Synthesis and unusual reactivity of N-tosyl-4,5-benzoazacyclodeca-2,6- diyne, yneamino-containing enediyne

Article abstract of DOI:10.1021/ja073614d

Substitution of the propargylic carbon for nitrogen in cyclic 10-membered ring enediynes results in at least 2 orders of magnitude enhancement of reactivity. The mechanism of cycloaromatization of aza-enediynes, however, switches from radical (Bergman) to

Full text of DOI:10.1021/ja073614d

Published on Web 09/18/2007
Synthesis and Unusual Reactivity of
N-Tosyl-4,5-benzoazacyclodeca-2,6-diyne, Yneamino-Containing Enediyne
Andrei Poloukhtine and Vladimir V. Popik*
Department of Chemistry, The UniVersity of Georgia, Athens, Georgia 30602
Received May 20, 2007; E-mail: vpopik@uga.edu
Scheme 2. Synthesis of aza-enediyne 1a
The extreme cytotoxicity of natural enediyne antibiotics is
attributed to the ability of the (Z)-3-ene-1,5-diyne fragment to
undergo Bergman cyclization1 and produce DNA-damaging p-
benzyne diradical.2 It is well-documented that the rate of this process
strongly depends on both the ring strain of enediyne-containing
cycle3 and the electronic properties of substituents.4-6 Recent
theoretical studies suggest that repulsion of the in-plane π-orbitals
of triple bonds destabilize the cyclization transition state, while
overlap of the out-of-plane π-orbitals produces the opposite effect
owing to pronounced aromatization.7 In accordance with this
hypothesis, there is theoretical, as well as experimental, evidence
that σ-acceptor and π-donor substituents at the acetylenic termini
enhance the rate of Bergman cyclization.3a,8 While replacing one
of the carbon atoms in the enediyne system with nitrogen allows
for the exploitation of heteroatom electronegativity,6 nitrogen
substituent in the propargylic position potentially allows for
benefiting from both rate-enhancing effects.8c,9
a Reagents and conditions: (a) N-[3-(t-butyldimethylsiloxy)propyl] tosyl
amide, CuSO4‚5H2O, 1,10-phenanthroline, K2CO3, toluene, 79%; (b) TBAF,
THF, 93%; (c) N-ethynyl-N-(3-hydroxypropyl) tosyl amide, Pd(PPh3)2Cl2,
CuI, Et3N, THF, 22%; (d) K2CO3, MeOH, 74%; (e) n-BuLi, NIS, THF,
79%; (f) Dess-Martin periodinane, CH2Cl2, 78%; (g) CrCl2, NiCl2, THF,
61%.
In this Communication we describe the synthesis and the
reactivity of the first cyclic aza-enediyne, in which a nitrogen atom
is directly connected to one of the alkyne termini. (Scheme 1).
1a in various solvents. Overnight heating of toluene and 1,4-
cyclohexadiene solutions of 1a at 40 °C resulted in the formation
of a complex mixture of 1:1 solvent adducts, which mass and NMR
spectra corresponded to the general formulae 11 and 11′ (Scheme
3). In benzene under these conditions the single major product 11a
was isolated (Scheme 3).10 Composition of product mixtures was
virtually the same in oxygenated or argon-saturated solvents. While
radical addition to 1,4-cyclohexadiene is a known process, the
formation of formal C-H insertion products with benzene and
toluene as well as regio- and 1:1 selectivity of the process are
inconsistent with p-benzyne reactivity.
Scheme 1
Scheme 3
Preparation of the target 8-hydroxy-N-tosyl-4,5-benzoazacyclo-
deca-2,6-diyne (1a) is outlined on the Scheme 2.10 Two methods
for the preparation of the key intermediate 8 were employed:
Sonogashira coupling of substituted tosyl yneamide with protected
o-iodophenylacetylene 6 and Cu(II)-mediated amidation11 of alkynyl
bromide 4 with corresponding tosyl amide. Iodination of the
terminal acetylene group in 8 followed by the oxidation of the
hydroxyl group gave aldehyde 10. The latter readily underwent
cyclization to the target aza-enediyne 1a under Nozaki-Hiyama-
Kishi conditions (Scheme 2).12
In methanol and 2-propanol at 40 °C aza-enediynes 1a,b
underwent rapid and clean conversion to the product of formal
