An expedient and divergent tandem one-pot synthesis of pyrimidin-2,4-diones using the blaise reaction intermediate

Article abstract of DOI:10.1021/ol401389j

A novel divergent tandem one-pot method for the synthesis of 3,5,6-trisubstituted 1H-pyrimidin-2,4-dione derivatives is developed. In the presence of 10 mol % of Cu(OAc)₂, the α-substituted Blaise reaction intermediates (R² ≠ H) reacted with isocyanates chemoselectively to afford pyrimidin-2,4-diones, whereas the α-unsubstituted Blaise reaction intermediate (R² = H) showed a propensity to be a C-nucleophile toward electrophiles, permitting the installation of different functionalities at the 5-position through sequential tandem reactions.

Full text of DOI:10.1021/ol401389j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Expedient and Divergent Tandem
One-Pot Synthesis of Pyrimidin-2,4-diones
Using the Blaise Reaction Intermediate
Yu Sung Chun, Zi Xuan, Ju Hyun Kim, and Sang-gi Lee*
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Korea
sanggi@ewha.ac.kr
Received May 17, 2013
ABSTRACT
A novel divergent tandem one-pot method for the synthesis of 3,5,6-trisubstituted 1H-pyrimidin-2,4-dione derivatives is developed. In the
presence of 10 mol % of Cu(OAc)2, the R-substituted Blaise reaction intermediates (R2 ¼ H) reacted with isocyanates chemoselectively to afford
pyrimidin-2,4-diones, whereas the R-unsubstituted Blaise reaction intermediate (R2 = H) showed a propensity to be a C-nucleophile toward
electrophiles, permitting the installation of different functionalities at the 5-position through sequential tandem reactions.
Divergent tandem synthesis provides quick access to
structurally diversified compounds from the same com-
mon starting material(s) and is a highly attractive tool
in the discovery of bioactive molecules and functional
materials.1 By virtue of being run in tandem, the value of
these reactions are greatly enhanced not only by the rapid
emergence molecular complexity but also by avoiding
the isolation of intermediates, thereby alleviating waste
generation.2 The success of a divergent tandem reaction
requires precise control of the chemo- and regioselectivity
and a careful selection of the reaction conditions informed
by understanding the reactivity of intermediates and sub-
strates. Therefore, the development of efficient divergent
tandem syntheses of biologically relevant compounds is
highly desirable. In this paper, we report an expedient and
divergent tandemone-pot synthesisof pyrimidin-2,4-dione
derivatives using the Blaise reaction intermediate (Scheme 1).
The pyrimidin-2,4-dione unit is a fundamental scaffold
in biomolecules, natural products, and pharmaceuticals
and represents an excellent template in many drug dis-
covery endeavors.3 Recent advances in transition-metal-
catalyzed cross-couplings of halogenated pyrimidin-
diones with metallic nucleophiles4 or direct CꢀH aryl-
ations of pyrimidindions provided new approaches to
aryl-substituted pyrimidindiones.5 However, all of these
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Chem. Abst. 2001, 135, 152820. (b) Theodoridis, G.; Crawford, S. D. PCT Int.
Appl. US 6277847 B1, 2001; Chem. Abst. 2001, 135, 180781. (c) Kameswaran,
V. PCT Int. Appl. US 6191275 B1, 2001; Chem. Abst. 2001, 134, 178567. (d)
Parker, W. B. Chem. Rev. 2009, 109, 2880. (e) Saladino, R.; Crestini, C.;
Palamara, A. T.; Danti, M. C.; Manetti, F.; Corelli, F.; Garaci, E.; Bitta, M.
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(g) Pan, X.; Wang, C.; Wang, F.; Li, P.; Hu, Z.; Shan, Y.; Zhang, J. Curr.
Med. Chem. 2011, 18, 4538. (h) Rewcastle, G. W. Pyrimidines and their
Benzo Derivatives. In Comprehensive Heterocyclic Chemistry III; Katritzky,
A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford,
2008; Vol. 8, pp 117ꢀ272.
