N-Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy

Article abstract of DOI:10.1002/anie.201905475

Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N-heterocyclic carbene (NHC) catalyzed reactions, in which β-unsubstituted conjugate acceptors undergo homoenolate formation and C?C bond formation twice, have been developed. Specifically, the all-carbon (5+1) annulations give a range of mono- and bicyclic cyclohexanones (31 examples). In the first family of annulations, β-unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

Full text of DOI:10.1002/anie.201905475

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
International Edition
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Accepted Article
Title: N-Heterocyclic carbene catalyzed (5 + 1) annulations exploiting a
vinyl dianion synthon strategy
Authors: Xuan B. Nguyen, Yuji Nakano, Nisharnthi M. Duggan, Lydia
Scott, Martin Breugst, and David W Lupton
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905475
Angew. Chem. 10.1002/ange.201905475
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10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
N-Heterocyclic carbene catalyzed (5 + 1) annulations exploiting a
vinyl dianion synthon strategy**
Xuan B. Nguyen,a Yuji Nakano,a Nisharnthi M. Duggan,a Lydia Scott,a Martin Breugstb
and David W. Luptona*
Abstract: Direct polarity inversion of conjugate acceptors provides a
valuable, although underdeveloped entry to homoenolates. As part of
studies focused on this topic we have designed and developed N-
heterocyclic carbene (NHC) catalyzed reactions in which
b-unsubstituted conjugate acceptors undergo homoenolate formation
and C-C bond formation twice. Specifically, this has allowed all-
carbon (5 + 1) annulations to give a range of mono- and bicyclic
cyclohexanones (31-examples). In the first family of annulations,
cyclohexanones. The reaction has been realized with inter- and
intra-molecular designs, and in some cases, with high levels of
enantioselectivity.
Organocatalytic access to homoenolates was first reported
by Price,[4a] who in 1962 utilized 1,4-addition of phosphines to
acrylonitrile, followed by tautomerization, to give b-phosphonium
ylides 1, and ultimately acrylonitrile hexamer 2 (eq. 1).[4] More
recently Fu[8a] reported a mechanistically related N-heterocyclic
carbene (NHC) catalyzed cyclization of 3 via homoenolate 4a,[9]
itself formed through 1,4-addition and tautomerization, to give
cyclopentane 5 (eq. 2). An orthogonal approach to homoenolates,
exploiting the more conventional 1,2-addition of NHCs to
a,b-unsaturated aldehydes (i.e. 6) was reported independently
b-unsubstituted acrylates tethered to
a divinyl ketone undergo
cycloisomerization provide hexahydroindenes and tetralins. In the
second, partially untethered substrates undergo an intermolecular (5
+ 1) annulation involving dimerization followed by cycloisomerization.
While enantioselectivity was not possible with the former, the latter
proved viable, allowing cyclohexanones to be produced with high
levels of enantiopurity (most >95:5 er), and exclusive
diastereoselectivity (>20:1 dr). Derivatizations and mechanistic
studies are also reported.
A) Organocatalysis via homoenolates
cat PPh3
R
R
PPh3
with EtOH
NC
NC
(1)
(2)
NC
Ar
CN
2,
R = CH2CH2CN
R
R
1
Introduction
N
N
cat.
NHC
N
Ar
Ar
Conjugate acceptors play a central role in chemical synthesis.[1]
Their reactions – most commonly 1,4-additions with nucleophiles
– proceed in a predictable fashion, allowing reliable use in target
focused studies. Inverting the polarity of conjugate acceptors
gives nucleophiles b- to the electron withdrawing group
- homoenolates.[2-4] While synthesis via stoichiometric generation
of homoenolates has received attention for more than 50-years,[2]
catalytic approaches have appeared more intermittently.[3,4] As
part of ongoing studies on the umpolung of conjugate
acceptors,[5,6] herein we report NHC-catalyzed[7] all-carbon (5 + 1)
annulations via a hitherto unreported vinyl dianion synthon
strategy. Specifically, b-unsubstituted conjugate acceptors
undergo homoenolate formation twice and couple to 5-carbon
bis-electrophiles to provide mono and bicyclic
MeO2C
MeO2C
5, 85% yield
Ar
MeO2C
4a
3
Br
Br
O
Ar
OH
Ar
N
cat.
