Three-Component Coupling of Aldehydes, 2-Aminopyridines, and Diazo Esters via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrido[1,2-a]pyrimidin-4-ones

Article abstract of DOI:10.1021/acs.orglett.9b00779

Imines formed in situ from 2-aminopyridines and aldehydes undergo Rh(III)-catalyzed imidoyl C-H activation and coupling with diazo esters to give pyrido[1,2-a]pyrimidin-4-ones. Aromatic and enolizable aliphatic aldehydes were both effective substrates, and a broad range of functional groups were incorporated at different sites on the heterocyclic products. In addition, methoxy and dimethylamino functionalities could be directly installed on the pyrimidine ring by employing trimethyl orthoformate or N,N-dimethylformamide dimethyl acetal in place of the aldehyde, respectively.

Full text of DOI:10.1021/acs.orglett.9b00779

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Three-Component Coupling of Aldehydes, 2‑Aminopyridines, and
Diazo Esters via Rhodium(III)-Catalyzed Imidoyl C−H Activation:
Synthesis of Pyrido[1,2‑a]pyrimidin-4-ones
Gia L. Hoang, Adam J. Zoll, and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: Imines formed in situ from 2-aminopyridines and
aldehydes undergo Rh(III)-catalyzed imidoyl C−H activation and
coupling with diazo esters to give pyrido[1,2-a]pyrimidin-4-ones.
Aromatic and enolizable aliphatic aldehydes were both effective
substrates, and a broad range of functional groups were incorporated
at different sites on the heterocyclic products. In addition, methoxy
and dimethylamino functionalities could be directly installed on the
pyrimidine ring by employing trimethyl orthoformate or N,N-
dimethylformamide dimethyl acetal in place of the aldehyde, respectively.
itrogen heterocycles are found in a large percentage of
this three-component reaction, with amide, ester, ether,
carbamate, halide, secondary anilide, sulfone, and phosphonate
functionalities all successfully incorporated.
N
drugs and clinical candidates.1 To enable efficient
syntheses of a range of different classes of nitrogen hetero-
cycles from readily available inputs, we have focused on
annulations that proceed through imidoyl C−H activation.2 A
central tenet of this approach is the vast number of aldehydes
and amines that theoretically could be used to generate imines
for annulations. We initially implemented this approach for N-
azolo imines 1, which can readily be prepared from amino
azoles and aldehydes (Scheme 1A). Specifically, Rh(III)-
catalyzed annulations of imines 1 with alkynes, diazo ketones,
sulfoxonium ylides, and dioxazolones provide rapid access to a
wide range of N-fused [5,6]-bicyclic heterocycles 2 and 3
(Scheme 1A).3,4 To further enhance reaction efficiency, we
also recently reported a three-component coupling of amino-
pyrazoles 4, aldehydes 5, and sulfoxonium ylides 6 that
proceeds via in situ imine formation and imidoyl C−H
activation to provide privileged pyrazolopyrimidines 7
(Scheme 1B).5
To expand upon the types of nitrogen heterocycles
accessible by imidoyl C−H activation, we have begun to
explore alternative imine coupling partners. Herein, we report
the rapid three-component synthesis of drug relevant [6,6]-
bicyclic heterocycles 10 from imines, formed in situ from 2-
aminopyridines 8 and aldehydes 5, and diazo esters 9 (Scheme
1C).6,7 The use of a commercially available and air stable
Rh(III) precatalyst, convenient benchtop set up, and short
reaction times with microwave (MW) heating further
facilitates the preparation of substituted heterocycles 10. A
broad scope was observed for both aromatic and enolizable
aliphatic aldehydes. Additionally, methoxy and dimethylamino
functionalities can be directly installed on the pyrimidine ring
by employing trimethyl orthoformate or N,N-dimethylforma-
mide dimethyl acetal in place of the aldehyde, respectively.
