Oxaziridine-mediated intramolecular amination of sp3-hybridized c-h bonds

Article abstract of DOI:10.1021/ja906183g

(Chemical Equation Presented) We describe a new oxaziridine-mediated approach to the amination of sp³-hybridized C-H bonds. In the presence of a copper(II) catalyst, N-sulfonyl oxaziridines participate in efficient intramolecular cyclization re

Full text of DOI:10.1021/ja906183g

Published on Web 08/17/2009
Oxaziridine-Mediated Intramolecular Amination of sp3-Hybridized C-H Bonds
Charles P. Allen, Tamas Benkovics, Amanda K. Turek, and Tehshik P. Yoon*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received July 23, 2009; E-mail: tyoon@chem.wisc.edu
1
Dioxiranes and oxaziridines are members of a class of three-
membered heterocyclic oxidants that perform a variety of atom-transfer
reactions.1,2 Among the most intriguing of these reactions is the
dioxirane-mediated hydroxylation of unactivated sp3-hybridized C-H
bonds.3 The intramolecular version of this reaction, first reported by
Yang, exhibits high regioselectivity for the δ position of the dioxirane.4
Oxaziridines, which are significantly more stable than dioxiranes, also
perform a variety of hydrocarbon oxidations; however, only oxaziri-
dines that bear strongly electron-withdrawing substituents have previ-
ously been shown to be reactive enough to oxidize C-H bonds.5 In
this communication, we report that activation of N-sulfonyl oxaziridines
using copper(II) induces the regioselective intramolecular amination
of sp3-hybridized C-H bonds.
at the γ methylene could be observed by H NMR analysis of the
unpurified reaction mixture. The product of the reaction is formed as
an inseparable mixture of ring-opened and -closed isomers, which
undergo efficient reductive amination to furnish a single tetrahydroiso-
quinoline product in 81% yield over two steps.
Table 1. Aminations with Dihydrostilbene-Derived Oxaziridinesa
Our lab has been investigating novel reactions of oxaziridines
that occur in the presence of transition-metal catalysts.6 Recently,
we discovered that the copper(II)-catalyzed aminohydroxylation
developed in our lab exhibits a marked rate acceleration in the
presence of anionic halide and pseudohalide additives.7 The
increased reactivity of this system led us to consider whether these
conditions might also enable the oxidative functionalization of
more challenging substrates such as alkanes.
As a starting point for our investigations, we prepared N-sulfonyl
oxaziridine 1 bearing an ortho alkyl substituent on the C-aryl group.
Subjecting 1 to conditions optimized for the aminohydroxylation7
afforded low yields of two regioisomeric aminals (2 and 3) resulting
from C-H bond amination (eq 1):
a See the Supporting Information for full experimental details.
b Isolated yields of the product after reductive amination. c Refers to the
yield of the isolated aminal, which was not stable under the reductive
amination conditions. Only the syn diastereomer was observed.
Table 1 summarizes experiments probing structural variation of the
dihydrostilbene-derived oxaziridine. The reaction appears to be
relatively insensitive to electronic perturbation of the tethering arene
(entries 2 and 3). Electron-donating and -withdrawing substituents on
the terminal arene are also tolerated (entries 4-8), although the reaction
times in the latter case prove to be longer. A variety of functional
groups are tolerated in the cyclization; the presence of ethers, esters,
aryl halides, carbamates, and alcohols do not affect the efficiency of
the reaction. In all cases, the amination is highly regioselective;
functionalization of the γ position is observed only when the length
of the tether is shortened by one carbon, although this modification
results in somewhat longer reaction times (entry 9).
We also explored the reactions of substrates bearing aliphatic
linkers (Table 2). Oxaziridine 5 undergoes efficient cyclization
under our optimized conditions and eliminates H2O upon treatment
with acid to furnish the corresponding enamide in good yield (entry
1). The presence of substituents that bias the conformation of the
chain toward cyclization proved to be essential for efficient
amination; the corresponding substrate lacking gem-dimethyl sub-
stituents produced the cyclized product in only 13% yield (entry
2). On the other hand, dioxolane-linked oxaziridines are also suitable
substrates for this method; acidic hydrolysis furnishes the corre-
This result was remarkable for several reasons. First, we were
surprised to observe formation of a new C-N bond, as we had
expected to observe oxygen atom transfer reactivity consistent with
the characteristic oxenoid reactivity of oxaziridines.8 To the best
of our knowledge, this represents the first example of formal
nitrogen atom transfer from an N-sulfonyl oxaziridine. Second, there
has been considerable interest in the development of methods for
the amination of sp3-hybridized C-H bonds.9 Our approach is a
mechanistically distinct complement to the metal nitrenoid chem-
