Unprecedented catalytic three component one-pot condensation reaction: An efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin- 2(1H)-ones

Full text of DOI:10.1021/jo970846u

3454
J . Org. Chem. 1998, 63, 3454-3457
Ta ble 1. Dih yd r op yr im id in on es Syn th esized Usin g th e
New Con d ition ver su s F olk er s’ con d ition s
Un p r eced en ted Ca ta lytic Th r ee Com p on en t
On e-P ot Con d en sa tion Rea ction : An
Efficien t Syn th esis of 5-Alk oxyca r bon yl-
4-a r yl-3,4-d ih yd r op yr im id in -2(1H)-on es
Essa H. Hu,* Daniel R. Sidler,* and Ulf-H. Dolling
yield (%)
Department of Process Research, Merck Research
Laboratories, P.O. Box 2000, Rahway, New J ersey 07065
entry
R1
R2
R3
R4
R5
a
b
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
F
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
82
81
85
89
90
88
88
87
95
92
82
83
79
84
90
81
94
85
92
91
85
70
96
55
42
25
66
64
62
42
28
56
41
61
41
40
46
44
66
71
37
56
54
32
10
62
Received May 12, 1997
Et
H
H
H
H
H
F
3
Et
OMe
Cl
NO2
F
H
OMe
Cl
NO2
F
H
OMe
Cl
NO2
F
H
OMe
Cl
NO2
H
In the past decade, 4-aryl-dihydropyrimidinones 1 have
emerged as the integral backbones of several calcium
channel blockers, antihypertensive agents, and alpha-1
a-antagonists.1 Strategies for the synthesis of the dihy-
dropyrimidinone nucleus have varied from one-pot to
multistep approaches. Biginelli’s initial one-pot reflux
of â-keto ester 2, aryl aldehyde 3, and urea, 4, with
catalytic acid in a protic solvent frequently afforded low
(20-50%) yields.2,3 Subsequent multistep syntheses
produced somewhat higher yields but lacked the simplic-
ity of the one-pot, one-step synthesis.3
4
Et
5
Et
6
Me
Me
Me
Me
Me
Et
7
H
H
H
H
F
H
H
H
H
F
H
H
H
H
H
H
Me
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
a
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
t-Bu
Ph
Me
Et
Et
Et
Et
Me
Et
H
H
Me
New reaction conditions: 1.3 equiv of BF3‚OEt2, 10 mol %
b
CuCl, 10 mol % AcOH, in THF, reflux 18 h. Folkers’ conditions:
4a
catalytic H2SO4, in EtOH, reflux 18 h.
18 h)4a,b to be the most effective for the one-pot synthesis
of our desired pyrimidinones. Both reaction conditions
utilized a 1:1:1.5 ratio of â-keto ester 2, aryl aldehyde 3,
and urea, 4, in a one-pot condensation. Compared to
Folkers’ conditions, our method consistently produced
higher yields.
Recently, we discovered a novel, one-pot combination
of BF3‚OEt2, transition metal salt, and proton source that
not only preserved the simplicity of Biginelli’s one-pot
reaction but also consistently produced 80-90% yields
of the dihydropyrimidin-2(1H)-ones. For comparison,
several 5-alkoxycarbonyl-4-aryl-dihydropyrimidinones 1
were synthesized using both our new conditions and
traditional Biginelli reaction conditions (Table 1). Among
the various conditions published for Biginelli’s reaction,4
we found Folkers’ variation (catalytic H2SO4/EtOH, reflux
This novel application of BF3‚OEt2, transition metal
salt, and proton source for heterocyclic synthesis stemmed
from the observation of a substantial yield increase when
a one-pot reaction in acetic acid was run with Cu(OAc)2
and BF3‚OEt2. Copper and BF3‚OEt2 were chosen as
additives for their known carbonyl-activating abilities.
While the amounts of acetic acid and copper have been
optimized to catalytic (10 mol %) levels, BF3‚OEt2 must
be used in slight excess (1.3 equiv). Boron trifluoride
etherate has been found to be the most effective Lewis
acid for this transformation, compared to BPh3, B(O-
CH3)3, B[N(CH3)2]3, BCl3, or TiCl4. Besides Cu(OAc)2,
several other transition metal salts, such as CuCl, CuCl2,
Cu2O, NiBr2, and Pd(OAc)2, were similarly efficacious for
the reaction. Catalytic acetic acid could be replaced by
other proton sources, such as TFA or MeOH; however,
replacement by mineral acids decreased reaction yields
appreciably. Although there is a range of options avail-
able for the transition metal salts and acid catalysts, each
component plays a critical role in the success of the reac-
(1) (a) Baldwin, J . J .; Claremon, D. A.; McClure, D. E. (Merck and
Co., Inc.). U.S. Patent 4,609,494, 1986. (b) Baldwin, J . J .; Ptizenberger,
S. M.; McClure, D. E. (Merck and Co., Inc.). U.S. Patent 4,675,321,
1987. (c) Atwal, K. S. (E. R. Squibb and Sons). U.S. Patent 4,684,655,
1987. (d) Atwal, K. S. (E. R. Squibb and Sons). U.S. Patent 4,684,656,
1987. (e) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu,
M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.;
Kawai, M.; Takeda, M.; Ishihara, T.; Funahashi, K.; Sato, F.; Morita,
M.; Noguchi, T. J . Med. Chem. 1989, 32, 2399. (f) Atwal, K. S.;
Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.; Swanson,
B. N.; Gougoutas, J . Z.; Schwartz, J .; Smillie, K. M.; Malley, M. F. J .
Med. Chem. 1990, 33, 2629. (g) Atwal, K. S.; Swanson, B. N.; Unger,
S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. J . Med.
Chem. 1991, 34, 806. (h) Nagarathnam, D.; Chiu, G.; Dhar, T.; Wong,
W.; Marzabadi, M.; Gluchowski, C.; Lagu, B.; Miao, S. PCT Int. Appl.
WO 96/14846.
(2) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Brown, D. J .
The Pyrimidines; Wiley: New York, 1962; Chapter 12, p 440. For a
review of the Biginelli reaction, see: Kappe, C. O. Tetrahedron 1993,
49, 6937.
(3) (a) Atwal, K. S.; O’Reilly, B. C.; Gougoutas, J . Z.; Malley, M. F.
Heterocycles 1987, 26, 1189. (b) Atwal, K. S.; Rovnyak, G. C.; O’Reilly,
B. C.; Schwartz, J . J . Org. Chem. 1989, 54, 5898. (c) Barluenga, J .;
Tomas, M.; Rubio, V.; Gotor, V. J . Chem. Commun. 1979, 675. (d)
Barluenga, J .; Tomas, M.; Ballesteros, A.; Lopez, L. A. Tetrahedron
Lett. 1989, 30, 4573. (e) Wipf, P.; Cunningham, A. Tetrahedron Lett.
1995, 36, 7819.
(4) (a) Folkers, K.; J ohnson, T. B. J . Am. Chem. Soc. 1933, 55, 2886.
(b) Folkers, K.; J ohnson, T. B. J . Am. Chem. Soc. 1933, 55, 3784. (c)
Kappe, C. O.; Roschger, P. J . Heterocycl. Chem. 1989, 26, 55. (d) Kappe,
C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.; Keller, W.
Tetrahedron 1992, 48, 5473. (e) Fissekis, J . D.; Sweet, F. J . Am. Chem.
Soc. 1973, 95, 8741. (f) Chiba, T.; Hirotoshi, S.; Kato, T. Heterocycles
1984, 22, 493. (g) Gupta, R.; Gupta, A.; Paul, S.; Kachroo, P. Indian J .
Chem. 1995, 34B, 151. (h) Gupta, R.; Gupta, A.; Paul, S.; Kachroo, P.
Indian J . Chem. 1995, 34B, 61.
S0022-3263(97)00846-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3455
tion. In fact, omission of any one of the three reagents,
BF3‚OEt2, transition metal salt, or proton source, from
the reaction conditions lowers the yield by 20-50%.
Our one-pot heterocycle synthesis seems to involve an
unusual cooperation of boron and its two cocatalysts.
BF3‚OEt2 and copper have been known to catalyze
Michael addition to R,â-unsaturated ketones via a boron-
copper complex.5 In these reports, premixed boron-
copper complexes enhanced the reaction performance.
However, when we premixed BF3‚OEt2 and the transition
metal salt in our reaction, no increase in the reaction rate
or yield was observed. Similarly, benzylidene 5 has been
postulated as a key intermediate in the mechanism of
the Biginelli reaction.4e Yet, when 5, prepared indepen-
dently by condensation of 2 and 3 under Lehnert’s
conditions,6 was combined with urea and subjected to the
one-pot BF3/Cu/acid conditions, only low (<5%) yields of
pyrimidinones 1 were obtained. In fact, when the reac-
tion of 2, 3, and 4 with BF3‚OEt2/Cu/acid was monitored
by HPLC, slow formation of 5 was seen as a reaction
either BF3 or the transition metal, is the key, rate-
limiting step. Subsequent addition of the â-keto ester
enolate, followed by cyclization and dehydration, would
afford the dihydropyrimidinone.
We have been unable to observe 6a or 6b by H or 13C
NMR or by in situ IR experiments. However, when the
reaction was run with a bulky â-keto ester substituent
(i.e., tert-butyl ketone 7) the intermediate ureide 8 was
1
byproduct in 1-2% yield. Thus, mechanistic pathways
proceeding through benzylidene intermediate 5 or mim-
icking the BF3‚OEt2-mediated organocuprate addition to
R,â-unsaturated ketones and esters seem unlikely.
