Palladium-Catalyzed Cyclocarbonylation of Pyridinylated Vinylogous Amides and Ureas to Generate Ring-Fused Pyridopyrimidinones

Article abstract of DOI:10.1021/acs.orglett.8b01275

As part of a program aimed at generating new heterocyclic frameworks for medicinal chemistry exploration, an efficient approach to the assembly of novel ring-fused pyridopyrimidinones was undertaken. Specifically, a collection of 11H-pyrido[2,1-b]quinazoline-1,11(2H)-diones and 2,3-dihydropyrido[1,2-a]pyrrolo[3,4-d]pyrimidine-1,10-diones was generated via a palladium-catalyzed, pyridine-directed, cyclocarbonylation of 2-pyridyl-linked vinylogous amides and ureas in yields of up to 90%.

Full text of DOI:10.1021/acs.orglett.8b01275

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Cyclocarbonylation of Pyridinylated
Vinylogous Amides and Ureas to Generate Ring-Fused
Pyridopyrimidinones
Gang Yan and Jennifer E. Golden*
Department of Pharmaceutical Sciences, School of Pharmacy, University of WisconsinMadison, Madison, Wisconsin 53705-2222,
United States
S
* Supporting Information
ABSTRACT: As part of a program aimed at generating new heterocyclic
frameworks for medicinal chemistry exploration, an efficient approach to
the assembly of novel ring-fused pyridopyrimidinones was undertaken.
Specifically, a collection of 11H-pyrido[2,1-b]quinazoline-1,11(2H)-diones
and 2,3-dihydropyrido[1,2-a]pyrrolo[3,4-d]pyrimidine-1,10-diones was
generated via a palladium-catalyzed, pyridine-directed, cyclocarbonylation
of 2-pyridyl-linked vinylogous amides and ureas in yields of up to 90%.
he pyridopyrimidinone core is a privileged scaffold with
diverse pharmacological activity depending on its
functionalization (Figure 1, red highlighting). For instance,
Scheme 1. General Approaches to Pyridopyrimidinones
T
coupling partners that are devoid of a bridging carbonyl group.
As a result, pyridine-directed CO insertions of metal-activated
C−H bonds have emerged as a powerful means to construct
similar heterocycles.16,17 For instance, CO insertion chemistry
was reported18 to form quinazolinones 13 or incognito
pyridopyrimidinones featuring an annulated phenyl ring (B,
Scheme 1). This precedent is considered along with the
suggestion that the cyclocarbonylation of a C(sp2)−H of a
vinylogous system affixed to a pyridyl moiety (C, Scheme 1)
might lead to differentiated scaffolds if suitable reaction
conditions can be identified.
To initiate this study, vinylogous substrates were prepared by
treating 2-aminopyridines with 1,3-cyclic diones under acid-
catalyzed conditions (Supporting Information (SI)).19 With
substrates in hand, parameters were screened to promote the
cyclocarbonylation (Table 1). A pilot reaction using vinylogous
amide 14a was attempted using palladium acetate-mediated
conditions reported by Zhu18 for the generation of quinazoli-
nones 13; however, product 15a was not obtained, presumably
due to vinylogous substrate instability in the harsh acidic
Figure 1. Pharmacological and structural diversity of derivatized
pyridopyrimidinones and prospective template opportunities.
the structural motif is exemplified by allergy drug Pemirolast1,2
1, antidepressant3 Lusaperidone 2, antihypertensive4 Seganserin
3, antiviral compound 4,5 antiulcer agent 5,6 and antiprolifer-
ative probe 6,7 just to name a few (Figure 1).8 Consequently, we
envisioned using this privileged template to design new
frameworks for medicinal chemistry optimization, as pyrido-
pyrimidinone-embedded structures 7 and 8 have yet to be
reported. As such, we explored strategies to efficiently construct
and diversify these scaffolds.
With the exception of compound 6, prepared by an unusual
naphthaquinone rearrangement,7 known compounds in Figure 1
were generally assembled by the condensation of 2-amino-
pyridines with β-keto esters,9,10 ethyl cyanoacetate,11 or other
carbonyl-containing partners3 as the key step (A, Scheme 1).12
However, the development of metal-catalyzed C−H activation
chemistry13−15 has opened up the possibility of employing
Received: April 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01275
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Organic Letters
Letter
Table 1. Vinylogous Amide Cyclocarbonylation
Optimization
Scheme 2. Survey of Substituted 2-Aminopyridyl Substrates
with an Appended NH-Cycloalkenone
a
a b
,
catalyst
(10 mol %)
ligand
(20 mol %)
oxidant
(3 equiv)
yield
b
entry
solvent
(%)
c
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(PhCN)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Cu(OAc)2
TFA
0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
10
48
0
PPh3
PPh3
PPh3
dppp
tdmpp
tbtfmpp
CH3PPh2
PPh3
PPh3
PPh3
trace
14
36
22
trace
12
41
11
24
75
90
d
e
f
g
air
K2S2O8
K2S2O8
K2S2O8
K2S2O8
PPh3
PPh3
PPh3
h
CH3CN
CH3CN
i
a
Reaction conditions: 14a (0.3 mmol), Pd catalyst (10 mol %), ligand
(20 mol %), oxidant (3 equiv), CO balloon (1 atm), solvent (2 mL),
b
c
d
100 °C, 15 h. Isolated yield of 15a. 70 °C, 3 h. dppp: 1,3-
bis(diphenylphosphino)propane. tdmpp: tris(2,6-dimethoxyphenyl)-
e
f
phosphine. tbtfmpp = tris[3,5-bis(trifluoromethyl)phenyl]phosphine.
