Cu(OAc)2-catalyzed tandem Blaise/Pinner-type reaction for one-pot synthesis of pyrimidin-4-ones

Article abstract of DOI:10.1021/ol303153g

A novel tandem Blaise/Pinner-type reaction for the one-pot synthesis of pyrimidin-4-ones is described. The Blaise reaction intermediate, formed by addition of a Reformatsky reagent to a nitrile, reacted with a second nitrile chemoselectively in the presen

Full text of DOI:10.1021/ol303153g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Cu(OAc)2‑Catalyzed Tandem
Blaise/Pinner-Type Reaction for
One-Pot Synthesis of Pyrimidin-4-ones
Yu Sung Chun, Ju Hyun Kim, Suh Young Choi, Young Ok Ko, and Sang-gi Lee*
Department of Chemistry and Nano Science (BK21), Ewha Womans University,
Seoul 120-750, Korea
sanggi@ewha.ac.kr
Received November 15, 2012
ABSTRACT
A novel tandem Blaise/Pinner-type reaction for the one-pot synthesis of pyrimidin-4-ones is described. The Blaise reaction intermediate, formed
by addition of a Reformatsky reagent to a nitrile, reacted with a second nitrile chemoselectively in the presence of a catalytic amount of Cu(OAc)2
to afford pyrimidin-4-ones.
Reactions that run in tandem can deliver substantial
increases in molecular complexity via one-pot opera-
tions without the need for the isolation of intermediates,
minimizing waste generation.1 Herein, we report an un-
preceedented tandem Blaise/Pinner-type reaction for the
one-pot synthesis of 2,5,6-trisubstituted pyrimidin-4-ones
(Scheme 1).
Pyrimidinone is a key scaffold in many natural com-
pounds and pharmaceuticals and represents physiochemi-
cally an excellent drug-like template in many drug dis-
covery studies.2 Although many different methods have
been developed to synthesize pyrimidinones,3 the most
technically feasible synthesis of these heterocyclic com-
pounds still relies on the classical condensation between
β-ketoester and amidines, and both of these compounds
can be synthesized from nitriles via the Blaise4 and Pinner
(1) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
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D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Furstner, A.
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McCann, J. A. B. Chem. Rev. 2006, 106, 506. (c) Parker, W. B. Chem.
Rev. 2009, 109, 2880. (d) Shi, F.; Ding, J.; Zhang, S.; Hao, W.-J.; Cheng,
C.; Tu, S. Bioorg. Med. Chem. Lett. 2011, 21, 1554. (e) Decvadas, B.;
Selness, S.; Xing, L.; Madsen, H. M.; Marrufo, L. D.; Shieh, H.;
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E. G.; Zhang, J.; Devraj, R. V.; Monahan, J. B. Bioorg. Med. Chem. Lett.
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Commun. 2008, 5098. (b) Ko, Y. O.; Chun, Y. S.; Park, C.-L.; Lee, Y.;
Shin, H.; Ahn, S.; Hong, J.; Lee, S.-g. Org. Biomol. Chem. 2009, 7, 1132.
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r
10.1021/ol303153g
XXXX American Chemical Society

reactions,5 respectively. In the course of our ongoing study
on the tandem use of Blaise reaction intermediates,6 we
envisioned that a chemoselective tandem coupling reaction
with a second nitrile could be a novel method for one-pot
synthesis of pyrimidin-4-ones.
InCl3, did not improve the reaction efficiency at all. Under
all of the examined conditions, there was no sign of the
formation of pyrazole, as observed in the work of
Glorius et al.7 Nevertheless, the formation of 6 implied
that the R-unsubstituted Blaise reaction intermediate 3aa
had a propensity to be a C-nucleophile reacting with benzo-
nitrile at the R-carbon first. The second nitrile then reacts at
the β-nitrogen to form the 5-benzoylated pyrimidinone 6.
