The Aza Diels-Alder Reaction on Brominated Conjugated Dienes

Article abstract of DOI:10.1002/ejoc.202100170

The use of electron-deficient dienes as substrates in the aza Diels-Alder reaction (ADA) has been studied scarcely. However, the ADA process offers a wide range of applications in organic synthesis. In this communication, the reaction between different brominated conjugated dienes and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), one of the most vigorous dienophiles, is reported. We have synthesized tricyclic compounds from acyclic substrates in only two steps, considering variables such as ring size and steric hindrance and substantially improved the results obtained with other dienophiles.

Full text of DOI:10.1002/ejoc.202100170

Communications
doi.org/10.1002/ejoc.202100170
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The Aza Diels-Alder Reaction on Brominated Conjugated
Dienes
Rafael G. Uceda,[a] Esther Roldan-Molina,[b] Jorge A. R. Navarro,*[b] and J. Enrique Oltra*[a]
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The use of electron-deficient dienes as substrates in the aza
Diels-Alder reaction (ADA) has been studied scarcely. However,
the ADA process offers a wide range of applications in organic
synthesis. In this communication, the reaction between differ-
ent brominated conjugated dienes and 4-phenyl-1,2,4-triazo-
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line-3,5-dione (PTAD), one of the most vigorous dienophiles, is
Figure 1. Chemical structures of the antibiotic X-14547 A, stenine and
(-)-longithorone A.
reported. We have synthesized tricyclic compounds from acyclic
substrates in only two steps, considering variables such as ring
size and steric hindrance and substantially improved the results
obtained with other dienophiles.
One of the most important goals in organic synthesis is to build
carbon-carbon (CÀ C) bonds and carbon-heteroatom (CÀ X)
bonds and thus be able to synthesize complex molecules
starting from simple substrates. The venerable Diels-Alder[1]
reaction is one of the most useful strategies for the synthesis of
highly functionalized molecules with biological activity,[2] such
as the antibiotic X-14547 A;[3] stenine,[4] with anthelmintic and
antitussive properties;[5] or cytotoxic[6] (À )-longithorone A,[7]
amongst many others (Figure 1).
The standard Diels-Alder reaction has been widely studied
and new variants has been reported in recent years. One of
these innovations is the aza Diels-Alder reaction (ADA),[8] which
involves nitrogen atoms and has been successfully used in the
synthesis of complex natural products, including (�)-lupinine[9]
and (�)-epi-lupinine,[9] alkaloids with cytotoxic properties;[10]
ipalbidine,[11] an analgesic;[12] and notapoditine B,[13] with
cytotoxic activity[13] (Figure 2).
The Diels-Alder reaction has normally been carried out using
dienes with electron donanting groups (EDG) and with
dienophiles which include electron withdrawing groups (EWG).
However, the usefulness and versatility of the ADA reaction
prompted us to study it under different conditions. We describe
the synthesis of several compounds using dienes with EWG in
this communication. These halo-dienes have been easily
Figure 2. Chemical structures of (�)-lupinine, (�)-epi-lupinine, (�)-ipalbidine
and notapoditine B.
synthesized following a methodology previously reported by
our group,[14] which is innovative and includes cross-coupling
reactions between ketones and alkynes. Moreover, the dien-
ophile used was the 4-phenyl-1,2,4-triazoline-3,5-dione (known
as PTAD), one of the most vigorous dienophiles.[15]
This procedure has provided complex tricyclic cycloadducts,
which are obtained from acyclic substrates with excellent yields.
This highlights the versatility and efficiency of our proposed
methodology.
The first chosen substrate to assay the methodology and to
optimize the reaction conditions was diene 5.[14] The reaction
between 5 and dienophile PTAD provided cycloadduct 10 with
an excellent yield of 92%. The overall yield from the acyclic
substrate 1 to tricyclic product 10 was 81%, which is note-
worthy when we take into account the acyclic structure of 1
and the complex chemical tetracyclic structure of 10
(Scheme 1).
After successfully obtaining 10, the synthesis of 11 was
attempted. The precursors 5 and 6 maintain structural likeness,
so reaction achievement was expected. The key step, the ADA
reaction between the dienophile and the diene 6, generated
product 11 (88%) (Scheme 2). Thus, the tricyclic compound was
obtained in two steps with an overall yield of 68%. This
synthesis was especially interesting when we take into account
that it gives a bicyclic carbocycle with two six-membered fused
rings, a common system in natural products.
[a] R. G. Uceda, Prof. J. E. Oltra
Department of Organic Chemistry
Faculty of Sciences, University of Granada
Campus Fuentenueva s/n, 18071, Granada, Spain
E-mail: joltra@ugr.es
http://organicsynthesis.ugr.es
[b] Dr. E. Roldan-Molina, Prof. J. A. R. Navarro
