The formation of medium-sized rings by the intramolecular cyclization of arylnitrenium ions

Article abstract of DOI:10.1016/S0040-4039(03)01591-0

The synthesis of an aminodibenzo[a,c]octadiene and an aminodibenzo[a,c]octatriene, guided by molecular mechanics calculations, was effected by the intramolecular cyclization of the corresponding open chain nitrenium ions. Also reported is the predicted failure to synthesize another aminodibenzo[a,c]octadiene using this method.

Full text of DOI:10.1016/S0040-4039(03)01591-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6965–6967
The formation of medium-sized rings by the intramolecular
cyclization of arylnitrenium ions
Rudolph A. Abramovitch,a,* Joseph Millerb,† and Antonio J. C. de Souzab
aDepartment of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
bUniversidad Estadual de Campinas, Campinas, SP 13100-000, Brazil
Received 2 June 2003; revised 23 June 2003; accepted 23 June 2003
Abstract—The synthesis of an aminodibenzo[a,c]octadiene and an aminodibenzo[a,c]octatriene, guided by molecular mechanics
calculations, was effected by the intramolecular cyclization of the corresponding open chain nitrenium ions. Also reported is the
predicted failure to synthesize another aminodibenzo[a,c]octadiene using this method.
© 2003 Elsevier Ltd. All rights reserved.
Intramolecular cyclizations of arylnitrenium ions have
led to a variety of important ring systems resulting from
CꢀC, NꢀC, and CꢀO bond formation. Thus, 9,10-dihy-
droaminophenanthrenes and a phenanthrene 9-carboxy-
late,1 isoquinoline alkaloids,2 4-aminobenzo[c]chroman,3
a dihydrophenanthridine,3 2-aminodibenzocycloheptadi-
ene,4 3-amino-6,7-dihydro-5H-dibenzo[a,c]cyclohepta-
dienone and a trifluoromethanesulfonyl enolate deriva-
tive (the latter incorporating 1,2,3-trimethoxy groups)
obtained in low to modest yields,4 all resulting from
intramolecular CꢀC bond formation, pyrimido[4,5-
b]indoles,5 a 16-membered aporphine-based ring system6
(both formed by NꢀC bond formation), and a variety of
lactones,7 resulting from OꢀC bond formation, among
many others, were synthesized in this way.
whose formation were predicted by MMX calcula-
tions on model precursors, and the failure of
an intramolecular cyclization, also predicted by such
simple calculations. There are a number of conforma-
tions with slightly higher energies (within <1 kcal) than
the computed global energy minimum one, which are
close in geometry to the GMMXE conformation. To
really predict the cyclization rate one would have
to evaluate the relative populations of all the low
energy minima. It seems, however, that the MM global
energy minimum conformation has some predictive
value as regards the feasibility of intramolecular
cyclization.
The starting material for the dibenzooctadiene was
1-(3-azidophenyl)-4-phenylbutane (1) which was syn-
thezised as shown below:
We now report the preparation of a new aminodiben-
zo[a,c]octadiene and a related dibenzocyclooctatriene,
Keywords: nitrenium; intramolecular cyclizations; medium-sized rings; MMX.
* Corresponding author. Tel. +1-864-656-5008; fax: +1-864-656-6613; e-mail: raa@clemson.edu
† Present address: Universidade Federal da Paraiba, Laboratorio de Tecnologia Farmaceutica, Campus Universitario, Caixa Postal 5009,
58051-970, Joao Pessoa, Brazil.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01591-0

