Enantioselective N-Heterocyclic Carbene Catalysis via Acyl Azolium without Exogenous Oxidants

Article abstract of DOI:10.1021/acscatal.0c02705

An approach to the α,β-unsaturated acyl azolium has been developed that exploits N-heterocyclic carbenes (NHCs) and acyl fluorides, without additional oxidants, bases, or preactivated pro-nucleophiles. These conditions have been applied in four classes of

Full text of DOI:10.1021/acscatal.0c02705

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Article
Enantioselective N-Heterocyclic Carbene Catalysis
via the Acyl Azolium without Exogenous Oxidants
Jing Cao, Rachel Gillard, Azar Jahanbakhsh, Martin Breugst, and David W. Lupton
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02705 • Publication Date (Web): 25 Aug 2020
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Enantioselective N-Heterocyclic Carbene Catalysis
via the Acyl Azolium without Exogenous Oxidants.
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a
a
b
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a
Jing Cao, Rachel Gillard, Azar Jahanbakhsh, Martin Breugst and David W. Lupton *
a) School of Chemistry, Monash University, Clayton 3800, Victoria, Australia. b) Department
für Chemie, Universität zu Köln, Germany.
ABSTRACT: An approach to the unsaturated acyl azolium has been developed that exploits
N-heterocyclic carbenes (NHCs) and acyl fluorides, without additional oxidants, bases, or
preactivated pro-nucleophiles. These conditions have been applied in 4-classes of NHC catalyzed
reaction. In all cases the expected products were produced with high yield and enantioselectivity,
using two sets of closely related reaction conditions, without additional optimization.
Keywords: Enantioselective catalysis; N-heterocyclic carbene; unsaturated acyl azolium; (3
+
3)-annulation; (3 + 2)-annulation; (4 + 2) annulation.
In recent years the versatility of acyl fluorides in organic synthesis has become more broadly
1
recognised. This can be traced to studies by Carpino who demonstrated their utility as alternatives
2
to acyl chlorides in peptide coupling reactions. Strikingly it was found that amide formation with
2
a
or without exogenous base, occurred with similar yield and rate (Figure 1A). In addition to amide
formation, the fluoride, acyl, or (after decarbonylation) alkyl fragments, derived from acyl
1
fluorides have been exploited in various reaction designs. In 2007 Lewis base catalysis with acyl
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fluorides was reported by Levacher who demonstrated that acyl pyridinium fluoride can be
generated in esterification reactions.3a Leveraging this observation we have found that
unsaturated acyl fluorides (i.e. 1) when exposed to N-heterocyclic carbenes (NHCs) can
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deliver unsaturated acyl azoliums (i.e. 2) which engage in various bond forming cascades.4
This was first demonstrated in 2009 with the annulation of TMS-enol ethers to give
4
a
dihydropyranones 3 (Figure 1B). While such chemistry has proven valuable this approach suffers
from limitations. Most notably, silicon masked nucleophiles, such as 4, are required. For example
when the TMS enol ether 4 is replaced by cyclohexanone the annulation reaction fails.
5
In contrast to the approach outlined above (Figure 1B) most NHC-organocatalysis involving
6
the unsaturated acyl azolium, is achieved by oxidation of the Breslow-intermediate (i.e. 5).
Specifically, this involves either redox isomerisation of aldehydes containing reducible
7
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functionality, or the use of enals (such as 6) in the presence of an external oxidant (Figure 1C).
8a
Most commonly the Kharasch oxidant (7), as introduced by Studer, is exploited, often with a
superstoichiometric base, to both generate the NHC and deprotonate the pro-nucleophilic partner.
While this strategy is common it exploits a high molecular weight oxidant that is relatively
expensive, and in its reduced form, must be removed. While efforts to introduce alternate oxidants
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have been made, surprisingly a general oxidant free approach to the acyl azolium is yet to be
established.
Recently we considered whether acyl fluorides could serve as acyl azolium precursors in the
absence of preactivated nucleophiles. If viable then such a scenario would provide an approach to
the acyl azoliums that avoids oxidants, bases, and the intermediacy of the Breslow intermediate.
Specifically, we postulated that by using an exogenous fluoride trap the acyl azolium could be
formed directly from the acyl fluoride (Figure 1D). In addition, having trapped the fluoride anion
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the resultant adduct might serve as a base to deprotonate the pro-nucleophile, thereby replacing
any additional base additives. Herein, we report studies on this concept that have been showcased
in the context of four NHC-catalyzed reactions. Using two sets of conditions, reactions of the
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
unsaturated acyl azolium 2 acyl azolium dienolate 8, and the, dienyl acyl azolium 9, have
been achieved. The approach is operationally simple and has been deployed in all designs using
the same azolium precatalyst, and without additional optimization.
Figure 1. A) Peptide coupling with acyl fluorides. B) Annulation of the unsaturated acyl
azolium using acyl fluorides. C) The unsaturated acyl azolium is commonly formed by
oxidation of the Breslow intermediate. D) Reaction design in which acyl azoliums are formed with
an exogenous trap for fluoride.
Reaction discovery commenced by examining the IMes catalysed annulation of cinnamoyl
t
fluoride (1a) with acetoacetone (10) in the absence of additives. Using KO Bu to generate the NHC
a 48% yield of dihydropyranone 11a was obtained (Figure 2A). This result suggests that potentially
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the design does not need an exogenous fluoride trap, and that fluoride itself can serve as a base,
although accumulation of HF likely quenches the catalyst. Using potassium hexamethyldisilazide
(KHMDS) to generate the NHC provides HMDS that we reasoned could serve to trap HF and
allow full conversion. In the event full conversion was observed after 4 hours, with
dihydropyranone 11a formed in 78% yield. When the same reaction was performed with additional
HMDS the yield was decreased slightly, but the reaction rate increased (Figure 2A). Next we
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examined the viability of HMDS to serve as a fluoride trap computationally. From these studies
it was possible to identify two thermodynamically and kinetically viable reactions between HF and
HMDS providing 2 equivalents of TMSF and one of ammonia (Figure 2B and supporting
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information). Consistent with these predictions, when the reaction was monitored by F-NMR,
formation of TMSF was observed as the acyl fluoride is consumed (Figure 2C).
Exploiting these insights we next developed an enantioselective version of the reaction (Figure
2D). In studies by Studer unsaturated acyl azolium annulations have been found to benefit
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from LiCl, thus the reaction of cinnamoyl fluoride (1) with acetoacetone (10) was examined
with a series of azolium salts, using KHMDS as base, and LiCl as additive. These studies identified
the Mes-indanol NHC A5 as being well suited to this chemistry providing 11a in 49% yield and
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2:8 er (Figure 2D, entry 2). The yield was increased by the addition of molecular sieves (Figure
8
g
D, entry 3), while introduction of an equivalent of HMDS increased the selectivity, with 11a
formed in 98:2 er, although with a slightly decreased yield of 65% (Figure 2D, entry 4).
Having developed a potentially general platform for enantioselective catalysis via the

