Intramolecular polar [4·+2] cycloadditions of aryl-1-aza-2-azoniaallene salts: Unprecedented reactivity leading to polycyclic protonated azomethine imines

Article abstract of DOI:10.1002/anie.201306553

Charged up: In the first example of the title salts undergoing a [4 ^·+2]cycloaddition reaction, the azo bond and one aromatic πbond make up the 4πcomponent. This reaction appears to be concerted and provides high yields of protonated azomethine imine products. Substituted alkenes provided products containing all-carbon or nitrogen-bearing quaternary centers in high yield.

Full text of DOI:10.1002/anie.201306553

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Angewandte
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DOI: 10.1002/anie.201306553
Heterocycles
Intramolecular Polar [4È+2] Cycloadditions of Aryl-1-aza-2-
azoniaallene Salts: Unprecedented Reactivity Leading to Polycyclic
Protonated Azomethine Imines**
Daniel A. Bercovici, Jodi M. Ogilvie, Nikolay Tsvetkov, and Matthias Brewer*
Polar cycloadditions, in which one of the reacting partners is
ionic, are less common than cycloadditions involving
uncharged or dipolar components, but often occur more
readily.[1] For example, whereas [4+2] cycloaddition reactions
that involve styrene subunits as the 4p component generally
require reactive dienophiles or harsh reaction conditions to
proceed,[2] the Povarov reaction, which is the stepwise[3]
[4È+2] cycloaddition of N-aryliminium ions with electron-
rich olefins, occurs readily at or below room temperature.[4,5]
The charge that is present in the ionic partner of polar
cycloadditions is often due to the presence of a heteroatom
and these systems can provide useful routes to heterocyclic
products,[1a] which are prevalent scaffolds in biologically
active molecules.[6] Although uncharged heteroallenes have
been used extensively in the preparation of heterocyclic
compounds,[7] cationic heteroallenes have received less atten-
tion. To this end, we have been exploring the use of 1-aza-2-
azoniaallene cations (e.g. 2, Scheme 1) in intramolecular
reactions as a means of preparing a variety of aza-hetero-
cycles. Herein we report our discovery that aryl-1-aza-2-
azoniaallene cations can react by an unprecedented intra-
molecular [4È+2] cycloaddition with pendant alkenes wherein
the azo bond and one aromatic p bond make up the
4p component.
Scheme 1. Varied reactivity of aryl-1-aza-2-azoniaallene salts.
1-Aza-2-azoniaallene cations are known to react by
several different pathways, thus leading to a variety of
products. For example, these species can add nucleophiles at
the carbon atom to provide azo products,[8] can undergo 3,3-
sigmatropic rearrangements,[9] and can react in stereospecific
À
intramolecular C H amination reactions to provide pyrazo-
lines by what appears to be a concerted nitrenoid-type
insertion (e.g. 2 to 3, Scheme 1).[10] In addition, these cationic
heteroallenes can act as 1,3-dipoles in [3+2] cycloaddition
reactions with a variety of p systems to provide five-mem-
bered-ring heterocycles.[11] We have taken advantage of this
latter reactivity to prepare bicyclic diazenium salts (e.g. 6a
and 6b, Scheme 1).[12]
[*] Dr. D. A. Bercovici,[+] Dr. J. M. Ogilvie[+,#], Dr. N. Tsvetkov,
Prof. M. Brewer
Department of Chemistry, University of Vermont
82 University Place, Burlington, VT 05405 (USA)
E-mail: Matthias.brewer@uvm.edu
While continuing our studies on intramolecular reactions
of 1-aza-2-azoniaallene cations we recently prepared the
heteroallene 8a (Scheme 1), which could in principle form
a 5,5-bridged bicyclic diazenium salt similar to 6b. However,
orbital alignment in the transition state leading to that
product would not be ideal; this asynchronous ring closure
would be Baldwin-disfavored in the same way that 5-
(enolendo)-exo-trig aldol condensations are disfavored.[13]
We were interested to observe that 8a in fact did not undergo
intramolecular [3+2] cycloaddition, but instead reacted by an
unprecedented intramolecular [4È+2] cycloaddition to pro-
vide a tricyclic protonated azomethine imine containing
a 1,2,3,4-tetrahydrocinnoline scaffold (9a, Scheme 1). Cinno-
line derivatives, including 1,2,3,4-tetrahydrocinnolines, show
diverse biological activity[14] and although tetrahydrocinno-
[+] These authors contributed equally to this work.
