Synthesis and Suzuki-Miyaura reactions of 5-halo-3,4-dihydropyrimidin-2(1H) -ones

Article abstract of DOI:10.1016/j.tetlet.2010.07.093

A novel synthesis of 6-methyl-4-phenyl-5-substituted-3,4-dihydropyrimidin- 2(1H)-ones from 6-methyl-4-phenyl-5-halo-3,4-dihydropyrimidin-2(1H)-ones via the Suzuki-Miyaura reaction is reported. These previously unknown heterocyclic halides are easily prepared using the Biginelli multicomponent reaction followed by halodecarboxylation. The effect of varied substitution at the C-4 position on the cross-coupling reaction is also examined.

Full text of DOI:10.1016/j.tetlet.2010.07.093

Tetrahedron Letters 51 (2010) 5103–5105
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Tetrahedron Letters
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Synthesis and Suzuki–Miyaura reactions of
5-halo-3,4-dihydropyrimidin-2(1H)-ones
*
Andrew J. Zych , Hong-Jun Wang, Samuel A. Sakwa
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthesis of 6-methyl-4-phenyl-5-substituted-3,4-dihydropyrimidin-2(1H)-ones from 6-methyl-
4-phenyl-5-halo-3,4-dihydropyrimidin-2(1H)-ones via the Suzuki–Miyaura reaction is reported. These
previously unknown heterocyclic halides are easily prepared using the Biginelli multicomponent reaction
followed by halodecarboxylation. The effect of varied substitution at the C-4 position on the cross-cou-
pling reaction is also examined.
Received 22 July 2009
Revised 15 July 2010
Accepted 16 July 2010
Available online 23 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) exhibit a spectrum
of interesting pharmacological properties.1 The synthesis of these
privileged structures has therefore received considerable attention.
Many improved variations of the original Biginelli multicomponent
reaction have been developed in recent years.2–4 A number of
methods for facile elaboration of DHPM scaffolds have also been
recently reported.5–8
Previous investigations have demonstrated that some 5-carbox-
ylic acid DHPMs readily decarboxylate at reflux in aqueous meth-
anolic sodium hydroxide.10 It was therefore speculated that the
application of Hunsdiecker-type chemistry could generate the de-
sired synthetically useful and previously unknown 5-halo DHPMs
(Fig. 2).
The Biginelli multicomponent condensation is quite general in
that a wide variety of aldehydes, ureas, and thioureas can partici-
pate. A variety of active methylene compounds can also be utilized
enabling diversity at the C-5 and C-6 positions (Fig. 1).9 However,
the availability of active methylene substrates and their potentially
variable ability to take part in the multicomponent condensation
might limit the application of this approach. Considering this, it
was envisioned that the synthesis of a halogenated intermediate
could facilitate the generation of C-5-substituted analogs via
cross-coupling reactions (Fig. 2). Significantly, this would allow ac-
cess to C-5 substitutions which might not be directly obtainable
from the Biginelli condensation.
Halodecarboxylation
Cross-Coupling
R1
O
R1
R1
R2
X
HN
OH
CH3
HN
HN
N
H
N
H
N
H
O
O
CH3
CH3
O
R1 = Ar, Bn, Alkyl
X = Br, I
R2 = Ar, HetAr, alkene
Figure 2. General scheme for synthesis and application of C-5 halogenated DHPMs.
Ph
O
Ph
O
O
H
NH2
OBn
HN
OBn
CH3
R
1 = CO2R, CO R, Ar, SO2R, PO(OR)2
R2 = Ar, Alkyl
3 = Ar, Alkyl
+
CeCl3·7H2O
O
NH2
O
CH3
EtOH, reflux
O
N
H
R3
+
R
R3
1 (70%)
Ph
O
H
R1
R2
R1
R2
Ph
O
4
NH2
3
HN
5
Na2CO3, NaX
Oxone®
Catalyst
X
AlCl3
CH2Cl2
2
6
HN
OH
CH3
HN
1
N
H
O
NH2
O
O
O
N
H
O
N
CH3
MeOH/H2O, rt
0 °C to rt
H
Figure 1. The Biginelli reaction
2 (94%)
3a (84%, X=Br)
3b (89%, X=I)
* Corresponding author. Tel.: +1 518 512 2000; fax: +1 518 512 2020.