unsaturated acyl azolium we examined its viability in four reaction designs – two involving
the unsaturated acyl azolium (i.e. 2c), one the acyl azolium dienolate (i.e. 8), and the last the
dienyl azolium (i.e. 9). In all cases conditions lacking additional HMDS (Conditions A, Figure
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D, entry 3) or with an additional 1 equivalent of HMDS (Conditions B, Figure 2D, entry 4) were
used. With most reactions the products were produced with serviceable yields and high
enantioselectivity. It would be imagined that dedicated re-optimization of any process would lead
to improved outcomes.
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A
C
2
2
0 mol% IMesHX
Ph
O
H
0 mol% Base,
Ph
O
additive, toluene, rt
20 minutes
1a
ref. C6H5F
TMSF
1a
F
Mes
N
Cl
N
O
O
O
O
Me Me
1a
40 minutes
Me Me
1
IMesHX Mes
10a
60 minutes
1
00
180 minutes
240 minutes
80
Base
additive yield
t-
60
KO Bu
-
-
48 %
78%
KHMDS
KHMDS HMDS 74%
40
D
20 mol% NHCHX
Ph
O
20 mol% KHMDS,
H
20
0
Ph
O
50 mol% LiCl, additives,
F
1a
toluene, rt
O
O
O
O
0
50
100
150
200
250
time (minutes)
10
Me Me
11a
Me Me
H3C
H3C
O
A1HBF , R3 = C F
O
B1HBF , R3 = t-Bu
4
3
4
6
5
3
A2HBF4, R = 2,4,6-Cl3C6H2
B2HBF4, R = Ph
B
A3HBF , R3 = PMP
Bn
3
N
4
N
B3HBF4, R = PMP
N
3
N
3
A4HBF4, R = 2,6-(CH3O)2C6H3
A5HBF4, R = Mes
B4HBF4, R = Mes
‡
– 1