We propose a mechanism similar to that of Folkers and
J ohnson4b and to that of Kappe7 for the Biginelli reaction
wherein formation of acyl imine intermediate 6, formed
by reaction of the aldehyde with urea and stabilized by
observed in a 1:1 ratio with the corresponding dihydro-
pyrimidinone 9 after 6 h. Continued reaction converted
8 into 9. In addition, isolated 8 could be resubjected to
the reaction conditions to afford 9. The inability of 5 to
undergo cyclization under these reaction conditions and
the observation of ureide 8 as a reaction intermediate
support this proposed mechanistic pathway.
In addition to its simplicity, this reaction has one
salient feature in its ability to tolerate a variety of
substituted â-keto esters and aryl aldehydes (Table 1).
Most literature examples of the Biginelli variants use
simple â-keto esters, such as methyl acetoacetate, in the
condensation reaction. The efficacy of Biginelli’s reaction
is substrate dependent with the use of more highly
functionalized or sterically encumbered keto esters lead-
ing to severely reduced yields. Likewise, existing syn-
thetic strategies have shown a great deal of variability
in yield depending on the aryl aldehyde used. As
evidenced in Table 1, our three-component reaction
afforded uniformly high yields, regardless of the keto
ester or aldehyde substituents.
The discovery and development of these catalytic
reaction conditions have led to a general method for the
direct preparation of substituted dihydropyrimidinones
in high yields from readily available starting materials.
Further investigations of the scope and mechanism of this
reaction are under way.
(5) Kocovsky, P.; Dvorak, D. Tetrahedron Lett. 1986, 27, 5015.
(6) Lehnert, W. Tetrahedron Lett. 1970, 4723.
(7) Kappe, C. O. J . Org. Chem. 1997, 62, 7201.

3456 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
for C14H15N3O5‚0.2(H2O): C, 54.44; H, 5.03; H, 13.60. Found:
C, 54.25; H, 5.09; N, 13.26.
Exp er im en ta l Section
Melting points were determined by using the Thomas-Hoover
capillary melting point apparatus and were uncorrected. IR
spectra were obtained as thin films on disposable, poly(tetrafluo-
roethylene) cards on a Nicolet Magna-IR spectrometer 550. 1H
and 13C spectra were recorded on a Bruker AM-250 NMR
spectrometer (operating at 250 and 62.9 MHz, respectively), and
the chemical shifts were reported in ppm (δ unit) downfield from
TMS. Elemental analyses were performed by Quantitative
Technologies Inc., Whitehouse, NJ . Water content was deter-
mined by Karl Fisher titration on the EM Science AquaStar
C2000 titrator.
4-(3,4-Diflu or op h en yl)-5-m eth oxyca r bon yl-6-m eth yl-3,4-
d ih yd r op yr im id in -2(1H)-on e: entry 6 (88% yield) mp 224-6
°C; IR (THF) 3368, 3227, 3102, 2952, 1698, 1644, 1611, 1516
1
cm-1; H NMR (DMSO-d6) δ 9.33 (s, 1H), 7.83 (s, 1H), 7.38 (m,
1H), 7.21 (m, 1H), 7.07 (m, 1H), 5.15 (d, 1H), 3.53 (s, 3H), 2.26
(s, 3H); 13C NMR (DMSO-d6) δ 165.5, 151.8, 149.3, 142.2, 122.7,
117.6, 115.2, 115.0, 98.2, 52.9, 50.7, 17.7; MS m/e 283 (M + H,
100), 265 (M + H, 20), 169 (M + H, 10), 148 (M + H, 15). Anal.
Calcd for C13H12N2O3F2‚0.(H2O): C, 54.78; H, 4.67; N, 9.83.
Found: C, 54.55; H, 4.36; N, 9.46.
5-Meth oxyca r bon yl-6-m eth yl-4-p h en yl-3,4-d ih yd r op yr i-
m id in -2(1H)-on e: entry 7 (88% yield) mp 209-212 °C; IR
(THF) 3361, 3231, 3089, 3030, 2945, 1750, 1705, 1650 cm-1; 1H
NMR (CDCl3) δ 8.08 (s, 1H), 7.30 (m, 5H), 5.70 (s, 1H), 5.39 (d,
J ) 2.7 Hz, 1H), 3.62 (s, 3H), 2.34 (s, 3H); 13C NMR (DMSO-d6)
δ 165.7, 152.0, 148.5, 144.6, 128.3, 127.2, 126.0, 98.9, 53.7, 50.7,
17.7; MS m/e 246.1 (20), 231.1 (28), 187.1 (27), 169.0 (100), 137.0
(41); HRMS calcd for C13H14N2O3 (M+) 246.1004, found 246.0999.
