Chemistry Reference
In-Depth Information
Enolate
alkylation
MeO
2
C
MeO
2
C
MeO
2
C
C
X
C
Rh
H
C
H
R
R
R
Scheme 4.20.
C -H activation of alkanes as a strategic organic reaction.
4.2.4.2. C-H Insertion α to Heteroatoms
Intermolecular C -H activation α to nitro-
gen with donor/acceptor-substituted carbenoids is a very favorable process due to the
activating nature of the adjacent nitrogen [213-217]. The products of this reaction are
derivatives of chiral β-amino acids, which are typically synthesized via asymmetric
Mannich reactions. Simple pyrrolidine systems were found to work particularly well in
this chemistry, but the scope has been extended to piperidine systems and also acyclic
amines [214-217]. The nitrogen functional group usually has to be protected since the
intermediate carbenoid readily undergoes formal insertion into the N-H bond via an
ionic mechanism [49] .
A range of aryldiazoacetates can be used, and excellent diastereo- and enantioselec-
tivities are observed in many cases [3]. C-H insertion into
N
- Boc pyrrolidine (
102
,
Scheme 4.21) with a range of aryldiazoacetates followed by deprotection afforded prod-
ucts
103
in 49-72% yield with impressive levels of stereoselectivity (91-94% de, 93-94%
ee) [215,217]. If an excess of methylphenyldiazoacetate is used in the reaction (Scheme
4.22 ), double C -H insertion readily occurs to produce the
C
2
- symmetric amine
105
in
78% yield and with 97% ee [215,217].
1)
Rh
2
(
S
-DOSP)
4
-50°C
Ar
Boc
N
Ar = Ph
2-Nap
4-(Cl)Ph
4-(Me)Ph
N
Ar
CO
2
Me
MeO
2
C
2) TFA
N
2
H
95
102
103
49-72% yield
91-94% de
93-94% ee
Scheme 4.21.
C -H insertion of
N
- Boc pyrrolidine.
1)
Rh
2
(
S
-DOSP)
4
-50°C
Ph
CO
2
Me
Boc
N
Ph
CO
2
Me
N
Ph
MeO
2
C
N
2
2) TFA
H
H
(6 eqv)
78% yield
97% ee
104
102
105
Scheme 4.22.
Double C - H insertion.
The reaction can readily be applied to substituted systems as well. An example is the
2 - substituted pyrrolidine
107
(Scheme 4.23), which has three potential sites for C- H
insertion but only forms one product [217]. By employing two equivalents of racemic
107
, an excellent kinetic resolution occurs to form exclusively product
108
in 85% yield