Finally, good functional group compatibility was observed for
We began our investigation by examining a large variety of
reaction parameters for coupling of 2-aminopyridine (8a),
aldehyde 5a, and diazo ester 9a to give pyridopyrimidinone
10aaa (Table 1). Good yields of 10aaa could be obtained by
straightforward benchtop set up using the commercially
available and air stable cationic catalyst [Cp*Rh(MeCN)3]-
(SbF6)2 with NaOAc, pivalic acid (PivOH), and 3 Å molecular
sieves as additives in hexafluoroisopropanol (HFIP) (0.2 M)
under microwave (MW) conditions at 140 °C for 1 h (entry 1,
Table 1). Switching the stoichiometry to limiting amounts of
aldehyde and 2 equiv of the aminopyridine led to a lower yield
(entry 2). When the noncationic rhodium precatalyst
[Cp*RhCl2]2 was used, only a slight reduction in yield was
observed (entry 3). As expected, when a Rh(III) catalyst was
not added, no product was obtained (entry 4). We observed
22% of competitive esterification of PivOH with diazo ester 9a,
which was used in excess (1.5 equiv). The stoichiometry of the
PivOH additive was therefore reduced to 1 equiv (entry 5) and
0.5 equiv (entry 6), which resulted in a reduction in the ester
byproduct to 13% and 6%, respectively. However, the yield of
the desired product 10aaa also decreased slightly. Moreover,
removing PivOH led to a significant drop in the yield of 10aaa
(entry 7). Acetic acid was less effective than PivOH (entry 8),
and the removal of NaOAc resulted in a moderately lower
yield (entry 9).
Complete consumption of the limiting aminopyridine 8a
was observed at 140 °C, but this does not establish whether or
not complete conversion of stable intermediates to 10aaa had
occurred (see Scheme 8 for proposed mechanism). The
Received: March 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Heterocycle Synthesis by Imidoyl C−H
Activation
Table 1. Reaction Parameters for Annulation to 10aaa
b
entry
variation
yield %
c
1
2
3
4
none
73 (74)
55
65
0
0.1 mmol 5a + 2 equiv 8a + 1.5 equiv 9a
[Cp*RhCl2]2 (5%)
no Rh
5
6
7
8
PivOH (1 equiv)
PivOH (0.5 equiv)
no PivOH
AcOH instead of PivOH
no NaOAc
150 °C
TFE as solvent
EtOH as solvent
dioxane as solvent
0.4 M
71
68
48
57
60
73
70
10
4
61
74
72
65
68
9
10
11
12
13
14
15
16
17
18
19
20
21
0.1 M
[Cp*Rh(MeCN)3](SbF6)2 (5%)
[Cp*Rh(MeCN)3](SbF6)2 (2%), 150 °C
no sieves
conventional heating, 100 °C, 20 h
[Cp*Co(MeCN)3](SbF6)2 (10%)
[Cp*IrCl2]2 (5%) and AgSbF6 (20%)
c
70 (72%)
0
72
reaction was therefore performed at a higher temperature;
however, an identical yield was obtained indicating that more
forcing conditions are not necessary (entry 10). An acidic
protic solvent was crucial for this transformation as
trifluoroethanol (TFE) was found to be equally effective as
HFIP (entry 11), but ethanol and dioxane only resulted in
formation of small amounts of the desired product (entries 12
and 13). Concentration has the potential to be an important
parameter for three-component coupling, but increasing the
concentration to 0.4 M led to only a slight reduction in yield
(entry 14), while lowering the concentration to 0.1 M had no
effect (entry 15). Consistent with our goal to provide access to
diverse pyridopyrimidinones 10 at short reaction times, we
chose 10 mol % catalyst loading for evaluating the substrate
scope. However, 5 and 2.5 mol % catalyst loading did afford
good yields of product (entries 16 and 17). Lower catalyst
loadings are therefore likely to be applicable to many starting
material combinations (see Scheme 6). It is also worth noting
that acceptable reaction yields were obtained without
molecular sieves (entry 18), and conventional heating at 100
°C for 20 h gave a comparable isolated yield to that observed
under microwave conditions (entry 19). Finally, we found that
Cp*Co(III) was not an effective catalyst (entry 20), whereas
Cp*Ir(III) was comparable to Cp*Rh(III) (entry 21).
a
Conditions: 8a (0.10 mmol), 5a (0.20 mmol), 9a (0.15 mmol).
b
Yields determined by 1H NMR integration relative to 1,3,5-
c
trimethoxybenzene as external standard. Isolated yield at 0.30
mmol scale of limiting reagent 8a.
ester (10haa) functionalities by employing the correspondingly
functionalized linear aldehydes was also demonstrated.