5-Meth oxyca r bon yl-4-(4-m eth oxyp h en yl)-6-m eth yl-3,4-
d ih yd r op yr im id in -2(1H)-on e: entry 8 (87% yield) mp 192-4
°C; IR (CHCl3) 3232, 3104, 3003, 2950, 2837, 1698, 1645, 1609,
Gen er a l P r oced u r e for th e Syn th esis of Dih yd r op yr i-
m id in on es. A 50 mL three-neck round-bottom flask under N2
and fitted with
a thermocouple and reflux condenser was
charged with sieve dried THF (30 mL), â-keto ester (15.4 mmol),
aryl aldehyde (15.4 mmol), urea (23.1 mmol), BF3‚OEt2 (20.0
mmol), CuCl (1.54 mmol), and glacial acetic acid (1.54 mmol).
The mixture was heated to reflux (at 65 °C) for 8-18 h. The
solution was cooled to room temperature and quenched with 10%
Na2CO3 (30 mL). EtOAc (30 mL) was added, the layers were
separated, and the green aqueous solution was removed. The
organic layer was distilled and replaced with toluene (ca. 40 mL),
cooled to room temperature, and aged overnight. The resulting
suspension was filtered in vacuo, and the collected solid was
rinsed with toluene (1 × 10 mL) and dried in vacuo at 40 °C to
afford the desired product as crystalline solid.
4-(3,4-Diflu or op h en yl)-6-et h yl-5-m et h oxyca r b on yl-3,4-
d ih yd r op yr im id in -2(1H)-on e: entry 1 (82% yield) mp 182-5
°C; IR (THF) 3237, 3112, 2960, 2879, 1701, 1634, 1517 cm-1; 1H
NMR (DMSO-d6) δ 9.31 (s, 1H), 7.80 (s, 1H), 7.40 (m, 1H), 7.20
(m, 1H), 7.06 (m, 1H), 5.14 (d, J ) 3.4 Hz, 1H), 3.54 (s, 3H),
2.65 (m, 2H), 1.11 (t, J ) 7.4 Hz, 3H); 13C NMR (DMSO-d6) δ
165.1, 154.8, 152.0, 142.2, 117.6, 117.4, 115.2, 114.9, 97.4, 52.8,
50.8, 24.0, 12.8; MS m/e 297 (M + H, 100), 279 (M + H, 37), 183
(M + H, 15), 148 (M + H, 30), 130 (M + H, 20). Anal. Calcd for
C14H14N2O3F2: C, 56.76; H, 4.76; N, 9.46. Found: C, 56.85; H,
4.70; N, 9.35.
1
1512 cm-1; H NMR (CDCl3) δ 8.54 (s, 1H), 7.23 (m, 2H), 6.82
(m, 2H), 5.97 (s, 1H), 5.31 (d, J ) 2.0 Hz, 1H), 3.77 (s, 3H), 3.61
(s, 3H), 2.31 (s, 3H); 13C NMR (CDCl3) δ 163.6, 151.0, 143.8,
133.5, 125.1, 111.5, 52.7, 52.5, 48.5, 16.1; MS m/e 276.1 (35),
261.1 (75), 217.1 (85), 169.0 (100), 137.0 (58); HRMS calcd for
C14H16N2O4 (M+) 276.1110, found 276.1079.
4-(4-Ch lor op h en yl)-5-m eth oxyca r bon yl-6-m eth yl-3,4-d i-
h yd r op yr im id in -2(1H)-on e: entry 9 (95% yield) mp 204-7 °C;
IR (THF) 3238, 3114, 2950, 2875, 1702, 1645 cm-1 1H NMR
;
(DMSO-d6) δ 9.27 (s, 1H), 7.78 (s, 1H), 7.38 (d, J ) 8.5 Hz,
2H), 7.25 (d, J ) 8.5 Hz, 2H), 5.14 (d, J ) 3.3 Hz, 1H), 3.53 (s,
3H), 2.25 (s, 3H); 13C NMR (DMSO-d6) δ 165.6, 151.9, 148.9,
143.5, 131.7, 128.3, 128.0, 98.5, 53.2, 50.7, 17.7; MS m/e
281 (M + H, 100), 263 (M + H, 20), 188 (M + H, 30), 169 (M +
H, 20), 148 (M + H, 37), 130 (M + H, 41). Anal. Calcd for
C13H13N2O3Cl‚0.1(H2O): C, 54.92; H, 4.75; N, 9.85. Found C,
54.96; H, 4.49; N, 9.85.