NHC
O
(3)
(4)
Ph
OHC
Ph
O
Ph
N
Ar
8
7
6
B) Mechanistic background
E2
E2
Y
EWG
EWG
E1
N
X
Ar
E1
9
12
NHC
-H
Y
Y
N
X
N
X
Ar
Ar
EWG
EWG
EWG
vinyl dianion
synthon (13)
E1
E2
4b
[*]
Mr. Xuan B. Nguyen, Dr. Yuji Nakano, Ms. Nisharnthi M. Duggan,
Ms. Lydia Scott, Professor David W. Lupton*
School of Chemistry, Monash University
Clayton 3800, Victoria, AUSTRALIA
Y
Y
N
X
N
X
Ar
Ar
EWG
-H
E2
E1
EWG
10
-NHC
E1
EWG
E1
Fax: (+) 61 3 9905 4597
4c
E-mail: david.lupton@monash.edu
E1
11
Priv.-Doz. Dr. Martin Breugst
C) Developed herein
Ar
O
•18 examples
•all >20:1 dr,
•most > 72% yield
Department für Chemie, Universität zu Köln, Greinstraße 4, 50939
Köln, Germany
EWG
(5)
(6)
H
E
The authors thank the Australian Research Council through the
Discovery program (DP170103567) for financial support and the
Regional Computing Center 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. We
thank Dr. Marc-Antoine Sani and Prof. Frances Separovic
(University of Melbourne) for help with CD analysis. DWL thanks Dr.
Amanda E. Lee for copy-editing.
15
EWG
EWG
cat. NHC
EWG
E
vinyl dianion
synthon (13)
O
14
•13 examples
•most >95:5 er,
•most > 85% yield
O
H
EWG
16
[**]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
Scheme 1. Background and mechanistic framework.
1
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10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
by Glorius[10a] and Bode[10b] (eq. 3). While various reactions
involving the Glorius/Bode approach (via homoenolate 7) have
been developed,[10c-h] the use of homoenolate 4a (i.e. eq. 2) is
more limited. Notably, studies from Matsuoka,[11] Glorius,[12] and
Berkessel[13] have reported dimerizations and oligomerizations,
while studies from our group have led to the discovery of
enantioselective cycloisomerization reactions.[5] Recently we
postulated that b-unsubstituted conjugate acceptors have the
potential to undergo multiple polarity inversions and C-C bond
forming reaction (eq. 4). In established reactions of unsubstituted
conjugate acceptors (i.e. 9)[5,8a,11-13] homoenolate 4b forms, then
undergoes C-C bond formation and elimination of the catalyst to
provide monosubstituted product 11. However, if catalyst
H
R2
R2
EWG
O
NHC
EWG
(7)
Key challenges:
tetrasubstituted olefin?
6-endo-trig cyclization?
O
H
R1 R1
Me
R1
R1
17
18
HO
H
O
H
Cl
HO
Me
O
Me
O
OH
H
O
Cl
O
HO
Me
O
O
O
O
taiwaniaquinol A (19)
tripartin (20)
teucvin (21)
iPr
elimination can be slowed, then formation of
a second
Scheme 2. Hydroindenes and hydrotetralins found in natural products
homoenolate (i.e. 4c) is possible providing a new approach to
b,b-substituted product 12 . The realization of such a design
potentially has broad significance, introducing a new route to tri or
tetra-substituted, and potentially enantioenriched, materials using
simple conjugate acceptors. The viability of the strategy is
supported by mechanistic studies of Matsuoka, which implicate
Following preparation of geminal-dimethyl acrylate 17a, its
cycloisomerization to give hexahydroindene 18a, was attempted.
While IMes (A) led to decomposition, the less nucleophilic[14]
NHCs B, C1 and C2 reacted to give catalyst-substrate adduct 22
(Table 1, entries 1-4).[15] This indicated the viability of the first
cyclization, however the design failed in the second, with the
enolate from the 5-exo-trig cyclisation preferentially adding to the
azolium to give 22 (for mechanism of formation see Scheme 3B).
To avoid formation of this species the more hindered triazolium
catalyst C3 was examined, however no reaction was observed
(Table 1, entry 5). An alternate approach to suppress formation of
1,1-adduct 22 involved removal of the dimethyl groups, positioned
to favor cyclization, but also likely to favor formation of 22. When
this substrate (i.e. 17b) was exposed to NHCs A, B, C1 and C2 it
was largely unreactive (Table 1, entry 6), however C3 gave
hexahydroindene 18b in 20% yield (Table 1, entry 7). The yield
was improved by increasing the catalyst loading (Table 1, entry
transient formation of
a second homoenolate in acrylate
dimerization,[9e] while Berkessel, during studyes with acrylamides
noted a trimerized side-product.[10] Despite this precedent, to the
best of our knowledge NHC-catalyzed methods exploiting multiple
homoenolates are yet to be reported.
