Iridium-catalyzed asymmetric [3+2] annulation of aromatic ketimines with alkynes via C-H activation: Unexpected inversion of the enantioselectivity induced by protic acids

Article abstract of DOI:10.1039/c6cc01398h

A cationic iridium/binap catalyst enabled the asymmetric [3+2] annulation of cyclic N-acyl ketimines with internal alkynes via C-H activation to give spiroaminoindene derivatives with high enantioselectivity. The stereochemical course of this annulation was switchable by acid additives.

Full text of DOI:10.1039/c6cc01398h

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DOI: 10.1039/C6CC01398H
Journal Name
COMMUNICATION
Iridium-catalyzed asymmetric [3 + 2] annulation
of aromatic ketimines with alkynes via C–H
activation: Unexpected inversion of the
enantioselectivity induced by protic acids
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Midori Nagamoto, Daisuke Yamauchi and Takahiro Nishimura*
A
cationic
asymmetric [3
ketimines with internal alkynes via C–H activation to
give spiroaminoindene derivatives with high
iridium/binap
catalyst
enabled
the
+
2] annulation of cyclic N-acyl
enantioselectivity. The stereochemical course of this
annulation was switchable by acid additives.
Transition metal-catalyzed direct functionalization of aromatic C–H
bonds has enabled
a short-step synthesis of various useful
compounds.1 The regioselective functionalization has been achieved
by use of directing groups, which are often involved in the reactions
leading to cyclic compounds through the catalytic process.2 In this
regard, there have been several successful reports on the formal [3 +
2] annulation reactions of aromatic imines or ketones with C–C
multiple bonds giving indene or indane derivatives in the presence of
Re,3 Ru,4 Rh,5 and Ir catalysts.6 The asymmetric annulation reaction
has also been reported by means of Rh5c,d and Ir6c catalysis giving
chiral 1-aminoindane derivatives with high enantioselectivity.
Recently, we reported that a cationic iridium(cod) complex
catalyzes a [3 + 2] annulation of aromatic ketimines with alkynes via
C–H activation to give spiroaminoindenes (Scheme 1a).7
Mechanistic studies revealed that the reaction proceeds via
sequential ortho-alkenylation and intramolecular cyclization. For
the development of the asymmetric reaction, we envisioned two
possible asymmetric induction methods in the light of the tandem
reaction mechanism, which involves the intramolecular cyclization
of the alkenylated intermediate C as the enantio-determining step.
One is a transfer of a transient axial chirality of the intermediate C to
the chiral annulation product 3,8 and the other is the use of the
cationic iridium species as a chiral Lewis acid to invoke the
enantioselective cyclization of the intermediate C.9 We tested
several chiral ligands for the Ir-catalyzed annulation of 3-hydroxy-3-
Scheme 1 Ir-catalyzed annulation of aromatic ketimines 1 with alkynes 2
phenylisoindolin-1-one (1a), which in situ generates an N-acyl
ketimine by dehydration,7 but only low levels of the asymmetric
induction were obtained (e.g., 25% ee with (R)-binap, Scheme 1b).
In contrast, it was found that the reaction of ketimines having
substituted phenyl groups gave the annulation products in high
yields and enantioselectivity. We also found that the stereochemical
course of this annulation was switchable by acid additives. Here we
report that the asymmetric [3 + 2] annulation of cyclic N-acyl
ketimines with internal alkynes via C–H activation to give chiral
spiroaminoindene derivatives.
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Table 1 Asymmetric annulation of 1a with alkynes 2a
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DOI: 10.1039/C6CC01398H
Entry Alkyne
Condition Yield
(%)
ee
(%)
1
R1 = R2 = Ph (2m)
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
81 (3bm) 88 (+)
94 (3bm) 83 (–)
Scheme 2 Ir-catalyzed asymmetric annulation of ketimine 1b with alkyne 2m
2
2m
3b
4
R1 = R2 = 4-MeC6H4 (2n)
68 (3bn)
89 (3bn)
73 (3bo)
97 (3bo)
53 (3bp)
50 (3bp)
72 (3bq)
98 (3bq)
89 (3br)
93 (3br)
52 (3bs)
71 (3bs)
56c (3bt)
92 (+)
76 (–)
93 (+)
59 (–)
83 (+)
87 (–)
92 (+)
79 (–)
87 (+)
82 (–)
84 (+)
85 (–)
73 (–)
2n
An enantiodivergent synthesis of both enantiomers has drawn a
lot of attention, particularly in the field of pharmaceutical chemistry
because an each enantiomer often exhibits different bioactivity.10 It
is an attractive and important challenge to induce both
enantioselectivities using a single chiral catalyst by changing the
reaction conditions such as the reaction temperature,11 solvents,12
and additives.13 We found that the enantiodivergent synthesis of the
annulation products formed from ketimines and alkynes under Ir
catalysis can be achieved by means of just a slight modification of
5
R1 = R2 = 4-MeOC6H4 (2o)
6
2o
7b
8
R1 = R2 = 4-CF3C6H4 (2p)
2p
9
R1 = R2 = 4-FC6H4 (2q)
10
11
12
13
14
15
16
17
18
2q
R1 = R2 = 4-ClC6H4 (2r)
2r
R1 = R2 = 3-ClC6H4 (2s)
the reaction conditions.
Treatment of 3-hydroxy-3-(3,5-
2s
R1 = Ph, R2 = n-Bu (2t)
dimethoxyphenyl)isoindolin-1-one (1b) with diphenylacetylene
(2m) in chlorobenzene in the presence of [Ir(cod)2]BF4 (5 mol%, cod
= 1,5-cyclooctadiene) and (R)-binap (7.5 mol%) at 80 °C for 20 h
gave the annulation product (+)-3bm in 79% yield with 85% ee