istry that has enjoyed the most success in this field. Finally, despite
the low regioselectivity observed in this initial experiment, we were
intrigued by the observation that the major product arose from
functionalization of the stronger, unactivated δ C-H bond rather
than the weaker neighboring benzylic γ C-H bond.
Given these results, we wondered whether an oxaziridine bearing
electronically similar γ and δ methylene units might exhibit a stronger
regiochemical preference. Indeed, under optimized conditions (2 mol
% CuCl2, 4 mol % LiCl, 0.1 M in acetone), dihydrostilbene-derived
oxaziridine 4 undergoes efficient intramolecular C-H amination with
exclusive functionalization at the δ position (eq 2); no trace of reaction
9
12560 J. AM. CHEM. SOC. 2009, 131, 12560–12561
10.1021/ja906183g CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthetic Manipulations of Aminal Intermediatesa
sponding 4-piperidones in good yield (entries 3-6). The amination
is not limited to benzylic C-H bonds; alkynes are efficient
activating groups as well (entry 7). Notably, cyclizations of
oxaziridines with aliphatic tethers are δ-selective even when the
functionalization occurs at unactivated methylene units (entry 8).
This high positional selectivity is observed even when an adjacent
benzylic methylene is present in the substrate (entry 9).10,11
Table 2. Aminations with Oxaziridines Bearing Aliphatic Tethersa
a Reagents and conditions: (a) 2-(trimethylsilyloxy)propene, BF3OEt2,
CH2Cl2, -78 to 23 °C; (b) allyltrimethylsilane, BF3OEt2, CH2Cl2, -78 to
23 °C; (c) methyltriphenylphosphonium bromide, n-BuLi, -78 to 23 °C;
(d) IBX, DMSO, 90 °C.
In summary, we have demonstrated that N-sulfonyl oxaziridines
participate in efficient, regioselective intramolecular C-H bond
amination reactions. This new reactivity is the first example of formal
nitrogen atom transfer from N-sulfonyl oxaziridines and constitutes a
fundamentally novel method for amination of sp3-hybridized C-H
bonds. The ability to construct the structurally diverse heterocyclic
compounds produced by this reaction should be useful in the synthesis
of biologically active and medicinally relevant organic compounds.
Acknowledgment. Financial support for this research was
provided by an NSF CAREER Award (CHE-0645447) and the NIH
(R01-GM084022). The NMR spectroscopy facility at UW-Madison
is funded by the NSF (CHE-9629688).
a See the Supporting Information for full experimental details.
b Isolated yields of the dihydropyridine product after treatment with
acid. c Reaction conducted using 10 mol % CuCl2 at 40 °C.
To account for the C-N bond-forming process, we propose a
mechanism consistent with our proposal for oxaziridine-mediated
aminohydroxylation7 (Scheme 1). Upon coordination to the copper
catalyst, the oxaziridine becomes activated toward substrate-induced
homolysis; regioselective abstraction of the δ C-H bond followed by
ring closure of the copper(III) sulfonamide onto the carbon-centered
radical yields the hemiaminal product of this process. The regiose-
lectivity observed in this reaction is identical to that observed in
intramolecular C-H bond oxidations mediated by dioxiranes.4 Thus,
we deduce that the transition states of these two oxidative processes
share a similar geometry. The regioselectivity of the hydrogen atom
abstraction could be due to the combined influence of the stereoelec-
tronic preferences of the oxaziridine and the geometrical constraints
imposed by the cyclic conformation of the transition state.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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Scheme 1. Proposed Mechanism
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While the N,O-aminal intermediates are generally not isolated,
they are amenable to a variety of synthetic manipulations (Scheme
2). Treatment of the unpurified reaction mixture from 4 with a silyl
enol ether in the presence of BF3 ·OEt2 produces the Mannich
addition product 6 in 58% yield with excellent diastereocontrol
(>10:1 trans:cis). Similarly, the same iminium intermediate can be
intercepted by an allyl silane under the identical conditions to afford
the allylated product 7 in 87% yield, again with good selectivity
for the trans diastereomer (5:1 d.r.). The aminal-aldehyde equi-
librium can also be exploited, and the open-chain aldehyde form
can undergo Wittig olefination to produce alkene 8 in 49% yield.
Finally, oxidation of the ring-closed aminal using IBX affords
N-sulfonyl isoquinoline 9 in 58% yield.
(10) No other products of C-H amination were observed; the mass balance in
these experiments consisted of the isomeric N-sulfonylated amides,
analogous to the products of Aube´’s copper(I)-catalyzed rearrangements
of oxaziridines. See: Aube´, J. Chem. Soc. ReV. 1997, 26, 269.
(11) Attempts to perform aminations of primary and tertiary C-H bonds have not been
successful. We attribute these results to the greater bond strength of primary C-H
bonds and the congested steric environment of tertiary C-H bonds.
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