Chemo- and Enantioselective Insertion of Furyl Carbene into the N?H Bond of 2-Pyridones

Article abstract of DOI:10.1002/anie.202104708

Asymmetric carbene insertion reactions represent one of the most important protocols to construct carbon–heteroatom bonds. The use of donor–acceptor diazo compounds bearing an ester group is however a prerequisite for achieving high enantioselectivity. Herein, we report a chemo- and enantioselective formal N?H insertion of 2-pyridones that has been accomplished for the first time with enynones as the donor–donor carbene precursors. DFT calculations indicate an unprecedented enantioselective 1,4-proton transfer from O to C. The rhodium catalyst provides a chiral pocket in which the steric repulsion and the π–π interaction of the propeller ligand play a critical role in determining the selectivities.

Full text of DOI:10.1002/anie.202104708

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Chemo- and Enantioselective Insertion of Furyl Carbene into the
N-H Bond of 2-Pyridones
Authors: Kai Wang, Ziye Liu, Guangyang Xu, Ying Shao, Shengbiao
Tang, Ping Chen, Xinhao Zhang, and Jiangtao Sun
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202104708
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10.1002/anie.202104708
Angewandte Chemie International Edition
COMMUNICATION
Chemo- and Enantioselective Insertion of Furyl Carbene into the
N-H Bond of 2-Pyridones
Kai Wang,† Ziye Liu,† Guangyang Xu, Ying Shao, Shengbiao Tang, Ping Chen, Xinhao Zhang* and
Jiangtao Sun*
Abstract: Asymmetric carbene insertion reactions represent one of
a) Enantioselective carbene insertions into X-H bonds
the most important protocols to construct carbon-heteroatom bonds.
donor
acceptor
X

[M]
The use of donor-acceptor diazo compounds bearing an ester group
is however a prerequisite for achieving high enantioselectivity.
Herein, we report a chemo- and enantioselective formal N-H
insertion of 2-pyridones that has been accomplished for the first time
with enynones as the donor-donor carbene precursors. DFT
calculations indicate an unprecedented enantioselective 1,4-proton
transfer from O to C. The rhodium catalyst provides a chiral pocket
in which the steric repulsion and the π-π interaction of the propeller
ligand play a critical role in determining the selectivities.
X
H
N2
H
a carbonyl or ester group
Type I
stepwise mechanism
[M]
concerted mechanism
chiral metal catalyst
H
X
H
X
[M]
1,2-proton transfer
X = Si
N
X = , S, O etc
Type II
chiral proton-shuttle transfer
achiral metal and
chiral phosphoric acid
H
O
P
O
O
O
X

O
[M]
H
OMe
b) Rh-catalyzed asymmetric B-H and Si-H bond insertion
R1
NMe3
SinBu3
R3
Rh2(R-BTPCP)4
H2B
R1
Me3N BH3
Chiral N-substituted 2-pyridones are key subunits in natural
products and pharmaceutical chemicals.1 However, the
ambident nucleophilic nature of 2-pyridones renders their
chemo- and enantioselective N-alkylation a significant challenge,
and successful examples of such reaction are rare.2 Metal-
carbene mediated alkylation of 2-pyridones with diazo
compounds appears to favor O-H over N-H insertion.3 To
finesse this limitation, we have developed an enantioselective,
rhodium-catalyzed dearomative N-alkylation of 2-oxypyridines
involving ylide formation and O-to-N acyl rearrangement.4
However, this protocol was also limited in its requirement for
donor-acceptor diazoacetates as the alkylation reagents. Thus,
the development of a novel insertion reaction, typically the use
of donor-donor carbene precursors in chemo- and
enantioselective N-alkylation of 2-pyridones is highly desirable.
Enantioselective carbene insertion into X-H bonds (X = N, O,
S, B, Si etc.) represents one of the most important strategies to
form heteroatom-carbon bonds.5 To date, many effective
approaches, including transition-metal catalysis6-8 and
cooperative catalysis by achiral metal and chiral proton-shuttle
transfer,9 have been established (Scheme 1a). The carbene
precursors used in enantioselective X-H insertion (XHI)
or
O
or
R1
+
O
O
DCE
R3
R3
H
H
nBu3Si
(X-H)
H
R2
R2
R2
Ph
[M]
O
X
Me
O
H
concerted mechanism
Me
c) Rh-catalyzed chemo- and enantioselective N-H bond insertion (this work)
R
R1
R3
R
R
Rh ( -TFPTTL)
2 S
4 (1 mol%)
N
H
O
O
+
N
OH
O
O
cyclopetane/Et2O (1:1)
3Å MS, 0 °C,
R1
R3
R2
R2
up to 99% ee
Ph
N
N
H
O
O
Me
H
H
chemoselective
enantioselective
atom economy
Rh2L4
Me
O
1,4-proton transfer
enantioselective 1,4-proton transfer
Scheme 1. Previous reports and our new strategy
insertion of electronphilic metal carbenes generated in situ from
readily avalible enynones11 into X-H bonds offers a different,
promising protocol for donor-donor carbene insertion reactions.
