Organic Letters
Letter
also opens the way to the use of related cyclopropanes without
a clear donor−acceptor substitution pattern.
energy, and this would explain the more selective formation of
adduct 5B for this particular type of highly activated donor−
acceptor cyclopropanes. Several diastereomers can be formed
during the process; the lower energy route has been considered
in each case (for the complete study, see SI).
We studied the process in detail by DFT methods to provide
a rationale of the observed results. We first studied the reaction
of indole 2a with cyclopropyl derivative A as a simplified
analogue of substrate 1a. At the same time, we also evaluated
the reaction using model cyclopropane B that would lead
selectively to the formation of product of general structure 5B.
Both attacks to C-2 and N of the indole moiety were
considered13 leading to adducts of type 3A (or 5B) and 4A
respectively (Scheme 3). The C-attack consists of two steps,
In conclusion, we have developed a Brønsted acid catalyzed
procedure for performing an unexplored (4 + 2) cyclo-
condensation between donor−acceptor cyclopropanes and C3-
substituted indoles. The methodology described herein
presents a broad scope regarding both counterparts of the
reaction, providing the corresponding 8,9-dihydropyrido[1,2-
a]indoles in good yields and with an excellent level of
selectivity. This reactivity pattern is particularly attractive, as it
shows the alternative behavior of N-unprotected C3-
substituted indoles, in which N and C-2 positions are
simultaneously alkylated due to their double nucleophilic
character and also forced by the presence of the C3-substituent
of the indole that directs the initial alkylation step to the C2-
position. Moreover, mechanistic investigations based on
computational studies are in concordance with the observed
experimental results.
Scheme 3. Two Favored Routes for the Reaction between
Model Cyclopropanes A and B and 3-Methylindole 2a and
the Calculated Energy Profiles (Relative Free Energies
Given in kcal/mol)
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures, characterization data of all
new compounds and copies of 1H and 13C NMR
spectra; reaction coordinates, computational details and
Cartesian coordinates of all stationary points (PDF)
Accession Codes
CCDC 2060969 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
Uxue Uria − Department of Organic and Inorganic Chemistry,
University of the Basque Country (UPV/EHU), 48080
Pedro Merino − Instituto de Biocomputación y Física de
Sistemas Complejos (BIFI), Universidad de Zaragoza, 50009
Jose L. Vicario − Department of Organic and Inorganic
Chemistry, University of the Basque Country (UPV/EHU),
i.e., formation of intermediate IN1A and then IN2A after an
H-transfer to recover indole aromaticity. Further cyclization of
IN2A and dehydration lead to the final product. The
alternative pathway leading to adducts of type 4A involves
the N-attack that results in the formation of IN3A (actually the
(SI)) which through concomitant C2-attack to the carbonyl
moiety and H-transfer yields IN4A, which after dehydration
provides the final product. The calculated energies for these
intermediates and the associated TS are also shown in Scheme
3. For both C-2 and N-attacks, the first step in which the
nucleophile-induced cyclopropane ring opening takes place is
the rate limiting step. For both cases A and B, the C-2 attack is
preferred over the N-attack, which showed to be higher in
Authors
Alesandere Ortega − Department of Organic and Inorganic
Chemistry, University of the Basque Country (UPV/EHU),
48080 Bilbao, Spain
Tomás Tejero − Instituto de Síntesis Química y Catálisis
Homogénea (ISQCH), Universidad de Zaragoza, CSIC,
50009 Zaragoza, Spain
2329
Org. Lett. 2021, 23, 2326−2331