Enantioselective N-Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

Article abstract of DOI:10.1002/anie.201812585

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza-Stetter reaction that proceeds via imine umpolung using N-heterocyclic carbene catalysis. The reaction proceeds with high l

Full text of DOI:10.1002/anie.201812585

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Enantioselective N-heterocyclic carbene catalysis exploiting imine
umpolung
Authors: Jared E. M. Fernando, Yuji Nakano, Changhe Zhang, and
David W Lupton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812585
Angew. Chem. 10.1002/ange.201812585
Link to VoR: http://dx.doi.org/10.1002/anie.201812585
http://dx.doi.org/10.1002/ange.201812585

Angewandte Chemie International Edition
10.1002/anie.201812585
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
NHC catalysis
Enantioselective N-heterocyclic carbene catalysis exploiting imine
umpolung.**
Jared E. M. Fernando, Yuji Nakano, Changhe Zhang, and David W. Lupton*
Abstract: The catalytic umpolung of imines remains an
underdeveloped approach to reaction discovery. Herein we report
an enantioselective aza-Stetter reaction that proceeds via imine
R2
N
umpolung using N-heterocyclic carbene catalysis. The reaction
proceeds with high levels of enantioselectivity (all ≥96:4 er) and
good generality (21 examples). Mechanistic studies consistent with
turnover limiting addition of the NHC to the immune are reported.
Z
Common Secondary
Intermediates
X
OH
R2
O
Y
R1
NHC (1)
N
acyl azolium
homoenolate
acyl azolium enol (enolate)
unsaturated acyl azolium
R
H
R
Z
X
Y
R1
3
Breslow (2)
N-Heterocyclic carbenes (NHC, i.e. 1) provide access to normal
and reverse polarity intermediates integral to many reactions.
[1]
Bode, 2005
CHO
O
While a wide range of reactive intermediates are accessible, they are
almost invariably formed via the Breslow intermediate (2), itself
derived from aldehyde substrates (i.e. 3). Alternate substrates for
SO
2
Ar
N
cat. NHC
N
2
SO Ar
(1)
Ph
"via homoenolate"
Ph
Tol
H
Tol
[2]
[3]
4 (Ar = 4-MeOPh)
5
NHC-catalysis are known, such as esters, ketones, and conjugate
Biju, 2017
N
[4]
acceptors, however these remain less commonly examined, with a
number of functional groups largely overlooked.
H
cat. NHC
N
(2)
"
via aza-Breslow"
Imines are easily prepared electrophiles that would appear well
suited to polarity inversion catalysis. Surprisingly enantioselective
reactions of such substrates, under any type of catalysis, have only
recently been reported, with access to 2-aza-anion intermediates
Ph
Ph
H
CO Et
2
6
CO
Et
7
2
Herein
Ph
N
Me
Ar2
O
Me
Ar2
O
[5,6]
enabling various alkylations.
NHC catalysis with imines has been
PG
H
PG
N
O
N
N
known since the early 2000s, however these studies demonstrate that
while they are viable as electrophilic partners, they do not undergo
(3)
N
Ar1
Ar1
H
[
7,8]
MeO
O
O
polarity inversion.
cinnamaldehydes with sulfonate-imine 4 to give pyrolidinone 5 (eq.
) in a reaction that proceeds via the homoenolate, not the imine
For example in 2005 Bode coupled
21 examples
8
9
10
all ≥ 96:4 er
1
[8b]
[9a]
[9b]
umpolung (aza-Breslow). Independent work of Hou and Chi
Figure 1.
has demonstrated that related Ts-imines can serve as precursor to the
sulfinate anion, presumably through fragmentation of the aza-
Breslow intermediate. However, it wasn’t until 2017 that Biju
reported cycloisomerization of imine 6 to indole 7 (eq. 2) in the first
providing a new enantioselective transformation, we felt that such
studies could facilitate access to secondary intermediates analogous
to those derived from the Breslow intermediate (Figure 1). Herein,
we report the enantioselective intermolecular aza-Stetter reaction
[10a]
NHC catalyzed reaction involving imine umpolung.
