Chemistry Reference
In-Depth Information
1.4.4 Amine
N
-Oxide Additives
Perhaps the most significant of all advances in the promotion of PK cyclisations, and in turn
the elevation of this method as a widely utilisable tool in organic synthesis, came with the
application of amine
N
-oxide additives, as first described by Schreiber
et al.
in 1990.
31
It
had been well-known that amine
N
-oxides could be employed to remove carbon monoxide
ligands from transition metal complexes by oxidation to carbon dioxide.
32
By extension
and when applied within the PK manifold, this would render the first step of this process
irreversible
and
potentially allow the use of significantly more mild reaction conditions.
As shown in Scheme 1.15, the use of
N
-methylmorpholine
N
-oxide (NMO) as the reaction
promoter allowed cyclisations to be performed under the remarkably mild conditions of
stirring at room temperature;
31
by way of further illustration of the effectiveness of this
N
-oxide method, the outcome of the annulation with the same substrate using the previ-
ously optimal dry state absorption method is provided for comparison.
22
Following this
publication by Schreiber, Jeong
et al
. divulged similarly mild and effective techniques with
the equivalent trimethylamine
N
-oxide (TMANO).
33
Co
2
(CO)
6
O
O
O
Conditions
Dry state adsorption: SiO
2
, O
2
, 55 °C, 1.5 h: 59%
22
N-oxide promotion: NMO, CH
2
Cl
2
, r.t., ~12 h: 92%
31
Scheme 1.15
In relation to these amine
N
-oxide promoted methods, it is important to note that the PK
reactions with such additives appear to be significantly more clean, with the final cyclopen-
tenone products normally requiring a trivial filtration or short silica column purification.
Having stated this, one issue that is often overlooked or dismissed within publications in this
area relates to the hydration state of the
N
-oxide additive used. More specifically, we
6, 34
and others
12a
have found that the monohydrate of NMO and the dihydrate of TMANO
offer optimal yields in most instances. The equivalent anhydrous
N
-oxides tend to lead to
varying degrees of alkyne decomplexation or decomposition, unless there is a requirement
for such, more active,
N
-oxides, for example, with less reactive alkyne complexes.
35
Additional techniques that have emerged around this area include the formulation and
use of recyclable polymer-supported amine
N
-oxides,
36
which provide the added advantage
of sequestering cobalt by-products to deliver an even cleaner reaction process, and the use
of molecular sieves in combination with
N
-oxide promoters.
37
As stated above, the emergence of
N
-oxide promoted PK methods has significantly
enhanced the preparative applicability of this annulation process. This point is beauti-
fully illustrated within Schreiber's total synthesis of the diterpene natural product, (
)-
epoxydictymene.
26, 31, 38
In this particular example, the central PK cyclisation proceeds
under extremely mild
N
-oxide conditions to deliver the desired cyclopentenone product
with elevated levels of selectivity over that obtained under the more standard thermal
protocol (Scheme 1.16).
+