G
= +95 kJ mol
N
3
BF4
N
BF4
H
N
G = – 82 kJ mol– 1
Ar
Ar
HF
HF
NH2
TMSF
TMSF
Me3Si
Me3Si
SiMe3
Me3Si
Yield (%)a
erb
entry
NHCHX
HMDS
Sieves
1
2
3
4
A1-B4
(See Supporting information, all er <85:15)


G‡ = +76 kJ mol
– 1
G = – 90 kJ mol– 1
A5HBF4
A5HBF4
A5HBF4
-
-
-
49
85
65
92:8
90:10
98:2
NH2
NH3
200 mg
200 mg
1 equiv.
Figure 2. A) Oxidant and base free annulation of acetoacetone 10a with acyl fluoride 1. B)
Computational modelling of HF reaction with HMDS. C) Reaction of 1a and 10a to give 11a
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monitored by F-NMR. D) Reaction optimization. (a) Isolated yield following flash column
chromatography. (b) Enantiomeric ratio determined by HPLC.
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The enantioselective synthesis of dihydropyranones was examined first (Table 1A). This reaction
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a
was first reported by our group in 2009, and has subsequently served as a testing ground for new
catalysts, or conditions for acyl azolium formation. While HMDS improved selectivity in the
optimisation studies the simpler conditions without its addition (Conditions A) were used in this
study, unless noted. Variation of the cinnamoyl fluoride (1a-e) was broadly tolerated with
pyranones 11a-e provided with good enantioselectivity (all >90:10 er). When using electron-rich
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(1b) or more hindered (1e) substrates the yield was decreased, which could be addressed somewhat
by adding HMDS. Similar outcomes were obtained with the sometimes challenging alkyl acyl
azolium precursors providing dihydropyranone 11f, and alternate 1,3-dicarbonyls giving 11g and
h. Finally, substrates with decreased acidity, such as 2-indanone could be converted (i.e. to 11i)
with high selectivity and yield using Conditions B.
In 2014 we reported a (3 + 2) annulation of the unsaturated acyl azolium using fluoride
induced ring opening of donor-acceptor cyclopropanes.4d,e Studies from Studer developed an
1
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oxidative approach to related materials, while Biju has developed analogous reactions, and
1
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Romo has examined similar annulations with isothiourea catalysts. Rather than directly examine
one of these designs we focused on the use of nitrile esters (i.e. 12) for the synthesis of cyclopentyl

