Organic Letters
Letter
conditions for aliphatic secondary amines (Table 1, entry 1).5f
Gratifyingly, 3-vinyldihydrobenzoxazine 2a was selectively
Scheme 2. Scope and Functional Group Tolerance for the
Tandem CAM/N−H Insertion of O-Tethered o-
a
Alkynylanilines
a
Table 1. Optimization of the Reaction Conditions
b
entry
deviation from standard conditions
product/yield (%)
1
2
3
4
none
2a/77
cd
,
5 mol % Rh2(OAc)4 instead of Cp*RuCl(cod)
5 mol % Rh2(esp)2 instead of Cp*RuCl(cod)
[Cp*Ru(CH3CN)3]PF6 instead of
Cp*RuCl(cod)
3a/15
cd
,
3a/8
3a + 4a/n.d.
c
5
6
7
8
EtO2CCHN2 instead of TMSCHN2
[Cp*RuCl]4 instead of Cp*RuCl(cod)
THF/MeOH/iPrOH/CH3CN instead of DCM
7.5 mol % of Cp*RuCl(cod)/DCE reflux/
2 mmol scale
complex mixture
c
2a/60
2a + 5a/10−31
c
2a/73
a
Reaction conditions: 1a (0.2 mmol), TMSCHN2 (1.5 equiv), and
b
solvent (0.15 M) with the indicated catalyst at rt. Isolated yields.
c
d
Incomplete consumption of 1a was observed. Slow addition of the
diazo compound over 1 h.
formed in 77% yield as a single Z stereoisomer12 in <10 min
of reaction at room temperature. A direct comparison between
the Cp*RuCl(cod) precatalyst and traditional Rh(II) catalysis
(Rh2(OAc)4, entry 2 and Rh2(esp)2, entry 3) highlights the
virtues of the half-sandwich ruthenium complex in promoting
CAM rather than direct N−H insertion. In fact, the reaction
proved to be very sensitive to the electronic nature of the
ruthenium precatalyst and the diazo compound as the use of
the cationic analog [Cp*Ru(CH3CN)3]PF6 (entry 4) or ethyl
diazoacetate (entry 5) gave rise to a mixture of the desilylated
product 4a together with minor amounts of the direct N−H
insertion product 3a and a complex mixture, respectively. The
use of the tetranuclear complex [Cp*RuCl]4 afforded a similar
result as Cp*RuCl(cod), but an incomplete consumption of 1a
was observed (entry 6), probably due to a faster deactivation of
the catalyst. The nature of the solvent also proved to be crucial
as the employment of more polar (protic and aprotic) solvents
led to low conversions (entry 7) and the formation of side
products of type 5a. Pleasingly, we discovered that it is possible
to scale up the reaction to 2 mmol and diminish the catalyst
loading from 10 to 7.5 mol % by using 1,2-dichloroethane as a
solvent at reflux (entry 8).
Having established the optimal reaction conditions for the
tandem CAM/N−H insertion reaction, we decided to explore
the scope and limitations of our methodology. First, O-
tethered o-alkynylanilines were tested (Scheme 2). The
cascade reaction tolerates any substitution pattern on the
aromatic ring, affording the corresponding 1,4-benzoxazines
2a−d from moderate to good yields. Substitution at the
propargylic position was also tolerated, albeit benzoxazine 2e
was obtained as a 1:1 mixture of diastereomers in 54% yield.13
Remarkably, the reaction proceeded with excellent chemo-
selectivity in the presence of a wide range of functional groups
such as halides (2g and 2h), ethers (2i), unprotected anilines
(2j), esters (2k), internal alkynes (2l), or terminal olefins
a
Conditions: Method A: 1 (0.2 mmol), TMSCHN2 (1.5 equiv),
CH2Cl2 (0.15 M), and Cp*RuCl(cod) (10 mol %) at rt for 10−15
min. Method B: Same conditions as method A but using 7.5 mol % of
Cp*RuCl(cod) and DCE as a solvent at reflux for 15 min.
(2m). Considering the slight excess of TMSCHN2 used for
this transformation, one might expect further evolution of the
final products 2 through N−H insertion of the resulting
secondary aniline, unselective N−H insertion with the primary
aniline 2j, CAM with the internal alkyne 2l, or metathesis/
cyclopropanation with the terminal olefin 2m; however, none
of these side reactions were detected in the analysis of the
crude mixtures.
The extension of the tandem CAM/N−H insertion to the
synthesis of other kinds of six-membered heterocycles was
subsequently analyzed (Scheme 3). To our delight, the
cyclization reaction allowed access to a variety of function-
alized tetrahydroquinoxalines (2n−p) and indoloquinoxalines
(2q), dihydrobenzothiazines (2r), or tetrahydroquinolines
(2s) from moderate to good yield. These results further
exemplify the excellent functional group tolerance toward
carbamates, sulfonamides, heteroaromatic systems, thioethers,
or silylethers. Curiously, these results are in striking contrast
with our previous experience with secondary benzylamines in
the tandem CAM/ylide rearrangement, where N-, S-, or C-
tethered o-alkynylamines were not tolerated.5f
According to precedent literature and the experimental
observations, a tentative mechanism was proposed (Scheme
4). The Cp*RuCl(cod) precatalyst would react with the diazo
compound to generate a ruthenium carbene that readily
coordinates to the o-alkynylaniline 1 (I). A chemo- and
B
Org. Lett. XXXX, XXX, XXX−XXX