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r
10.1021/ol401389j
XXXX American Chemical Society

intermediate A in tandem schemes,9 it was observed that
the C-/N-chemoselectivity of intermediate A was largely
determined by the R-substituent; i.e., R-unsubstituted
A (R2 = H) generally showed a propensity to be a
C-nucleophile, whereas R-substituted A (R2 ¼ H) acts as
a N-nucelophile.9i,j On the basis of these observations, we
envisioned that a chemoselective tandem coupling reaction
of A with isocyanates could provide a novel one-pot
method for the synthesis of pyrimidin-2,4-diones that does
not require the isolation of β-enaminoesters. When the
addition of R-substituted A (R2 ¼ H) to isocyanates
proceeds chemoselectively at the nitrogen atom, 3,5,6-
trisubstituted pyrimidin-2,4-diones are obtained in a one-
pot manner (path a in Scheme 1). In addition, the C-nu-
cleophilic character of R-unsubstituted A allows us to
design the sequential tandem reaction with an isocyanate
and a carbonylating agent such as triphosgene (path b in
Scheme 1), or with an appropriate electrophile and an
isocyanate (path c in Scheme 1), enhancing the divergency
of accessible pyrimidin-2,4-diones.
We first investigated the effects of R-substituents on the
reactivity and C-/N-chemoselectivity of A toward isocya-
nate electrophiles. The tandem reaction of R-unsubstituted
Aaa (R1 = Ph, R2 = H, R = Et), formedbythe reactionof
benzonitrile (1a) and a Reformatsky reagent generated
in situ from ethyl R-bromoacetate (2a), with 1.1 equiv of
phenyl isocyanate 3a at 40 °C afforded the R-carboamoy-
lated β-enaminoester 5 in 92% yield. This result clearly
indicates that the R-unsubstituted intermediate Aaa has a
propensity to act as a C-nucleophile toward isocyanate
electrophiles. In contrast, the R-methyl substituted inter-
mediate Aab (R1 = Ph, R2 = Me, R = Me), formed with
2b, showed its N-nucleophilic nature, and thus reacted
with 3a to afford the pyrimidin-2,4-dione 4a. However, its
reactivity is not sufficiently high yielding only 58% of 4a
(Scheme 2b). The reaction efficiency was not significantly
improved by either increasing the reaction temperature or
the addition of an equivalent of base such as NaH or
NaHMDS. Under these reaction conditions, the phenyl
methyl carbamate was formed as a major side product,
which implied that methoxyzinc bromide, generated dur-
ing pyrimidindione ring formation, could also react with
phenyl isocyanate, decreasing the yield of product. To
address this problem, we attempted to increase the electro-
philicity of the isocyanate using a Lewis acid. To our
delight, we found that, in the presence of 10 mol %
Cu(OAc)2, the first coupling reaction of Aab with 1.5 equiv
of 3a proceeded very cleanly at room temperature
Scheme 1. Strategy for the Divergent Tandem Synthesis of
Pyrimidin-2,4-diones Using the Blaise Reaction Intermediate
methods are based on a pre-existing pyrimidindione moi-
ety. Hence, the de novo construction of the pyrimidin-2,4-
dione scaffold from a readily available starting material
has continued to draw much interest. Prominent methods
for the synthesis of pyrimidin-2,4-diones include the annu-
lative condensation of β-keto esters with urea derivatives6
or the coupling of R-seleno β-aminoester with isocyanates,
followed by oxidative olefination.7 However, these reac-
tions generally required prolonged reaction times at ele-
vated temperatures. Recently, Fustero and co-workers
reported on the use of β-enaminoesters, which reacted
with isocyanates to synthesize pyrimidin-2,4-diones
through a chemoselective couplingꢀcyclization cascade
reaction.8 Nevertheless, the reported protocols relied on
the prerequisite synthesis of β-enaminoesters by the reac-
tion of a nitrile with lithium ester enolate, formed from
LDA and alkanoates at ꢀ78 °C, and necessitated an excess
of a strong base, NaH, for the coupling of the isolated
β-enaminoesters with isocyanates.