[#] Nꢀe Wyman.
[**] We thank Dr. M. I. Javed for obtaining a preliminary result for this
project, Bruce O’Rourke for obtaining mass spectral data, Dr. Bruce
Deker for assistance with NMR characterization, and Prof. Rory
Waterman for X-ray data collection and structure determination.
Financial support was provided by the National Science Foundation
under CHE-0748058 and through instrumentation grants CHE-
1039436, CHE-1126265, and CHE-0821501. This work was made
possible by use of a facility supported by the Vermont Genetics
Network through Grant Number 8P20GM103449 from the INBRE
Program of the National Institute of General Medical Sciences
(NIGMS), a component of the National Institutes of Health (NIH).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306553.
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lines can be prepared by several classical methods,[15] the
development of new methods to prepare this useful scaffold
continues to be an active area of research.[16] The unprece-
dented nature of this reaction, the uniqueness of the
protonated azomethine imine products,[17] and the potential
that these products will have diverse reactivity, and thus be
useful synthetic intermediates, encouraged us to examine this
polar cycloaddition in more detail. Our preliminary results
are presented here.
facilitated by the adjacent oxygen center, but this product
was not observed.
We next examined the scope of this reaction with respect
to alkene substitution. We were pleased to observe that the a-
chloroazo compounds 7e and 7 f (Table 2, entries 5 and 6),
which contained a di- and trisubstituted olefin respectively,
provided excellent yields (97% and 98%, respectively) of the
desired product. Importantly, these examples show that this
transformation can efficiently form nitrogen-bearing and all-
carbon quaternary centers.
In an effort to gain some understanding of the concerted
nature of the bond-forming events, we prepared trans and cis
alkenes 7g and 7h, respectively (Table 2, entries 7 and 8) and
subjected each to the cyclization conditions. The cycloaddi-
tion reaction proved to be stereospecific. Each substrate led
to a unique diastereomer of the product, thus suggesting that
the cycloaddition process is concerted.[21]
Our first task was to optimize the reaction conditions for
the conversion of 7a into 9a (Table 1) . Our initial results
were obtained by adding 1.2 equivalents of SbCl5 to a solution
Table 1: Assessment of Lewis acids.
Incorporation of the alkene component into a ring
provided the tetracyclic products 9i and 9j (Table 2, entries 9
and 10) as single diastereomers in high yield. These results
highlight the ability of this transformation to provide
structurally complex products from structurally simple start-
ing materials.
Entry
Lewis acid
Yield [%][a]
1
2
3
4
SbCl5
AlCl3
86
84
70
84
The electronic nature of the dienophile can have a dra-
matic effect on the efficiency of polar cycloadditions. For
example, the Povarov reaction fails when the dienophile is
electron deficient.[4d] To test the scope of this reaction with
respect to the electronics of the pendant dienophile we
prepared the cyclization precursors 7k and 7l (Table 2,
entries 11 and 12) which contain electron-rich and electron-
deficient olefins, respectively. The electron-rich olefin (7k)
was surprisingly difficult to prepare as both it and the
hydrazone precursor decomposed readily. Treating 7k under
the reaction conditions provided the cycloaddition product 9k
in a modest 33% yield. We suspect that this low yield is not
due to the cycloaddition step itself, but rather to the instability
of 7k which became noticeably dark in color while setting up
the reaction. It is interesting to note that this highly electron-
rich olefin reacted to provide a single diastereomer of
product. In view of the cationic nature of the heteroallene
intermediate, we expected an electron-deficient alkene to be
a poor reaction partner. We were surprised to observe that 7l
(entry 12) provided the cycloadduct 9l in 93% yield. This high
yield further demonstrates the broad scope of this reaction.
