AuCl3 catalyzed [3 + 2 + 1] cycloaddition: First use of aldehyde as a carbon monoxide-like one carbon synthon for triple C-C coupling

Article abstract of DOI:10.1039/c3ra47093h

A new [3 + 2 + 1] cycloaddition strategy is demonstrated using an aldehyde, an aldimine of a glycine ester and a terminal triple bond with AuCl₃ catalyst. Aldehyde is exploited as the first alternative to the crucial partner CO for triple C-C coupled annulation for the synthesis of novel fused-tricyclic heterocycles.

Full text of DOI:10.1039/c3ra47093h

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AuCl3 catalyzed [3 + 2 + 1] cycloaddition: first use of
aldehyde as a carbon monoxide-like one carbon
synthon for triple C–C coupling†
Cite this: RSC Adv., 2014, 4, 10204
Received 27th November 2013
Accepted 18th December 2013
*
Krishnanka S. Gayen and Dilip K. Maiti
DOI: 10.1039/c3ra47093h
www.rsc.org/advances
A new [3 + 2 + 1] cycloaddition strategy is demonstrated using an heterocyclic scaffolds, only a limited number of synthetic
aldehyde, an aldimine of a glycine ester and a terminal triple bond with methods were developed such as the cycloaddition of nitriles
AuCl3 catalyst. Aldehyde is exploited as the first alternative to the and imines.6 Therefore, development of a conceptually different
crucial partner CO for triple C–C coupled annulation for the synthesis catalytic synthetic approach is desirable to afford a new class of
of novel fused-tricyclic heterocycles.
5H-benzopyrano[4,3-c]pyridines (4).
In our initial experiments we were looking for a powerful
metal catalyst for the triple C–C coupled intermolecular
cycloaddition between the three, two and one units (I) of 1a
and 3a.
The cycloaddition reaction is an attractive synthetic tool in
organic chemistry which is most frequently used for the direct
construction of valuable ring structures.1 Since the pioneering
discovery of CO insertion reactions from carbene chromium
carbonyls,2 the formal [3 + 2 + 1] cycloaddition approach has
found innovative applications in the direct synthesis of difficult-
to-access functionalized cyclohexanone and other valuable
compounds.3 Carbon monoxide is the crucial one carbon
partner in the cycloaddition assembly for dual C–C coupling.
Only a few examples are reported to date which may be due to
the unavailability of alternative one carbon synthons. Less
hazardous and readily available aldehydes (RCH]O) can be
utilized as a one carbon synthon for the [3 + 2 + 1] strategy which
has the advantage of a triple C–C coupling involving both C]O
and C–H. This approach does not need the specially designed
reaction set up required for CO which is undetectable to human
senses and a “silent killer”.4 We used the aldehyde group of O-
propargyl salicylaldehyde (1a, Scheme 1), its terminal alkyne
residue and ethyl glycinate aldimine (3a) to undergo a [3 + 2 + 1]
cycloaddition through the formation of a complex assembly
(I, Scheme 1). The natural polycyclic and fused-chromone
pyridines are used as traditional medicines and displayed
anticancer, antimalarial, antiulcer, antiinammatory, anti-
hepatitis, protein kinase and acetylcholine esterase inhibition
activities.5 In spite of the practical importance of the
To our embarrassment, the [3 + 2 + 1] intermolecular
cycloaddition was unsuccessful during our survey with
prospective rare-earth7 (CeCl3, Yb(OTf)3, La(OTf)3 etc.) and
transition metal8 catalysts (CuI, FeCl3, PdCl2, RuCl3, RhCl3,
[Ir(COD)Cl]2, AgOTf, PtBr2 etc.) under reuxing conditions in
toluene. Gold compounds are so Lewis acids and have
recently emerged as a powerful catalyst for alkyne, allene and
C–H activated functionalization.9 We found AuCl3 (3 mol%) to
be an efficient catalyst to afford the desired compound 5-
hydro-1-(2-prop-2-ynyloxyphenyl)-3-ethoxycarbonylbenzopyrano
[4,3-c]pyridine (4a) in a 61% yield aer reuxing in toluene for
9 h. The moderate yield was attributed to the formation of a
Department of Chemistry, University of Calcutta, University College of Science, 92, A.
P. C. Road, Kolkata 700009, India. E-mail: dkmchem@caluniv.ac.in; Fax: +91-33-
2351-9755; Tel: +91-33-2350-9937
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, NMR spectra, and CIF le. CCDC 938786. For ESI and
crystallographic data in CIF see DOI: 10.1039/c3ra47093h
Scheme 1 [3 + 2 + 1] cycloaddition with one carbon aldehyde
synthon.
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With this initial success we further optimized the [3 + 2 + 1]
cycloaddition reaction to prepare the imine 3a in situ and the
reaction proceeded smoothly by treatment of 2 mmol of alde-
hyde (1a) and 1 mmol of glycine ester (2a) to afford 4a with a
slightly lower yield (55%, entry 1, Scheme 2). The scope of the
reaction was explored with unsubstituted and activated phenyl
rings which proceeded well with different glycine esters (4b–o,
entries 1–14). The structure of this new class of fused-hetero-
cyclic compounds was established by single crystal XRD. The
structure of 4m (Scheme 2) and the spectroscopic data (FT-IR,
NMR and ESI-MS) of all the new compounds are in the ESI.† The
involvement of the C–H of the aldehyde in the cycloaddition was
further conrmed by carrying out a reaction using the corre-
sponding ketimine (3p) and ketone (1h) as the reactants (entry
16) which did not proceed at all. Herein, the terminal triple
bond is a crucial partner in the assembly (I, Scheme 1) because
the reactions were completely blocked on replacement of the
propargyloxy group by allyloxy (1i, 3q, entry 17) and also the
methylpropargyloxy group (R2 ¼ Me, 1j, 3r, entry 18). Moreover,
the free triple bond in the imine (3) has a role during
construction of the desired 5H-benzopyrano[4,3-c]pyridine
skeleton because the corresponding benzyloxy substituted
imine (3s) could not synthesize compound 6s on treatment of 1a
in an unsymmetrical coupling reaction (entry 19). The possi-
bility of the AuCl3-catalyzed [3 + 2 + 1] cycloaddition reaction
through formation of an allene-type intermediate10 was also
nullied by executing the reaction with a dimethyl propargyl
precursor (3o, entry 15) which afforded the desired tricyclic
heterocycle 4o.
To realize the electronic requirements of the [3 + 2 + 1]
reaction in the transition state, crossover experiments were
executed between two different imines [3t (R1 ¼ 3-OMe) and 3m
(R1 ¼ 5-NO2), Scheme 3] and unsubstituted O-propargyl salicy-
laldehyde (1a). Interestingly, we observed the occurrence of
transimination under the catalytic conditions to form corre-
sponding aldehydes 1A (1a,k) from imines 3 (3t,m), imine 3A
from the aldehyde 1a and in situ generated ethyl glycinate (2a)
from 3. The construction of the four possible 5H-benzopyrano
[4,3-c]pyridines are depicted in Scheme 3. Surprisingly, out of
the four possible products, the imine 3t bearing the NO2 group
produced 4a (entry 1, table in Scheme 2) as the sole product
which was generated from the relatively electron rich tran-
siminated imine 3a. However, in the second experiment with
aldimine (3m) bearing the activated aromatic nucleus afforded
the desired compound 4t as a major product along with 4m in
3 : 1 yield ratio. The other two possible compounds were not
found in the post reaction mixture. These crossover experi-
ments indicated that the transition state of the new [3 + 2 + 1]
cycloaddition reaction is assisted by electron donating and un-
favoured by electron withdrawing substituents present in the
aromatic ring of the imines (3) and aldehydes (1).
Scheme 2 Synthesized 5H-benzopyrano[4,3-c]pyridines (4).
Interestingly, Grigg et al.11a and Tsuge et al.11b reported the
classical [3 + 2] intramolecular 1,3-dipolar cycloaddition (DC)
involving Grigg's dipole11c (path c, II, Scheme 4) generated in situ
small amount of the corresponding intramolecular [3 + 2] through 1,2-prototropic shi under heating conditions (1–2
cycloaddition product 4-hydro-2-ethoxycarbonyl-1H-benzopyr- days) using phenyl glycinate and non-terminal alkyne deriva-
ano[4,3-b]pyrrole (5a) from 3a.
tives of 3a to afford the corresponding cycloadduct of III along
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pyridines (9) involving a new [3 + 2 + 1] strategy. The synthesis of
this compound is unknown in the literature.13 Herein, the C3–H
bonds of the 3,3-dimethoxyethoxy group of the aldehyde (7) and
CH2 of imine (8) are expected to undergo activation with AuCl3
and the subsequent elimination of MeOH to afford 9 through
the [3 + 2 + 1] cycloaddition.
In conclusion, we have demonstrated the rst example to use
aldehyde as a carbon monoxide-like one carbon synthon for a
triple C–C coupled [3 + 2 + 1] cycloaddition strategy. AuCl3
catalyzed multi C–H bond activated formal cycloaddition leads
to the construction of valuable tricyclic N-heterocycles such as
5H-benzopyrano[4,3-c]pyridine and benzofurano[4,3-b]pyridine
in a single operation. The new [3 + 2 + 1] cycloaddition
approach, use of aldehyde for triple C–C coupling one carbon
synthon and powerful C–H activation capability of AuCl3 will
nd important applications in synthetic chemistry.
Scheme 3 Cross coupling reaction with the transimination.
Financial support from DST (SR/S1/OC-05/2012 and SR/NM/
NS-29/2010), CRNN and research fellowship from CSIR (SPM),
India are gratefully acknowledged.
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