6-E t h yl-5-m et h oxyca r b on yl-4-p h en yl-3,4-d ih yd r op yr i-
5-Meth oxyca r bon yl-6-m eth yl-4-(4-n itr op h en yl)-3,4-d ih y-
d r op yr im id in -2(1H)-on e: entry 10 (92% yield) mp 235-7 °C;
m id in -2(1H)-on e: entry 2 (81% yield) mp 133-5 °C; IR (CHCl3)
3224, 3108, 3026, 2954, 1700, 1640 cm-1 1H NMR (CDCl3) δ
;
IR (DMF) 3366, 3233, 3113, 2951, 1703, 1643, 1598, 1520 cm-1
;
8.43 (s, 1H), 7.28 (m, 5H), 6.07 (s, 1H), 5.36 (d, J ) 2.8 Hz, 1H),
3.61 (s, 3H), 2.71 (m, 2H), 1.20 (t, J ) 7.5 Hz, 3H); 13C NMR
(CDCl3) δ 165.8, 156.8, 152.3, 143.7, 128.8, 127.9, 126.4, 100.2,
55.5, 51.1, 25.3, 12.5, 11.6; MS m/e 260.1 (50), 245.1 (59), 201.1
(72), 183.0 (100), 151.0 (95); HRMS calcd for C14H16N2O3 (M+)
260.1161, found 260.1180.
1H NMR (DMSO-d6) δ 9.39 (s, 1H), 8.20 (d, J ) 8.4 Hz, 2H),
7.93 (s, 1H), 7.50 (d, J ) 8.4 Hz, 2H), 5.28 (s, 1H), 3.53 (s, 3H),
2.27 (s, 3H); 13C NMR (DMSO-d6) δ 165.5, 151.7, 149.5, 146.6,
127.5, 123.7, 97.9, 53.4, 50.8, 17.8; MS m/e 276.1 (25), 232.1 (15),
186.1 (15), 169.1 (100), 137.0 (48); HRMS calcd for C13H13N3O5
(M+) 291.0855, found 291.0883.
6-Eth yl-5-m eth oxyca r bon yl-4-(4-m eth oxyp h en yl)-3,4-d i-
4-(3,4-Diflu or op h en yl)-5-eth oxyca r bon yl-6-eth yl-3,4-d i-
h yd r op yr im id in -2(1H)-on e: entry 11 (82% yield) mp 146-8
h yd r op yr im id in -2(1H)-on e: entry 3 (85% yield) mp 105-7 °C;
1
IR (CHCl3) 3230, 3112, 2954, 1710, 1644, 1512 cm-1; H NMR
°C; IR (CHCl3) 3236, 3110, 2980, 2940, 1705, 1643, 1517 cm-1
;
(CDCl3) δ 8.46 (s, 1H), 7.21 (m, 2H), 6.81 (d, J ) 8.6 Hz, 2H),
6.09 (s, 1H), 5.32 (s, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 2.71 (m, 2H),
1.21 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3) δ 165.8, 159.3, 159.3,
151.8, 136.2, 127.6, 114.1, 100.5, 55.2, 54.9, 54.9, 50.9, 25.2, 12.4;
MS m/e 290.1 (30), 275.1 (65), 231.1 (85), 183.1 (100), 151.0 (58);
HRMS calcd for C15H18N2O4 (M+) 290.1267, found 290.1266.
1H NMR (CDCl3) δ 8.46 (s, 1H), 7.06 (m, 3H), 6.39 (s, 1H), 5.33
(d, J ) 3.0 Hz, 1H), 4.08 (m, 2H), 2.70 (m, 2H), 1.19 (m, 6H);
13C NMR (CDCl3) δ 165.0, 153.8, 152.3, 140.8, 122.5, 117.6,
117.3, 115.7, 115.5, 100.0, 60.2, 54.6, 25.3, 14.1, 12.5; MS m/e
311 (M + H, 100), 293 (M + H, 18), 197 (M + H, 10), 148 (M +
H, 15), 114 (M + H, 10). Anal. Calcd for C15H16N2O3F2: C,
58.06; H, 5.20; N, 9.03. Found: C, 57.66; H, 5.38; N, 8.98.
5-Eth oxyca r bon yl-6-eth yl-4-p h en yl-3,4-d ih yd r op yr im i-
d in -2(1H)-on e: entry 12 (83% yield) mp 128-131 °C; IR
(CHCl3) 3230, 3106, 3030, 2979, 2938, 1701, 1641 cm-1; 1H NMR
(CDCl3) δ 8.73 (s, 1H), 7.26 (m, 5H), 6.42 (s, 1H), 5.35 (d, J )
2.5 Hz, 1H), 4.05 (q, J ) 7.1 Hz, 2H), 2.69 (m, 2H), 1.16 (m,
6H); 13C NMR (CDCl3) δ 165.4, 154.2, 152.2, 143.9, 128.7, 127.8,
126.5, 100.3, 59.9, 55.4, 25.2, 14.1, 12.6; MS m/e 275 (M + H,
100), 257 (M + H, 21), 197 (M + H, 15), 148 (M + H, 15). Anal.
Calcd for C15H18N2O3‚0.1(H2O): C, 65.25; H, 6.65; N, 10.15.
Found: C, 65.04; H, 6.44; N, 10.15.