Subsequently, the aza-Breslow has been invoked in the oxidation of
[10b]
[10c]
[11]
imines to amides,
and a quinolone synthesis.
While these
(
eq. 3).
allowing imines (i.e. 8) to couple with 3-methylene-chroman-2-ones
i.e. 9) to provide highly enantioenriched γ−imino lactones (10).
While the enantioselective reaction requires 3-methylene-chroman-
The reaction proceeds with excellent enantioselectivity
reports demonstrate the viability of the aza-Breslow in reaction
discovery key challenges remain−perhaps most notably regarding
enantioselectivity. As part of our interest in NHC catalysis with
unconventional substrates we commenced studies on this topic. In
addition to
(
2
-ones, achiral catalysts allow use of simpler acrylates.
We postulated that the imine protecting group would be most
influential on aza-Breslow formation, and hence reaction viability.
Thus, studies commenced by screening a number of protected
aldimines (8a-e) using achiral catalyst A1 (Table 1, entries 1 and 2).
When heated in THF at reflux imines 8a-d gave no coupled
products, with 8a, b and d isolated unchanged, while 8c gave the
[
∗]
Mr. Jared E. M. Fernando, Dr Yuji Nakano, Dr Changhe Zhang and
Professor David W. Lupton*
School of Chemistry, Monash University
Clayton 3800, Victoria, AUSTRALIA
Fax: (+) 61 3 9905 4597
[9c]
product of sulfinate addition. In contrast benzoyl imine 8e gave
enone 12e in 82% isolated yield. The unique viability of this imine
we believe is due to a combination of its electron-withdrawing
capacity, combined with enhanced stability compared to 8c.
Formation of 12e is consistent with either the polarity inverted
E-mail: david.lupton@monash.edu
[
∗∗] The authors thank the Australian Research Council through the
Discovery program (DP150101522) for financial support and
Dr Craig Forsyth (Monash University) for X-ray crystallography.
[4]
conjugate acceptor, or the imine, followed by isomerization.
Various mechanistic studies support the later (vide infra). Attention
was now directed the enantioselective variant. While catalysts A2-4
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201812585
withdrawing groups (i.e. 9f) at the 3-, 4-, and 5- positions. All gave
aza-Stetter products (10n-t) with excellent enantioselectivity (≥96:4
er). Yields suggest a sensitivity to
and A7 gave no coupled material (Table 1, entry 3) the more
1
2
[13]
nucleophilic A5 (R = 4-MeOC
6
H
4
)
and A8 (R = 2,6-MeO
2
C
6
H-
Table 2. Scope of the enantioselective aza-Stetter.
[14]
3
)
gave enamine 11e, and isomeric enone 12e, in comparable
yields (Table 1, entry 6). Shorter reaction times, in higher boiling
dioxane, somewhat suppressed isomerization allowing γ−imino ester
4
1
4
R
1
R
3
5
10 mol% A5•HBF
,
3
5
4
t
1
0 mol% BuOK,
PG
H
PG
1
0e to be isolated in 50% yield with excellent enantiopurity (98:2
N
t
BuOH THF, Δ, 2 h
N
(
5)
Bn
Me
O
er) (Table 1, entry 7). A similar outcome was achieved with indanol
A9, while pyrrolidine A10 exclusively gave enone 12e, and catalyst
A11 gave no coupled products (Table 1, entries 8-10). With catalyst
A5, the outcome was improved in lower boiling THF (Table 1, entry
O
Ar1
Me
Ar1
BF4
O
H
N
O
O
8
9
10
N
N
A5•HBF4
PMP
1
1
a
b
t
[15a]
entry Ar
PG
9 (R )
Product 10
Yield 10 er
1
9
1), while an equivalent of BuOH
gave 10e in 77% yield and
1
Ph
Bz
"
9a (H)
e
f
77
67
80
52
88
73
61
59
60
78
79
61
45
64
75
49
63
81
68
99:1
98:2
99:1
98:2
99:1
98:2
98:2
99:1
98:2
99:1
99:1
99:1
98:2
97:3
98:2
96:4
96:4
98:2
>99:1
9:1 enantiomeric ratio (Table 2, entry 12).
