Catalytic metallonitrene/alkyne metathesis: A powerful cascade process for the synthesis of nitrogen-containing molecules

Article abstract of DOI:10.1021/ja7111788

A conceptually novel metallonitrene/alkyne metathesis cascade reaction has been developed for the construction of nitrogen-containing compounds from simple alkyne starting materials. Rhodium(II) tetracarboxylate salts are efficient catalysts for this reaction, in which an electrophilic rhodium nitrene is trapped by an alkyne, resulting in the formation of a new C-N bond and the generation of a reactive metallocarbene for cascade reaction. The reaction is tolerant of both alkyl and aryl substituents on the alkyne, and proceeds at room temperature in a variety of common solvents. The modular nature of the reaction allows for the rapid construction of congested bicyclic systems from remarkably simple alkyne starting materials. Copyright

Full text of DOI:10.1021/ja7111788

Published on Web 03/20/2008
Catalytic Metallonitrene/Alkyne Metathesis: A Powerful Cascade
Process for the Synthesis of Nitrogen-Containing Molecules
Aaron R. Thornton and Simon B. Blakey*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Received December 17, 2007; E-mail: sblakey@emory.edu
Table 1. Optimization of Reaction Parameters for the
Metallonitrene/Alkyne Metathesis Reaction
The direct incorporation of nitrogen-containing functionality
into simple organic hydrocarbons represents an attractive
strategy for the synthesis of biologically important natural
products, pharmaceutical agents, and novel materials. Transition
metal catalysts capable of supporting reactive metallonitrenes
have been developed for both C–H amination1,2 and olefin
aziridination reactions.3 In this context, considerable effort has
been invested exploring many different metal catalysts. Rh,4
Cu,5 Ru,6 Mn,7 and Ag,8 supported by a diverse range of ligands,
are all commonly utilized. Despite this catalyst diversity, the
chemistry of reactive metallonitrenes remains limited to two
general classes of reaction (C–H amination, olefin aziridination).
The rich chemistry of analogous metallocarbene species9 stands
in stark contrast to the paucity of metallonitrene chemistry, and
has inspired us to investigate catalysts that utilize metallonitrenes
for conceptually novel C–N bond forming reactions.
entry
catalyst
solvent
% yielda
1
2
3
4
5
6
7
Rh2(OAc)4
Rh2(TPA)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
IPACe
72
78
b
85 (67)d
85
c
73
81
84
Et2O
t-BuOMe
In this Communication, we report the development of a new
metallonitrene/alkyne metathesis reaction (eq 1). We envisaged
a process in which a metallonitrene species would react with
an alkyne, leading to a zwitterionic intermediate. A [1,3] metal
shift would complete the metathesis, generating a new imine
and a reactive metallocarbene to cascade into further C–C, C–O,
or C–N bond-forming reactions.
a Determined by GC assay. b TPA ) triphenylacetate. c Rh2(esp)2
)
Rh2(R,R,R′,R′-tetramethyl-1,3-benzenedipropionate). d isolated yield.
e IPAC ) i-propylacetate.
nitrene intermediate 3 generating a transient vinyl cation 4
(Scheme 1). This vinyl cation can undergo a [1,3] rhodium shift,
to give the anticipated intermediate metallocarbene 5, or collapse
directly to oxonium ylide 6. Subsequent rearrangement produces
N-sulfonyl imine 7 and stereoselective reduction gives the stable
bicyclic product 2.11
Scheme 1. Proposed Mechanism for the Rh(II)-Catalyzed Cascade
Reaction
Dirhodium(II) tetracarboxylate salts were identified as prom-
ising catalysts for this metathesis reaction, as they are known
to support both reactive metallonitrene and metallocarbene
ligands. Equally importantly, they have also been shown to
catalyze metallocarbene/alkyne metathesis cascades analogous
to the new reaction outlined in eq 1.10
We initiated our study by examining the oxidative cyclization
of sulfamate ester 1 using a variety of dirhodium(II) tetracar-
boxylate salts as catalysts (Table 1). To our delight, treatment
of 1 with stoichiometric bisacetoxyiodobenzene and catalytic
Rh2(OAc)4 gave, after reductive workup, oxathiazepane 2 (72%
conversion, entry 1). This cascade process results in the forma-
tion of a new C–N bond, a C–O bond, and a C–C bond, and