4-(4-Ch lor op h en yl)-6-eth yl-5-m eth oxyca r bon yl-3,4-d ih y-
d r op yr im id in -2(1H)-on e: entry 4 (89% yield) mp 149-152 °C;
1
IR (CH2Cl2) 3236, 3107, 2973, 2947, 1702, 1642 cm-1; H NMR
(CDCl3) δ 8.69 (s, 1H), 7.21 (m, 4H), 6.70 (s, 1H), 5.31 (d, J )
2.9 Hz, 1H), 3.61 (s, 3H), 2.67 (m, 2H), 1.17 (t, J ) 7.4 Hz, 3H);
13C NMR (CDCl3) δ 165.6, 154.3, 152.6, 142.2, 133.6, 128.9,
127.8, 99.9, 54.6, 51.2, 25.2, 12.5l; MS m/e 295 (M + H, 100),
277 (M + H, 25), 183 (M + H, 26), 148 (M + H, 37), 130 (M + H,
31). Anal. Calcd for C14H15N2O3Cl: C, 57.05; H, 5.13; N, 9.50.
Found: C, 56.84; H, 5.20; N, 9.43.
5-Met h oxyca r b on yl-6-et h yl-4-(4-n it r op h en yl)-3,4-d ih y-
d r op yr im id in -2(1H)-on e: entry 5 (90% yield) mp 184-7 °C;
5-E t h oxyca r b on yl-6-et h yl-4-(4-m et h oxyp h en yl)-3,4-d i-
h yd r oyp r im id in -2(1H)-on e: entry 13 (79% yield) mp 145-8
°C; IR (CH2Cl2) 3232, 3105, 2978, 2937, 1693, 1643, 1610, 1586,
1519 cm-1; 1H NMR (CDCl3) δ 8.69 (s, 1H), 7.20 (d, J ) 8.5 Hz,
2H), 6.79 (d, J ) 8.5 Hz, 2H), 6.39 (s, 1H), 5.31 (s, 1H), 4.05 (q,
J ) 7.0 Hz, 2H), 3.75 (s, 3H), 2.69 (m, 2H), 1.18 (m, 6H); 13C
NMR (CDCl3) δ 165.3, 159.3, 153.3, 151.4, 136.3, 127.7, 114.1,
100.8, 59.8, 55.2, 25.2, 14.0, 12.4; MS m/e 305 (M + H, 100),
IR (THF) 3239, 3112, 2973, 2877, 1705, 1643, 1608, 1523 cm-1
;
1H NMR (DMSO-d6) δ 9.37 (s, 1H), 8.21 (d, J ) 8.7 Hz, 2H),
7.89 (s, 1H), 7.50 (d, J ) 8.7 Hz, 2H), 5.27 (d, J ) 3.4 Hz, 1H),
3.54 (s, 3H), 2.70 (m, 2H), 1.12 (t, J ) 7.4 Hz, 3H); 13C NMR
(DMSO-d6) δ 165.0, 155.0, 151.9, 151.7, 146.6, 127.4, 123.8, 53.3,
50.8, 24.0, 12.8; MS m/e 306 (M + H, 75), 188 (M + H, 42), 183
(M + H, 15), 148 (M + H, 45), 130 (M + H, 100). Anal. Calcd

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3457
287 (M + H, 25), 275 (M + H, 20), 197 (M + H, 25), 136 (M + H,
26). Anal. Calcd for C16H20N2O4‚0.1(H2O): C, 62.77; H, 6.65;
N, 9.15. Found: C, 62.52; H, 6.50; N, 9.10.
m/e 261.1 (100), 217.1 (70), 183.1 (52), 155.0 (50), 137.0 (25);
HRMS calcd for C15H18N2O4 (M+) 290.1267, found 290.1286.
4-(4-Ch lor op h en yl)-5-eth oxyca r bon yl-6-m eth yl-3,4-d ih y-
4-(4-Ch lor op h en yl)-5-et h oxyca r b on yl-6-et h yl-3,4-d ih y-
d r op yr im id in -2(1H)-on e: entry 14 (84% yield) mp 140-2 °C;
d r op yr im id in -2(1H)-on e: entry 19 (92% yield) mp 213-5 °C;
IR (THF) 3233, 3093, 2976, 2933, 1701, 1643 cm-1 1H NMR
;
IR (THF) 3235, 3112, 2978, 2938, 2876, 1697, 1643 cm-1 1H
;
(DMSO-d6) δ 7.39 (d, J ) 8.4 Hz, 2H), 7.24 (d, J ) 8.4 Hz, 2H),
5.13 (s, 1H), 3.97 (q, J ) 7.1 Hz, 2H), 2.25 (s, 3H), 1.09 (t, J )
7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 151.8, 143.7, 131.7, 128.3,
128.1, 98.7, 59.1, 53.3, 17.7, 13.9; MS m/e 265.0 (65), 221.0 (35),
183.1 (100), 155.0 (42), 137.0 (35); HRMS calcd for C14H15N2O3-
Cl (M+) 294.0771, found 294.0787.