2
4-MeOC
6
H
4
4
"
"
"
"
"
"
"
"
Table 1. Discovery of the enantioselective aza-Stetter.
3
3-MeOC H
"
g
h
i
6
4
4-BrC
6
H
4
"
1
1
1
0 mol% NHC•HX,
t
0 mol% BuOK,
0 mol% tBuOH,
5
2-thiophenyl
Ph
"
Pg
H
Pg
10
N
N
6
(4-MeO)Bz
j
solvent, Δ, 4 h
O
O
(4)
Ph
Ph
R
7
4-BrC
6
H
4
"
k
l
H
8
O
9a
O
8
4-MeOC
Ph
6
H
4
"
NHC•HX
Bz
c
HN
9
(4-Cl)Bz
m
N
A1, R = PMP
BF
4
Ph
10
11
12
13
14
4-MeC
2-thiophenyl
6
H
4
(4-MeO)Bz 9b (4-Me)
n
o
p
q
r
N
BF4
N
N
BF4
N
11e
R
A2, R = C6F5
A3, R = Cl3C6H2
Me A4, R = Ph
O
N
O
O
Bz
Bz
"
"
Bn Me
Bz
N
N
HN
PMP
PMP
N
4-MeC
Ph
6 4
H
BF4
A5, R = PMP
A6, R = Mes
A7, R = t-Bu
N
N
O
A9
A10, R = Bn
A11,
R =C(Ph)2OH
Ph
(4-MeO)Bz 9c (4-MeO)
Bz 9d (4-Et)
(4-MeO)Bz 9e (3,5-Me
N
R
12e
A8, R = 2,6-MeO2C6H3
4-MeOC
H
4
6
a
b
c
1
1
1
1
1
5
6
7
8
9
Ph
"
2
)
s
t
entry NHC
Imine
solvent 10:11:12 yield
er
-
"
9f (4-Br)
1
A1
8a (Boc), 8b
THF
-
0
(
(
(
Ac), 8c
Ts), 8d
P(O)Ph
"
"
u
v
w
2-thiophenyl
3-MeOC
Bz
"
X
2
O
2
3
4
5
6
A1
8e (Bz)
8e (Bz)
8e (Bz)
8e (Bz)
8e (Bz)
THF
THF
THF
THF
THF
-
82 (12e)
0
-
-
-
-
-
6
H
4
9g
(X = CH)
O
A2-4, A7
A5
-
2
2
0
1
2-thiophenyl
3-MeOC
"
"
9h (X = N)
x
y
47
44
98:2
96:4
0:5:2
-
49 (11e)
trace
6
H
4
A6
A8
0:0:1
46 (12e)
[a] Isolated yield of 10 [b] By HPLC with chiral stationary phases [c] Compound
10m contaminated by ~10% of inseparable byproduct, likely 11m and 12m.
d
7
A5
A9
8e (Bz)
Dioxane
5:0:3
50
98:2
98:2
d
d
8
9
1
1
1
8e (Bz)
8e (Bz)
8e (Bz)
8e (Bz)
8e (Bz)
Dioxane
Dioxane
Dioxane
THF
2:1:0
0:0:1
-
43
e
A10
A11
A5
A5
1
80 (12e)
ND
electronics, with the electron rich and poor products 10q and t
formed in modest yields of 45 and 49% (Table 2, entries 10-16).
Finally naphthalene and quinoline derived chromanones (9g and 9h)
coupled with various imines to give the expected products 10u-y
with excellent enantioselectivity (all ≥96:4 er), although the
heterocyclic products formed with modest yields (Table 2, entries
d
0
1
2
0
-
d
7:1:0
8:1:0
65
77
98:2
99:1
df
THF
[
a] Ratio by H NMR analysis [b] Isolated yield [c] By HPLC with a chiral
t
stationary phase. [d] 2h [e] ND = not determined. [f] 100 mol% BuOH
2
0-21).
