Iron-Catalyzed Carbamoylation of Enamides with Formamides as a Direct Approach to N-Acyl Enamine Amides

Article abstract of DOI:10.1021/acscatal.9b02635

The robustness of iron catalysis enabling the oxidative coupling reactions of enamides with formamides is described. Routing from readily accessible feedstocks, the efficient approach is implemented to furnish a broad array of value-added N-acyl enamine a

Full text of DOI:10.1021/acscatal.9b02635

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Letter
Iron-Catalyzed Carbamoylation of Enamides with
Formamides as a Direct Approach to N-Acyl Enamine Amides
Zhen-Yao Shen, Jun-Kee Cheng, Cong Wang, Chao Yuan, Teck-Peng Loh, and Xu-Hong Hu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02635 • Publication Date (Web): 26 Jul 2019
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ACS Catalysis
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Iron-Catalyzed Carbamoylation of Enamides with Formamides as a
Direct Approach to N-Acyl Enamine Amides
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Zhen-Yao Shen,†,§ Jun-Kee Cheng,‡,§ Cong Wang,† Chao Yuan,† Teck-Peng Loh,*,†,‡ and Xu-
Hong Hu*,†
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371, Singapore
ABSTRACT: The robustness of iron catalysis enabling the unprecedented oxidative coupling reactions of enamides with
formamides is described. Routing from readily accessible feedstocks, the efficient approach is implemented to furnish a
broad array of value-added N-acyl enamine amide derivatives, which serve as versatile precursors of biologically relevant
N-heterocycles including pyrimidin-4-ones and 4-hydroxypyridin-2-ones. Preliminary mechanistic studies supported the
notion that this direct carbamoylation reaction proceeded through an aminoacyl radical species.
KEYWORDS: oxidative coupling, enamide, formamide, iron, radicals
Enamides are versatile reactive intermediates for the
synthesis of nitrogen-containing building blocks due to
their intrinsically tempered nucleophilicity.1 Their
amenability to participate in an array of selective
functionalization reactions, as rendered by dual
characteristics, coupled with transition metal catalysis has
indisputably boosted their synthetic values.2 Direct olefinic
C−H functionalization of enamides has emerged as a useful
synthetic platform to prepare various multisubstituted
amine and olefin derivatives,3 serving as the pivotal
structural motifs in natural products as well as organic
materials. Consequently, the use of activated coupling
partners,4 often involving halides, organometallic reagents,
and acrylates, based on C−H bond functionalization have
been investigated to introduce different molecular entities
onto enamide scaffolds, including aryl,5 alkenyl,6 alkynyl,7
alkyl,8 acyl,9 etc.10 Despite these impressive progress, an
appealing alternative strategy to realize the oxidative
cross-coupling of enamides with simple hydrocarbons in
an efficient and selective manner is highly desirable yet
remains an underdeveloped area for C−C bond formation.11
which the stereoselectivity could be controlled by the
amide moiety. If realized, the protocol would grant a direct
access to value-added N-acyl enamine amides. Notably,
pertaining to the presence of N,O-functionalities in the
scaffold, these compounds can be facilely derived into
many important bioactive molecules such as β-amino
amides upon reduction15 and pyrimidin-4-ones upon
cyclodehydration.16 In fact, thanks to the elegant
contributions by Ellman,17 Chang,18 Li,19 and Luo,20 the
target molecules have been efficiently assembled via C−H
activation protocols, including C−H carbamoylation of
enamides with isocynates or isocyanides, as well as C−H
amidation of acrylamides with acyl azides or dioxazolones
(Scheme 1a). Herein, we disclose a strategically distinct
approach to N-acyl enamine amides via the oxidative
coupling between enamides and formamides by
environmentally friendly iron catalysis, which notably
circumvents the use of precious transition metals and toxic
reagents. Further, the present transformation contributes
to a new reaction pattern for enamides to forge C−C bond
via a free-radical pathway in addition to C−H activation,
which is relatively scarce in the enamide chemistry.