NMR (CDCl3) δ 8.54 (s, 1H), 7.24 (m, 4H), 6.41 (s, 1H), 5.34 (d,
J ) 2.9 Hz, 1H), 4.07 (q, J ) 7.1 Hz, 2H), 2.67 (m, 2H), 1.17 (q,
J ) 7.1 Hz, 6H); 13C NMR (CDCl3) δ 165.1, 153.9, 152.1, 142.3,
133.6, 128.8, 127.9, 100.2, 60.1, 54.9, 25.3, 14.1, 12.5; MS m/e
309 (M + H, 100), 311 (M + H, 30), 291 (M + H, 25), 148 (M +
H, 30), 130 (M + H, 40). Anal. Calcd for C15H17N2O3Cl‚0.1-
(H2O): C, 58.01; H, 5.58; N, 9.02. Found: C, 57.64; H, 5.59; N,
9.03.
5-Eth oxyca r bon yl-6-m eth yl-4-(4-n itr op h en yl)-3,4-d ih y-
d r op yr im id in -2(1H)-on e: entry 20 (91% yield) mp 208-211
°C; IR (THF) 3230, 3109, 2977, 1701, 1641, 1591, 1520 cm-1; 1H
NMR (DMSO-d6) δ 9.37 (s, 1H), 8.20 (d, J ) 8.7 Hz, 2H), 7.91
(d, J ) 2.46 Hz, 1H), 7.50 (d, J ) 8.7 Hz, 2H), 5.27 (d, J ) 1.6
Hz, 1H), 3.98 (q, J ) 7.1 Hz, 2H), 2.27 (s, 3H), 1.09 (t, J ) 7.1
Hz, 3H); 13C NMR (DMSO-d6) δ 164.9, 151.9, 151.7, 149.3, 146.6,
127.5, 123.7, 59.3, 53.6, 17.8, 13.9; MS m/e 276.1 (75), 183.1 (100),
169.1 (30), 155.0 (40), 137.0 (48); HRMS calcd for C14H15N3O5
(M+) 305.1012, found 305.0980.
5-Eth oxyca r bon yl-6-eth yl-4-(4-n itr op h en yl)-3,4-d ih yd r o-
p yr im id in -2(1H)-on e: entry 15 (90% yield) mp 221-4 °C; IR
(THF) 3224, 3107, 2976, 2936, 2875, 1700, 1638, 1596, 1519
1
cm-1; H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.20 (m, 2H), 7.86 (s,
1H), 7.49 (m, 2H), 5.27 (d, J ) 3.4 Hz, 1H), 3.99 (q, J ) 7.1 Hz,
2H), 2.65 (m, 2H), 1.12 (m, 6H); 13C NMR (DMSO-d6) δ 164.6,
154.7, 151.9, 146.6, 132.0, 127.5, 123.7, 97.3, 59.3, 53.5, 24.0,
13.8, 12.8; MS m/e 321 (M + H, 21), 320 (M + H, 70), 188 (M +
H, 25), 148 (M + H, 30), 130 (M + H, 100). Anal. Calcd for
Com p ou n d 8: inseparable 1:1 mixture of diastereomers; IR
(CH2Cl2) 3478, 3377, 2970, 1739, 1708, 1688 cm-1; 1H NMR (CD3-
CN) δ 7.26 (m, 12H), 6.77 (d, J ) 9.7, 1H), 6.56 (d, J ) 9.8, 1H),
5.55 (m, 1H), 5.50 (m, 1H), 5.10 (br s, 2H), 4.59 (d, J ) 6.5, 1H),
4.57 (d, J ) 9.2, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 0.93 (s, 9H), 0.90
(s, 9H); 13C NMR (CD3CN) δ 210.9, 208.0, 169.3, 169.0, 159.4,
142.2, 141.9, 129.4, 128.5, 128.4, 128.4, 127.9, 59.7, 57.9, 55.4,
55.1, 53.2, 53.2, 46.3, 46.2, 26.4, 26.1, 26.0.
C
15H17N3O5: C, 56.42; H, 5.37; N, 13.16. Found: C, 56.02; H,
5.45; N, 12.96.