6966
R. A. Abramo6itch et al. / Tetrahedron Letters 44 (2003) 6965–6967
A
shorter route starting with m-nitrophenyl
chromatography. The other tarry products eluted could
not be identified.
triphenylphosphonium bromide and cinnamaldehyde
resulted in a lower overall yield of product owing to the
low yield of Wittig product formed. Treatment of 1
with a few drops of trifluoromethanesulfonic acid in
trifluoroacetic acid solution at 0°C gave a 28% (after
purification) of 3-aminodibenzo[a,c]octadiene (2)
A much better source of aminodibenzo[a,c]octatriene
(and eventual octadienes via the reduction of the triene)
derivatives is azide 5. MMX calculations indicated that
the predicted distance between the vacant position para
The low yield of intramolecular cyclization product is
in complete agreement with the earlier result from the
cyclization of 1-(4-azidophenyl)-4-phenylbutane to give
a compound in 1% yield to which structure 3b was
assigned (a trace of material to which structure 3a was
assigned and was only detectable by GC/MS).8 Owing
to the trace quantities obtained, no spectroscopic stud-
ies other than the mass spectrum were obtained at the
time. It seems more likely to us now in retrospect that
the compounds were the CꢀC intramolecular cycliza-
tion products 3c. The global minimum energy confor-
mation of the model for the nitrenium ion leading to
putative compounds 3 [1-(4-nitrophenyl)-4-phenylbu-
tane: there are no MM parameters for the nitrenium
group,9 so we used the strong electron-withdrawing
nitro group instead] is the ‘linear’ conformation. A
somewhat bent conformation lies about 1 kcal above
the global energy minimum conformation, and the
computed distance between two of the ortho groups in
Figure 2. MMX global energy minimum conformation of
1-(3-nitrophenyl)-4-phenylbutane.
,
the two rings is 6.753 A (see Fig. 1). On the other hand,
the global energy minimum conformation of 1-(3-nitro-
phenyl)-4-phenylbutane is slightly bent (Fig. 2), and the
predicted distance between the carbon para to the nitro
group and an ortho carbon in the other aryl group is
,
4.409 A, close enough that some intramolecular CꢀC
bond formation might be expected. This was indeed the
case, and 2 was obtained in 28% yield after column
Figure 1. MMX bent conformation of 1-(4-nitrophenyl)-4-
phenylbutane.
Figure 3. MMX global energy minimum conformation of 4.

R. A. Abramo6itch et al. / Tetrahedron Letters 44 (2003) 6965–6967
6967
Scheme 1.
to the nitro group and one of the ortho positions of the
phenyl group is 4.299 A (Fig. 3). In addition, of course,
take place. In actual practice, the only pure product
from 7 obtained on treatment with TFMAS at 0°C and
isolated by column chromatography was trifluoro-
methylsulfonate 9 (35% yield), resulting from the nucle-
ophilic addition of CF3SO2O− to the arylnitrenium ion.
Such ‘undesired’ products have been reported
before.4,7,10 These reactions may be viewed as the intro-
duction of a protected hydroxyl group into an aniline
ring system, and as such may be useful.
,
the alkene group imparts some rigidity to the chain,
which is lacking in the precursor to 2. Azide 5 was
synthesized as shown in Scheme 1. Generation of the
nitrenium ion with TFMSA at 0°C gave a 70% yield of
6. The latter’s functionalities would permit the synthesis
of
a
wide variety of substituted dibenzo-
[a,c]cycloheptatrienes.
1-(3-Azidophenyl)-2,2-dicarbethoxy-4-phenylbutane (7)
was synthesized from diethyl 2-phenethylmalonate and
3-nitrobenzyl bromide, followed by reduction of the
nitro- to amine and thence to the azide, which would
References
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serve as
a
precusor to 3-aminodibenzo[a,c]-
cyclooctadiene diethyl carboxylate if the conformation
of the nitrenium ion was suitable to achieve ring-clo-
sure. The global energy minimum conformation
(MMX) of the nitro precursor 8 is shown in Figure 4,
which predicts that no intramolecular cyclization would
4. Abramovtich, R. A.; Jeyaraman, R.; Yannakopoulou, K.
J. Chem. Soc., Chem. Commun. 1985, 1107.
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9. The electron-withdrawing nitro group is used as a substi-
tute for the nitrenium ion group since parameters for the
latter are not available in MMX.
10. Abramovitch, R. A.; Rauter, A. P.; da Silva Pinto, O.,
2002, unpublished results.
Figure 4. MMX global energy minimum conformation of 8.