lactones. Without optimization, using Conditions A, the coupling of a range of cinnamoyl
fluorides 1 with various nitriles 12 gave eight cyclopentyl lactones 13a-e (Table 1B). The
absolute stereochemistry of these materials was determined through single crystal x-ray analysis
1
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of 13f and 13c and extrapolated for all structures. In contrast to the (3 + 3) annulation, this
reaction showed significant sensitivity to the electronics of the acyl azolium. Thus, while
cinnamoyl fluoride 1a and 4-chlorocinnamoyl fluoride 1d gave the cyclopentyl products with only
moderate enantioenrichment (i.e. 13a, 79:21 and 13d, 80:20 er) the more electron rich 4-MeO, 4-
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Me, and 4-(Me) N containing cinnamoyl fluorides gave cyclopentanes 13b, c and e with high
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enantioselectivity (>99:1, 88:12 and 90:10 er respectively) while 2-napthyl containing
cyclopentane 13f formed in 52% yield and 93:7 er. A similar, although less pronounced sensitivity
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to electronics was observed in our earlier studies on enantioselective (3 + 2) annulations. Next
the ester group was modified allowing ethyl ester containing 13g to be produced in 93:7 er, while
the PMP ester 13h was formed with 85:15 er.
Table 1. Examples of (3 + 3) and (3 + 2) annulations of the unsaturated acyl azolium.a,b
O
R1
O
2
0 mol% A5HBF4
R1
O
R1
NC
20 mol% KHMDS, LiCl,
4
O
1
F
O
A MS, toluene, 0 ºC
O
O
or
O
O
NC
Me
Me
N
R1
N
O
NHC
4
or
R2
R3
R O2C
N
Mes
R2
R3
R O C
4
O
via
A5
2
10
12
2
11a-i
13a-h
A
B
O
MeO
Ph
O
O
R1
O
O
R1
O
O
O
O
O
O
O
O
NC
MeO2C
Me
NC
2
OEt Me
1h, 84% y, 91:9 er
Me
Me Me
1a, R1 = Ph, 85% y,
Me Me
EtO C
1
13a, R1 = Ph, 65% y,
1
11f, 78% y, 92:8 er
13f, 52% y,
13g, 52% y,
MeO
c
9
0:10 er
7:1 dr, 79:21 er
12:1 dr, 93:7 er
12:1 dr, 93:7 er
1
b, R1 = 4-MeOC H , 52% y,
b, R = 4-MeOC6H4, 88% y,
6
4
MeO
c
O
7:1 dr, >99:1 er
O
93:7 er
Ph
O
1
c, R1 = 4-MeC H , 43% y,
c, R = 4-MeC6H4, 80% y,
0:10 er
6 4
9
O
7:1 dr, 88:12 er
O
O
O
1
d, R1 = 4-ClC H , 43% y,
d, R = 4-ClC6H4, 79% y,
0:10 er
6 4
NC
O
9
7
:1 dr, 80:20 er
Me
1
Ph Ph
1g, 52% y, 85:15 er
1
2 6 4
e, R = 4-NMe C H , 40% y,
PMP
e, R = 2-Napthyl, 54% y,
13h, 41% y,
6:1 dr, 85:15 er
4:6 erc
8:1 dr, 90:10 er
9
11i, 62% y, 95:5 erc
1
O
[a] Isolated yield [b] Enantiomeric excess determined by HPLC. [c] Conditions B (Figure 2D,
entry 4).
1
5
In 2013 Chi demonstrated that alkyl group on the unsaturated acyl azolium, by the action of
16
additional base, allows access to the acyl azolium dienolate (i.e. Table 2, 8). To examine the
viability of our conditions with this type of reaction design we performed the coupling of methyl
cinnamoyl fluoride 14 with hydrazone 15 (Table 2). Using the reaction conditions exploited for
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the earlier transformations the expected product formed, although the yield was modest. However,
with additional HMDS the annulation could be achieved with piperidone 16a formed in >99:1 er
and 83% isolated yield. This outcome could be reproduced with an array of methyl cinnamoyl
fluorides 14 and hydrazones 15 coupled in high yield and enantioselectivity (all 99:1 er or greater).
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Table 2. Examples of (4 + 2) annulations of the acyl azolium dienolate.a,b
[a] Isolated yield [b] Enantiomeric excess determined by HPLC.
Finally we examined the reaction of the dienyl acyl azolium (i.e. 9, Table 3). This type of species
17
was first reported in 2015, with the first enantioselective design introduced by our group in
1
8
2
018. Using conditions lacking HMDS an array of tri and tetracyclic products were produced
(19a-f). Specifically, annulated dienyl acyl fluorides 17 coupled with acyclic ketoesters 18 to give
tricycles 19a-d in greater than 97:3 er (Table 3). In addition, when the coupling was performed
with cyclic keto esters the tetracyles 19e and f formed with excellent enantioselectivity (97:3 and
9
8:2 er respectively) and diastereoselectivity, something not possible using our earlier approach
which proceeded with poor enantioselectivity.
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Table 3. Examples of annulation of the dienyl acyl azolium.a,b
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[a] Isolated yield [b] Enantiomeric excess determined by HPLC.
While mechanistic features of each reaction are distinct, there are a number of events that are
likely to be common to this approach. Considering the dihydropyranone synthesis (i.e. 11) the
reaction likely commences with the formation of NHC A5 and HMDS, by deprotonation of the
azolium A5HBF4 with KHMDS (Figure 3). Substitution of the acyl fluoride by A5 with resultant
fluoride mediated desilylation of HMDS then gives unsaturated acyl azolium 2d, TMSF and
TMS amide 20. The later deprotonates 1,3-dicarbonyl 10a to give enolate 21 which unites with
the unsaturated acyl azolium as described elsewhere.19 Depending on the presence of
additional HMDS subsequent turn-overs either involve desilylation of the HMDS or the silyl amide
2
2. In most cases in which the yield is modest the products were accompanied by the primary
amide of the acyl fluoride. We believe that this side reaction occurs with sluggish reactions and
likely involves either coupling between the acyl azolium 2d or acyl fluoride 1a and TMS amide
20 followed by hydrolytic workup.
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Figure 3. Mechanistic proposal.
Reactions of the unsaturated acyl azolium have emerged in the last decade as a highly diverse
array of complexity generating processes. They are often enantioselective, and can involve a
cascade of CC, CO and CN bond forming events. Herein, we report a route to the

