The ruthenium-catalyzed C-H functionalization of enamides with isocyanates: Easy entry to pyrimidin-4-ones

Article abstract of DOI:10.1039/c9cc03612a

Ruthenium-catalyzed heteroannulation between enamides and isocyanates has been realized as a complementary approach to conventional strategies for the synthesis of pyrimidin-4-ones. High step-A nd atom-economy was achieved for the rapid construction of such privileged scaffolds, which are found in a multitude of pharmaceutical compounds. The generality and practicability of this transformation were reflected by the broad scope of substrates with diverse functional groups, large-scale synthesis, and late-stage diversification.

Full text of DOI:10.1039/c9cc03612a

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DOI: 10.1039/C9CC03612A
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Ruthenium-catalyzed C–H functionalization of enamides with
isocyanates: easy entry to pyrimidin-4-ones
Pengfei Shi,a Song Li,a Lu-Min Hu,a Cong Wang,a Teck-Peng Loh*ab and Xu-Hong Hu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Ruthenium-catalyzed heteroannulation between enamides ester5 and β-keto amide (Scheme 1a).6 The requisite utilization of
and isocyanates has been realized as a complementary prefunctionalized starting materials and low step- and atom-
approach to the conventional strategies for pyrimidin-4-ones economy intrigued synthetic chemists to search for alternative
synthesis. High step- and atom-economy was achieved for the approach. Very recently, Wang disclosed an attractive NHC-catalzyed
rapid construction of such privileged scaffolds found in a annulation of ynals with amidine for the formation of the pyrimidin-
multitude of pharmaceutical compounds. The generality and 4-one skeleton (Scheme 1b).7 Considering the pivotal role and
practicability of this transformation was reflected by a broad structural diversity of pyrimidin-4-ones in the context of drug
scope of substrates with diverse functional groups, large-scale discovery, the development of a practical and efficient method
synthesis, and late-stage diversification.
towards such privileged framework is still in demand.
Among the tremendous advances of transition metal-catalyzed
Among the various nitrogen-containing heterocycles, pyrimidin-
4-ones govern an indispensable position owing to their remarkable
physiochemical properties in pharmaceutical research.1 Specifically,
serving as the key constituents of RNA and DNA nucleobases,
pyrimidin-4-one moieties are also embedded in many biologically
active molecules as marketed drugs and clinical candidates (Fig. 1).2
C–H
bond
functionalization
reactions,
tandem
C–H
activation/annulation approach represents a unique atom-effective
synthetic platform for the construction of complex carbo- and
heterocycles.8 In particular, C–H aminocarbonylation reactions with
isocyanates,9 as contributed by the research groups of
Kuninobu/Takai,10 Bergman/Ellman,11 Cheng,12 Ackermann,13 Li,14
and others,15 have been accomplished to assemble multifarious
amide moieties by the action of transition metals. Nevertheless,
tandem C–H aminocarbonylation/annulation process, which enables
facile access to nitrogen-containing heterocycles,16 is still a
challenging task and less developed as compared to the analogous
annulation across alkene and alkyne.8 Notably, an early example of
Rh-catalyzed coupling of enamides with isocyanates was elegantly
demonstrated by Bergman/Ellman, in which only two cases were
presented to access pyrimidin-4-ones (Scheme 1c).11a Furthermore,
substrate compatibility with alkyl isocyanates for such tandem
transformations was frustrated by seemingly unsolvable issue.
Within our ongoing interest in alkenyl C–H bond functionalizations,17
we herein describe a general approach to privileged pyrimidin-4-one
ring systems via the unprecedented Ru-catalzyed heteroannulation
of enamide with isocyanates (Scheme 1d). The catalytic protocol is
featured by multi-faceted aspects: 1) rare direct addition of alkenyl
C–H bond to isocyanates by using relatively inexpensive ruthenium
catalysis, 2) ample substrate scope including both aryl and alkyl
substituted enamides and isocyanates, 3) practical manipulation for
large-scale synthesis of multisubstituted pyrimidin-4-ones in one-pot
process, 4) late-stage modification of complex molecules.
O
O
O
OH
H
N
H
Br
Me
Br
N
N
N
NH
OH
N
H
Me
N
NH
N
H
N
N
H
NH2
N
N
Me
H
Me
Sapropterin
(antidiabetes drug)
Temelastine
(antihistaminic drug)
PDE III inhibitor
O
O
N
OH
NC
N
N
H
O
N
CN
N
Br
N
O
N
N
N
H
NH2
N
Cl
OMe
Me
antimitotic agent
(IC50 = 12.5 µM)
USP7 inhibitor
(IC50 = 0.1 µM)
DPP-4 inhibitor
(IC50 = 5 nM)
Fig. 1 Representative structures of pharmacologically active pyrimidin-4-one
derivatives.