Scheme 1. Classical Stepwise and Tandem One-Pot
Blaise/Pinner-Type Methods for Pyrimidin-4-ones
Scheme 2. Initial Experiments for Tandem One-Pot
Blaise/Pinner Synthesis of Pyrimidin-4-ones
The Blaise reaction intermediate is a zinc bromide com-
plex of β-enaminoesters that combines the C-/N-divalent
nucleophilicity of an enamine with the electrophilicity
of R,β-unsaturated ester moieties, and we considered it a
potentially fruitful candidate for undergoing tandem CÀC
and/or NÀC bond-forming reactions. Previously, we found
that the R-unsubstituted Blaise reaction intermediate
3aa, formed by reaction of the Reformatsky reagent,
generated in situ from ethyl R-bromoacetate (2a) and zinc,
acts as a C-nucleophile toward 1-alkynes, an isoelectronic
variant of nitrile, to give R-vinylated β-enaminoesters.6c
Moreover, in related work, Glorius and co-workers
recently reported that N-arylated β-enaminoesters could
be oxidatively coupled with nitriles in the presence of a
stoichiometric amount of Cu(OAc)2 to provide pyrazoles.7
Therefore, the success of our tandem approach for the one-
pot synthesis of pyrimidinones could be determined by
the chemoselectivity of the Blaise reaction intermediate
toward nitriles.
In order to investigate the intrinsic reactivity and chemo-
selectivity of the R-unsubstituted Blaise reaction inter-
mediate toward nitriles, the tandem reaction of 3aa with
excess benzonitrile was carried out in THF or 1,4-dioxane
reflux. However, the Blaise reaction intermediate 3aa
was not altered, even after 12 h, and only ethyl 2-amino-
2-phenylacrylate, the Blaise reaction product, was isolated
in 90% yield. These results suggested that the reactivity of
the 3aa toward weak nitrile electrophiles was too low for
application to an efficient reaction process. Moreover, in
the presence of a stoichiometric amount of Cu(OAc)2, the
tandem reaction became quite complex, and 5-benzoylated
2,6-diphenylpyrimidine-4-one 6 could only be isolated in
13% yield (Scheme 2a). Other Lewis acid catalysts, such as
ZnCl2, Zn(OAc)2, Zn(OTf)2, CuCl, CuCl2, In(OTf)3, and
As we expected, the reactivity and chemoselectivity were
dramatically increased with the R-methyl substituted
Blaise reaction intermediate 3ab, which was formed by
reaction of benzonitrile and the Reformatsky reagent
obtainedfrom methylR-bromopropionate2b. The tandem
coupling reaction of 3ab with benzonitrile (2.0 equiv) at
105 °C in 1,4-dioxane for 16 h, in the presence of only 10
mol % of Cu(OAc)2, afforded the 5-methyl-2,6-diphenyl-
pyrimidin-4-one 5a in an 80% yield (Scheme 2b). Later we
found that methanesulfonic acid was also an efficient
catalyst for this tandem coupling reaction. Thus, the
tandem reaction of 3ab with benzonitrile at 90 °C in the
presence of 30 mol % methanesulfonic acid afforded 5a in
a 78% yield after 24 h (entry 2, Table 1). When the same
reaction was carried out in the absence of the catalyst, only
less than 5% of pyrimidin-4-one 5a was formed, and the
dimerized 2-(β-enamino)-1,3-oxazine-6-one 7 could be
isolated in 62% yield as a major product (Scheme 2c).8
The structure of 7 was determined by X-ray analysis (see
Supporting Information).9 These results clearly indicated
that the R-substituted Blaise reaction intermediate acts
as an N-nucleophile.10 However, its reactivity is not suf-
ficiently high to react with a weak nitrile electrophile.
(8) A reported method for 2-(β-enamino)-1,3-oxazine-6-ones is
dimerization of imidoylketenes, prepared by flash vacuum thermolysis
of corresponding pyrrolediones; see: George, L.; Bernhardt, P. V.; Netsch,
K.-P.; Wentrup, C. Org. Biomol. Chem. 2004, 2, 3518.
(9) The CIF deposition number: CCDC 908745.
(10) Kim, J. H.; Shin, H.; Lee, S.-g. J. Org. Chem. 2012, 77, 1560.
(7) Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed. 2010,
49, 7790.
B
Org. Lett., Vol. XX, No. XX, XXXX

To accomplish the chemoselective tandem reaction of the
Blaise reaction intermediate with a nitrile to afford 2,5,
6-trisubstituted pyrimidin-4-ones, activation of the nitrile
using a catalytic amount of Cu(OAc)2 or methanesulfonic
acid is necessary.
