Endo-selective enyne ring-closing metathesis promoted by stereogenic-at-W mono-pyrrolide complexes

Article abstract of DOI:10.1021/ol1030525

The utility of W-alkylidene complexes for enyne ring-closing metathesis is demonstrated in a direct comparison with Mo-based analogs. Tungsten complexes lead to less alkyne oligomerization and higher levels of endo-selectivity and enantioselectivity.

Full text of DOI:10.1021/ol1030525

ORGANIC
LETTERS
2011
Vol. 13, No. 4
784–787
Endo-Selective Enyne Ring-Closing
Metathesis Promoted by Stereogenic-at-W
Mono-Pyrrolide Complexes
Yu Zhao,† Amir H. Hoveyda,*,‡ and Richard R. Schrock*,†
Department of Chemistry, Merkert Chemistry Center, Boston College Chestnut Hill,
Massachusetts 02467, United States, and Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139, United States
amir.hoveyda@bc.edu; rrs@mit.edu
Received December 16, 2010
ABSTRACT
The utility of W-alkylidene complexes for enyne ring-closing metathesis is demonstrated in a direct comparison with Mo-based analogs. Tungsten
complexes lead to less alkyne oligomerization and higher levels of endo-selectivity and enantioselectivity.
Although high oxidation state W-based imido alkyli-
dene bis-alkoxide complexes were the first well-defined
olefin metathesis catalysts to be developed,1 they have not
been explored in chemical synthesis as extensively as
related Mo catalysts.2 Among the reasons for Mo catalysts
being preferred are the relatively high stability of tungsta-
cyclobutane intermediates toward loss of olefin, a per-
ceived higher sensitivity of tungsten complexes to certain
functional groups, and commercial availability of some
Mo complexes. In virtually no olefin metathesis reactions
have activities and selectivities of tungsten and molybde-
num catalysts been compared directly in more than a
cursory manner.
Recently, we have turned to an exploration of mono-
aryloxide pyrrolide (MAP) imido alkylidene catalysts,3
which are highly reactive and selective for a variety of
olefin metathesis processes.4 In the process, we discovered
that W-based catalysts can be dramatically more selective
than Mo-based catalysts, for example, for homocoupling
of terminal olefins to generate Z internal olefins with high
selectivity.5 Structural and kinetic studies of tungsten and
(4) Enantioselective RCM: (a) Malcolmson, S. J.; Meek, S. J.; Sat-
tely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456, 933–937.
(b) Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943–953. (c) Meek,
S. J.; Malcolmson, S. J.; Li, B.; Schrock, R. R.; Hoveyda, A. H. J.
Am. Chem. Soc. 2009, 131, 16407–16409. Enantioselective ring opening-
cross metathesis:(d) Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 3844–3845. Ring-opening metathesis
polymerization:(e) Flook, M. M.; Jiang, A. J.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 7962–7963. (f) Flook, M. M.; Gerber,
L. C. H.; Debelouchina, G. T.; Schrock, R. R. Macromolecules 2010, 43,
7515–7522. Ethenolysis reactions:(g) Marinescu, S. C.; Schrock, R. R.;
† Massachusetts Institute of Technology.
‡ Boston College Chestnut Hill.
(1) (a) Schaverien, C. J.; Dewan, J. C.; Schrock, R. R. J. Am. Chem.
Soc. 1986, 108, 2771–2773. (b) Schrock, R. R. Chem. Rev. 2002, 102,
145–180.
€
(2) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4592–4633.
Muller, P.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 10840–10841.
(5) Jiang, A. J.; Zhao, Y.; Hoveyda, A. H.; Schrock, R. R. J. Am.
(3) Schrock, R. R. Chem. Rev. 2009, 109, 3211–3226.
Chem. Soc. 2009, 131, 16630–16631.
r
10.1021/ol1030525
Published on Web 01/20/2011
2011 American Chemical Society