g
h
i
Air/CO = 1:1. 80 °C. 80 °C, 3 h, CH3CN (1 mL).
environment (entry 1). Encouragingly, the replacement of TFA
in this reaction with 1,4-dioxane afforded a modest 10% yield of
pyridopyrimidinone 15a, along with a substantial amount of
recovered starting material (entry 2).
As solvents and the catalyst loading were screened, the effect
of adding PPh3 as a potential ligand was examined. To our
delight, a 48% yield of 15a was obtained with a combination of
PPh3 (20 mol %), Pd(OAc)2 (10 mol %), and potassium
persulfate (3 equiv) as an oxidant in 1,4-dioxane at 100 °C for 15
h (entry 3). The exchange of triphenylphosphine for triphenyl-
phosphine oxide was examined to assess the role of the latter as
an in-situ-generated oxidant;20 however, product conversion
was poor (SI). Changing the palladium catalyst (entries 4 and
5), the phosphine ligands bearing electron-donating or electron-
withdrawing substituents (entries 6−9), or the identity or
equivalency of the oxidant (entries 10 and 11 and SI) was less
effective. While toluene and DMF were inferior to the use of 1,4-
dioxane, switching to acetonitrile afforded 15a in 75% yield after
15 h at a lower temperature (80 °C) and with full conversion
based on TLC (entry 14). Monitoring the reactions by TLC
revealed that full conversion to the product occurred after only 3
h, affording isolated 15a with an optimized 90% yield (entry 15).
Notably, the solubility of the persulfate oxidant in acetonitrile
was better than in dioxane or other solvents, likely contributing
to the improved outcome. Performing the reaction on a 10
mmol (1.88 g) scale afforded a 68% yield of 15a after 4 h under
the same conditions.
a
Reaction conditions: 14a−y (0.3 mmol), Pd(OAc)2 (10 mol %),
PPh3 (20 mol %), K2S2O8 (3 equiv), CO balloon (1 atm), CH3CN (1
mL), 80 °C. Each yield is averaged from n ≥ 2 reactions.
b
or those bearing a methyl group at any one of the C3−C6 2-
aminopyridyl ring positions afforded moderate to good yields of
the corresponding pyridopyrimidinone products (15a−e).
While the C6-methyl pyridyl substrate performed well to afford
pyridopyrimidinone 15e (67%), substrates with a C6−F or C6−
OCH3 group were unreactive under these conditions. It is
reasoned that the electron-withdrawing fluorine atom suffi-
ciently attenuates the coordinating ability of the adjacent
pyridine nitrogen such that the reaction is not fruitful. While the
C6−OCH3 substituent has an opposing resonance effect, it
appears that the inductive effect of the ortho-methoxy group
prevails. The importance of the coordinating capability of the
pyridine nitrogen in this reaction is supported by the failure of
reactions using pyrazines in place of the pyridyl group, as the
additional ring nitrogen inductively draws electron density away
from the coordinating nitrogen, which is speculated to be
integral to the key cyclization event. (See the proposed
mechanism in Scheme 6.)
With an optimized protocol in hand, we assessed the
performance of substrates bearing different pyridine ring
substitutions of 2-aminopyridyl-NH-cyclohexenones 14a−r
and 2-aminopyridyl-NH-cycloalkenones 14s−y (Scheme 2).
Reactions were worked up after the starting material was
consumed, as judged by TLC. Unsubstituted pyridyl substrates
Product yields were not generally influenced by varying the
electronic character of the aminopyridyl C5 substituent. For
example, 2-aminopyridyl substrates with C5-methyl (14d), C5-
B
DOI: 10.1021/acs.orglett.8b01275
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Letter
methoxy (14h), C5-phenyl (14j), C5-halides (14m−o), C5-
ester (14f), or a C5-CF3 group (14r) were successfully
converted to the desired products in 51−84% yields.