Attempts to expand the range of conjugate acceptors met with
limited success. For example, chalcone, cyclohexan-2-one, 2-amino
acrylates, and methylmethacrylate failed to couple with various
imines. In these cases the acceptor was often isolated while the
imine gave aza-benzoin 13 (eq. 6). In contrast to the benzoin
Having achieved a highly enantioselective reaction, generality
was examined with twelves aryl and heteroaryl aldimines and seven
chromanones (Table 2). Aldimines bearing electron-donating,
withdrawing, and heteroaromatic Ar substituents all coupled to
lactone 9a to give aza-Stetter products 10e-i with high enantiopurity
1
[15b]
condensation, which is often reversible,
serve as an aza-Breslow precursor,
aza-benzoin 13 does not
thereby impacting the
[17]
(
all ≥98:2 er), and highest yields using electron rich imines (Table 2,
generality of the aza-Stetter reaction. However, when the achiral
catalyst A1 was used methylacrylate, methylmethacrylate, and
acrylonitrile gave aza-Stetter products 10z-ab and the related
enamine 13g (eq. 7 and 8). These reactions suggest that alternate
variants of the enantioselective aza-Stetter reactions may well be
viable in the future.
entries 1-5). Unfortunately, aliphatic imines bearing acidic
α−protons, such as the imine of iso-butyraldehyde, underwent facile
isomerization to the enamine, a common limitation in imine based
[16]
catalysis.
Next, the imine protection was modified, with 4-
MeOBz and 4-ClBz protected aldimines reacting to give the four
products 10j-m with 59-73% yield and ≥98:2 er (Table 2, entries 6-
9
).
Next we examined a series of chromanone derivatives bearing
alkyl (i.e. 9b, d and e), electron-releasing (i.e. 9c), or electron-
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201812585
1
electronics of the imine Ar group (8e cf. 8f). Taken together these
results are consistent with turn over limiting addition of the NHC to
the imine to afford 17. Further support for this interpretation can be
Bz
Table 1,
entry 12
NHBz
NHBz
Ar
[20]
derived from studies into the order of the reaction.
Preliminary
N
various
acceptors
(see text)
Ar
NHBz
(6)
Ar
Ar
studies show the reaction to be close to 0 in chromanone (0.30), and
first order in NHC (0.74) and imine (1.12). Unfortunately, while
Ar
NHBz
[7,8]
8
f, Ar = 4-MeOC6H4
cis-13f: trans-13f 47% y, 1:1 dr
related aza-Breslow intermediates have been isolated,
this was
not possible with benzoyl imine 8, with all attempts leading to
formation of aza-Benzoin 13. Thus we propose turn over limiting
addition of the NHC to the imine, followed by BuOH mediated
Bz
N
10 mol% A1•HBF ,
Bz
4
t
N
R
t
1
0 mol% BuOK,
R
t
OMe
BuOH THF, Δ, 2 h
Ar
OMe
Ar
(7)
tautomerization to afford aza-Breslow 18, which undergoes 1,4-
O
addition to chromanone 9 to provide enolate 19. Diastereoselective
8
f, g and i
O
1
1
1
0z, Ar = 4-MeOC6H4, R = H, 42% y
0aa, Ar = 2-thiophene, R = H, 54% y
0ab, Ar = 3-MeOC6H4, R = Me 17% y
[21]
protonation provides 20
with elimination of the catalyst
completing the cycle.
Bz
Bz
N
HN
1
0 mol% A1•HBF4,
Table 1,
entry 12
Bz
t
Bz
Bz
1
0 mol% BuOK,
N
HN
Ph
HN
Ph
t
CN
(8)
10e
BuOH THF, Δ, 2 h
(9)
O
O
O
CN
Ph
10e:11e:12e = 7:7:6
-MeOC6H4
H
H
O
O
O
OMe
OMe
8
g
11g, 43% y
10e
11e
12e
4
4-MeOC6H4
C(O)
Derivatization was undertaken to examine the reactivity of the
products and allow absolute configuration to be determined (Scheme
10 mol% A5•HBF4,
t
C(O)
10 mol% BuOK,
BuOH THF, Δ, 2 h
N
t
N
(10)
2
1
). Exhaustive addition of PhMgBr to 10j gave triphenyl benzamide
4j, while at lower temperature chemoselective addition of PhMgBr
O
O
Ar
H/D
Ar
H
D-8j, Ar = Ph
O
9a
O
gave diketone 15j. Some erosion of enantiopurity was observed in
both cases. Finally hydrolysis gave γ−keto ester 16j, which allowed
absolute configuration to be determined via x-ray crystallographic
8n, Ar = 4-MeC H4
10j:10n = 1:1
6
Ar2
1
0 mol% A5•HBF4,
C(O)Ar2
t
C(O)
N
10 mol% BuOK,
[
18]
N
t
analysis.