4-(3,4-Diflu or op h en yl)-5-et h oxyca r b on yl-6-m et h yl-3,4-
d ih yd r op yr im id in -2(1H)-on e: entry 16 (81% yield) mp 185-6
°C; IR (THF) 3240, 3115, 2980, 2941, 1704, 1647, 1517 cm-1; 1H
NMR (DMSO-d6) δ 9.30 (s, 1H), 7.81 (s, 1H), 7.39 (m, 1H), 7.21
(m, 1H), 7.07 (m, 1H), 5.15 (d, J ) 3.3 Hz, 1H), 3.98 (m, 2H),
2.26 (s, 3H), 1.08 (t, J ) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ
165.0, 151.7, 149.0, 142.4, 122.8, 117.5, 117.3, 115.3, 115.0, 59.2,
53.0, 17.7, 13.9; MS m/e 298 (M + H, 15), 297 (M + H, 100), 279
(M + H, 15), 183 (M + H, 10), 148 (M + H, 15). Anal. Calcd for
C14H14N2O3F2‚0.1(H2O): C, 56.41; H, 4.80; N, 9.40. Found: C,
56.34; H, 4.75; N, 9.34.
Com p ou n d 9: entry 21 (88% yield); IR (CH2Cl2) 3246, 3185,
2952, 1693, 1682 cm-1; 1H NMR (CDCl3) δ 7.23 (s, 6H), 7.18 (s,
1H), 5.14 (d, J ) 2.8 Hz, 1H), 3.49 (s, 3H), 1.27 (s, 9H); 13C NMR
(CDCl3) δ 167.6, 153.9, 149.1, 142.3, 128.4, 127.6, 126.4, 102.1,
56.6, 51.1, 35.5, 28.1.
5-E t h oxyca r b on yl-4,6-d ip h en yl-3,4-d ih yd r op yr im id in -
5-E t h oxyca r b on yl-6-m et h yl-4-p h en yl-3,4-d ih yd r op yr i-
m id in -2(1H)-on e: entry 17 (94% yield) mp 202-4 °C; IR (THF)
2(1H)-on e: entry 22 (70% yield) mp 157-9 °C; IR (CH2Cl2)
1
3214, 3086, 2980, 1699, 1651 cm-1; H NMR (CDCl3) δ 7.79 (s,
1
3235, 3109, 2976, 2936, 1725, 1702, 1648, 1599 cm-1; H NMR
1H), 7.37 (m, 10H), 6.55 (s, 1H), 5.43 (s, 1H), 3.84 (q, J ) 7.0
Hz, 2H), 0.83 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 165.3,
153.2, 147.1, 143.5, 135.1, 129.5, 128.8, 128.2, 128.1, 128.0, 126.6,
102.4, 60.0, 55.8, 13.6. Anal. Calcd for C19H18N2O3: C, 70.79;
H, 5.63; N, 8.69. Found: C, 71.01; H, 5.70; N, 8.59.
(DMSO-d6) δ 9.21 (s, 1H), 7.76 (d, J ) 2.5 Hz, 1H), 7.27 (m, 5H),
5.15 (d, J ) 3.2 Hz, 1H), 3.98 (q, J ) 7.1 Hz, 2H), 2.25 (s, 3H),
1.09 (t, J ) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 165.2, 152.0,
148.2, 144.7, 128.3, 127.1, 126.1, 99.2, 59.1, 53.9, 17.7, 13.9; MS
m/e 261 (M + H, 100), 243 (M + H, 52), 213 (M + H, 15), 217 (M
+ H, 15), 148 (M + H, 32). Anal. Calcd for C14H16N2O3: C,
64.60; H, 6.20; N, 10.76. Found: C, 64.38; H, 6.28; N, 10.65.
5-Eth oxyca r bon yl-4-(4-m eth oxyp h en yl)-6-m eth yl-3,4-d i-
h yd r op yr im id in -2(1H)-on e: entry 18 (85% yield) mp 201-3
°C; IR (THF) 3225, 3098, 2928, 2835, 1710, 1651, 1613, 1583,
1513 cm-1; 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 7.65 (s, 1H), 7.14
(d, J ) 8.7 Hz, 2H), 6.87 (d, J ) 8.7 Hz, 2H), 5.09 (d, J ) 3.2 Hz,
1H), 3.97 (q, J )7.1 Hz, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 1.10 (t,
J ) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 165.3, 158.0, 152.0,
147.5, 136.9, 127.3, 113.6, 99.9, 59.0, 54.9, 53.2, 17.6, 14.0; MS
4-(2,5-Dim et h ylp h en yl)-5-m et h oxyca r b on yl-6-m et h yl-
3,4-d ih yd r op yr im id in -2(1H)-on e: entry 23 (96% yield) mp
275-7 °C; IR (CH2Cl2): 3356, 3201, 3083, 2943, 1697, 1641 cm-1
;
1H NMR (DMSO-d6) δ 9.15 (s, 1H), 7.60 (s, 1H), 6.96 (m, 3H),
5.36 (d, J ) 2.5, 1H), 3.45 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 2.20
(s, 3H); 13C NMR (DMSO-d6) δ 165.7, 151.5, 148.3, 143.0, 135.1,
131.5, 130.1, 127.8, 126.9, 99.0, 50.6, 50.4, 20.8, 18.1, 17.7. Anal.
Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C,
65.82; H, 6.60; N, 10.15.
J O970846U