Synthesis of (2S)-isopropyl-5-alkynylpyrimidin-2-ones: Precursors of β-aminoacids

Article abstract of DOI:10.1016/j.tetlet.2010.12.087

The efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of (2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-one with, arylethynyl-, heteroarylethynyl-, and alkylethynyltrifluoroborate salts is reported. The standard protocol was evaluat

Full text of DOI:10.1016/j.tetlet.2010.12.087

Tetrahedron Letters 52 (2011) 1014–1019
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (2S)-isopropyl-5-alkynylpyrimidin-2-ones: precursors
of b-aminoacids
Hélio A. Stefani a, , Monica F. Z. J. Amaral a, Eusebio Juaristi b
⇑
a Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil
b Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07000 México, DF, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of (2S)-isopropyl-5-iodo-2,3-
dihydro-4(H)-pyrimidin-4-one with, arylethynyl-, heteroarylethynyl-, and alkylethynyltrifluoroborate
salts is reported. The standard protocol was evaluated and optimized in order to gain access to suitable
precursors of enantiopure 2-substituted b-amino acids. The scope and limitations of this methodology are
discussed.
Received 11 November 2010
Revised 15 December 2010
Accepted 19 December 2010
Available online 24 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki-Miyaura
5-Iodopyrimidinone
Alkynyltrifluoroborates
Cross-coupling reaction
b-Aminoacids
1. Introduction
As part of their efforts to synthesize enantiomerically pure
2-substituted b-amino acids, Juaristi et al. recently reported the
The cross-coupling reaction between organic halides, or related
electrophiles, with organometallic reagents constitutes one of the
most direct methods for the formation of C–C bonds.1 In particular,
the Suzuki-Miyaura and the Sonogashira palladium-catalyzed
cross-coupling reactions of organoboron compounds with organic
halides are remarkably useful tools in organic synthesis. These
reactions have been extensively employed in academic laborato-
ries as well as in pharmaceutical and other fine-chemical indus-
tries to synthesize a large variety of organic molecules.2
convenient preparation of a suitable precursor, (2S)-isopropyl-5-
iodo-2,3-dihydro-(4H)-pyrimidin-4-one, (S)-1, by decarboxylation
of perhydropyrimidinone-6-carboxylic acid with diacetoxyiodo-
benzene (DIB) and iodine in the presence of BF3ꢀEt2O (Scheme 1).5,6
Iodopyrimidinone (S)-1 was successfully employed in Sono-
gashira cross-coupling reactions that afforded the corresponding
acetylenic intermediates, which were hydrogenated and hydro-
lyzed to afford highly enantioenriched
a-substituted b-amino acids
(Scheme 2).6
In this context, organoboron compounds are among the most
widely used organometallic reagents for carbon–carbon bond for-
mation.3 Among the most commonly used organoboron com-
pounds are boronic acids and boronate esters; nevertheless, these
compounds present some drawbacks, including their low stability,
the rather high price of some derivatives, as well as their high sen-
sitivity to air and moisture. To solve these limitations, alternative
organoboron reagents have recently been developed in the form
of potassium organotrifluoroborate salts.4 These reagents have
turned out to be quite stable in the presence of air and moisture,
they usually exist as crystalline solids, are easily prepared from
inexpensive starting materials, and actually exhibit greater
nucleophilicity.4
We report herein an alternative procedure for the synthesis
of (2S)-isopropyl-5-alkynylpyrimidin-2-ones by means of the
Suzuki-Miyaura palladium-catalyzed cross-coupling reaction be-
tween
(2S)-isopropyl-5-iodo-2,3-dihydro-(4H)-pyrimidin-2-one
and potassium alkynyltrifluoroborates,7,8 using palladium acetate
as the catalyst.
2. Results and discussion
The starting material (2S)-isopropyl-5-iodo-2,3-dihydro-(4H)-
pyrimidinone, (S)-1, and alkynyltrifluoroborate salts 2a–r were
prepared using procedures described in the literature.5,8 With the
required reagents in hand, we proceeded to examine the cross-
coupling reaction of iodoenone (S)-1 with phenylethynyl-
trifluoroborate (2a) as model substrates (Table 1).
Of the various palladium catalysts tested, Pd(OAc)2 and PdCl2
proved most satisfactory in terms of the product yield and reaction
⇑
Corresponding author.
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.087

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 1014–1019
1015
H
O
O
O
H
H2N
H2N
N
N
1. DIB / I2
1. KOH, (CH3)2CH-CHO
I
N
N
2. BF3 Et2O
CH2Cl2, rt
2. C6H5COCl, NaHCO3
H2O, 0 oC
CO2H
O
O
CO2H
C6H5
C6H5
(S)-asparagine
(S)-1
Scheme 1. Preparation of enantiopure 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-one (S)-1.
Table 2
O
H
O
H
O
Cross-coupling reaction of 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrim-
idin-4-one, (S)-1, with potassium phenyltrifluoroborate, 2a, to afford the acetylenic
derivative (S)-3a. Screening of the base
N
N
N
HO
Sonogashira
coupling
1. H
R'
2. H3O+
R
O
2
R
O
I
N
H2N
R'
BF3K
H
O
H
O
N
C6H5
ee = 96%
N
N
Pd(OAc)2
C6H5
I
+
N
1,4-Dioxane/H2O
Base, 110 ºC, N2
Scheme 2. Hydrogenation of the unsaturated C–C moieties in the Sonogashira
products followed by acid hydrolysis to afford highly enantioenriched a-substituted
O
O
C6H5
b-amino acids.6
C6H5
(S)-3a
(S)-1
2a
Entry
Basea
Yieldb (%)
Table 1
Cross-coupling reaction of 1-benzoyl-(2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrim-
idin-4-one, (S)-1, with potassium phenyltrifluoroborate, 2a, to afford the acetylenic
derivative (S)-3a. Screening of the catalyst
1
2
3
4
5
6
Et3N
44
45
39
32
53
22
K2CO3
DIPEA
Cs2CO3
(iPr)2NH
NaOH
H
O
BF3K
H
O
N
N
N
Catalyst
I
+
N
1,4-Dioxane/H2O
K2CO3, 110 ºC, N2
a
Two equivalents of base were employed.
Isolated yield.
O
O
b
C6H5
C6H5
(S)-3a
(S)-1
2a
Entry
Catalysta
Yieldb (%)
aqueous mixture of THF/H2O (5:1) led to 12% yield. The highest
yield was achieved in acetonitrile and 1,4-dioxane/H2O (3:1) as
the solvent, affording the cross-coupled product in 53% yield.
Catalyst loading was also studied, indicating that the use of
5 mol % of Pd(OAc)2 was most effective, affording 73% yield of
the desired cross-coupled product in addition to a relatively small
amount (10%) of the homocoupled product. In contrast, when the
catalyst loading was increased to 9 and 15 mol %, reaction yields
dropped considerably (14% and 29%, respectively).
Finally, the potential effect of additives was examined. For this,
several additives including AgOAc and Ag2O were tested. However,
no reaction was observed under these conditions, probably due to
palladium catalyst poisoning by silver, which can oxidize Pd0 to
Pd2. On the other hand, the phosphine additives Ph3P, PCy3, and
S-Phos led to moderate reaction yields (59%, 63%, and 61%,
respectively).
1
2
3
4
5
6
7
8
PdCl2
Pd2(dba)3
30
22
20
45
nr
nr
20
25
PdCl2(dppf)ꢀCH2Cl2
Pd(OAc)2
No catalyst
NiBr(dppe)
PdCl2(3-pyridyl)
Pd(PPh3)4
a
9 mol % catalyst.
Isolated yield.
b
rate. Pd2(dba)3, PdCl2(dppf)ꢀCH2Cl2, and PdCl2(3-pyridyl) were
found to be less efficient. No reaction took place in the absence
of a catalyst or in the presence of NiBr(dppe).
Once Pd(OAc)2 and PdCl2 were identified as the best catalysts,
the influence of the base employed on the cross-coupling reaction
was examined. Inorganic bases, such as potassium carbonate, ce-
sium carbonate, and sodium hydroxide (Table 2, entries 2, 4, and
6, respectively), led to a decrease in the yield of the desired product
and to an increased formation of the homocoupled (diacetylenic)
product in 5–10% yield. The unsatisfactory reaction yield observed
with the use of NaOH as the base was a consequence of dehalogen-
ation of (2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-one,
leading to the corresponding dehalogenated pyrimidinone.
Although the reaction yield remained low in the presence of ter-
tiary amines such as triethylamine (TEA) or diisopropylethylamine
(DIPEA) (Table 2, entries 1 and 3, respectively), with the secondary
amine diisopropylamine as base, the desired product was formed
in 53% yield (Table 2, entry 5).
Thus, it was deemed that the optimum conditions11 for the
cross-coupling reaction of interest involve the use of (2S)-isopro-
pyl-5-iodopyrimidinone [(S)-1, 1.0 equiv), potassium arylethynyl-,
and heteroarylethynyltrifluoro-borate salt 2a–r (1.2 equiv), Pd(OAc)2
(5 mol %), and (iPr)2NH (3.0 equiv) in an acetonitrile solvent at
reflux temperature (Table 3).
It was observed that electron-deficient alkenes give either low
yields (Table 3, substrates 2b, 2f, 2j, 2l, and 2p) or not react to form
the coupled product (Table 3, entries 2d, 2g–i, and 2r) probably
due to the low reactivity of these salts. On the other hand, elec-
tron-rich and electron-neutral alkynes gave moderate to good
yields of the corresponding coupled products.
In order to gain further insight into the reaction of interest,
in situ ReactIR technology9,10 was employed to monitor the conver-
sion of (2S)-isopropyl-5-iodo-2,3-dihydro-(4H)-pyrimidin-2-one,
(S)-1, to the corresponding 5-phenylalkynylpyrimidinone 3a. As
can been seen in Figure 1, following addition of phenyl alkynyltri-
fluoroborate salt to the iodopyrimidinone, a sharp peak appeared
The influence of the reaction solvent was also investigated. No
reaction occurred in methanol, water,
mixture of H2O–tetrabutylammonium hydroxide, using Pd(OAc)2
as the catalyst and diisopropylamine as the base. The use of an
a,a,a-trifluorotoluene, or a

