Chemistry Reference
In-Depth Information
Classical cyclofunctionalization
R
3
R
3
R
3
R
3
E
R
2
E
R
2
R
2
not
O
N
O
N
R
2
HN
O
HN
O
R
1
E
R
1
E
R
1
R
1
551
553
554
(Thermodyamic product)
552
(
Kinetic product
)
N-Oxidation
E
+
= X
2
, [O], RSeX, RSX, Hg(II)
Nitrenium cyclofunctionalization
R
3
Nuc
R
3
R
3
R
3
Nuc
R
2
or
O
O
N
N
R
2
N
O
R
2
N
R
1
O
R
2
R
1
Nuc
R
1
R
1
555
556
557
558
SCHEME 10.92.
modest diastereoselectivity. From a mechanistic standpoint, it was suggested that
these transformations proceed via aryl nitrenium ion
560
, which undergoes concerted
alkene cycloaddition to form a bicyclic aziridinium ion
. Regioselective ion pair
collapse of this highly strained intermediate at the more accessible, external position
would then give rise to the observed products. In commonwithmany other iodine(III)-
mediated oxidations, the use of nonnucleophilic protic solvents, and in particular
trifluoroethanol (TFE), proved to be of central importance to the success of this
transformation (Scheme 10.93). Indeed, treatment of
561
with PIFA in CH
2
Cl
2
failed
to mediate cyclization and instead led to the unproductive formation of a nitrogen-
centered, amidyl radical, whose presence was confirmed by EPR spectroscopy.
Intriguingly, nitrenium ions
559
565
560
, show no
propensity to undergo alkene addition and instead react with the neighboring arene to
form annulation or spirocyclization products. While acknowledging the difficultly in
rationalizing this remarkable observation, the authors suggest that the failure of aryl
nitrenium ions
, the oxygen-stabilized analogs of
to undergo attack at the aromatic site may be a consequence of the
greater steric encumbrance associated with these larger electrophiles.
Expanding upon their initial findings, Tellitu
et al.
have found that both
unsaturated
N-
phenyl and
N-
naphthyl-substituted substrates also undergo amidohy-
droxylation (entry 1), thus corroborating the need for an amide substituent capable of
supporting acyl nitrenium ion formation (Table 10.10). These studies have also
revealed that 2-, 3- and 4-substituted 2-hydroxymethylpyrrolidine derivatives
560
are
accessible in reasonable yield from the corresponding pent-4-enamide derivatives
(entries 2-4). Unfortunately, 1,2-disubstituted and trisubstituted alkene substrates
fail to undergo efficient amidohydroxylation (entry 5), generate complex mixtures of
products (entry 6), or, as in the case of
570
, undergo competitive iodine(III) addition
reactions at the electron-rich alkene (entry 7).
568h
