Angewandte
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sec-butyllithium did not lead to ring expansion. Instead, a 1,2-
acyl shift, resulting from attack of the benzylic anion on the
urea carbonyl group, generated the aminoamide 5 (Table 1,
entries 1 and 2).[11] Since sec-BuLi also gave alkylated
byproducts[10d] as a consequence of nucleophilic attack on
the urea, LDA was used as the base in all subsequent
reactions.
N,N’-Dimethylpropylideneurea (DMPU) can dramati-
cally alter the reaction pathways of organolithium species in
solution when used as a ligand or cosolvent.[10f,12] Significantly,
treatment of 3a with LDA in the presence of DMPU
completely suppressed the acyl shift leading to 5 and gave
instead the ring-expanded benzodiazocine 4a in good yield
(Table 1, entry 4). An even higher yield of benzodiazocine 4b
was obtained with the 5-chloroindoline-derived urea 3b
(entry 5).
These conditions (2 equiv LDA; 5 equiv DMPU; THF,
ꢀ788C, 1–16 h) were applied successfully to a series of ureas
(6a–i) derived from commercially available 6-membered
heterocycles, and allowed the synthesis of a range of
substituted 9-membered benzodiazonines (7a–j) in good to
excellent yield (Scheme 2). Ring expansion of 6a generated
7a in good yield on a scale of both 0.4 mmol and 3 mmol, with
X-ray crystallography confirming the benzodiazonine struc-
ture of 7a.[19] The ring-expansion reaction is insensitive to
both electronic or steric demands, giving the ring expansion
products with electronically diverse (7b, 7c) or hindered
ortho-substituted (7d) migrating substituents in good to
excellent yields.
Heteroaromatic (2-pyridyl and 2-thiophenyl) rings may be
incorporated into the migrating aryl ring (7e) or a to the
benzylic anions (7 f, 7g). Higher temperatures are required
for the reactions of pyridyl-containing substrates to reach
completion. By contrast, the 2-thiophenyl-stabilized anion
derived from 6g rearranged successfully to 7g even in the
absence of DMPU. Incorporation of a heteroatom into the
tether through expansion of urea 6h, which is derived from
commercially available benzomorpholine, gave the benzox-
adiazonine 7h. Replacing the N-methyl substituent with
a tert-butyl group substantially decreased the rate of the
reaction of 6i, which required elevated temperature to obtain
a good yield of the ring-expansion product 7i.
Chiral substrates 8 and 9 were made from enantiopure
(S)-a-methylbenzylamine and were ring-expanded under the
same conditions (Scheme 3). Each gave a product (10 and 11)
with a new quaternary center within the expanded 8- or 9-
membered ring. Both rearrangements were stereospecific,
with only slight erosion of e.r. in the case of 11, and must
proceed through a configurationally stable organolithium
intermediate.[13]
The method was also applicable to the synthesis of bicyclic
structures through migratory ring fusion (Scheme 3). The
unsymmetrical ureas 12, formed by coupling two isomeric 6-
membered nitrogen heterocycles, underwent ring expansion
through insertion of the tetrahydroisoquinoline ring into the
tetrahydroquinoline. The diazabicyclo[7.4.0]tetradecane
products 13a and 13b were formed at ꢀ408C in excellent
yield, highlighting the way that structural complexity is
rapidly generated from the simple urea precursor.
Scheme 2. Ring expansions to yield 9-membered nitrogen heterocycles.
[a] Yield in parenthesis: reaction conducted on 0.4 mmol scale.
[b] Yield in parenthesis: reaction conducted on 3 mmol scale. [c] Reac-
tion run at ꢀ608C. [d] Reaction run at ꢀ308C. [e] Reaction run at
ꢀ408C without DMPU. [f] Reaction run at ꢀ108C.
Having made 8- and 9-membered heterocycles in just two
or three steps from commercially available 5- and 6-mem-
bered precursors, we extended the ring-expansion method to
larger ring sizes (Scheme 4). The requisite 7-, 8- and 9-
membered ureas 14 were made either from a commercially
available precursor (14a, two steps from benzazepine) or by
using reported procedures (14b and 14c[14]). All three ureas
underwent ring expansion to give 10-, 11- and 12-membered
heterocycles in good yields.[15]
Chiral starting materials with substituents in the expand-
ing ring underwent migratory ring expansion with complete
diastereoselectivity (Scheme 5). 2-Substituted indolines, pre-
pared from the corresponding 2-substituted indoles,[16] were
converted into the starting ureas 16. Ring-expansion of
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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