Alkyne cross metathesis reactions of extended scope

Article abstract of DOI:10.1021/ol0068795

equation presented A catalyst formed in situ from Mo[N(t-Bu)(Ar)]₃ 1 (Ar = 3,5-dimethylphenyl) and CH₂Cl₂ in toluene effects cross metathesis reactions of functionalized alkynes that are beyond reach of more traditional promotors. An application to the synthesis of prostaglandin E₂ (PGE₂) 19 and the acetylated PGE derivative 18b shows the compatibility of this method with sensitive substrates.

Full text of DOI:10.1021/ol0068795

ORGANIC
LETTERS
2001
Vol. 3, No. 2
221-223
Alkyne Cross Metathesis Reactions of
Extended Scope
Alois Fu1rstner* and Christian Mathes
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received November 16, 2000
ABSTRACT
A catalyst formed in situ from Mo[N(t-Bu)(Ar)]3 1 (Ar ) 3,5-dimethylphenyl) and CH Cl2 in toluene effects cross metathesis reactions of
2
functionalized alkynes that are beyond reach of more traditional promotors. An application to the synthesis of prostaglandin E (PGE ) 19 and
2
2
the acetylated PGE derivative 18b shows the compatibility of this method with sensitive substrates.
As compared with the metathesis of alkenes that has seen a
prolific growth during the past decade,1 metathesis of alkynes
is still in its infancy. Only recently it has been shown that
this transformation holds great promise for advanced organic
synthesis and polymer chemistry. In particular, various
applications to ring-closing alkyne metathesis,2-4 alkyne
homodimerization,5 cyclooligomerization,6 or polymerization
reactions7 display a remarkably wide scope. A largely
unexplored field of application, however, is alkyne cross
metathesis (ACM). The very limited number of successful
examples reported in the literature8 rely on a structurally
unknown catalyst formed in situ from Mo(CO)6 and phenol
additives; though optimized by Bunz,9d this system requires
rather harsh conditions (130-140 °C)9 that preclude ap-
plications to elaborate and highly functionalized substrates.
Therefore we were prompted to investigate if more
efficient catalysts upgrade the profile of this particular
transformation. Most promising is the molybdenum complex
Mo[N(t-Bu)(Ar)]3 1 (Ar ) 3,5-dimethylphenyl) activated in
situ by CH2Cl2,3,10 because this reagent combination performs
particularly well in macrocyclization reactions.3,4
(1) Recent reviews: (a) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140;
Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (c) Schuster, M.; Blechert, S. Angew. Chem.
1997, 109, 2124; Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Fu¨rstner,
A. Top. Catal. 1997, 4, 285.
(2) Fu¨rstner, A.; Seidel, G. Angew. Chem. 1998, 110, 1758; Angew.
Chem., Int. Ed. Engl. 1998, 37, 1734.
The superiority of 1/CH2Cl2 is evident from the ho-
modimerization and prototype cross metathesis reactions
compiled in Table 1. It is remarkable that substrates bearing
electron-donating or electron-withdrawing substitutents are
converted with similar ease. Note that alkynes 3-8 es-
(3) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999,
121, 9453.
(4) (a) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc.
1999, 121, 11108. (b) Fu¨rstner, A.; Grela, K. Angew. Chem. 2000, 112,
1292; Angew. Chem., Int. Ed. 2000, 39, 1234. (c) Fu¨rstner, A.; Rumbo, A.
J. Org. Chem. 2000, 65, 2608. (d) Fu¨rstner, A.; Seidel, G. J. Organomet.
Chem. 2000, 606, 75. (e) Fu¨rstner, A.; Radkowski, K.; Grabowski, J.; Wirtz,
C.; Mynott, R. J. Org. Chem. 2000, 65, 8758.
(5) Fu¨rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463.
(6) Ge, P.-H.; Fu, W.; Herrmann, W. A.; Herdtweck, E.; Campana, C.;
Adams, R. D.; Bunz, U. H. F. Angew. Chem. 2000, 112, 3753.
(7) (a) Krouse, S. A.; Schrock, R. R. Macromolecules 1989, 22, 2569.
(b) Zhang, X.-P. Bazan, G. C. Macromolecules 1994, 27, 4627. (c) Weiss,
K.; Michel, A.; Auth, E.-M.; Bunz, U. H. F.; Mangel, T.; Mu¨llen, K. Angew.
Chem., Int. Ed. Engl. 1997, 36, 506. (d) Kloppenburg, L.; Jones, D.; Bunz,
U. H. F. Macromolecules 1999, 32, 4194. (e) Kloppenburg, L.; Song, D.;
Bunz, U. H. F. J. Am. Chem. Soc. 1998, 120, 7973.
10.1021/ol0068795 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/29/2000