Conventional synthesis of pyrimidin-4-ones usually relies on
Pinner condensation of β-keto ester with amidine,3 cycloaddition
reaction of 1,3-diaza-1,3-butadiene with ketene,4 and multistep
manipulations starting from appropriate precursors, such as β-amino
a. Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering,
Nanjing Tech University, Nanjing 211816, China. E-mail: ias_xhhu@njtech.edu.cn
b. Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. E-mail: teckpeng@ntu.edu.sg
† Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
a) Traditional methods
O
R3
N
10
11c
12d
MesCO2H
MesCO2H
MesCO2H
THF
THF
THF
83
View Article Online
R3
O
R2
DOI: 10.1039/C9CC03612A
HN
75
OR4
+
C
+
N
SMe
HN
Pinner condensation
R2
R4
0
O
N
R1
O
R3
R2
R1
a
Reaction conditions (unless otherwise specified): 1a (0.75 mmol), 2a (0.3
N
R1
mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%), and additive (0.45
mmol) in a solvent ( 2 mL) at 100 °C for 16 h. b Yields of isolated products. c 80
°C. d Without [RuCl2(p-cymene)]2. Piv = pivalic. Ad = adamantyl. Mes = 2,4,6-
trimethylphenyl.
NH2
O
e
s
i
w
p
e
t
Drawbacks:
R1
R1
OR4
or
s
1) required use of prefunctionalized reagents
2) limited substrate scope
3) formation of undesired side products
4) low conversion or long reaction time
O
O
NHR3
b) NHC-catalyzed annulation of ynal with amidine7
With the optimized conditions established, the substrate scope
of enamides were initially investigated and the results are
summarized in Scheme 2. The heteroannulation process are
compatible with a wide range of functional groups including
trifluoromethyl (3ca), cyano (3da), halide (3ea–ia), methoxy (3ja),
and acetal (3ka). It should be noted that increasing steric hindrance
posed by ortho-position led to a significant decrease in reactivity. 2-
Naphthyl enamide proceeded smoothly to give the corresponding
pyrimidin-4-one in good yield (3la). Aside from aryl enamides,
thiophenyl enamide proved to be competent substrate (3ma).
Pleasingly, a set of cyclic enamides, derived from tetralone,
benzosuberone, and chromanone, were uniformly applied to the
new catalytic system, permitting access to polyfused pyrimidin-4-
ones (3na–pa). To our satisfaction, sterically hindered alkyl enamides
also reacted without difficulty to give the expected products in good
yields (3qa and 3ra). When cyclopropyl enamide (1s) was subjected
to the standard conditions, only 28% yield of the desired pyrimidin-
4-one (3sa) was obtained, which is likely due to the instability of 1s
in the current acidic environment. The diversity of enamides was
further replenished by employing other N-acyl enamides, as
exemplified by propionyl and isobutyryl substituents, giving rise to
the corresponding pyrimidin-4-ones (3ta and 3ua) in yields of 91%
and 55%, respectively. However, no desired products were detected
when the electron-deficient and primary alkyl enamides were used
as substrates (1v and 1w).21
O
N
R2
R3
O
NHC
[O]
HN
HN
+
H
R1
N
R2
R3
R1
c) Rh-catalyzed heteroannulation of enamide with isocyanate (only two cases)11a
O
O
C
N
Rh
O
O
Ph
+
+
N
N
R1
N
Me
R3
R1 = Ph, t-Bu
Ph
R4
R1
N
O
Me
H
d) This work
R2
R1
H
R2
R1
R4
R3
O
C
N
Ru
H2O
+
N
H
N




Easy access to privileged pyrimidin-4-ones
Ample scope of enamides and isocyanates
Versatile ruthenium catalyst
Late-stage modification
Scheme 1 Synthetic strategies for the construction of pyrimidin-4-ones.
For the optimization experiments, we selected easily accessible
N-acetyl enamine18 1a and p-tolyl isocyanate 2a as model substrates
in the Ru-catalzyed heteroannulation reaction (Table 1). To our
delight, the catalytic system by employing [RuCl2(p-cymene)]2 and
AgSbF6 in 1,2-DCE at 100 °C enabled the annulation to afford 3aa in
52% yield (entry 1). Solvent screening revealed that THF was the
optimal medium for this transformation (entries 2–5). The addition
of a base like NaOAc failed to improve the yield (entry 6). Somewhat
interestingly, the addition of acetic acid enhanced the catalytic
performance (entry 7), although it was reported that the presence of
Brønsted acids typically resulted in the hydrolysis of enamides.19 We
then evaluated the effect of acids and found that sterically congested
carboxylic acid, namely 2,4,6-trimethylbenzoic acid,20 gave the
highest yield at the current stage (entries 8–10). Lowering the
reaction temperature marginally reduced the yield (entry 11).
Furthermore, 3aa was not formed in the absence of the ruthenium
complex (entry 12).