generates a sterically congested bicyclic system from a remark-
ably simple starting material, demonstrating the power of this
new metallonitrene reaction. The reaction is efficiently catalyzed
by a range of dirhodium(II) tetracarboxylate salts (entries 1–3)
in a variety of common solvents (entries 3–7). The electron
deficient Rh2(TFA)4 failed to give the desired metathesis
product. Du Bois’ Rh2(esp)2 catalyst is particularly effective
for all the substrates we have investigated to date (Table 2).2e
Mechanistically, cyclization of the sulfamate ester onto the
distal alkyne carbon precludes a [2 + 2] metathesis mechanism.
We propose that that the alkyne attacks the electrophilic rhodium
When substrate 1 is exposed to Rh2(esp)2 in the absence of
an oxidant, no reaction is observed and starting material is
cleanly recovered after 24 h. Similarly no reaction is observed
when the sulfamate ester is replaced with a methyl ether, and
the reaction is conducted in the presence of both Rh2(esp)2 and
stoichiometric oxidant. These experiments indicate that the
rhodium(II) catalyst does not promote the reaction by activating
the alkyne for attack by the allyl ether (Scheme 2), and strongly
suggest that the reaction is initiated by metallonitrene formation.
9
5020 J. AM. CHEM. SOC. 2008, 130, 5020–5021
10.1021/ja7111788 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for the Intramolecular Metallonitrene/
alcohol-based substrates (e.g., entry 4). Instead, products arising
from intermolecular metallonitrene insertion into the activated
benzylic C–H bonds of the substrate were observed.
Alkyne Metathesis Cascadea
When the tether length is extended (e.g., substrate 8, entry
5), preference for seven-membered ring formation remains, and
the product resulting from cyclization onto the proximal carbon
of the alkyne is observed, albeit in reduced yield. In this case
competitive metallonitrene insertion into the propargylic C–H
bond is also observed.11b To date we have demonstrated that
7,6 and 7,5 bicyclic ring systems can be readily assembled using
this methodology and that benzyl and allyl units are cleanly
transferred in the cascade process.
Alkyl and aryl substituents are tolerated at either terminus of
the alkyne, leading to a diverse array of products. The reaction of
substrate 9 (entry 6) is particularly noteworthy, as the geometric
preference for seven-membered ring formation remains dominant,
despite the fact that formation of the regioisomeric six-membered
ring product would proceed via a benzylic cation intermediate.
Although the sulfonyl imine generated in the cascade process
can be isolated,11 we have found it operationally convenient to
reduce the imine in situ with sodium borohydride. Additionally,
the imine can be trapped in situ with Grignard reagents, increasing
the molecular complexity generated in the reaction (entries 7, 9).
The cyclic sulfamate ester is readily displaced under mild
conditions, revealing both the amine and alcohol functionality,
facilitating further elaboration of the products from this reaction.2b
In summary, we have developed a conceptually novel
catalytic metallonitrene reaction for the construction of nitrogen
containing compounds. The cascade process facilitates the
assembly of complex bicyclic structures from readily assembled
alkyne starting materials.
Acknowledgment. We thank Kenneth Hardcastle and Rui
Cao for X-ray crystallography.
Supporting Information Available: Experimental procedures,
structural proofs, 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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a Reaction conditions: 2 mol % Rh2(esp)2, 1.1 equiv PhI(OAc)2,
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The intramolecular metallonitrene/alkyne metathesis reaction
is effective for cyclizing sulfamate esters of homopropargylic
alcohols, giving seven-membered ring products exclusively
(Table 2, entries 1–3, 5–9). However, the geometric constraints
of the sulfamate ester tether prevent cyclization of propargyl
(11) (a) The imine products can be isolated, but are sensitive to hydrolysis on
purification. (b) See Supporting Information for details.
JA7111788
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