Expanding the scope of C-H amination through catalyst design

Article abstract of DOI:10.1021/ja0446294

Analysis of the mechanism for Rh-mediated C-H amination has led to the development of a remarkably effective dinuclear Rh catalyst derived from 1,3-benzenedipropionic acid. This unique complex, Rh₂(esp)₂, is capable of promoting both

Full text of DOI:10.1021/ja0446294

Published on Web 11/09/2004
Expanding the Scope of C-H Amination through Catalyst Design
Christine G. Espino, Kristin Williams Fiori, Mihyong Kim, and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received September 3, 2004; E-mail: jdubois@stanford.edu
Catalytic methods for intramolecular C-H bond amination are
finding increased application in synthesis owing to their efficiency,
predictable selectivity, and the value of the heterocycles produced
(Figure 1).1-3 To add further to the versatility of such processes,
we have endeavored to gain mechanistic knowledge that could aid
with the invention of new, robust catalyst systems. These efforts
have culminated in the design and synthesis of Rh2(esp)2, a tethered
dicarboxylate-derived complex that shows superior catalytic activity
for intramolecular C-H oxidation with sulfamate, sulfamide, and
urea substrates. Of added note, the marked performance of Rh2(esp)2
has allowed us to delineate effective protocols for the intermolecular
conversion of C-H bonds to C-N centers. Collectively, such
findings advance C-H amination as a general tool for the
construction of nitrogen-containing structures.
Figure 2. Preparation and X-ray analysis of [Rh2(esp)2‚(acetone)2].
Scheme 1
Figure 1. Rh-catalyzed oxidation of sulfamate and carbamate esters.
(Figure 2).11 Ligand metathesis has been conducted routinely on
300 mg of the starting trifluoroacetate dimer, and the desired
complex is readily isolated by chromatography on silica gel. Single-
crystal X-ray analysis of Rh2(esp)2 confirmed an initial structural
assignment based on 1H NMR and mass spectrometry. The ORTEP
diagram shows the m-xylene spacer to be an optimal bridge for
the two carboxylate moieties. Additionally, two acetone solvent
molecules are coordinated in axial positions along the Rh-Rh
vector, the site at which it is assumed substrate binding and
oxidation occur.
An understanding of the reaction mechanism for Rh-promoted
nitrene insertion is of principal importance for further development
of such processes. Our investigation thus far has provided direct
evidence that the dinuclear Rh catalyst undergoes structural changes
within minutes of initiating the reaction.4 The inclusion of MgO
or other soluble bases (e.g., 2,6-di-tert-butylpyridine) seemed to
have little effect in preventing speciation of the Rh complex.
Tetracarboxylate Rh dimers, while stable to many conditions,
including strong acid, participate freely in ligand exchange reac-
tions.5 We hypothesized that carboxylate detachment from the
dinuclear Rh core was responsible for catalyst degradation. Ac-
cordingly, the joining of two carboxylate ligands through an
appropriately spaced linker would confer added stability to these
complexes.6 In the event that carboxylate shifts were to occur, the
chelate effect would disfavor complete ligand dissociation from
the metal centers.7 Such strategies for catalyst design are inspired
by the inventive work of Taber and Davies for Rh-mediated
diazodecomposition reactions.8,9
m-Benzenedipropionic acid 1 was selected for exploratory studies
as this ligand had been shown to exchange with Rh2(O2CCF3)4 to
give Rh2(mbdp)(O2CCF3)2 2 (Scheme 1).8,10 In our hands, however,
2 proved catalytically inactive for C-H amination with sulfamates.
Attempts to replace the two trifluoroacetate groups in the Taber
complex with a second m-benzenedipropionate were unsuccessful,
affording only intractable polymeric materials. We reasoned that
substitution of the methylene groups in 1 would confer some degree
of preorganization to an otherwise conformationally unconstrained
ligand.6 The tetramethylated m-benzenedipropionic acid 4 was
identified and could be conveniently accessed in gram quantities
from the commercial xylene dichloride 3. Substitution of this
dicarboxylate onto Rh2(O2CCF3)4 proceeded with remarkable
facility and afforded the desired Rh2(esp)2 complex in 64% yield
Rh2(esp)2 has proven to be an exceptionally effective and general
catalyst for C-H amination. Nitrene insertion of substrates pos-
sessing 3° C-H bonds (e.g., 5) may be conducted at catalyst
loadings as low as 0.15 mol %; quantitative conversion of starting
material to product is observed (Figure 3). By contrast, reaction of
sulfamate 5 using the isosteric Rh2(O2CtBu)4 complex (0.15 mol
%) furnishes only 20% of the desired heterocycle. Considerable
benefit is gained from Rh2(esp)2 for oxidation of substrates having
unactivated methylene units. In one such example, a 1 mol % charge
of Rh2(esp)2 is sufficient for the complete reaction of n-butylsulfa-
mate 7. It should be noted that sulfamates exemplified by 7 offer
perhaps the most stringent test for new catalysts as such compounds
have proven to be among the most difficult for efficient
oxidation.1a,b,12 Accordingly, five times as much Rh2(O2CtBu)4 must
be used with 7 to reach only moderate levels of oxathiazinane
formation (∼75%).13
The dramatic improvement in catalyst activity witnessed with
Rh2(esp)2 and sulfamates extends to alternative substrate types. For
the first time, we are able to effect high yields of heterocyclic
product formation with urea 9 and sulfamide 11 starting materials
(Figure 4).14 Such reactions afford a direct synthesis of 1,2- and
1,3-diamine derivatives from easily accessible starting materials.15
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10.1021/ja0446294 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Acknowledgment. The authors thank X. Ottenwaelder and
X. Xie for performing the X-ray crystallographic analysis.
C.G.E. and K.W.F. gratefully acknowledge the National Science
Foundation for pre-doctoral awards. C.G.E. is also the recipient
of graduate fellowships from Pfizer and the ACS Division of
Organic Chemistry, sponsored by Merck Research Laboratories.
This work has been supported by a grant from the NSF (CHE-
0110362) and through generous gifts from Abbott, Amgen,
Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Glaxo-
SmithKline, Merck, Pfizer, and Roche.
Figure 3. Comparative data of Rh2(esp)2 and Rh2(O2CtBu)4 as catalysts
for intramolecular C-H amination with sulfamates.
Supporting Information Available: Experimental protocols for
the preparation of Rh2(esp)2 and all reactions performed with this
catalyst are included along with analytical and X-ray crystallographic
data. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For recent reviews on C-H amination, see: (a) Dauban, P.; Dodd, R. H.
Synlett 2003, 1571-1586. (b) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103,
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600. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
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Figure 4. Oxidative cyclization of urea and sulfamide substrates.
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4559.
Figure 5. Intermolecular C-H insertion with catalytic Rh2(esp)2.
Encouraged by the performance of Rh2(esp)2 for intramolecular
C-H amination, a preliminary examination was made of the
corresponding intermolecular oxidation reaction (Figure 5). Prior
reports of such processes using Mn, Fe, Ru, Rh, and Cu complexes
suffer from low product conversions and/or a requirement for excess
substrate (5-100 equiv).1,3,16 By employing trichloroethylsulfamate
14 as the N-atom source,17 we have found that 2 mol % Rh2(esp)2
is sufficient to convert 1 equiv of ethylanisole 13 to the aminated
product 15 in 71% yield. Higher yields of 15 (84%) may be obtained
with 2 equiv of substrate. Similar findings have been recorded for
C-H insertion with cyclooctane 16. These results stand in contrast
to intermolecular experiments performed with 2 mol % Rh2(O2CtBu)4,
which gives at best 20% yield of insertion product 17 when 5 equiv
of cyclooctane is employed.
Guided by mechanistic postulates and prior art, we have prepared
and characterized Rh2(esp)2, a novel catalyst for C-H amination
reactions that operates with uncommon activity. Despite the nonrigid
nature of the tethered dicarboxylate ligand, Rh2(esp)2 assembles in
high yield and is considerably more resilient as a catalyst than its
mono-carboxylate counterpart. The invention of dimeric Rh struc-
tures based on analogous ligand designs should further enable
methods for both intra- and intermolecular C-H amination.
(11) See Supporting Information for details.
(12) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210-4212.
(13) Espino, C. G. Ph.D. Thesis, Stanford University, Stanford, CA, 2004.
(14) Analogous reactions performed using Rh2(oct)4 or Rh2(O2CCPh3)4 afforded
product yields below 40%. A full account of studies with urea and
sulfamide substrates will be forthcoming.
(15) For alternative methods to cyclic sulfamides and applications thereof,
see: (a) Nicolaou, K. C.; Longbottom, D. A.; Snyder, S. A.; Nalbanadian,
A. Z.; Huang, X. Angew. Chem., Int. Ed. 2002, 41, 3866-3870 and
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L.; Aouf, N.-E.; Montero, J.-L. Tetrahedron 2003, 59, 6051-6056.
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(17) We have employed 14 previously for intermolecular olefin aziridination
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