O
Me
R2
R1
H
C
O
N
N
[RuCl2(p-cymene)]2 (5 mol%)
O
R2
R1
AgSbF6 (20 mol%)
+
N
3
R3
N
MesCO2H, THF
100 ºC, 16 h
H
R3
1
Me
2a
3ba
):
(
3da
R = p-Me (
R = p-CF3
R = p-CN (
O
50%
83%
70%
97%
98%
60%
54%
36%
53%
O
3ca
):
):
):
p-tol
p-tol
N
N
3ea
R = p-F (
Table 1 Conditions screening for the Ru-catalyzed heteroannulation between
enamine and isocyanatea
O
O
N
Me
N
Me
3fa
R = p-Cl ( ):
R
3ga
R = p-Br ( ):
3ha
R = o-F ( ):
Me
3ka
: 74%
3ia
R = o-Cl ( ):
R = m-OMe ( ):
O
O
N
C
H
3ja
N
[RuCl2(p-cymene)]2 (5 mol%)
O
N
AgSbF6 (20 mol%)
+
O
O
O
N
O
N
N
Me
additive, solvent
100 ºC, 16 h
p-tol
p-tol
Me
p-tol
p-tol
Me
H
N
O
N
n
N
S
N
Me
N
Me
3aa
Me
1a
N
Me
2a
Entry
Additive
—
Solvent
1,2-DCE
Toluene
DMSO
1,4-Dioxane
THF
Yield (%)b
3na
3oa)
n = 1 (
n = 2 (
): 77%
: 63%
3pa
: 90%
3ma
: 81%
3la
O
: 87%
1
2
3
4
5
6
7
8
9
52
50
<5
26
58
32
65
70
74
O
N
N
O
O
p-tol
—
p-tol
p-tol
N
p-tol
N
—
N
R3
N
Me
N
Me
—
N
t-Bu
Me
R3 = Et (
3ta)
R3 = i-Pr (
: 91%
—
3ra
: 81%
3sa
: 28%
3qa
: 64%
3ua
): 55%
NaOAc
AcOH
PivOH
THF
examples of currently unsuccessful enamides
THF
H
H
O
O
THF
MeO
N
Me
N
Me
H
H
1-AdCO2H
THF
O
1w
1v
2 | J. Name., 2012, 00, 1-3
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Scheme 2 Scope with respect to enamides. The reactions were run on a 0.3 amount of 1a and 1a-d2 (Scheme 5b). A KIE value of V4ie.3w AsrutigclgeeOsntleinde
mmol scale in 2 mL THF.
that C–H cleavage might be involved in the rDatOeI-:d1e0.t1e0r3m9/inCi9nCgCs0t3e6p1.2A
a)
O
O
Thereafter, our efforts focused on exploring the scope with
respect to isocyanate substrates. As indicated in Scheme 3, a series
of phenyl isocyanates decorated with either electron-donating or
electon-withdrawing substituents at the para-, meta-, or ortho-
positions reacted with 1a, leading to the desired products in modest
to good yields (3ab–al). Similar efficiency was observed by using 1-
naphthyl isocyanate (3am) as the partner. Moreover, alkyl
isocyanates possessing benzyl and regular alkyl groups readily
underwent the annulation to generate the corresponding products
in 54–72% yields (3an–aq).
H
C
[RuCl2(p-cymene)]2
O
N
(5 mol%)
N
Br
+
N
Me
AgSbF6 (20 mol%)
MesCO2H, THF
100 ºC, 16 h
N
Me
H
Br
3ah
: 83%
1a
2h
(0.99 g)
(3.5 mmol)
O
b)
C
N
Me
N
H
[RuCl2(p-cymene)]2
O
N
(8 mol%)
O
N
+
N
Me
AgSbF6 (32 mol%)
MesCO2H, THF
100 ºC, 16 h
O
H
N
N
C
Me
1a
O
2r
3ar
: 90%
p-tol
c)
O
O
O
H
H
Me
N
[RuCl2(p-cymene)]2 (5 mol%)
R4
Me
O
O
AgSbF6 (20 mol%)
N
N
C
H
2a
+
N
R4
N
N
Me
[RuCl2(p-cymene)]2
(5 mol%)
MesCO2H, THF
100 ºC, 16 h
H
N
3
Me
H
H
2
1a
AgSbF6 (20 mol%)
MesCO2H, THF
100 ºC, 16 h
H
H
H
H
H
3ab
):
R = p-F (
92%
74%
71%
23%
84%
84%
85%
48%
60%
54%
61%
MeO
O
R
MeO
3ac
):
R = p-Cl (
R = p-CF3
R = p-CN (
O
N
4
5
, derived from pregnenolone
: 88%
3ad
):
3ae
(
N
):
N
Me
Me
N
N
Me
3af
R = p-OMe ( ):
2a
N
H
N
3ag
R = m-Me ( ):
Me
O
p-tol
[RuCl2(p-cymene)]2
(5 mol%)
3ah
R = m-Br ( ):
3ai
R = m-C(O)Me ( ):
H
H
3am
: 70%
O
3aj
R = o-Me ( ):
AgSbF6 (20 mol%)
MesCO2H, THF
100 ºC, 16 h
H
H
H
H
3ak
R = o-Cl ( ):
3al
R = H ( ):
BnO
BnO
7
, 59%
6
, derived from estrone
O
O
N
O
N
O
N
Me
Et
n-Bu
1a
N
N
N
N
d)
O
N
Me
OMe
O
[RuCl2(p-cymene)]2
(5 mol%)
N
Me
Me
Me
Me
Me
N
OMe
AgSbF6 (20 mol%)
MesCO2H, THF
100 ºC, 16 h
O
N
Me
Me
C
3aq
: 54%
3an
: 72%
3ap
: 56%
3ao
: 66%
O
8
, derived from L-leucine
9
: 59%, >99% ee
Scheme 3 Scope with respect to isocyanates. The reactions were run on a 0.3
Scheme 4 Synthetic utility of the Ru-catalzyed heteroannulation reaction.