Methoxy (10iaa) or dimethylamino (10jaa) functionalities
were also installed directly onto the pyrimidine ring by
employing trimethyl orthoformate and N,N-dimethylforma-
mide dimethyl acetal in place of the aldehyde, respectively.
Under the standard conditions, only a trace amount of 10kaa
was obtained from sterically hindered pivaldehyde.
We next evaluated the scope of aromatic aldehydes (Scheme
3). Benzaldehyde is a good coupling partner, giving bicyclic
product 10laa in high yield. Para-substituted electron-rich and
deficient benzaldehydes provided good yields of products
10maa and 10naa, respectively, establishing that the reaction is
effective regardless of the electronic properties of the aldehyde
input. Benzaldehydes substituted at the meta- and ortho-
positions were also effective coupling partners as exemplified
by the halo substituted products 10oaa and 10paa,
respectively, although a lower yield was observed for the
ortho-substituted derivative. An acidic secondary anilide could
also be incorporated under standard conditions to give 10qaa.
The five-membered pyrazole-, furan-, and thiophene carbox-
aldehydes also provided 10raa to 10taa in good yields (63−
77%).
Using the optimal reaction conditions (i.e., entry 1, Table
1), we first explored the scope of aliphatic aldehydes for three-
component coupling with 2-aminopyridine (8a) and diazo
ester 9a (Scheme 2). A series of cyclic, α-branched
carboxaldehydes gave 10aaa to 10daa in good yields (64−
74%). Acetaldehyde and a β-branched aldehyde were also
effective coupling partners affording 10eaa (47%) and 10faa
(67%), respectively. The incorporation of ether (10gaa) and
The influence of the substitution pattern of the employed 2-
aminopyridines is provided in Scheme 4. A series of methyl-
B
DOI: 10.1021/acs.orglett.9b00779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Aliphatic Aldehydes
Scheme 3. Scope of Aromatic Aldehydes
a
Standard conditions: (a) 8a (0.30 mmol), 5 (0.60 mmol), and 9a
(0.45 mmol); (b) 10 equiv (3.0 mmol) trimethyl orthoformate was
used in place of 5, no molecular sieves; (c) 1.1 equiv (0.33 mmol)
N,N-dimethylformamide dimethyl acetal in place of 5. Isolated yields
are reported.
a
Standard conditions: 8a (0.30 mmol), 5 (0.60 mmol), and 9a (0.45
mmol). Isolated yields are reported.
amination with aniline and morpholine also proceeded in very
high yields to give the secondary aniline 12 and tertiary amine
13, respectively.10 Saponification of the ester in 10aid also
provided 14, with the carboxylic acid functionality amenable to
further synthetic elaboration.
substituted 2-aminopyridines at the 3-, 4-, and 5-positions were
effective coupling partners affording 10aba to 10ada in good to
excellent yields (73−94%). However, 6-methyl-2-aminopyr-
idine was not effective; only trace amount of bicyclic product
10aea was observed. Methoxy (10afa), bromo (10aga), and
fluoro (10aha) substituents were also incorporated using the
correspondingly substituted aminopyridines 8.
Finally, the scope of diazo esters was examined (Scheme 5).
In addition to employing the benzylamide diazo ester 9a,
which provided products with an unbranched N-benzyl amide
substituent, N-α-branched secondary amides can also be
obtained in good yield as exemplified by the isopropyl amide
product 10aab. Tertiary amides could also be prepared in
reasonable yield as demonstrated by 10aac. Symmetrical diazo
malonates were also effective partners and provided the
corresponding ester-containing bicyclic products 10aad (76%)
and 10aae (62%). Moreover, the reaction is not limited to
carboxylic acid derivatives, as exemplified by the preparation of
phosphonate 10aaf and sulfone 10aag.
