10.1002/anie.202010528
Angewandte Chemie International Edition
RESEARCH ARTICLE
this case the cyclization reaction does not occur, and instead the
intermediate boronic acid evolves through an alternative reaction
pathway. The remarkable difference in the activation Gibbs free
energies of both processes could be understood considering
that the transition state TS1 features a nearly perfect six-
membered ring chair-like arrangement (scheme 5, C), while TS2
consists on a less favoured seven-membered ring.[27]
reactions with cyclopentanone and cyclohexanone derived -
azido-N-tosylhydrazones are highly diastereoselective providing
the bicyclic amines as single diastereoisomers. The mechanism
proposed is supported by DFT computations and comprises two
consecutive concerted carboborylation processes
diastereoseletive carboborylation of the diazoalkane generated
from the N-tosylhydrazone, and the intramolecular
–
a
The diastereoselectivity observed in the synthesis of
octahydroindoles 10 and octahydrocyclopenta[b]pyrroles 13 can
be also rationalized in agreement with the mechanistic proposal,
and considering 1) a diastereoselective carboborylation of the
diazo compound,[28,29] 2) a stereoretentive carboborylation of the
azide. Retention of configuration on the latter step is expected
considering that 1,2-migrations of boronate complexes are
stereospecific and proceed with retention of configuration on the
migrating group.[17a,20,30] Therefore we propose that the
stereochemistry must be defined in the first step. DFT-based
computations were carried out on these stereoselective
reactions to support this proposal (see SI for a complete
discussion). We assumed the decomposition of the N-
tosylhydrazone to give the diazoalkane F as a preliminary step,
and studied the model reaction between F and phenylboronic
acid (scheme 5, D). The modeling studies indicate that formation
of the tertiary boronic acid G through the transition state TS(F-G)
is favoured by 3.9 kcal·mol-1 towards the formation of the
diastereomer G’ through the analogous TS(F-G’). Both transition
carboborylation of the azide. This last step takes place through a
chair-like transition state. Considering the wide availability of
boronic acids, the simple synthesis of the precursor -
azidoketones, and the wide scope already shown of the reaction,
we consider that this novel transformation will be very useful for
the synthesis of pyrrolidine-containing structures and to
introduce the interesting pyrrolidine moiety into different natural
and unnatural structures.
Acknowledgements
Financial support of this work by Ministerio de Economía y
Competitividad (MINECO) of Spain: Grants CTQ2016-76794-P
(AEI/FEDER, UE) and PID2019-107580GB-I00 and Consejería
de Empleo, Industria y Turismo del Principado de Asturias
(Spain): (grant IDI/2018/000231).
A
Clarín postdoctoral
fellowship (Principado de Asturias, Spain) to L. F. is gratefully
acknowledged.
states show
a similar structure that corresponds to an
asynchronous concerted process where the boron atom
approaches the carbon of the diazoalkane through an equatorial
trajectory, and the aryl group occupies a pseudoaxial disposition,
nearly antiperiplanar with the leaving N2 molecule. However, this
structure is much less favoured in TS(G’-H’) due to the
destabilizing interaction between the aryl group and the
azidoethyl substituent that are in a syn arrangement. Then, the
intramolecular stereoretentive amination of the boronic acid G,
through the cyclic transition state TS(G-H) (Gact = 28.4
kcal·mol-1), gives the cis-fused bicyclic systems H observed.
According to the computations, if the diastereomeric boronic
acid G’ were formed, it should also undergo the cyclization
through the same type of concerted 1,2-alkyl migration through
TS(G’-H’) (Gact = 27.5 kcal·mol-1) to give H’, because the
energy barriers for both pathways are of the same magnitude.
However, the trans-fused diastereoisomers H’ have not been
observed experimentally. Therefore, the combination of
experimental and computational evidences rule out the
possibility of the formation of G’, and support that the
diastereoselectivity of the reactions is determined in the
carboborylation of the cyclic diazo compound.
Keywords: Pyrrolidine • Azide • Boronic acid • N-tosylhydrazone
• Metal-free
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Conclusion
We have presented herein a novel synthesis of 2,2-disubstituted
pyrrolidines that takes place through a transition-metal free
domino cyclization. The mechanism involves the carboborylation
of a N-tosylhydrazone with a boronic acid followed by the
intramolecular capture of the transient boronic acid by an azide
through a second carboborylation event. Synthetically, the
reaction features wide scope, as both aryl and alkylboronic acids
are competent substrates in the transformation, allowing for the
preparation of diversely substituted pyrrolidines. Moreover, the
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7
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