Table 1. Tandem One-Pot Blaise/Pinner Synthesis of
Pyrimidin-4-onesa
We next explored the substrate scope of this reaction by
using 10 mol % Cu(OAc)2 (Table 1). The Blaise reaction
intermediates 3, formed by reaction of a Reformatsky
reagent, generated in situ from 2b, with various aromatic
nitriles having electron-donating methyl (1b) and methoxy
(1c) substituents and electron-withdrawing bromide (1d)
and ester (1e) substituents, and benzylnitrile (1f), were
reacted with benzonitrile to afford the corresponding
pyrimidin-4-ones 5aÀ5f in good yields (entries 1À7,
Table 1). The second nitrile 4 could also be varied. Thus,
the Blaise reaction intermediate 3ab reacted with aromatic
nitriles bearing electron-donating methyl (4b) (entry 8,
Table 1) and methoxy groups (4c) (entry 9, Table 1) as
well as a withdrawing ester group 4d (entry 10, Table 1) to
afford the corresponding pyrimidin-4-ones 5gÀ5i in good
yields. The heteroaromatic 2-furylnitrile could also be
employed as a second nitrile to afford the corresponding
2-furyl substitutedpyrimidin-4-one5j in a 68% yield (entry
11, Table 1). A tandem reaction of 3ab with benzyl nitrile
also proceeded successfully to afford 2-benzyl substituted
pyrimidin-4-one 5k in a 77% yield (entry 12, Table 1). 2,6-
Diaryl 5l and difuryl-substituted pyrimidin-4-ones 5m
could also be synthesized efficiently (entries 13 and 14,
Table 1). However, the Blaise reaction intermediates,
prepared from aliphatic nitriles 1iÀ1j, were not effective
under standard conditions. For example, the tandem
reaction of intermediate 3ia, prepared from butyronitrile
1i, with 3-phenylpropionitrile using 10 mol % Cu(OAc)2
was quite messy, and only an 18% yield of pyrimidin-4-one
5n was isolated (entry 15, Table 1). Fortunately, we found
that methanesulfonic acid was effective for this reaction,
and thus, the tandem reaction at 90 °C for 24 h in the
presence of 30 mol % methanesulfonic acid afforded 5n in
a 60% yield (entry 16, Table 1). At a higher reaction tem-
perature (ca. 105 °C), the Blaise reaction intermediate
decomposed. Under the same reaction conditions, steri-
cally bulky 2,6-diisobutyl substituted pyrimidin-4-one 5o
can be synthesized in a 45% yield (entry 17). Varia-
tion of the Reformatsky reagents, generated from ethyl
R-bromophenylacetate 2c and ethyl 2-bromopentanoate
2d, allowed us to introduce different substituent (R2)
groups at the 5-position to afford pyrimidin-4-ones
5pÀ5r (entries 18À20, Table 1).
entry
1, R1
2, R2
Me (b)
4, R3
Ph (a)
5 (%)b
1
Ph (a)
Ph (a)
5a (80)
5a (78)
5b (71)
5c (71)
2c
3
Me (b)
Me (b)
Me (b)
Ph (a)
Ph (a)
Ph (a)
2-MeC6H4 (b)
4-
4
MeOC6H4 (c)
4-BrC6H4 (d)
5
Me (b)
Ph (a)
Ph (a)
Ph (a)
5d (71)
5e (71)
5f (74)
6
4-MeO2CC6H4 (e) Me (b)
7
Bn (f)
Ph (a)
Ph (a)
Ph (a)
Me (b)
Me (b)
Me (b)
Me (b)
8
3-Me-C6H4 (b) 5g (72)
4-MeOC6H4 (c) 5h (60)
9
10
4-
5i (68)
MeO2CC6H4 (d)
2-furyl (e)
Bn (f)
11
12
13
14
15
Ph (a)
Me (b)
Me (b)
Me (b)
Me (b)
Me (b)
Me (b)
Me (b)
Ph (c)
5j (68)
5k (77)
5l (72)
5m (70)
Ph (a)
4-MeC6H4 (g)
2-furyl (h)
nbutyl (i)
4-MeC6H4 (g)
2-furyl (e)
PhCH2CH2 (h) 5n (18)
PhCH2CH2 (h) 5n (60)
Me2CHCH2 (i) 5o (45)
16c nbutyl (i)
17c Me2CHCH2 (j)
18c nbutyl (i)
Ph (a)
5p (67)
5q (60)
5r (54)
19
20
Ph (a)
Ph (a)
nPropyl (d) Ph (a)
Ph (c) Ph (a)
a Reaction conditions: nitrile 1 (3.0 mmol), Zn (6.0 mmol), and
ethyl R-bromoalkanoate (2, 4.5 mmol) in 1,4-dioxane (1.5 mL). 4 and
Cu(OAc)2 (0.3 mmol) were added when nitrile 1 was converted to the
intermediate 3 in >97% by GC, and the reaction was continued until all
of 3 was consumed by TLC and GC. b Isolated yield of average two
runs. c Reaction was carried out at 90 °C in the presence of 30 mol %
methanesulfonic acid instead of Cu(OAc)2.
second nitrile, in the presence of the Cu(OAc)2 catalyst,
provided the 5-vinylated pyrimidin-4-one 5s in a 78%
yield. The structure of 5s was unambiguously determined
by NMR analysis as well as X-ray analysis. Figure 1
shows the X-ray crystal structure of 5s.11 Variation of the
1-alkyne was also possible as exemplified by the synthesis
of 5t in a 75% yield. Under the same reaction conditions,
the sequential tandem reaction of the Blaise reaction inter-
mediate 3ha (formed from furylnitrile 1h) with phenylace-
tylene and benzonitrile afforded pyrimidinone 5u in a 61%
yield.
It was found that the tandem reaction of a Blaise reac-
tion intermediate, derived from an aliphatic nitrile, also
proceeded with phenylacetylene to form intermediate 8,
but the coupling with the second nitrile was less efficient,
even in the presence of 30 mol % methanesulfonic
acid, resulting in 1-alkyl-5-vinylated pyrimidin-4-one 5v
in a 44% yield. Nevertheless, it is noteworthy that in this
In our previous mechanistic study of the tandem reac-
tion of R-unsubstituted Blaise reaction intermediate 3aa
with terminal alkyne,6c we proposed that the zinc bromide
complex 8 could be formed as a second intermediate,
which led us to consider the possibility for a chemoselec-
tive double tandem reaction with 1-alkyne and nitrile
affording 5-vinylated pyrimidin-4-ones (Scheme 3). Thus,
the R-unsubstituted Blaise reaction intermediate 3aa
(R1 = Ph) reacted first with 1.1 equiv of phenylacetylene
in 1,4-dioxane at 80 °C to form the second intermediate 8.
The tandem reaction of 8 with 2.0 equiv of benzonitrile as a
(11) The CIF deposition number: CCDC 908746.
Org. Lett., Vol. XX, No. XX, XXXX
C

The following mechanism can be proposed (Scheme 4).
The weakly electrophilic nitrile could be activated by
the Lewis acidic Cu(OAc)2, allowing the chemoselective
nucleophilic addition of the Blaise reaction intermediate
via its nitrogen atom. The intramolecular cyclization
of A then eliminates EtOZnBr to furnish the pyrimidin-
4-one 5.
Scheme 3. Tandem One-Pot Synthesis of 5-Vinylated
Pyrimidin-4-ones
Scheme 4. Proposed Reaction Mechanism
In summary, we have developed a novel tandem one-
pot method for the synthesis of 2,5,6-trisubstituted
pyrimidin-4-ones from Reformatsky reagents and two
nitriles via the Cu(OAc)2-catalyzed chemoselective cou-
pling of a Blaise reaction intermediate with a nitrile. The
sequential chemoselective tandem reaction of the Blaise
reaction intermediate with terminal alkynes and nitriles
has allowed for the synthesis of 5-vinylated pyrimidin-
4-ones. Considering the ready availability of the starting
materials and the one-pot operation, the presented
tandem protocol could be a useful method for diversity-
oriented synthesis of pyrimidinones.
Acknowledgment. This work was supported by the
Korea Research Foundation (KRF-20120005673). Y.S.C.
thanks Ewha Womans University for RP-support. We
thank the Korea Basic Science Institute for HR-MS
analysis.
Supporting Information Available. Experimental details
and spectral data of 5aÀ5v, 6, and 7 and the copies of their
1H, 13C NMR, and HRMS spectra. X-ray data of 5s and 7.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. X-ray crystal structure of 5s.
tandem procedure, four different CÀC/CÀC/NÀC/NÀC
bonds can be sequentially formed in one pot.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX