Synthesis of Polysubstituted Benzoic Esters from 1,2-Dihydropyridines and Its Application to the Synthesis of Fluorenones

Article abstract of DOI:10.1021/acs.orglett.6b01260

A convenient, instrumentally simple, and efficient methodology to transform 1,2-dihydropyridines into benzoic esters is described. The generated multisubstituted benzoic esters feature different topologies spanning from simple aromatic rings to fused benz

Full text of DOI:10.1021/acs.orglett.6b01260

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted Benzoic Esters from 1,2-
Dihydropyridines and Its Application to the Synthesis of Fluorenones
David Tejedor,* Mary Cruz Prieto-Ramírez, Mariana Ingold,† Margot Chicon,
́
and Fernando García-Tellado*
Departamento de Química Biolog
Investigaciones Científicas, Avenida Astrofísico Francisco San
́
ica y Biotecnología, Instituto de Productos Naturales y Agrobiología, Consejo Superior de
chez 3, 38206 La Laguna, Tenerife, Spain
́
S
* Supporting Information
ABSTRACT: A convenient, instrumentally simple, and efficient
methodology to transform 1,2-dihydropyridines into benzoic esters
is described. The generated multisubstituted benzoic esters feature
different topologies spanning from simple aromatic rings to fused
benzocycloalkane systems. As an extension of this methodology,
these benzoic esters are efficiently transformed into an array of
fluorenone frameworks featuring interesting and novel topological
patterns.
n recent years, we have been interested in the study of the
propargyl Claisen rearrangement of propargyl vinyl ethers
transformation. Although a number of benzannulation-based
synthetic methodologies for accessing benzoic esters are
known,4 their direct assembly from propargyl vinyl ethers (1-
oxatrienes) should constitute a novel synthetic avenue to highly
substituted benzoic esters.2 Since we anticipated that it would
be difficult to reverse the energetic signature of the
salicylaldehyde pathway to obtain benzoic esters 6 as the
major products from the starting PVEs 1, we envisioned an
indirect synthetic strategy to obtain these compounds via the
formation of the corresponding 1,2-dihydropyridines (1,2-
DHPs, 7)5 (Scheme 2) and their subsequent rearrangement to
benzoate derivatives 6. The approach takes advantage of the
I
(PVEs, 1) under different reaction conditions.1 In the absence
of additional reagents, these compounds rearrange to valuable
polysubstituted salicylaldehyde derivatives 5 when they are
submitted to microwave (MW) irradiation in the presence of
catalytic amounts of imidazole.2 During the course of this
research, we have observed on certain occasions the presence of
small amounts of the benzoic ester side product 6 (Scheme 1).
Scheme 1. PVEs Rearrange into Salicylaldehydes under
Microwave Irradiation
Scheme 2. Indirect Synthesis of Benzoic Esters 6 from PVEs
1 via the Formation of 1,2-dihydropyridines 7
Theoretical calculations on the proposed mechanism for the
formation of the desired salicylaldehydes indeed revealed the
possibility of obtaining benzoic esters by a slightly different and
more energetic mechanistic pathway involving the intermediate
enol ester 4 instead of the enol aldehyde 3.2 Because of the
importance of benzoic esters as building blocks in the industrial
production of fine chemicals, agrochemicals, pharmaceuticals,
and materials,3 we decided to undertake the study of this
Received: April 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01260
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
straightforward formation of 1,2-DHPs from the reaction of
PVEs with primary amines at elevated temperatures6 and the
expected reactivity of the dihydropyridine ring toward electro-
philes (Scheme 2). We envisioned that in the presence of a
suitable electrophile, the C−N bond should be activated via the
formation of the corresponding ammonium derivative 8, which
should collapse to the corresponding enamine−triene inter-
mediate 9 by a controlled C−N bond-breaking process. This
intermediate should be well-suited to host a tandem [3,3]-
sigmatropic rearrangement/amine elimination to deliver the
expected benzoate core. In this communication, we report our
results on the development of this strategy as well as its
application to the synthesis of novel substituted fluorenones 10,
an important structural motif present in some natural products
and in a variety of molecules of biological (pharmaceutical) or
physical (materials) relevance.7
We undertook this study by exploring the reaction of readily
available 1,2-DHP 7a6a with different electrophiles under
different conditions (Table 1). Although N-iodosuccinimide
Table 1. Study of the Electrophile-Assisted Rearrangement
of 1,2-DHP 7a into Benzoate 6a
yield (%)
Figure 1. Scope of the electrophile-assisted rearrangement of 1,2-
DHPs 7 into benzoates 6.
a
entry
electrophile (mol %)
solvent
7a
6a
1
2
3
4
5
6
7
8
−
I2 (20)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DME
MeCN
DCE
DCE
MeOH
90
0
3
62
55
70
40
34
48
32
32
57
57
0
of the aromatic R1 substituent did not play an important role in
the reaction outcome (compare the pairs 6a/6g, 6a/6f, and 6c/
6h). We were pleased to observe that the reaction was also
tolerant of aliphatic substituents at R1 position. This was the
case for 1,2-DHP 7k (R1 = n-Bu), which delivered the
corresponding benzoate derivative 6k in 62% yield. This result
highlights the importance of the extra stabilization of enamine−
triene intermediate 9 (Scheme 2) by the aromatic substituent
R1 in the energetic pathway of the process and thus in the
efficiency of the reaction. More intriguing was the influence of
the substitution pattern at C2 of the starting 1,2-DHP 7. The
absence of a cycle or the presence of a large-sized one (12-
membered ring) seemed to have a deleterious effect on the
reaction (compare 6a−d with 6e, 6i, and 6j). In these cases, the