On the other hand, N,N-dimethylformamide (DMF) and
its variants have been intensively exploited as a carbamoyl
source via acyl C−H activation in Heck-type
carbamoylation.12 The application of this well-established
protocol on unsaturated substrates, however, largely
resulted in the hydrocarbamoylation adducts.13 Only two
precedent exceptions have emerged for iron-catalyzed E-
selective carbamoylation and carbooxygenation of styrenes
which assembled α,β-unsaturated amides and β-peroxy
amides,14 respectively. Inspired by the above studies, we
speculated that the feasibility of the direct coupling of
enamides with formamides via aminoacyl radical species in
Scheme 1. Direct Synthesis of N-Acyl Enamine Amides
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a) Known strategies for the formation of N-acyl enamine amides via C-H activation
less efficient (entries 8−10). In addition, no desired
product was observed when other common oxidants
were employed (entries 11 13) by using FeCl2 as catalyst,
R3
R4
1
2
3
4
5
6
7
8
N
N
−
R1
O
Rh
Ir
(ref. 17)
N
(ref. 18)
O
R2
except for di-tert-butyl peroxide (DTBP), which
delivered 81% yield of 3aa as the optimum (entry 14).
Control experiment in the absence of FeCl2 gave no
product (entry 15). Despite the satisfactory results
obtained under the neat conditions at the current
stage, we were interested in pursuing the reaction with
stoichiometric amounts of DMF instead of behaving as
a solvent. Our focus was then to identify an adequate
medium for this transformation. Using 1,2-
dichloroethane (DCE) as solvent, a decreased amount
of DMF (12 equiv) led to a sluggish conversion (entry
16). Pleasingly, elevating the temperature to 80 °C and
increasing the loading of DTBP to 5.0 equiv,
remarkably improved the yield from 13% to 45%
(entries 17 and 18). A subsequent solvent modification
showed that chlorobenzene was the best choice,
furnishing a compromised 49% yield of 3aa (entries
19‒23). Considering the beneficial role of base for
pyrimidin-4-ones
C
R4
N3
O
R3
O
O
H
O
R3
NH
R3
NH
O
H
R1
NHR4
R1
R1
NHR4
R2
O
N
R2
R2
O
O
R3
C
N
R4
(ref. 20)
O
Co
(ref. 19)
Pd
9
R3
NH
O
10
11
12
13
14
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18
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21
22
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R1
NHR4
R2
-amino amides
b) Fe-catalyzed carbamoylation of enamides with formamides (this work)
O
O
R3
R2
Ar
NH
Fe
R2
Ar
NH
O
O
H
+
N
R3
H
R4
oxidative coupling
N
R1
R1
R4
Preliminary investigation began with the oxidative
coupling of N-(1-phenylvinyl)acetamide (1a) with
DMF (2a) as model substrates. To our delight, the
coupling product 3aa was obtained in 46% yield using
1 equiv of 1a, DMF as solvent, tert-butyl hydroperoxide
(TBHP) as oxidant in the presence of FeCl3 (15 mol%)
radical-mediated C
bases were examined, among which KOAc was found
to be suitable promoter (entries 24 28). Attempts to
−C double bond formation, a set of
o
at 65 C. After extensive screening of iron salts, we
−
found that FeCl2 catalyzed the reaction in higher yield
(entries 1−7). Other inexpensive first-row transition
decrease the stoichiometry of DMF affected the
reaction negatively (entry 29).
metal salts, such as CuCl2, MnCl2, and CoCl2, proved
Table 1. Optimizations for the oxidative coupling of 1a and 2aa
O
O
O
[M] salt (15 mol%)
oxidant (3.0 equiv)
H
Me
NH
O
Me
NH
+
N
Me
H
additive, solvent
N2
NMe2
Me
3aa
2a
1a
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17b
18b
19b
20b
21b
22b
[M] salt
FeCl3
FeBr3
Fe(OTf)3
FeBr2
FeI2
Fe(OTf)2
FeCl2
CuCl2
MnCl2
CoCl2
FeCl2
FeCl2
FeCl2
FeCl2
-
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
Oxidant (equiv)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
BPO (3.0)
Additive
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
Temp (°C)
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
Time (h)
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
13
Yieldb (%)
46
20
<5
35
n.d.
23
72
16
12
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
13
n.d.
n.d.
n.d.
81
n.d.
13
40
45
6
17
CHP (3.0)
K2S2O8 (3.0)
DTBP (3.0)
DTBP (3.0)
DTBP (3.0)
DTBP (3.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DCE
DCE
80
80
80
80
80
80
13
13
13
13
DMSO
Toluene
THF
12
24
tAmOH
13
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ACS Catalysis
23b
24b
25b
26b
27b
28b
29c
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
DTBP (5.0)
-
PhCl
80
80
80
80
80
80
80
13
13
13
13
13
13
13
49
58
32
<5
13
1
2
3
4
5
6
7
CsOAc
DABCO
KOtBu
K2CO3
KOAc
KOAc
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
68
51
8
9
aUnless otherwise noted, reaction was performed with 1a (0.2 mmol), Fe salt (15 mol%), oxidant (3.0 equiv), and additive (30 mol%) in
solvent (0.8 mL) under N2. Isolated yield. b12 equiv of 2a used. c8 equiv of 2a used. n.d. = not detected. BPO = dibenzoyl peroxide. CHP
= cumyl hydroperoxide.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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Conditions: 1 (0.2 mmol), 2a (0.8 mL), FeCl2 (0.03 mol), DTBP
(0.6 mmol), N2, 65 °C, 2.5 h. a24 h. b12 h. c80 °C, 13 h.
Using the optimal conditions uncovered in Table 1,
entry 14, the substrate generality with respect to the
enamides was examined in the Fe-catalyzed oxidative
Next, the compatibility of formamide derivatives
with 1a as an enamide partner was investigated using
the reaction conditions described in Table 1, entry 28.
The results were summarized in Scheme 3. Broadly,
both mono- and di-substituted formamides could be
coupling with 2a (Scheme 2). A variety of N-
vinylacetamides tested underwent carbamoylation
smoothly under our catalytic protocol, providing
various N-acyl enamine amides in good yields and with
complete Z-selectivity, irrespective of the electronic
and steric properties of substituents on the phenyl ring.
Functional moieties of synthetic potential such as
halides, methoxy, trifluoromethyl, sulfonyl, and cyano
groups, were well tolerated. Naphthalenyl and
thiophenyl substituted enamides could also deliver
the coupling products in 84% and 52% yields (3ka and
3la), respectively. Nonetheless, by switching to cyclic
enamide, moderate conversion into the corresponding
product 3ma was observed even after a prolonged
installed onto β-C
good yields. Specifically, beyond dialkyl chain
substituted formamides (3ab ad), a range of aza-
−H bond of enamides in moderate to
−
cyclic derivatives embedding pyrrolidine, piperidine,
morpholine, and piperazine, underwent the reaction
smoothly to afford the products (3ae−ah). Regarding
the scope of N-monosubstituted formamides, ethyl
and cyclohexyl groups as the representative aliphatic
substitution showed higher reactivity than aryl
substituted derivative toward this transformation (3ai
and 3aj vs. 3ak). N,N-diphenylformamide failed to
produce the desired product under the standard
conditions (3am). It is worth mentioning that N-
formylglycinate of biological relevance turned out to
be a competent substrate (3al).
reaction time. Along with N-acetyl enamides (1a−m),
replacing substitution pattern with other acyl groups
at the nitrogen atom, such as N-propionyl and
isobutyryl substituents, did not influence the reaction
efficiency (3na and 3oa).
Scheme 2. Substrate Scope of Enamides
O
O
Scheme 3. Substrate Scope of Formamides
O
N
FeCl2 (15 mol%)
DTBP (3.0 equiv)
R2
Ar
NH
O
R2
Ar
NH
+
O
H
O
FeCl2 (15 mol%)
DTBP (5.0 equiv)
Me
Me
R3
H
N2, 65 oC, 2.5 h
Me
NH
O
N
O
Me
Me
NH
+
R1 Me
3
N
R3
R1
R4
H
KOAc (30 mol%)
PhCl, N2
80 oC, 5~14 h
2a
1
H
N
R4
O
O
O
O
2
1a
3
Me
NH
O
Me
NH
O
Me
NH
O
Me
NH
O
O
O
O
O
NMe2
Br
NMe2
NMe2
NMe2
Me
NH
O
Me
NH
O
Me
NH
O
Me
NH
O
NC
F3C
NiPr2
N
NEt2
NBu2
3aa
: 81% yield
3ba
: 72% yield
3ca
: 67% yield
3da
: 74% yield
a
3ad
3ae
: 75% yield
(6 h)
: 46% yield
O
O
3ac
: 86% yield
(6 h)
3ab
: 60% yield
(13 h)
O
(14 h)
Me
NH
O
Me
NH
O
Me
NH
O
O
O
O
O
NMe2
NMe2
NMe2
Me
NH
O
Me
NH
O
Me
NH
O
Me
NH
O
Me
O
MeO2S
N
N
NHEt
N
OMe
3fa
: 70% yield
3ea
3ga
: 79% yield
: 62% yield
N
O
Boc
O
O
O
O
3af
3ag
: 48% yield
(5 h)
: 60% yield
(5 h)
3ah
: 35% yield
(6 h)
3ai
: 53% yield
(5 h)
Me
NH
Cl
Me
NH
O
Me
NH
O
Me
NH
Br
O
O
O
O
O
NMe2
NMe2
NMe2
NMe2
Me
NH
O
Me
NH
O
Me
NH
O
Me
NH
O
F
a
3ia
: 79% yield
3ja
: 70% yield
3ka
: 84% yield
3ha
: 60% yield
N
H
CO2Et
NHPh
N
NPh2
H
O
O
O
O
3ak
: 30% yield
(6 h)
3al
: 57% yield
(13 h)
3am
(6 h)
: n.d.
3aj
: 50% yield
(7.5 h)
iPr
NH
O
Me
NH
O
Et
NH
O
Me
NH
O
NMe2
NMe2
NMe2
NMe2
Conditions: 1a (0.2 mmol), 2 (12 equiv), FeCl2 (0.03 mmol), DTBP
(0.6 mmol), KOAc (0.06 mmol), PhCl (0.8 mL), N2, 80 °C, 5 h.
aWithout KOAc.
S
b
c
c
3ma
: 48% yield
3na
: 84% yield
3oa
: 71% yield
3la
: 52% yield
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a) Radical-trapping experiment
O
O
O
N
1
2
3
4
5
6
7
8
FeCl2 (15 mol%)
DTBP (3.0 equiv)
Have established the substrate generality and
limitation of the present method, we sought to further
illustrate the synthetic utility of the products. As can
be expected from the precedent literatures,16
subjecting the coupled products N-ethyl, phenyl and
H
Me
NH
O
Me
NH
+
O
+
Me
H
N
TEMPO (1 equiv)
N2, 65 oC, 2.5 h
NMe2
: n.d.
O
NMe2
Me
1a
2a
(0.8 mL)
3aa
7
: 11% yield
(0.2 mmol)
b) Kinetic isotope effect studies
competitive experiment
cyclohexyl
hexamethyldisilazane (KHMDS) in THF solution
afforded the cyclodehydration products (4ai ak),
amides
(3ai−
ak)
to
potassium
2a
O
(0.4 mL)
O
FeCl2 (15 mol%)
DTBP (3.0 equiv)
+
Me
NH
O
−
Me
NH
O
CD3
3aa
+
N2, 65 oC, 20 min
+
H
N
D
9
namely pyrimidin-4-ones, which act as significant
pharmacophores within drug discovery enterprise
(Scheme 4a).21 Intriguingly, exposure of benzyl
protected amides 5 under the same basic conditions
led to the quick assembly of 4-hydroxypyridin-2-ones
6 via cyclodeamination process. As depicted in
Scheme 4b, a set of electronically and sterically varied
amides 3 were exemplified to assess the breadth of this
novel transformation, which serves as a convenient
alternative protocol to other condensation methods
for the synthesis of such privileged frameworks.22
N
CD3
CD3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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45
46
47
48
49
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52
53
54
55
56
57
58
59
60
D3C
2a
3aa
-d6
1a
kH/kD = 3.3
-d7 (0.4 mL)
18% combined yield
(0.2 mmol)
parallel experiments
O
2a
(0.8 mL)
O
or
O
FeCl2 (15 mol%)
DTBP (3.0 equiv)
Me
NH
O
Me
NH
CD3
or
3aa
H
N
+
D
N2, 65 oC, 20 min
CD3
N
CD3
D3C
1a
3aa
-d6
kH/kD = 3.1
(0.2 mmol)
2a-d7 (0.8 mL)
On the basis of the above experimental findings
combined with precedent reports,14 a plausible mechanism
was proposed for the current oxidative carbamoylation
reaction shown in Scheme 6. The initial step involves
Fe(II)-mediated decomposition of DTBP to tert-butoxyl
radical and tert-butoxide anion via a single-electron-
transfer (SET) redox reaction.23 The aminoacyl radical A
generated in situ by homolytic cleavage of formyl C(sp2)−H
bond, which is clearly evidenced by a radical-trapping
experiment, will then add to the double bond of enamide
at the β position. Of note, iron salt could serve as Lewis
acid to coordinate with the nitrogen and oxygen atoms,
which thereby accounts for the exclusive stereoselectivity
of the reaction. Fe(III) then oxidizes the benzylic radical B
to the corresponding cation C via SET process, along with
the regeneration of Fe(II) species. It is feasible that alkyl
cation C can be isomerized to more stable iminium ion D.