Recently, Zhu and co-workers reported the first highly
enantioselective furyl-carbene insertion into
a heteroatom-
carbon bond, a reaction useful in the synthesis of organoboron
compounds.12a Subsequently, they developed an asymmetric
rhodium-catalyzed Si-H bond insertion reaction which also used
enynones as carbene precursors.12b In mechanism, it is
commonly accepted that the XHI reactions catalyzed by a chiral
metal complex probably proceed by ylide formation and 1,2-
proton transfer for heteroatoms such as, N, O, and S, that bear
lone-pair electrons, and a concerted mechanism for Si-H bond
insertion (Scheme 1a).5c Similarly, furyl-carbene insertion into
soft nucleophiles (B-H and Si-H) is thought to proceed via a
concerted mechanism. Inspired by these seminal research and
continuing our interest in metal-carbene chemistry, we report
here an unprecedented enantioselective rhodium-catalyzed
selective N-alkylation reaction of 2-pyridones with enynones via
novel reaction pathway consisting of ylide formation followed by
an enantioselective 1,4-proton transfer (Scheme 1c).
reactions
however are strictly limited to stablized diazo
compounds bearing either a carbonyl or an ester group which
can delocalize the negative charge on the carbon atom.
Furthermore, without an electron-withdrawing group, the donor-
donor diazo compounds are easily to form azines, making the
enantioselective insertion reaction a formidable challenge.8f,10 In
this respect, the enantioselective transition-metal-catalyzed
[a] K. Wang, G. Xu, Y. Shao, S. Tang, Prof. Dr. J. Sun
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology,
School of Petrochemical Engineering, Changzhou University, 1 Gehu Road,
213164 Changzhou, China
E-mail: jtsun@cczu.edu.cn
Dr. Z. Liu, Prof. Dr. X. Zhang
Shenzhen Bay Laboratory, State Key Laboratory of Chemical Oncogeomics,
Peking University Shenzhen Graduate School, Shenzhen 518055, China.
Email：zhangxinhao@pku.edu.cn
We began our study with 2-pyridone (1a) and enynone (2a)
as model substrates to establish the optimal reaction conditions
Dr. P. Chen,
Shenzhen Jingtai Technology Co., Ltd. (XtalPi), Shenzhen, 518000, China
[†] K. Wang and Z. Liu contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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10.1002/anie.202104708
Angewandte Chemie International Edition
COMMUNICATION
(Table 1). Performing the reactions in diethyl ether at room
temperature with 1 mol% of catalyst loading, a range of chiral
dirhodium tetracarboxylate catalysts was examined. The first
phthalimido catalyst studied, Rh2(S-PTA)4 (C1) gave the desired
product 3aa in 52% yield with 82% enantiomeric excess (ee)
(entry 1), whereas bulky Rh2(S-PTTL)4 (C2) gave 3aa in higher
yield but with a slightly lower ee (entry 2). In contrast, a benzyl
substituted phthalimido catalyst Rh2(S-PTPA)4 (C3) gave both a
decreased yield and ee (entry 3). The enantioselectivity of 3aa
was improved to 90% ee when Rh2(S-TFPTTL)4 (C4) was used
as the catalyst (entry 4). Replacement of the fluorine
substituents in the phthalimido aryl ring by chlorine (C5) or
bromine (C6) resulted in low yields and decreased ee values,
and inversion of the configuration (entries 5 and 6). Attempts to
use more bulky rhodium catalysts (C7 and C8) and failed to
improve the reaction (entries 7 and 8), while Rh2(S-NTTL)4 (C9)
exhibited both low catalytic activity and selectivity (entry 9).