molybdenum MAP complexes suggest that methylidene
intermediates can be relatively stable and long-lived.6
Accordingly, if both Mo and W MAP methylidene species
are long-lived in the appropriate circumstances, higher
turnover numbers should be obtained.
Table 1. Enyne Metathesis of 1 with Mo- and W-based MAP
Catalystsa
Scheme 1. Various Modes of Reaction in Enyne RCM
a Reactions were performed under N2 atmosphere with 5 mol %
catalyst in C6H6 at 22 °C. b Conv was based on consumption of
substrate. c Ratios were determined by analysis of 1H NMR spectra of
unpurified reaction mixtures.
We began by examining enyne metathesis by Mo- and
W-catalysts of tosylamide 1 (Table 1). We found that a
W-based catalyst provides levels of selectivity and reactiv-
ity at least as high as the analogous Mo-based variant.
Table 2. More Efficient and Selective Enyne Metathesis with
W-based Catalystsa
One property of Mo-MAP complexes is their ability to
catalyze enyne metathesis reactions to give endo products
preferentially (Scheme 1);7 such cyclic dienes are virtually
inaccessible through enyne reactions catalyzed by Ru
carbenes.8 Although some enyne reactions catalyzed by
Ru complexes have been proposed to follow a mechanism
in which the olefin binds to the metal first (Scheme 1), we
have suggested that the endo product v is generated when
the terminal alkyne binds initially to Mo, affording a β-
metallacyclobutane intermediate iii. Conversely, the exo
product ix is formed through the intermediate R-metalla-
cyclobutane vii. Mixtures of endo- and exo-products form
through the competitive reaction pathways shown in
Scheme 1. One of the limitations in enyne metathesis by
Mo-based MAP complexes might arise from multiple
reactions that involve a terminal acetylene (i.e., oligomer-
ization or polymerization).9 The yields and purity of enyne
metathesis products prepared through the use of Mo
catalysts therefore can be limited. As a consequence of
the superior selectivity of tungsten catalysts for Z-selective
homocoupling of terminal olefins, presumably as a result
of the better-controlled reactivity of W-complexes,5 we felt
compelled to explore the ability of such complexes in
promoting enyne RCM reactions.
a-c See Table 1.
Encouragedby these results, weturned tosubstrates that
undergo facile oligomerization in the presence of Mo-
catalysts. As the data in Table 2 illustrate, in the case of
enyne metathesis of 4, where a medium ring is generated,
and of 6, where the rate of ring-closure is slower, presum-
ably as a consequence of increased substitution at the
alkene, relatively high dilution conditions proved to be
necessary for Mo-catalyzed processes (1 ꢀ 10-3 and 2 ꢀ
10-3 M, respectively).7b When the reactions were carried
out at a concentration of 0.01 M, <40% enyne metathesis
products were obtained with the Mo-F6 complex
(Table 1) and separation of the desired product from
oligomeric side products proved difficult (Table 2).
€
(6) (a) Jiang, A. J.; Simpson, J. H.; Muller, P.; Schrock, R. R. J. Am.
Chem. Soc. 2009, 131, 7770–7780. (b) Schrock, R. R.; King, A. J.;
€
Marinescu, S. C.; Simpson, J. H.; Muller, P. Organometallics 2010, 29,
5241–5251.
€
(7) (a) Singh, R.; Schrock, R. R.; Muller, P.; Hoveyda, A. H. J. Am.
Chem. Soc. 2007, 129, 12654–12655. (b) Lee, Y.-J.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 10652–10661.
(8) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382.
(9) (a) Schrock, R. R. In Metathesis Polymerization of Olefins and
Polymerization of Alkynes; Imamoglu, Y., Ed.; Kluwer: Norwell, MA,
1998; p 357. (b) Schrock, R. R.; Luo, S.; Lee, J. C., Jr.; Zanetti, N. C.;
Davis, W. M. J. Am. Chem. Soc. 1996, 118, 3883–3895. (c) Fox, H. H.;
Schrock, R. R. Organometallics 1992, 11, 2763–2765.
Org. Lett., Vol. 13, No. 4, 2011
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In contrast, RCM performed in the presence of W-F6 at a
concentration of 0.05 M yielded endo products 5 and 7 in
60-70% isolated yield.10 When the above transformations
were carried out with W-F6 at a concentration of 0.01 M,
the yield was >90%. A similar trend was observed for
other substrates, such as the aryl-substituted tosylamides 8
and 14, as well as the anilines 10 and 12; use of W-F6 led to
the enyne metathesis products in higher yields.
Table 4. Mo- and W-Catalyzed Enantioselective Ring-Closing
Enyne Metathesisa
Table 3. Enhanced endo-Selectivity by W-based Catalystsa
a-c See Table 1. d Determined by chiral HPLC analysis.
products remained the same, which implies that such reac-
tions proceed through a true enyne metathesis pathway.
a-c See Table 1. d Catalyst (10 mol %) was used.
At least in certain cases, W-based catalysts are more
endo-selective than Mo-based alkylidenes. As shown in
Table 3, enyne metathesis of internal alkyne substrates 16
with Mo-F6 yielded a mixture of endo- and exo-products
in a ratio of 5:1. It is plausible that the sterically less
accessible internal alkyne discourages Mo-alkylidene al-
kyne association as depicted in ii in Scheme 1, pathway 1,
leading to partial reaction through pathway 3 and initia-
tion at the alkene site. An indiscriminate R- and β-addition
of the alkylidene to the internal alkyne may also be
responsible for the low selectivity. The use of W-F6
resulted in a much-improved endo-selectivity of 10:1, albeit
with a lower reaction efficiency; a 10 mol % loading was
necessary to achieve full conversion to the desired product.
We have previously reported examples of enantioselective
enyne metathesis desymmetrization reactions performed
under ethylene. Such processes likely involve cross-metath-
esis with ethylene, followed by enantioselective RCM of the
tetraene intermediate.7b We report here that W-based
catalysts provide enhanced endo- as well as enantioselec-
tivity for desymmetrization of aniline dienyne 12. As
summarized in Table 4, under otherwise identical condi-
tions, while Mo-based catalyst 20 provided a 2.5:1 mixture
of 13 and 19, with only 21% ee for the major isomer 13, the
corresponding W-catalyst 21 yielded a higher ratio (8:1
favoring 13) with an ee of 70%. Both catalysts can be
generated in situ from alcoholysis of the corresponding bis-
pyrrolide complexes. We note that, unlike the reaction
performed in the presence of W-F6, which cleanly yielded
the desired product, the reaction catalyzed by 20 and 21 led
to a significant amount of oligomerization (20-30%).
When the same transformations were carried out in the
presence of ethylene, the endo- and enantioselectivities of the
Table 5. Investigation of Imido Groups for Enantioselective
Ring-Closing Enyne Metathesisa
a-d See Table 4.
We carried out further structural optimization of the
W-based MAP catalysts for enyne metathesis of 12. Initial
efforts focused on screening of various imido groups
(Table 5). Out of four aryl imido groups investigated, the
original 2,6-di-iso-propylphenylimido complexes (as in 21)
emerged as optimal, especially in terms of enantioselec-
tivity. The effect of different chiral phenoxides derived
from monoprotected BINOL or octahydro-BINOLs were
examined next (Table 6). Whereas incorporation of differ-
ent substitution at the 3,30 positions of the chiral diols
(different halides in entries 1, 2, 4 and 5, as well as Me in
entry 3 in Table 6) resulted in less enantioselective reac-
tions, catalyst 22 with a methyl ether unit on the chiral
aryloxide was more reactive and promoted more selective
reactions; cyclic diene 13 was formed in 60% isolated yield
and 81% ee (entry 6, Table 6).11 Further solvent screening
(Table 7) identified diethyl ether as the optimal solvent in
terms of endo-selectivity and enantioselectivity (91% ee),
although the yield of the isolated product was only 35% as
a consequence of significant competitive oligomerization.
(10) See Supporting Information for a direct comparison of crude
NMR spectra of reactions performed with Mo-F6 and W-F6 com-
plexes.
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Org. Lett., Vol. 13, No. 4, 2011