mmol scale in 2 mL THF.
H/D
18% D
H
[RuCl2(p-cymene)]2 (2 mol%)
The robustness of the Ru-catalzyed heteroannulation reaction
was further illustrated by an array of useful experiments. A gram-
scale reaction of 1a with 2h was performed to assess the scalability
of this transformation, and the product 3ah was obtained in a
comparable yield (Scheme 4a). Additionally, the synthetic utility of
this strategy could be easily extended to the generation of
multisubstituted bipyrimidin-4-one (3ar) in one step when
diisocyanate 2r was employed with the aid of a higher catalyst
loading (Scheme 4b). Remarkably, the promising functional group
compatibility prompted us to examine its potential application to the
late-stage modifications of bioactive natural products. Installation of
valuable pyrimidin-4-one motif to pregnenolone (4) and estrone
derivatives (6), acting as the representatives of complex acyclic and
cyclic enamides, were successfully accomplished to deliver the target
steroidal products (5 and 7) in satisfactory yields (Scheme 4c). It was
significant to highlight that isocyanate 8 derived from amino acid L-
leucine participated well in the reaction that produced the desired
pyrimidin-4-one 9 bearing a chiral component (Scheme 4d).
a)
O
O
AgSbF6 (8 mol%)
N
Me
N
H
Me
MesCO2D, THF
100 ºC, 1 h
H
43%
1n 1n
-d1
/
1n
Me
O
b)
2a
D
D
O
D/H
[RuCl2(p-cymene)]2 (5 mol%)
AgSbF6 (20 mol%)
N
N
H
Me
+
1a
N
Me
MesCO2H, THF
100 ºC, 1 h
1a-
d2
3aa 3aa
/ -d1
KIE = 4.3
Scheme 5 Preliminary mechanistic study.
In conclusion, we have developed a practical and scalable
method to access multisubtituted pyrimidin-4-one derivatives from
readily available enamides and isocyanates under versatile
ruthenium catalysis. The transformation involves a tandem alkenyl
C–H aminocarbonylation/annulation process with excellent step-
and atom-economy, liberating one water as innocuous waste. The
robustness of this heteroannulation reaction is demonstrated by a
broad scope of enamides and isocyanates with diverse functional
groups. Furthermore, under redox-neutral and mild conditions,
valuable pyrimidin-4-one motifs could also be effectively assembled
into bioactive compounds with potential for further applications in
drug design. Overall, we anticipate that the protocol and the
resulting products will set a beneficial stage in chemical science.
Financial support from the National NSFC (21702106), the
Natural Science Foundation of Jiangsu Province (BK20170967), and
Finally, preliminary mechanistic study was investigated through
deuterium labeling experiments. When exposing N-acetyl enamine
1n to the catalytic system in the absence of 2a but with the addition
of MesCO2D, a H/D scrambling was observed at the olefinic position
(Scheme 5a), thus indicating the reversible C–H metallation mode. To
probe the relevance of C–H activation, an intermolecular kinetic
isotope effect (KIE) for acylation was measured using an equimolar
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
9
For reviews on isocyanide insertion chemistry, see: (a) G. Qiu,
DOI: 10.1039/C9CC03612A
Wang, B. Xu, Chin. J. Org. Chem., 2015, 35, 588.
the Start-up Grant from Nanjing Tech University (39839101,
39837101) is gratefully acknowledged.
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Conflicts of interest
There are no conflicts to declare.
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Table of Contents
O
R2
R1
H
R2
R1
R4
R3
O
C
N
Ru
O
N
+
H2O
+
R3
N
N
R4
H