Ruthenium-catalyzed ring-closing metathesis to form tetrasubstituted olefins

Article abstract of DOI:10.1021/ol070194o

Figure presented Increased efficiency for ring-closing metathesis to form tetrasubstituted olefins using N-heterocyclic carbene ligated ruthenium catalysts was achieved by reducing the size of the substituants at the ortho positions of the N-bound aryl ri

Full text of DOI:10.1021/ol070194o

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1339-1342
Ruthenium-Catalyzed Ring-Closing
Metathesis to Form Tetrasubstituted
Olefins
Jacob M. Berlin, Katie Campbell, Tobias Ritter, Timothy W. Funk,
Anatoly Chlenov,† and Robert H. Grubbs*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
California 91125
rhg@caltech.edu
Received January 25, 2007
ABSTRACT
Increased efficiency for ring-closing metathesis to form tetrasubstituted olefins using N-heterocyclic carbene ligated ruthenium catalysts was
achieved by reducing the size of the substituents at the ortho positions of the N-bound aryl rings.
Olefin metathesis has emerged as a versatile and powerful
tool for organic and polymer chemistry.1 Ruthenium-based
N-heterocyclic carbene complexes, such as 2-4, possess
activity similar to molybdenum-based complexes, such as
1, yet display high functional group tolerance and air and
moisture stability (Figure 1).2 Nevertheless, there remain
transformations for which molybdenum-based catalysts are
significantly more efficient, such as ring-closing metathesis
(RCM) to form tetrasubstituted olefins.3 In this communica-
tion, we present new ruthenium complexes with increased
efficiency for this transformation.
(3) For progress toward efficient ruthenium-catalyzed RCM to form
tetrasubstituted olefins, see: (a) Kirkland, T. A.; Grubbs, R. H. J. Org.
Chem. 1997, 62, 7310. (b) Clavier, H.; Audic, N.; Guillemin, J.-C.; Mauduit,
M. J. Organomet. Chem. 2005, 690, 3585. (c) Fu¨rstner, A.; Ackermann,
L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel,
O. R. Chem.-Eur. J. 2001, 7, 3236. (d) Michrowska, A.; Bujok, R.;
Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc.
2004, 126, 9318. (e) Fu¨rstner, A.; Ackermann, L.; Beck, K.; Hori, H.; Koch,
D.; Langemann, K.; Liebl, M.; Six, C.; Leitner, W. J. Am. Chem. Soc. 2001,
123, 9000. (f) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204. (g) Ackermann, L.; Fu¨rstner,
A.; Weskamp, T.; Kohl, F. J.; Hermann, W. A. Tetrahedron Lett. 1999,
40, 4787. (h) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (i) Jafarpour, L.; Nolan, S. P. Org. Lett.
2000, 2, 4075. (j) Louie, J.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001,
40, 247. (k) Yao, Q. Org. Lett. 2002, 4, 427. (l) Yao, Q.; Zhang, Y. J. Am.
Chem. Soc. 2004, 126, 74. (m) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan,
S.; Mioskowski, C. Org. Lett. 2000, 2, 1517. (n) Andreana, P. R.; McLellan,
J. S.; Chen, Y.; Wang, P. G. Org. Lett. 2002, 4, 3875. (o) Yao, Q.; Motta,
A. R. Tetrahedron Lett. 2004, 45, 2447.
† Current address: Materia, Inc. 12 N. Altadena Dr., Pasadena, California
91107.
(1) For recent reviews on olefin metathesis, see: (a) Grubbs, R. H.
Handbook of Metathesis; Wiley-VCH: Weinheim, 2003. (b) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012. (c) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
(2) (a) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann,
W. A. Angew. Chem., Int. Ed. 1998, 37, 2490. (b) Weskamp, T.; Kohl, F.
J.; Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem., Int. Ed.
1999, 38, 2416. (c) Huang, J.; Stevens, E. D.; Nolan, S. P.; Peterson, J. L.
J. Am. Chem. Soc. 1999, 121, 2674. (d) Fu¨rstner, A.; Ackermann, L.; Gabor,
B.; Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R.
Chem.-Eur. J. 2001, 7, 3236.
10.1021/ol070194o CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/08/2007

would be effective for the preparation of tetrasubstituted
olefins. Thus, three catalysts (10-12, Figure 2) were
Figure 1. Olefin metathesis catalysts 1-4.
Recently, we developed a standard set of activity com-
parisons for olefin metathesis catalysts.4 During this work,
it was observed that diethyl dimethallylmalonate (5) is a very
challenging substrate for catalysts 2 and 3 (eq 1).
Figure 2. Catalysts 10-12, which show increased efficiency for
RCM to form tetrasubstituted olefins.
prepared with reduced bulk at the ortho positions of the
N-bound aryl rings. Catalyst 10 possesses fluorines at all
four ortho positions.6 Striving to place the smallest possible
substituents at the ortho positions, 11 and 12 were prepared
containing ortho-hydrogens at those positions.7
To compare catalysts 10-12 to catalysts 2 and 3, the ring-
closing reaction of diene 5 using these catalysts was
monitored over time (Figure 3). These reactions were
In the course of our recent work on ruthenium-catalyzed
enantioselective metathesis, a five-membered ring containing
a tetrasubstituted olefin was unexpectedly isolated from the
asymmetric ring-closing reaction of triene 7 catalyzed by
complex 4 (eq 2).5
When triene 7 was treated with achiral catalyst 3, only
the trisubstituted olefin 8 was observed. However, when
catalyst 4 was used, a 70:30 ratio of 8 to the tetrasubstituted
olefin 9 was obtained. We hypothesized that the absence of
one ortho substituent on each N-bound aryl ring of catalyst
4 resulted in the additional space necessary for formation of
the more sterically demanding tetrasubstituted olefin.
It was proposed that catalysts with even less bulk at the
ortho positions than the isopropyl/proton combination of 4
Figure 3. RCM of diethyl dimethallylmalonate (5) at 30 °C.
performed under the conditions developed for standard
activity comparisons (eq 1). All three of the new catalysts
performed significantly better in this reaction than either 2
or 3. Catalysts 10-12 all eventually reached similar conver-
(4) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H.
Organometallics 2006, 25, 5740.
(5) (a) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840. (b) Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2006, 45, 7591.
(6) Ritter, T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128,
11768.
(7) Attempts to replace the tert-butyl groups in 12 with smaller
substituents have resulted in unsuccessful catalyst synthesis.
1340
Org. Lett., Vol. 9, No. 7, 2007

sions. When the reaction temperature was increased to 60
°C, the ring-closing reactions of 5 using catalysts 10-12
reached their maximal conversions in under 24 h.
Using these conditions, catalysts 10-12 were compared
to catalyst 3 for a number of substrates (Table 1). Substrate
product and 40% conversion to the rearranged byproduct.
Interestingly, catalyst 10 gave 43% conversion to the ring-
closed product and no byproduct formation. Ruthenium
hydride species formed from the decomposition of ruthenium
olefin metathesis catalysts are known to catalyze the migra-
tion of olefins at 40 °C in CD2Cl2.9 Repeating the reactions
using 3 and 13 with 10% 2,6-dichloroquinone added to
consume any hydride formed,10 catalyst 3 gave very poor
conversion, but catalyst 12 gave 78% conversion to the ring-
closed product with no byproduct formation. Overall, catalyst
12 performed as well as or better than 3 for all of the
substrates.
Table 1. RCM to Form Tetrasubstituted Olefins*
One concern that remained was the prolonged reaction
time and elevated temperature necessary for these ring-
closing reactions. As can be seen in Figure 3, the ring-closing
reaction of 5 with catalyst 12 displays an induction period,
illustrated by the “S”-shaped reaction profile. This induction
period is even more evident in ring-closing reactions of less-
hindered substrates.11 It was thus proposed that slow initiation
was the primary challenge to catalyst 12’s activity and was
responsible for the need for elevated temperature and
prolonged reaction time.
It is well-known that the initiation rates of catalysts such
as 12 can be altered by varying the ligand trans to the NHC.12
Unfortunately, efforts to vary this position for 12 have been
unsuccessful thus far; however, the unsaturated NHC ana-
logue of 12 is able to accommodate a variety of ligands trans
to the NHC (Figure 4).
a
* NR ) no reaction. CDCl3 used as solvent due to the poor solubility
b
c
of 10 in aromatic solvents. Reaction time: 96 h. Isolated yield not
determined due to product volatility. d 75% consumption of 17. e 10% 2,6-
dichlorobenzoquinone was added. Without 2,6-dichlorobenzoquinone: 60%
conversion to RCM product, 95% consumption of 17.
Figure 4. Unsaturate NHC analogues of 12.
Indeed, the three catalysts 20-22 show dramatically
different reaction profiles (Figure 5). Catalyst 20 performs
the reaction more slowly than 12, as was expected because
the unsaturated analogue of the parent catalyst 2 is less active
5 proved to be uniquely challenging for catalyst 3; for all of
the other substrates, 3 performed in a more similar fashion
to 10-12. None of the catalysts showed any conversion for
18 or 19, precursors to an electron-deficient tetrasubstituted
olefin and a tetrasubstituted olefin in a macrocycle, respec-
tively.8 Substrate 17 warrants further discussion. Use of
catalyst 3 gave a mixture of three compounds, with 43%
conversion to the ring-closed product, 32% conversion to a
rearranged byproduct, and 25% remaining starting material
(17). Use of catalyst 12 resulted in complete consumption
of 17, but with only 60% conversion to the ring-closed
(8) In reference 3f, it was reported that 17 could be ring closed in 43%
yield using the variant of 3 where the NHC is unsaturated. Despite efforts
to reproduce this result under conditions identical to those reported, no
conversion was observed.
(9) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414.
(10) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(11) See Supporting Information for graphs.
Org. Lett., Vol. 9, No. 7, 2007
1341

N-bound aryl rings. All three catalysts performed more
efficiently than known catalysts in the standard ring-closing
reaction of 5 to prepare a tetrasubstituted olefin (6). A brief
examination of other substrates demonstrated that catalyst
12 is the most promising of the new catalysts. Continued
modification of catalyst 12 led to catalyst 22, which shows
extremely promising reactivity for RCM to prepare tetra-
substituted olefins.
Acknowledgment. We gratefully acknowledge Alexandre
Pletnev of Materia, Inc. for work on the synthesis of 12 and
Jean Li of The California Institute of Technology for
preparing 14 and 18. T.R. thanks the German Academic
Exchange Service (DAAD) for a postdoctoral fellowship.
K.C. thanks the NSERC for a postdoctoral fellowship.
Supporting Information Available: Synthesis, charac-
terization, and NMR spectra of new compounds and further
activity plots for 10-12 and 20-22. Reaction conditions for
RCM are also included. This material is available free of
charge via the Internet at http://pubs.acs.org.
Figure 5. Comparison of catalysts 20, 21, and 22 to 12 for RCM
of diethyl dimethallylmalonate (5) at 30 °C.
than 2.13 Catalyst 21 displayed a dramatically enhanced rate
of initiation, reaching 43% conversion in just 1 h, but this
catalyst also displayed dramatically reduced stability, as the
maximal conversion was only 51%. Catalyst 22 was prepared
to test a rapidly initiating catalyst that lacked phosphine, and
pleasingly rapid initiation and good stability were observed
as 90% conversion was achieved in just 1.5 h!14
OL070194O
(12) (a) Hejl, A.; Day, M. W.; Grubbs, R. H. Organometallics 2006,
25, 6149. (b) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.;
Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318. (c) Love, J.
A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 10103. (d) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002,
41, 2403.
(13) For example, see: Sanford, M. S.; Love, J. A.; Grubbs, R. H. J.
Am. Chem. Soc. 2001, 123, 6543.
(14) A more detailed graph for the use of catalyst 22 is included in the
Supporting Information.
On the basis of an unexpected result from enantioselective
ring-closing metathesis, three new catalysts (10-12) were
prepared with reduced bulk at the ortho positions of the
1342
Org. Lett., Vol. 9, No. 7, 2007