Table 6. Investigation of Aryloxide Groups for Enantioselective
Ring-Closing Enyne Metathesisa
Table 7. Solvent Effect in W-Catalyzed Enantioselective Ring-
Closing Enyne Metathesisa
a-d See Table 4.
W-based catalysts along with Mo-based catalysts in the
context of various applications. The strategies outlined
above, involving Mo- as well as W-based catalysts for
olefin metathesis, will constitute a critical and unique
attribute of the future studies in these laboratories.
a-d See Table 4.
In conclusion, we have demonstrated that W-based
MAP complexes promote more efficient and endo-selective
enyne RCM than the corresponding Mo-based variants;
the most notable distinction is fewer side reactions with
W-based system. The observations described above, along
with the findings concerning Z-selective homocoupling of
terminal olefins,5 underline the importance of examining
Acknowledgment. Financial support was provided by
the National Institutes of Health (GM-59426 to R.R. S.
and A.H.H.). Dr. Annie J. King (MIT) and Dr. Yeon-Ju
Lee (Boston College) are acknowledged for experimental
assistance and helpful discussions.
Supporting Information Available. Experimental proce-
dures and spectral data for products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) Other catalysts possessing a methyl ether of the other chiral diols
were also tested; metathesis reactions withsuch complexes proved tobe less
enantioselective. See the Supporting Information for more screening data.
Org. Lett., Vol. 13, No. 4, 2011
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