Solvent screening was conducted using C4 as the catalyst
(entries 10-14). In addition to diethyl ether, dichloroethane
(DCE), dichloromethane (DCM), cyclohexane, cyclopentane and
methyl tert-butyl ether (MTBE) all proved to be suitable solvents,
delivering 3aa in moderate to good yields and with good ee. The
enantioselectivity of the reaction with 3aa was further improved
when it was performed in mixed solvents. The use of
cyclopentane/Et2O in a 1:1 ratio furnished 3aa in 90% yield and
with 93% ee (entry 15). Both the yield and ee were slightly
increased at low temperatures and with the addition of 3 Å
molecular sieves (MS) (entries 16 and 17).
Under the optimal reaction conditions, the substrate scope
with respect to the carbonyl-ene-yne (2) was evaluated (Scheme
2). Generally, the reaction of aryl terminated carbonyl-ene-ynes
(2, R1 = aryl group) with 2-hydroxy pyridine (1a) delivers the
products (3aa-3am) in ≤95% yield and with
≤
99%
enantioselectivity. A variety of electron-donating as well as
electron-withdrawing groups at the ortho-, meta-, and para-
positions of the aryl ring (R1) were tolerated. The absolute
configuration of 3aa was unambiguously confirmed by X-ray
diffraction analysis.13 A heteroaryl-terminated substrate was
used to give the insertion product (3an) in 92% yield and 97%
ee. Notably, the reaction of alkyl-terminated substrates (R1
=
alkyl) with 1a delivered the corresponding products 3ao and 3ap,
in good yields but with low enantioselectivity under the standard
reaction conditions. These results were significantly improved
when Rh2(S-PTTL)4 was used as the catalyst. In addition to the
acetyl group, alkynes substituted with either a propionyl (3aq),
an isobutyryl (3ar), a benzoyl (3as), or ester groups (3at and
3au) at R2 are all amenable to this reaction, providing the
corresponding products in good yields and with good ee values.
Subsequently, the scope of the 2-hydroxy pyridines in this
enantioselective Rh-catalyzed dearomative amination was
explored. It was found that a range of functional groups on the
pyridine ring are tolerated. The electron-rich pyridines bearing 3-
methyl (3ca), 4-methyl (3da), and 5-methyl (3ha) performed well
in the reaction, affording the corresponding products in high
yields (80-92%) and with excellent ee values (93-96%). A 4-
benzyloxy substituted pyridine gave the product (3ga) in 52%
yield and 96% ee. The pyridines substituted with halogen groups
such as 3-chloro (3ba), 4-bromo (3ea), 5-fluoro (3ia), 5-bromo
(3ja) and 5-iodo (3ka) were all compatible with the reaction,
producing the resulting N-functionalized 2-pyridones which are
amenable to further elaboration via common C-X bond coupling
reactions. The electron-deficient pyridines bearing 4-methyl
formate (3fa), 5-methyl formate (3ma), and 5-trifluoromethyl (3la)
groups are all tolerated in this reaction delivering the
corresponding products in ≤82% yields and ee values ranging
from 89% to 96% ee. Pyridine with an aldehyde group at C5 also
reacted well with 2a, furnishing the desired product (3na) in
moderate yield and 92% ee.
Further elaboration reactions were conducted and are shown
in Scheme 3. Subjecting 3ka to palladium-catalyzed Suzuki-
Miyaura coupling with phenylboronic acid gave 4 in 74% yield
and 98% ee. Treatment of 3ka with phenylacetylene under
palladium-catalyzed Sonogashira-coupling, produced 5 in 88%
yield and 98% ee. The reaction of the pyridazine (6) with 2a led
to the chiral N-alkylated product 7 in 51% yield with 82% ee
(Scheme 3b). Moreover, the asymmetric insertion reaction
between 1a and donor/acceptor diazo (8) was performed,
affording 37% yield of O-alkylated product (9) and N-alkylated
product (10) in 24% yield and 72% ee (Scheme 3c). Moreover,
the reaction of 1a with unsymmetric diaryldiazomethane
delivered azine 13 in 83% yield without the detection of insertion
product 12 (Scheme 3d). Treatment of enynone 2a with aniline
with this established catalytic system, no reaction occurred
under an argon atmosphere, namely, the N-H insertion product
14 was not obtained. Performing the reaction under air led to the
formation of imine 15 in 37% yield (Scheme 3e).
Table 1. Selected optimization[a]
Ph
Me
N
O
O
O
O
[Rh] (1
mol%)
+
Ph
Me
Me
solvent
N
OH
Me
3aa
1a
2a
C1
O
, Rh2(S-PTA)4 (X = H, R = Me)
C2, Rh2(S-PTTL)4 (X = H, R = tBu)
C3
X
X
X
X
, Rh2(S-PTPA)4 (X = H, R = Bn)
O
O
C4, Rh2(S-TFPTTL)4 (X = F, R = tBu)
C5
C6, Rh2(S-TBPTTL)4 (X = Br, R = tBu)
O
N
Rh
Rh
, Rh2(S-TCPTTL)4 (X = Cl, R = tBu)
N
O
Rh
O
O
O
R
O
Rh C7
, Rh2(S-PTAD)4 (X = H, R = adamantyl)
4
C9
C8, Rh2(S-TFPTAD)4 (X = F, R = adamantyl)
, Rh2(S-NTTL)4
4
Yield
(%)[b]
Ee
Entry
[Rh]
C1
Solvent
(%)[c]
1
2
3
4
5
6
7
8
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
52
86
35
84
50
41
63
62
8
70
62
78
80
82
90
92
94
82
78
25
90
-20
-40
75
82
-20
74
75
90
92
91
93
96
96
C2
C3
C4
C5
C6
C7
C8
C9
C4
C4
C4
C4
C4
C4
C4
C4
9
Et2O
DCE
DCM
10
11
12
13
14
15
16[d]
17[d,e]
cyclohexane
cyclopentane
MTBE
cyclopentane/Et2O (1:1)
cyclopentane/Et2O (1:1)
cyclopentane/Et2O (1:1)
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol), [Rh] (1 mol%), solvent
(2.0 mL) at rt. [b] Isolated yields. [c] The ee values were determined by HPLC
analysis. [d] Reactions were performed at 0 oC. [e] 20 mg 3 Å MS was added.
This article is protected by copyright. All rights reserved.

10.1002/anie.202104708
Angewandte Chemie International Edition
COMMUNICATION
R
R1
O
O
R3
N
O
O
C4 (1 mol%)
Me
Me
+
R
O
=
R1
Furyl
cyclopetane/Et2O (1:1)
3Å MS, 0 °C,
R3
N
OH
R2
1
2
R2
3
for simplicity
N
O
N
O
N
O
N
O
N
O
N
O
Furyl
Furyl
Furyl
Furyl
Furyl
Ph
3aa
94%, 96% ee
Furyl
Me
F
MeO
Cl
EtO2C
3ad
92%, 91% ee
3ae
63%, 91% ee
3ac
3ab
3af
85%, 93% ee
89%, 97% ee
77%, 87% ee
N
O
F
N
O
N
O
N
O
N
O
N
O
N
O
Me
Me
Me
Me
MeO
F
Furyl
Furyl
Furyl
Furyl
Furyl
Furyl
Furyl
3ag
3ah
3ai
3aj
3ak
3al
3am
Me
Ph
95%, 96% ee
93%, 96% ee
79%, 90% ee
94%, 97% ee
89%, 99% ee
51%, 84% ee
76%, 94% ee
N
O
O
N
O
O
N
O
O
N
O
N
O
O
N
O
N
O
Ph
Ph
Furyl
Ph
Ph
iPr
iPr
Ph
Me
Furyl
Et
Et
Me
Furyl
3ap
81%, <5 % ee
85%, 85% ee[b]
3ao
3at
3as
78%, 91% ee
S
OMe
3an
92%, 97% ee
3ar
3aq
90%, 96% ee
74%, 15 % ee
82%, 85% ee[b]
O
66%, 79% ee
O
O
O
86%, 95% ee
CO2Me
OBn
Me
Br
Cl
Me
N
O
O
N
O
N
O
N
O
N
O
N
O
N
O
Ph
Ph
Furyl
Ph
Furyl
Ph
Furyl
Ph
Furyl
3ga
52%, 96% ee
Ph
Furyl
3da
Ph
Furyl
3ba
88%, 91% ee
3ca
92%, 96% ee
3fa
64%, 89% ee
3ea
88%, 90% ee
3au
OEt
80%, 93% ee
O
73%, 85% ee
Me
MeO2C
OHC
I
F3C
F
Br
N
O
N
O
N
O
N
O
N
O
N
O
N
O
Ph
3ma
82%, 95% ee
Furyl
Ph
Furyl
Ph
Furyl
Ph
3la
80%, 96% ee
Furyl
Ph
Furyl
Ph
Furyl
Ph
Furyl
3ia
3ja
3ka
96%, 97% ee
3na
3ha
95%, 96% ee
86%, 98% ee
46%, 92% ee
91%, 96% ee
Scheme 2. Substrate scope. [a] Reaction conditions: 1 (0.1 mmol), 2 (0.11 mmol), Rh2(S-TFPTTL)4 (1 mol%) in 2 mL of cyclopentane/Et2O (1:1), 20 mg 3Å MS, 0
oC, 12-72 h; [b] 1 (0.1 mmol), 2 (0.11 mmol), Rh2(S-PTTL)4 (1 mol%) in 2 mL of cyclopentane/Et2O (1:1), 20 mg 3Å MS, -20 oC, 12 h; [c] Isolated yields.
Ph
Ph
leading to the N- or O-alkylation products and Figure S2
Ph
PhB(OH)2
a)
3ka
presented the free energy profile. The relative free energies of
TS1 and TS1O-NH almost parallel the relative stabilities of 2-
hydroxypyridine and 2-pyridone - a finding which is consistent
with the reaction of benzotriazole.15 Although O-alkylation
pathway is preferred at the nucleophilic addition step, the barrier
for the subsequent proton-transfer is high due to the steric
repulsion in the catalyst pocket. And the N-alkylation with a
barrier of 13.4 kcal/mol, is more favorable. Computation with a
simplified model Rh2(OPiv)4 further supports the conclusion
(Figures S3-S4).
Pd(PPh3)Cl2, CuI
Et3N, r.t.
N
O
Pd(dppf)Cl2, Et3N, 80C
N
O
Ph
Furyl
Ph
Furyl
4 (74%, 98% ee)
5
(88%, 98% ee)
Cl
C4 (1 mol%)
b)
c)
Cl
OH
2a
+
N
cyclopetane/Et2O (1:1)
3Å MS, 0 °C,
N
O
N
N
6
Ph
Furyl
7 (51%, 82% ee)
Ph
CO2Me
C4
(1 mol%)
+
N
O
N
O
+
cyclopetane/Et2O (1:1)
3Å MS, 0 °C,

N2
N
OH
Ph
CO2Me
Ph
9 (
CO2Me
8
1a
)
37%
10 (24% , 72% ee)
d)
e)
Ph
N2 Me
C4
(1 mol%)
N

O
N
Me
+
+
Ph
N
OH
cyclopetane/Et2O (1:1,)
3Å MS, 0 °C
Me
N
O-alkylation
Ph
N-alkylation
Ph
1a
Me
12
11
Ar
Ph
13 (83%)
NPh
(0%)
Ar
Ph
N
N
O
NHPh
H
N
O
N
OH
OH
H
O
C4
(1 mol%)
[M]
C4
(1 mol%)
O
Ph
[M]
TS1O-NH
9.5(0.2)
Me
PhNH2
+
2a
Ph
Me
O
cyclopetane/Et2O (1:1)
PyrN-OH
4.1(5.8)
PyrO-NH
0.0(0.0)
cyclopetane/Et2O (1:1)
3Å MS, 0 °C
under argon
TS1 r. d. s.
13.4(2.4)
3Å MS, 0 °C
under air
O
Me
Me
15 (37%)
14
(0%)
R3
R3
Ar
Ph
R2
R2
O
Scheme 3. Application and elaboration
O
O
O
Ar
Ph
N
N
N
H
N
H
H
H
O
O
H
H
[M]
TS2FuRh
7.6(-1.5)
Ph
[M]
Ph
DFT calculations were performed in an attempt to understand
the reaction mechanism. The calculation began with the 2-furyl-
metal carbenoid (Int1) whose formation using an enynone as the
carbene precursor has been well documented.14
ProO-NH
5.8(15.9)
Pro
-1.8(8.4)
TS2O-NHFuRh
22.4(13.1)
r. d. s.
Scheme 4. N- and O-alkylation of 2-pyridone with Rh2(S-TFPTTL)4 carbene.
Unlike 2-oxypyridines which react with Rh-carbene only at its
N-site,4 2-pyridone is a more challenging substrate. As shown in
Scheme 4 and Figure S1, 2-pyridone (PyrO-NH) is more stable
than its isomer 2-hydroxypyridine (PyrN-OH) and its isomerization
is feasible. Scheme 4 summarized the most favorable pathways
Subsequent
analysis
focused
on
origin
of
the
enantioselectivity. The free energy profiles of both the R and S
pathways are depicted in Figure 1. The nucleophilic attack of 2-
hydroxypyridine on the carbene (TS1) forms a chiral center
which is then conservatively transformed to a product via
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10.1002/anie.202104708
Angewandte Chemie International Edition
COMMUNICATION
TS2FuRh (Figure S5). Dissociation of the Rh catalyst to form
Int3 was found to be energetically unlikely and consequently the
chirality determined in TS1 is not diminished via an achiral
transition state (TS2). The chiral environment of the catalyst was
examined. Rh2(S-TFPTTL)4 carbene was reported to adopt an
α,α,α,α-chiral crown conformation in which the carbene binds in
the pocket created by the four phthalimido groups (Figure
S6).16,17 A comprehensive conformational search of TS1 was
conducted by rotating the three dihedral angles Ψ1, Ψ2 and Ψ3
(Figures S7).
