Angewandte
Communications
Chemie
[a,b,c]
Since
a
MBH-reaction-based approach for the
Table 2: Scope of b-monosubstituted enones.
cyclopenta[b]annulation of heteroarenes has not been de-
[9]
scribed thus far, and since ready access to the proposed
starting compounds (Scheme 1c) can be achieved in a method
[10]
described earlier by our research group, we proceeded to
identify optimized reaction conditions for b-monosubstituted
enones appended to heteroaryl carbaldehydes. Accordingly,
(
E)-2-hexenoyl benzothiophene-3-carbaldehyde (1a) was
[11]
chosen as the model substrate. Various nucleophilic triggers
and solvent combinations were investigated, and the results
are summarized in Table 1. Initial assessment with typical
[
a]
Table 1: Optimization of the reaction parameters.
[b]
[c]
Entry
Nucleophilic
Solvent
t
Yield [%] (E/Z)
trigger (mol%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
DBU (20)
toluene
toluene
DMF
6 h
3 h
1.5 h
5 h
7 h
63 (6:1)
69 (8:1)
71 (7:1)
63 (7:1)
79 (6:1)
–
90 (8:1)
92 (11:1)
86 (8:1)
93 (10:1)
91 (9:1)
93 (10:1)
85 (10:1)
79 (9:1)
89 (8:1)
DABCO (20)
DABCO (20)
DMAP (20)
Imidazole (20)
CH Cl
2
2
toluene
CH Cl
PPh (10)
48 h
3
2
2
2
2
2
2
PPh Et (10)
CH Cl
10 min
10 min
30 min
5 min
5 min
5 min
20 min
20 min
10 min
2
2
PPhMe (10)
CH Cl
2
2
PCy (10)
CH Cl
3
2
0
1
2
3
4
5
PMe (10)
CH Cl
3
2
PMe (10)
DMF
toluene
NMF
3
PMe (10)
3
[
a] Reaction conditions: To a 5 mL glass vial filled with 1 (0.1 mmol) in
PMe (10)
3
toluene (1 mL), PMe (0.01 mmol) was introduced at room temperature
3
PMe (10)
formamide
3
(RT) under nitrogen atmosphere. Stirring continued at RT until
PMe (10)
CH CN
3
3
1
disappeared (by TLC). [b] Yield of product isolated after silica gel
1
[
a] Reaction conditions: To a 5 mL glass vial filled with 1a (0.1 mmol) in
column chromatography. [c] E/Z ratios determined by H NMR analysis
an appropriate solvent (1 mL), a catalyst (0.01 mmol) was introduced at
room temperature (RT) under a nitrogen atmosphere. Stirring continued
at RT until 1a disappeared, as monitored by TLC. [b] Yield of product
isolated after silica gel column chromatography. [c] Determined by
of the crude reaction mixture. [d] See the Supporting Information.
1
H NMR analysis on the crude reaction mixture. DBU=1,8-
of b-alkyl and b-aryl enones appended to benzothiophene-
and thiophene-3-carbaldehydes proceeded smoothly in excel-
lent yields (2b–f). Pleasingly, our attempts to extend this
method for the synthesis of functionalized indanones and
pyrindanones were also successful (2g–v). It is worth noting
that the presence of electron-donating groups (such as -Me,
-OMe) either on the aryl ring or on the b-substituents has no
considerable impact on the efficiency of the reaction (for
example, 2k–n and 2p–r). As a substantial advancement,
indanones and pyrindanones possessing a tetrasubstituted
carbon atom could also be efficiently generated within a few
minutes by this method (2s, 2t, and 2v). Therefore, com-
diazabicyclo[5.4.0]undec-7-ene, DABCO=1,4-diazabicyclo[2.2.2]octane,
DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide,
NMF=N-methylformamide.
amine-based Lewis bases was found to be very encouraging.
The desired cyclopentannulated benzothiophene 2a was
[12]
formed in good yields (entries 1–5). The structure of 2a
was deduced from the spectral data, and the predicted
E geometry of the double bond was confirmed by single-
crystal X-ray diffraction analysis (see below). In contrast,
[
13]
among the organophosphines screened, except PPh , a pro-
pounds possessing poor electrophiles such as ketones were
also demonstrated to be excellent substrates under these
reaction conditions.
3
nounced improvement in yield and reaction time were
observed (entries 6–9). Strikingly, phosphines require only
a few minutes for complete conversion, with PMe delivering
the best result (entry 10). Brief solvent screening (entries 11–
Having realized the extremely facile transformation of b-
monosubstituted enones, we turned our attention to the
previously unexplored b,b-disubstituted analogues. Towards
this end, a wide variety of b,b-disubstituted enones tethered to
heteroaryl and aryl carbaldehydes (1w–aq) were synthesized.
From the results shown in Table 3, it can be realized that the
3
1
5) prompted us to consider toluene in place of the volatile
chlorinated solvent DCM for further studies.
With the optimal reaction conditions in hand, we sought
to expand the substrate scope (Table 2). Cyclopentannulation
1
778
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Angew. Chem. Int. Ed. 2016, 55, 1777 –1781