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Benzo-fused
rings are prevalent in pharmacologically active drugs. For example, Lotensin is
an ACE-inhibitor drug marketed for the treatment of
hypertension, and OPC-31260
is a highly potent nonpeptide AVP V2 receptor
antagonist undergoing Phase II clinical trials in the treatment of Hyponatremia.
In this project, we investigated
the use of several
transition-metal catalysed reactions for the
construction of medium-sized (7- to 10-membered) benzofused heterocyclic rings.
Conformational analyses were performed, whenever
possible, using a combination of X-ray crystallography
(solid-state structure) VT NMR (solution behaviour), and
molecular mechanics.
(i) Tandem Heck-isomerisation-aryl amin(d)ation
(ii) Stille-coupling/Ring Closing Metathesis
(iii) Intramolecular Heck arylation
(i) Tandem Heck-isomerisation-Buchwald-Hartwig aryl
amination
(Tom Rising, Rachael Priestley,
Maryiam Qadir)
A
strategy involving palladium-catalysed C-C and C-N
bond-forming steps have been successfully applied to the
synthesis of 1-benzazepine structures (Scheme 1).
Scheme 1
(R = H, Ph, Me): (i)
Tandem Heck-isomerisation: Pd(OAc)2, Cl-,
base, DMF, 40-80 oC; (ii) a. BnNH2,
Ti(Oi-Pr)4, NaBH4, THF; b.
H+, H2O; (iii)
Palladium-catalysed aryl amidation: Pd(dba)2,
PPh3, KOt-Bu, 100 oC.
In the first bond forming step, a tandem Heck-double
bond isomerisation process between 2-iodobromobenzene
and a homoallylic alcohol was used to synthesise
the ketone intermediate I (in one-pot), which was
subjected to a reductive amination reaction with
benzylamine. Finally, an intramolecular
palladium-catalysed aryl amidation reaction was used for
the ring cyclisation step, and a number of 2-alkyl and
2-aryl benzazepine rings may be constructed in this way.
A limitation of this strategy is the size of R. When R =
tert-butyl, a competitive b-H
elimination occurs to give the dehalogenated imine
III as the only product (Scheme 2).
Scheme 2. Competitive
b-H elimiation when R =
tert-butyl.
(ii) Stille-coupling/Ring-Closing Metathesis
(Maryiam Qadir)
Scheme 3.
(i) NaH, THF; (ii) Stile cross coupling: (allyl)SnBu3,
Pd(OAc)2, PPh3, LiCl; (iii)
Ring-closing metathesis: Grubbs' catalyst, toluene
or CH2Cl2 (Table 1); (iv) H2,
Pd/C.
Seven- to ten-membered rings (dihydro-benzazepine, benzazocine,
benzazonine and benzazepine, respectively) VIa-d have been synthesised, using a Stille coupling to install an
aryl allyl unit, and a ring-closing metathesis for the cyclisation (Scheme 3). These rings may be reduced to
afford the saturated VIIa-c and N-benzyl
analogues VIIIa-c.
The solid-state
structures of these usual ring sizes were determined
by single-crystal X-ray crystallography (figure 1).
In most cases,
the
amide moiety in these benzo-fused rings favours N-pyramidisation
(with the exception of the ten-membered benzazecine,
which adopts an amide twist).
VIa VIb VIc
VId
VIIa
VIIb
VIIc
Figure 1. Solid-state
structures of 7- to 10-membered rings determined by
X-ray crystallography.
Molecular mechanics calculations revealed a direct
correlation between the amide twist (t)
and ring stability. Namely, the dynamic behaviour of the
heterocycles were found to be dependent also on the
extent and nature of the amide distortion. We concluded
that ring strain of these medium-sized heterocyclic
rings is relieved through amide distortion, which leads
to a more stable structure.
(iii) Intramolecular Heck arylation reaction
(Maryiam Qadir, Emma Cropper)
We have also used the intramolecular
Heck arylation reaction for the construction of the
7-membered benzazepine ring structure (Scheme 4).
Scheme 4. Intramolecular Heck arylation. Unusual effect
of ligand on ring cyclisation.
Interesting, we found that
the use of >3 equivalents of PPh3 suppressed
endo cyclization, affording the 7-exo
product exclusively. Thus, the amount of ligand clearly
dictates the nature of the transition state and its
subsequent C-C formation.
The intramolecular Heck Reaction
may by used to construct benzolactams containing 6-8
membered heterocyclic rings (Scheme 5). Using 4
equivalents of PPh3, the cyclisation occurred
exclusively in an exo- manner. The solid-state
stuctures of the - and 8-membered heterocyclic rings
have also been obtained.
Scheme 5.
Regioselective Heck cyclisation of 6-8 membered
benzolactams. The Heck
cyclisation of medium-sized rings is found to be highly
sensitive to the catalytic conditions. Most notably, by
adopting a ligandless (Jeffery's) catalyst precursors,
the chemoselective biaryl coupling occurred in
preference over coupling with the terminal alkene,
giving the dihydrophenanthridine as the only product
(Scheme 6).
Scheme 6. Chemoselective Heck cyclisation. |