A plausible mechanism for this three-component coupling
reaction is depicted in Scheme 8. We propose that imine A,
formed in situ from 2-aminopyridine 8 and aldehyde 5,
undergoes concerted metalation-deprotonation to give rhoda-
cycle B. Evidence for rhodacycle B is suggested by a previous
report of Rh(III)-catalyzed C−H oxidation of imine A in the
presence of Cu(OAc)2.11,12 Moreover, we have reported the X-
ray structural characterization of an analogous neutral
rhodacycle derived from [Cp*RhCl2]2 and N-2-imidazo
benzaldimine and further showed that it is catalytically
competent for other types of annulation reactions.3 Carbene
insertion of diazo ester 9 with release of N2 then provides the
six-membered rhodacycle C.8 Protonolysis affords ester D and
regenerates the Rh(III) catalyst. Under the reaction conditions,
lactamization of D then provides the N-fused [6,6]-bicyclic
heterocycle product 10.13
To demonstrate the scalability of this method, a 2 mmol
scale reaction was carried out for the preparation of 10aid at a
lower catalyst loading of 5 mol % (Scheme 6). Pyridopyr-
imidinone 10aid was then employed for further trans-
formations (Scheme 7). The chlorine substituent provides a
versatile site for diversification. For example, Suzuki cross-
coupling provided 11 in 95%,9 while Buchwald−Hartwig
In conclusion, imines formed in situ from 2-aminopyridines
and aldehydes undergo Rh(III)-catalyzed imidoyl C−H
activation and coupling with diazo esters to give pyrido[1,2-
a]pyrimidin-4-ones. Both aromatic and enolizable aliphatic
aldehydes are effective substrates. Methoxy and dimethylamino
functionalities could also be directly installed on the
C
DOI: 10.1021/acs.orglett.9b00779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Influence of the Substitution Pattern of the
Employed 2-Aminopyridines
Scheme 6. A 2 mmol Scale Reaction at 5 mol % Catalyst
a
Scheme 7. Product Diversification
a
Standard conditions: 8 (0.30 mmol), 5a (0.60 mmol), and 9a (0.45
mmol). Isolated yields are reported.
a
Scheme 5. Scope of Diazo Esters
Scheme 8. Proposed Catalytic Cycle for Annulation
a
Standard conditions: (a) 8a (0.30 mmol), 5a (0.60 mmol), and 9
aldehyde, respectively, and a broad range of functional groups
are compatible with the reaction conditions. The synthesis of
additional classes of nitrogen heterocycles by annulations
proceeding via imidoyl C−H activation of different types of
imines will be reported in due course.
(0.45 mmol); (b) 3 equiv of diazophosphonate 9f (0.90 mmol) were
used. Isolated yields are reported.
pyrimidine ring by employing trimethyl orthoformate and
N,N-dimethylformamide dimethyl acetal in place of the
D
DOI: 10.1021/acs.orglett.9b00779
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
presence of 2 equiv of Cu(OAc)2 by Rh(III)-catalyzed C−H
oxidation of in situ formed imine to the corresponding amide
followed by further aromatic C−H functionalization: Zhang, Y.; Zhu,
H.; Huang, Y.; Hu, Q.; He, Y.; Wen, Y.; Zhu, G. Org. Lett. 2019, 21,
1273.
(13) Heterocycle synthesis by a related lactamization following
Co(III)-catalyzed directed coupling of aryl and alkenyl C−H bonds
with diazo esters: Zhao, D.; Kim, J. H.; Stegemann, L.; Strassert, C.
A.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 4508.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00779.
■
S
Procedure details and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
ORCID
Gia L. Hoang: 0000-0003-2332-1854
Jonathan A. Ellman: 0000-0001-9320-5512
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The NIH (R35GM122473) is gratefully acknowledged for
supporting this work.
■
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DOI: 10.1021/acs.orglett.9b00779
Org. Lett. XXXX, XXX, XXX−XXX