The addition of a Reformatsky reagent to nitriles (Blaise
reaction) is known to proceed via the zinc bromide com-
plex of β-enaminoester intermediate A that combines the
C-/N- ambident nucleophilicity of enamines with electro-
philic β-unsaturated ester moieties (Scheme 1). During
the course of our recent research program on the use of
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B
Org. Lett., Vol. XX, No. XX, XXXX

(full consumption of Aab evidenced by TLC). Subsequent
intramolecular cyclization in THF at reflux afforded the
desired 4a in 82% yield.
Table 1. Tandem One-Pot Synthesis of Pyrimidin-2,4-dionesa
Scheme 2. Intrinsic Reactivity and C-/N-Chemoselectivity of
the Blaise Reaction Intermediates toward Isocyanates
entry
1, R1
2, R2
3, R3
4, yield (%)b
1
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
nPr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
82
75
82
81
79
94
63
52
51
84
66
79
46
67
82
90
89
2
3-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
C6F5
3
4
5
6
7
2-furyl
PhCH2
PhCH2CH2
Ph
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
nBu
4j
Ph
4k
4l
Ph
Ph
4m
4n
4o
4p
4q
With the optimized reaction conditions in hand, we next
explored the scope and limitation of this reaction. We were
pleased to find that R-methyl substituted intermediates A
(R2 = CH3), formed from R-bromopropionate 2b and aryl
nitriles having different substituents on the aryl moiety,
could be reacted with phenyl isocyanate (3a) to afford the
corresponding pyrimidin-2,4-diones 4aꢀ4e in high yields
(entries 1ꢀ5, Table 1). In particular, the intermediate A
derived from pentafluorobenzonitrile afforded pyrimidin-
2,4-dione 4f in an excellent yield of 94% (entry 6, Table 1).
Additionally, the reaction with a heteroaromatic 2-furoni-
trile afforded the corresponding 6-furylated pyrimidin-2,4-
dione 4g in 63% yield (entry 7, Table 1). The alkyl nitrile-
derived intermediates A (R1 = PhCH2CH2 and Bn) were
also reacted with phenyl isocyanate (3a) to give the corre-
sponding pyrimidin-2,4-diones 4h and 4i, albeit with some-
what lower yields (entries 8 and 9, Table 1).
3-Me-C6H4
4-Me-C6H4
Ph
4-Me-C6H4
4-Me-C6H4
Ph
Ph
Ph
a Reaction conditions: nitrile 1 (3.0 mmol), Zn (6.0 mmol), ethyl
R-bromoalkanoate (2, 4.5 mmol) in THF (1.5 mL). A solution of 3
(4.5 mmol) in THF (1.0 mL) and Cu(OAc)2 (0.3 mmol) were added when
nitrile 1 was converted to the intermediate A 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.
Next, we investigated the scope and limitations of this
reaction with various isocyanates, while using the inter-
mediate A derived from benzonitrile (1a) and R-bromo-
propionate 2b. Aryl isocyanates having varied substituents
successfully participated in the reaction to afford the
corresponding products 4jꢀ4l in good yields (entries
10ꢀ12, Table 1). The tandem reaction with an alkyl
isocyanate also proceeded to furnish the 3,5-dialkyl sub-
stituted pyrimidin-2,4-diones 4m, albeit at the expense of a
decreased yield of 46% (entry 13, Table 1). Structural
variation in the Reformatsky reagent was also well toler-
ated, as both intermediates Aac (R1 = Ph, R2 = n-Pr, R =
Me) and Aad (R1 = Ph, R2 = Ph, R = Me) gave the
desired products 4p and 4q in high yields (entries 16 and 17,
Table 1). The structures of all products were unambigously
determined by spectroscopic analyses and further con-
firmed with an X-ray diffraction study for 4c (Figure 1).10
Figure 1. X-ray crystal structure of 4c.
In order to increase the divergency of accessible pro-
ducts, we next turned our attention to the reaction of
the R-unsubstituted intermediate A (R2 = H) showing
a propensity to be a C-nucleophile (paths b and c in
Scheme 1). As anticipated, the sequential tandem reaction
of Aaa (R1 = Ph, R2 = H, R = Et) with phenyl isocyanate
3a, producing a zinc bromide complex of R-carbamoylated
β-enaminoester B as a second intermediate, followed by a
reaction with a carbonylating agent, triphosgene, afforded
the corresponding 5-ester-functionalized pyrimidin-2,4-
dione 4r in 73% yield (Scheme 3). Variation of either
(10) CCDC 938319. For X-ray crystal data, see Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Sequential Tandem Reactions of R-Unsubstituted
Blaise Reaction Intermediates with Isocyanates and Triphosgene
Scheme 4. Sequential Tandem Reactions of R-Unsubstituted
Blaise Reaction Intermediate with Various Electrophiles and
Phenyl Isocyanate
nitrile or isocyanate exerted little influence in this reaction
and allowed the synthesis of pyrimidin-2,4-diones4sꢀ4u in
moderate to good yields in a tandem one-pot manner.
The divergency of products could further be increased
by the sequential reaction of the intermediate B with
another isocyanate in the presence of Cu(OAc)2 catalyst.
Thus the tandem reaction of R-unsubstituted intermediate
Aaa (R1 = Ph, R2 = H, R = Et) first with 1.1 equiv of
phenyl isocyanate, giving intermediate B, and then with
phenyl isocyante in the presence of 10 mol % Cu(OAc)2
gave the pyrimidin-2,4-dione 4v in 67% yield (Scheme 4).
This strategy could also extended by substituting as the
initial electrophile phenyl isocyanate for 1-alkynes9c and
N-bromosuccinimide (NBS). For example, the reaction of
Aaa with phenylacetylene, followed by phenyl isocyanate
3a, in the presence of 10 mol % Cu(OAc)2 afforded the
5-vinyl substituted pyrimidin-2,4-dione 4w in 75% yield.
When N-bromosuccinimide (NBS) was employed as the
electrophile, the 5-bromo-substituted product 4x was iso-
lated in 60% yield.
In summary, we have developed a novel tandem one-pot
divergent method for the synthesis of 3,5,6-trisubstituted
pyrimidin-2,4-ones using the Blaise reaction intermediate.
In the presence of 10 mol % of Cu(OAc)2, the R-substi-
tuted Blaise reaction intermediates (R2 ¼H), which are
formed by the reaction of Reformatsky reagents with
nitriles, reacted with isocyanates chemoselectively to af-
ford pyrimidin-2,4-diones, whereas the R-unsubstituted
Blaise reaction intermediate (R2 = H) showed a propen-
sity to be a C-nucleophile allowing for sequential tandem
reactions that enabled the installation of varied function-
alities such as ester, vinyl, bromide, and amide at the
C5-position. The presented tandem protocol could find
utility in the preparation of a focused chemical library of
pyrimidin-2,4-diones.
Acknowledgment. This work was supported by the
Korea Research Foundation (KRF-2013035117). Y.S.C.
thanks Ewha Womans University for RP-support. We
thank Dr. Y. M. Kim and Prof. J. Bouffard at Ewha
Womans University for X-ray analysis and helpful discus-
sions, respectively. We thank the Korea Basic Science
Institute for HR-MS analysis.
Supporting Information Available. Experimental details
and spectral data of 4aꢀ4x, 5 and copies of their 1H and 13
C
NMR spectra. X-ray data of 4c. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX