aimed at dramatically decreasing catalyst loadings for the
synthesis of carbamate-protected cyclic amines from the typi-
cally reported 2-5 mol %1g,4 (i.e., 20,000-50,000 ppm) to
as low as 500 ppm. In order to examine the widest possible
variety of catalysts and conditions, we have utilized the
precision and consistency of Symyx robotic technology to
quickly screen a large number of RCM reactions using ppm
catalyst loadings.8 Several groups have recently demonstrated
the value of robotic systems to study catalyst efficiencies,
reaction conditions and new applications in olefin metathe-
sis.6 Aiming to limit the economic and environmental costs
of the process, we performed our screening in as concentrated
a state as possible, up to the use of neat reagents.
Due to the wide variety of catalysts now available, the
judicious choice of one catalyst for any particular application
can be a daunting challenge. There are many substrate-
dependent variables as well as catalyst stability, activity, and
initiation rate considerations that determine catalyst efficiency
for a given reaction. Therefore, it is important to examine
and understand trends in relative catalyst efficiencies based
on both reaction conditions and substrate design. With this
in mind, several commercially available catalysts along with
recently reported variants were utilized in this study (Figure
1), reaffirming the notion that no single catalyst is best for
all olefin metathesis applications.1f,6c,d
Our research focused on the RCM of carbamate-protected
acyclic amines to form the corresponding di-, tri-, and
tetrasubstituted five-, six-, and seven-membered carbamate-
protected cyclic amines (eq 1); where m and n ) 1 or 2,
which are valuable intermediates in organic synthesis and
pharmaceuticals.3h,j
Initial reaction parameters were chosen on the basis of
the results from a recent complementary study on catalyst
efficiency.6a In that work methylene chloride, a solvent often
used in olefin metathesis reactions, was shown to greatly
decrease catalyst efficiency and was therefore not utilized
in our experiments.6a Instead, methyl tert-butyl ether (MTBE)
and toluene were utilized. Both solvents consistently provided
excellent yields throughout our studies. MTBE, in particular,
is a prudent alternative to chlorinated solvents and other
peroxide-forming ethers.
Figure 1. Ruthenium-based olefin metathesis catalysts (Mes )
2,4,6-trimethylphenyl).
ing N-aryl steric bulk (7 and 8) on the N-heterocyclic carbene
(NHC) and adding methyl groups to the backbone (9 and
10) have greatly increased activity and stability, allowing
for efficient synthesis of highly hindered olefin products.5d,e,6
Despite their effectiveness, the use of homogeneous olefin
metathesis is limited by high catalyst costs and the often difficult
purification of products from residual ruthenium.7 A unified
approach to address both of these issues is to use lower catalyst
loadings in the metathesis event. Herein we report our studies
While increased temperatures have previously been shown
to improve metathesis efficiency,6c,3h temperatures above 55
°C decreased assay consistency and resulted in solvent losses.
(5) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751–
1753. (c) Romero, P. E.; Piers, W. E.; McDonald, R. Ang. Chem., Int. Ed.
2004, 43, 6161–6165. (d) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin,
J. M.; Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592. (e) Chung,
C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693–2696.
(3) For recent examples, see: (a) Enquist, J. E.; Stoltz, B. M. Nature
2008, 453, 1228–1231. (b) White, D. E.; Stewart, I. C.; Grubbs, R. H.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810–811. (c) Pfeiffer, M. W. B.;
Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–5335. (d) Humphrey,
J. M.; Liao, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin,
S. F. J. Am. Chem. Soc. 2002, 124, 8584–8592. (e) Martin, S. F.; Humphrey,
J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866–867. (f)
Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew.
Chem., Int. Ed. 1997, 36, 166–168. (g) Ferguson, M. L.; O’Leary, D. J.;
Grubbs, R. H. Org. Synth. 2003, 80, 85–88. (h) Wang, H.; Goodman, S. N.;
Dai, Q.; Stockdale, G. W.; Clark, W. M., Jr. Org. Process DeV. 2008, 12,
226–234. (i) Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process
DeV. 2005, 9, 513–515. (j) Peakdales Moleculars spirodiamines http://
(6) (a) Kuhn, K. M.; Bourg, J. B.; Chung, C. K.; Virgil, S. C.; Grubbs,
R. H. J. Am. Chem. Soc. 2009, 131, 5313–5320. (b) Matson, J. M.; Virgil,
S. C.; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 3355–3362. (c) Bieniek,
M.; Michrowska, A.; Usanov, D. L.; Grela, K. Chem.sEur. J. 2008, 14,
806–818. (d) Blacquiere, J. M.; Jurca, T.; Weiss, J.; Fogg, D. E. AdV. Synth.
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(7) Governmental recommendations for residual ruthenium in pharma-
ceuticals are now routinely less than 10 ppm. For recent guidelines, see:
(a) Zaidi, K. Pharmacopeial Forum 2008, 34, 1345–1348. (b) Criteria given
in the EMEA Guideline on the Specification Limits for Residues of Metal
(8) See Supporting Information for details on the use of the Symyx robot.
Ethylene was vented to the glovebox in these reactions.
(4) (a) Fu, G. C.; Nguyen, S.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856–9857. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
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