E-mail address: andrew.zych@amriglobal.com (A.J. Zych).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.093

5104
A. J. Zych et al. / Tetrahedron Letters 51 (2010) 5103–5105
A 5-carboxylic acid DHPM 2 was synthesized in two steps
at 60 °C could also be used for debenzylation of 1. However, alumi-
num trichloride provided superior yields and greater operational
simplicity upon scale-up.13 Treatment of 2 with OxoneÒ and a so-
dium halide in basic aqueous methanol followed by filtration gave
good yields of bromide 3a or iodide 3b.14 Other decarboxylative
halogenation conditions including NBS with a variety of bases,
pyridinium bromide perbromide, and tetrabutylammonium bro-
mide/Dess–Martin reagent gave inferior results.15–17 Attempts to
synthesize 5-halo DHPMs directly from a multicomponent conden-
sation of benzaldehyde, urea, and haloacetones gave only traces of
the desired products.
(Scheme 1). The benzyl ester 1 was generated utilizing a cerium(III)
chloride-catalyzed protocol that provided a yield comparable to re-
cent literature examples.11 An analogous methyl ester was origi-
nally synthesized but was difficult to hydrolyze to the carboxylic
acid despite a report to the contrary.10 The resistance of 5-carbox-
ylic acid esters of DHPMs to hydrolysis has been noted in some
instances.12 Deprotection of 1 to the carboxylic acid 2 was
accomplished in an excellent yield using aluminum trichloride.
Hydrogenation with palladium on carbon in ethanol at room
temperature or treatment with iodotrimethylsilane in chloroform
The first cross-coupling method tested on the 5-halo DHPMs 3
was the Suzuki–Miyaura reaction, which was chosen for its
well-developed protocols and for the vast number of boronic acids
and esters available for building structurally diverse analogs
(Table 1). Several Suzuki coupling protocols (A–D) were screened
for this preliminary investigation and the best of these unoptim-
ized results are summarized in Table 1.
In general, aryl boronic acids are coupled adequately with
DHPMs (3a–b) in either anhydrous or aqueous conditions.18 How-
ever, sterically hindered or electron-deficient aryl boronic acids
gave generally inferior results (Table 1, entries 12–16) and in some
cases failed to yield any significant amount of products (Table 1,
entries 7 and 8).
Conditions A and B (alkyl phosphine ligand in anhydrous tetra-
hydrofuran with potassium fluoride base, rt and 60 °C, respec-
tively) gave good to excellent yields with electron-rich and
electron-neutral aryl boronic acid substrates without steric hinder-
ance (Table 1, entries 1, 2, 5, 6, 9–11). Condition C (dppf ligand in
1,4-dioxane with aqueous sodium carbonate) gave inferior results
for phenyl boronic acid (Table 1, entry 3), but gave an improved re-
sult for the electron-deficient 4-fluorophenyl boronic acid (Table 1,
entries 14 and 15 versus 12 and 13). Condition D (N-heterocyclic
carbene ligand in 1,4-dioxane with sodium tert-butoxide base)
failed to give any detectable products (Table 1, entry 4).
Table 1
Suzuki–Miyaura reactions of 5-halo-DHPMs
Ph
Ph
X
R
R-B(OH)2
HN
HN
conditions A-D
O
N
H
CH3
O
N
H
CH3
3a (X = Br)
3b (X = I)
4 (0-92%)
Entry R-B(OH)2
Halide, coupling
protocol
Isolated yield
(%), 4
1
3a, A
92
B(OH)2
2
3
4
3b, A
3b, C
3b, D
90
67
n.d.a
5
3a, A
72
90
H3C
H3C
B(OH)2
B(OH)2
6
3a, A
B(OH)2
CH3
7
3a, A
>10b
Pyridyl and vinyl boronic acids could also be coupled in moder-
ate yields (Table 1, entries 17 and 18). The two different DHPM ha-
lides, iodide 3b and bromide 3a, gave results comparable to one
another (Table 1, entries 1 and 2, 14 and 15).