formation of the desired products was accompanied by the
formation of a significant amount of the aromatized but
decarboxylated hydrocarbon (see the Supporting Information).
At this time we do not have a clear explanation to account for
the observed amplified decarboxylation of these substrates
other than that acyclic substituents at R2 and R3 might enhance
the flexibility of enamine−triene intermediate 9 and retard the
electrocyclization leading to the desired product (Scheme 2). In
terms of chemical diversity and complexity, the process was
able to generate a wide array of polysubstituted benzoic esters 6
with topologies including bi- and terphenyls and more complex
fused benzocycloalkane systems spanning from 2,3-dihydro-1H-
indenes (6a-like) or 5,6,7,8-tetrahydronaphthalene (6b-like) to
5,6,7,8,9,10,11,12,13,14-decahydrobenzo[12]annulenes (6e-
like). The access to these complex topologies from simple
linear precursors (PVEs) highlights the complexity-generating
power of this protocol and its practical utility for accessing
relevant structural motifs incorporating benzene−cycloalkane
I2 (10)
6
NIS (50)
NBS (50)
NCS (50)
NIS (100)
NIS (20)
NIS (20)
NIS (50)
NIS (50)
NaI (50)
CSA (100)
CSA (100)
0
18
32
0
35
35
0
b
9
10
11
12
13
0
100
0
70
95
c
14
0
a
Abbreviations: DCE = 1,2-dichloroethane; DME = 1,2-dimethoxy-
ethane; NIS = N-iodosuccinimide; NBS = N-bromosuccinimide; NCS
= N-chlorosuccinimide; CSA = ( )-camphorsulfonic acid. 4 h. 1%
b
c
yield of decarboxylated 6a.
(NIS) proved to be a good substoichiomteric electrophile for
this transformation (entry 4), the best results were achieved
when camphorsulfonic acid was used in stoichiometric amounts
with methanol as the solvent (entry 14). Under these
conditions, the reaction delivered benzoate derivative 6a nearly
quantitatively (95% isolated yield). The rest of the starting
material was transformed into the corresponding decarboxy-
lated derivative (traces).
Once the best reaction conditions were found, we next
studied the scope of the reaction (Figure 1). It was found that
the reaction was general and highly efficient for 1,2-DHPs 7
bearing a medium-sized ring incorporated into their structures
(R2 and R3 embedded into a five- to eight-membered ring) and
an aromatic R1 substituent (6a−d, 6f−h). The electronic nature
B
DOI: 10.1021/acs.orglett.6b01260
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
annulated rings.8 The sensibility of the PVEs to Brønsted acids
(they are activated enol ethers) did not allow the development
of a catalytic version of the reaction via in situ formation of the
1,2-DHP intermediates and their subsequent rearrangement.
With the standardized protocol in hand, we decided to
transform these complex benzoic esters 6 bearing an ortho aryl
substituent (R1 = Ar) into the corresponding fluorenone
derivatives 10 (Figure 2). Among the plethora of synthetic
In summary, we have reported a convenient, instrumentally
simple, and efficient methodology to transform propargyl vinyl
ethers armed with two substituents at the propargylic position
into polysubstituted benzoic esters featuring different top-
ologies spanning from simple aromatic rings to fused
benzocycloalkane systems. As an extension of this method-
ology, we have efficiently transformed the o-arylbenzoic esters
into an array of fluorenone frameworks featuring interesting
topological patterns. In this context, fluorenones 10b and 10c
constitute the fluorene framework of a family of carbapenem
antibacterial small molecules.11 The study of the properties of
these fluorenones is under way in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01260.
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*Tel.: (int) 34 922 256847, ext. 248/249/250. Fax: (int) 34
922 260135. E-mail: fgarcia@ipna.csic.es.
*E-mail: dtejedor@ipna.csic.es.
Present Address
†
́
M.I. is on leave from the Departamento de Quimica Organ
́
ica,
́
Facultad de Quimica, Universidad de la Republica, Montevideo,
Uruguay.
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Spanish Ministerio de
́
Economia y Competitividad (MINECO) and the European
Regional Development Fund (CTQ2011-28417-C02-02 and
CTQ2015-63894-P). M.C.P.-R. thanks the Spanish Ministerio
Figure 2. Acid-assisted formation of fluorenones 10 from benzoates 6.
de Educacion
the Agencia Nacional de Investigacion
(ANII) for a scholarship. The authors thank technician Mr.
́
y Ciencia (MEC) for an FPI Grant. M.I. thanks
methods described for the synthesis of fluorenones,9 the
Friedel−Crafts-type acylation of biarylcarboxylic acids and
derivatives constitutes one of the most used and practical
ones.10 We carried out these transformations using sulfuric acid
as the activating agent and solvent (Figure 2). In general, these
novel fluorenones were obtained in high yields (∼90% average
yield) independent of the cycloalkane ring size. As could be
expected, the substitution on the aromatic ring brought
important differences in the yield of the reaction, and the
presence of a methoxy substituent at the 4′-position of 1,1′-
biphenyl-2-carboxylate 6h reduced the yield from 90% to 26%
(compare 10d and 10h). Moreover, halogens or alkyl groups at
this position were well-tolerated (e.g., 10f and 10g). It has been
reported that the presence of acceptor−donor substituents on
the aromatic ring has an influence on the electrooptical
properties of fluorenes.7d From this perspective, this fluorenone
synthesis constitutes a convenient and practical synthetic
methodology to construct novel fluorene frameworks incorpo-
rating a varied and rich substitution pattern on the aromatic
rings for use in materials science. On the other hand, the
influence of the cycloalkane-fused motif on the properties of
these fluorenone derivatives remains to be explored.
́
e Innovacion of Uruguay
́
́
Angel Cristo Guijarro Men
assistance.
́
dez (IPNA) for his experimental
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