo≡Mo(OCMe
3
) (Schrock, R. R.
Polyhedron
1995, 14, 3177; Krouse, S. A. et al.,
Macromolecules
1989, 22, 2569; Zhang, X-P. et al.,
Macromolecules
1994, 27, 4627) and complexes containing a Re≡Re triple bond (Diefenbach, S. P. U.S. Pat. No. 4,698,451, 06. Okt. 1987; Chem. Abstr. 1988, 108, 40092 m).
In the literature both diynes and cycloalkynes have only been used as starting materials for polymerization reactions via alkyne metathesis. Surprisingly, however, we have found that diynes having suitable chain lengths used as substrates can be closed in the presence of suitable catalysts with a high selectivity to yield cycloalkynes, provided the formed cycloalkynes have 12 or more ring atoms (scheme 2).
Furthermore, it turned out that diynes having suitable chain lengths and used as substrates can also be closed with high selectivity to yield cycloalkynes having from 9-11 ring atoms, provided the diyne substrates are conformationally pre-organized for the ring closure by one or several structural elements. Said structural elements comprise rigid backbones, annellated rings, pre-existing double bonds, hydrogen bonds, geminal dialkyl groups, a coordination at metal centers, chiral centers, supramolecular structures.
This access to said class of substances, which is improved and shortened as compared with the previously used methods for preparing cycloalkynes, is important since various cycloalkynes as such are interesting as antibiotics (confer Nicolauo K. C.
Angew. Chem.
1991, 103, 1453) and can be converted into other macrocyclic products of economic importance such as, e.g., pharmaceuticals, pheromones, agrochemicals, crown ethers, odorous substances, perfume ingredients, or flavoring agents by existing methods.
The selectivity of this reaction depends in particular on the structure of the substrates, the used catalyst, the reaction conditions, and the ring strain within the prepared cycloalkyne. The formation of the cycloalkynes is favored by performing the reaction under high dilution in an organic solvent which does not deactivate the catalyst. When determining the concentration of the substrate in the reaction medium, the effective molarity parameter thereof has to be considered (Mandolini, L.
Adv. Phys. Org. Chem.
1986, 22, 1). According to the present invention, cycloalkadiyne products can also be obtained at higher concentrations by a cyclodimerization of the diyne substrates according to scheme 3.
In the present invention all metal compounds being active in alkyne metatheses may be catalysts or pre-catalysts regardless of whether they are initially introduced homogeneously or heterogeneously into the reaction medium. The catalysts can be employed in an isolated form or formed in situ within the reaction medium from suitable precursors. The used amount of catalyst is not critical, with preferred amounts of catalyst being within the range from 0.01-10%, based on the used substrate.
Transition metal alkylidyne complexes, transition metal compounds forming alkylidyne complexes under reaction conditions, and transition metal compounds with metal-metal triple bonds are preferred catalysts or pre-catalysts.
The abbreviations used in the following text indicate: i-Pr=isopropyl; t-Bu=tertiary butyl; Ph=phenyl; acac=acetylacetonate; Ar=aryl; gem=geminal; Me=methyl.
Complexes of the general type M(≡CR
1
)(OR
2
)
3
with
M=Mo, W
R
1
=C
1
-C
20
alkyl, aryl, alkenyl, alkylthio, dialkylamino, preferably CMe
3
, Ph
R
2
=C
1
-C
20
alkyl, aryl, preferably CMe
3
, CH(CF
3
)
2
, CMe
2
CF
3
, CMe(CF
3
)
2
, C(CF
3
)
3
, C
6
H
3
Me
2
, C
6
H
3
i-Pr
2
, C
6
H
3
t-Bu
2
are especially preferred catalysts or pre-catalysts.
Especially preferred catalysts or pre-catalysts are also complexes of the general type Re(≡CR
1
)(═NAr)(OR
2
)
2
with
R
1
=C
1
-C
20
alkyl, aryl, alkenyl, preferably CMe
3
, Ph
Ar=C
6
-C
20
aryl
R
2
=C
1
-C
20
alkyl, aryl, preferably CMe
3
, CH(CF
3
)
2
, CMe
2
CF
3
, CMe(CF
3
)
2
, C(CF
3
)
3
, C
6
H
3
Me
2
, C
6
H
3
i-Pr
2
, C
6
H
3
t-Bu
2
Especially preferred catalysts or pre-catalysts are also complexes of the general type (RO)
3
M≡M(OR)
3
with
M=Mo, W
R=C
1
-C
20
alkyl, aryl, preferably CMe
3
, CH(CF

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