1016
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 1014–1019
Table 3
Pd(OAc)2 catalyzed Suzuki-Miyaura cross-coupling reaction of 1-benzoyl-(2S) isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-one, (S)-1, with potassium akynyltrifluoroborates,
2a–r, to afford the acetylenic derivatives (S)-3a–r
H
O
H
O
N
N
N
Pd(OAc)2
R
I
+
R
BF3K
N
(iPr)2NH, MeCN
N2, 80 ºC
O
O
C6H5
C6H5
2a-r
(S)-3a-r
(S)-1
Entry
ArBF3K (2)a
Reaction time (h)
Product (3)
Yield (%)b
BF3K
O
HN
1
3
73
N
Bz
2a
3a
O
BF3K
HN
HN
2
24
25b
2b
N
Bz
3b
3c
3d
O
BF3K
3
3
65
N
Bz
2c
O
BF3K
HN
4
24
nr
N
Bz
2d
OMe
BF3K
O
5
3
85
HN
HN
MeO
2e
N
Bz
3e
O
BF3K
6
24
15b
N
Bz
2f
3f

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 1014–1019
1017
Table 3 (continued)
Entry
ArBF3K (2)a
Reaction time (h)
Product (3)
Yield (%)b
O
O
HN
O
BF K
3
7
3
nr
N
Bz
2g
3g
O
BF3K
HN
NO2
8
24
nr
N
Bz
NO2
2h
3h
BF3K
O
S
S
HN
HN
9
24
nr
N
Bz
2i
3i
F
O
F
BF K
3
10
11
12
13
3
35
N
Bz
2j
3j
OMe
O
MeO
BF3K
HN
2
3
3
65
N
Bz
2k
3k
F
F
O
F
HN
HN
30
F
BF3K
N
Bz
2l
3l
(CH2)4CH3
O
H3C(H2C)4
BF3K
60
N
Bz
2m
3m
(continued on next page)

1018
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 1014–1019
Table 3 (continued)
Entry
ArBF3K (2)a
Reaction time (h)
Product (3)
Yield (%)b
OMe
O
HN
14
15
16
2
87
MeO
BF3K
N
Bz
2n
2n
O
S
BF K
3
HN
N
Bz
3
78
3o
S
2o
CF3
O
F3C
BF3K
HN
3
15
2p
N
Bz
3p
O
N
BF3K
HN
HN
17
3
92
N
N
Bz
2q
3q
3r
O
SiMe3
Me3Si
BF3K
18
24
nr
N
Bz
2r
a
Isolated yields.
GC-MS yield.
b
at 1151 cmꢁ1. The intensity of this peak gradually decreased and a
new peak appeared at 1008 cmꢁ1. It was deduced that the reaction
presented an induction period of approximately 15 min, associated
with the formation of palladium(0) (1151 cmꢁ1 peak). After this
time, cross-coupling took place quickly, leading to the formation of
the product (1008 cmꢁ1 peak), with up to 95% conversion in 50 min.
The rest of the reaction time was consumed in the conversion of the
remaining 5% (Fig. 1).
3. Conclusion
In summary, we have developed an efficient methodology for
the introduction of arylacetylenes at the C(5) position of pyrimi-
din-4-ones using Suzuki-Miyaura cross-coupling protocols. This
reaction system tolerates various functional groups at the aromatic
rings of aryl alkynyltrifluoroborate salts. Conversion of the acetylenic
Figure 1. Reaction course observed by in situ IR spectroscopy (3D plots).

