Enantioselective N-Heterocyclic Carbene Catalyzed Synthesis of Functionalized Indenes

Article abstract of DOI:10.1021/acs.orglett.7b01981

An enantioselective NHC (N-heterocyclic carbene) catalyzed synthesis of indenes from bifunctional α,β-unsaturated acyl fluorides and TMS enol ethers has been discovered. The reaction has broad generality (31 examples) and proceeds with high levels of enantioselectivity (most >92:8 er). Mechanistically the reaction likely occurs via a Michael/β-lactonization/decarboxylation sequence. Derivatization studies and limitations are discussed.

Full text of DOI:10.1021/acs.orglett.7b01981

Letter
pubs.acs.org/OrgLett
Enantioselective N‑Heterocyclic Carbene Catalyzed Synthesis of
Functionalized Indenes
Changhe Zhang and David W. Lupton*
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
S
* Supporting Information
ABSTRACT: An enantioselective NHC (N-heterocyclic car-
bene) catalyzed synthesis of indenes from bifunctional α,β-
unsaturated acyl fluorides and TMS enol ethers has been
discovered. The reaction has broad generality (31 examples)
and proceeds with high levels of enantioselectivity (most >92:8
er). Mechanistically the reaction likely occurs via a Michael/β-
lactonization/decarboxylation sequence. Derivatization studies
and limitations are discussed.
ver the past 10 years N-heterocyclic carbene (NHC)
Scheme 1. Background and Reaction Design
O
catalysis1 via the α,β-unsaturated acyl azolium (1) has
played an important role in enabling new reactions.1m Typically
this intermediate undergoes annulation with bis-nucleophiles,
of which malonate-type enolates are most common. Recently
bifunctional reagents (i.e., 2) have allowed more complicated
cascades to be discovered, delivering various bicyclic-products
(i.e., 3a).2,3 Strikingly the orthogonal approach, in which
bifunctional α,β-unsaturated acyl azoliums (i.e., 4) are coupled
with simple nucleophiles, are far less developed. Indeed, to the
best of our knowledge, only a single report by Studer has
demonstrated this strategy, in this case providing tricyclic δ-
lactones (i.e., 5a) with excellent enantioselectivity via a
Michael/Michael/δ-lactonization cascade.4 To expand NHC-
catalysis with bifunctional acyl azolium catalysis we envisaged a
synthesis of enantioenriched indenes (eq 1).
While simple indenes are readily accessible,5 methods for the
assembly of enantioenriched indenes are more limited, despite
utility in medicinal chemistry (Scheme 1B).6 To date a handful
of methods have been developed which exploit transition metal
catalysis to give enantioenriched indenes,7 while fewer
enantioselective organocatalytic approaches are known.8,9 To
improve access to homochiral indenes we envisaged a
bifunctional acyl azolium strategy (eq 1). Realization of this
design would be the second example of a bifunctional acyl
azolium reaction, and the first that exploits β-lactonization
chemistry in the cyclization. Herein, we report studies on this
topic, which have allowed the enantioselective NHC-catalyzed
synthesis of 31 poly substituted indenes (i.e., 6). This
represents one of the largest collections of enantioenriched
indenes, with 30 being new materials. In addition, oxidative and
reductive derivatizations are reported to further build molecular
complexity.
