Organic Letters
Letter
We performed the cyclization with amide 3 on a 1.0 mmol
scale using our optimized conditions. For practical purposes,
linked to the use of microwave irradiation and the limit
imposed by the size of the microreactors, it was carried out at a
concentration of 0.08 M. To our satisfaction, the spirocycle 5
was obtained in an excellent 98% yield. In a second larger scale
reaction (2.6 mmol), increasing the reaction concentration to
0.26 M was successfully achieved while simultaneously
decreasing the catalyst loading to only 1.0 mol %. Once
again, we observed no changes in outcome or yield (96%).
One real advantage of our process is that microwave irradiation
is only 5 min on whatever scale performed for the majority of
our substrates. Cyclization is also independent of the reaction
concentration, and no intermolecular side reactions occur.
Extending the scope of the reaction in the oxygen series gave
the N-allyl derivative (31) in moderate yield (Figure 2). The
use of a dipropargyl-substituted amide led to a unique tricyclic
structure, which was obtained in good yield through a double
in situ cyclization process (32). The corresponding endo
product (33) could be prepared by performing the reaction in
DMF, which presumably reduces the catalytic efficiency by
complexation of the gold catalyst. One limitation that we found
in both series was the absence of cyclization when an ester was
present in the starting material (30 and 34). Surprisingly, the
unreacted esters were fully recovered in both cases. This
constraint was lifted with the removal of the carbonyl group
and the use of a simple ether, which gave compound 35
quantitatively.
We then decided to apply the spirocyclization reaction to a
more complex chiral substrate. Several amide derivatives were
prepared from a protected quinic acid derivative in good yields.
(See the SI for the preparation of starting compounds.)
Cyclization was performed in the presence of a catalytic
amount of PTSA·H2O in all cases to give the corresponding
spirocycles 36−39. No racemization of the chiral quaternary
stereocenter was observed (1H NMR), and the tricyclic
product 39 was obtained as a separable mixture of
diastereomers.
Our next steps were devoted to further transforming our
molecules through the selective deprotection of the amino
groups or double-bond reduction. The hydrogenation of
compound 5 in the presence of palladium chloride allowed
the removal of the benzyl carbamate in 70% yield, with no
observed reduction of the double bond (Scheme 4).
Conventional alkene reduction methods (H2, Pd/C, or Pt)
were unsuccessful, with the recovery of the unreacted starting
material. Ionic conditions were then tried, and whereas the use
of triethylsilane/trifluoroacetic acid failed with compound 5, it
proved to be successful starting from spirocycle 9.33 The
desired spiromorpholinone 41 was isolated in 84% yield.
In conclusion, we have developed a spirocyclization reaction
based on the intramolecular gold-catalyzed hydroamination
and hydroalkoxylation of alkynes. Both tertiary alcohols and
protected amines react to form new heterospirocycles in good
to excellent yields under microwave irradiation in only a few
minutes with low catalyst loading. We have prepared a small
library of spirocycles containing dihydro-pyrazinone and
-oxazinone cores, with no further oxidation of the final
product. Gram quantities were also prepared in a practical and
robust manner with an even lower catalyst loading. We have
likewise proven the compatibility of the method toward
asymmetric centers as well as common protective groups. As
an added bonus, a tandem reaction to give unique tricyclic
spirocycles (32 and 39) was observed, and the catalyst
reactivity could be altered using DMF as a coordinating
solvent. Further reactions such as isomerization, reduction, and
selective deprotection increase the significance of the present
work and offer possibilities for the use of these spirocyles as
candidates to increase molecular diversity in medicinal
chemistry.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
1
Experimental procedures and H NMR and 13C NMR
Accession Codes
CCDC 2009173 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
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Karen Ple − Institut de Chimie Organique et Analytique,
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Universite d’Orleans, CNRS UMR 7311, 45067 Cedex 2
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Sylvain Routier − Institut de Chimie Organique et Analytique,
Scheme 4. Protecting Group Removal and Double-Bond
Reduction
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Universite d’Orleans, CNRS UMR 7311, 45067 Cedex 2
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Authors
Kossi Efouako Soklou − Institut de Chimie Organique et
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Analytique, Universite d’Orleans, CNRS UMR 7311, 45067
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Cedex 2 Orleans, France
Hamid Marzag − Institut de Chimie Organique et Analytique,
Universite d’Orleans, CNRS UMR 7311, 45067 Cedex 2
Orleans, France
Jean-Philippe Bouillon − Normandie Universite, COBRA,
CNRS UMR 6014, Universite de Rouen, 76000 Rouen, France
Mathieu Marchivie − Universite de Bordeaux, ICMCB CNRS-
UMR 5026, 33608 Pessac, France
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Org. Lett. XXXX, XXX, XXX−XXX