Scheme 1. ACM of Substrate 5 with a Set of Symmetrical
Alkynes 9a-d (1.5 equiv) Catalyzed by 1 (10 mol %)/CH2Cl2
in Toluene at 80 °C
Table 1. Comparison of Homodimerization and Alkyne Cross
Metathesis Reactions of Substituted Propynyl Benzene
Derivatives Promoted by Two Different Catalyst Systems
even remains the largely preferred pathway if a 1:1 mixture
of propynyl benzene 11 and the nonsymmetrical alkyne 12
is exposed to 1/CH2Cl2 (Scheme 2); homodimerization of
Scheme 2. ACM of Two Non-Symmetrical Alkynes (1 equiv
each) Catalyzed by 1 (10 mol %)/CH2Cl2 in Toluene at 80 °C
the individual substrates does not seriously compete under
these conditions (only 9% of tolane derived from 11 are
formed).
The ACM reactions compiled in Scheme 3 deserve
sentially fail to react or decompose in the presence of the
traditional promotor system Mo(CO)6/p-chlorophenol.9d
The generality of ACM catalyzed by 1/CH2Cl2 is further
illustrated by Scheme 1 compiling reactions of substrate 5
with differently functionalized symmetrical alkynes 9a-d.
The yields obtained and the selectivity for cross metathesis
over homodimerization of 5 are excellent in all cases. ACM
Scheme 3. ACM of C-Silylated Alkynes with 5-Decyne (1.5
equiv) Catalyzed by 1 (10 mol %)/CH2Cl2 in Toluene at 80 °C
(8) A few prototype ACM reactions of simple substrates catalyzed by
Mo(CO)6 in the presence of phenol additives have been reported: (a)
Mortreux, A.; Delgrange, J. C.; Blanchard, M.; Lubochinsky, B. J. Mol.
Catal. 1977, 2, 73. (b) Kaneta, N.; Hikichi, K.; Asaka, S.-I.; Uemura, M.;
Mori, M. Chem. Lett. 1995, 1055. (c) A single example of an ACM reaction
using a defined tungsten alkylidyne catalyst was described by Schrock et
al. without specifying the yield obtained; cf.: Sancho, J.; Schrock, R. R. J.
Mol. Catal. 1982, 15, 75.
(9) (a) Mortreux, A.; Blanchard, M. J. Chem. Soc., Chem. Commun. 1974,
786. (b) Villemin, D.; Cadiot, P. Tetrahedron Lett. 1982, 23, 5139. (c)
Kaneta, N.; Hirai, T.; Mori, M. Chem. Lett. 1995, 627. (d) Pschirer, N. G.;
Bunz, U. H. F. Tetrahedron Lett. 1999, 40, 2481.
(10) (a) For an excellent review on the preparation of 1 and its reactions
with small inorganic molecules, see: Cummins, C. C. Chem. Commun. 1998,
1777. (b) Laplaza, C. E.; Odom, A. L.; Davis, W. M.; Cummins, C. C.;
Protasiewicz, J. D. J. Am. Chem. Soc. 1995, 117, 4999 and literature cited
therein.
particular mention. Terminal alkynes or C-silylated alkynes
are not amenable to productive metathesis so far; in fact,
compound 14a (X ) H) does not homodimerize at all on
exposure to 1/CH2Cl2 under standard reaction conditions.
222
Org. Lett., Vol. 3, No. 2, 2001

Therefore we were surprised to find that this and related
substrates undergo smooth ACM with 5-decyne to afford
the desired cross metathesis products 15a-c in respectable
yields. To the best of our knowledge, these are the first
examples of metathesis reactions involving C-silylated start-
ing materials.
Scheme 5a
ACM of alkynes bearing only alkyl substitutents on the
triple bond can also be carried out, although they were found
to be slightly less efficient. This is evident from the
“scrambling” processes depicted in Scheme 4.11 They are,
Scheme 4. Scrambling of Functionalized Alkynes Catalyzed
by 1 (5 mol %)/CH2Cl2 in Toluene at 80 °C11
a [a] 1 (10 mol %), CH2Cl2/toluene, 80 °C, 51% (18a), 44%
(18b); [b] H2 (1 atm), Lindlar catalyst, CH2Cl2, 87%; [c] aq HF,
THF, 88%.
however, synthetically useful if one of the reaction partners
is readily available and can be used in slight excess.
rigorously distinguishes between the reactive alkyne unit and
the inert alkene entity of 16.
This possibility is illustrated by an application to the
synthesis of prostaglandin E2 19 and the 15-O-acetylated
PGE2 derivative 18b (R ) Ac) (Scheme 5). Thus, reaction
of compound 16a (R ) TES) bearing a 2-butynyl group as
a truncated R-side chain12 with an excess of alkyne 17 (2
equiv) affords the cross metathesis product 18a in 51% yield;
homodimerization of 16a is not observed at all under these
conditions. Subsequent Lindlar reduction of 18a followed
by deprotection of the silyl groups with aqueous HF in THF
delivers PGE2 methyl ester 19. The synthesis of the acetylated
analogue 18b (R ) Ac) from 16b proceeds in a similar
fashion. These examples attest to the mildness of the method
as well as to the exceptional tolerance of the catalyst, which
preserves the labile aldol unit of these prostanoids and does
not epimerize the chiral center R to the ketone to any
appreciable extent. It is also noteworthy that the catalyst
In summary, it has been shown that ACM is a highly
selective and efficient transformation if the recently disclosed
catalyst system 1/CH2Cl2 is employed. This particular reagent
combination allows extension of the scope of this transfor-
mation to C-silylated alkynes and tolerates polar function-
alities as diverse as ether, ester, nitrile, trifluoromethyl,
aldehyde, acetal, alkyl chloride, sulfone, ketone, silyl ether,
and pre-exisiting alkene groups. Further studies on alkyne
metathesis effected by this and related catalysts will be
disclosed in due course.
Acknowledgment. Generous financial support by the
Deutsche Forschungsgemeinschaft (Leibniz program) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
We thank Dr. K. Grela for preparing alkyne 16.
Supporting Information Available: Representative pro-
cedure for ACM, as well as full spectroscopic characteriza-
tion of all homodimerization and cross metathesis products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) The scramblings depicted in Scheme 4 are carried out with a 1:1
mixture of the symmetrical starting materials; the yields indicated refer to
the CM product.
(12) The preparation of 16 by a “three component coupling” reaction is
described in detail in a more comprehensive study on the synthesis of
prostanoids by ring-closing alkyne metathesis and ACM: Fu¨rstner, A.;
Grela, K.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 2000, 122, 11799.
OL0068795
Org. Lett., Vol. 3, No. 2, 2001
223