strength, studies commenced with TMS enol ether 8a and
bifunctional acyl azolium precursor 7a. When exposed to a
series of NHCs bearing N-substituents known to give more
nucleophilic catalysts,11 the expected indene 6a formed with
good levels of enantioinduction although poor yield (Table 1,
entries 1−4). The unsuitability of weakly nucleophilic catalysts
A5 (N-C6F5) and A6 (N-2,4,6-Cl3C6H2) was confirmed with
Use of acyl fluorides (i.e., 7) as acyl azolium precursors,
although less common in acyl azolium catalysis than aldehydes,
allows coupling with keto enolates rather than malonate-type
nucleophiles used under oxidative conditions.10 Building on our
knowledge of such substrates, and taking advantage of this
Received: June 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01981
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Organic Letters
Letter
Table 1. Optimization of the Synthesis of Indene 6a
Table 2. Scope of the Enantioselective Indene Synthesis
a
b
entry
NHC·BF4
base
solvent
% yield
er
1
A1
A2
A3
A4
A5/A6
B1
B2
B3
B1
″
KHMDS
THF
13
78:22
″
86:14
71:29
−
91:9
79:21
61:39
73:27
94:6
−
2
″
″
″
″
″
″
″
″
″
″
″
″
″
″
″
19
3
11
4
5
5
trace
42
6
7
20
8
13
9
DMF
dioxane
THF
″
50
10
11
12
13
″
15
″
Cs2CO3
H+ sponge
KHMDS
trace
16
″
″
94:6
c
″
42
97:3
a
b
Isolated yield following column chromatography. Enantiomeric ratio
by HPLC over chiral stationary phase. Catalyst B1 isolated from
c
potassium tetrafluoroborate byproduct (see Supporting Information).
both providing only a trace of indene 6a (Table 1, entry 5).
Next, the three most successful N-substituents [Mes, t-Bu, and
2,6-(CH3O)2C6H3]12 were examined on the indanol scaffold
(Table 1, entries 6−8). While all were viable, catalyst B1 was
the most useful, improving enantioselectivity (to 91:9 er) and
yield (to 42%) (Table 1, entry 6). Exploiting catalyst B1 with
alternate bases for NHC generation and solvents was examined;
however, such conditions failed to improve the yield or
enantioselectivity of the reaction (Table 1, entries 9−12). In
contrast, performing the reaction in the absence of salt
byproducts13 improved the enantioselectivity to 97:3 er without
changing the yield (Table 1, entry 13). Unfortunately, extensive
modification of reaction conditions failed to increase the yield,
which remained moderate due to competing dihydropyranone
formation (6a′) and Claisen condensation (6a″).14 Never-
theless serviceable conditions had been identified, with the
coupling of 8a and 7a defining one of the poorer outcomes of
the study, with most transformations proceeding with better
yield and >92:8 er (vide infra).
Examination of the scope commenced by modifying the
TMS enol ether partner 8. Alternate electron-rich and -poor
acetophenone derived TMS enol ethers reacted smoothly to
give indenes (6a−j) with yields between 42% and 66% and
good levels of enantioselectivity (77:23 er to 99:1 er). Electron-
poor substrates (Table 2, entries 5−10) generally gave higher
yields, although at times at the expense of enantioselectivity.
Heteroaryl TMS enol ethers were well suited to the reaction
with 2-furyl containing indene 6k and 2-pyrdyl indene 6l
formed in 58% and 60% yield and good enantioselectivity (92:8
er and 93:7 er respectively) (Table 2, entries 11 and 12). The
a
b
Isolated yield following column chromatography. Enantiomeric ratio
c
by HPLC over chiral stationary phase. 1 mmol scale.
TMS enol ether of acetone was also viable with indene 6m
formed with high enantioselectivity (95:5 er); however, the
yield was poor. Next, modification of the acyl azolium precursor
7 was examined with electron-rich R2 groups. When coupled to
electron-rich, -neutral, or -poor TMS enol ethers, indenes 6n−
B
DOI: 10.1021/acs.orglett.7b01981
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
q formed in 91:9, 97:3, 89:11, and 71:29 er (Table 2, entries
14−17). The same electronic trends regarding yield and
enantioselectivity were observed as discussed previously, while
in general all reactions were slightly less selective than the
variant bearing an electron-withdrawing R2 group. The
selectivity of the reaction was decreased significantly with a
2,3-dimethoxyaryl R2 substituent giving indene 6r in 54:46 er
(Table 2, entry 18). Indenes bearing a 5-methoxy group (i.e.,
6s−w) were formed with comparable yield (48−66%) and
enantioselectivity (83:17−97:3 er) compared to the unsub-
stituted variants (Table 2, entries 19−23). Similarly, indenes
bearing a 6-Br (6x) or 6-CH3 group (6y) could be prepared, in
this case with 95:5 and 98:2 er (Table 2, entries 24 and 25).