In view of the similarity between 5 and 8a (Scheme 1),
which are identical except for the length of the tether that
separates the heteroallene from the pendent alkene, it is
interesting that 5 provides only the diazenium salt product
and none of the corresponding protonated azomethine imine.
In addition, intermolecular cycloadditions of 1-aza-2-azo-
niaallene cations proceed by the [3È+2] manifold[11a–g] and
taken together these facts indicate that the [3È+2] pathway is
intrinsically more favorable than the alternative [4È+2]
cycloaddition described here. It seems likely that this latter
reaction occurs in the cases described here because of the
orbital alignment constraints discussed above, which stem
from the intramolecular nature of these reactions.
AgOTf[b,c]
TMSOTf[c,d]
1
[a] Yield determined by H NMR spectroscopy using an internal
standard, and based on the limiting reagent. [b] Reaction conducted at
room temperature for 2 h. [c] 1 equiv of Lewis acid was used. [d] Reaction
conducted at room temperature for 24 h. Tf=trifluoromethanesulfonyl,
TMS=trimethylsilyl.
of 7a in CH2Cl2 at À788C, with warming to room temper-
ature. After some experimentation, we discovered that using
a slight deficiency of SbCl5 (0.95 equiv) resulted in cleaner
crude reaction mixtures. Alternative Lewis acids were
screened and while we were pleased to see that AlCl3,
AgOTf, and TMSOTf could each mediate the reaction, they
did not improve the yield or product purity compared to the
use of SbCl5. However, the triflate counter ion did give
a product that was more crystalline, and allowed us to confirm
the structure of 9a by X-ray crystallography.[18] Factoring in
both cost and the simplicity of using a liquid Lewis acid
caused us to select SbCl5 as the Lewis acid of choice for
further studies.
With optimized reaction conditions in hand, we next
explored the scope of this intramolecular cycloaddition
(Table 2).[19] We were pleased to note that increased sub-
stitution adjacent to the heteroallene carbon atom was well
tolerated. The more sterically hindered isopropyl derivative
7b (entry 2) provided the desired product in 88% yield,
whereas the cyclohexanone-derived a-chloroazo 7c (entry 3)
provided the tetracycle 9c in 83% yield as a 2:1 mixture of
diastereomers.[20] Incorporation of a silyloxy group adjacent
to the heteroallene carbon atom was also well tolerated and
the silyl ether 7d provided the more-heteroatom-rich product
9d in 71% yield (entry 4). In this case, one could envision the
cationic heteroallene intermediate undergoing a competitive
1,2-hydride migration to the electrophilic carbon atom
In conclusion, we have discovered an unprecedented
reactivity of aryl-1-aza-2-azoniaallene salts. The [4È+2] cyclo-
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Table 2: Substrate scope.
Entry
Substrate
Product
Yield
[%][a]
Entry
Substrate
Product
Yield
[%][a]
1
86
88
7
81
82
2
3
8
9
83
(2:1 d.r.)
89
85
4
71
10
5
6
97
98
11
12
33
93
1
[a] Yield determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
addition reaction described herein is likely concerted and
provides high yields of protonated azomethine imine products
which contain a 1,2,3,4-tetrahydrocinnoline core. This reac-
tion occurs at low temperature, is quite general with respect to
alkene substitution, and delivers products which contain all-
carbon or nitrogen-bearing quaternary centers in high yield.
Further studies on the scope and mechanism of this trans-
formation including computational studies and application of
this cycloaddition in natural product synthesis are planned.
Received: July 26, 2013
Revised: September 24, 2013
Published online: November 11, 2013
Keywords: cumulenes · cycloaddition · heterocycles ·
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Lewis acids · synthetic methods
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[19] The crude reaction mixtures were triturated with petroleum
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fully described in the Supporting Information.
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