(Scheme 2). To our surprise, the presence of a carboxylic acid
inverted the enantioselectivity giving (–)-3bm under otherwise the
same reaction conditions; the reaction in the presence of benzoic
acid (10 mol%) gave (–)-3bm in 81% yield with 84% ee. The same
inverse effect of the enantioselectivity was also observed in the
presence of acetic acid (83% ee) and pivalic acid (50% ee).
2t
50d (3bt) 92 (+)
R1 = R2 = n-Pr (2u)
34 (3bu)
23 (3bu)
37 (+)
57 (+)
2u
a
Condition A: 1b (0.20 mmol), alkyne 2 (0.30 mmol), [Ir(cod)2]BF4 (5
mol%), and (R)-binap (7.5 mol%) in PhCl (0.80 mL) at 80 °C for 48 h.
Condition B: With PhCO2H (10 mol%). Isolated yields are shown and the ee
was determined by chiral HPLC analysis. b [Ir(cod)2]BF4 (10 mol%) and (R)-
binap (15 mol%). c Combined yield of two regioisomers (97/3). d Combined
yield of two regioisomers (99/1).
The enantiodivergent synthesis of the annulation products can be
achieved in the reaction of 1b with several internal alkynes 2 (Table
1). The reactions of symmetrically substituted diaryl acetylenes
2m–2s gave the corresponding annulation products (+)-3bm–3bs
with 83–93% ee in the absence of benzoic acid (Condition A, odd
entries of 1–14). In contrast, the reactions in the presence of benzoic
acid (Condition B) gave (–)-3bm–3bs with 59–85% ee (even entries
of 1–14). The reaction of 1-phenyl-1-hexyne (2t) gave 3bt with
high regioselectivity and good enantioselectivity under both
Conditions A and B (entries 15 and 16). In contrast, the switch of
the enantioselectivity was not observed in the reaction of 1-octyne
(2u); the reaction gave (+)-3bu with moderate ee under both
Conditions A and B (entries 17 and 18). The absolute configuration
of (+)-3br obtained under Condition A was determined to be S by X-
ray crystallographic analysis.14
The inversion of enantioselectivity was also observed in the reaction
of 1d having a 3,4,5-trimethoxyphenyl group (86% ee (+) under
Condition A and 33% ee (–) under Condition B). In contrast, in the
reaction of 1e substituted with a 2,5-dimethoxypheny group and 1f
having
a 3-methoxy-5-methyl group, the inversion of the
enantioselectivity did not take place.
The reaction of hemiaminals bearing monosubstituted aryl
groups was also conducted in order to gain some insight into the
origin of the enantioselectivity (Scheme 4). The reaction of 1g
having a meta-methoxyphenyl group gave an isomeric mixture of
3gm and 3gm' with good regioselectivity (Scheme 4a). The
enantioselectivity of the major regioisomer 3gm, which was formed
via C–H activation at the less sterically hindered ortho-position, was
much higher than that of 3gm' under both Conditions A and B. The
inversion of enantioselectivity was only observed for the major
regioisomer 3gm. It should be noted that the ee of 3gm' was much
lower than that of 3gm, although it was expected that the methoxy
group can restrict the axial rotation of the alkenylated intermediate
Scheme 3 summarizes the results obtained for the reaction of
several hemiaminals 1 with diphenylacetylene 2m. The reaction of
1c, having a 3,5-dibenzyloxyphenyl group gave (+)-3cm with 93%
ee under Condition A, and (–)-3cm with 42% ee under Condition B.
2 | J. Name., 2012, 00, 1-3
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Scheme 3 Asymmetric annulation of hemiaminals 1 with 2m
formed via C–H activation at the more sterically hindered ortho-
position. These results are consistent with the chiral Lewis acid-
induced cyclization rather than the chirality transfer as the enantio-
determining step. The reactions of 1h and 1i, having a methyl and a
chloro group at the meta-position respectively, gave the
corresponding annulation products.
The inversion of the
enantioselectivity was observed in both cases, albeit with the low ee
(Scheme 4b). In contrast, the inversion was not observed in the
reaction of 1j having an ortho-methoxyphenyl group, while a
decrease of the ee was observed in the presence of the acid (Scheme
4c). The para-methoxy group on 1k had no effect on the
asymmetric induction in the absence of acid (Scheme 4d). The
reaction of 1k in the presence of the acid gave 3km with 20% ee.
Hemiaminal 1a having a non-substituted phenyl group exhibited a
similar reactivity and selectivity to 1k. These results indicate that,
the meta-substituent of the aromatic rings, which undergo the C–H
activation, play some roles in the inversion of the enantioselectivity
in the presence of the acid, regardless of their electronic character.
Although we assume that the asymmetric induction is due to the
chiral Lewis acid catalyst shown in Scheme 1, the acid additive
might alter the reaction mechanism, which may result in the different
stereochemical outcome.15,16 At this stage, the exact roles of the acid
additives and the substituents on aryl group remain unclear.
Scheme 4 Annulation of monosubstituted hemiaminals 1 with 2m.
This work was supported by JSPS KAKENHI Grant No.
15H03810. M.N. thanks the JSPS for Research Fellowship for
Young Scientists.
Notes and references
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2
In summary, we have developed an asymmetric [3 + 2]
annulation of cyclic N-acyl ketimines with alkynes by a cationic
iridium/binap catalyst. The enantioselectivity was found to be
switchable by acid additives.
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