Encouraged by these results, DHPM iodides 8a–d with varied
substituents at the C-4 position (substituted aryl, benzyl, and alkyl)
were synthesized (Scheme 2). The effect of scaffold modification on
the cross-coupling reaction was then examined (Table 2).
8
9
3a, B
3a, A
>10b
86
H3CO
H3CO
B(OH)2
B(OH)2
10
3a, A
78
11
12
3a, A
3a, A
91
B(OH)2
B(OH)2
R
>5b
F
O
R
O
>5b
58
53
O
H
13
14
15
3a, B
3a, C
3b, C
NH2 5a-d
OBn
CH3
CeCl3·7H2O
HN
OBn
CH3
+
O
NH2
O
EtOH, reflux
O
N
H
B(OH)2
16
3a, C
27
5a (R = 4-Cl-Ph)
6a (71%)
6b (83%)
6c (27%)
6d (83%)
5b (R = 4-OMe-Ph)
5c (R = Bn)
Cl
N
5d (R = cHex)
B(OH)2
OCH3
R
O
R
17
18
3a, C
3a, C
45
40
Na2CO3, NaI
I
AlCl3
HN
Oxone ®
OH
CH3
HN
CH2Cl2
O
N
H
O
N
H
CH3
MeOH/H2O, rt
0 °C to rt
B(OH)2
7a (84%)
7b (78%)*
7c (50%)
7d (7%)7
8a (81%)
8b (88%)
8c (74%)*
8d (92%)
Reaction conditions: (A) 2.0 equiv RB(OH)2, 5.0 equiv KF, 0.05 equiv Pd2(dba)3,
0.05 equiv Pd(tBu3P)2, tetrahydrofuran, rt, 18 h; (B) same as (A), reaction conducted
at 60 °C, 18 h; (C) 2.2 equiv RB(OH)2, 0.05 equiv PdCl2(dppf), 4.0 equiv aq Na2CO3,
1,4-dioxane, 70 °C, 18 h; (D) 1.2 equiv RB(OH)2, 1.5 equiv NaOtBu, 0.05 equiv PEP-
PSI-iPr, 1,4-dioxane 80 °C, 18 h.
*Pd/C, 1 atm H2
DMF, rt
*NIS, NaHCO3
DMF, rt
a
Not detected by LC–MS.
Yield estimated by LC–MS.
b
Scheme 2.

A. J. Zych et al. / Tetrahedron Letters 51 (2010) 5103–5105
5105
Table 2
11822; (c) Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett. 2003, 44, 857;
Representative procedure for the synthesis of 1: benzaldehyde (10.2 mL,
0.10 mol), benzyl acetoacetate (17.9 mL, 0.10 mol), urea (10.82 g, 0.18 mol),
and cerium trichloride heptahydrate (7.45 g, 0.02 mol) were combined in
ethanol (50 mL) and heated at reflux for 1.5 h. The mixture was allowed to cool
for several hours and the resulting precipitate was filtered, washed with water
and ethanol, and dried under high vacuum to furnish 1 (22.5 g, 70% yield) as a
white solid. 1H NMR (300 MHz, DMSO-d6) d 9.26 (s, 1H), 7.79 (s, 1H), 7.40–7.10
(m, 10H), 5.19–5.03 (m, 3H), 2.30 (s, 3H).