BuOH THF, Δ, 2 h
(
11)
O
O
Ar1
Ar1
H
Ar1
10e Ph
10j Ph
10m Ph
Ar2
Ph
H
O
HO
8
e,j,m
O
and f
9a
4-MeOC6H4 10e:10j = 1.2:1
10e:10m = 1:2.5
PG
PG
Ph
4-ClC6H4
N
PhMgBr (5 equiv.),
78 ºC → rt, 4 h
NH
Ph
-
10f 4-MeOC6H4 Ph
1
0e:10f = 1.9:1
O
Ph
14j, 45% y,
Ph
H
H
O
Bz
Me
Bn
Bz
H
O
90:10 er
N
Me
N
1
0j, PG = 4-MeOBz
(
98:2 er)
HO
O
O
Ph
N
N
Ph
H
PhMgBr (5 equiv.),
78 ºC, 2 h
10e
8e
O
-
O
N
PMP
Me
A5
Ph
Ph
H
15j, 68% y,
Me
Me
Bz
Bn
Bz
Ph
Bn
Me
O
87:13 er
N
N
H
MeCN/H
2
O,
O
O
HBr, 15 min
O
N
N
O
H
Ph
O
N
N
N
N
O
20
PMP
17
PMP
Ph
H
O
tBuOH
1
6j, 92% y, 97:3 er
Me
Me
Bz
Bn
Me
Bz
Ph
Bn
Me
O
Scheme 2. Derivatization studies with aza-Stetter product 10j and ORTEP of
ketone 16j.
NH
Ph
NH
O
O
N
N
O
N
N
N
From our optimization and scope studies it appears that the aza-
Breslow is less reactive than the Breslow, and that catalysis requires
highly nucleophilic NHCs. To gain a more detailed mechanistic
picture studies commenced by examining the significance of
enamine and enone formation observed during optimization. When
imine 10e was resubjected to the reaction conditions a 7:7:6 mixture
of 10e, 11e, and 12e formed (Scheme 3, eq. 9). In contrast,
resubjection of enamine 11e, or enone 12e failed to produce 10e,
with 11e and 12e returned, along with decomposition products.
These results are consistent with imine umpolung leading to 10e,
rather than homoenolate formation providing 11e or 12e, which
isomerizes to 10e. Next the turnover limiting step was examined.
N
1
9
9a
18
PMP
PMP
Scheme 3. Mechanistic studies.
A wealth of reactions exploit the Breslow intermediate en route
to diverse secondary intermediates. While our studies suggest that
the aza-Breslow is less reactive than the Breslow, we expect related,
as well as unique, enantioselective reactions designs to be possible
via analogous secondary intermediates. Certain studies on this topic
are ongoing.
[
19a]
Competition between D-8j and 8n, with associated controls,
Received:
((will
be
filled
in
by
the
editorial
staff))
showed lack of a primary KIE (eq. 10), thus deprotonation is
unlikely to be turnover limiting. When competition studies with
electronically differentiated protecting groups (i.e. 8e cf. 8j and 8e cf.
m) were undertaken it demonstrated that the reaction is enhanced
by electron-withdrawing imine protection (eq. 11).
Published online on ((will be filled in by the editorial staff))
Keywords: enantioselective catalysis • N-heterocyclic carbene •
8
[19b]
imine umpolung • Stetter •
This trend
was also observed with competitions involving manipulation of the
3
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201812585
S. Ye, J. Org. Chem. 2007, 72, 7466-7468; (e) Y.-R. Zhang, L. He, X.
Wu, P.-L. Shao, S. Ye Org. Lett. 2008, 10, 277-280; (f) X. Zhao, D. A.
DiRocco, T. Rovis, J. Am. Chem. Soc. 2011, 133, 12466-12469; (g) D.
A. DiRocco, T. Rovis, Angew. Chem. Int. Ed. 2012, 51, 5904-5906; (h)
D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2012, 134, 8094−8097; (i)
L.-H. Sun, Z.-Q. Liang, W.-Q. Jia, S. Ye, Angew. Chem., Int. Ed. 2013,
[
1] For selected reviews on NHC catalysis see: (a) M. N. Hopkinson, C.
Richter, M. Schedler, F. Glorius, Nature, 2014, 510, 485–496; (b) D. M.
Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev.
2
Synthesis 2012, 44, 2295–2309; (d) A. Grossmann, D. Enders, Angew.
Chem. Int. Ed. 2012, 51, 314–325; (e) S. J. Ryan, L. Candish, D. W.
Lupton, Chem. Soc. Rev. 2013, 42, 4906–4917; (f) S. De Sarkar, A.
Biswas, R. C. Samanta, A. Studer, Chem. Eur. J. 2013, 19, 4664–4678;
(
2
1
5
2, 5803-5806; (j) J. Xu, C. Mou, T. Zhu, B.-A. Song, Y. R. Chi, Org.
Lett. 2014, 16, 3272-3275; (k) M. M. D. Wilde, M. Gravel, Org. Lett.
014, 16, 5308-5311; (l) J. C. Wu, C. G. Zhao, J. Wang, J. Am. Chem.
Soc. 2016, 138, 4706–4709; (m) D. M. Flanigan, T. Rovis, Chem. Sci.
017, 8, 6566–6569. (n) J. Sun, C. Mou, Z. Wang, F. He, J. Wu, Y. R.
Chi, Org. Lett., 2018, 20, 5969-5972
9] Fragmentation of Ts-imines see: a) D.-D., Chen, X.-L.
015, 115, 9307–9387; (c) J. Douglas, G. Churchill, A. D. Smith,
2
2
g) C. Zhang, J. F. Hooper, D. W. Lupton, ACS Catal. 2017, 7, 2583–
596; (h) M. H. Wang, K. A. Scheidt, Angew. Chem. Int. Ed. 2016, 55,
4912–14922. (i) J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A. Scheidt,
[
Hou, L.-X. Dai J. Org. Chem. 2008, 73, 5578-5581; b) Z.
Jin, J. Xu, S. Yang, B.-A. Song, Y. R. Chi Angew. Chem.
Int. Ed. 2013, 52, 12354-12358; (c) Using imine 8c
fragmentation and sulfonate addition gave 10c, see SI for
details.
Ts
O
Angew. Chem. Int. Ed. 2012, 51, 11686-11698.
2] For a highlight on ester oxidation state NHC catalysis see: (a) P.
[
O
10c
Chauhan, D. Enders, Angew. Chem. Int. Ed. 2014, 53,1485. For selected
examples of ester and derivatives see: (b) S. J. Ryan, L. Candish, D. W.
Lupton, J. Am. Chem. Soc. 2009, 131, 14176; (c) L. Hao, Y. Du, H. Lv,
X. Chen, H. Jiang, Y. Shao, Y. R. Chi, Org. Lett. 2012, 14, 2154; (d) Z.
Fu, J. Xu, T. Zhu, W. W, Y. Leong, Y. R. Chi, Nature Chem. 2013, 5,
[
10] For NHC-catalysis via imine umpolung (a) A. Patra, S. Mukherjee,
T. K. Das, S. Jain, R. G. Gonnade, A. T. Biju, Angew. Chem. Int. Ed.
2
1
017, 56, 2730-2734; (b) G. Wang, Z. Fu, W. Huang, Org. Lett. 2017,
9, 3362-3365; (c) A. Patra, F. Gelat, X. Pannecoucke, T. Poisson, T.
8
35; Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.;
Besset, A. T. Biju, Org. Lett. 2018, 20, 1086-1089.
11] For reviews on the enantioselective Stetter reaction see: (a) M.
Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 10589. (j) Chen, X.-Y.;
Gao, Z.-H.; Song, C.-Y.; Zhang, C.-L.; Wang, Z.-X.; Ye, S. Angew.
