Organic Letters
Letter
The success of this approach is documented here (Scheme 1,
bottom).
Scheme 2. Substrate Scope
For the initial proof-of-concept experiments and the
subsequent optimization of the reaction conditions, 2-
azidoallyl diphenylmethyl ether (1a) was selected as the
substrate, and Togni’s trifluomethylating reagent 2 was
activated by the addition of FeCl2 (20 mol %). A short
screening (Table 1) revealed that DCM, dichloroethane
Table 1. Optimization Studies
entry
solvent
DCE
1,4-dioxane
1,4-dioxane
DCM
DCM
DCM
DMF
DCM
2 (equiv)
T (°C)
time (h)
3a (%)
1
2
3
4
2.5
2.5
2.5
1.1
1.5
3.5
2.5
2.5
80
80
40
36
36
36
rt
24
24
1
24
24
24
0.5
0.5
45
55
70
34
33
80
73
75
a
5
b
6
7
8
rt
a
b
With CuI (20 mol %) instead of FeCl2. With 30 mol % of FeCl2.
a
b
With a freshly prepared batch of Togni’s reagent. Containing
c
d
unidentified impurities. Reaction time of 3 h. For the X-ray crystal
structure of 3n shown at the right: The thermal displacement
parameters are shown at the 50% probability level.
(DCE), 1,4-dioxane, and DMF were suitable solvents. The
reaction temperature could be varied from 80 °C to ambient
temperature, with the latter being superior. Substituting FeCl2
by the more commonly used CuI also led to product formation
(Table 1, entry 5). Finally, reacting 1a with 2.5 equiv of 2 and
20 mol % FeCl2 in dry DCM at ambient temperature for 30
min provided 4-(2,2,2-trifluoroethyl)-substituted 3-oxazoline
3a in 75% yield (Table 1, entry 8). Although an increase in the
yield of 3a to 80% was observed when a combination of 3.5
equiv of 2 and 30 mol % FeCl2 was applied in DCM at 36 °C
(Table 1, entry 6), the former conditions were considered
satisfying for the subsequent substrate studies.
Next, the substrate scope was evaluated (Scheme 2). In the
first series, 2-azidoallyl diarylmethyl ethers (1b−e) with two
identical 4-substituted aryl groups were applied. While the
yields of the resulting 3-oxazolines with 4-chloro-, 4-fluoro-,
and 4-methyl substituents (3b, 3c, and 3e, respectively) were
good (ranging from 75% to 98%), 4-methoxy-substituted
product 3d was isolated in only ∼45% yield (containing
significant amounts of unknown impurities). Hence, the
electron-donating effect of the substituent appeared to hamper
the formation of the heterocycle presumably by unduly radical
or cation stabilization. The use of freshly prepared Togni’s
reagent proved to be beneficial. 2-Azidoallyl arylphenylmethyl
ethers 1f−k with different substituents on the aryl group
showed analogous trends. The position of the aryl substituent
was important as revealed by comparing the result of the
cyclization of 3-substituted substrate 1h with that of its 4-
substituted counterpart 1e. Both starting materials led to the
corresponding 3-oxazolines 3h and 3e, respectively, but for the
latter product, the yield was significanly higher (63% vs 81%).
Also, 2-azidoallyl 1-phenylalkyl ethers 1j and 1k cyclized,
illustrating that more alkyl substituents were tolerated. In this
manner, 3-oxazolines 3j and 3k bearing trifluoromethyl and
methyl groups, respectively, were obtained albeit in only
moderate and low yields (64% and 35%, respectively).
Probably, these substituents decreased the radical stability
and the rate of 1,5-HAT.22 Also, thioether 1l reacted affording
3-thiazoline 3l in 63% yield. The moderate yield of 3l could be
due to a general sensitivity of such compounds, matching
earlier observations reported by Asinger and Offermanns.23
Starting from 3-azido homoallyl ether 1m and involving a 1,6-
HAT, 5,6-dihydro-2H-1,3-oxazine 3m was obtained in 98%
yield (after reaction for 3 h). Finally, ether 1n with an
additional methyl group at the oxygen-bearing carbon (as
compared to 1a) was applied, which led to 3-oxazoline 3n in
98% yield after only a few minutes. The molecular structure of
this product was confirmed by single-crystal X-ray structure
analysis.24,25
To evaluate the assumed intermediacy of radicals and a 1,5-
HAT as well as the energy barriers of the underlying
mechanism, the reaction path was investigated with DFT
calculations using Gaussian09 version D.01.26 All calculations
were performed with the functional M06-2X and Grimme’s D3
dispersion correction.27,28 Optimizations were carried out with
the def2-SVP basis set.29 For final structures, a single-point
calculation with the def2-TZVP basis set and the IEFPCM
solvent model for DCM was added.29,30 A description of the
tion. The energy values for barriers and intermediates are
presented in Scheme 3.
Most intermediates contain two energetic values: the left
one refers to the calculated minimum based on an IRC
calculation after the previous transition state, and the right
value to the minimum calculated based on an IRC calculation
of the following transition state. The difference in energy is
caused by conformer changes. The transformation is initiated
by the reaction of Togni’s reagent with the iron(II) salt,
B
Org. Lett. XXXX, XXX, XXX−XXX
Bolm, Carsten