Suzuki–Miyaura reactions of 5-iodo-DHPMs with varied substitution at C-4
R
R
I
Ph
Ph-B(OH)2
Condition C
HN
HN
O
N
H
CH3
O
N
H
CH3
12. Kappe, C. O. Tetrahedron 1993, 32, 6938.
8a-d
9a-d
13. Reference for the palladium catalyzed deprotection of 1: Desai, B.; Dallinger,
D.; Oliver Kappe, C. O. Tetrahedron 2006 62, 4651. Representative procedure for
the synthesis of 2: aluminum trichloride (11.11 g, 83.54 mmol) was added to a
Entry
R
Halide
Isolated yield (%), 9
1
2
3
4
4-Cl-Ph
4-OMe-Ph
Bn
8a
8b
8c
8d
68
81
46
49
stirred, ice-cooled mixture of benzyl ester
1 (13.45 g, 41.77 mmol) in
methylene chloride (400 mL) under a dry nitrogen atmosphere. The reaction
was removed from the ice-bath after 1 h and allowed to warm to rt. After 3 h
the mixture was again cooled by ice-bath, 1 N aqueous hydrochloric acid
(150 mL) was added, followed by diethyl ether (100 mL), and the mixture was
stirred for 10 min. The mixture was filtered, rinsed with additional 1 N aqueous
HCl (300 mL), diethyl ether (300 mL), and dried under high vacuum. The crude
product was dissolved in 2 N aqueous sodium hydroxide (175 mL), filtered,
cooled in an ice-bath, and the pH was adjusted to 5 with concd hydrochloric
acid. Filtration of the resultant precipitate, followed by a water wash and
drying under high vacuum gave 2 (9.10 g, 94% yield) as a white solid. 1H NMR
(300 MHz, DMSO-d6) d 11.92 (s, 1H), 9.07 (s, 1H), 7.68 (s, 1H), 7.40–7.20 (m,
5H), 5.12 (s, 1H), 2.27 (s, 3H).
cHex
Condition C: 2.2 equiv RB(OH)2, 0.05 equiv PdCl2(dppf), 4.0 equiv aq. Na2CO3, 1,4-
dioxane, 70 °C, 8–18 h.
The new DHPM halides 8a–d were coupled with phenyl boronic
acid using protocol C from Table 1. Both iodide 8a with an electron-
withdrawing substituent and iodide 8b with an electron-donating
substituent gave results similar to the unsubstituted phenyl scaf-
fold (Table 2, entries 1 and 2, compared to 67% yield for 3b). The
benzyl- and alkyl-substituted compounds 8c–d also coupled suc-
cessfully but with diminished yields compared to the C-4 aryl com-
pounds (Table 2, entries 3 and 4). These examples demonstrate
that the Suzuki–Miyaura reaction can tolerate a fair range of vari-
ability at the C-4 position.
In conclusion, a novel synthesis of 5-substituted DHPMs 4, 9 via
the Suzuki–Miyaura reaction with 5-halo DHPMs 3, and 8 has been
developed. This initial investigation demonstrates the utility of this
approach for installing diversity at the C-5 position of the DHPM
scaffold. Further development of this Suzuki reaction for a wider
range of substrates, including organotrifluoroborates, is ongoing.
The application of 5-halo DHPMs to additional cross-coupling reac-
tions, such as the Heck, Stille, Sonogashira, and Buchwald/Hartwig
reactions, is also under active examination.
14. (a) Lee, K. J.; Lim, K. W.; Chi, D. Y. Bull. Korean Chem. Soc. 2001, 22, 549; (b)
Representative procedure for the synthesis of 3b: Carboxylic acid 2 (232 mg,
1.0 mmol), sodium iodide (750 mg, 5.0 mmol), and sodium carbonate (106 mg,
1.0 mmol) were combined in a mixture of water (8 mL) and methanol (8 mL).
Stirring and sonication gave a clear, colorless solution to which was added
OxoneÒ (431 mg, 0.7 mmol). The now bright orange solution was protected
from light and stirred at room temperature for 20 min. Filtration of the
resultant solid, followed by a water wash, and drying under high vacuum gave
3b (195 mg, 89% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d 6) d
8.76 (s, 1H), 7.44–7.20 (m, 6H), 4.93 (s, 1H), 1.95 (s, 3H); ESI-MS m/z 315
[M+H]+. Synthesis of 3a: same as the above procedure with sodium bromide in
place of sodium iodide. Note: some bromination of 6-methyl position was
observed when greater equivalents of OxoneÒ were used.; Reference for
bromination of DMPM 6-methyl position: (c) Khanetskyy, B.; Dallinger, D.;
Oliver Kappe, C. O. J. Comb. Chem. 2004, 6, 884.