A key challenge in realizing the reaction design outlined
above is the control of chemoselectivity, in a catalytic reaction
that couples three electrophillic fragments. To render this problem
tractable we aimed to exploit the kinetic advantage of
intramolecularity, by initially targeting (5 + 1) annulations (eq. 5)
using tethered acrylate 14 (Scheme 1C). In addition to enabling
reaction discovery, such substrates could provide a valuable
route to hydroindenes and tetralins (i.e. 15). Alternately, if two of
the three electrophiles are tethered then an intermolecular (5 + 1)
reaction (eq. 6), involving dimerization and cycloisomerization,
should give cyclohexanones (i.e. 16). Herein, we report studies
on these reactions that have allowed the discovery of NHC-
catalyzed all-carbon (5 + 1) annulations that take advantage of
the formation, and electrophile coupling, of two homoenolate
intermediates.
o
10), and by performing the reaction at 50 C (Table 1, entry 11),
with (5 + 1) adduct 18b now isolated in 61% yield. With conditions
for the formation of the desired product identified, attention was
directed to an enantioselective variant of the reaction. Screening
some of the more useful chiral NHCs (i.e. D1-F5) against both
triene 17a and 17b, and at various temperatures, was conducted
(Table 1, entry 12 and see SI for details). Unfortunately, in no
cases was the expected product observed, with triene 17
generally re-isolated. The lack of reactivity was attributed to the
a-substituent that hinders 1,4-addition with more sterically
encumbered chiral NHCs. This is supported by subsequent
studies into the intermolecular (5 + 1) annulation which could be
achieved with chiral NHCs (vide infra). While disappointing, the
success of the non-enantioselective version was gratifying,
demonstrating for the first time the application of the proposed
vinyl dianion 13 in NHC-catalysis. In addition hexahydroindene
17b contains a tetrasubstituted olefin, functionality often difficult
to prepare with ylide chemistry or cross-metathesis,[16] embedded
in a potentially valuable functionalized bicycle. Thus, studies
continued with the non-enantioselective variant of the reaction.
Results and Discussion
Studies commenced by identifying acrylate 17 as a suitable fully
tethered tris-electrophile, for model studies (Scheme 2). By
varying tether length, this type of substrate should deliver
hexahydroindenes (i.e. 18) and tetralins; materials found in
medicinal and natural products chemistry (i.e. 19, 20 and 21).
Additionally acrylate 17 should be easily prepared in a handful of
steps, through enamine alkylation followed by olefination.
2
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10.1002/anie.201905475
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RESEARCH ARTICLE
Table 1. Selected optimization of the intramolecular (5 + 1) annulation.
introduction of
a
methyl or homobenzyl group allowing
hexahydroindenes 18u and v to be prepared in good yield, and
with moderate substrate controlled diastereoselectivity (2:1 and
4:1 dr respectively). Finally, a longer tether gave tetrahydrotetralin
18w in 49% isolated yield as a single diastereoisomer.
Ph
H
Ph
20 mol% NHC•HX
20 mol% KHMDS,
temp. time
EtO2C
O
EtO2C
(8)
O
H
17a (R1 = Me)
b (R1 = H)
R1 R1
18b
(>20:1 dr)
R1
Table 2. Scope of the intramolecular (5 + 1) annulation.a,b
R1
Ph
Ph
Mes
Ar
N
N
N
N
N
N
N
Ar
N
Ar
20 mol% C3,
20 mol% KHMDS, THF,
50 ºC, 2-16 h
N
O
N
Ar
EtO2C
N
Mes
EWG
R
O
EWG
R
BF4
ClO4
Ph
Cl
Ph
(9)
Mes
N
B
C1, Ar = Ph
A
N
H
C2, Ar = PMP
C3, Ar = Mes
O
n
n
22
PMP = 4-(MeO)C6H4
Me
BF4
N
17b-w
Me
18b-w (all >20:1 dr)
C3
R2
R2
R2
N
N
N
N
N
N
R2
R1
Ar
N
N
N
O
O
BF4
BF4
BF4
Ph
O
F1, R2 = Mes
F2, R2 = Ph
F3, R2 = t-Bu
Me
3
R
Me
O
O
O
EtO2C
EtO2C
EtO2C
E1,
D1, R2 = PMP, R3 = Bn
D2, R2 = PMP, R3 = C(OH)Ph2
R2 = PMP
E2,
F4,R2 = 2,6-(MeO)2C6H3
F5,R2 = 2,4,6-Cl3C6H2
H
H
H
D3, R2 = 2,6-(MeO)2C6H3, R3 = CHPh2
R2 = Mes
Monosubstituted (R2 = H)
18l, 72% y
23m, Ar = 2,4-(MeO)2C6H3,
37% y
18b, R1 = H, 52% y (61% y)c
c, R1 = 4-Me, 61% y
d, R1 = 4-OMe, 67% y
e, R1 = 4-NMe2, 74% y
f, R1 = 2-OMe, 70% y
g, R1 = 4-Cl, 0% y
yield (%)a
MeO
entry
NHC
•
HX
17
T (°C)
solvent
OMe
1
2
3
4
5
6
7
8
9
A
a
a
a
a
a
b
b
b
b
67
67
67
67
67
rt
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
DMF
decomp.