The former was used to determine absolute stereochemistry
through X-ray crystallographic studies.15 Next, introduction of
aliphatic R2 substituents was examined. This had little impact
on the yield or enantioselectivity of the reaction with indenes
bearing a methyl (6z) or isopropyl group (6za−zc) formed in
91:9, 98:2, 94:6, and 88:12 er (Table 2, entries 26−29). The
reaction tolerated trisubstituted TMS enol ethers giving indene
6zd with high enantioselectivity (97:3 er), although with
moderate diastereoselectivity (3:1 dr) and yield (44%) (Table
2, entry 30). Finally, benzoannulation of the indene was
possible with cyclopenta[a]naphthalene 6ze formed in 72%
yield but with moderate enantioselectivity (60:40 er) (Table 2,
entry 31).
Scheme 2. Derivatization, Ester Enolates, and Plausible
Reaction Mechanism
Simple derivatization of indene product 6c was examined
(Scheme 2, eqs 4 and 5). Hydrogenation gave rise to 1,3-
disubstuted indane 9c without significant loss of enantiopurity
(95:5 er from 99:1 er), >20:1 dr, and in 80% yield (eq 4). Using
the same indene oxone based epoxidation afforded epoxide 10c
in 72% yield, as a 2:1 mixture of diastereoisomers, with both
isomers found to have greater than 97:3 er (eq 5).
The use of ester enolates in acyl azolium catalysis is yet to be
reported, with most work relying on malonate nucleophiles.
Pleasingly ester enolates (i.e., derived from 11) gave the
expected indene (eq 6); however, the enantioselectivitiy was
low. We believe this implicates a background reaction that
occurs with more nucleophilic substrates.16,17
Mechanistically the desired reaction commences with NHC
defluorination/desilylation of the acyl fluoride 7 and TMS enol
ether 8 to give acyl azolium 13 and enolate 14. With ketone
enolates, 1,4-addition to the acyl azolium gives acyl azolium
enolate 15. With ester enolates, the related, and non-
enantioselective, addition to the acyl fluoride 7 can occur. In
addition to such pathways the undesired Claisen condensation
can occur to give 6″. Following the desired Michael addition to
give 15 a pseudoconcerted (2 + 2) cycloaddition gives lactol
16,18 which, after expulsion of NHC B1 and decarboxylation,
affords indene 6. Alternately proton transfer from acyl azolium
enolate 15 and lactonization give dihydropyranone 6′.
azolium reactions is the discovery of acyl azolium analogs of
greater electrophilicity. We are currently studying the electro-
philcity of acyl azolium, and related structures, and will report a
comprehensive survey of their properties in due course.17
ASSOCIATED CONTENT
* Supporting Information
The chemistry of the α,β-unsaturated acyl azolium has
proven highly useful for reaction discovery over the past
decade. Herein, we report the second bifunctional acyl azolium
based reaction design, and the first exploiting β-lactonization
cyclization. Specifically the enantioselective synthesis of indenes
has been developed, and a comprehensive survey of scope was
performed (31 examples). The reaction is viable with various
ketone enolates, although ester enolates react with low
enantioselectivity. In general the yields are acceptable, although
compromised by competing side reactions. Clearly a frontier
that the NHC catalysis community must address to enhance
the utility of these already highly valuable α,β-unsaturated acyl
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01981.
Experimental procedures, 1H and 13C NMR of new
materials and HPLC traces of chiral materials (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: david.lupton@monash.edu.
C
DOI: 10.1021/acs.orglett.7b01981
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
Lop
́
ez-Per
́
ez, S.; Frigola, J.; Merce,
̀
R. J. Med. Chem. 2009, 52, 675−
687. For applications in catalysis, see: (d) Leino, R.; Lehmus, P.;
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David W. Lupton: 0000-0002-0958-4298
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
D.W.L. thanks the ARC for financial support through the
Future Fellowship and Discovery programs.
■
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