15. Beswick, P.; Bingham, S.; Bountra, C.; Brown, T.; Browning, K.; Campbell, I.;
Chessell, I.; Clayton, N.; Collins, S.; Corfield, J.; Guntrip, S.; Haslam, C.; Lambeth,
P.; Lucas, F.; Mathews, N.; Murkit, G.; Naylor, A.; Pegg, N.; Pickup, E.; Player, H.;
Price, H.; Stevens, A.; Stratton, S.; Wiseman, J. Bioorg. Med. Chem. Lett. 2004, 14,
5445.
16. Kato, T.; Tejima, M.; Ebiike, H.; Achiwa, K. Chem. Pharm. Bull. 1996, 44, 1132.
17. Telvekar, V. N.; Arote, N. D.; Herlekar, O. P. Synlett 2005, 16, 2495.
18. Representative procedures for the Suzuki–Miyaura coupling (Table 1, entry 9,
Method A): Bromide 3a (106 mg, 0.40 mmol), 4-methoxyphenyl boronic acid
(122 mg, 0.80 mmol), bis(tri-t-butylphosphine)palladium (10 mg, 0.02 mmol),
tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), potassium fluoride
(116 mg, 2.0 mmol), and tetrahydrofuran (2 mL) were combined in a sealed
vial. The mixture was purged with nitrogen for several minutes and stirred for
15 h at room temperature. The reaction was concentrated under reduced
pressure and purified by flash chromatography (silica gel, 100% ethyl acetate)
to yield the aryl product 4 as a white solid (101 mg, 86% yield). 1H NMR
(300 MHz, CDCl3) d 7.20–7.11 (m, 5H), 6.85 (d, 2H, J = 6.6 Hz), 6.76 (d, 2H,
J = 6.8 Hz), 6.32 (s, 1H), 5.22 (s, 1H), 5.12 (s, 1H), 3.76 (s, 3H), 1.76 (s, 3H); ESI-
MS m/z 295 [M+H]+ (Table 1, entry 15, Method C): Iodide 3b (63 mg,
0.20 mmol), 4-fluorophenyl boronic acid (62 mg, 0.44 mmol), 1,10-
bis(diphenylphosphino)ferrocene-palladium dichloride (7 mg, 0.01 mmol),
Acknowledgments
The authors wish to acknowledge and thank the AMRI
Medicinal Chemistry Department for support and funding as well
as R. Jason Herr for many helpful discussions.
References and notes
1. Review: Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
2. Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1.
3. Zumpe, F. L.; Flüß, M.; Schmitz, K.; Lender, A. Tetrahedron Lett. 2007, 48, 1421.
4. Suzuki, I.; Iwata, Y.; Takeda, K. Tetrahedron Lett. 2008, 49, 3238.
5. Schmidt, R. J.; Lombardo, L. J.; Traeger, S. C.; Williams, D. K. Tetrahedron Lett.
2008, 49, 3009.
6. Kappe, C. O.; Prokopcová, H.; Pisani, L. Synlett 2007, 1, 43.
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Islami, M. R.; Kalantari, M. Bioorg. Med. Chem. Lett. 2006, 16, 4479.
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9315.
and dry 1,4-dioxane (1 mL) were combined in
a sealed vial, stirred, and
purged with nitrogen for several minutes. A solution of sodium carbonate
(85 mg, 0.80 mmol) in water (1 mL) was added, the vial resealed, purged again
with nitrogen for several minutes and then heated at 70 °C for 14 h while
stirring. The reaction mixture was cooled, diluted with satd brine solution
(5 mL), and extracted with ethyl acetate (10 mL). The ethyl acetate solution
was dried over sodium sulfate, filtered, concentrated under reduced pressure,
and purified by flash chromatography (silica gel, 0–5% methanol/methylene
chloride) to yield the aryl product 4 as a tan solid (30 mg, 53% yield). 1H NMR
(300 MHz, CDCl3) d 7.30–7.18 (m, 3H), 7.17–7.12 (m, 2H), 6.95–6.85 (m, 4H),
6.47 (s, 1H), 5.23 (s, 1H), 5.11 (s, 1H) 1.77 (s, 3H); ESI-MS m/z 283 [M+H]+.
11. (a) Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587; (b)
Cepanec, I.; Litvic´, M.; Filipan-Litvic´, M.; Grüngold, I. Tetrahedron 2007, 63,