40 (22)
85 (22)
90 (22)
NR
Ar
B
O
Ph(O)C
h, R1 = 4-Br, 0% y
O
RO2C
C1
C2
C3
Disubstituted (R2 = OMe)
H
18q, Ar = 2,4-(MeO)2C6H3,
79% y
H
18i, R1 = 4-OMe, 72% y
j, R1 = 5-OMe, 81% y
k, R1 = 6-OMe, 0% y
18n, R = Me, 65% y
o, R = tBu, 75% y
p, R = Bn, 67% y
A,B,C1,C2
C3
NR
Ar
O
Ar
Ar
O
rt
20
S
O
O
O
NC
C3
rt
-
C3
C3b
C3b
rt
16
H
H
Br
H
10
11
12
b
rt
THF
THF
THF
41
18r, Ar = 2,4-(MeO)2C6H3,
71% y
18s, Ar = 2,4-(MeO)2C6H3, 18t, Ar = 2,4-(MeO)2C6H3,
68% y
61% y
b
50
61
NRc
Ar
Ar
Ar
O
D1-F5
a/b
rt or 50
O
O
EtO2C
EtO2C
Me
EtO2C
[a] Yield following isolation by flash column chromatography. [b] 30 mol%
catalyst. [c] See SI for details
H
H
H
Ph
18u, Ar = 2,4-(MeO)2C6H3, 18v, Ar = 2,4-(MeO)2C6H3, 18w, Ar = 2,4-(MeO)2C6H3,
71% y, 2:1 dr
73% y, 4:1 dr
49% y
The generality of the intramolecular (5 + 1) annulation was
explored through variation to (1) the aryl substituent, (2) the
electron withdrawing functionality and (3) the length, and degree
of substitution, on the tether (Table 2). Early in these studies it
became evident that returning to 20 mol% C3 did not impact the
yield significantly, thus all reactions were performed with this
loading. The reaction proved sensitive to the electronics of the
aryl group. Thus, mono-substituted aromatics bearing electron-
neutral (17b) or electron-releasing (17c-f) substituents reacted
successfully to give hexahydroindenes 18b-f (61-74% yield, all
>20:1 dr), however 4-chloro and 4-bromo aryl containing trienes
(17g and h) were isolated from the reaction mixture unchanged.
Further increasing electron donation generally improved the
outcome, with 2,4- and 2,5-dimethoxy aryl containing
hexahydroindenes 18i and j formed in 72% and 81% yield,
however the more sterically congested 2,6-dimethoxyaryl triene
17k was unreactive. Heteroaromatic groups could be
incorporated, with 2-furyl hexahydroindene 18l formed in 72%
yield, however replacing the aryl substituent with a styrenyl group
was not possible, with the reaction prematurely terminated to give
cyclopentene 23m (37% yield). Attention now moved to the
electron-withdrawing functionality. Alternate esters were readily
accommodated, with methyl, t-butyl and benzyl ester containing
hexahydroindenes 18n-p formed in 65-75% yield. Similarly, the
ester could be replaced with an aryl ketone (18q and r),
heteroaryl ketone (18s), or nitrile (18t) without impacting reaction
viability. Next, changes to the tether were examined with the
[a] Isolated yield. [b] dr determined by 1H-NMR analysis [c] 30 mol% catalyst.
To gain an appreciation for the mechanism, the order of the
reaction was determined and found to be 0.01 in catalyst,[17]
indicating that addition of the NHC to substrate 17 is unlikely to
be turnover limiting. Next, studies to probe the impact of the salt
and protic byproducts formed during NHC generation were
undertaken (Scheme 3A). By changing from KHMDS to NaHMDS
and LiHMDS a reduction in yield was observed (Scheme 3), while
the presence of both HMDS and KBF4, were essential for viability.
Although it was not possible to identify any intermediates through
monitoring experiments, the results presented above, and the
isolation of catalyst-substrate 22 in optimization experiments, are
consistent with a turnover limiting step involving formation, or
reaction, of the second homoenolate. Overall a mechanism for
the transformation can be proposed (Scheme 3B) in which
addition of NHC C3 and tautomerization occurs to give the first
homoenolate 4d. Cyclization then gives enolate 10a which, when
germinal demethylation is present (R = Me) undergoes undesired
addition to the azolium to give spirocyclic adduct 22. In the
absence of substituents (R = H) tautomerization, cyclization then
elimination of C3 gives the (5 + 1) adduct 18.
3
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10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
A) Salt and additive effects
Ar
Reaction discovery commenced by examining the proposed
transformation of bis-conjugate acceptor 26a using the Enders
TPT catalyst B.[9a] While the reaction failed in toluene, THF, and
DMF, in 1,2-dichloroethane (DCE) cyclohexanone 28a formed in
38% yield (Table 3, entries 1-4). It was envisaged that the lack of
an a-substituent in the conjugate acceptor undergoing polarity
inversion would facilitate enantioselective catalysis. This proved
to be the case, with enantioselective variants possible using three
catalysts in which the para-methoxyphenyl (PMP) N-substituent is
appended to various chiral scaffolds (D1, E1 and F6). While all
were viable, morpholinone F6 was the best lead, giving
cyclohexanone 28a in 65% yield and 93:7 enantiomeric ratio
(Table 3, entry 7). Optimization with respect to the N-
substituent[14] on the morpholinone scaffold (Table 3, entries 7-12)
identified N-Mes catalyst F1 as ideal, with cyclohexanone 28a
now produced in 98% yield and with excellent enantioselectivity
(98:2 er) (Table 3, entry 10). Given the high selectivity observed
with E1, N-Mes indanol catalyst ent-C2 was examined, however
this did not improve the outcome (Table 3, entry 13).
H
Ar
20 mol% C3,
20 mol% MHMDS,
THF, 50 °C, 6 h
EtO2C
O
EtO2C
(10)
O
H
18k
17k,
Ar = 2,4-(MeO)2C6H3
Counter ion effect
Salt and additive effect
MHMDS
yield
72%
44%
17%
KBF4
HMDS yield
K
N
Y
N
N
N
Y
9%
Na
Li
37%
39%
B) Plausible mechanism
H
Ph
Ph
EtO2C
O
EtO2C
O
H
R
R
R
18
R
17
N
N
addition/
tautomerization
N
N
Mes
N
C3
N
N
R
Ph
N
Mes
EtO2C
Ph
Mes
N
O
N
EtO2C
H
H
R
O
R
R
4d
Table 3. Selected optimization of the intermolecular (5 + 1) annulation.
N
N
N
Mes
Mes
N
N
CO2Et
CO2Et
EtO2C
EtO2C
Me
Me
Me
Me
20 mol% NHC•HX,
20 mol% KHMDS,
solvent, temp., 14 h
O
O
Ph
Ph
10a
Me
Me
4e
(13)
R
R
O
O
O
O
R
R
Me
Me
H
CO2Et
22 R = Me
26a
28a
EtO2C
R
Ph
R
N
N
R
N
N
N
N
N
N
N
Ph
Scheme 3. Mechanistic studies
N
N
O
BF4
N
O
F1, R = Mes
F2, R = Ph
F3, R = t-Bu
ClO4
BF4
Ph
BF4
Ph
Ph
Me
E1,
R = PMP
E2,
R = Mes
Me
B
D1,
F4,R = 2,6-(MeO)2C6H3
F6, R = PMP
F7, R = C6F5
R = PMP
PMP = 4-(MeO)C6H4
Having established the viability of an intramolecular (5 + 1)
annulation, attention was directed towards intermolecular
transformations (Scheme 4). It was hoped to both expand the
generality of the vinyl dianion synthon 13 and achieve an
enantioselective reaction design. In earlier work, we examined
bis-electrophile 24 in an attempted cycloisomerization, however
we simply observed dimerization (to give 25), with no competitive
cycloisomerization, or cycloisomerization post dimerization. (eq.
11).[11a] To favor conformers more likely to cyclize, we focused on
deletion of the ester linkage and introduction of geminal
substitution.[18] In addition, switching from the 1,6-diene within 24
to a 1,5-diene in our new substrate (i.e. 26) was hoped to favor
cyclization.[18b]
entry
NHC
•
HX
T (°C)
solvent
yielda
erb
1
B
110
toluene
-
-
-
2
"
66
80
84
"
THF
-
3
"
DMF
-
-
4
"
C2H4Cl2
38
39
38
65
-
-
5
D1
E1
F6
F7
F2
F1
F3
F5
"
"
"
"
"
"
"
"
"
86:32
92:8
93:7
-
6
"
7
"
8
"
9
"
84
98
87
-
93:7
98:2
80:20
-
10
11
12
13
"
"
"
A) Previous studies
ent-E2
"
98
24:76
6
O
CO2Me
O
O
CO2Me
NHC
[a] Isolated yield [b] Enantiomeric ratio by HPLC over chiral stationary phases.
1
(11)
O
O
O
MeO2C
O
MeO2C
O
24
25
The intermolecular (5
+
1) annulation’s generality was
B) Developed herein
investigated by variation to the electron withdrawing functionality
and R-substituents (Table 4). Methyl, t-butyl and benzyl esters
26b-d (Table 4, entries 2-4) all gave the expected products (28b-
d) with high enantiopurity (all ≥97:3 er) and in high yield (all
≥85%). Similarly, t-butyl, methyl, and phenyl ketones were
tolerated, providing cyclohexanones 28e-g, however the
enantioselectivity was diminished (Table 4, entries 5-7). In
contrast, Weinreb amide 26h gave the corresponding
cyclohexanone 28h with excellent enantioselectivity, as did 2-
pyridyl sulfone 26i (98:2 er and 97:3 er respectively).
EWG
EWG
NHC
R
R
R
O
R
O
R
(12)
5
R
Key challenges:
5-exo-trig cf. 6-exo-trig?
enantioselectivity?
1
O
O
R
R
H
26
28
EWG
EWG
Scheme 4. Background and reaction proposal.
4
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10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
Spirocyclobutyl, spirocyclopentenyl and spirocyclohexyl ketones
28j-l were all prepared with high enantiopurity (all ≥95:5 er) and
yield (Table 4, entries 10-12). Surprisingly, introduction of n-hexyl
R-groups was not possible (Table 4, entry 13), although diallyl
substrate 26n gave the expected cyclohexanone 28n in excellent
yield and with excellent enantioselectivity (94:6 er) (Table 4, entry
14).
which dimerization precedes cyclization. The mixture of 28o and
29o was re-subjected to the reaction conditions, whereupon the
mixture was re-isolated in an unchanged ratio. This outcome
suggests that dimer 29o is not an intermediate en route to 28o,
with elimination of the NHC only occurring following both C-C
bond forming reactions. Next, we examined the cross coupling of
bis-Michael acceptors 26a and 26h (Scheme 5b). Of the four
Due to challenges recrystallizing materials for X-ray
analysis, absolute configuration was assigned by circular
dichroism (CD) of cyclohexanone 28h, with comparison to
computationally determined spectra.[19]
A) Solvent and salt effects
CO2Me
CO2Me
10 mol% F1
Me
O
10 mol% base
Me
Me
solvent, 84 °C, 16 h
Me
(15)
Me
O
Me
Table 4. Scope of the enantioselective intermolecular (5 + 1) annulation.
O
H
26b
28b
yield
LiHMDS 37%
CO2Me
er
solvent
DCE
"salt free" base
EWG
EWG
N
Y
Y
79:21
96:4
20 mol% F1
20 mol% KHMDS
DCE, Δ, 2-16 h
R
R
O
R
O
R
DCE
KHMDS
KHMDS
99%
99%
R
O
R
(14)
toluene
94:6
Mes
N
O
N
R
R
H
EWG
O
N
O
BF4
N
EWG
O
28a-n
26a-n
Me
N
Ph
O
Me
Me
Me
F1
Me
Me
N
O
Table 3,
entry 10
Me
(16)
entry
28
R
EWG
yielda
erb
Me
O
Me
O
O
Me
Me
Me
29o
1
a
b
c
d
e
f
Me
CO2Et
98
85
90
89
88
66
61
92
68
95
73
92
-
98:2
O
H
O
26o
O
2
"
CO2Me
CO2t-Bu
CO2Bn
98:2
97:3
97:3
88:12
84:16
70:30
98:2
93:7
97:3
95:5
96:4
-
N
74%, 28o:29o (2:1)
N
Table 3,
entry 10
3
"
28o
unchanged
4
"
CO2Et
B) Cross-over studies
CO2Et
5
"
C(O)t-Bu
C(O)Me
C(O)Ph
Me
Me
Me
6
"
O
O
Me
7
g
h
i
"
Me
Me
Me
Me
O
Me
Me
O
O
8
"
C(O)N(OMe)Me
H
H
9
"
S(O)22-Pyridyl
O
CO2Et
umpolung
of 26a
Me
(0% yield)
N
OMe
28aʹ
10
11
12
13
14
j
-(CH2)3-
CO2Et
28a
26a
CO2Et
O
(30% yield)
k
l
-CH2CH=CHCH2-
-(CH2)5-
CO2Et
Me
OMe
Me
OMe
"
"
"
N
N
umpolung
of 26h
m
n
-C6H13
OMe
O
O
N
Me
Me
O
Me
Me
-CH2CH=CH2
83
94:6
O
O
Me
Me
Me
[a] Yield following isolation by column chromatography [b] Enantiomeric ratio
determined by HPLC over chiral stationary phases.
Me
Me
O
O
Me
Me
H
H
26h
O
CO2Et
28h
(20% yield)
28hʹ
(19% yield)
Me
N
OMe
A number of mechanistic questions emerged during studies into
the intermolecular (5 + 1) annulation. Firstly, the reaction
displayed a significant solvent effect, with DCE proving essential
to the reaction’s success. It was postulated that the salts
generated during NHC formation may affect the reaction outcome
as had been observed with the intramolecular version of the
annulation, and that DCE may play a weak coordinating role.[20]
To probe this, LiHMDS was used for NHC generation and the
reaction repeated (Scheme 5a). This had a drastic effect on both
yield and enantioselectivity.[21] Removal of KBF4 following
carbene formation had little influence on the outcome when
performed in DCE – however, it allowed the reaction to be carried
out in toluene (a previously unviable solvent), providing 28b in
quantitative yield and with high enantioselectivity (94:6). These
results suggest that DCE attenuates the negative impact of
potassium salts, or more strongly coordinating lithium salts, on
reactivity and selectivity.
C) Plausible mechanism
EWG
EWG
R
R
R
O
R
Me
Bn
Me
O
R
O
N
O
R
H
28
26
N
EWG
N
Mes
EWG
EWG
F1
R
R
O
R
R
R
N
O
Mes
O
R
H
N
N
N
N
N
EWG
R
Mes
R
30
33
26
R
R
EWG
O
O
EWG
EWG
EWG
R
R
R
R
N
N
N
O
O
Whether the two C-C bond forming reactions are punctuated
by elimination and readdition of the NHC was clarified by the
reaction of amide 26o (eq. 16). When this amide was exposed to
the reaction conditions, an inseparable mixture of cyclohexanone
28o and dimer 29o was produced. The absence of any cyclized,
but not dimerized, products from 26o implicates a sequence in
N
N
N
32
31
Mes
Mes
Scheme 5. Mechanistic studies.
5
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10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
expected products, cyclohexanone 28a , derived from the
¢
Conclusion
homoenolate of 26a coupling with Weinreb amide 26h, was the
only one to not be observed. This result can be rationalized by
product determining cyclization of the second homoenolate. This
reaction is slow with the less electrophilic Weinreb amide
Direct polarity inversion of conjugate acceptors to give
homoenolates is a relatively underdeveloped field, with Lewis
base catalysts providing notable approaches. Herein, we have
exploited b-unsubstituted substrates, and developed (5 + 1)
annulations that exploit sequential polarity inversion allowing two
electrophiles to replace two C-H bonds of the olefin. In the first
family of reactions, cycloisomerization has been developed as a
novel approach to hexahydroindenes and tetralins. This was
possible using a tether through the a-substituent of the conjugate
acceptor. The reaction proceeds via a 5-exo-trig followed by 6-
endo-trig cyclization into the divinyl ketone functionality.
Unfortunately, and likely due to the steric bulk of the
a-substituent, it was not possible to achieve enantioselectivity
with this design. In our second reaction design the tether was
removed and a dimerization/cycloisomerization was exploited to
assemble cyclohexanones in a (5 + 1) fashion, in this case using
a,b-unsaturated ketones rather than esters as the homoenolate
precursor. In contrast to the previous study, this reaction could be
catalyzed by chiral NHCs allowing an enantioselective variant to
be developed. Across the two reaction types, 31 (5 + 1)
annulations have been achieved, with 13 as enantioselective
transformations.