Finally, the olefinic functionality is restored upon
deprotonation to afford the carbamoylation product.
When the reaction was run in PhCl medium, the use of
KOAc leads to the enhancement of the chemical yield
might due to its beneficial role in the β-H elimination step.
Scheme 4. Synthetic Utility of Some Coupling
Products
a) Synthesis of multisubsituted pyrimidin-4-ones
O
Me
R
O
KHMDS (3 equiv)
THF, 80 o
Me
NH
O
N
N
R
C
4ai
4aj
, R = Et, 73% yield (6 h)
, R = Cy, 68% yield (8 h)
N
H
4ak
, R = Ph, 81% yield (7 h)
3ai ak
-
4ai ak
-
b) Cyclodeamination reaction toward the assembly of 4-hydroxypyridin-2-ones
O
O
O
Bn
Bn
Bn
KHMDS (3 equiv)
THF, 80 oC, 3 h
Me
NH
3
O
Me
N
O
N
BnBr
NaH, THF
0 oC to rt, 15 h
NMe2
O
NMe2
OH
OH
R
R
R
5
6
O
O
O
N
Bn
Bn
Bn
N
N
N
OH
OH
OH
R
Cl
OMe
6da
R = CF3,
: 67% yield
: 90% yield)
: 68% yield
6ka
: 73% yield
: 95% yield)
6ia
5ia
(
5da
(
6ga
5ga
(
: 57% yield
: 85% yield)
: 80% yield
: 88% yield)
5ka
(
6fa
R = Me,
5fa
(
: 96% yield)
Several experiments were carried out to elucidate the
mechanism of this catalytic reaction. As expected, addition
of a stoichiometric amount of a known radical quencher,
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), to the
reaction system resulted in no detectable amidation
product 3aa; instead, carbamoylated TEMPO adduct 7 was
formed in 11% yield, which indicated the intermediacy of
an aminoacyl radical species in the process (Scheme 5a).
Furthermore, the deuterium kinetic isotope effect (KIE) for
the carbamoylation was studied to better understand the
process of the C−H bond cleavage. The value of KIE = 3.3
from intermolecular competitive reaction as well as the
value of KIE = 3.1 from two parallel experiments revealed
that the cleavage of formyl C−H bond might be involved in
the rate-determining step (Scheme 5b).
Scheme 6. Proposed Mechanism for Fe-Catalyzed
Oxidative Carbamoylation
tBuO
FeII
tBuO
FeIII
+
tBuOOtBu
+
+
O
O
tBuO
+
+
tBuOH
H
NMe2
O
NMe2
A
2a
FeIII
O
FeII
AcHN
AcHN
Ph
AcHN
O
NMe2
+
Ph
NMe2
Ph
NMe2
SET
C
FeIII
B
1a
AcHN
Ph
O
AcHN
Ph
O
NMe2
NMe2
H
3aa
KOAc
D
Scheme 5. Mechanistic Studies
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(3) For reviews on transition metal-catalyzed olefinic C–H
functionalization, see: (a) McDonald, R. I.; Liu, G.; Stahl, S. S.
In summary, the development of a practical method for
the synthesis of N-acyl enamine amides via Fe-catalyzed
oxidative coupling of enamides and formamides has been
reported. Under neat conditions or PhCl as solvent,
synthetically useful yields and complete Z-selectivities of
the target products were achieved. Apart from the
generality of the reaction with respect to a broad substrate
scope as well as excellent functional group tolerance,
conversion of the N-acyl enamine amides products into
biologically important pyrimidin-4-ones and 4-
hydroxypyridin-2-ones demonstrates the versatility of
the transformation. Moreover, control experiments
disclosed a preliminary radical mechanism. Further
extensions of this approach and deeper mechanistic
studies are currently underway in our laboratory.