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 1014–1019
1019
6. (a) Díaz-Sánchez, B. R.; Iglesias-Arteaga, M. A.; Melgar-Fernández, R.; Juaristi, E.
J. Org. Chem. 2007, 72, 4822–4825.
products to enantiomerically pure or enantioenriched
a-alkyl b-
amino acids is possible via a hydrogenation-hydrolysis protocol.6
7. (a) Cella, R.; Cunha, R. L. O. R.; Reis, A. E. S.; Pimenta, D. C.; Klitzke, C. F.; Stefani,
H. A. J. Org. Chem. 2006, 71, 244–250; (b) Vieira, A. S.; Ferreira, F. P.; Fiorante, P.
F.; Guadagnin, R. C.; Stefani, H. A. Tetrahedron 2008, 64, 3306–3314; (c) Vieira,
A. S.; Fiorante, P. F.; Hough, T. L. S.; Ferreira, F. P.; Lüdtke, D. S.; Stefani, H. A. Org.
Lett. 2008, 10, 5215–5218; (d) Vieira, A. S.; Fiorante, P. F.; Zukerman-Schpector,
J.; Alves, D.; Botteselle, G. V.; Stefani, H. A. Tetrahedron 2008, 64, 7234–7241; (e)
Guadagnin, R. C.; Suganuma, C. A.; Singh, F. V.; Vieira, A. S.; Cella, R.; Stefani, H.
A. Tetrahedron Lett. 2008, 49, 4713–4716; (f) Botteselle, G. V.; Hough, T. L. S.;
Venturoso, R. C.; Cella, R.; Vieira, A. S.; Stefani, H. A. Aust. J. Chem. 2008, 61, 870–
873.
Acknowledgments
We gratefully acknowledge financial support from FAPESP (07/
59404-2) and CNPq for fellowships to HAS (300.613/2007-5) and
M.F.Z.J.A. We are grateful to Dr. Wes Walker and Mettler Toledo
for assistance with the ReactIR experiments.
8. Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416–8423.
9. (a) Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 12276–12278.
10. Hong, K. B.; Donahue, M. G.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 2323–
2328.
Supplementary data
11. Representative procedure for the Suzuki-Miyaura cross-coupling reaction of
Supplementary data (experimental procedures, spectral data
and copies of spectra for all compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2010.12.087.
iodenone with alkynyltrifluoroborate salts: To
a solution of potassium
alkynyltrifluoroborate (1.2 mmol), iodopyrimidinone (1.0 mmol), Pd(OAc)2
(5 mmol %, 11.2 mg), (iPr)2NH (2.0 mmol, 202.4 mg, 0.3 mL) and 10 mL of
degassed acetonitrile were added. The reaction was heated to 80 °C and
monitored by TLC and/or GC. Upon completion, the reaction mixture was
cooled to room temperature and was then transferred to an extraction funnel
and extracted with three (3 ꢂ 20 mL) portions of ethyl acetate, and the
combined organic phases were dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude 5-alkynylpyrimidinone was purified by
flash chromatography (hexanes/EtOAc, 1:1) to afford the desired product as a
brown solid (see Table 3).
References and notes
1. (a) Phapale, V. B.; Cárdenas, D. J. Chem. Soc. Rev. 2009, 38, 1598–1607; (b)
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998.
2. Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–2440.
3. (a) Matteson, D. Stereodirected Synthesis with Organoboranes; Springer Verlag:
Berlin, 1995; (b) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London, 1988.
4. (a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49–56; (b) Stefani,
H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623; (c) Molander, G. A.; Ellis,
N. Acc. Chem. Res. 2007, 40, 275; (d) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108,
288.
(S)-1-Benzoyl-2-isopropyl-5-(phenylethynyl)-2,3-dihydropyrimidin-4-(1H)-one
(3a). Isolated yield 78%, brown solid, mp = 248.2–249.5 °C (dec); literature6
mp = 249–251 °C (dec). ½a D25
ꢃ
+659.0 (c 1, CHCl3); literature6 a 2D0
½ ꢃ +652.8 (c 1,
CHCl3). 1H RMN (300 MHz, CDCl3) d (ppm) 7.45–7.59 (m, 7H); 7.27–7.29 (m,
4H); 6.74 (d, J = 3.96 Hz, 1H); 5.66 (t, J = 6.2 Hz, 1H); 2.36–2.43 (m, 1H); 1.08 (d,
J = 6.7 Hz, 3H); 0.99 (d, J = 6.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) d (ppm):
168.2; 162.1; 140.7; 132.4; 131.9; 131.6 (2C); 129.0 (2C); 128.6; 128.4 (2C);
128.2 (2C); 122.7; 101.3; 92.4; 82.1; 69.4; 33.0; 18.3; 17.5. MS: m/z (%): 344 (4,
M+); 239 (5); 274 (5); 207 (5); 105 (100); 77 (50); 71 (37); 43 (61).
5. Iglesias-Arteaga, M. A.; Avila-Ortiz, C. G.; Juaristi, E. Tetrahedron Lett. 2002, 43,
5297–5300.