Organic Letters
Letter
Scheme 1. A Proposed Mechanism for the Transformation
of Enones to Aziridines
Scheme 3. Proposed Mechanism for Nitrile Formation
To adapt this process fully to flow, we chose reagents that
would facilitate a more homogeneous reaction, yielding n-
zwitterion condenses with aldehyde 4a to form its imine,
followed by loss of water. Under these basic conditions,
removal of the α-proton provides the desired nitrile. This
provides orthogonal conditions to many extant methods for
this transformation, which often require a strong acid or an
Bu N and t-BuOK in t-BuOH as the optimal surrogate leaving
3
group and base, respectively. Under homogeneous conditions,
we were pleased to observe an 89% yield of aziridine 3 in just 5
min at room temperature. The aziridination process was then
telescoped with the chloramine generation in flow. The second
reactor was heated to 80 °C, allowing the hydrazinium
intermediate to be formed within the span of a 1 min residence
time. The combined residence time for the total process was
approximately 3 min, corresponding to a production of 3 at a
rate of 0.75 g/h and a yield of 74% (based on 2).
We then set out to perform a more complete investigation of
the substrate scope of the aziridination reaction. To our
surprise, while testing an aziridination on aldehyde 4a, we
discovered that the aldehyde was cleanly converted to its
corresponding nitrile. Examining the reaction scope showed
that, using the same conditions, unsaturated aldehydes gave
their synthetically valuable nitriles in good to excellent yields in
just 3 min (Scheme 2). In the case of 5e and 5g, clogging of
10,11
additional chemical oxidant.
We wished to extend the use of chloramine as a readily
available chemical oxidant for the transformation of thioethers.
We observed that sufficiently polarizable, nucleophilic
thioethers readily underwent amination with chloramine,
yielding free sulfilimines, which thus far have seen limited
12
use due to their instability. Though the methods for
synthesizing the analogous sulfoxides and, more recently, the
medicinally potent sulfoximines have received considerable
attention, sulfilimines have been limited by the need for
13,14
nitrogen protection.
Current synthetic methods for sulfilimines typically require
the use of stoichiometric hypervalent iodine reagents, a
transition metal catalyst, and/or variability in either the
15
thioether reactant or the amine reactant, but rarely both.
Scheme 2. Flow Schematic for Nitrile Synthesis (top) and
a
However, taking advantage of the benefits of continuous flow,
we envisioned that addition of 1 to a thioether, then trapped
by an acylating electrophile, would result in a diverse array of
desired sulfilimines without the need to isolate the unstable
intermediates. To this end, we attempted the formation of the
free sulfilimine by the reaction of chloramine and a thioether,
followed by addition of acetyl chloride.
Product Scope of Unsaturated Nitriles (bottom)
Though the resulting N-acetyl sulfilimines were stable
enough to allow us to observe their formation via LC-MS,
their scale-up and isolation provided sulfoxide 7 instead of the
acetylated sulfilimine as the major product. Although
hydrolysis during workup was initially suspected, bypassing
an aqueous quench still led to primarily sulfoxide 7, indicating
that perhaps another mechanism was at play. Moreover, the
typical routes of decomposition for sulfilimines involve an
extrusion of ammonia to revert to the thioether starting
material, not hydrolysis to sulfoxide. Furthermore, acetyl
chloride was necessary to yield meaningful amounts of 7;
without an acylating reagent, only starting material was
observed, as is expected for the decomposition of free
a
Yields, in parentheses, are isolated yields following column
chromatography.
12
the flow system was observed at the junction with the addition
to ensure an increased level of mixing at the cross section,
thereby attenuating clogging.
Both electron-rich and electron-poor aryl substituents were
tolerated, as were benzothiophenes (5f) and protected indoles
sulfilimines. In light of these difficulties, we switched focus
toward optimizing the synthesis of sulfoxides.
As sulfoxides were the major product of our attempts toward
sulfilimines, their synthesis required little variation from our
method at that point. In continuous flow, a mere 3 s of
residence time was optimal for sulfoxide formation, as shown
in Scheme 4. Moreover, under these conditions, there was
minimal risk of overoxidation to the sulfone, as sulfoxides were
found to be unreactive in the presence of 1. Unfortunately,
while the conditions provided diaryl sulfoxides and alkyl-aryl
(
5g). However, aldehydes containing an unprotected N−H, as
well as saturated aldehydes, did not participate in the reaction.
A potential mechanism is shown in Scheme 3, in which the
B
Org. Lett. XXXX, XXX, XXX−XXX
Danahy, Kelley E.