Conjugate acceptors are ubiquitous materials in synthetic
chemistry, with their transformations generally drawing upon
Michael’s pioneering studies some 150 years ago.[1e] If chemistry
of similar generality could be developed in which conjugate
acceptors react as b-nucleophiles, then a wealth of known
materials, from commodity chemicals to advanced intermediates,
could be reexamined in an entirely new way. To achieve this a
number of significant challenges remain to be addressed. These
are largely associated with the chemoselectivity required to allow
cross-couplings or, as an extension to the studies reported herein,
to allow the development of three component couplings. Studies
towards these ends remain a focus of our ongoing research.
conjugate acceptor (to give 28a ), thus allowing reversions, and
¢
more facile couplings. Formation of 28h occurs following
complete consumption of 26a. Thus, a viable mechanism for the
reaction (Scheme 5c) involves formation of homoenolate 30 from
bis-Michael acceptor 26 and NHC F1, which couples with the
second conjugate acceptor to give enolate 31, and ultimately the
second homoenolate 32. Finally, product determining cyclization
(32®33) and elimination of the catalyst (33®28) completes the
catalytic cycle.
Having developed the NHC-catalyzed (5 + 1) annulation we
undertook preliminary derivatization studies to gain an
appreciation for the fundamental reactivity of the products. First
subjection of cyclohexanone 28a to Luche’s reduction conditions
allowed the formation of cyclohexanol 34a as
a single
diastereoisomer. Increasing the stoichiometry of NaBH4 allowed
further reduction of the a,b-unsaturated ketone, to give 35a,
however this occurred with no diastereoselectivity. Finally,
hydrogenation of (5 + 1) adduct 28a gave cyclohexanone 36a
with high substrate controlled diastereoselectivity. In terms of
hexahydroindene 18k it was possible to achieve NaBH4 reduction
to give alcohol 37k in 91% yield, while exhaustive reduction with
LiAlH4 gave diol 38k. Hydrogenation of indene 18k was not
possible, presumably due to the tetra-substituted nature of the
olefin, although amines could be condensed to give enamine 39o
in 78% isolated yield.
CO2Et
CO2Et
A) 1 equiv. NaBH4,
CeCl3•7H2O, MeOH,
0 °C or rt, 10 min
or
H
Me
Me
Me
Me
OH
Me
O
Me
B) 4 equiv. NaBH4,
CeCl3•7H2O, MeOH,
0 °C → 4 h
X
O
Me
Me
H
CO2Et
H
CO2Et
Keywords: N-heterocyclic carbene • catalysis • homoenolate • vinyl
28a
34a, X = "O", 88% y
35a, X = "HO", 68% y, 1:1 dr
dianion synthon • enantioselectivity
CO2Et
CO2Et
Me
Me
Me
Me
cat. Pd/C, H2,
MeOH, rt, 14 h
O
O
Me
Me
H
[1] For selected recent reviews on conjugate addition reactions: a) S. R.
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Me
Me
O
O
H
H
CO2Et
CO2Et
36a, 98% y, >10:1 dr
28a
MeO
MeO
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OMe
H
OMe
A) 1 equiv. NaBH4,
MeOH, -10 °C → rt
or
H
H
OH
O
EtO2C
R
B) 1 equiv. LiAlH4,
THF, -10 °C
H
H
37k, R =CO2Et 91% y, 6:1 dr
38k, R = CH2OH, 87% y, 4:1 dr
18k
MeO
MeO
OMe
H
OMe
H
BnNH2, 80 ºC
tBuO2C
tBuO2C
O
NHBn
H
H
18o
39o 78% y
Scheme 6. Derivatization studies.
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6
This article is protected by copyright. All rights reserved.

10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
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10.1002/anie.201905475
Angewandte Chemie International Edition
RESEARCH ARTICLE
• 18 examples
• all >20:1 dr,
Ar
O
NHC Catalysis
• most > 72% yield
EWG
H
E
Xuan B. Nguyen, Yuji Nakano,
Nisharnthi M. Duggan, Lydia Scott,
Martin Breugst and David W. Lupton
EWG
cat. NHC
EWG
E
vinyl dianion
synthon
EWG
O
__________
Page – Page
• 13 examples
• most >95:5 er,
• most > 85% yield
O
H
N-Heterocyclic carbene catalyzed (5 +
1) annulations exploiting a bis-vinyl
anion synthon strategy.
EWG
Two C C bonds are formed between three conjugate acceptors by NHC
-
catalyzed polarity inversion of a,b-unsaturated ketones and esters. Inter and
intramolecular (5 + 1) annulations are possible exploiting an unusual vinyl dianion
synthon (shown) strategy. The reaction provides access to mono- and bicyclic
cyclohexanones in good yield, high diastereoselectivity, and in the former case, with
high enantioenrichment (most >95:5 er). Mechanistic studies, and derivatizations
are also reported.
8
This article is protected by copyright. All rights reserved.