Angewandte
Communications
Chemie
Table 1: Scope with respect to the substrates (1a–l) and yields for the
final step of their preparation.
radicals with simple aromatics are endergonic and, thus,
should be reversible (Scheme 2). If necessary, one can further
deactivate the alkyl radical by attaching a radical stabilizing
group at the terminal alkene carbon atom of the precursor
(i.e., methyl versus ester). Intriguingly, the deactivating effect
of the ester functionality operates only for the alkyl radical
(see the Supporting Information for additional analysis).
Encouraged by these findings, we have prepared the
substrates 1a–l in several efficient steps starting from 2-
bromobenzaldehyde (Scheme 3). The preparatory stage of
Scheme 3. General synthetic approach to the substrates for radical
cyclizations. DMF=N,N-dimethylformamide, PTSA=p-toluenesulfonic
acid, THF=tetrahydrofuran.
Yield is that of isolated product.
the synthesis provided monoprotected phthalaldehyde by
acetal formation and subsequent ortho formylation. Reaction
of the aldehyde with alkynyllithium compounds yielded
propargylic intermediates (o-methoxyprop-2-ynyl acetal
arenes) after in situ addition of methyl iodide. Acid hydrolysis
deprotected the second aldehyde from which a library of
skipped 1,6-enyne substrates [3-(2-(1-methoxy-3-phenylprop-
2-yn-1-yl)phenyl) acrylates (1)] was generated by a Wittig
reaction. The scope of prepared substrates is shown in
Table 1.
The screening of radical reagents and initiators for the
model transformation of 1a into 2a revealed that, similar to
our earlier experience,[9,12] the combination of Bu3SnH and
AIBN in refluxing toluene was efficient whereas silicon
reagents did not provide a successful cascade (Table 2, entries
1 and 2). The reaction conditions were further optimized by
changing molar ratios of Bu3SnH/ AIBN and varying flow
rate using a syringe pump. We found that maintaining steady
concentration of AIBN is preferred over the addition of
initiator in a single portion in the beginning of reaction. The
addition of a Bu3SnH/AIBN mixture in 2 mL of toluene, at
a flow rate of 1 mLhÀ1, to the 0.04m solution of substrate in
toluene (1108C) provided 2a in excellent (91%) yield.
Structures of the products were determined by a combination
of spectroscopic methods and, in the case of 2c, by X-ray
crystallography (Figure 1).
Table 2: Screening conditions.
Entry
Reagent/Initiator
Conditions
Yield [%][b]
1
2
3
4
5
6
No reagent/initiator
Et3SiH/AIBN
Bu3SnH/AIBN
PPh3SnH/AIBN
Bu3SnH/ABCN
Bu3SnH/DTBPB
Toluene, 16 h, 1108C
Toluene, 16 h, 808C
Toluene, 10 h, 1108C
Toluene, 14 h, 1108C
Toluene, 14 h, 1108C
Toluene, 14 h, 1108C
SM
mix
91
52
63
58
[a] Reagent: 1.3 equiv. Initiator: 0.4 equiv. [b] Product yields are reported
after purification from a silica gel column. SM=starting material,
mix=mixture of products. ABCN=1,1’-azobis(cyclohexanecarbonitrile),
AIBN=2,2’-azobis(2-methylpropionitrile), DTBPB=2,2-bis(tert-butyl-
peroxy)butane.
in the removal of the directing OMe group by radical b-
scission (Scheme 4). In contrast, the radical density in the
alkyne–ene cascade never “arrives back” at the correct
position to assist the aromatization step. Remarkably, aroma-
tization still occurs readily under the reaction conditions,
possibly as a simple 1,4-elimination of methanol.
The presence of Bu3Sn and ester groups in the products
opens convenient opportunities for further synthetic trans-
formations. Not only can the tin functionality directly react
with electrophiles, but the polarity of these naphthalene
building blocks can be reversed by conversion of stannanes
into iodides (Scheme 5), so a variety of electrophilic naphthyl
building blocks is now readily available. Furthermore, the
ester group can be converted into an acylating Friedel–Crafts
With the optimized reaction conditions in hand, we
examined the substrate scope by testing reactivity of the
additional 3-[2-(1-methoxy-3-phenylprop-2-yn-1-yl)phenyl]
acrylates (1b–i; Table 3). The radical cyclization is fully
compatible with both the acceptor and donor substituents, as
well as aliphatic chains at the alkyne termini.
The absence of final closure at the terminal aryl group has
a mechanistic consequence. In the all-alkyne cascade the final
attack at the Ph ring creates a p-radical center, thus assisting
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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