Department of Inorganic Chemistry
Faculty of Sciences, University of Granada
Campus Fuentenueva s/n, 18071, Granada, Spain
E-mail: jarn@ugr.es
These two syntheses were useful for verifying the success of
the reaction with carbocyclic dienes. After studying the
behaviour of the carbocyclic dienes, we continued our study
https://fqm195.ugr.es
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100170
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Scheme 1. Synthesis of cycloadduct 10 [81% overall yield].
Scheme 4. Synthesis of cycloadduct 13 [74% overall yield].
proved. The overall yield in two steps of this latter trial was
74%. All these results show the efficacy of our ADA method-
ology to synthesise highly functionalized compounds in just a
few steps with excellent yields, even with dienes supporting
halogen atoms and/or the presence of steric hindrance.
In this study, tricyclic compounds have been obtained from
simple substrates in two steps with excellent overall yields (68–
81%), a remarkable achievement in view of the electron-
deficient dienes used. These results are still more interesting
considering previous results.
Scheme 2. Synthesis of cycloadduct 11 [68% overall yield].
PTAD is a vigorous but seldom used dienophile.[15] This
compound reacts quantitatively with simple dienes, such as 1,3-
butadiene, (Z,E)-2,4-hexadiene or (Z,Z)-2,4-hexadiene,[16] but the
yield drops with steric hindrance. This variable has been studied
using dienes with 2,2-diphenylcyclopropyls as substituents,[17]
giving 75% yield. In this study, by making use of dienes with
EWG and having studied the steric hindrance, we were able to
achieve a higher yield. Previous studies had considered the
reactivity of PTAD as a dienophile with activated dienes, using
1,3-dimethoxy-1,3-butadiene (82%),[18] 1,2-dipropoxy-1,3-buta-
diene (84%)[19] or nitrogenated dienes, such as triphenylaza-
diene (33%)[20] or N,N’-diphenylazadiene (30–49%).[19] All of
these studies gave inferior results when compared to ours,
although they used more activated dienes for the Diels-Alder
reactions. Neither studies using cyclic dienes[21] such as cyclo-
pentadiene (46%) nor 1,3,5-cycloheptatriene (48%) were able
to produce better results. The conclusion is clear: the proposed
methodology provides complex and functionalized structure
from simple substrates, with excellent yields.
Furthermore, our group have already studied the reactivity
of the dienes we used in the Diels-Alder reactions.[14] In this
study the chosen dienophile was tetracyanoetylene, one of the
most used and well-known dienophiles. The results have been
published, but it should be noted that PTAD improves the yield
(8–15% interval) in every diene. Moreover, it is noteworthy that
polycyclic products 10–13 have a bromine atom substituent
which can act as another branching point for further function-
alization. For these reasons, we want to highlight the behaviour
of PTAD as a dienophile which provides very satisfactory yields
even when using dienes with EWG groups.
with diene 7, which includes a nitrogen atom. This trial was
important to demonstrate the capacity of the methodology to
synthesize tetranitrogenated heterocycles. Finally, treatment of
diene 7 with dienophile PTAD produced product 12 (90%)
(Scheme 3). The above results support the versatility of our
method for complex carbocyclic and heterocyclic cycloadducts.
At this point, three complex compounds were synthesized
from simple substrates in only two steps. Furthermore, quite
satisfactory overall yields were obtained. Moreover, an addi-
tional synthesis was planned to study a relevant variable, the
steric hindrance. Diene 8 was chosen to study this aspect
because it incorporates an ethyl group instead of a methyl
substituent, such as dienes 5–7 have.
Treatment of diene 8 with PTAD provided product 13
(Scheme 4) with quite a satisfactory yield but slightly lower
(85%) than the 10–12 syntheses (88–92%). The compatibility
between the methodology and the steric hindrance was
Scheme 3. Synthesis of cycloadduct 12 [74% overall yield].
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Communications
doi.org/10.1002/ejoc.202100170
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The authors acknowledge support from the Junta de Andalucía
(Project P18-RT-612). E. Roldan-Molina is grateful to the University
of Granada (UGR) for her research contract. R. G. Uceda acknowl-
edges the University of Granada (UGR) for his scholarship for
undergraduates to do research. The authors are grateful to Dr.
Angela Tate for her revision of the English text.
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Conflict of Interest
The authors declare no conflict of interest.
*
Keywords: Diels-Alder reaction · Halogenated dienes · PTAD
Synthesis
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Manuscript received: February 10, 2021
Revised manuscript received: March 11, 2021
Accepted manuscript online: March 15, 2021
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