1
2
3
4
5
6
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8
Palladium(II)-Catalyzed
Nucleopalladation:
Alkene
Stereochemical
Functionalization
Pathways
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and
Enantioselective Catalytic Applications. Chem. Rev. 2011, 111,
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N.; Chausset-Boissarie, L.; Belhomme, M.-C.; Poisson, T.;
Pannecoucke, X.; Gillaizeau, I. Copper-Catalyzed Direct Arylation
of Cyclic Enamides Using Diaryliodonium Salts. Org. Lett. 2013,
15, 278−281. (g) Lei, Z.-Q.; Ye, J.-H.; Sun, J.; Shi, Z.-J. Direct Alkenyl
C–H Functionalization of Cyclic Enamines with Carboxylic Acids
via Rh Catalysis Assisted by Hydrogen Bonding. Org. Chem. Front.
2014, 1, 634−638.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.0000000.
Detailed experimental procedures and characterization
data.
AUTHOR INFORMATION
Corresponding Author
*E-mail: teckpeng@ntu.edu.sg
*E-mail: ias_xhhu@njtech.edu.cn
ORCID
Xu-Hong Hu: 0000-0001-6584-2901
Teck-Peng Loh: 0000-0002-2936-337X
(6) (a) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. RhIII-
Catalyzed Oxidative Olefination of Vinylic C–H Bonds: Efficient
and Selective Access to Di-unsaturated α-Amino Acid Derivatives
and Other Linear 1,3-Butadienes. Chem. – Eur. J. 2011, 17, 7167−7171.
(b) Xu, Y.-H.; Chok, Y. K.; Loh, T.-P. Synthesis and
Author Contributions
§Z.Y.S. and J.K.C. contributed equally.
Characterization of
A Cyclic Vinylpalladium(II) Complex:
Notes
Vinylpalladium Species as the Possible Intermediate in the
Catalytic Direct Olefination Reaction of Enamide. Chem. Sci. 2011,
2, 1822−1825. (c) Gigant, N.; Gillaizeau, I. Palladium(II)-Catalyzed
Direct Alkenylation of Nonaromatic Enamides. Org. Lett. 2012, 14,
3304−3307.
(7) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. Pyrrole Synthesis
via Allylic sp3 C−H Activation of Enamines Followed by
Intermolecular Coupling with Unactivated Alkynes. J. Am. Chem.
Soc. 2010, 132, 9585−9587. (b) Wang, L.; Ackermann, L. Versatile
Pyrrole Synthesis through Ruthenium(II)-Catalyzed Alkene C−H
Bond Functionalization on Enamines. Org. Lett. 2013, 15, 176−179.
(c) Feng, C.; Feng, D.; Loh, T.-P. Rhodium(III)-Catalyzed Olefinic
C−H Alkynylation of Enamides at Room Temperature. Chem.
Commun. 2014, 50, 9865−9868. (d) Xu, Y.-H.; Zhang, Q.-C.; He,
T.; Meng, F.-F.; Loh, T.-P. Palladium-Catalyzed Direct
Alkynylation of N-Vinylacetamides. Adv. Synth. Catal. 2014, 356,
1539−1534.
(8) (a) Wang, Z.; Reinus, B. J.; Dong, G. Catalytic Intermolecular
C-Alkylation of 1,2-Diketones with Simple Olefins: A Recyclable
Directing Group Strategy. J. Am. Chem. Soc. 2012, 134, 13954−13957.
(b) Ding, R.; Huang, Z.-D.; Liu, Z.-L.; Wang, T.-X.; Xu, Y.-H.; Loh,
T.-P. Palladium-Catalyzed Cross-Coupling of Enamides with
Sterically Hindered α-Bromocarbonyls. Chem. Commun. 2016, 52,
5617−5620.
(9) (a) Wang, H.; Guo, L.-N.; Duan, X.-H. Decarboxylative
Acylation of Cyclic Enamides with α-Oxocarboxylic Acids by
Palladium-Catalyzed C−H Activation at Room Temperature. Org.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National NSFC (21702106), the
Natural Science Foundation of Jiangsu Province
(BK20170967), and the Start-up Grant from Nanjing Tech
University (39839101, 39837101) is gratefully acknowledged.
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Table of Contents
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R2
R3
O
N
N
O
O
Ar
R1
R3
R2
Ar
NH
R2
Ar
NH
O
Fe
O
H
pyrimidin-4-ones
+
N
R3
H
R4
O
oxidative
coupling
N
R4
R1
R1
R5
N
 Iron catalysis
 Readily accessible substrates
Complete Z-selectivity
 Value-added products

Ar
OH
R1
9
4-hydroxypyridin-2-ones
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