excellent enantioselectivity. The reaction represents the first
example of formal N-H insertion reaction with donor-donor furyl
carbene precursors. DFT calculations revealed that the N-
alkylation is more favorable than O-alkylation of 2-pyridone with
Rh2(S-TFPTTL)4 carbene. The reaction proceeds through
enantioselective pyridinium ylide formation and sequential 1,4-
proton transfer. The steric repulsion and π-π interaction in the
catalyst pocket account for the chemo- and enantioselectivity.
Acknowledgements
G (H)
L = S_TFPTTL
kcal/mol
We thank the NSFC (21971026, 21933004), the Jiangsu Key
Laboratory of Advanced Catalytic Materials and Technology
(BM2012110), the Key-Area Research and Development
Program of Guangdong Province (2020B010188001) and the
Shenzhen San-Ming Project (SZSM201809085) for their
financial support.
Ph
Ph
Ph
N
N
N
H
O
O
O
OH
L4Rh2
Me
O
Me
O
O
Me
O
O
H
H
L4Rh2
Me
Me
Me
TS2FuRh
TS1
TS2
TS2
Int3
32.4(41.2)
32.7(40.2)
TS1-R
16.4(5.8)
N
O
O
TS2FuRh-R
14.6(4.0)
Int2-S
9.3(-2.2)
Int2-R
Ph
Me
Me
Keywords: insertion • carbene • proton transfer• 2-pyridone•
Rh2L4
N
OH
TS1-S
13.4(2.4)
9.0(-2.5)
asymmetric catalysis
TS2FuRh-S
7.6(-1.5)
O
PyrN-OH
Pro
[1]
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Int1
0.0(0.0)
Pro
-1.8(8.4)
O
Me
Ph
Me
O
Ph
O
N
N
Rh2L4
O
Me
OH
L4Rh2
Me
O
H
Int4FuRh-R
-13.9(-24.0)
O
L4Rh2
Ph
O
Me
Int3
Int2
Int1
Me
Int4FuRh-S
-15.8(-24.7)
Figure 1. The free energy profile for the favorable pathway.
All the resulting conformations are listed in Figure S7 and the
most favorable R/S couple (TS1-R and TS1-S) are shown in
Figure 2. The free energy of TS1-R is 3.0 kcal/mol higher than
TS1-S, again consistent with experimental observation. The
phenyl and furan rings in the Rh-carbene and the pyridine ring of
2-pyridone restrict the C-N bond rotation in TS1, and these three
aryl components form an interesting π-π interaction with the
propeller ligand environment. A stronger π-π interaction is found
between the furan ring and TFPT in TS1-S (~3.72 Å, dihedral
angle ~19.78°) than the same interaction is in TS1-R (~4.52 Å,
dihedral angle ~38.02°) and accounts for the enantioselectivity.
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13.4(2.4)
TS1-R
16.4(5.8)
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Figure 2. DFT calculations. The origin of enantioselectivity.
In conclusion, we have realized
a
chemo- and
enantioselective formal N-H insertion reaction of 2-pyridones by
using enynones as donor-donor carbene precursors, providing
the N-alkylated pyridines in moderate to good yields and with
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Kai Wang, Ziye liu, Guangyang Xu, Ying
Shao, Shengbiao Tang, Ping Chen,
Xinhao Zhang* and Jiangtao Sun*
Page No. – Page No.
Chemo- and Enantioselective
Insertion of Furyl Carbene into the N-
H Bond of 2-Pyridones
A chemo- and enantioselective formal N-
H insertion has been accomplished for the first time by using enynones as the donor-
donor carbene precursors. Distinct with the selective O-
H insertion of pyridones for diazo compounds, this reaction occurs exclusively on the desired nitrogen
atom. DFT calculations indicate an unprecedented enantioselective O-to-C 1,4-proton transfer.
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