unsaturated acyl azolium that avoids commonly exploited exogenous oxidants and/or bases.
The conditions are compatible with reaction designs involving both the acyl azolium and acyl
azolium enolate. While the designs examined here provide a general indication of the generality
of this approach, we believe that the strength of this strategy reside in reaction designs that are not
compatible with the intermediacy of the Breslow-intermediate. Studies on this topic are ongoing.
ASSOCIATED CONTENT
Supporting Information. Supporting information documenting methods to prepare all
1
13
materials, along with appropriate H-NMR C-NMR, HPLC traces are contained.
,
AUTHOR INFORMATION
Corresponding Author
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*
david.lupton@monash.edu.
Funding Sources
There are no conflicts to declare
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ACKNOWLEDGMENT
DWL thanks the Australian Research Council for financial support through the Discovery Program
(DP1701013567). We are grateful to the Regional Computing Centre of the University of Cologne
for providing computing time of the DFG-funded High Performance Computing (HPC) System
CHEOPS as well as for their support.
GRAPHICAL ABSTRACT
:
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1
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Angew. Chem. Int. Ed. 2020, 59, 3190-3194.
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) For general NHC catalysis see: a) Enders, D.; Niemeier, O.; Henseler, A., Organocatalysis by
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2, 4906; for cooperative catalysis: g) Wang, M. H.; Scheidt, K. A., Cooperative Catalysis and
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6
) For reviews examining the chemistry of the unsaturated acyl azolium see: a) De Sarkar, S.;
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S. R.; Mukherjee, S.; Biju, A. T., NHC-Catalyzed Generation of Unsaturated Acylazoliums
for the Enantioselective Synthesis of Heterocycles and Carbocycles. Acc. Chem. Res. 2019, 52,
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0
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7
) For examples of access to the acyl azolium by redox isomerization: a) K. Zeitler.,
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Esterification. Org. Lett., 2006, 8, 637–640; from bromo enals a) Sun, F.-G.; Sun, L.-H.; Ye,
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Dicarbonyl Compounds. Adv. Synth. Cat., 2011, 353, 3134; from bromo enals c) Wang, G.;
Chen, X.; Miao, G.; Yao, W.; Ma, C., Divergent NHC-Catalyzed Oxidative Transformations of 3-
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2013, 78, 6223.
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) For examples of access to the acyl azolium using external oxidants, see: a) Castells, J.; Llitjos,
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510; d) Delany, E. G.; Fagan, C.-L.; Gundala, S.; Zeitler, K.; Connon, S. J., Aerobic Oxidation
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Q.; Zhou, J.; Zeng X.; Zhong, G., N-Heterocyclic Carbene/Lewis Acid Catalyzed
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Oxidants for Oxidative Carbene Organocatalysis by Radical Processes. Angew. Chem. Int. Ed.
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017, 56, 2942.
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3
0) Studies performed using the DLPNO-CCSD(T)/def2TZVPP/SMD//TPSS-D3/6-
1+G(d,p)/SMD calculations, see ESI for details.
1
1) Bera, S.; Samanta, R. C.; Daniliuc, C. G.; Studer, A., Asymmetric Synthesis of Highly
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Acid. Angew. Chem. Int. Ed. 2014, 53, 9622.
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2) Mondal, S.; Yetra, S. R.; Patra, A.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T., N-Heterocyclic
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3) Liu, G.; Shirley, M. E.; Van, K. N.; McFarlin, R. L.; Romo, D., Rapid Assembly of Complex
Cyclopentanes Employing Chiral, Unsaturated Acylammonium Intermediates. Nat. Chem.
2013, 5, 1049.
1
4) Single crystal X-ray analysis of cyclopentyl lactones 13c and 13f using CuK radiation for
determination of absolute stereochemistry (CCDC 2008449 and 2008450). This data can be
obtained free of charge from The Cambridge Crystallographic Data Centre.
1
5) Xu, J. F.; Jin, Z. C.; Chi, Y. R., Organocatalytic Enantioselective Aminoalkylation of
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6) For reviews covering other routes to the acyl azolium dienolate see: Vora, H. U.; Wheeler,
P.; Rovis, T., Exploiting Acyl and Enol Azolium Intermediates via N‐Heterocyclic
Carbene‐Catalyzed Reactions of Reducible Aldehydes. Adv. Synth. Catal. 2012, 354, 1617;
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(e) Douglas, J.; Churchill, G.; Smith, A. D., NHCs in Asymmetric Organocatalysis: Recent
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9) For mechanistic studies into the dihydropyranone synthesis see: For discussions regarding
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,4- addition see (a) J. Mahatthananchai, J. Kaeobamrung, and J. W. Bode., Chiral N-
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Catalyzed Annulation Reactions of Unsaturated Acyl Azoliums. Chem. Sci. 2012, 3, 2346;
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