Catalytic C-H amination for the preparation of substituted 1,2-diamines

Article abstract of DOI:10.1021/ja803344v

Rhodium-catalyzed C-H insertion of hydroxylamine-derived sulfamate esters makes possible the synthesis of unique oxathiadiazinane heterocycles, which upon mild reduction furnish differentially substituted 1,2-diamine products. This highly chemo- and diastereoselective transformation underscores the power of catalytic C-H functionalization as a general approach to C-N bond construction. Copyright

Full text of DOI:10.1021/ja803344v

Published on Web 08/05/2008
Catalytic C-H Amination for the Preparation of Substituted 1,2-Diamines
David E. Olson and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received May 6, 2008; E-mail: jdubois@stanford.edu
Table 1. Evaluating Reaction Conditions for C-H Amination
Vicinal diamines appear frequently as structural units in
biological and medicinal molecules of interest and as auxiliary
groups or ligands for catalytic processes.1 The rich and varied
applications for 1,2-diamines belie the rather modest number of
general methods for the efficient preparation of such com-
pounds.2 Accordingly, we have attempted to capitalize on the
power of sulfamate ester C-H amination to address this problem
(Figure 1).
Figure 1. A two-step protocol for the preparation of 1,2-diamines.
The high performance of sulfamate esters in amination reactions
and their propensity to form six-membered oxathiazinane products
inspired our investigation of sulfamates fashioned from N-alkyl-
hydroxylamines.3 Catalytic C-H insertion of such substrates affords
unique [1,2,3,6]-oxathiadiazinane-2,2-dioxide heterocycles that can,
in principle, be reduced to yield differentially protected 1,2-
diamines.4 Rhodium-catalyzed intramolecular C-H insertion of
ureas and guanidines also gives cyclic products, which may be ring-
opened to furnish analogous diamine derivatives;5 however, hy-
drolysis of such heterocycles generally requires forcing conditions
incompatible with other attendant functional groups.2i,5,6
Initial attempts to effect intramolecular C-H insertion with
O-sulfamoyl-N-alkylhydroxylamine derivatives using a dirhod-
ium catalyst and PhI(OAc)2 led only to rapid substrate decom-
position. We ascribed this result to the presence of the
nucleophilic hydroxylamine moiety and thus proceeded to
examine the effect of an electron-withdrawing substituent on
the nitrogen center. While some success was realized with
N-Boc- and N-formyl-derived substrates (entries 1 and 2, Table
1), the positive influence of the sulfonyl group on the reaction
outcome was pronounced (entries 3 and 4). The stark differences
in performance between these substrates may be due to the planar
nature of the nitrogen center (sp2-like) in both the Boc and
formyl structures, which we believe induces considerable strain
in the developing product, thereby disfavoring cyclization.
Accordingly, the p-methoxybenzenesulfonyl (Mbs) derivative
was selected for further optimization studies.
The incorporation of an Mbs group in our substrate design has
facilitated the preparation of these unique sulfamate starting
materials. Such compounds are easily synthesized under Mitsunobu
conditions from simple alcohols and MbsNHOSO2NH2, a crystalline
reagent available from MbsCl in two steps.7 Oxidative cyclization
of this class of sulfamate esters occurs most effectively when
catalyzed by either Rh2(oct)4 or Rh2(esp)2 (entries 4 and 10, Table
1).8 The influence of solvent on reaction performance reveals
benzene and EtOAc to be optimal (entries 4 and 7), and, as with
other C-H amination protocols that we have developed, MgO is a
useful additive for this process.
a Reactions were performed with 2 mol % of catalyst, 2.3 equiv of
MgO, and 1.1 equiv of PhI(OAc)2. b Isolated yields; values in
parentheses denote percent conversions based on integration of the
unpurified 1H NMR spectrum.
Evaluation of the reaction scope highlights a substrate profile
similar to other Rh-catalyzed C-H amination processes (Table 2).
Hydroxylamine-derived sulfamates display a strong bias to form
six-membered ring products; in addition, oxidation of 3° C-H
bonds is generally most effective. One of these examples (entry
2), in which amination is achieved at an R-carbonyl center, affords
a product heterocycle that may be transformed into the correspond-
ing R,ꢀ-diaminopropionic acid. This type of structure appears with
some frequency in both natural and synthetic molecules of import.9
In addition to 3° C-H oxidation, amination of R-ethereal and
benzylic C-H bonds is also quite favorable (entries 4 and 5). In
these instances, however, direct isolation of the resulting oxathia-
diazinanes is impaired due to their instability on silica gel.
Fortunately, the yields of the insertion reactions are sufficiently
high in most cases to enable subsequent manipulation of the
unpurified materials (vide infra). Finally and as noted previously
with unsaturated sulfamate derivatives, intramolecular aziridination
is quite efficient and often outcompetes the C-H insertion event
(entries 6-8).3
The ease with which oxathiadiazinane heterocycles may be
converted to the corresponding 1,2-diamine products is a
hallmark of this chemistry (Figure 2). Reduction of the N-O
bond using Zn(Cu) couple followed by treatment with methanolic
HCl affords the monoprotected 1,2-diamine in high yield. The
effectiveness of these conditions and the performance of the
C-H insertion make possible direct reduction of heterocyclic
products that are otherwise difficult to isolate using chromato-
graphic methods. Examples of this two-step protocol are shown
in Figure 2. Following the C-H insertion event, filtration of
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2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Oxidative Cyclization of Novel Sulfamate Esters
the reaction mixture and subsequent treatment with Zn(Cu)
furnishes the desired diamine. These findings also reveal that
1,2-diamine products can be generated with modest to high levels
of diastereocontrol from chiral starting materials.
Rhodium-catalyzed C-H oxidation affords a unique family
of oxathiadiazinane structures that serve as intermediates en route
to differentially protected 1,2-diamines. The high levels of
chemoselectivity and broad substrate scope exemplary of related
amination reactions underscore this method.3 This chemistry is
further enabled with the advent of straightforward protocols for
assembling the requisite hydroxylamine-derived substrates and
for the reductive opening of the product heterocycles. The
availability of such technologies should elevate Rh-catalyzed
C-H amination as a general method for C-N bond formation
in synthesis.
Acknowledgment. We thank Dr. Benjamin Brodsky and
Nichole D. Litvinas for helpful discussions. D.E.O. gratefully
acknowledges Eli Lily for a graduate fellowship. This work has
been supported by the National Institutes of Health and by generous
gifts from Pfizer, Amgen, and GlaxoSmithKline.
Supporting Information Available: Experimental details and
analytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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equiv of MgO, and 1.1 equiv of PhI(OAc)2. b Conversion based on
integration of the unpurified 1H NMR spectrum. c Reaction performed
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Figure 2. Reductive N-O cleavage furnishes 1,2-diamine derivatives.
Products purified by HPLC using H2O/CH3CN/CF3CO2H.
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