K. Huard and H. Lebel
À
Table 2. Rhodium-catalyzed intermolecular C H insertion reactions with
(Table 1, entries 12 and 13). Furthermore, the magnesium
oxide and sodium, calcium, and barium carbonate bases did
not appear to be strong or soluble enough to generate the
metal–nitrene species, and most of the starting material was
recovered (Table 1, entries 14–18). Only the more expensive
cesium carbonate could be used to produce the desired oxa-
zolidinone in high yields (Table 1, entry 19). From these re-
sults, we concluded that combining N-tosyloxycarbamates
N-tosyloxycarbamates 7–12.[a]
with [Rh2(tpa)4]and potassium carbonate gave the optimal
G
À
conditions for performing intramolecular C H amination re-
actions because it avoided formation of the free nitrene re-
sponsible for the nonselective reaction pathway (see below
for mechanistic considerations).
The optimization of the reaction conditions was achieved
on a 0.5 mmol scale by addition of a mixture of base and
catalyst to a solution of N-tosyloxycarbamate in the requi-
site solvent. Anhydrous conditions were not required, so
wet solvent and nondried vessels were used. When we
scaled up the reaction to more than 1 mmol, we discovered
that not only were anhydrous reaction conditions not neces-
sary, but that the addition of water was indeed required.
Furthermore, we observed that the reaction became very
exothermic when the base and the catalyst were added. To
overcome these problems, we changed the order of addition;
thus either a solution of N-tosyloxycarbamate in CH2Cl2 was
slowly added to a mixture of base and catalyst in CH2Cl2/
water (8:1), or a solution of base in water was slowly added
to a mixture of N-tosyloxycarbamate and catalyst in CH2Cl2.
Entry
Starting
material
Solvent
Cyclohexane
[equiv]
Yield[b]
[%]
AHCTREUNG
1
2
3
4
5
6
7
8
9
7
8
9
10
11
12
12
12
12
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TCE
10
10
10
10
10
5
10
5
5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
30
80
92
85
74
TCE
PhCl
[a]All reactions were run in the indicated solvent (0.5 m) at 258C for 16 h
with K2CO3 (3 equiv). [b]Isolated yields.
À
When performing the intramolecular C H amination on a
50 mmol scale, it was also possible to decrease the catalyst
loading to 1 mol%.[20]
We also tested various N-tosyloxycarbamates to develop
À
the first rhodium-catalyzed intermolecular C H amination
reaction with this reagent (Table 2). The challenge was to
find a reagent that would not react intramolecularly and
À
that contained less reactive or no active C H bonds.
Scheme 2. Synthesis and thermal stability of N-tosyloxycarbamates.
Starting materials that contained simple alkyl chains, such
as methyl or ethyl groups, were found to be quite unstable,
and readily decomposed under typical reaction conditions
with cyclohexane (10 equiv; Table 2, entries 1 and 2). Allyl-
and benzyl-N-tosyloxycarbamates led to a mixture of prod-
ucts, whereas reagents that contained halogen-substituted
alkyl chains showed good reactivity (Table 2, entries 3–6).
The optimal result was obtained with 2,2,2-trichloroethyl N-
tosyloxycarbamate (12), which led to Troc-protected cyclo-
hexylamine 25 in 80% yield when the reaction was run in
CH2Cl2 with cyclohexane (5 equiv; Table 2, entry 6).[21] Fur-
ther optimization led to 85% yield of the desired product
by starting from cyclohexane (5 equiv) in tetrachloroethane
(TCE) (entry 8).[9k,t]
periments were run with 12 and cyclohexylmethyl tosyloxy-
carbamate, and both proved to be stable up to 1808C.
Scope of the reaction: A variety of substituted oxazolidi-
À
nones were prepared from N-tosyloxycarbamates by C H
amination reactions and isolated in yields of 41–92%
À
(Table 3). C H bond insertion is effective at benzylic posi-
tions (Table 3, entries 1 and 2) and ethereal positions
(Table 3, entry 3). The amination also proceeded very well
À
with tertiary C H bonds (Table 3, entries 4 and 5). Further-
more, the oxazolidinones that resulted from the insertion of
À
the nitrene into a deactivated secondary or primary C H
The purification of both oxazolidinone and Troc–amine
products was very simple because potassium tosylate, the
only stoichiometric byproduct formed, was simply removed
by filtration or an aqueous workup. Furthermore, N-tosyl-
bond were isolated in yields of 64% and 41%, respectively
(Table 3, entries 6 and 7). This is quite spectacular because
it is one of the first examples of such a reaction taking place
at a primary non-benzylic position, which clearly illustrates
À
A
the power of this method. The formation of the C N bond
is also stereospecific because the reaction of a chiral, enan-
mercially available alcohols and were all crystalline com-
pounds (Scheme 2). Thermogravimetric analysis (TGA) ex-
tioenriched N-tosyloxycarbamate occurred with complete
6224
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6222 – 6230