Chem. Int. Ed. 2014, 53, 11611. (k) Jin, Z.; Chen, S.; Wang, Y.; Zheng,
P.; Yang, S.; Chi, Y. R. Angew. Chem. Int. Ed. 2014, 53, 13506
[
Christmann, Angew. Chem. Int. Ed. 2005, 44, 2632–2634; (b) J. Read de
Alaniz, T. Rovis, Synlett. 2009, 1189–1207. For important early
contributions see: (c) D. Enders, J. Han, A. Henseler, Chem. Commun.,
[
3] For selected examples see: (a) P.-C. Chiang, M. Rommel, J. W.
2
008, 3989; (d) Q. Liu, S. Perreault, T. Rovis, J. Am. Chem. Soc. 2008,
30, 14066
Bode, J. Am. Chem. Soc. 2009, 131, 871; (b) B.-S. Li, Y. Wang, Z. Jin,
P. Zheng, R. Ganguly, Y. R. Chi, Nat. Commun. 2015, 6, 6207.
1
[
12] For NHC nucleophilicity see (a) B. Maji, M. Breugst, H. Mayr,
[
(
4] For selected examples of homoenolate formation by 1,4-addition see:
a) C. Fischer, S. W. Smith, D. A. Powell, G. C. Fu, J. Am. Chem. Soc.
Angew. Chem. Int. Ed. 2011, 50, 6915-6919; (b) A. Levens, F. An, M.
Breugst, H. Mayr, D. W. Lupton, Org. Lett. 2016, 18, 3566–3569 and
references therein.
2
006, 128, 1472–1473; (b) S.-I. Matsuoka, Y. Ota, A. Washio, A.
Katada, K. Ichioka, K. Takagi, M. Suzuki, Org. Lett. 2011, 13, 3722–
725; (c) A. T. Biju, M. Padmanaban, N. E. Wurz, F. Glorius, Angew.
[
2
[
2
13] T. Jousseaume, N. E. Wurz, F. Glorius, Angew. Chem. Int. Ed.
011, 50, 1410-1414.
14] L. Candish, C. M. Forsyth, D. W. Lupton, Angew. Chem. Int. Ed.
013, 52, 9149-9152.
3
Chem. Int. Ed. 2011, 50, 8412–8415; (d) Y. Nakano, D. W. Lupton,
Angew. Chem. Int. Ed. 2016, 55, 3135–3139; (e) L. Scott, Y. Nakano, C.
Zhang, D. W. Lupton, Angew. Chem. Int. Ed. 2018, 57, 10299-10303;
for a review discussing NHC 1,4-addition: (f) X.-Y. Chen, S. Ye, Org.
Biomol. Chem. 2013, 11, 7991–7998.
t
[15] For the benzoin with BuOH see: (a) Y. Hachisu, J. W. Bode, K.
Suzuki, J. Am. Chem. Soc. 2003, 125, 8432-8433. For a review on the
NHC catalysed benzoin see: (b) R. S. Menon, A. T. Biju, V. Nair, Beil. J.
Org. Chem. 2016, 12, 444.
[
5] For selected stoichiometric imine umpolung chemistry: (a) A. I.
Meyers, Aldrichimica Acta 1985, 18, 59 (b) R. Brehme, D. Enders, R.
Fernandez, J. M. Lassaletta, Eur. J. Org. Chem. 2007, 5629–5660 and
references therein.
[
2
16] See (a) J. L. G. Ruano, J. Alemán, M. B. Cid, A. Parra, Org. Lett.
005, 7, 179; (b) J. Vesely, R. Rios Chem. Soc. Rev. 2014, 43, 611 and
[
6] For selected examples, and reviews, regarding 2-azaallyl anion
mediated imine umpolung see: (a) S. Tang, Z. Zhang, J. Sun, D. Niu, J.
J. Chruma, Chem. Rev. 2018, 118, 10393; (a) P. Finkbeiner, B. J.
Nachtsheim, Nachrichten aus der Chemie, 2015, 63, 1089-1093; (b) A.
references therein for imine to enamine isomerization with electron-poor
imines.