insertion into O-H bond of the solvent (2a,b, Scheme 1). No
hydrogen abstraction products (11 or 11′, R ) H) were detected.
While the formation of O-H insertion byproducts in the course of
Myers-Saito cycloaromatization of allene-eneynes was reported
in a couple of cases,14 such clean and efficient reaction is unknown
for enediyne compounds. Furthermore, cycloaromatization of aza-
enediyne 1a to 5-alkoxy-1,2,3,4-tetrahydrobezo[g]quinoline (2a)
exhibits strong acid catalysis. Thus, in the presence of 1.5 × 10-4
M of toluenesulfonic acid the half-life time of 1a in 2-propanol at
25 °C dropped down to 5 min. This observation is in a sharp contrast
with carbocyclic enediynes, where the rate of cyclization is
independent of the acid concentration.15 Cycloaromatization of 1a
The rate of cycloaromatization of 1a at 40 °C was measured
using 1H NMR (ca. 25 mM in CDCl3) and UV spectroscopy (ca. 2
× 10-4 M in 2-propanol and hexanes). Aza-enediyne 1a was found
be more than 2 orders of magnitude more reactive than its
carbocyclic analogue (τ1/2 ) 9240 min at 40 °C in neat 1,4-
cyclohexadiene13). In addition, the rate of cycloaromatization of
1a was higher in polar solvents, for example, at 40 °C half-life
time of 1a was 105 min in hexane, 65 min in chloroform, and 20
min in 2-propanol.
Surprisingly, the expected Bergman cyclization product (11, R
) H, Scheme 3) was not detected in thermolyses of aza-enediyne
9
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10.1021/ja073614d CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
in methanol was also accompanied by etherification of the hydroxy
group (3, Scheme 1).
subsequent SN2 substitution of a protonated hydroxy group. We
believe that the formation of 11a in benzene also proceeds via a
Friedel-Crafts-type reaction of the cation 16 with the solvent.
Acyclic ketenimmonium cation 15A formed by the protonation
of 12 should exist predominantly in the less hindered conformation
15A1, which cannot cyclize but rather adds alcohol to give 18. The
unstable imide enol ether 18 is hydrolyzed upon workup to imide
13. Traces of the cyclization product 14 are, apparently, produced
Cycloaromatization of 1a was ca. two times slower in 2-propanol-
d1 and in methanol-d1. The substantial solvent isotope in normal
direction (kH/kD ≈ 2) indicates that proton transfer is at least partially
rate-determining. Incorporation of deuterium into the reaction
product (2a-d2, Scheme 4) provides further evidence against
diradical mechanism since p-benzene should preferentially abstract
protium from the methine group of the solvent.
from the minor conformer 15A2
.
In conclusion, the replacement of a propargylic carbon in 3,4-
benzocyclodeca-1,5-diyne with a nitrogen atom resulted in dramatic
enhancement of the enediyne reactivity. The cycloaromatization
reaction of aza-enediynes 1a,b proceeds by a new polar mechanism
via the intermediate formation of ketenimmonium cation. The latter
undergoes rapid cyclization to give phenyl cation, which is trapped
by a solvent.
Scheme 4
Acknowledgment. Authors thank the NSF (Grant CHE-
0449478) and Georgia Cancer Coalition for the support of this
project.
In contrast to 1a, only traces of the O-H insertion product 14
were detected in the thermolysis of acyclic enediyne-sulfonamide
12 in 2-propanol, while imide 13 was isolated in 72% yield (Scheme
5).10 The acyclic compound is less reactive and requires 4 h heating
at 160 °C in 2-propanol to achieve full conversion. The product of
conventional Bergman reaction, 2-(N-propyl-N-tosyl)-3-propyl-
naphthalene, has not been detected in reaction mixtures.
Supporting Information Available: Experimental procedures, and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Scheme 6
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