Comparatively, the C4 position was more sensitive to
substitution, affording the corresponding C8-substituted
products, methyl (15c), methoxy (15g), and phenyl (15k)
derivatives, in yields of 44−68%. Nonetheless, a reasonable
tolerance for C4/C5-disubstitution was observed with the
formation of ring-fused pyridoisoquinolinone 15l (47%).
Substrates bearing C3 substitution were synthetically more
challenging to obtain; however, a few examples were explored.
Pyridopyrimidinones with methyl (15b), benzyloxy (15i), and
fluorine (15p) substituents were obtained in yields of 32−75%,
and a 3,5-difluorinated substrate was also cyclocarbonylated in
good yield (15q, 68%). Augmentation of the unsaturated
carbonyl partner appended to the 2-aminopyridyl directing
group was also investigated. A cyclopentanone-fused pyridopyr-
imidonone (15s) was obtained in 85% yield, while the yield of a
seven-membered ring fused analog (15t) was diminished,
presumably due to increased steric congestion adjacent to the
C−H inactivation site. Several 2-aminopyridyl substrates with
NH-appended C3-substituted cyclohexenones were trans-
formed to the corresponding products (15u−y) in 49−63%
yields.
Scheme 4. Attempted Synthesis of an N-Benzyl Pyridone-
Fused Pyridopyrimidinone
Mechanistic insights were gleaned by synthesizing deuterium-
labeled 3-(pyridin-2-ylamino)cyclohex-2-enone 14a-D5 and
executing experiments with nonisotopically labeled substrate
14a to enable a determination of the kinetic isotope effects
(Scheme 5).24 An intermolecular competition experiment was
Scheme 5. Evaluation of Kinetic Isotope Effects
Given the tolerance of the reaction for a variety of vinylogous
amide substrates, we also examined the productivity of the
reaction using a vinylogous urea (Scheme 3). A reported
Scheme 3. Synthesis of NH-Pyridyl Vinylogous Ureas
carried out in which a 1:1 mixture of nonisotopically labeled 14a
and deuterated 14a-D5 was submitted to the standard reaction
1
conditions. After 15 min, examination by H NMR showed a
1.99:1 ratio of 15a to 15a-D4. Parallel experiments were also
performed in which 14a or 14a-D5 was individually subjected to
the optimized conditions and 1H NMR data were taken at three
time points (5, 10, and 15 min) to calculate a kH/kD value of
1.76. These combined results indicate that the C−H bond
activation step might be the turnover-determining step or C−H
activation might be a reversible step that occurs beforehand.24
A possible mechanism using the conversion of 14a to 15a that
takes into account the observations from this work (Scheme 6)
is shown. As first proposed by Zhu,18 it is reasoned that the basic
procedure was adapted to prepare N-benzyl- or N-4-
fluorobenzylpyrrolidine-2,4-diones 17a,b.21,22 These substrates
were then independently treated with 2-aminopyridine to afford
requisite vinylogous ureas 14z and 14aa. Submission of each to
the optimized conditions smoothly afforded corresponding
pyrrolidinone-fused pyridopyrimidinones 15z and 15aa in 80
and 58% yields, respectively.
While five-membered vinylogous ureas 14z-aa were success-
fully transformed to the desired products, six-membered variants
did not fare as well. To explore this reaction, 1-benzylpiperidine-
2,4-dione 18 was prepared by a four-step protocol23 and
subsequently converted to vinylogous urea 14bb (Scheme 4).
After 30 min of reaction time under the standard conditions
described herein, the starting material was consumed, only trace
Scheme 6. Mechanistic Rationale for Pyridopyrimidinone
Formation
1
amounts of desired product 15bb could be detected by H
NMR, and oxidized vinylogous urea 14bb was isolated in 53%
yield. Interestingly, cyclocarbonylated product 15cc, expected
from 14cc, was not detected, even after prolonging the reaction
for 5 h, and 15bb was not generated in any greater quantity.
Isolation of 14cc from the reaction and resubmission to the
reaction conditions resulted in the isolation of 15cc in 18% yield
after 4 h. Prolonging the reaction time and/or adding additional
catalyst and/or oxidant did not enhance the outcome.
C
DOI: 10.1021/acs.orglett.8b01275
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Organic Letters
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ligand exchange of acetate with CO forms complex A. Insertion
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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/acs.orglett.8b01275.
■
S
Experimental procedures and full analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jennifer.golden@wisc.edu
ORCID
Jennifer E. Golden: 0000-0002-6813-3710
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.E.G. acknowledges institutional support from the Office of the
Vice Chancellor for Research and Graduate Education at the
University of WisconsinMadison with funding from the
Wisconsin Alumni Research Foundation (WARF): UW2020
infrastructure grant (JEG, PI). This work made use of the
instrumentation at the UW−Madison Medicinal Chemistry
Center, funded by the UW School of Pharmacy.
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DOI: 10.1021/acs.orglett.8b01275
Org. Lett. XXXX, XXX, XXX−XXX