Angewandte
Communications
Chemie
Table 1: Effect of reaction conditions.[a]
were either moderately or substantially rich in the Z isomer,
with typical E/Z ratios ranging from 1:2 to 1:7. We were
intrigued to find that the 2-phenyl-3-methylindanone deriv-
ative 2g could be obtained from 1g, having a modest E/Z
ratio (1:2.5), with high enantio- and diastereoselectivities
(96% ee, 20:1 d.r.), which were comparable to that of 2g
obtained from (E)-1g (see Table 2). Likewise, a series of 2-
aryl-3-methyl (or ethyl) indanones (2h–n) were obtained in
good yields with high enantio- and diastereoselectivities
regardless of the E/Z ratio of the starting material, while
a modest diastereoselectivity was observed for 2k bearing a 4-
trifluoromethyl group. 2-Butyl-3-methylindanone (2o) was
also obtained in a highly enantio- and diastereoselective
manner from the corresponding substrate with an E/Z ratio of
1:7. Furthermore, a series of substrates bearing aryl and
methyl groups at the R1 and R2 positions, respectively,
underwent enantioselective cyclization to give the corre-
sponding 2-methyl-3-arylindanones 2p–w, albeit with some-
what lower diastereoselectivities (< 10:1). Here, 4-dimethy-
lamino and 4-trifluoromethyl groups on the aryl ring lowered
the enantioselectivity (2t and 2u), and the substrate bearing
a 2-thienyl group exhibited a sharp drop in the enantio- and
diastereoselectivities (2w). Last but not least, 2-butyl-3-
phenylindanone (2x) was obtained in a good yield with
moderate enantioselectivity. Note that an attempt on cycliza-
tion of a substrate analogous to 1p, which contains an alkyl
(CH2CH2) tether instead of the benzene tether, failed to
produce the desired cyclopentanone derivative.
Entry Catalytic system
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
CoCl2/(R,R)-BDPP (10%), Zn, MeCN
CoCl2/(R,R)-BDPP (5%), Zn, DMF
CoBr2/(R,R)-BDPP (5%), Zn, DMF
CoBr2/(R,R)-BDPP (5%), Mn, DMF
CoI2/(R,R)-BDPP (5%), Mn, DMF
CoBr2/(R,R)-BDPP (5%), Mn, MeCN
CoBr2/(R,R)-Ph-BPE (5%), Mn, DMF
CoBr2/(R,R)-Me-Duphos (5%), Mn, DMF
CoBr2/(R)-Prophos (5%), Mn, DMF
CoBr2/(R)-Segphos (5%), Mn, DMF
9
49
75
95 (92)
75
12
85
66
42
n.d.
92
92
92
92
n.d.
85
46
7
10
16
75
[a] The reaction was performed on a 0.1 mmol scale at a concentration of
0.3 M. [b] Determined by GC using mesitylene as an internal standard.
Yield of isolated product (for a 0.3 mmol scale reaction) is shown within
the parentheses. [c] Determined by HPLC using a chiral stationary phase.
DMF=N,N-dimethylformamide, n.d.=not determined.
Having clarified the scope of the 2,3-disubstituted inda-
none synthesis, we became interested in the reaction pathway
of the present cyclization and the origin of the low sensitivity
of the enantioselectivity to the E/Z ratio of the starting
material. To gain insight into these issues, experiments using
deuterium-labeled substrates were performed (Scheme 2).
The stereochemically pure substrate bearing a deuterated
DMF as the solvent, the same catalytic system (with 5 mol%
loading) promoted the reaction to a considerable extent to
afford 2a in 49% yield with 92% ee and greater than 20:1 d.r.
(entry 2). The yield was further improved by changing the
precatalyst and the reductant to CoBr2 and Mn, respectively.
Thus, 2a was obtained in 92% yield upon isolation without
change of the enantio- and diastereoselectivties (entry 4),
while replacement of CoBr2 with CoI2 led to a slight decrease
in the yield (entry 5). Regardless of the precatalyst and the
reductant, the reaction proved sluggish in MeCN (entry 6),
and no product formation was observed in other solvents such
as THF and toluene (data not shown). Among the chiral
diphosphines tested, (R,R)-Ph-BPE induced a good level of
efficiency and enantioselectivity (entry 7), while the rest
showed unsatisfactory performances (entries 8–10).
Table 2: Cyclization of 2-alkenylbenzaldehydes with high E/Z ratios
(>20:1).[a]
With the new optimized catalytic system in hand, we
explored the scope with respect to the 2-alkenylbenzalde-
hydes for the present 2,3-disubstituted indanone synthesis.
First, we focused on a small set of substrates [(E)-1b–g] which
could be prepared with high E selectivity (> 20:1) by either
the cobalt-catalyzed migratory arylzincation[19] or cobalt-
catalyzed,
aldimine-directed
alkyne
hydroarylation
(Table 2).[20] As a result, indanone derivatives bearing 2,3-
dibutyl (2b–e), 2,3-diphenyl (2 f), or 2-phenyl-3-methyl (2g)
groups, and different substituents on the benzo moiety, were
synthesized in good yields with ee values around or higher
than 90% and d.r. values around or higher than 20:1.
In the next set of experiments, we examined reactions of
the 2-alkenylbenzaldehydes 1g–x prepared by Wittig olefina-
tion (Table 3). Except for a few cases, these starting materials
[a] The reaction was performed on a 0.3 mmol scale under the reaction
conditions in Table 1, entry 4. Diastereomer ratio (d.r.) was determined
by GC analysis of the crude reaction mixture.
2
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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