[17] Subjection of 13f to the reaction conditions with acceptor 9a failed
to provide imine 10f.
A. Yeagley, J. J. Chruma, Org. Lett. 2007, 9, 2879-2882; (c) Y. Zhu, S.
L. Buchwald, J. Am. Chem. Soc. 2014, 136, 4500−4503; (d) Y. Wu, L.
Hu, Z. Li, L. Deng, Nature, 2015, 523, 445-450; (e) J. Liu, C-G. Cao, H-
B. Sun, X. Zhang, D. Niu, J. Am. Chem. Soc. 2016, 138, 13103-13106;
[18] Single crystal X-ray analysis of g-ketoester 18j using CuK
radiation for absolute stereochemistry (CCDC 1862310). These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre.
(
f) M. Li, O. Gutierrez, S. Berritt, A. Pascual-Escudero, A. Yeşilçimen,
X. Yang, J. Adrio, G. Huang, E. Nakamaru-Ogiso, M. C. Kozlowski, P.
J. Walsh, Nature Chemistry, 2017, 9, 997-1004. (g) C-X. Zhuo, A.
Fürstner, J. Am. Chem. Soc. 2018, 140, 10514-10523.
[19] (a) Competition between 8j and n was performed and the ratio
10j:10n determined as background for eq. 9. (b) To assess whether the
product ratio in the competition relates to kinetics or stability of the
1
[
7] For stoichiometric encorporation of NHCs to imines or imminiums
product, the competition between 8n and 8j was monitored by H-NMR,
see: (a) S. Simonovic, J.-C. Frison, H. Koyuncu, A. C. Whitwood, R. E.
Douthwaite, Org. Lett. 2009, 11, 245-247; (b) D. A. DiRocco, K. M.
Oberg, T. Rovis, J. Am. Chem. Soc. 2012, 134, 6143-6145.
see SI. The product ratio is constant over the entire reaction, consistent
with a kinetic interpretation.
[20] See SI for details. While these results are consistent with the
[
8] For selected reactions involving NHC catalysis with addition of
proposed mechanism to enhance the accuracy work is ongoing.
reactive intermediates to imine and derivatives see: (a) J. A. Murry, D. E. [21] For enantiodeterming protonation in a related reaction of the
Frantz, A. Soheili, R. Tillyer, E. J. J. Grabowski, P. J. Reider, J. Am.
Chem. Soc. 2001, 123, 9696-9697; (b) M. He, J. W. Bode, Org. Lett.
Breslow intermediate see: (a) F. Liu, X. Bugaut, M. Schedler, R.
Fröhlich, F. Glorius, Angew. Chem. Int. Ed. 2011, 50, 12626-12630. (b)
R. Kuniyil, R. B. Sunoj, Org. Lett. 2013, 15, 5040-5043.
2
005, 7, 3131-3134; (c) S. M. Mennen, J. D. Gipson, Y. R. Kim, S. J.
Miller, J. Am. Chem. Soc. 2005, 127, 1654-1655; (d) L. He, T.-Y. Jian,
4
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201812585
Ph
Me
NHC Catalysis
Me
NHC =
Bz
H
N
O
Bz
N
N
N
N
O
O
Jared E. M. Fernando, Yuji Nakano,
Changhe Zhang and David W. Lupton*
Ph
Ph
7% yield, 99:1 er
plus 20 other examples.
H
O
7
O
MeO
_
_________ Page – Page
Me
Bz
Ph
Bn
N
Me
NH
O
Imine umpolung
N
Enantioselective N-heterocyclic carbene
catalysis exploiting imine umpolung.
N
PMP
6 4
PMP = 4-MeOC H
aza-Breslow
Imine umpolung is an underdeveloped area of enantioselective catalysis despite
providing a new entry to nitrogenous compounds of potential utility. Herein, we
report the use of NHCs, to catalyze an enantioselective aza-Stetter reaction. In
contrast to the chemistry of acyl umpolung with NHCs this reaction requires highly
nucleophilic catalysts. The reaction is highly enantioselective (all ≥96:4 er) with
various imines and 3-methylenechroman-2-ones coupled to give γ−imino lactones.
5
This article is protected by copyright. All rights reserved.